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Abstracts

Poster Session 1 Diagnosis and differential diagnosis P261 There is less MRI brain lesions and no characteristic MRI brain findings in IIDDs patients with positive AQP4 serology among Malaysians S. Abdullah1, F. Fadzil2, N. Ramli2, C.T. Tan1 1Medicine, 2Radiology, University Malaya Medical Centre, Kuala Lumpur, Malaysia Background and objective: The recently introduced International Consensus diagnostic criteria for diagnosis of neuromyelitis spectrum disorder include patients who are seronegative for AQP4 antibody. The criteria is dependent on typical MRI changes in the spinal cord, optic nerve and brain. This study aims to determine whether there are significant differences in the MRI brain images between AQP4 positive and negative patients with IIDDs Method: MRI brain of patients with a diagnosis of IIDDs presented to the Hospital from 2010 to 2015 was analysed. The MRI was assessed by 2 radiologists blinded to the AQP4 status, on features said to be typical of NMOSD and MS. Results: Thirty nine patients fulfilled the criteria and was included in the study. They consisted of 19 AQP4 seropositive and 20 AQP4 seronegative patients. The mean age was older (37.0 vs 28.8 years) among the AQP4 positive group. The majority of the patients were ethnic Chinese (72%), followed by the Malays and Indians. Those with AQP4 seropositive status generally has less brain lesions, with significantly less fulfilling the McDonald DIS criteria as compared with those with AQP4 seronegative status (15.8% vs 60.0%, p=0.004). None of the seven cerebral MRI features highlighted in NMOSD 2015 diagnostic criteria, said to be characteristic of NMOSD was more common among the AQP4 positive patients. These features were in fact seen less frequently among the AQP4 seropositive patients. An example was the extensive hemispheric lesion seen in 10.5% of AQP4 seropositive patients vs 45% of those AQP4 seronegative group. Conclusion: There was no characteristic MRI brain features in the Malaysian AQP4 seropositive IIDM patients versus those who are seronegative. This could be a reflection of ethnic difference. Disclosure This article is original and it has not been published. On behalf of all the authors, I declare that the enclosed manuscript in its present form has not been published elsewhere, in whole or in part. The testing for serum anti AQP4 antibody was funded by the High Impact Research Grant (UM.C/HIR/MOHE/H-20001-E000037). P262 Relevance of serum anti-MOG antibodies for diagnosis and characterization of CNS demyelinating disorders S. Mariotto1, S. Ferrari1, S. Monaco1, M.D. Benedetti1, M. Turatti1, M. Calabrese1, D. Alberti1, A. Farinazzo1, R. Capra2, N. De Rossi2, L. Deotto3, A. Bonora4, A. Pavone5, M. Cadaldini6,

A. Polo7, M.R. Bianchi7, R. Bombardi8, G. Cantalupo9, K. Shanda10, M. Reindl10, A. Gajofatto1 1Neurosciences, Biomedicine and Movement Sciences, Neurology Unit, University of Verona, Verona, 2ASST, Spedali Civili, Multiple Sclerosis Centre, Montichiari, 3AOUI, Verona, Neurology Unit, 4AOUI Verona, Section of Ophthalmology, University of Verona, Verona, 5Arnas Garibaldi Hospital, Neurology Unit, Catania, 6Monselice-Este Hospital, Neurology Unit, Padova, 7Mater Salutis Hospital, Legnago, Section of Neurology, Verona, 8Neurology Unit, Bassano del Grappa Hospital, Bassano del Grappa, 9Section of Child Neurology, University of Verona, Verona, Italy, 10Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria Background: Considerable efforts have been devoted to the search of diagnostic serological and cerebrospinal fluid (CSF) markers of inflammatory demyelinating CNS disorders. Recently, the presence of circulating anti-myelin oligodendrocyte glycoprotein antibodies (MOG-abs) has been described in patients with multiple sclerosis (MS), acute disseminated encephalomyelitis, acute myelitis (AM), optic neuritis (ON), and neuromyelitis optica spectrum disorders (NMOSD), particularly in anti-aquaporin 4 antibody (AQP4-ab) seronegative cases. To date, several areas of uncertainty still remain regarding the actual significance of MOGabs detection, including the appropriate clinical setting in which the test is indicated, in addition to its diagnostic and predictive value. Goals: - To assess serum MOG-abs status of AQP4-ab negative patients with an initial suspect of NMOSD - To analyze the association between the presence of MOGabs and clinical, MRI, and laboratory findings - To determine a MOG-abs positive clinically significant titre cut-off - To clarify if MOG-abs positivity is associated with a distinct demyelinating condition Methods: We identified stored serum samples of patients with suspected NMOSD sent to Verona Neuropathology laboratory between 03/2014 and 03/2016 for AQP4-abs assay resulting to be negative. Live-cells (HEK293A) staining immunofluorescence assay was used for the detection of MOG-abs. We retrospectively collected and analyzed clinical, MRI and CSF data of tested patients and divided them in five groups based on the final diagnosis: 1) NMOSD; 2) isolated ON and/or AM (ION/AM); 3) MS or clinically isolated syndrome (CIS) suggestive of MS; 4) other inflammatory CNS disorders; 5) non-inflammatory conditions. Results: We analyzed the samples of 157 eligible patients with the following final diagnosis: 4 NMOSD, 75 ION/AM, 58 CIS/ MS, 13 other inflammatory disorders, and 7 non-inflammatory conditions. Of these, 29 were MOG-abs positive with 1:20 titre in

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Poster Session 1, 22(S3) 9, 1:40 in 10, 1:80 in 5, and ⩾1:160 in 5 cases. All patients with a titre ⩾1:160 had a final diagnosis of ION/AM while patients with lower titres had CIS/MS in 10 cases, ION/AM in 13, and another inflammatory disorder in one. Conclusions: MOG-abs testing should be included in the diagnostic evaluation of patients with ON and/or AM who are antiAQP4 abs negative, as high titre positivity seems to identify a subgroup of cases not related to MS, NMOSD, or other definite inflammatory disorders. Disclosure S. Mariotto, S. Ferrari, S. Monaco, M.D. Benedetti, M. Turatti, D. Alberti, A. Farinazzo, R. Capra, L. Deotto, A. Bonora, A. Pavone, A. Polo, M.R. Bianchi, R. Bombardi, K. Shanda: nothing to disclose. M. Calabrese: Advisory Board membership: Bayer-Schering, Genzyme, Biogen Idec. Payment for development of educational presentations including service on speakers bureaus: BiogenElan, Genzyme, TEVA, Bayer-Schering. Travel/accomodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen Idec, Merck Serono, Bayer-Schering, TEVA. N. De Rossi: presentations for Biogen, TEVA; travel support to attend scientific meetings by Biogen, Merck Serono, TEVA. M. Cadaldini: travel support to attend scientific meetings by Merck Serono, Bayer, Genzyme, TEVA. M. Reindl: funded by the project BIG WIG MS from the Austrian Federal Ministery of Sciences. A. Gajofatto: travel support to attend scientific meetings by Almirall, Biogen, Merck, and Novartis. P263 Susac syndome: a differencial diagnosis of white matter lesions a Latin American series M. Marrodan1, J. Correale1, M. Amaya2, L. Alessandro1, A. Köhler1, M. Fiol1 1Neurology, FLENI, Buenos Aires, 2Neurology, Marcial Quiroga Hospital, San Juan, Argentina Introduction: Susac Syndrome (SuS) is an infrequent autoimmune endotheliopathy. While the disease affects brain, inner ear and retina, clinical manifestations can not be concomitant. Brain lesions could require differential diagnosis with multiple sclerosis (MS). Because SuS is a disabling disease, early detection is essential to provide adequate immunosupressive treatment. Objectives: The aim of this research is to analyze clinical presentation, ancillary methods, differential diagnoses, evolution and treatment in patient with SuS. Methods: A retrospective review was carried out in 6 adult patients with SuS from January 2007 to April 2016 in an Argentinian center. Results: The middle age at diagnosis was 36 years old (range 22-52) with male dominance (M/F:5/1). The clinical triad was complete in 50% of cases. 3 patients just suffered visual and encephalic disturbances but one of them presented asintomathic unilateral lower tones hypoacusia in audiometry (AT). Fluorescein angiography (FA) showed abnormalities in all cases. The cognitive evaluation showed multidomain compromise in 4 cases. Regarding MRI findings, all patients presented typical corpus callosum images known as “snowball lesions” and periventricular lesions. Three cases had fornix microinfractions, 4 cases had

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yuxtacortical involvement and 2 cases presented infrantentorial infractions and lesions with contrast enhancement. For acute treatment: 5 patients received treatment with corticosteroids (CE) and 4 of them in combination with IV immunoglobulins. Cyclophosphamide and mycophenolate mofetil were employed for 5 patients as maintenance strategy. One patient received rituximab and 1 patient received azathioprine. All cases presented at least 1 relapse (range: 1-3). One patient did not complete the follow-up. Conclusions: Typical SuS clinical triad could not be present from the beginning, MRI, FA and audiometry should be performed as soon as SuS is suspected to detect subclinical compromise. It is important to suspect SuS as differential diagnosis for MS, through corpus callosum typical lesions and fornix microinfractions in MRI, typical FA and AT findings. Treatment must be as aggressive as necessary to prevent permanent disability. Disclosure Mariano Marrodan has nothing to disclose related to this abstract. Jorge Correale has nothing to disclose related to this Abstract. Lucas Alessandro has nothing to disclose related to this Abstract. Mariela Amaya has nothing to disclose related to this Abstract. Alejandro Köhler has nothing to disclose related to this Abstract. Marcela Fiol has nothing to disclose related to this Abstract. P264 A novel bio-marker for early detection and characterization of multiple sclerosis A. Horowitz1,2, I. Tavor3, C. Hoffmann3, S. Miron4, A. Achiron4, Y. Assaf1,2 1Department of Neurobiology, 2Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 3Department of Diagnostic Imaging, 4Multiple Sclerosis Center, Sheba Medical Center, Ramat Gan, Israel Introduction: Early characterization and treatment, as well as personalized therapy of Multiple Sclerosis (MS) patients, are currently the leading challenges in the field of MS. Since MS diagnosis is straightforward and drugs that affect MS pathogenesis do exist, there is a great need for a specific biomarker that derives from the biological characterization features of the disease. some of such biological disease related features are axon diameter distribution (ADD) and axon Conduction Velocity (ACV) which have been recently demonstrated in vivo, in the Human brain, and revealed the ADD as a novel microstructural biomarker that is related directly to a physiological property (ACV). These two axon related properties, ADD and ACV affect dramatically axonal function on health as well as diseased conditions. In this study we demonstrated the axon diameter dynamics as a novel biomarker for MS early detection and progression. Methods: 25 healthy subjects and 21 MS patients underwent an MRI scan using AxCaliber protocol at the sagittal plane, perpendicular to the corpus callosum (CC). The series of diffusion images were used to calculate the ADD in the form of gamma function following the representation of each CC voxel by gamma-distribution expected value. Results: Our results revealing variation of the ADD within and between both groups, along the CC. While in the healthy subjects,

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the expected pattern of small axons in the genu, moderate in the splenium and larger in the body parts was observed, in MS subjects that is not the case. It seems that the body parts of the CC are affected more than the anterior and posterior parts, whereas the former demonstrated 20% decrease in axon diameter, the latter showed 10% (genu) and 15% (splenium). Moreover, when comparing the callosal sections between healthy and MS groups, a significant differences in axonal morphology were found at all callosal sections (r< 0.035). Conclusions: The results of this study demonstrate that the ADD, as computed from AxCaliber, is sensitive to the fine microstructural properties of the white matter and can detect abnormalities in axon sizes. The ability to characterize the dynamics of axon diameter in both healthy and MS patients may act as a new biomarker of white matter neurodegenerative processes. Moreover, the variability within the MS group may implicate on different phases during MS cycle and may serve as a new practical in-vivo tool for MS pathology evolution. Disclosure Assaf Horowitz: Nothing to Disclose P265 Corpus callosum lesions in Susac syndrome may facilitate diagnosis in cases with an incomplete triad: proposed diagnostic criteria for Susac syndrome G. Paton1, K. McMullen2, A. Traboulsee2, M. Carruthers3, R. Carruthers2 1Pediatric Neurology, University of British Columbia, 2UBC MS/ NMO Clinic, 3Division of Rheumatology, University of British Columbia, Vancouver, BC, Canada Background: There are no diagnostic criteria that formally recognize limited forms of Susac syndrome (SS), a rare autoimmune endotheliopathy causing micro-infarctions and neurologic dysfunction. Only 13% of cases have the classic triad of SS at disease onset. Although neither part of the classic triad nor present in all patients, corpus callosum (CC) lesions may be pathognomonic for SS if seen. Diagnostic criteria for SS that recognizes early will both enhance clinical care and facilitate research. Goal: Review 50 most recent reported cases of SS and Propose Diagnostic Criteria. Methods: PubMed search (April 2016) of “Susac”, “Susac syndrome”, “Susac´s” and “Susac´s syndrome.” Cases were reviewed for: 1) presenting symptoms, 2 ) whether an MR was done at disease outset and 3) whether CC lesions were reported. Results: 46 cases were previously unpublished. Previously published cases were not reviewed. Of the newly reported cases, 35 cases had an MR with first symptoms. 30 (86%) of those patients did not have the full triad. 28/35 patients (80%) had CC lesions. Reported lesion characteristics included: T1 hypointense (n=10, 28%), T2 hyperintense (n=19, 54%), Snowball (n=8, 23%), DWIrestricted (n=3, 8%), and Gadolinium-enhancing (n=2, 6%). The time from presenting symptom to next event ranged from one day to 160 weeks (mean 21 weeks, median 4 weeks in 16 cases with specified relapse-free intervals). Diagnostic Criteria for SS should be based on Core Features (presenting subacutely, either alone or simultaneously):

1. encephalopathy or neuropsychiatric syndrome including but not limited to psychosis, paranoia, delusions, memory loss 2. SNHL (unilateral or bilateral) 3. BRAO or arterial wall hyper-fluorescence with or without visual change SS can be diagnosed if the full triad of core features is present. SS Limited disease (SSLD) can be diagnosed when 2/3 of the core criteria are present. Probable SS can be entertained when one core feature is accompanied by CC lesions. In 35 patients with an MR done with first symptoms, 5 had SS, 11 had SSLD and 14 had Probable SS, 2 had isolated BRAO and 3 had isolated NPSE. CC lesions may be a specific biomarker for SS, but more validation is needed. Diagnostic criteria such as the ones proposed above could enable researchers to study patients with earlier forms of the disease. Disclosure Gillian Paton has nothing to disclose. Katrina McMullen received salary support from Roche and Guthy-Jackson. TT has received consulting fees from for Genzyme, Roche, Teva and Biogen. TT receives research support from Genzyme, Roche, Chugai and Biogen. Mollie Carruthers has received consulting fees from AmGen and Roche. RC is a site PI for studies funded by MedImmune, Seattle Genetics and Guthy Jackson. RC has received speaking fees for unbranded lectures from Biogen, Genzyme, Novartis, and Teva and has received consulting fees from EMD Serono, and Genzyme. P266 Acute disseminated encephalomyelitis in China, Singapore, and Japan: characterization and comparison with the U.S.A D.L.H. Koelman1,2, D.C. Benkeser3, Y. Xu4, S.X. Neo5, K. Tan5, M. Katsuno6, G. Sobue6, J. Natsume6, M. Carone7, F.J. Mateen1,8 1Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States, 2University of Amsterdam Academic Medical Center, Amsterdam, The Netherlands, 3Group in Biostatistics, University of California, Berkeley, Berkeley, CA, United States, 4Peking Union Medical College Hospital, Beijing, China, 5National Neuroscience Institute, Singapore, Singapore, 6Nagoya University Graduate School of Medicine, Nagoya, Japan, 7University of Washington, Seattle, WA, 8Harvard Medical School, Boston, MA, United States Background: Ethnicity-related differences in the incidence of acute disseminated encephalomyelitis (ADEM) have been reported, but little is known on the difference in presenting features between two ethnically- and geographically-distinct populations. When comparing Asian and U.S. populations, the relative prevalence of CNS demyelinating diseases is different, with neuromyelitis optica spectrum disorder (NMOSD) being more commonly diagnosed in Asia, and multiple sclerosis more commonly diagnosed in U.S. cohorts. Objective: To assess for potential differences in the clinical presentation and outcomes of patients diagnosed with ADEM between an Asian and existing U.S. cohort.


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Poster Session 1, 22(S3) Methods: Medical records of patients who presented with ADEM (ICD-9 323.61 and 323.81) at large referral hospitals in China, Singapore, and Japan (years 1992-2015) were retrospectively reviewed and data were collected in a centralized database. The Asian and U.S. cohort were standardized to a 35% pediatric population to facilitate the comparison. The inclusion criteria and data collection tool were identical for all study sites. Results: There were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (interquartile range 1-10) months. The prevalence difference of spinal cord involvement on MRI was 26%, and higher in the Asian than in the U.S. cohort (95% confidence interval (CI) 0-52%; p=0.05; 63% vs. 37%). The patients in the Asian cohort exhibited a 39% lower prevalence of preceding events within 4 weeks of onset (95% CI 12-65% lower; p< 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7-39% lower; p< 0.01, 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset. Outcome was favorable at last known follow up (modified Rankin Scale score ⩽ 2) in approximately two-thirds (64%) of Asian ADEM patients. Conclusions: A high proportion of Asian patients presented with spinal cord lesions. It is unknown whether this is related to the relatively higher prevalence of NMOSD in Asia, vulnerability to spinal cord demyelination, other genetic or environmental factors, or a spurious association. Rates of subsequent relapsing CNS demyelinating disease appear similar in both locations. Disclosure Diederik L.H. Koelman: nothing to disclose. David C. Benkeser: nothing to disclose. Yan Xu: nothing to disclose. Shermyn X. Neo: nothing to disclose. Kevin Tan: nothing to disclose. Masahisa Katsuno: nothing to disclose. Gen Sobue: nothing to disclose. Jun Natsume: nothing to disclose. Marco Carone: nothing to disclose. Farrah J. Mateen: nothing to disclose. P267 Cognitive profile in neuromiyelitis optica spectrum disorder B. Altunrende, A. Yabalak, E. Polat, M. Kocaslan, B. Topcular, G. Akman Neurology, Istanbul Bilim University, Istanbul, Turkey Objective: The aim of this study was to investigate cognitive function in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD) in Turkish population. Methods: Twenty-two patients with the diagnosis of NMOSD according to the new criteria1 underwent neuropsychological tests (Brief Repetable Battery-Neuropsychology (BRB-N), Addenbrooke’s Cognitive Examination (ACE-R) and Beck Depression Invantery (BDI)). Cognitive impairment was considered if at least two cognitive domains were inferior to the 5th percentile for normal values for BRB-N test. The specificity and sensitivity of ACE-R test on detecting cognitive impairment were assessed through ACE-R test results. Results: The mean age of the patients was 42,86±10,98 (25-65). 45,5% (n=10) of the patients had cognitive impairment and 50%

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(n=11) had depression. The group with cognitive impairment had significantly older age, lower educational status, higher EDSS and BDI scores. The mostly affected cognitive profile was found to be memory impairment, attention and processing dysfunction. When the specificity and sensitivity of ACE-R test on NMOSD patients were evaluated, diagnostic level of the test was found to be statistically good since it can detect cognitive impairment with a sensitivity of 88% and specificity of 75% on a cut off level of 82,5. Conclusions: In our study, approximately half of the patients had depression or cognitive impairment. It has been concluded that ACE-R test can be used to detect cognitive impairment in NMOSD patients. Since cognitive impairment and depression are frequent in NMOSD patients, for their quality of life, it is important to evaluate these aspects of the disease. References 1 Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729. Disclosure Burcu Altunrende: Nothing to disclose. Ahmet Yabalak: Nothing to disclose. Emrah Polat: Nothing to disclose. Meryem Kocaslan: Nothing to disclose. Bariş Topçular: Nothing to disclose. Gülşen Akman Demir: Nothing to disclose. P268 Core CSF findings to support the diagnosis of MS: oligoclonal bands or kappa free light chains? A. Emersic1, V. Anadolli2, M. Krsnik3, U. Rot1 1Department of Neurology, University Medical Centre Ljubljana, 2Faculty of Medicine, University of Ljubljana, 3Clinical Institute of Clinical Chemistry and Biochemistry, University Medical Centre, Ljubljana, Slovenia Background: Although cerebrospinal fluid (CSF) analysis is no longer necessary in the diagnostic work-up of multiple sclerosis (MS) evidence of intrathecal immunoglobulin G (IgG) production is highly supportive for the disease. Detection of CSF specific IgG oligoclonal bands (OCB) obtained with isoelectric focusing and subsequent immunoblotting still holds a status of the gold standard method, despite being technically demanding, enabling only qualitative IgG determination and subjective interpretation. Quantification of CSF kappa free light chains (KFLC), rather than intact immunoglobulin molecules, could represent an alternative easier to standardize method with comparable diagnostic accuracy. Objective: In our study we aimed to compare diagnostic accuracy of our ultrasensitive OCB assay and intrathecal KFLC synthesis. Methods: KFLC concentration was measured by nephelometry in paired serum and CSF samples of patients with MS (n = 80, 54 females) and non-inflammatory neurological diseases (n = 48, 26 females). KFLC indices and intrathecal KFLC fractions were calculated by previously defined formulae and used as main quantitative measures of intrathecal KFLC production. OCB assay consisted of agarose isoelectric focusing and IgG immunodetection by alkaline phosphatase-labelled anti-IgG antibody which


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was reported to be at least four times more sensitive than the standard peroxidase method. Results: Diagnostic sensitivity of intrathecal KFLC synthesis was 97.4 % and 96.2 % for the KFLC index and intrathecal KFLC fraction respectively, compared to 90.0 % reached with the ultrasensitive OCB assay. Diagnostic specificity was 97.5 % for both intrathecal KFLC synthesis measures and 100 % for OCB. Importantly, 4 out of 7 OCB negative MS patients had elevated KFLC index when considering previously reported cut-off (⩾ 5.9). CSF KFLC concentration alone was significantly higher in MS (median 1.7 mg/l, range 0.9 - 4.6 mg/l) than in comparison group (median 0.1 mg/l, range 0.1 - 0.2 mg/l; p < 0.0001) and similar was observed for the CSF KFLC to total protein ratio (0.46 % vs. 0.03 %, p < 0.0001). Conclusion: Our results further underline the relevance of KFLC as a diagnostic biomarker in MS. Intrathecal KFLC synthesis is the first quantitative measure that demonstrates comparable diagnostic accuracy as OCB while overcoming several drawbacks of OCB assays. Disclosure Andreja Emersic: nothing to disclose Vanesa Anadolli: nothing to disclose Mladen Krsnik: nothing to disclose Uros Rot received grants/research support from Biogen Idec and consultation fees/travel grants from Bayer, Biogen Idec, Genzyme, Merck-Serono, Novartis and Teva. Support by the University Medical Centre Ljubljana research programme is acknowledged. P269 Brain magnetic resonance imaging characteristics of neuromyelitis optica spectrum disorder in a cohort of Latin American patients E. Carnero Contentti1, V. Daccach Marques2, I. Soto3, A.A.B. Antunes Barreira2, E. Armas4, E. Chiganer5, C. de Aquino Cruz2, J.L. Di Pace5, J.P. Hryb5, C. Lavigne Moreira2, C. Lessa5, O.M. Molina3, A. Soto6, V. Tkachuk7, A. Caride1 1Department of Neuroscience, Hospital Alemán, Buenos Aires, Argentina, 2Departamento de Neurociências e Ciências do Comportamento, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Sao Pablo, Brazil, 3Neurology Department, Hospital Universitario de Maracaibo, Maracaibo, 4Neurology Department, Hospital Universitario de Caracas, Caracas, Bolivarian Republic of Venezuela, 5Neurology Department, University of Buenos Aires, Hospital Carlos G. Durand, Buenos Aires, Argentina, 6Neurology Department, Hospital Domingo Luciani, Caracas, Bolivarian Republic of Venezuela, 7Neurology Department, Hospital Jose de San Martin, Buenos Aires, Argentina Background: Brain magnetic resonance imaging (MRI) lesions on T2-weighted or fluid-attenuated inversion recovery sequences are commonly seen in patients with neuromyelitis optica spectrum disorder (NMOsd). “Typical” NMO lesions are generally used with reference to lesions located at sites of high aquaporin 4 (AQP4) expressions. However, the exact frequency is unclear with differences between the regions that were evaluated.

Objectives: To report brain MRI characteristics (localization and configuration) abnormalities at diagnosis in a cohort of NMOsd Latin American patients. Methods: Multicenter retrospective study from Argentina, Brazil and Venezuela that included 79 patients with NMOsd. We analyzed MRI characteristics at diagnosis using medical records database. Patients’ demographic, clinical and laboratory data were collected. Results: The prevalence of brain MRI abnormalities was 81.02% (64/79) at the onset of disease. Forty-two patients (53.17%) showed at least one kind of brain “typical” abnormality on MRI. Non-typical lesions were observed in 46.83% (37/79) and 59.45% (22/37) had nonspecific abnormalities. Characteristic brain MRI abnormalities were classified in lesions involving the dorsal medulla (area postrema, 16.46%), brainstem/cerebellum (32.91%,), hypothalamus (6.33%), thalamus (7.59%), periependymal surfaces of the third ventricle (11.39%), corticospinal tract lesions (8.86%), corpus callosum (13.92%), hemispheric white matter lesions (1.26%) and nonspecific white matter abnormalities (62.03%). Nine (11.39%) patients showed gadolinium-enhancing lesions. AQP4 antibody seropositive proportion was 63.63% (42/66) and nonavailable 16.46%. Characteristic brain MRI abnormalities do not differ significantly between seropositive and seronegative patients. Conclusion: This study showed high frequency of brain typical MRI abnormalities and it is not associated with serological status. Recognize these lesions could help us differentiate multiple sclerosis of NMOds and early initiation of effective immunosuppressive therapy to preventing attack-related disability. Disclosure nothing to disclose

MS variants P270 Identification and measurement of cervical spinal cord atrophy in neuromyelitis optica spectrum disorders (NMOSD) and correlation with clinical characteristics and cervical spinal cord MRI data F. Lersy, V. Noblet, A. Fitsiori, N. Collongues, M. Fleury, L. Kremer, J.-L. Dietemann, J. De Sèze, S. Kremer CHU de Strasbourg, Strasbourg, France Introduction: The spinal cord is one of the two main targets of neuromyelitis optica (NMO). Numerous studies have assessed cervical spinal cord atrophy in multiple sclerosis, while only a few studies have focused on NMO. The aim of this study was to highlight cervical spinal cord atrophy in NMO patients as compared to controls and to assess correlations between atrophy and clinical characteristics and cervical spinal cord MRI data. Methods: This prospective study investigated 15 patients with a diagnosis of NMOSD and 15 healthy controls. The whole cervical spinal cord was explored by MRI with a sagittal T2 3D sequence. The cross-sectional area (CSA) was estimate at every level of cup. This measurement was then averaged on the whole cervical spinal cord, providing a single measurement for every subject, denoted as mean-CSA. Results: Mean-CSA was 68.5 mm² in the population of NMO patients and 72.8 mm² in the population of healthy subjects. NMO patients had significantly smaller cervical spinal cord area than


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Poster Session 1, 22(S3) healthy controls (Ttest = 0.009). Cervical spinal cord atrophy was associated with clinical signs of medullary involvement (Ttest = 0.0006).There was a tendency toward a relation between cervical spinal cord atrophy and the Expanded Disability Status Scale (EDSS) (Ttest = 0.07). This correlation seems statistically significant (Ttest < 0.05) at the level of the upper cervical spinal cord (C2-C3). Conclusion: This study provides the first evidence of cervical spinal cord atrophy in NMOSD by studying the entire cervical spinal cord. Upper cervical spinal cord atrophy was substantially correlated to clinical disability and seems more involved in the development of clinical disability in NMOSD patients in comparison to the lower cervical spinal cord. Disclosure The authors declare no conflict of interest P271 Characterization of seronegative neuromyelitis optica in 2016 L. Pandit1, D. Sato2, S. Siritho3, I. Nakashima4, K. Kaneko4, V. Morale5, D. Callegaro5, G. Rodrigues dos Passos6, K. Fujihara4 1K.S.Hegde Medical Academy, Nitte University, Mangalore, India, 2Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil, 3Bumrungrad International Hospital, Bangkok & Siriraj Hospital, Mahidol University, Bangkok, Thailand, 4Tohoku University Graduate School of Medicine, Sendai, Japan, 5University of Sao Paulo, Sao Pablo, 6University of Sao Paulo, Sao Paulo, Brazil Objective: To evaluate the clinical features of patients with Neuromyelitis optica (NMO) diagnosed by Wingerchuck 2006 criteria (who also fulfilled new IPND criteria), who were seronegative for both anti-MOG and anti-AQP4 antibody (Ab). Methods: In this multicentre collaboration (India, Brazil, Thailand and Japan), sera of 190 consecutive NMO patients were tested by CBA at Tohoku University,Japan for Anti-AQP4 and anti-MOG antibody using live transfected cells with AQP4-M23 or full-length MOG. Results: Among them 34 (17.9%) patients were seronegative for both anti-MOG and anti-AQP4 Ab and all had a relapsing disease course. There were 20 women and 14 men who had the first attack at a median age of 26 (8-56) years. The initial attack was located in the spinal cord in 74.3%. During a follow up of 7.0 years (range 1-38), attack frequency was 3 (1- 18) and last EDSS 4.3 (0-10). Severe visual loss (VA < 20/200) was seen in 20.6%. Bilateral optic neuritis (20.6%), simultaneous myelitis and ON (5.8%) and area postrema syndrome (14.7%) were less common than reported in anti-AQP4+ patients. MRI of the spinal cord showed longitudinally extensive myelitis in cervical/dorsal (45.7%) and dorsal (34.3%) regions of the cord. Brain MRI was abnormal in 68.5% and most often showed atypical subcortical white matter lesions. Overall they were treated with corticosteroids and/or immunosuppressants. Conclusions: Seronegative NMO had a relapsing course, no gender predilection, and relatively early onset of disease. Relapsing disease may require the initiation of long-term immunosuppression.

Nakashima I: nothing to disclose Kaneko K: nothing to disclose Morale V: nothing to disclose Callegaro D: nothing to disclose Rodrigues dos Passos G: nothing to disclose Becker J: nothing to disclose Fujihara K: nothing to disclose

P272 Genotypic influences on surface expression of co-stimulatory receptors suggests a role for B-cell subtypes in the development of multiple sclerosis D. He, B. Fiddes, J. Jones, W. Liao, A. Compston, A. Coles, M. Ban, S. Sawcer University of Cambridge School of Medicine, Cambridge, United Kingdom Objectives: Although more than a 100 susceptibility loci for multiple sclerosis (MS) have been identified via genome wide association studies (GWAS), our understanding of the implicated molecular mechanisms remains limited. Given the importance of the interaction between B and T cells in the development of an immune reaction the fact that the genes for the co-stimulatory receptors CD40 and CD86 each lie close to genetic variants independently associated with MS suggests that these genes may be involved in the development of the disease. We have previously shown that that the MS associated SNP rs9282641, which lies within the CD86 gene, influences the surface expression of this gene in B cells. We therefore wanted to extend our analysis of co-stimulatory surface receptors and function in this important cell type. It is our hypothesis that MS predisposing genotypes may act by reducing B cell regulatory function, by for example, reducing the production of anti-inflammatory cytokines such as IL10. Methods: In an extension of our previous analysis we have genotyped a second MS associated SNP (rs4810485) in 162 individuals and measured the surface expression of CD40 in resting (unstimulated) B cells from these individuals. The surface expression of CD40 and CD86 together with the production of IL10 is also being assessed in B cells activated through co-culturing PBMCs with CD40L-transfected L cells. All individuals included in this study are healthy controls recruited through the Cambridge BioResource. Results: We have found a highly significant association between CD40 expression and the genotype at rs4810485. The risk allele (T) at rs4810485 resulting in lower expression of CD40 in all tested B cell sub-types. Comparing B cell subtypes shows that the naïve B cells have the lowest expression of CD86 and the highest expression of CD40, with the respective MS risk alleles increasing CD86 expression (rs9282641) and reducing CD40 expression (rs4810485). The effects of these two SNPs on the expression of these genes is also being examined in stimulated B cells. Conclusions: Our study shows that the two MS associated SNPs rs9282641 and rs4810485 alter the expression of co-stimulatory receptors in naïve B cells. This work suggests that naïve B cells may be involved in the development of MS.

Disclosure Pandit L: nothing to disclose Sato D: nothing to disclose Siritho S: nothing to disclose

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Disclosure D. He is supported by Chinese Scholarship Council and the research is founded by The Multiple Sclerosis Society


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B. Fiddes is supported by the Sackler studentship J. Jones: nothing to disclose W. Liao: nothing to disclose A. Compton: nothing to disclose A. Coles: nothing to disclose M. Ban: nothing to disclose S. Sawcer: nothing to disclose P273 Is Radiologically isolated syndrome uncommon as thought? Prevalance of radiologically isolated syndrome in a doublecenter, population-based study N. Oztekin1, M.F. Oztekin2, S. Bilen1, F. Ak1 1Neurology, MOH Ankara Numune Training and Research Hospital, 2Neurology, MOH Ankara Diskapi Teaching and Research Hospital, Ankara, Turkey Background and objective: With increasing availability of magnetic resonance imaging (MRI), there is also an increase in incidental abnormal findings suggestive of multiple sclerosis in people without multiple sclerosis symptoms and with normal neurological findings.These cases are classified as radiologically isolated syndrome (RIS) and the prevalence of RIS is not certain. The aim of this study was to determine the prevalence of RIS in two tertiary centers in a region with a high prevalence for MS. Method: This is a retrospective cohort study conducted in 2016. All brain MRI examinations performed at two tertiary centers refered by a a neurologist for various complaints i.e. headache, dizziness, vertigo and other nospesific symptoms, none suggestive of a demyelinating process. A total of 2417 patients were included and analysed in the Neurology departments of these two centers. Age range was 18-65 and only 4 patients wih RIS were identified which is equivalent to 0.16%.Only two patient with RIS developed symptoms consistent with MS within 3 months, accompanied with radiological progression and was diagnosed as MS. Conclusions: Although RIS, according to present criteria, is an ascertined as an uncommon finding, our results revealed that it is not that uncommon as previously reported.Larger multicenter studies are needed in order to study the prognosis of RIS and rate of conversion to MS. Disclosure M.F. Oztekin: nothing to disclose N. Oztekin: nothing to disclose S.Bilen: nothing to disclose F.Ak: nothing to disclose

P274 Depression in patients with neuromyelitis optica spectrum disorder J.M. Seok1,2, M. Choi1,2, Y.S. Kim1,2, E.B. Cho3, H.L. Lee4, S.-Y. Kang5, K.H. Lee1,2, B.J. Kim1,2, J.-H. Min1,2 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2Neuroscience Center, Samsung Medical Center, Seoul, 3Department of Neurology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, 4Department of Neurology, Chungbuk National

University Hospital, Chungbuk National University College of Medicine, Chungbuk, 5Department of Neurology, College of Medicine, Jeju National University, Jeju, Republic of Korea Background and objective: Depression in chronic neuroinflammatory diseases are common, and regarded as a major burden of disease. About 25 to 50% of patients with multiple sclerosis (MS) develop a type of depression over the disease course. And the factors that affect the depression have been studied well; disease duration and fatigue were related closely. However, the issues of depression are largely unknown in patients with neuromyelitis optica spectrum disorder (NMOSD). We aimed to elucidate the depression and its contributory factors in patients with NMOSD. Methods: We prospectively studied NMOSD patients who were in remission and seropositive for aquaporin-4 antibody. Depression and health-related quality of life were evaluated in enrolled patients, using the revised Beck Depression Inventory (BDI-II) and the short form 36 health survey questionnaire version 2 (SF-36v2), respectively. Demographic and clinical findings of enrolled patients were reviewed. Results: A total of 33 patients were evaluated (28 females; age, 47.2 ± 13.7 years). The median EDSS score was 2.0 (range 0 to 8.0). 51.5% of NMOSD patients were depressed, having 14 or more of BDI-II score. And the BDI-II score correlated positively with Expanded disability status scale (EDSS) (r = 0.433, p = 0.012) but not associated with the disease duration or the location of central nervous system (CNS) involvement. There were significant correlations between health-related quality of life score by SF-36v2 and depression by BDI-II score (mental component score: r = -0.617, p < 0.001; physical component score: r = -0.449, p = 0.010). Multiple linear regression analysis showed that the degree of depression was independently associated with mental health summary scale of SF-36v2 (B=−0.875; 95%CI −1.372 to −0.377; p = 0.001). Conclusion: Our study suggested that the depression was common, and had a significant impact on the mental quality of life in patients with NMOSD. Disclosure J.M.S: Nothing to disclose M.C: Nothing to disclose Y.S.K: Nothing to disclose E.B.C: Nothing to disclose H.L.L: Nothing to disclose S.Y.K: Nothing to disclose K.H.L: Nothing to disclose B.J.K: Nothing to disclose J.H.M: Nothing to disclose P275 Tumefactive multiple sclerosis: diagnostic enigma and therapeutic challenge H. Algahtani1, M. Hmoud2, H. Abobaker1, F. Alzahrani2, B. Shirah2 1King Abdulaziz Medical City/ King Saud bin Abdulaziz University for Health Sciences, 2King Abdullah International Medical Research Center / King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia


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Poster Session 1, 22(S3) Introduction: Tumefactive multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by lesions measuring more than 2 cm. The disease incidence is 1 to 2 per 100 cases of multiple sclerosis; and 3 cases per million yearly in the general population. Methods: A systematic review was done using four databases. We used the following key terms (tumefactive multiple sclerosis, tumefactive demyelinating lesions, demyelinating pseudotumor). The inclusion criteria for this review included all papers that has full patients’ data. Out of 1170 articles, 87 articles met the inclusion criteria. For statistical analysis of dichotomous variables we measured the proportion and 95% confidence interval (CI). For continuous variables, we measured the mean, standard deviation (SD), and 95% CI. All data were entered and analyzed using SPSS software version 22. Results: One-hundred-six patients’ data were analyzed out of 400 identified in the literature. Mean age of the patients was 33 years of age (±15). Majority of the patients were females (73%). Motor (65%), cranial nerves (33%) and sensory involvement (30%) were the commonest clinical manifestations. Oligoclonal bands came positive in 44 patients (42%). Brain biopsy was done in 51 patients (48%). Deep white matter, parietal and frontal lobes involvements were the commonest radiological manifestations. Forty-six patients (43%) were misdiagnosed initially. Steroids were implemented in the initial management in 83 patients (78%). Plasma exchange (PLEX) was used in 9 patients (10%), and IVIG in 2 patients (2%). Disease modifying therapies (DMT) were used in 15 patients (14%). Conclusions: Tumefactive multiple sclerosis is a diagnostic challenge since it can mimic multiple conditions. Biopsy is highly recommended, especially, for those with no pre-existing multiple sclerosis, unusual presentation or non-conclusive magnetic imaging. Plasma exchange and intravenous immunoglobulin can be used as second-line in steroid resistant cases. Disclosure The authors have no conflict of interest to report. P276 Clinical course of primary progressive multiple sclerosis: fast and slow progression C. Legarda, M. Gurevich, D. Magalashvili, M. Dolev, A. Achiron Sheba Medical Center, Ramat Gan, Israel Background: The clinical course of primary progressive multiple sclerosis (PPMS) is highly variable and unpredictable. In some patients, disability progresses fast causing deterioration within few years, while in others progression is fairly slowly. In the current study we analyzed different progression rates and associated demographic and clinical parameters in a large PPMS cohort. Methods: We divided PPMS patients with a long-follow-up into sub-groups according to the time from onset they reached neurological disability by the Expanded Disability Status Scale (EDSS) of at least 3.0. PPMS patients that progressed to EDSS⩾3.0 within 2 years from onset were defined as Fast progressing; those that reached EDSS⩾3.0 within 5 years or later were defined as Slow progressing, and patients that attained EDSS⩾3.0 between 2 to 5 years from onset were defined as Intermediate progressing.

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In the Fast progressing group, patients that further progressed to EDSS⩾6.0 within 5 years were defined as Persistently Fast progressing. In the Slow progressing group patients reaching EDSS⩾6 within 10 years were defined as Persistently Slow progressing. Clinical and demographical parameters at onset were compared between the groups. Result: Progression rates of 163 PPMS patients, age at onset 40.9±10.6 years, 53.4% males, were analyzed. The Fast progressing patients represent 53% and the Slow progressing patients 26% of the PPMS population. Persistently Fast and Persistently Slow progressing patients represent 16% and 21% of the PPMS population. Both Fast progressing and Persistently Fast progressing groups are characterized by significantly higher EDSS at onset as compared to Slow and Persistently Slow progressing patients, p< 0.001. This difference in disability was associated with higher proportion of pyramidal, cerebellar and visual deficits at onset. Conclusions: PPMS patients present with different rates of progression. Fast clinical progression is more common and is associated with higher disability at onset. Disclosure Legarda Carolina has nothing to disclose Gurevich Michael has nothing to disclose Magalashvili David has nothing to disclose Dolev Mark has nothing to disclose Achiron Anat received personal compensation from Teva Pharmaceutical Industries, Sanofi-Genzyme and Novartis for serving on scientific advisory board and as a consultant. P277 Malignant multiple sclerosis: prevalence, demographic and clinical prognostic factors identified in Brazilian cohort C.C. Vasconcelos1, F.C.A. Hampshire1, J.C.K. Aurenção1, A. Bergmann2, R.M.P. Alvarenga1,3 1Pos Graduação de Neurologia, Universidade Federal do Estado do Rio de Janeiro, 2Pesquisa, Instituto Nacional do Cancer, 3Neurologia, Hospital Federal da Lagoa, Rio de Janeiro, Brazil Introduction: In multiple sclerosis (MS) certain patients reach greater degrees of disability within a short period of time. This severe progressive form is referred to as malignant multiple sclerosis (MMS) when an Expanded Disability Status Scale (EDSS) score of 6 is reached within five years of disease onset. Objective: To analyzed a cohort of Brazilian patients to identify cases of MMS and potential prognostic factors related to more severe progression. Methods: In this observational study was performed a retrospective analysis of demographic and clinical data collected from medical records of 293 MS patients according to McDonald et al criteria. The patients have been regularly followed up at the Hospital Federal da Lagoa in Rio de Janeiro, Brazil. Based on time to reach EDSS 6, patients were classified as malignant-MS (MMS) up to five years, or non-malignant-MS (NMMS) above five years. Student’s t-test, Kaplan-Meier analysis, odds ratios and 95% confidence intervals were used. Results: Twenty-five (8,53%) patients were found to have MMS and were compared with the remaining 268 (91,47%). Women (52%), non-white patients (52%). Relapsing Remitting MS (RRMS) was more common than primary-progressive form (PPMS)


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in non-malignant-MS (93.7% versus 68%; p< 0.001), whereas PPMS was more prevalent in malignant-MS (32% versus 5.2%; p< 0.001). Between the groups, significant differences were found for sex, ethnicity, recovery after the first attack, number of relapses during first year and time between the first two attacks. Regarding to clinical progression, the risk for progression was 10-fold greater for patients with MMS (OR=14.5; 95%CI: 4.4-48.1) and 35.5% of MMS patients had reached secondary progression versus 3.6% in NMMS (p< 0.001). Conclusions: According to the generally accepted concept of MMS, less than 10% of patients in this Brazilian cohort were MMS. Identifying demographic and clinical prognostic factors may make early treatment with more effective drugs more feasible. Disclosure Claudia Vasconcelos: nothing to disclose Fabricio Hampshire-Araújo: nothing to disclose Juliana CK Aurenção: nothing to disclose Anke Bergmann: nothing to disclose Regina M Papais-Alvarenga: nothing to disclose P278 Atypical myelitis of multiple sclerosis: description of a French cohort C. Lambert1, L. Kremer1, C. Lebrun2, M. Cohen2, P. Labauge3, J. De Sèze1, N. Collongues1 1Hôpital de Hautepierre, Strasbourg, 2Hopital Pasteur - Service de Neurologie, Nice, 3Hopital Gui de Chauliac, Montpellier, France Introduction: The “atypical” myelitis of multiple sclerosis (MS), are characterized by longitudinally extensive myelitis (affecting >3 vertebral segments, transverse myelitis (> 50% of spinal cord in the axial plane), anterior, or central cord lesions. The aim of this study is to collect atypical cases of myelitis related to MS to better characterize this population. Methods: This study is observational, retrospective, multicenter, and includes incident cases between 2012 and 2016. Ten patients were included in Strasbourg, Nice and Montpellier in France. We collected demographic information, clinical and radiological characteristics of myelitis, laboratory results including CSF, brain IRM, treatment, and clinical follow-up. Results: All patients fulfilled 2010 Macdonald criteria. The mean age was 40,4 years, the sex ratio woman / man was 1,5/1. Myelitis was the first relapse for 8 patients and the second for 2 patients. Intrathecal synthesis of immunoglobulin was found in all cases. On spinal cord MRI, we observed 4 longitudinally extensive myelitis, 6 transverse myelitis, 2 central cord lesions and 2 transverse and longitudinally extensive myelitis. The median EDSS was 4 [1-8] during the relapse, 3 [0-6,5] after 6 months and 3 [0-7] after a mean follow-up of 3 +/- 10 years. Myelitis occurred as a second relapse for 3 patients. Three patients experienced a progressive course of the disease. Three other patients had not new symptoms and one patient had a cerebellar peduncle lesion. Discussion: the small size of our cohort is a consequent of the rarity of this clinical manifestation in MS. Extensive myelitis represents the main manifestation in our cohort. A better recovery than in the neuromyelitis optica spectrum or the systemic diseases seems to emerge.

Conclusion: The atypical presentation of myelitis in MS is mainly characterized by longitudinally and transverse extensive myelitis. It seems to be a specific entity as defined by its disease course and its potential for recovery. Disclosure Nothing to disclose P279 Is cognitive impairment common in neuromyelitis optica spectrum disorders (NMOSD)? A. Orviz García, M. Valles Salgado, J. Matías-Guiu Antem, I. González-Suárez, C. Oreja-Guevara Hospital Clínico San Carlos, Madrid, Spain Introduction and background: NMOSD and multiple sclerosis (MS) are both relapsing central nervous system (CNS) inflamatory disease with similar clinical features at the beggining. Cognitive decline is often present in MS, even since early stages, and seems to correlate with brain atrophy, therefore with a neurodegenerative process independent on number of relapses. Until now, there are very few and controversy evidences of cognitive impairmenti n NMOSD and not evidence of global axonal degeneration out of relapses. Methods: NMOSD patients were recruited from a reference Multiple Sclerosis Center. Cross-sectional study was carried out. A wide batery of specific neuropsychological tests was used to evaluate every cognitive domain: concentration/attention (Verbal Span, PASAT), language (ACE-III subtest), basic and complex executive function (SDMT, A and B form of TMT, categorial and formal recall), memory (FCSR, FCRO), visuospatial and visuoperceptive function (VOSP, Benton JLO) and also depression and fatigue scales. Cognitive impairment was diagnosed when low scores were yielded in two tests for an specific domain (adjusted by level of education and age), at least in two different domains. Results: Ten patients were examinated, with a median age of 40 years old (rank 21-69) and a disease duration of 4.42 years (rank 1.75-10.75). The mean EDSS was 3.0 (rank 1.0-6.0). Only one patient (female and 42 years old) meet criteria of cognitive impairment, showing deficiency in executive and visuoperceptive function. Two patients presented decline in frontal execution but no other domain, both associated with mild and moderate deppresion in Beck Inventary Scale (BIS). More than 50% patients showed high levels of fatigue. Conclusions: Despite long median disease duration of our patients, cognitive impairment was very rare. Mainly affected domains were frontal execution and visuoperceptive function. This results could reflect the absence or low degree of global progressive degeneration in NMOSD patients and could help us to distinguish from MS. Disclosure Aida Orviz García: nothing to disclose María Valles Salgado: nothing to disclose Jordi Matías-Guiu Antem: nothing to disclose Inés González Suárez: nothing to disclose Celia Oreja-Guevara: nothing to disclose


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Poster Session 1, 22(S3) P280 The diagnostic and prognostic value of MRI for evaluating atypical idiopathic inflammatory demyelinating lesions A. Soysal, Z. Özdemir, E. Acar, M. Ozerden, N. Kale Neurology, Bakirkoy Training and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey Introduction: Diagnosing a demyelination in atypical cases has always been challenging, sometimes leading to a biopsy.Recent literature has radiologically classified atypical demyelinating lesions as: ring like, Balo-like, infiltrative, megacystic and unclassified. In this study we aim to assess the demographics, clinical and radiological findings in patients with atypical lesions. Methods: The records of 320 patients with demyelinating disorders have been retrospectively assessed using Imed database. Patients with atypical lesions and whose MRI evaluations were available were included. Clinical and radiological findings were evaluated and lesions were classified according to the recommended criteria. Results: 23 patients (16 females) were included, mean age was 34.26±6.12 years (26-49). 12 patients also had diffusion weighted MRI (DWI) as well. When lesions were classified, 13 patients had ring-like, 1 patient had Balo-like, 2 patients had megacystic, 4 patients had infiltrative lesions and 3 patients had unclassified lesions. When available DWI’s were evaluted, restriction was observed in contrast enhancing sites in ring like lesions, area around infiltrative lesions and also outside the demyelination in Balo like lesions. When prognostic factors were evaluated, 2 patients with infiltrative lesions had additional lesions on follow up and had to go under biopsy. 2 patients were lost despite aggresive treatment. Balo-like patient was evaluated as ADEM and did not have further relapses. The17 patients from the study group converted to MS on follow-up. Discussion: Eventhough diagnosing atypical lesions is not always easy, the prognosis is not different from MS lesions. Mostly, ringlike lesions seem to convert to MS with recurrent relapses, however infiltrative lesions seem to have a poorer outcome especially if patients have additional relapses. DWI may also be of help for diagnosing these cases. Disclosure Nothing to disclose P281 Investigating the choroid in neuromyelitis optica spectrum disorder using optical coherence tomography M.M. Bertsch-Gout, C. Szewcyk, A. Javed, J. Bernard Neurology, University of Chicago, Chicago, IL, United States Objective: To investigate the difference in submacular choroid thickness between subjects with neuromyelitis optica spectrum disorder (NMOSD) and healthy controls (HC) using spectral domain optical coherence tomography (SD-OCT). Background: Vascular dysregulation has repeatedly been suggested as a potential source of the widespread inner-retinal thinning seen in patients with NMOSD. To date, no studies have used OCT to measure NMOSD choroid thickness, thinning of which is thought to be indicative of reduced submacular ocular perfusion.

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Methods: SD-OCT was performed on NMOSD and HC subjects matched for age, race and gender. Enhanced Depth Imaging (EDI) was used to capture the submacular choroid, which was manually segmented. Choroid volumes and thicknesses were then statistically compared between conditions. Results: OCT measurements of 8 NMOSD eyes and 8 HC eyes were analyzed. No statistically significant difference in submacular total choroid volume was found (P=.40). Additionally, no significant thinning was found in the submacular choroid within a 3mm or 6mm foveal ring (P=.22 and P=.50, respectively). Despite the lack of statically significant results, all beta coefficient signs supported the hypothesis that NMOSD eyes have thinner choroids than HC eyes, with the 3mm foveal ring comparison yielding a beta coefficient larger than its standard error (B=-28.41, SE=23.21). Conclusion: This is the first OCT study to investigate choroid measurements in NMOSD compared to HC. No statistically significant differences were found. Relatively large standard errors in all comparisons suggest that this was due to the distributions of the NMOSD and HC submacular choroid OCT measurements largely overlapping and/or the preliminary nature of this study’s sample-size. Future directions for this study include the collection of a larger sample-size as well as the inclusion of multiple sclerosis (MS) eyes. Disclosure Mr. Bertsch-Gout has nothing to disclose. Dr. Javed has received consultant fees from Teva, Bayer, Novartis, Questcor and Biogen, and has been a speaker for Bayer, Teva, Biogen, Novartis, and Questcor. Dr. Bernard has received grant support from Biogen Idec and has served as a consultant for Novartis. P282 Cross-modal plasticity among sensory networks in neuromyelitis optica spectrum disorders A. d’Ambrosio1, M.A. Rocca2, F. Savoldi2, P. Valsasina2, M. Radaelli3, P. Preziosa2, G. Comi3, A. Falini4, M. Filippi2 1San Raffaele Scientific Institute, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 3Department of Neurology, 4Department of Neuroradiology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Aims: We compared resting state (RS) functional connectivity (FC) within and among RS networks between patients with neuromyelitis optica spectrum disorder (NMOSD, 2015 criteria), isolated recurrent optic neuritis (ON) and recurrent myelitis. Methods: RS fMRI was acquired from 30 NMOSD, 11 ON, 12 myelitis patients and 30 healthy controls (HC). RS FC within and between the main sensory and motor networks as well as correlations with motor performance were assessed using SPM12. Results: Compared with HC, NMOSD patients showed decreased RS FC of the secondary visual network. They also showed increased RS FC of the visual and auditory networks vs HC, ON and myelitis. No sensorimotor RS FC abnormalities were detected. ON patients experienced decreased RS FC of the visual and auditory networks and increased RS FC of primary visual regions. Myelitis patients had reduced RS FC of the sensorimotor, visual


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and auditory networks vs HC, NMOSD and ON. They also showed increased RS FC of the precuneus (sensorimotor network) and cerebellum (visual network). In all groups, decreased RS FC correlated with poor motor performance. In myelitis increased precuneus RS FC correlated with better motor performance. FNC between motor and visual RSNs was increased in NMOSD, while FNC was markedly decreased between primary and secondary visual RSNs in ON. Conclusions: In recurrent ON and myelitis, abnormal RS FC was observed in networks primarily affected by the pathological process. NMOSD showed decreased visual system RS FC and increased RS FC in other sensory networks, suggesting crossmodal plasticity among different sensory modalities. Disclosure Drs dÁmbrosio, Savoldi, Valsasina, Radaelli, Preziosa, and Falini. Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). P283 Proposed revised criteria for the diagnosis of CLIPPERS G. Taieb, P. Labauge, CLIPPERS French Group University Center Hospital, Montpellier, France Objective: The aim of this study is to propose revised criteria for the diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Background: CLIPPERS is an inflammatory disorder of unknown origin defined by 1) subacute brainstem signs and symptoms; accompanied by 2) punctate and curvilinear enhancing lesions predominantly involving the pons; with a 3) prompt steroid sensitivity; in 4) absence of alternative diagnosis. When the brain biopsy is performed, 5) perivascular lympho-histiocytic infiltrates are seen. However, since its first description in 2010, multiple sclerosis, primary arteritis of the CNS, primary CNS lymphoma and lymphomatoid granulomatosis could fulfil, at least initially, all these CLIPPERS criteria including histological features.

Methods: In our previously reported French study, included 12 patients, CLIPPERS had a relapsing-remitting course in absence of immunosuppressive therapy. Relapses fitted always the four first criteria and occurred only when steroid dosage was below 20 mg/day. Therefore we propose to add this sixth criterion into the CLIPPERS definition, in order to evaluate its ability to distinguish CLIPPERS from its related diseases. Results: Among our 22 patients fulfilling the first diagnostic criteria set for CLIPPERS, 4 progressed eventually to a well-defined disease: multiple sclerosis (n=1), primary arteritis of the CNS (n=1), primary CNS lymphoma (n=1), and lymphomatoid granulomatosis (n=1). Except in the patient having lymphomatoid granulomatosis, a brain biopsy was performed during the first attack and fitted the fifth criterion. However, within 2 years after the initial diagnosis of CLIPPERS, relapses did never fit the sixth criterion in all of these four patients. Conclusions: If we consider that CLIPPERS is new disorder and not a pre stage of well-defined diseases, our results suggest that this sixth criterion may be useful to distinguish CLIPPERS from its related diseases, and should be added in the CLIPPERS criteria. References 1. Taieb G, Duflos C, Renard D, et al. (2012) Long-term outcomes of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive series of 12 patients. Arch Neurol 69:847-55. Disclosure Guillaume Taieb: nothing to disclosure Pierre Labauge: nothing to disclosure and the French CLIPPERS group: nothing to disclosure

Paediatric MS P284 The incidence of paediatric-onset acquired demyelinating syndromes of the central nervous system in Denmark: a nationwide register-based study M.S. Boesen1,2, M. Magyari2,3, N. Koch-Henriksen2,4, L.C. Thygesen5, P. Born1, P. Uldall1, M. Blinkenberg3 1Department of Paediatrics, Rigshospitalet, University of Copenhagen, 2The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, 3Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, 4Department of Clinical Epidemiology, University of Aarhus, Clinical Institute, Aarhus, 5National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark Background: The incidence of acquired demyelinating syndromes (ADS) has not previously been estimated in Denmark in persons less than 18 years of age. Globally, few nationwide studies of the incidence of ADS have been published. Aim: To determine the nationwide age- and sex-specific incidence of paediatric-onset ADS in Denmark from 1977 through 2015. Methods: The nationwide Danish Multiple Sclerosis (MS) Registry provided cases of paediatric-onset MS. Furthermore, the


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Poster Session 1, 22(S3) National Patient Register was utilized to identify cases of paediatric-onset non-MS ADS of the central nervous system (International Classification of Diseases 8 or 10 in brackets): optic neuritis (“367.02”, “367.01”, “H46”), transverse myelitis (“323.02”, “G37.3”), neuromyelitis optica (“341.00”, “G36.0”), acute demyelinating encephalomyelitis (“323.03”, “323.04”, “G04.0”), or demyelinating disease of central nervous system (“G36” “G36.8”, “G36.9”, “G37.8”, “G37.9”). Age- and sex-specific incidence rates including 95% confidence interval (95% CI) were estimated by the Poisson regression model. Results: Based on 458 cases of MS and 690 cases of non-MS ADS with onset before 18 years of age, our study showed that the incidence rate per 100,000 person-years of MS was 0.58 (95% CI: 0.49-0.69) in males, and 1.42 (95% CI: 1.28-1.59) in females, and 0.99 (95% CI: 0.91-1.09) for both sexes. The female-to-male ratio was 2.32, and the median age at onset was 16 years with a range from 4-17 years. 143 cases of MS had onset before 15 years of age which resulted in an incidence rate of 0.52 (95% CI: 0.42-0.63) in females, and 0.24 (95% CI: 0.18-0.32) in males, and 0.38 (95% CI: 0.32-0.44) for both sexes. In contrast, the incidence rate of non-MS ADS was 1.25 (95% CI: 1.12-1.41) in males, and 1.75 (95% CI: 1.59-1.93) in females, and 1.50 (95% CI: 1.39-1.61) for both sexes. The female-to-male ratio was 1.33 with a median age at onset of 13 years and a range from 0-17 years. Conclusion: The estimated age-specific incidence of paediatriconset MS in Denmark is comparable with existing European epidemiological studies of paediatric-onset MS. Only 1/3 of the patients were 14 years and below at onset. This can be explained by a steadily increasing MS incidence through adolescence, particularly in females from 15 years of age and onwards. The incidence of non-MS ADS was 1.5 times higher than the rate of MS and almost twice as high as previously reported in the Netherlands. Disclosure Magnus Boesen has received financial support for the current PhD project from Novartis, Teva, and Genzyme; received honoraria for lecturing from Novartis and support for congress participation from Teva. Melinda Magyari has served on scientific advisory board for Biogen Idec and Novartis, Merck Serono, has received honoraria for lecturing from Biogen Idec, Merck Serono, Novartis, Genzyme, has received support for congress participation from Biogen Idec, Novartis, Genzyme, and Teva. Nils Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis. Lau Caspar Thygesen has received honoraria for lecturing from Rigshospitalet (Copenhagen, Denmark), Statistics Denmark and Sanofi-Avensis. Peter Born has nothing to disclose in relation to the content of this study Peter Uldall has nothing to disclose in relation to the content of this study Morten Blinkenberg has served on scientific advisory boards for Biogen Idec, Merck-Serono, Novartis, Sanofi-Aventis and Teva; received speaker honoraria from Biogen Idec, Merck-Serono, Bayer-Schering, Novartis, Teva, Roche and Sanofi-Aventis; received consulting honoraria from the Danish Multiple Sclerosis

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Society, Biogen Idec and Merck-Serono; has received funding for travel from Biogen Idec, Merck-Serono, Sanofi-Aventis, Genzyme and Solvay Pharma. P285 Fingolimod in active pediatric onset multiple sclerosis P. Huppke, H. Hummel, W. Stark, J. Gärtner University Medical Center, Georg August University, Göttingen, Germany Background: The prognosis of patients with active multiple sclerosis (MS) has improved significantly due to the introduction of novel therapeutics. In pediatric MS, however, these drugs are often commenced late or not at all because use has not been approved below 18 years of age, consequently little experience with treatment in this age group exists. Methods: Retrospective single center study in the German center for pediatric MS in Göttingen on 18 patients with pediatric onset MS. Relapse rates and MRI activity 6 and 12 months before commencement were compared to the corresponding time periods after treatment; patients were monitored for side effects. Results: Mean age at manifestation was 13y, mean age at commencement of fingolimod 17y and mean follow-up was 10.3 months. 12 patients received fingolimod because of progressive disease under treatment with either interferon beta or glatiramer acetate. Treatment with fingolimod led to an 80% reduction in relapse rate in the 6 months and 67% in the 12 months interval. Mean number of new T2 lesions dropped by 81% at 6 months and 74% at 12 months. Mean number of gadolinium enhancing lesions after 6 months was 89% lower than at commencement of treatment and 71% lower after 12 months. 6 of the 18 patients had been previously treated with natalizumab and had been free of relapses and MRI activity for 12 months. 3 experienced relapses and 5 showed new T2 lesions or contrast enhancing lesions on MRI while treated with fingolimod. 3 of these patients were switched to alemtuzumab after 6 months. For all 18 patients no serious side effects were observed. 2 patients showed intermittent lymphopenia and 2 experienced burning pains in the feet leading to discontinuation of fingolimod in one patient. Conclusions: The data on our first 18 pediatric MS patients treated with fingolimoid are in accordance with adult MS data and indicate that the efficiency of fingolimod is superior to interferon beta and glatiramer acetate but inferior to natalizumab. Serious side effects were not observed. The results from the ongoing clinical trial (PARADIGMS) must be awaited before clear recommendations regarding safety and efficacy of fingolimod in this age group can be made. Nevertheless, for the time being the pediatric MS patient group apparently best treated with fingolimod seems to be the one with positive JC virus antibodies and active but not highly active MS. Disclosure P Huppke has received honoraria and consultancy fees from Bayer Vital, Biogen Idec, and Novartis and has received research grant support from Biogen. H Hummel: has received travel stipends from Bayer Vital W Stark: nothing to disclose J Gärtner has received honoraria and consultancy fees from Bayer Vital, Biogen Idec, Teva, and Novartis and has received research grant support from Novartis and Biogen.


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P286 Different B-cell patterns in the cerebrospinal fluid of patients with pediatric-onset compared with adult-onset multiple sclerosis B. Wildemann1, A. Schwarz1, B. Balint2, M. Korporal-Kuhnke1, S. Jarius1, A. Fürwentsches3, K. Engelhardt3, C. Bussmann3, F. Ebinger3,4 1Dept. of Neurology, University Hospital of Heidelberg, Heidelberg, Germany, 2Sobell Dept. of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom, 3Dept. of Pediatric Neurology, University Hospital of Heidelberg, Heidelberg, 4Dept. of Child and Adolescent Medicine, St. Vincenz-Krankenhaus, Paderborn, Germany Background: Compelling evidence suggests an important role of B cells in MS pathology. This underlined by positive treatment effects of B-cell depleting monoclonal antibodies. In adult patients (adMS), B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby antigen-experienced memory B-cells accumulate in the CSF. Pediatric-onset MS comprises 2 - 5% of all MS-cases but currently no data is available about the distribution of B-cell subsets in this cohort. Objectives: The aim of this study was to comparatively assess the B-cell composition in blood and CSF of patients with peMS and adMS. Methods: We obtained blood and CSF samples from 24 peMS patients (mean age 16.5 yrs) and from 40 adMS patients (mean age 33.6 yrs). Blood specimens from 66 healthy donors (HC, 1-55 yrs) served as controls. Combined detection of CD20, CD27, CD38, CD138, HLA-DR, and IgD by multi-colour flow cytometry allowed identification of naive, transitional, isotype classswitched memory (CSM), non-switched memory (USM) and double-negative memory B-cell subsets as well as plasma blasts (PB) and mature plasma cells (PC). FACS data were correlated with concentrations of B-cell specific cytokines (interleukin-6, CXCL-13) as determined by ELISA. Results: B-cell patterns in CSF differed between peMS and adMS: During acute relapse high frequencies of CSM B cells and mature PC were present in the CSF of adult patients, whereas USM B cells and PB were the dominating B-cell subsets in peMS CSF samples. Conclusion: We here demonstrate distinct changes in intrathecal B-cell homeostasis in peMS patients detectable during active disease. These observations emphasis the particular importance of B lymphocytes for disease progression in the earliest clinical stages of MS. Disclosure Supported by grants the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), “Understand MS” and Research Consortium 3: “Prognostic and Treatment markers”) and Novartis. Funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the abstract for publication. AS, BB, MK, SJ, AF, AE, CB, FE, and JH have nothing to disclose. BW has received honoraria for speaking/consulting and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono,

Genzyme, a Sanofi Company Novartis Pharmaceuticals, Teva Pharma GmbH, and research grants from Biogen Idec, MerckSerono, Novartis Pharmaceuticals, Teva Pharma GmbH, the German Ministry of Education and Research, the Dietmar Hopp Foundation, and the Tschira Foundation. P287 Associations between the gut microbiota and immune markers in paediatric multiple sclerosis and controls H. Tremlett1, D. Fadrosh2, A. Faruqi2, J. Hart2, S. Roalstad3, J. Graves2, C. Spencer2, S. Lynch2, S. Zamvil2, E. Waubant2, US Network of Pediatric MS Centers 1University of British Columbia, Vancouver, BC, Canada, 2University of California, San Francisco, CA, 3University of Utah, Salt Lake City, UT, United States Background and objective: Little is known of the association(s) between gut microbiota profiles and host immunological markers; we explored these in children with and without multiple sclerosis (MS). Methods: Children ⩽18 years old attending a University of California, San Francisco, USA paediatric clinic provided stool and blood. MS cases were within 2 years of onset. Controls were free from autoimmune disorders (asthma and eczema allowed). Fecal 16S rRNA gene profiles were generated on an Illumina Miseq platform. Peripheral blood mononuclear cells were isolated, and Treg (CD4+CD25hiCD127lowFoxP3+) frequency and CD4+ T-cell intracellular cytokine production evaluated by flow cytometry. Associations between microbiota diversity, phylumlevel abundances and immune markers were explored using Pearson’s correlation (r) and adjusted linear regression, expressed as beta coefficients and 95% confidence intervals (CIs). Results: Twenty-four children (15 relapsing-remitting MS and 9 controls), averaging 12.6 years were included. The mean MS disease duration was 10.0 months and 7 were disease-modifying drug exposed (DMD) at sample collection. Although immune markers (e.g. Th2, Th17, Tregs) did not differ between cases and controls (p>0.05), divergent gut microbiota associations occurred; richness correlated positively with Th17 for cases (r=+0.665, p=0.018), but not controls (r=-0.644, p=0.061). Fusobacteria abundance was associated with Tregs for controls (r=+0.829, p=0.006; age-adjusted beta=0.32; 95%CI: 0.11-0.53, p=0.009), but not cases (r=-0.069, p=0.808). Bacteroidetes inversely associated with Th17 for cases (r=-0.719, p=0.008), not controls (r=+0.320, p=0.401). Findings remained significant for cases when disease duration or DMD adjusted (beta=-4.9e-6; 95%CI: -9.0 to -1.0), p=0.013 and -3.9e-6; 95%CI: -7.0 to -0.7, p=0.021, respectively). Conclusions: Associations were found between gut microbiota and host immunological (blood) markers which differed for children with and without MS. Our observations motivate further exploration to both validate findings and to understand the potential disruption of the microbiota-immune balance so early in the MS course. Disclosure Helen Tremlett is funded by the Canada Research Chair program. She has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health


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Poster Session 1, 22(S3) Research, and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). Unless otherwise stated, all speaker honoraria were either donated to an MS charity or to an unrestricted grant for use by her research group. Douglas Fadrosh has no disclosures Ali Faruqi has no disclosures Feng Zhu has no disclosures Janace Hart has no disclosures Shelly Roalstad has no disclosures Jennifer Graves is funded by the Race to Erase MS and the National MS Society Collin Spencer has no disclosures Susan Lynch is funded by the NIH, Sloan Foundation, Cystic Fibrosis Foundation, Broad Foundation, Jannsen Pharmaceuticals, Gilead and Pfizer. She has recently or currently acts as an ad hoc consultant for Janssen Pharmaceuticals, Regeneron, Boston Consulting Group, Theravance and Novartis. She volunteers as a members of the Scientific Advisory Board of Second Genome and has received honoraria for lectures from American Thoracic Society, American Academy of Allergy Asthma and Immunology, Georgia Regents University, Alta Bates and Kaiser Permanente. She holds four patents and has received royalties for IP licensed by KaloBIos Inc. Scott Zamvil receives research grant support from the NIH (1RO1 NS092835 ), the NMSS (RG 4768, RG5180. RG5179), The Guthy Jackson Charitable Foundation, The Maisin Foundation, Biogen Idec, Inc. and Teva Pharmaceuticals, Inc. Currently, Dr. Zamvil serves Deputy Editor of Neurology, Neuroimmunology and Neuroinflammation and is a member of the advisory board for the International Society of Neuroimmunology. He has served as a consultant and received honoraria from Biogen-Idec, EMD-Serono, Genzyme, Novartis, Questcor, Roche, and Teva Pharmaceuticals, Inc., and has served or serves on Data Safety Monitoring Boards for Lilly, BioMS, Teva and Opexa Therapeutics Emmanuelle Waubant is funded by the NIH, the NMSS, and the Race to Erase MS. She volunteers on an advisory board for a Novartis trial. She has received honorarium or travel support from ACTRIMS, ECTRIMS, and AAN. The US Network of Pediatric MS Centers (authors listed in alphabetical order): Greg Aaen1, Jan-Anita Belman2, Leslie Benson3, Brittan Browning4, Charlie Casper4, Tanuja Chitnis3, Marc Gorman3, Yolanda Harris5, Lauren Krupp2, Tim E Lotze6, Sabina Lulu7, Jayne Ness5, Cody Olsen4, Erik Roan4, Moses Rodriguez8, John Rose4, Timothy C Simmons4, Mendelt Tillema8, Wendy Weber4, Bianca Weinstock-Guttman9 1. Loma Linda University, Loma Linda, CA, United States; 2. Stony Brook University, Stony Brook, NY, United States; 3. Harvard University, Cambridge, MA, United States; 4. University of Utah, Salt Lake City, UT, United States; 5. Mayo Clinic, Rochester, MN, United States; 6. Baylor College of Medicine, Houston, TX, United States; 7. University of California, San Francisco, San Francisco, CA, United States; 8. University of Alabama, Birmingham, AL, United States; 9. State University of New York at Buffalo, Buffalo, NY, United States

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P288 Disease course after CIS in children versus adults: a prospective cohort study R. van der Vuurst de Vries, D.E. van Pelt, J.Y. Mescheriakova, Y.Y. Wong, I.A. Ketelslegers, D.A.M. Siepman, C.E. CatsmanBarrevoets, R.F. Neuteboom, R.Q. Hintzen Erasmus MC, Rotterdam, The Netherlands Background: Clinically Isolated Syndrome (CIS) is a first demyelinating event of the CNS and can be a single event. After CIS a chronic disease course with ongoing inflammation and relapses might occur, resulting in a diagnosis of multiple sclerosis (MS). Whether children and adults with CIS have the same disease course has not been prospectively explored yet. Methods: Patients with CIS, whose age ranged from 1-50 years, were prospectively followed. We divided the patients in four different age groups: patients 1-10, 11-16, 17-29, and 30-50 years old. Among these groups demographic data, disease course, time to MS diagnosis and annualised relapse rates (ARR) were compared. Results: We included 383 CIS patients, of whom 218 (56.9%) were diagnosed with MS. 11-16 year-old children had the highest rate of MS conversion (85% versus 51% in the other age groups together, p< 0.01) and the shortest time to MS diagnosis (median time 2.6 months (IQR: 0.62-5.94) versus 7.8 months (IQR: 2.025.5) in the other age groups together, p< 0.01). Highest ARR were found in 1-10 year-old children with MS (ARR: 0.79), followed by 11-16 year-old children with MS (ARR: 0.62). In 30-50 year-old adults with MS the ARR was 0.41. Conclusion: Children with CIS tend to have a more inflammatory disease course appearing from the high relapse rate in all children, and the highest rate of MS conversion in 11-16 year-old children. This supports early initiation of first-line disease modifying therapy in children with CIS who are at high risk for a future MS diagnosis. Disclosure RM van der Vuurst de Vries: nothing to disclose ED van Pelt: nothing to disclose JM Mescheriakova: nothing to disclose YYM Wong: nothing to disclose IA Ketelslegers: nothing to disclose TAM Siepman: nothing to disclose CE Catsman-Berrevoets: nothing to disclose RF Neuteboom: nothing to disclose RQ Hintzen: nothing to disclose. P289 Disrupted cognitive development following acute demyelinating syndrome: a longitudinal study E. De Somma1, M. Sadeghi1, J. O’Mahony2, B. Brooks3, A. Yeh2, B. Banwell2,4, C. Till1,2 1York University, 2Hospital for Sick Children, Toronto, ON, 3Alberta Children’s Hospital, Calgary, AB, Canada, 4Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States Background: Disrupted development of working memory and processing speed is a potential outcome in children with acquired demyelinating syndromes (ADS) due to injury to maturing neural


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networks. Longitudinal cognitive evaluations of childhood ADS have not been previously reported. Objective: To examine changes in working memory and processing speed using serial cognitive testing within the first two years post-ADS, and clinical-demographic predictors of age-expected cognitive maturation. Methods: Participants included 37 youth with ADS recruited from two children´s hospitals, 12 of whom were subsequently diagnosed with MS. Of these patients, 27 (17 monophasic ADS; 10 MS) underwent two neuropsychological evaluations, conducted at 6 and 24 months post-ADS. Change in age-normed scores on the Oral Symbol Digit Modalities Test (SDMT) and the WJ-III Auditory Working Memory (AWM) and Visual Matching (VM) subtests were examined using repeated measures ANOVA and Reliable Change Index (RCI) analyses. Changes in cognitive scores were correlated with age at incident demyelinating event (mean=11.2±2.6) and socioeconomic status (SES) using Spearman correlation. Results: Patients lost to attrition did not differ from those retested with respect to age at onset, disease severity, and IQ. Patients with MS were older at onset (13.0±2.2 yrs) as compared to children with monophasic ADS (11.1±2.6 yrs; p=.063). Both groups showed higher z-scores at baseline in comparison with follow-up on the SDMT (p=.040), AWM (p=.007) and VM (p=.045). Across groups, RCI analyses showed a significant decline in age-expected performance over time among 11%, 26%, and 15% of patients on the SDMT, AWM and VM subtests, respectively. Decline on these measures was equally likely among MS and monophasic ADS patients. Lower z-score at follow-up was associated with lower SES on VM (r=.52, p=.028) and older age at onset on the SDMT (r=-.41, p=.052). Conclusion: Both monophasic ADS and MS confer a risk for declining cognitive efficiency over time. Older age at onset may increase the vulnerability for cognitive slowing given that white matter pathways supporting neural efficiency are maturing. The relationship between SES and cognitive slowing suggests that environmental factors can be targeted to improve cognitive outcomes. Further research will determine if monophasic ADS patients “catch up” over time, and the potential for cognitive deterioration in children with chronic demyelination. Disclosure Elisea De Somma: Nothing to disclose Mahsa Sadeghi: Nothing to disclose Julia O´Mahony: Nothing to disclose Brian Brooks: Nothing to disclose Ann Yeh: Nothing to disclose Brenda Banwell: Dr Banwell serves as a consultant to Novartis, and as an advisor for clinical trials for Biogen, Sanofi, and Tevaneuroscience Christine Till: Nothing to disclose Source of Funding: This project was supported by the Multiple Sclerosis Society Scientific Research Foundation. P290 PARADIGMS baseline characteristics: a randomised, double-blind study of fingolimod in paediatric patients with multiple sclerosis T. Chitnis1, D.L. Arnold2,3, B. Banwell4, W. Brück5, A. Ghezzi6, G. Giovannoni7, B. Greenberg8, L. Krupp9, K. Rostasy10,

M. Tardieu11, E. Waubant12, J. Wolinsky13, A. Bar-Or14, T. Stites15, M. Merschhemke16, J. Gärtner17 1Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston, MA, United States, 2NeuroRx Research, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 4The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 5Dept. of Neuropathology, University Medical Centre, Göttingen, Germany, 6Ospedale di Gallarate, Gallarate, Italy, 7Blizard Institute, Barts and The London School of Medical Centre and Dentistry, Queen Mary University of London, London, United Kingdom, 8University of Texas Southwestern Medical Center, Children’s Health, Dallas, TX, 9Pediatric MS Center at NYU Langone, New York, NY, United States, 10Division of Paediatric Neurology, Children’s Hospital Datteln, University Witten/Herdecke, Recklinghausen, Germany, 11Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France, 12Department of Neurology, University of California, San Francisco, CA, 13McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States, 14Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 15Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 16Novartis Pharma AG, Basel, Switzerland, 17Department of Paediatrics and Adolescent Medicine, German Centre for Multiple Sclerosis in Childhood and Adolescence University Medical Centre, Göttingen, Germany Background: Approximately 3–5% of patients with multiple sclerosis (MS) experience disease onset before18 years of age with 2–3 times more frequent relapses than adults. PARADIGMS is the first global, controlled study investigating the efficacy and safety of fingolimod up to 0.5 mg vs interferon (IFN) β-1a in paediatric patients. Objective: To present baseline characteristics of the first 190 patients randomised in the PARADIGMS study. Design and methods: PARADIGMS is an ongoing 24-month, double-blind, double-dummy, randomised, active-controlled, parallel-group, multicentre global study conducted in patients with MS aged between 10 to < 18 years. Patients were randomised to receive either oral fingolimod once-daily (dose adjusted for body weight) or intramuscular IFN β-1a 30 µg once weekly. Eligibility criteria included: MS diagnosis as defined by the revised consensus definition for paediatric MS consistent with 2010 McDonald criteria, at least 1 relapse during the previous year or 2 relapses in the previous two years or 1 or more gadolinium-enhancing (Gd+) lesions in the previous 6 months prior to enrolment. Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Here we present the baseline demographic, disease and clinical characteristics. Results: Baseline data are reported here for the first 190 randomised patients. The mean±SD age was 15.3±1.82 years, with more patients in the age group of >14 to ⩽16 years (41%), followed by >16 years (31%) and 10% of patients were ⩽12 years. The majority of patients were female (63%) and Caucasian (88%). Only 6 (3%) patients were pre-pubertal (Tanner Stage less than 2). The mean±SD duration of MS since first symptom was 2.1±1.92 years; mean number of relapses in the last 12 and 12–24 months before screening was 1.5 and 0.9 respectively. Median EDSS at baseline was 1.5 (range 0.0-5.5). At baseline, the mean±SD


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Poster Session 1, 22(S3) number of Gd+ lesions was 3.1±6.56 with 49% of patients free from Gd+ lesions. Conclusions: Paediatric MS patients enrolled in the PARADIGMS study were representative of known paediatric MS cohorts, with a high frequency of relapses and Gd+ lesions early in their course and had a preponderance of post-pubertal patients. The PARADIGMS study has successfully met the overall recruitment target. However recruitment remains open to enrol additional eligible pre-pubertal patients; updated numbers will be presented at the meeting. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. The following authors have received compensation for serving as consultants or speakers, or they or the institutions they work for have received research support from the companies indicated: Tanuja Chitnis received personal compensation for advisory boards/consulting for Hoffman-La Roche, Biogen and Novartis Pharmaceuticals and financial support for research activities from Biogen, Merck Serono and Novartis Pharmaceuticals. Douglas L Arnold has received honoraria from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, Hoffman-La Roche and Sanofi-Aventis, has received research support from Novartis and Biogen, and has an equity interest in NeuroRx Research, which performed the MRI analysis for the trial. Brenda Banwell has served as an unpaid consultant to BiogenIdec, Novartis, Teva Neuroscience, and Merck-Serono; as a remunerated central MRI reviewer for the present trial, and she is Chief Editor for MS and Related Disorders and funded by Canadian MS scientific research foundation (CMSRF), Canadian Multiple Sclerosis Society (CMSS), National Multiple Sclerosis Society (NMSS), and Canadian Institutes of Health Research (CIHR). Wolfgang Brück has received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, SanofiAventis and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. Dr Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders. Angelo Ghezzi received honoraria for speaking from Almirall, Biogen Idec, Merck Serono, Novartis, Genzyme and SanofiAventis; and for consultancy from Merck Serono, Biogen Idec, Teva and Novartis Pharmaceuticals. Gavin Giovannoni has received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, SanofiGenzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, SanofiAventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. Benjamin Greenberg has received compensation for consulting services from EMD Serono and Novartis. He has received grant support from Chugai, Biogen, Acorda, Medimmune, PCORI, NIH and Guthy Jackson Charitable Foundation. Lauren Krupp has received personal compensation for activities as a speaker, consultant and/or participant on an advisory board

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from Biogen Idec, Novartis Pharmaceuticals, Teva Neurosciences, and Multicell; royalty or license fees from ER Squibb & Sons, Avenir, Johnson & Johnson, and Osmotica; grant support from the National Multiple Sclerosis Society, National Institutes of Health, and the Department of Defense; and research support from Novartis, Biogen Idec, Celgene Corporation, and Genentech. She has also received support from the Lourie Foundation, Slomo and Cindy Silvian Foundation, and the Multiple Sclerosis Foundation. Kevin Rostasy has served as consultant for PARADIGMS study. Received sponsoring for lecture and symposia from Merck Serono. Marc Tardieu is a member of scientific boards for Novartis, Sanofi and Uniqure. Emmanuelle Waubant is funded by the NIH, NMSS and Race to Erase MS. She volunteers on an advisory board for a Novartis trial. She is site PI for clinical trials with Roche and Novartis. Jerry Wolinsky in the last 3 years has received compensation for service on steering committees or data monitoring boards for F. Hoffmann-La Roche Ltd., Medday Pharmaceuticals, Novartis, Sanofi Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, EMD Serono, Forward Pharma, Genentech, Inc., F. Hoffmann-La Roche Ltd., Novartis, Sanofi Genzyme, Takeda, Teva, and XenoPort; research support from, Sanofi Genzyme, the NIH and the NMSS through the University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH. Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, GuthyJackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, SanofiGenzyme, Teva Neuroscience, Wyeth. Jutta Gärtner has received honoraria and consultancy fees from Bayer Vital, Biogen, Merck Serono, Teva, and Novartis and has received research grant support from Novartis and Biogen. Tracy Stites and Martin Merschhemke are employees of Novartis. P291 Health-related quality of life in paediatric onset multiple sclerosis H. Bullock, A. Kuczynski, G. Lehmann, T. Murphy, C. Hemingway Great Ormond Street Hospital, London, United Kingdom Background: Optimising Health-Related Quality of Life (HRQoL) is an important outcome in the management and treatment of chronic medical conditions. There is evidence that HRQoL is compromised in adults with Adult-Onset Multiple Sclerosis. This suggests that HRQoL is also at risk in young people with Paediatric-Onset Multiple Sclerosis (POMS). Objective: To describe HRQoL in a clinical sample of young people with POMS. Method: The Pediatric Quality of Life Inventory (PedsQL) is a widely-used multidimensional measure of HRQoL in children and young people. The PedsQL was completed by young people with


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POMS and their parents attending a specialist clinic, close to the time of diagnosis (T1 Self/Proxy n=41/35, mean age = 163/159m) and at approximately 14-20 month intervals (T2 n=28/28; T3 n=15/12). T1 data were analysed cross-sectionally, including comparison with published UK data for healthy young people. T1 data were also compared longitudinally with those at T2 and T3. Results: Young people with POMS and their parents reported similar levels of HRQoL at T1 on all PedsQL scores, including the Total (p=0.875). Both Self and Proxy scores were statistically significantly lower than the healthy comparison group on the Physical, Emotional, and School dimensions and summary scores (p< 0.001, except Proxy Psychosocial p=0.002) but not the Social dimension. Longitudinal comparisons of data at T1, T2, and T3 did not indicate significant differences over time. Conclusion: Young people with POMS are at significant risk of lower HRQoL than healthy peers in several aspects of physical and psychological functioning. This is evident soon after diagnosis and may remain stable at least over a period of 2-3 years. HRQoL should be measured as part of routine clinical care. Further research should consider both modifiable and non-modifiable factors influencing HRQoL in POMS. Disclosure Hayley Bullock: nothing to disclose Adam Kuczynski: nothing to disclose Georgina Lehmann: nothing to disclose Tara Murphy: nothing to disclose Cheryl Hemingway: Biogen - educational grants, consulting, Merck-Serono- educational grant and Bayer- educational grant. P292 Towards an improved classification of relapsing demyelinating syndromes of the central nervous system in children Y. Hacohen1,2, K.M. Mankad3, W.K. Chong3, F. Barkhof4, M. Lim5, E. Wassmer6, O. Ciccarelli2, C. Hemingway1, on behalf of United Kingdom Childhood Inflammatory Demyelination (UK-CID) 1Department of Paediatric Neurology, Great Ormond Street Hospital for Children, 2Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, 3Paediatric Neuroradiology, Great Ormond Street Hospital for Children, 4Institutes of Neurology and Biomedical Engineering, UCL, 5Children’s Neurosciences, Evelina Children’s Hospital @ Guy’s and St Thomas’ NHSFoundation Trust, King’s Health Partners Academic Health Science Centre, 6Department of Paediatric Neurology, Birmingham Children’s Hospital, London, United Kingdom Background: Paediatric relapsing demyelinating syndromes (RDS) of the CNS define a group of diseases with different phenotypes. MRI findings and biomarkers, such as AQP4 antibodies (Abs), are an integral part of the diagnostic criteria for patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) respectively. We investigated a large cohort of paediatric RDS using clinical assessments, MRIs and laboratory tests, to explore whether the diagnostic process of RDS could be simplified and improved.

Methods: Children with RDS were recruited from three paediatric neurology centres (2 in London and 1 in Birmingham) between September 2014 and September 2015. Data including demographics, clinical findings and laboratory results were reviewed by an adjudication panel and clinical diagnosis confirmed. Brain and spinal cord MRI scans were reviewed by a neuroradiologist, blinded to the clinical diagnosis. Results: 62/110 (56.4%) children were diagnosed with MS, and the remainder 48/110 (43.6%) were diagnosed as follows: 28/110 (25.4%) with NMOSD, 14/110 (12.7%) with multiphasic disseminated encephalomyelitis (MDEM), and 6/110 (5.4%) with relapsing idiopathic optic neuritis (RION). Blinded MRI review revealed abnormalities typical of adult MS in 97% of paediatric MS cases, which were absent in 100% of children with RDS other than MS. MOG and AQP4-Abs were found exclusively in the non-MS group (34/41, 83% vs 0/56, p< 0.0001). OCBs were more frequent in the MS group (52/57, 91% vs 6/42, 14%, p< 0.001) as was EBV-IgG (48/48, 100% vs 12/26, 46%, p< 0.001). AQP4-Abs were seen exclusively in the NMOSD group, while MOG-Abs were seen in 58% of NMOSD patients (none of which had AQP4-Ab), 100% of MDEM and 33% of RION. AQP4-Ab positive children were older, were more likely to presented with area postrema syndrome, had higher EDSS and a shorter time to relapse than patients with MOG-Abs. MOG-Ab positive cases presented with ill-defined lesions often involving the cerebellar peduncles (54%), frequently at time of relapse. This was absent in AQP4-Ab cases, who instead showed involvement of the dorsal brainstem (88%). Conclusion: Paediatric MS has the same clinical, CSF and MRI features as adult MS, but differs from other paediatric RDS. Children with MOG-Ab differ in their presentation and in MRI pattern from MS and NMOSD AQP4-Ab positive. Combining blood, CSF and MRI biomarkers with clinical features improves classification of paediatric RDS. Disclosure Yael Hacohen; nothing to disclose Kshitij Mankad; nothing to disclose W. Kling Chong; nothing to disclose Frederik Barkhof is a board member of Brain, Neurology, Eur Radiology, Radiology, Neuroradiology, Multiple sclerosis Journal and serves as consultant for Bayer-Schering Pharma, SanofiAventis, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme. Ming Lim receives research grants from Action Medical Research, DES society, GOSH charity, National Institute of Health Research (NIHR UK), MS Society, SPARKS charity and; receives research support grants from the London Clinical Research Network and Evelina Appeal; is an editorial board member for European Journal of Paediatric Neurology; has received consultation fees from CSL Behring; received travel grants from Merck Serono; and awarded educational grants to organize meetings by Novartis, Biogen Idec, Merck Serono and Bayer Evangeline Wassmer; nothing to disclose Olga Ciccarelli is an Associate Editor of Neurology and serves as a consultant for GE Healthcare, Novartis, Roche, Biogen, Genzyme and Teva. Cheryl Hemingway; nothing to disclose


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Poster Session 1, 22(S3) P293 Interferon beta-1b in treatment-naïve paediatric patients with relapsing-remitting MS: 2-year results from the BETAPAEDIC study J. Gärtner1, W. Brück1, A. Weddige1, H. Hummel1, C. Norenberg2, J.-P. Bugge3 1University Medical Center, Göttingen, 2Bayer Pharma AG, Wuppertal, 3Bayer Pharma AG, Berlin, Germany Background: BETAPAEDIC is the first prospective, international, multicentre, observational study to assess the safety and tolerability of interferon beta-1b (IFNB-1b) in paediatric patients with relapsing-remitting MS (RRMS). Objective: To present 2-year results from BETAPAEDIC. Methods: Treatment-naïve patients (12-16 years) diagnosed with RRMS according to McDonald (2005) or Poser criteria and scheduled by the investigator to be treated with IFNB-1b were enrolled. Follow-up visits were planned for every 6 months for 2 years. Clinical efficacy was evaluated by annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) progression (>=1.0step increase relative to baseline), and MRI. Neuropsychological function was measured by WISC-IV, SPM+, Beery VMI, and d2 at baseline and Year 2. Fatigue was assessed by the Fatigue Severity Scale (FSS), with scores >4 indicating fatigue. Enrollment is complete and outcomes after 2 years in patients with available data are reported. Results: 68 patients were enrolled (mean age: 14.2 years; female:male 3.5:1). Mean time since disease onset was 0.98 years with a mean time since diagnosis of 0.52 years. 67.6% of patients were diagnosed by both McDonald and Poser criteria and 32.4% by McDonald only. In the 2 years prior to entry, 98.5% reported >=1 clinical event and EDSS progression (mean ARR: 1.1). Mean ARR in the 2-year observation period was 0.65 (n=59). Based on available data, 50.8% (30/59) had no relapses and 74.1% (40/54) of patients had no EDSS progression while 43.1% (25/58) were relapse- and progression-free from baseline to last follow-up visit. MRI scans indicated the presence of new T2 or Gd+ lesions (relative to baseline) in 77.2% (44/57) or 52.6% (30/57) of patients, respectively. 15.5% of patients with MRI assessment had NEDA-3 (no relapses, disease progression, or MRI activity [new T2 and Gd+ lesions]). Cognitive performance was within normal ranges at baseline and at the last follow-up visit. Mean total FSS score was 2.9, mean FSS VAS was 3.9 (n=29), indicating no fatigue; however, in 26 patients the mean total FSS score was >4 at some point during the study. Preliminary analyses revealed no unexpected safety signals. The most frequent adverse events were flulike symptoms, headache, injection site reactions, and elevations of liver transaminases. Conclusions: 2-year results from BETAPAEDIC suggest that IFNB-1b is an effective treatment with a favourable safety profile for paediatric patients. Disclosure J Gärtner has received honoraria and consultancy fees from Bayer Vital, Biogen, Merck Serono, Teva, and Novartis and has received research grant support from Novartis and Biogen. W Brück has received honoraria for lectures from Bayer Vital, Teva Pharma, Sanofi-Aventis, Genzyme, Novartis, Biogen and Merck-Serono and is member of Advisory Boards for Teva,

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Genzyme, Novartis and Biogen. W Brück has received research grants from Teva Pharma, Novartis and Biogen. A Weddige has received consultancy fees from Bayer Pharma AG. H Hummel has received honoraria from Bayer Pharma AG for a lecture. C Norenberg is a salaried employee of Bayer Pharma AG. JP Bugge is a salaried employee of Bayer Pharma AG. P294 Compensatory recruitment during executive control processing in cognitively preserved patients with paediatriconset multiple sclerosis E. Barlow-Krelina1, G. Turner1, M. Lysenko1, N. Akbar2, B. Banwell3,4, E.A. Yeh3, C. Till1,3 1York University, Toronto, ON, Canada, 2Kessler Foundation, West Orange, NJ, United States, 3The Hospital for Sick Children, Toronto, ON, Canada, 4Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: Cognitive impairment occurs in only 30% of paediatric MS patients, despite a high lesion volume and reduction in age-expected brain volumes. The current study aims to identify whether patients who are cognitively preserved demonstrate compensatory recruitment, using a working memory task as a representative cognitive measure. Method: Twenty-four patients with paediatric-onset MS were recruited and screened for cognitive impairment using a test battery based on the Brief Neuropsychological Battery for Children. Twenty patients were considered cognitively intact (performance < 1.5 SD below normative data on < 2 tests) and were included (mean age = 18.7 ± 2.8; 15 female) and matched for age and sex with 20 healthy controls (HCs). Participants completed a working memory task (Alphaspan) while undergoing functional magnetic resonance imaging on a 3T scanner. Participants were asked to study a set of letter strings and then to either maintain the letter set (low executive demand (ED)) or to manipulate the letters into alphabetical order (high ED). Only correct trials were analyzed. Results: MS patients did not differ from HCs with respect to accuracy on the task, however, a 0.21s slower response time was observed in MS patients, collapsing across task conditions, t(38) = 2.15, p = 0.038. Areas demonstrating significant change in activation across the maintain and manipulate conditions were flagged as regions of interest for group comparisons. MS patients showed greater activation than HCs in the right middle frontal and left medial frontal gyri on the maintenance condition (p < 0.05). A trend was observed between higher activation in these two regions and poorer accuracy scores for the maintenance condition in MS patients (r = -0.32, p = 0.083; r = -0.37, p = 0.056, respectively). Activation in these regions was higher in the manipulation than in the maintain condition, but did not differ between groups at this task level. Conclusion: Increased activation in the right middle and left medial frontal gyri occur for MS patients and HCs as a task becomes more challenging. MS patients had greater activation of these regions relative to HCs during the maintenance task, potentially reflecting compensatory processes required for storage of information. Findings suggest that compensatory recruitment may


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be more apparent in conditions typically requiring lower ED, with a possible ceiling effect as greater executive control is required for a task. Disclosure Ms. Barlow-Krelina has nothing to disclose. Dr. Turner has nothing to disclose. Ms. Lysenko has nothing to disclose. Dr. Akbar has nothing to disclose. Dr. Banwell serves as a consultant to Novartis, and as an advisor for clinical trials for Biogen Idec, Sanofi, and Tevaneuroscience. Dr. Yeh has received a speaker´s honorarium from Novartis. Dr. Till has has nothing to disclose. This project was funded by the Scottish Rite Charitable Foundation. P295 Diet is associated with relapse rate in pediatric multiple sclerosis S. Azary1, J. Graves1, T. Schreiner2, A. Waldman3, T. Lotze4, A. Belman5, B. Greenberg6, B. Weinstock-Guttman7, G. Aaen8, J.-M. Tillema9, J. Hart10, J. Ness11, Y. Harris11, J. Rubin12, M. Candee13, L. Krupp5, M. Gorman14, L. Benson15, M. Rodriguez9, T. Chitnis15, S. Mar16, I. Kahn17, J. Rose18, S. Roalstad12, M. Waltz13, T.C. Casper12, E. Waubant1 1Multiple Sclerosis Center, University of California, San Francisco, CA, 2Neurology, University of Colorado School of Medicine, Aurora, CO, 3Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, 4Child Neurology, Texas Children’s Hospital, Houston, TX, 5Pediatric MS Center, Neurology, New York University School of Medicine, New York, NY, 6Neurology, Childrens Health Dallas and University of Texas Southwestern, Dallas, TX, 7Neurology, State University of New York, New York, NY, 8Neurology, Loma Linda University, Loma Linda, CA, 9Neurology, Mayo Clinic, Rochester, MN, 10Regional Pediatric MS Center, Neurology, University of California, San Francisco, CA, 11Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 12Neurology, Ann & Robert Lurie Children’s Hospital of Chicago, Chicago, IL, 13Pediatrics, University of Utah, Salt Lake City, UT, 14Neurology, Boston Children’s Hospital; and Women’s Hospital, 15Partners Pediatric MS Center, Boston, MA, 16Neurology, Washington University School of Medicine, St. Louis, MO, 17Children’s National Medical Center, Washington, DC, 18Neurology, University of Utah, Salt Lake City, UT, United States Background: A possible role of high-fat diet in the exacerbation of EAE, the animal model for MS has been reported. However, the role of diet in the risk of MS relapse is not known. Methods: This project stems from an ongoing case-control study of environmental risk factors in pediatric MS at 16 US centers that enrolled patients with CIS or MS with onset before 18 years of age and less than 4 year duration. Dietary fat, vegetable, fiber, fruits, carbohydrates, protein, sugar, dairy, and iron intake in the week before enrollment were assessed using the validated self-reported Block Kids Food Screener (NutritionQuest). Patients who had available prospective relapse data entered in the Pediatric MS Network registry after enrollment in the case-control study were included in this analysis. Multivariate Cox proportional hazard

model was used to estimate the hazard ratio and 95% CI of the time to the relapse following study enrollment. The model was adjusted for age, gender, race/ethnicity, body mass index, type of disease-modifying treatment. Results: 219 patients with early pediatric relapsing-remitting MS were included in this study (61.2% female, 39.3% non-whites, mean age 15.1 years, mean disease duration at enrollment 10.8 months). Median follow-up time after completion of food frequency questionnaire was 1.8 year (0.1-4.1). In multivariable analyses, each 1% increase in energy intake from fat increased the hazard of relapse by 4% (adjusted hazard rate (HR) 1.04, CI:1.0-1.08, p=0.04). Patients with high vegetable intake had a lower hazard of relapses (adjusted HR: 0.58, CI:0.35-0.96, p=0.03). Total energy intake, percent of energy from carbohydrates and proteins, fruits, and fibers were not associated with risk of relapse. Conclusion: This study suggests that high energy intake from fat may increase the risk of MS relapse in children while vegetable intake may be protective. These findings if confirmed may have direct clinical implications for dietary recommendations for patients with MS. Disclosure Authors have no relevant disclosures. P296 Relationship of self-reported mood and fatigue to selfreported cognitive functioning in pediatric-onset multiple sclerosis patients M. Lysenko1, N. Akbar2, E.A. Yeh3, B.L. Banwell3,4, C. Till1,3 1York University, Toronto, ON, Canada, 2Kessler Foundation, West Orange, NJ, United States, 3The Hospital for Sick Children, Toronto, ON, Canada, 4The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States Objective: The Multiple Sclerosis Neuropsychology Questionnaire (MSNQ) is a 15-item self-report questionnaire used to screen for cognitive complaints in patients with multiple sclerosis (MS). Previous studies in adults with MS have shown that psychosocial factors, particularly mood and fatigue, have a major influence on patients’ perception of cognition. This study examined whether a similar relationship between depression and fatigue and self-reported cognitive complaints is found in pediatric-onset MS patients. Methods: Twenty-five pediatric-onset MS patients [mean (SD) age= 18.82 (2.94) yrs; range: 13-24 yrs] completed self-reported measures of cognitive complaints (MSNQ), fatigue (Pediatric Quality of Life Inventory; PedQoL) and mood (Centre for Epidemiological Studies Depression Scale; CES-D), and underwent neuropsychological testing. Hierarchical regression was used to examine whether the neuropsychological composite score (derived from testing) predicts cognitive complaints on the MSNQ after controlling for depression and fatigue. Results: Overall levels of fatigue and depression were mild [PedQoL= 59.42 (18.94); CES-D=15.60 (13.16)] and performance on the neuropsychological composite was in the average range (z=0.03 (0.73). Cognitive complaints on the MSNQ correlated with more symptoms of fatigue, as indicated by a low score


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Poster Session 1, 22(S3) on the PedQoL (r=-0.78, p< 0.0001), and more symptoms of depression (r=0.72, p< 0.0001), but not with neuropsychological composite score (r=-0.09, p=0.66). Neuropsychological composite score did not significantly predict MSNQ scores over and above fatigue and mood scores [ΔR2=0.011, F(1,20)=44.33, p=0.42). Findings did not change when examining the subset of patients who were < 19 years at time of testing (n=16). Conclusion: Self-report measures of fatigue and depression were stronger predictors of cognitive complaints than were objectively measured cognitive functions in this cohort. These findings highlight the major influence of psychosocial factors on the self-perception of cognitive abilities and thus should be taken into consideration when interpreting self-reported cognitive complaints in both adolescents and young adults with MS. Disclosure Dr. Banwell serves as a consultant to Novartis, and as an advisor for clinical trials for Biogen Idec, Sanofi, and Tevaneuroscience. All other authors have nothing to declare. P297 Cortico-thalamic connectivity abnormalities as structural substrate of fatigue in pediatric multiple sclerosis E. De Meo1, M.A. Rocca2, E. Pagani2, L. Moiola3, A. Ghezzi4, P. Veggiotti5, R. Capra6, M.P. Amato7, L. Vacchi2, A. Fiorino3, L. Pippolo4, M.C. Pera5, G. Comi3, A. Falini8, M. Filippi2 1San Raffaele Scientific Institute, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 3Department of Neurology, S. Raffaele Scientific Institute, VitaSalute San Raffaele University, Milan, 4MS Center, Ospedale di Gallarate, Gallarate, 5Department of Child Neurology and Psychiatry, C. Mondino National Neurological Institute, Pavia, 6MS Center, Spedali Civili of Brescia, Brescia, 7Department of Neurology, University of Florence, Florence, 8Department of Neuroradiology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Background: Fatigue is well characterized as a disabling symptom in adult MS patients, while there is limited available information in pediatric patients although it has been reported in a sizable proportion of children and adolescents with MS. Functional and structural thalamic abnormalities have been related to fatigue, in particular in early MS. Aims: This study has been conducted with the aim to identify the contribution of microstructural thalamic and cortico-thalamic connection damage to determine fatigue in pediatric MS patients. Methods: Using a 3.0 T scanner, dual-echo, 3D T1-weighted and diffusion tensor (DT) MRI scans were acquired from 50 pediatric MS patients and 26 gender- and age-matched healthy controls (HC). Diffusion Tractography-Based Parcellation was used to segment the thalamus into connectivity defined regions (CDRs) and to trace cortico-thalamic connections. Fatigue was assessed with Fatigue Severity Scale (FSS). Between-group differences of CDRs and cortico-thalamic tract DT MRI metrics were assessed using Mann-Whitney test. The relationships of DTI metrics of thalamic CDR and cortico-thalamic tract with FSS scores were tested using the Spearman’s Rank correlation coefficient. Results: Pediatric MS patients and HC showed lower factional anisotropy (FA) and higher mean diffusivity (MD) in the temporalCDR (T-CDR) bilaterally as well as in several cortico-thalamic

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tracts. Although no correlation was found between fatigue and DT metrics in CDRs, fatigue severity was significantly related to increased MD in bilateral frontal cortico-thalamic tracts (r=0.43, p=0.005; r=0.39, p=0.001) and occipital (O-T) cortico-thalamic tracts (r=0.32, p=0.04; r=0.36, p=0.02). Higher FSS score was significantly correlated with reduced FA in the right post-central thalamic tract (r=-0.38, p=0.01) and left O-T tract (r=-0.34, p=0.03). Conclusions: As demonstrated in adult MS patients, also in pediatric MS patients fatigue was associated to a widespread normal appearing white matter damage. This study confirmed the involvement of frontal lobes and specifically of their thalamic connections in determining fatigue, whereas no association was found between FSS scores and thalamic damage, suggesting that fatigue in the earliest phases of the disease is mainly due to NAWM pathology. Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2011/R/19 & FISM 2012/R/8). Disclosure Drs De Meo, Pagani, Moiola, Veggiotti, Vacchi, Fiorino, Pippolo, Pera, and Falini have nothing to disclose. Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. A Ghezzi has received honoraria for speaking from Biogen, Merck Serono, Novartis, and Sanofi-Aventis; for consultancy from Merck Serono, Teva, and Novartis; and support for participation in national and international congresses from Bayer-Schering, Biogen-Dompè, Merck Serono, Novartis, and Sanofi-Aventis. Ruggero Capra received consulting fees from Novartis,Merck Serono, BiogenIdec and lecture fees fromBayer, BiogenIdec, Dompé, Genzyme and Sanofi-Aventis. Maria P Amato serves on scientific advisory boards for BiogenIdec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis. Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Natural course P298 An EDSS-based definition of secondary progressive multiple sclerosis C. Diaz-Cruz1, A.S. Chua1, B.C. Healy1,2, N. Sattarnezhad1, B.I. Glanz1, H.L. Weiner1, T. Chitnis1,3


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1Partners

Multiple Sclerosis Center, Brigham and Women’s Hospital, Harvard Medical School, 2Biostatistics Center, 3Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston, MA, United States Objective: To assess the impact of different definitions of secondary progressive multiple sclerosis (SPMS) on clinical trial design. Background: Clinical trials and observational studies have used different definitions of SPMS. Expert consensus has defined SPMS as a phenotype “diagnosed retrospectively by a history of gradual worsening after an initial relapsing disease course”. However, a standardized definition of “gradual worsening” and the minimum time needed to confirm it is lacking. Methods: Patients in the Comprehensive Longitudinal Investigation of Multiple Sclerosis (MS) at the Brigham and Women’s Hospital (CLIMB) with relapsing-onset MS were eligible. We evaluated 9 definitions of SPMS using 3 expanded disability status scale (EDSS) score ranges (3-6.5, 3.5-6.5, 4-6.5) and 3 time intervals (12, 24, 36 months) during which the EDSS was required to remain within the specified range (screening phase). We also tested each definition only in patients with no relapses during the screening phase. In order to simulate a 2-year clinical trial, patients satisfying any of the definitions with at least 2 years of follow-up after the screening phase were included in the analysis. For each definition, we calculated the proportion of patients experiencing confirmed disability worsening at 6 months (CDW6), defined as EDSS increase ⩾1 if baseline EDSS⩽5.5 or EDSS increase ⩾0.5 if baseline EDSS⩾6. We also calculated the proportion of patients who maintained the CDW6 for the remainder of follow up. Results: 623 patients satisfied at least one definition of SPMS and 402 had at least 2 years of follow up (31% males, mean age at onset 34±11 years, mean disease duration 15±9 years). The percentage of patients experiencing CDW6 over two years ranged between 15-22%. In those experiencing CDW6, the proportion of patients maintaining the confirmed EDSS for all subsequent visits varied between 56-67%, 70-75% and 55-71% when the lowest EDSS in the screening phase was set to 3.0, 3.5 or 4.0, respectively (median (IQR) follow up after CDW6, 46 (65) months). Similar results were obtained when we excluded patients who had relapses during the screening phase. Conclusions: Regardless of the duration of the screening phase, a similar proportion of patients experienced CDW6 and maintained the EDSS score after the confirmed progression date. Our results indicate that it may be possible to reduce screening periods when recruiting patients for SPMS trials. Disclosure Camilo Diaz-Cruz received research support from Merck Serono and Google Life Sciences. Alicia S. Chua has received research support from Google Life Sciences. Brian C. Healy was on the Biogen Worldwide Medical Biostatistics Multiple Sclerosis Advisory Board and received grant support from Genzyme, Merck Serono, Novartis and Google Life Sciences. Neda Sattarnezhad received research support from Merck Serono and Google Life Sciences. Bonnie I. Glanz received research support from Merck Serono and Google Life Sciences.

Howard L. Weiner has received personal compensation for consulting, speaking activities and has served on the scientific advisory board of companies including Biogen Idec, Novartis, EMD Serono and Teva and research support from Google Life Sciences. Tanuja Chitnis: Consulting for: Biogen-Idec, Novartis, RocheGenetech. Advisory boards: Serves on advisory boards for pediatric clinical trials for Novartis and Genzyme-Sanofi. Research support: Serono, Biogen, Novartis, Google Life Sciences P299 Estimating the long-term effect of drugs in multiple sclerosis C. Cordioli1, S. Rasia1, F. Gallo2, R. Capra1, M.P. Sormani2 1Multiple Sclerosis Centre, Spedali Civili, Montichiari, 2Section of Biostatistics, Department of Health Sciences (DISSAL), University of Genoa, Genova, Italy Background: In multiple sclerosis (MS) there is no certainty to what extent the short-term effects of drugs translate into long-term benefits for patients. Observational studies devoted to clarify this issue are affected by selection bias: treated and untreated patients are different and their difference is likely related to prognosis. Goals: To evaluate whether the introduction of therapies changed the MS prognosis, assessing the age at which patients diagnosed in different periods (pre and post therapies approval) reached EDSS milestones, with no comparisons of treated and untreated patients. Methods: We retrospectively analysed a large dataset of MS outpatients evaluated at the MS Centre of Montichiari (Brescia, Italy) between 1985 and 2013, with an initial RRMS course and age at diagnosis 18-60 years. Age at which patients reached EDSS 6 was compared according to year of diagnosis (grouping patients diagnosed in 1980-1990, 1991-1995, 1996-2000, 2001-2005, 20062010, 2011+), by a Cox model adjusted for mean age at diagnosis and EDSS visits frequency. Results: 1324 RRMS patients were included. The average age at onset was 32.4 years (SD= 9.6, range =13-59 years) and the average age at diagnosis was 35.6 years (SD= 10.0, 18-60 years). The age at diagnosis increased from 32 to 37 years (p< 0.001) in more recent years. Patients diagnosed in more recent periods reached EDSS=6 at higher age: taking patients diagnosed before 1990 as a reference, the probability to reach EDSS=6 was similar in patients diagnosed in the period 1991-1995 (HR=1.09), it was reduced by 15% in patients diagnosed in 1996-2000 (HR=0.85, p=0.44), by 37% in patients diagnosed in 2001-2005 (HR=0.63, p=0.05), by 46% in patients diagnosed in 2006-2010 (HR=0.54, p< 0.02). The proportion of patients diagnosed before 2000 who reached EDSS=6 at the age of 50 years was 27% and 15% after 2000 (p< 0.001). Conclusions: A clear modification of MS course is observed after 2000, with 4 years delay since 1996 (introduction of first DMTs in Italy), when the proportion of patients steadily treated was increasing. A second leap coincides with the introduction of second-line treatments (natalizumab, fingolimod). Disclosure Cinzia Cordioli: consulting fees from Merk-Serono; Sarah Rasia: nothing to disclose; Ruggero Capra: received consulting fees from Novartis, Biogen and lecture fees and/or travel grants from Novartis, BiogenIdec, Genzyme and Sanofi-Aventis.


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Poster Session 1, 22(S3) Maria Pia Sormani: received personal compensation for consulting services and for speaking activities from Novartis, Roche, Genzyme, Merck Serono, Teva, Synthon and Biogen Idec; Fabio Gallo: nothing to disclose. P300 Prognosis in multiple sclerosis: a UK national survey L. Dennison1, M. Brown2, S. Kirby1, I. Galea2 1Centre for Community and Clinical Applications of Health Psychology, Department of Psychology, 2Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom Background: Multiple sclerosis (MS) is renowned for its variable trajectory. Recent advances in individualised prognostication include the development of an online analytical processing (OLAP) tool. Prognostication supported by this tool might promote better-informed treatment decision-making and reduce uncertainty and distress. There is little existing research documenting current provision of prognosis information or the attitudes and preferences of people with MS (pwMS) towards prognosis information. This study explored these issues and determined factors associated with prognosis communication preferences and experiences. Methods: 3175 members of the UK MS Register completed an online survey about experiences of prognosis-related communication, prognosis information preferences and attitudes towards obtaining personalised estimates from the OLAP tool. MS type, time since symptom onset and diagnosis, coping (brief-COPE), threat information response styles (MBSS), quality of life (EQ5D), MS impact (MSIS), anxiety and depression (HADS) data were also collected. Results: 53.1% of respondents had never discussed long-term prognosis at neurology appointments. Only a minority (45.8%) felt clear about their prognosis. 76% currently had strong preferences for prognosis information and most (92.8%) anticipated wanting to use the OLAP tool. Participants perceived the tool as relevant at various time-points, acceptable in various settings and felt that prognosis information could inform medical and personal decision-making. Logistic regression analysis found that a comprehensive set of clinical and psychological variables predicted limited variance (3-9%) in whether participants had discussed prognosis, had high preferences for prognosis information, and wanted to use the tool. Conclusions: In the first large-scale study on this topic we documented limited prognosis communication between health professionals and pwMS and identified an appetite for prognosis information generally and the OLAP tool specifically. The study also highlighted a significant minority of pwMS who have no desire for prognosis forecasting. The tool requires careful study in a clinical context, considering potential benefits and harms and distinguishing which pwMS will want it and benefit from it. Disclosure Dr Ian Galea receives research support from Medical Research Council, Engineering and Physical Sciences Research Council, Multiple Sclerosis Society, Wellcome Trust, National Institute for Health Research, Bio Products Laboratory Limited, Evgen, Merck-Serono, BUPA, IQ Products, Peel Medical Research Trust,

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Royal College of Surgeons of Edinburgh, Association of British Neurologists, Wessex Medical Research, Smile for Wessex, University of Southampton. Dr Galea is first author on a publication describing the OLAP tool. Mrs Martina Brown was funded by the National Institute of Health Research, and this project contributed to a postgraduate degree at the University of Southampton. Dr Laura Dennison and Dr Sarah Kirby have no conflicts of interest to disclose.

P301 Excess mortality among MS patients in Denmark has dropped significantly over the last six decades N. Koch-Henriksen1,2, B. Laursen3, M. Magyari4,5 1Department of Clinical Epidemiology, University of Aarhus, Clinical Institute, Aarhus N, 2The Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Rigshospitalet, 3National Institute of Public Health, University of Southern Denmark, 4The Danish Multiple Sclerosis Registry, 5Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Background: Several studies have investigated the mortality of patients with MS compared with controls or population, but trends in survival are poorly described. Objective: To investigate trends in excess all-cause mortality of MS patients over the last 60 years in Denmark. Methods: The nationwide population-based Danish MS Registry has at an almost complete level collected information on all Danish citizens with onset of MS since 1948. The Danish national registers and, since 1968, the Civil Registration System have provided complete follow-up of vital status for all individuals. The study included all Danish MS patients with onset 1950-1999 with follow-up in 2015. Five ten-year onset cohorts from 1950-1959 to 1990-1999 were included. Expected numbers of deaths were calculated from sex, age, and calendar year-specific population life tables provided by Statistics Denmark. Analyses were right truncated at 15 years after onset for comparison between the cohorts. Excess mortality was calculated as standardized mortality ratio (SMR), that is, observed/expected number of deaths. Test for trends was done by linear regression weighted by number of deceased patients in each onset cohort. Results: 14,196 MS cases were followed. The observed number of deaths within 15 years from onset was 1,727. The 15-year SMRs (with 95% CI) were for the 1950-1959-onset cohort 4.27 (3.87-4.70); for the 1960-1969-onset cohort 3.41 (3.03-3.82); for the 1970-1979-onset cohort 2.61 (2.33-2.93); for the 1980-1989onset cohort 2.30 (2.06-2.56); and for the 1990-1999-onset cohort 1.96 (1.76-2.17), while the mean age of onset increased from 33 to 36 years through the cohorts. The test for trend showed a significant decrease of SMR of -0.579 per decade (95% CI −0.72; −0.44 p = 0.0042). There was no significant difference in the trend between the two sexes. Conclusion: In this 60-year population based study we found that the all-cause excess mortality in the first 15 years after clinical onset has dropped significantly in MS patients over the years since 1950, but they still live shorter than an age and sex matched background population The decrease in mortality with time surpasses that of the population. Excess mortality started to decrease


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already decades before disease modifying drugs became available. It may be attributed to milder disease in recent onset cohorts, improvement of care, or better treatment of life-threatening comorbidities and complications. Disclosure N. Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis. M. Magyari has served on scientific advisory board for BiogenIdec and TEVA and has received honoraria for lecturing from BiogenIdec, MerckSerono, Sanofi-Aventis, and Teva. She has received support for congress participation from BiogenIdec, MerckSerono, Novartis, and Genzyme. Bjarne Lauersen has nothing to disclose P302 Neuropsychological features can help in predicting disease evolution in benign multiple sclerosis patients: a 12 year study L. Razzolini1, M.L. Stromillo2, E. Portaccio1, B. Goretti1, C. Niccolai1, M. Giannini1, L. Pastò1, I. Righini1, B.B. Hakiki1, M. Battaglini2, A. Giorgio2, M.L. Bartolozzi3, L. Guidi3, N. De Stefano2, M.P. Amato1 1NEUROFARBA, Section of Neurosciences, University of Florence, Florence, 2Department of Neurological and Behavioral Sciences, University of Siena, Siena, 3Hospital of Empoli, Florence, Italy Background: In a previous 5-year follow-up study on benign multiple sclerosis (BMS), we found that presence of cognitive impairment (CI) and higher cortical and subcortical magnetic resonance (MR) brain damage was related to higher risk of shifting to a no longer benign (NLB) course. Objectives: To assess longer-term role of neuropsychological and MR parameters in predicting disease evolution in BMS patients. Methods: At baseline, 46 BMS patients (Expanded Disability Status Scale (EDSS) score< 3.0 and disease duration>15 years) underwent neuropsychological assessment through the Rao’s Brief Repeatable Battery and brain MRI quantitative measurement of T2 and T1 lesion volumes (T2LV and T1LV), total and regional brain volumes and magnetization transfer ratio (MTr). After a mean follow-up of 12.5+0.4 years, patients still having an EDSS score< 3.5 were classified as “still benign” (SB), whereas patients having an EDSS score>4.0 and/or shifting to a secondary progressive (SP) course were defined as NLB. Possible prognostic predictors were assessed through a multivariate Cox survival analysis. Results: At baseline, severe cognitive impairment (CI, failure of > 3 tests) was detected in 13 (28.3%) patients. By the end of the 12-year follow-up period, 13 patients (28.3%) were classified as NBL. Among these, 7 (15.2%) shifted to an SP course. Baseline predictors of NLB disease course after 12 years were CI (53.8% vs 15.2% patients, p=0.007), higher T1LV (10.0+6.3vs 5.7+5.6 cm3, p=0.045) and, marginally, male sex (53.8% vs 24.2% patients, p=0.054). In the multivariate analysis, CI was the only significant predictor of NLB status (HR=5.2;95%CI 1.7-15.5;p=0.003).

Moreover, predictors of SP status were higher age at baseline (HR=1.2;95%CI 1.1-1.3;p=0.003) and, marginally, T1LV (HR=1.1;95%CI 1.0-1.3;p=0.075). Conclusions: These findings highlight the need to include cognitive preservation in the definition of BMS and provide further long-term evidence for the prognostic role of CI in BMS patients. Disclosure Dr. Lorenzo Razzolini: received research support from Novartis. Dr. Maria Laura Stromillo: nothing to disclose. Dr. Emilio Portaccio has served on scientific advisory boards for Biogen Idec, Merck Serono and Genzyme;received speaker´s honoraria from Biogen Idec, Teva, Novartis and Genzyme; received research support from Merk Serono. Dr. Benedetta Goretti: nothing to disclose. Dr. Claudia Niccolai: nothing to disclose. Dr. Marta Giannini has served on scientific advisory boards for Biogen Idec; received speaker´s honoraria from Biogen Idec and Genzyme; received research support from Teva. Dr. Luisa Pastò: received research support from BIogen Idec. Dr. Isabella Righini: received research support from Novartis. Dr. Badia Bahia Hakiki: has served on scientific advisory boards for Novartis; received speaker´s honoraria from Biogen Idec and TEVA; received research support from Teva. Dr. Battaglini M: nothing to disclose. Dr. Antonio Giorgio: nothing to disclose Dr. Maria Letizia Bartolozzi: received research support from Novartis; received speaker´s honoraria from Biogen Idec and Genzyme. Dr Leonello Guidi: nothing to disclose. Prof. Nicola De Stefano: has received honoraria from Schering, Biogen Idec, Teva Pharmaceutical Industries, Novartis, Genzyme, and Merck Serono SA for consulting services, speaking, and travel support. He serves on advisory boards for Biogen Idec, Merck Serono SA, Novartis and Genzyme. Prof. Maria Pia Amato has served on scientific advisory boards for Biogen Idec, Merck Serono; received speaker´s honoraria and research support from Biogen Idec, Merck Serono, Novartis, Almirall, Teva and Genzyme. P303 Survival and mortality in multiple sclerosis: a 60-year longitudinal population study H.M. Lunde1, J. Assmuss2, K.-M. Myhr3,4, L. Bø3,4, N. Grytten4 1Department of Clinical Medicine, KG Jebsen MS Research Centre, University of Bergen, 2Competence Centre for Clinical Research, 3Department of Neurology, Haukeland University Hospital, The Norwegian Multiple Sclerosis Centre, 4Department of Clinical Medicine, KG Jebsen MS Research Centre, University of Bergen,Norway, Bergen, Norway Introduction: Mortality studies in MS have shown inconsistent results. We aimed to investigate survival, and mortality in a population based multiple sclerosis (MS) cohort. Methods: The study comprised all incident MS patients (N=1388) with onset during 1953-2012 in Hordaland County, Western Norway. Patient information was obtained from patient records at Haukeland University Hospital and linked to the Norwegian Causes of Death (COD) registry. Survival and patient characteristics (sex, age,


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Poster Session 1, 22(S3) disease course) were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality in MS relative to the general population was examined using standardized mortality ratio (SMR). Results: Of 1388 patients, 291 had deceased, mainly of MS (56.4 %). Median survival age was 74.7 years in MS and 81.8 years in the general population (p< 0.001). Women had longer median life expectancy (77.2 years) than men (72.2 years, p=0.003) and patients with relapsing remitting MS (RRMS) survived longer (77.8 years) than patients with primary progressive MS (PPMS) (71.4 years, p< 0.001). Median survival from disease onset was longer in RRMS (42.8 years) than in PPMS (25.5 years, p< 0.001). Overall SMR was 2.71 ( 95 % CI: 2.4, 3.0); in RRMS 2.4 ( 95 % CI: 2.1, 2.7) and 3.9 (95 % CI: 3.1, 4.7) in PPMS. SMR from disease onset during 1953-1974 was 3.1 (95 % CI: 2.7, 3.6), during 1975-1996, 2.6 (95 % CI: 2.2, 3.1) and during 1997-2012: 0.7 (95 % CI: 0.3,1.5). Conclusion: The longest follow-up period of 60 years on survival and mortality in MS is here reported. MS had a 7- year lower median survival age than the general population. Risk of death was almost threefold higher in MS relative to the general population. However, an encouraging decrease in mortality was observed during the last 40 years. Disclosure Hanne Marie Bøe Lunde: nothing to disclose Jorg Assmuss: nothing to disclose Kjell-Morten Myhr: nothing to disclose Lars Bø: nothing to disclose Nina Grytten: nothing to disclose P304 Amount and time to maximal recovery from multiple sclerosis relapses declines with age B.L. Conway1, B. Zeydan1, M. Novotna1, M.M. Paz Soldan2, M. Tutuncu3, A. Siva3, M. Rodriguez1, O.H. Kantarci1 1Neurology, Mayo Clinic College of Medicine, Rochester, MN, 2Neurology, University of Utah, Salt Lake City, UT, United States, 3Neurology, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey Background: Incomplete recovery from relapses in multiple sclerosis (MS) results in permanent disability. Incomplete recovery from the initial MS relapse leads to an earlier onset of progressive MS. Identification of an age at which incomplete recovery becomes more likely may guide treatment decisions. Methods: Patients (89 relapsing-remitting MS, 28 progressive MS) were selected from the Olmsted County population-based MS cohort. The first and last ever relapses were identified and assessed for recovery. Outcome measures were: 1) amount of recovery from each relapse, combining clinical evaluations and patient-reported improvement (almost complete to complete recovery, average recovery, and minimal to no recovery) and 2) duration to maximal recovery (< 1 month, 1-6 months, >6 months). Duration of active disease was defined as the time elapsed from the first to the last relapse. The impact of age, sex, and disease duration on relapse recovery was studied (Chi-squared/ Kruskal-Wallis analyses).

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Results: A total of 202 relapses (158 relapsing remitting MS, 44 progressive MS) with sufficient information for rating were identified. Relapses occurring after onset of progressive MS were excluded. A normal distribution of relapses for age was obtained with a mean age of 37.4±11.7. Duration of active disease ranged from 0.1 to 49 years (mean 14.3 years ±11.2). Almost complete to complete recovery was observed in 108 relapses (53.5%), whereas minimal to no recovery was observed in 7 relapses (3.5%). Older age was associated with poor relapse recovery (p=0.04) and longer duration to maximal recovery (p=0.01). No subjective or objective recovery from a relapse was only observed in patients older than median 53 years of age (range 46.1-59.7). Neither time between first and last relapse nor sex had an impact on relapse recovery (p>0.05). Conclusion: Relapse recovery is an age-dependent phenomenon that starts to decline by the fifth decade. Sex and duration of active disease does not appear to impact relapse recovery. Disclosure B. Conway: Nothing to disclose. B. Zeydan: Received support from the Turkish Neurological Society. M. Novotna: Received support from the European Regional Development Fund - Project FNUSA-ICRC (No. CZ.1.05/ 1.1.00/02.0123), European Social Fund and the State Budget of the Czech Republic. MM. Paz Soldan: Received research funding from NIH, the National MS Society, and the Western Institute for Biomedical Research. M. Tutuncu: Nothing to disclose. A. Siva: Received research grants to my department from The Scientific and Technological Research Council of Turkey - Health Sciences Research Grants numbers: 109S070 and 112S052; and also unrestricted research grants from Merck-Serono to our Clinical Neuroimmunology Unit. Honoraria or consultation fees and/or travel and registration coverage for attending several national or international congresses or symposia, from Merck Serono, Biogen Idec/Gen Pharma of Turkey, Novartis, Genzyme, Teva and Roche. Educational presentations at programmes & symposia prepared by Excemed internationally and at national meetings and symposia sponsored by Merck-Serono; Novartis, Teva and Biogen Idec/Gen Pharma of Turkey. M. Rodriguez: Nothing to disclose. OH. Kantarci: Received support from the European Regional Developmental Fund - Project FNUSA-ICRC (No. CZ.1.05/ 1.1.00/02.0123); Gave and organized scientific presentations at meetings supported by Novartis Pharmaceuticals, but has received no personal compensation; Presented as an invited professor in Biogen Pharmaceuticals, but received no personal compensation. P305 Longitudinal follow-up of fatigue in CIS patients: a prospective study R. van der Vuurst de Vries1, J.J. van den Dorpel1, J.Y. Mescheriakova1, T.F. Runia1, N. Jafari1, T.A. Siepman1, D. Rizopoulos2, E.W. Steyerberg3, R.Q. Hintzen1 1Department of Neurology, MS centre ErasMS, 2Department of Biostatistics, 3Department of Public Health, Erasmus Medical Centre, Rotterdam, The Netherlands


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Background and Objective: Fatigue is a common symptom in MS, reported by more than 75% of MS patients. In an earlier study we showed that fatigue is not only a common symptom in patients at time of CIS (46%), but also predicts a subsequent diagnosis of CDMS and is associated with a shorter time to a next attack after CIS. Furthermore, in another study, fatigue in patients with MS has been found predictive of disease progression. The first aim of this study was to explore the longitudinal course of fatigue during follow-up after CIS. The second aim was to study the association of fatigue at time of CIS and disability when reaching MS diagnosis. Methods: In this study 235 CIS patients, aged between 18 and 50 years, were prospectively followed. CIS patients with comorbidities other than depression, which are likely to cause fatigue, were excluded from the analysis. Patients filled in the Krupp’s Fatigue Severity Scale (FSS) at baseline and annually. When they reached CDMS diagnosis, EDSS was also obtained annually. Mixed effects models were used to analyse the longitudinal FSS measurements and to evaluate the association between the baseline FSS and EDSS during follow-up. Results: In this prospective study 89 out of 235 CIS patients were diagnosed with CDMS (mean follow up 53.1 months (SD ±29.5)). Fatigue at baseline was validated as an independent predictor for CDMS (HR 2.9, 95% CI:1.8-4.9). At time of CIS, patients who were diagnosed with CDMS during follow-up had a significantly higher FSS score than monophasic CIS patients. We found a nonlinear average longitudinal evolution of FSS in time and this evolution was not altered after CDMS diagnosis (p=0.44). However, we found a significant increase of FSS score by 0.86 units when patients experienced a second attack after CIS (p=0.01). Additionally, we found that a high FSS score at baseline (>5.0) showed a trend towards a higher EDSS during follow-up (0.9 points higher EDSS) (p=0.1). Conclusions: Fatigue, which is often present at time of CIS, persists over time and may increase after a second attack. A high FSS score at CIS might be associated with disability after CDMS diagnosis. Disclosure RM van der Vuurst de Vries: nothing to disclose JJA van den Dorpel: nothing to disclose JY Mescheriakova: nothing to disclose TF Runia: nothing to disclose N Jafari: nothing to disclose DAM Siepman: nothing to disclose D Rizopoulos: nothing to disclose EW Steyerberg: nothing to disclose RQ Hintzen: nothing to disclose Funding The study was supported by the Dutch MS research Foundation.

Epidemiology P306 Shift work at young age and risk of multiple sclerosis S. Gustavsen1, H.B. Søndergaard1, D.B. Oturai1, B. Laursen2, J.H. Laursen1, M. Magyari3, H. Ullum4, M.A.H. Larsen4, F. Sellebjerg1, A.B. Oturai1 1Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, 2The National Institute of Public Health, University of Southern Denmark, 3The Danish Multiple Sclerosis Registry,

Rigshospitalet, University of Copenhagen, 4Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Background: The aetiology of multiple sclerosis (MS) is still unknown but epidemiological studies suggest a complex interplay between genetic and environmental triggering factors. A low 30% concordance rate among monozygotic twins strongly suggests a dominant contribution of environmental factors such as geographical location, smoking, diet, low sunlight exposure, vitamin D deficiency, infectious agents and toxins. Recently, one study found that shift work at young age is associated with an increased risk of developing MS. Goal: The aim of this study was to investigate the association between shift work at young age and the risk of developing MS in a Danish cohort. Methods: We performed a large case-control study including 1785 patients diagnosed with MS and 4194 controls. MS patients were recruited from the Danish Multiple Sclerosis Biobank and controls from The Danish Blood Donor Study. Information on working patterns and lifestyle factors was obtained using a comprehensive lifestyle-environmental factor questionnaire. Participants were enrolled between 2009 and 2014. Logistic regression models investigated the association between shift work at age 15-19 years and the subsequent risk of MS and were controlled for effects due to established MS risk factors. Results: A statistically significant association with MS was observed when total numbers of night shifts were compared with non-shift workers. For every additional 100 night shifts the odds ratio (OR) for MS was 1.20 (95% confidence interval (CI), 1.071.33, p = 0.001). Increasing intensity of shift work also increased MS risk. For every additional night per month the OR was 1.04 (95% CI, 1.01-1.06, p = 0.003). Duration of shift work in years was not associated with risk of MS. Conclusion: We found that an increase in the total number of night shifts and the intensity of shift work at age 15-19 years were associated with increased risk of MS, whereas no association was found between the duration of shift work and risk of MS. Thus, this study supports the presence of a significant association between shift work at young age and MS risk. Disclosure Annette Bang Oturai has served on scientific advisory boards for Biogen Idec; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, TEVA, Biogen, Novartis and Genzyme. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Genzyme (Sanofi-aventis) and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough. His laboratory has received research support from Biogen Idec, Bayer Schering, Merck Serono, SanofiAventis and Novartis.


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Poster Session 1, 22(S3) Helle Bach Søndergaard has received support for congress participation from TEVA and Genzyme. Julie Hejgaard Laursen has received honoraria for lecturing from Merck Serono and has had travel expenses reimbursed by Teva, Almirall and Merck Serono. Melinda Magyari has served on scientific advisory board for BiogenIdec and TEVA and has received honoraria for lecturing from BiogenIdec, MerckSerono, Sanofi-Aventis, and Teva. She has received support for congress participation from BiogenIdec, MerckSerono, Novartis, and Genzyme. Bjarne Laursen, Henrik Ullum, Margit Anita Hørup Larsen, Ditte Oturai and Stefan Gustasven have nothing to disclose. P307 Socioeconomic status may influence delay to access to second line disease modifying treatments in RRMS patients F. Calocer1,2, O. Dejardin3, K. Droulon4, N. Derache1,4, G. Defer1,2 1Department of Neurology, University Hospital Center of Caen, 2U 919 INSERM Unit, 3U 1086 INSERM Unit, 4Low-Normandy Multiple Sclerosis Network, Caen, France Background: Socioeconomic status (SES) plays an important role in various chronic or severe diseases including neurological ones, where delays stand as relevant care quality markers. To measure social inequalities in health issues a recent European Deprivation Index (EDI), has proved to be a pertinent comparative tool. Diagnostic and disease modifying treatments (DMTs) delays tend to be reduced by evolution of MS diagnosis criteria especially McDonald 2001 criteria and the evidence of early DMT initiation benefit in Relapsing Remitting Multiple Sclerosis (RRMS). Objective: To identify the influence of SES on the delay between first and second line DMTs in RRMS patients. Methods: 933 patients ‘files with an initial RRMS diagnosis (Poser and 2001 McDonald criteria) during the period [19822011] were extracted for the study from the database of LowerNormandy MS network part of the French Observatory of MS (OFSEP). Cut-off date was fixed at the end of February 2015. Cyclophosphamide, mitoxantrone, natalizumab, and fingolimod were retained as second line DMTs. We performed Cox multivariate proportional hazard model adjusted on clinical variables to assessed association between social deprivation (measured by EDI) and delay to access a second line DMT. Results: Mean age at second line DMTs initiation was 39.49 years (SD ±10,08). Median time to access second line DMTs was 10.83 years for patients diagnosed from 1982 to 2000 compared to 5.00 years for patients diagnosed from 2001 to 2011. No significant influence of SES was observed on delay to access a second line DMT if first line DMT exposure time was less than 5 years. After 5 years of first line DMT exposure, risk to access a second line DMT was 3 times higher for RRMS patients with the lowest EDI (socially favoured patients) HR=3.14 95% IC [1,72-5,72] compared to patients with higher EDIs. Conclusion: In MS social inequalities seem to influence with a time dependent effect access to second line DMTs. Disclosure Calocer: nothing to disclosure Dejardin: nothing to disclosure

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Droulon: nothing to disclosure Derache: nothing to disclosure Defer: nothing to disclosure P308 Lifestyle and socio-demographic determinants of mental and physical health-related quality of life in people with multiple sclerosis C.H. Marck, A. De Livera, C. Brown, S. Neate, K. Taylor, T. Weiland, G. Jelinek University of Melbourne, Melbourne, VIC, Australia Background: People with Multiple Sclerosis (MS), a chronic neurological disorder, often experience progressive physical disability, fatigue, pain, depression and a range of other mental and physical symptoms negatively impacting on their quality of life (QOL). The physical and mental health related QOL of people with MS is increasingly recognised as a key outcome in clinical studies, and may predict the course of disability progression. Modifiable lifestyle factors, such as smoking, physical activity and vitamin D, play a significant role in the development and progression of MS. Few studies to date have looked at associations of a comprehensive suite of modifiable factors lifestyle and QOL. Methods: Using patient-reported data from 2312 people with MS, regression models incorporating socio-demographic, clinical and lifestyle factors were used to predict associations with mental and physical QOL, measured with the Multiple Sclerosis Quality of Life (MSQOL-54) Instrument. Results: Participants were on average 45.6 years old, 82.4% were women, from 54 countries around the world, mostly with a partner (74.1%), and with a university degree (59.5%). Several modifiable factors were associated with physical and mental health composite (PHC and MHC) of the MSQOL-54. While controlling for socio-demographic factors and level of disability, low, compared to moderate and high physical activity, was associated with a 6 and 10 points lower score on the PHC and 3-4 and 6 points lower score on the MHC respectively; not smoking versus currently smoking was associated with 4-5 points higher PHC and 7 point higher MHC; improvement in diet of 20/100 points was associated with a 3 point higher PHC and 5 point higher MHC. Body mass index, number of comorbidities, meditation frequency, omega 3 and vitamin D supplementation showed significant, but small, associations, while alcohol intake did not. Conclusion: The associations between modifiable lifestyle factors and QOL suggest there is potential for secondary prevention of the known deterioration of QOL for people with MS through lifestyle risk factor modification. Disclosure The Bloom Foundation and the Horne Family Charitable Trust supported this study Claudia H Marck, nothing to disclose Alysha M De Livera, nothing to disclose Chelsea Brown, nothing to disclose Sandra L Neate, nothing to disclose Keryn L Taylor facilitates educational lifestyle interventions for people with MS Tracey J Weiland, nothing to disclose


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George A Jelinek receives royalties from his book “Overcoming Multiple Sclerosis”. P309 Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study C.H. Marck1, P.L. Jelinek2, T.J. Weiland1, J.S. Hocking1, K.L. Taylor1, S.L. Neate1, N.G. Pereira3, G.A. Jelinek1 1Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, 2Notre Dame University, Fremantle, WA, 3Box Hill Hospital, Box Hill, VIC, Australia Background: Sexual dysfunction (SD) is very common in people with multiple sclerosis (PwMS) and contributes a significant burden of disease, particularly for young people. SD has direct neurologically mediated and indirect contributions via depression and fatigue, which occur commonly in PwMS. Modifiable factors may represent potential targets for treatment and prevention of SD. Objective: We aimed to assess the prevalence of SD and explore associations between SD and demographic and modifiable risk factors, as well as depression and fatigue in a large cohort of PwMS. Methods: We analysed self-reported data from a large, international sample of PwMS recruited via Web 2.0 platforms, including demographic, lifestyle and disease characteristics. Specific sexual function questions included 4 items from the sexual function scale and 1 item regarding satisfaction with sexual function, part of the MS Quality of Life-54 instrument. Results: Of 2062 PwMS from 54 countries completing questions on sexual function, 81.1% were women, mean age 45 years, mostly (62.8%) with relapsing-remitting MS. The majority (54.5%) reported one or more problems with sexual function and were classified as having SD. Lack of sexual interest (41.8% of women), and difficulty with erection (40.7% of men) were most common. The median total sexual function score was 75.0 out of 100, and 43.7% were satisfied with their sexual function. Regression modeling revealed significant independent associations between sexual function and satisfaction and a range of demographic factors, including age, but not gender, as well as depression risk, antidepressant use, and fatigue in PwMS. Conclusion: In addition to associations of depression risk and fatigue with SD and lack of satisfaction with sexual function, this cross-sectional study shows that modifiable lifestyle factors diet and physical activity were associated with the outcomes, independent of their previously demonstrated strong associations with depression and fatigue. Planned longitudinal follow-up of this sample may help clarify these associations and the underlying mechanisms. There is significant potential to prevent and treat SD in PwMS by addressing depression and fatigue and their determinants. Clinicians and PwMS should be aware of SD and associated factors as part of a comprehensive preventive approach to managing MS. Disclosure The Bloom Foundation and the Horne Family Charitable Trust supported this study. Claudia H Marck: nothing to disclose Pia L Jelinek: nothing to disclose

Tracey J Weiland: nothing to disclose Jane S Hocking: nothing to disclose Keryn L Taylor: facilitates educational lifestyle interventions for people with MS Sandra L Neate: nothing to disclose Naresh G Pereira: nothing to disclose George A Jelinek: receives royalties from his book “Overcoming Multiple Sclerosis”

P310 Clinical electronic consent for the UK MS Register R.M. Middleton1, D.V. Ford1, H. Lockhart-Jones1, D. Naeh1, A. Akbari1, O. Pearson2 1Medicine, Swansea University, 2Neurology, ABMU, Swansea, United Kingdom Objectives: The UK MS Register is an observational research study capturing data from People with MS(PwMS), the NHS and carries out linkage with routine data. There are 14,000 PwMS submitting Patient Reported outcome Measures (PRoMS) and over 3500 patients consenting at NHS sites. A goal of the UK MS Register from the outset was that it be paperless. However, the process of informed consent requires signatures from patient and clinician. Clinical participants are consented using a triplicate consent form. Electronic consent has a number of benefits: Tablet computers are already in use at sites Printing costs reduced Participant expectations Improved content and user experience, ie improved feedback, or multimedia elements Ever increasing familiarity with tablet devices Approach: Changing consent methodology is complex, all documentation, processes and changes are reviewed by an ethics committee. A privacy protecting, secure software package (iConsent) was developed by modifying an existing package from the Welsh Cancer Bank. The software is server based, running on a Secured MS SQLServer 2014 and developed in .net to iOS/Android tablets. The practitioner taking consent explains the process, hands the potential participant the tablet. They then work through the package, page by page. Lastly, they fill in some demographics, and are presented with the consent form, they then use a stylus to sign. The practitioner then countersigns. Once completed a digitally signed, secure pdf is generated. Links are sent by email to the participant, the Register and unit administrator. The pdf is functionally identical to paper. Results: The South West Central Bristol ethics committee approved the software following guidance on security and documentation design. Staff were trained in system usage. A number patients were successfully e-consented, of note was a potential issue with some patients and how MS impacts their ability to sign without resting a hand on the screen. Conclusion: Patients who have been e-consented have expressed satisfaction in ease of use and experience. Patients being unable to rest their hands on the screen is being examined. Newer devices can ignore inputs other than the stylus. e-Consent will not be appropriate for all MS patients.


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Poster Session 1, 22(S3) The MS Register intends to use the software in more site for patient consent, the final paper will incorporate more results as the platform is rolled out. Disclosure The authors have nothing to disclose P311 Accuracy of onset age and prodromal phase of multiple sclerosis in a nationwide cohort in Sweden: a translational study from administrative data to clinical practice O. Beiki1,2, A. Manouchehrinia1, J. Hillert1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, 2Kermanshah University of Medical Sciences, Kermanshah, Islamic Republic of Iran Background: Multiple sclerosis (MS) is a chronic disabling neurological disease typically manifest in young adults aged between 20 and 40. Age at the onset of MS is often assigned retrospectively and is based on several factors including patients’ recollection of the first neurological symptom and therefore presumably less reliable. In addition, early MS/non-MS symptoms can be assigned mistakenly for another. We investigated accuracy of onset age and the prodromal phase of MS using number of sick leave days in a population-based cohort of MS patients and nonMS controls. Methods: Clinical and demographic data and number of sickness absence days from MS patients and age, sex and area of residence matched controls were obtained from three Swedish nationwide databases. We employed joinpoint regression models to identify significant deviations in the age-specific trend of sickness absence spells in MS patients at the time of MS onset in relation to the changes in controls. Results: 10,852 MS patients and 202,976 controls were included. The mean number of age-specific (18 to 55) sick leave days increased by an average of 0.94 (95%Confidence Intervals (CI): 0.89 to 0.99) in MS patients compared with 0.63 (95%CI: 0.58 to 0.67) in controls. The sharpest increase in the mean number of sick leave days overlapped the recorded onset age, however, in the 30-34 and 35-39 onset age groups sickness absence days in about 41% of individuals started to increase from seven years before the recorded onset age. Conclusions: Even though recorded onset age in MS is appeared to be of reasonable accuracy, MS patients’ general state of health, as measured by number of sickness absence days, started to deteriorate several years before the clinical manifestation of the disease. Investigations of the causes of sickness absence long before recorded onset age might give a clue about the temporal aspects of etiologic or triggering event(s) of MS. Our finding in a real-world setting warrant further observational studies and will inform design of new clinical trials for MS. Disclosure Omid Beiki: nothing to disclose Ali Manouchehrinia: nothing to disclose Jan Hillert: JH has received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and SanofiAventis. He has served as P.I. for projects, or received unrestricted

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research support from, Biogen, Merck-Serono, Sanofi-Genzyme and Novartis. P312 Historical but not current vitamin D & sun parameters are associated with a more favourable multiple sclerosis clinical course: data from the Ausimmune Longitudinal Study at 5 years S. Simpson Jr.1,2, I. van der Mei1, R. Lucas3, A.-L. Ponsonby4, L. Blizzard1, B. Taylor1 1Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 2Turning Point, Monash University, Fitzroy, VIC, 3National Centre for Epidemiology & Population Health, Australian National University, Canberra, ACT, 4Murdoch Childrens Research Institute, Parkville, VIC, Australia Background: Vitamin D and sun exposure have been among the most consistent predictors of MS onset and clinical course in established disease, but there have been comparatively few studies in early disease. Aim(s) and objective(s): Evaluate vitamin D & sun parameters associations with subsequent occurrence of conversion to clinically definite MS (CDMS) and relapse in a prospectively monitored cohort from their referral event to 5-year review. Method and approach: We followed a cohort of 279 persons with a first clinical diagnosis of CNS demyelination (FCD) to 5 years from initial participation in the Ausimmune Study (baseline). Sun exposure was measured by questionnaire historical & recent periods, and annually during the study. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured at baseline, 2/3-year and 5-year reviews. CDMS and relapse history were assessed by neurologist and medical record review. Results and findings: At 5-year review, 202/279 persons had converted to CDMS and had 395 relapses. Neither baseline nor longitudinally measured 25(OH)D were associated with CDMS or relapse. Current sun exposure behaviour was inversely associated with CDMS and relapse but became non-significant on adjustment. Importantly, however, historical sun exposure showed the expected significant inverse associations with CDMS and relapse. Also, increasing sun exposure during the study was associated with better clinical outcomes. Discussion and conclusions: Historical sun exposure is validated in its association with MS clinical course in early disease. However, absolute within-study sun & vitamin D measures showed no association with clinical outcomes. It is possible that changing behaviours associated with a diagnosis of FDE may have altered the expected associations. Disclosure The authors have no conflicts of interest to disclose. P313 Changes in sun & vitamin D behaviours and their relationships with vitamin D during five years of follow-up in Ausimmune Longitudinal Study cohort S. Simpson Jr.1,2, I. van der Mei2, R. Lucas3, A.-L. Ponsonby4, L. Blizzard2, B. Taylor2 1Turning Point, Monash University, Fitzroy, VIC, 2Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS,


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Centre for Epidemiology & Population Health, Australian National University, Canberra, ACT, 4Murdoch Childrens Research Institute, Parkville, VIC, Australia Background: Vitamin D and sun exposure have been among the strongest and most consistent predictors of MS onset and clinical course. We sought to evaluate the distribution and determinants of serum 25-hydroxyvitamin D (25(OH)D) and how these relationships change over time. Method and approach: Cohort of 279 persons with first demyelinating event (FDE) from the Ausimmune Study in Brisbane, Newcastle, Geelong and Tasmania, recruited 2004-7 and followed up to 5-yr review. Historical (6, 11, 16 and 21 years-old) sun behaviour parameters queried at baseline. Contemporaneous sun behaviours queried thereafter at annual in-person or CATI review. Serum for measuring 25-hydroxyvitamin D (25(OH)D) taken at face-to-face reviews (baseline, 2/3 and 5-yr) and deseasonalised by sinusoidal adjustment. Results and findings: Serum 25(OH)D increased significantly over the study, from 62.6nmol/L to 69.5nmol/L (p< 0.001). Total UV load and sun-related attire changed significantly in favour of increased sun exposure, and high-dose vitamin D supplementation use increased 18-fold. Classic predictors of 25(OH)D like latitude and sun behaviours showed little of the expected associations. When stratified by review, however, latitude and sun behaviours showed the expected inverse gradients at early timepoints but attenuated or even reversed thereafter. Adjustment for supplementation and sun-related behaviour explained some but not all of these changes. Discussion and conclusions: Using one of the largest prospective cohort studies examining the relationship of environmental/ behavioural predictors of clinical course in early MS, we have shown significant and marked changes in sun & vitamin D-related behaviours. Disclosure The authors have no conflicts of interest to disclose. P314 Infection-related health care utilization among people with and without MS J.M.A. Wijnands1, E. Kingwell2, F. Zhu2, Y. Zhao2, J.D. Fisk3, C. Evans4, R.A. Marrie5,6, H. Tremlett2 1Medicine, Neurology, 2Medicine (Neurology), University of British Columbia, Vancouver, BC, 3Psychiatry and Medicine, Dalhousie University, Halifax, NS, 4Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, 5Internal Medicine, 6Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada Background: Little is known about the rates and types of infections that prompt medical care in the multiple sclerosis (MS) population. We examined the infection-related health care utilization and the types of infections encountered in outpatient and inpatient settings in people with and without MS. Methods: We performed a retrospective cohort study in British Columbia (BC), Canada using population-based health administrative data. People with MS were identified using a validated algorithm and followed from their first demyelinating disease-related

claim (index date: 1996-2013) until the earliest of death, emigration from BC, or the study end (December 31st, 2013). Population controls were matched with MS cases by exact year of birth, sex, and postal code at index date. The monthly rate of infection-related physician visits and prescriptions for anti-infectives filled, and the likelihood of hospital admissions for infections, were compared between populations using negative binomial regression and logistic regression. Models were adjusted for sex, age, year of index date, socioeconomic status, use of immunomodulators and immunosuppressive therapies for non-MS indications, and number of comorbid conditions. Differences in association by sex and age were examined by subgroup analyses. To account for disease modifying drug (DMD) use in MS patients, follow-up was censored at DMD initiation in complimentary analyses. Results: We identified 7,179 persons with MS and 35,837 matched controls (mean age 45.4 years; 73.8% women). During follow-up, people with MS had 41% more infection-related physician visits (adjusted rate ratio [aRR] 1.41; 95%CI 1.36-1.47), filled 57% more prescriptions for anti-infectives (aRR 1.57; 95%CI 1.49-1.65), and were more likely to be hospitalized for infections (adjusted odds ratio [aOR] 2.40; 95%CI 2.17-2.66) than their matched controls. The difference in health care utilization was greater among men than women and increased with age. Censoring at DMD initiation did not change the interpretation of the findings. Among the most common infections, people with MS had significantly more medical encounters for urinary tract infections, pneumonia, intestinal infectious diseases, infections of the skin, and sepsis. Conclusion: Our findings indicated an increased infection-related health care utilization in both the outpatient and inpatient setting in people with MS. These results have relevance for the care of people with MS. Disclosure J.M.A. Wijnands: Nothing to disclose. E. Kingwell: Nothing to disclose. F. Zhu: Nothing to disclose. Y. Zhao: Dr. Zhao receives research funding from the NMSS, and received funding from the CIHR, the MSSOC, and the Milan & Maureen Ilich Foundation. J.D. Fisk: Dr. Fisk receives funding from the Canadian Institutes of Health Research (CIHR), MS Society of Canada, National Multiple Sclerosis Society and the Dalhousie Medical Research Foundation; consultation and distribution royalties from MAPI Research Trust, as well as speakers honoraria and travel expenses from EMD Serono (2013, 2014). C. Evans: Nothing to disclose. R.A. Marrie: Dr. Marrie has funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Rx & D Health Research Foundation, Research Manitoba and sanofi-aventis (clinical trial). H. Tremlett: Dr. Tremlett is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received research support from: the Multiple Sclerosis Society of Canada, the Michael Smith Foundation, for Health Research Scholar, the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences, from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS


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Poster Session 1, 22(S3) (2011, 2012, 2013, 2014, 2015), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). Speaker honoraria are either, declined or donated to an MS charity or used as an unrestricted grant by her research group. P315 Multiple sclerosis prevalence and incidence in Tehran, Iran S. Eskandarieh, M.A. Sahraian, A.N. Moghadasi, A.R. Azimi, N. Sistany Allahabadi MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Background: Several reports from Iran have indicated a rise in MS incidence and prevalence in recent years. A retrospective population-based study was conducted to evaluate MS incidence and prevalence in Tehran province. Methods: Iranian MS Society records were studied to obtain annual incidence data of patients from 1999 to 2015. The ageadjusted prevalence rates were calculated based on year of diagnosis and the 2000-2025 WHO standard population. We used linear regression and Mann-Kendall trend test to study prevalence and incidence rate. Results: On the prevalence day 16447 patients lived in Tehran, totally 24.6% of patients were male and 75.4% were female. The male to female ratio during 1999-2015 is 1: 3.06. The point prevalence of MS in 2015 is 115.94 and incidence of MS in 2013 is 6.37 per 100,000 populations. The age standardized MS prevalence rate for male was 63.23 per 100000 and for female was 197.21. Mean age at disease onset is 28.36 years old with a minimum 3 years and maximum of 87 years old. Mean age at disease onset for male patients is 29.01 years old and for female patients is 28.15 years old with Mode of 25.0 years old. Based on logistic regression analysis, age groups are significantly associated with MS (P < 0.05), age group under18 years old (OR ＝ 1.757; 95％ CI ＝1.358 - 2.237); and 18-27 years old (OR ＝ 1.557; 95％ CI ＝1.247− 1.945). Conclusions: A significantly increasing trend in MS prevalence was observed via Join point regression analysis in different years during last decade. According to this study during the last 16 years, Tehran is amongst regions with the highest prevalence of MS in Asia. Disclosure nothing to disclose P316 The utility of instrumental activities of daily living to predict disability A. Salter1, R.J. Fox2, T. Tyry3, G. Cutter4, R.A. Marrie5 1Biostatistics, Washington University School of Medicine, St. Louis, MO, 2Cleveland Clinic, Cleveland, OH, 3Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 4Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States, 5University of Manitoba, Winnipeg, MB, Canada

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Background: Instrumental activities of daily living (IADLs) assess the ability of a person to perform tasks necessary for independent living. Accumulation of disability in MS impacts a person’s ability to perform IADLs. Impaired IADLs may predict future disability progression. Objective: To evaluate the utility of IADLs to discriminate between disability levels and to determine whether IADLs can be used to predict future changes in disability. Methods: The NARCOMS Registry Fall 2006 update survey asked participants to complete the Lawton IADL survey which measures whether assistance is needed to perform 8 tasks, such as grocery shopping, doing housework, and handling finances. Scores range from 8 to 24 with 24 indicating that no help is needed for any task. The Patient Determined Disease Steps (PDDS) is measure of disability which is highly correlated with the EDSS and is asked in each semi-annual NARCOMS update survey. Longitudinal PDDS data from up to 18 subsequent update surveys through the Spring 2015 were identified for the Fall 2006 respondents to model the trajectory of disability change over time. Crosssectional analyses and longitudinal analyses used linear and repeated measures regression methods respectively. Results: Of the respondents to the Fall 2006 survey, 9661 had data for the IADLs and PDDS questions. These participants had a median (25%, 75%) of 13 (6, 17) follow-up surveys. 11.8% (n=1138) of them had 17 surveys while 20.8% (n=2007) had all 18. 76.3% (n=7374) were female, 92.6% (n=8612) Caucasian, the mean (SD) age in 2006 was 52 (10.5). Over two-thirds of the participants reported a vascular or mental comorbidity. Median (25%, 75%) PDDS was 4 (1, 6) [Early Cane (Mild Disability, Bilateral Support)] and mean (SD) disease duration 14 years (9.4). Mean (SD) IADL score was 20.5 (3.7) and the proportion needing no help on any tasks dropped markedly between PDDS level 1 and 3 (0, 84.2%; 1, 60.7%; 2, 26.9%; 3, 29%). In univariate analyses as disability level increased, the IADL score decreased (r=-0.726, p< 0.0001) and the relationship persisted after controlling for age (p=0.63), sex (p< 0.0001) and current health status (p< 0.0001). The adjusted longitudinal model showed that lower IADL scores were independently associated with greater trajectories of disability change. Conclusion: Even mild disability is associated with impairment in activities associated with independent living, and impaired IADLs predict future disability progression. Disclosure Dr. Salter has nothing to disclose. Dr. Fox has received consultant fees from Biogen Idec, GlaxoSmithKline, Novartis, Questcor, Teva, and Xenoport; grant and research support from Novartis. Dr. Tyry has nothing to disclose. Dr. Cutter: Data and Safety MonitoringBoards: Apotek, BiogenIdec, Cleveland Clinic (Vivus), Glaxo Smith Klein Pharmaceuticals, GileadPharmaceuticals, Horizen Pharmaceuticals, Modigenetech/ Prolor, Merck/Ono Pharmaceuticals, Merck,Merck/Pfizer, Neuren, Sanofi-Aventis, Teva, Washington University, NHLBI (Protocol ReviewCommittee), NINDS, NICHD (OPRU oversight committee); Consulting or Advisory Boards: Consortium ofMS Centers (grant), D3 (Drug Discovery and Development), Genentech, Genzyme, JannsenPharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos,Roche,


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EMD Serono, Teva pharmaceuticals, TGTherapeutics Inc., Transparency Life Sciences. Dr. Marrie has conducted clinical trials for Sanofi Aventis, has received research funding from CIHR, MS Society of Canada, National MS Society, CMSC, MS Scientific Research Foundation, Research Manitoba. P317 An adverse lipid profile and increased body mass index significantly predicts clinical course after a first demyelinating event I. van der Mei1, P. Tettey1, S. Simpson Jr.1, B. Taylor1, R. Lucas2, A.-L. Ponsonby3 1Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 2National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, 3Murdoch Childrens Research Institute, Melbourne, VIC, Australia Background: Data on whether the accumulation of disability and relapse may be influenced by serum lipid levels and body mass index (BMI) in patients with a first clinical diagnosis of demyelination is limited. We aimed to investigate whether there were any associations between lipid-related variables at cohort entry and conversion to clinically definite MS (CDMS), time to subsequent relapse and progression in disability. Methods: A cohort of 279 patients with a first clinical diagnosis of demyelination from the Ausimmune Study was prospectively followed up to 5-year review. Height and weight were measured and serum samples taken at baseline to measure lipid profile and apolipoprotein levels. Associations with conversion to CDMS and hazard of relapse were assessed using survival analysis and associations with annual change in disability were evaluated using linear regression. Results: Higher body mass index (BMI) (Adjusted hazard ratio (AHR) 1.04 (95% CI 1.01, 1.08) p=0.014) and triglyceride levels (AHR 1.20 (95% CI 1.03, 1.40) p=0.021) at cohort entry were associated with increased risk of subsequent relapse while lipidrelated measures were not significantly associated with conversion to CDMS. In addition, higher BMI (β 0.01 (95% CI 0.001, 0.13) p=0.010) and the ratio of total cholesterol over high density lipoprotein (TC/HDL ratio) (β 0.05 (95% CI 0.001, 0.10) p=0.044) at cohort entry were associated with a higher subsequent annual change in disability. Conclusions: In this prospective study, we have demonstrated that higher BMI and triglycerides at first clinical diagnosis of CNS demyelination were associated with increased hazard of relapse, and a higher BMI and TC/HDL ratio were associated with a higher rate in disability progression. Improving lipid profile and losing weight into the healthy range may improve the disease course of MS. Disclosure Authors have no relevant disclosures. P318 Anti-HHV6 IgG levels are associated with hazard of conversion to clinically definite multiple sclerosis after CIS

C. Tao1, S. Simpson Jr.1, R. Lucas2, B. Taylor1, I. Van der Mei1 1Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 2National Centre for Epidemiology & Population Health, Australian National University, Canberra, ACT, Australia Background: Infections with Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV6) have been implicated in multiple sclerosis (MS) onset. Few studies have evaluated the role of viral parameters on MS clinical course. Objective: We evaluated associations between EBV and HHV6 viral markers and the subsequent hazard of conversion to clinically definite MS (CDMS), relapses and annualised change of Expanded Disability Status Scale (EDSS) post clinically isolated syndrome (CIS). Method: In a prospective cohort study, we followed a total of 279 cases for at least 5 years post CIS. Serological viral biomarkers were measured at baseline. CDMS and relapse for each person were recorded by in-person reviews and medical record reviews. Results: Baseline anti-HHV6 IgG was significantly associated with the risk of conversion to CDMS (p=0.05) and most prominent in higher latitudes(Tasmania) (p=0.04). For the relapse analysis, we did not observe a statistical significant association with antiHHV6 IgG, but when we restricted our analysis to Tasmania this became significant (p=0.03). We observed a weak dose-dependent association between anti-HHV6 IgG and annualised change of EDSS (p=0.10), those with anti-HHV6 IgG⩾640 showed a 0.11 increase (p=0.06) when compared to those with anti-HHV6 IgG⩽40. Baseline EBV DNA positivity was associated with a faster conversion to CDMS (HR 2.23; p=0.02) in multivariable model, but there was no association with relapses. Other EBV specific immune response such as Epstein-Barr virus nuclear antigen, early antigen (diffuse and restricted, EA-D and EA-R) and viral capsid antigen were not associated with MS progression. Conclusion: These results suggest a significant association between baseline higher anti-HHV6 IgG and subsequent risk of conversion to CDMS. In the relapse analysis, the association exhibited a latitudinal effect and only influenced those living at higher latitude. Disclosure Authors have no relevant disclosures P319 Influence of environmental factors on bone mineral density and trabecular bone score in Danish MS patients A.G. Olsson1, H.B. Søndergaard1, F. Sellebjerg1, P.S. Oturai2, A.B. Oturai1 1Neurology, Copenhagen University Hospital Rigshospitalet, Danish Multiple Sclerosis Center, 2Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Background: MS patients are at increased risk of reduced bone mineral density (BMD) and fractures. To date, the etiology of bone loss in MS is unclear. As we previously reported (Olsson et al. MS Journal 2015), age, body mass index (BMI) and disease severity were the principal factors associated with reduced BMD


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Poster Session 1, 22(S3) in our cohort. Trabecular bone score (TBS) is a recently developed analytical tool that provides a measurement of the threedimensional bone microarchitecture. Decreased TBS predicts an increased fracture risk independently of BMD. To date, no studies have investigated the TBS in MS patients. Objectives: To assess bone quality in MS patients by TBS and to evaluate potential risk factors that may affect BMD and TBS in patients with MS. Methods: 260 patients from the Danish MS Center were included in the study. Data on BMD - measured by dual x-ray absorptiometry (DXA) in the period 2012 to 2013 - were previously published. The antero-posterior spine images from these scans were reanalysed and TBS was calculated using the TBS iNsight software (MediMaps®, Merignac, France). Students t-test and univariate regression analyses were performed with additional information on smoking, alcohol, sun exposure, physical activity, diet, BMI at year 20, and vitamin D supplements - all parameters were obtained from questionnaires. Disease severity was assessed by the Expanded Disability Status Scale (EDSS). Results: The TBS values were not significantly different from those of an age-matched reference population. Low TBS was associated with high age (p< 0.0001) and high EDSS (p=0.021). Low BMI at 20 years of age was associated with low BMD in both lumbar spine (p=0.016) and femur (p< 0.005). Neither the number of smoking pack-years nor alcohol consumption was associated with BMD. When dichotomized into never smokers and ever smokers, lower BMD in lumbar spine was found in the group of ever smokers (p=0.018). Patients reporting regular physical activity between age 15-19 years had higher BMD in lumbar spine than patients reporting inactivity or occasional activity in this period (p=0.021). Conclusion: Reduced TBS was not prevalent in patients with MS, suggesting that BMD alone, and not the bone microarchitecture, is affected in patients with MS. As in the background population avoiding smoking, performing regular physical activity and maintaining a normal BMI in late adolescence likely contribute to a better bone health in MS. Disclosure Anna Gabriella Olsson has received support for congress participation from Biogen Idec, Novartis, Roche and Teva. Helle Bach Søndergaard has received support for congress participation from Biogen Idec, Genzyme and Teva. Finn Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva. Peter Sandor Oturai: nothing to disclose. Annette Bang Oturai has served on scientific advisory boards for Biogen Idec; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, TEVA, Biogen, Novartis and Genzyme.

MS and gender P320 Oral contraceptives and MS disease activity in a modern real-world cohort

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R. Bove1,2, K. Rankin3, A.S. Chua3, T. Saraceno2, N. Sattarnezhad3, E. Greeke3, F. Stuart3, A. LaRussa3, B.I. Glanz2, B.C. Healy2, T. Chitnis2 1University of California, San Francisco, CA, 2Brigham and Women’s Hospital, Harvard Medical School, 3Brigham and Women’s Hospital, Boston, MA, United States Background: There is uncertainty surrounding the effect of oral contraceptives (OCs) on multiple sclerosis (MS) risk and course, perhaps due to epochal factors. Objective: To determine whether OC use is associated with lower relapse rate in a contemporary cohort of women with MS using injectable disease modifying therapies (DMTs). Methods: We identified 179 women with MS/CIS, aged 18-50, prospectively followed as part of the CLIMB study who initiated an injectable DMT (glatiramer acetate or interferons) at our Center within 2 years of first symptom onset, and with known OC use patterns. OC pill (estrogen, progestogen, or combination) use at the time of DMT initiation was classified as: current/past/never. Relapses and annual EDSS examinations were collected by MS experts. We compared annualized relapse rate from baseline DMT start across OC use categories using a negative binomial regression model (univariate and multivariate) with disease duration at last visit as the offset parameter. To assess the association between OC use and longitudinal change in EDSS we used a mixed effects proportional odds cumulative logit model, with a random intercept and slope, and including disease duration offset by year. We adjusted for age at DMT start, and BMI in a subset (n=118). Results: In this cohort of 179 women, mean ages for current, past and never OC users were 31.6 (n=49), 40.3 (n=56) and 38.1 (n=74) years, respectively (p< 0.05); mean disease duration (1.3 years) and median baseline EDSS (1.0) did not differ between groups. Annualized relapse rate was lower among past OC users compared to never OC users (0.27 vs. 0.46, p=0.020). This same trend was observed after adjusting for age (p=0.032) and both age and BMI (n=118; 0.70 vs. 1.19, p=0.058). Current OC users also had a non-significant lower relapse rate compared to never OC users (0.43 vs 0.46, p=0.75). Participants with current (log odds=0.11, 95% CI=(-0.24, 0.03), p=0.1314) or past (log odds=-0.02, 95% CI=(-0.15, 0.10), p=0.73) OC use had a non-significant lower log odds of reaching a higher EDSS than did participants with no prior OC use, over a mean observation period of 8.2 years. Conclusions: Prior use of exogenous contraceptive hormones appeared associated with a decreased risk of relapses in a contemporary, real-world cohort of women with early MS starting injectable DMTs. Limitations included insufficient power to assess differences in OC formulations. Disclosure Study funding: research support from the National MS Society, the American Brain Foundation, and the NIH K12 program R. Bove: has received research support from the National MS Society, the American Brain Foundation, and the NIH K12 program. Nothing to disclose. K. Rankin: nothing to disclose. A. Chua has received support from Verily Life Sciences T. Saraceno has received support from Verily Life Sciences N. Sattarnezhad has received research support from Merck Serono E. Greeke: nothing to disclose.


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F. Stuart: nothing to disclose. A. LaRussa: nothing to disclose. B.I. Glanz has received research support from Merck Serono and Verily Life Sciences B.C. Healy has received grant support from Novartis, Merck Serono, Genzyme and Verily Life Sciences. I am also on the Biogen Idec Worldwide Medical Biostatistics MS Advisory Board. T. Chitnis has received consulting fees from Biogen-Idec, Novartis, Roche-Genetech; serves on advisory boards for pediatric clinical trials for Novartis and Genzyme-Sanofi; and has received research support from Serono, Biogen-Idec and Novartis. P321 Plasma osteopontin levels and expression of cytokine receptors and regulatory T cells in peripheral blood lymphocytes during pregnancy in neuromyelitis optica spectrum disorder and multiple sclerosis Y. Shimizu, R. Ikeguchi, K. Kitagawa Neurology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan Objective: To determine and distinguish between immunological mechanisms of exacerbation of pregnant neuromyelitis optica spectrum disorder (NMOSD) and pregnant multiple sclerosis (MS). Background: The risk of pregnant MS relapse and of exacerbation of NMOSD of pregnant patients is known to particularly increase in the 1st postpartum period, with the risk of exacerbation of NMOSD being higher than the risk of MS relapse. However the pathogenesis of this difference has not been clearly elucidated. Subjects and methods: The subjects were 10 pregnant women who were diagnosed as relapsing-remitting MS (mean age 30.7 years; 5 following IFNb therapy and 5 not treated) and 4 pregnant NMOSD patients (mean age 33.8 years; 3 treated with prednisolone alone or in combination with an immune-suppressant and 1 not treated). All NMOSD patients were positive for anti-AQP4 antibodies. We examined changes in CD4+Th1/Th2, (CD4+CXCR3+/ CD4+CCR4 ratio), CD8+Th1(Tc1)/Th2(Tc2), (CD8+CXCR3+/ CD8+CCR4+ ratio), and Treg (CD25+CD4+CD127±) in PBMCs and measured plasma OPN before pregnancy, at each trimester during pregnancy (1st, DP1; 2nd, DP2; 3rd, DP3) and at each trimester postpartum (1st, PP1; 2nd, PP2; 3rd, PP3). Results: No Th2 shift was observed during pregnancy in either MS or NMOSD. Treg was increased in the latter part of the each pregnancy. Tc1 cells and plasma OPN were higher in the PP1 phase than in the other phases in both MS and NMOSD, but plasma OPN of NMOSD in PP1 was significantly higher than that of MS (p< 0.05). Conclusion: Plasma OPN, which reflects acceleration of Th1 and Th17, was significantly higher in PP1 of NMOSD patients than in PP1 of MS. Thus, the pathogenesis of NMOSD may be more exacerbated with pregnancy than the pathogenesis of MS. Our results suggested that more strict stabilization of disease activity is necessary for patients with NMOSD who hope to undergo pregnancy than for patients with MS. Disclosure Shimisu Y. has received honoraria for talks from Bayer Yakuhin, and has received personal compensation for consulting services from Biogen Idec Japan, Teijin Pharma, and Novartis Pharma.

Ikeguchi R: nothing to disclose. Kitagawa K. received honoraria for talks from Sanofi Aventis and Daiichi Sankyo.

P322 Pregnancy protects against long-term disability accrual in relapsing-remitting MS V.G. Jokubaitis1,2, T. Kalincik1,2, J. Lorscheider1,2, T. Spelman1, D. Horakova3, P. Duquette4, M. Girard4, A. Prat4, G. Izquierdo5, P. Grammond6, E. Pucci7, F. Grand’Maison8, F. Granella9, P. Sola10, R. Bergamaschi11, G. Iuliano12, D. Spitaleri13, S. Hodgkinson14, J. Olascoaga15, F. Verheul16, P. McCombe17, C. Rozsa18, J. Lechner-Scott19,20, M. Terzi21, S. Hughes22, M.-L. Saladino23, A. Lugaresi24,25, M. Trojano26, H. Butzkueven1,2,27, on behalf of the MSBase Study Group 1Department of Medicine (RMH), University of Melbourne, 2Deparment of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia, 3Department of Neurology and Center for Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 4Hopital Notre Dame, Montreal, QC, Canada, 5Hospital Universitario Virgen Macarena, Seville, Spain, 6Hotel-Dieu de Levis, Lévis, QC, Canada, 7ASUR Marche, AV3, Macerata, Italy, 8Neuro Rive-Sud, Hôpital Charles LeMoyne, Greenfield Park, QC, Canada, 9University of Parma, Parma, 10Nuovo Ospedale Civile Sant’Agostino/Estense, Modena, 11Mondino National Neurological Institute of Pavia, Pavia, 12Ospedali Riuniti di Salerno, Salerno, 13AORN San Giuseppe Moscati, Avellino, Italy, 14Department of Neurology, Liverpool Hospital, Liverpool, NSW, Australia, 15Hospital Donostia, San Sebastian, Spain, 16Groene Hart Ziekenhuis, Gouda, The Netherlands, 17Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia, 18Jahn Ferenc Teaching Hospital, Budapest, Hungary, 19Department of Neurology, John Hunter Hospital, 20School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia, 21Medical Faculty, 19 Mavis University, Samsun, Turkey, 22Royal Victoria Hospital, Belfast, United Kingdom, 23INEBA, Buenos Aires, Argentina, 24DIBINEM, Universita di Bologna, 25IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, 26Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari, Bari, Italy, 27Department of Neurology, Box Hill Hospital, Monash University, Box Hill, VIC, Australia Background: The long-term effects of pregnancy on the accumulation of disability in relapsing-remitting MS (RRMS) are poorly understood. Past studies report contradictory findings including: worsening of disability, no change, or benefit. Objective: To determine the effect of pregnancy on 10-year EDSS outcomes in a relapsing-remitting cohort of women who initiated injectable disease-modifying therapy (DMT). Methods: Using data obtained from MSBase, we identified females with RRMS followed for a minimum 10-years after initiating treatment with their first injectable DMT. Patients were subsequently prospectively monitored on any approved DMT including switches, or no therapy. Median EDSS score changes over a 10-year period were determined. All reported pregnancies, including those that were prematurely terminated, were included in median quantile regression analyses. All analyses were adjusted


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Poster Session 1, 22(S3) for age, disease duration, baseline EDSS, DMT use, annualised relapse rate, and location. Sensitivity analyses were performed including propensity score matching on baseline and time-varying covariates. Results: We identified 1830 females meeting inclusion criteria. 368 pregnancies for 296 females were reported, resulting in 304 live births for 226 women. 223 (61%) of pregnancies were conceived whilst on therapy. Women spent an average 82.5% of the observation period on therapy. EDSS scores increased by a median 1 point (interquartile range (IQR): 0, 2) at 10 years post-baseline. Pregnancies were independently associated with lower EDSS scores over the 10-year observation period (β-coefficient -0.27/ term pregnancy; p=0.05). On adjusted analysis, comparing the proportion of follow-up spent pregnant (β-coef -3.17; p=0.01) to that spent on first-line therapy (β-coef -0.71; p< 0.001), we found that pregnancy was 4.5x more therapeutically potent than injectable DMT. Propensity score matching identified 145 women with at least 1 live birth pregnancy matched to 145 women with no pregnancies. Median 10 year EDSS score changes were significantly lower (p=0.029) in the pregnancy group (0.5; IQR: 0,1.5) relative to the no pregnancy group (1; IQR: 0,2). Conclusion: Our study provides evidence of long-term benefit of pregnancy in women with relapsing-remitting MS who initiated injectable DMT, with a dose-response effect on disability accrual. Further we demonstrate that pregnancy is more effective in preventing disability accrual than first-line DMT in this context. Disclosure This investigator-initiated analysis was supported by a project grant from the NHMRC Project Grant [Grant ID 1032484], and an NHMRC Centre for Research Excellence Grant [Grant ID 1001216]. VJ has received conference travel support from Merck, Novartis and speakers honoraria from Novartis and Biogen. TS received compensation for travel from Biogen. TK served on scientific advisory boards for Novartis, Merck and Biogen, has received conference travel support and/or speaker honoraria from Novartis, Biogen, Sanofi, Genzyme, Teva and Merck and has received research support from Biogen. JL has accepted conference travel support from Novartis and has received research support from Biogen. DH received speaker honoraria and consulting fees from Biogen, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen. PD served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He has received funding for investigatorinitiated trials from Biogen, Novartis, and Genzyme. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD Serono. AP Nothing to disclose. GIz received speaking honoraria from Biogen, Novartis, Sanofi, Merck Serono and Teva. PG is a Novartis, Teva-neuroscience, Biogen and Genzyme advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience, and received grants for travel from Teva-Neuroscience and Novartis. EP served on scientific advisory boards for Merck Serono, Genzyme and Biogen; he has received honoraria and travel grants

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from Sanofi, Novartis, Bayer Schering, Biogen, Merck Serono, Genzyme and Teva. FGM received honoraria or research funding from Biogen, Genzyme, Novartis, and Teva Neurosciences. FG served on scientific advisory boards for Biogen Idec, Novartis and Sanofi and received funding for travel and speaker honoraria from Biogen Idec and Merck Serono. PS received travel grants and speaking honoraria from Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi/Genzyme and Teva. RB received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva; research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva; congress and travel/accommodation expense compensations by Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva GIu had travel/accommodation/meeting expenses funded by Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi Aventis, and Teva. DS received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi and compensation for travel from Novartis, Biogen, Sanofi, Teva and Merck-Serono. SH received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. JO serves on scientific advisory boards for Biogen, Genzyme and Novartis; has received speaker honoraria from Biogen, BayerSchering, Genzyme, Merck-Serono, Novartis and Teva and research grants from Biogen, Merck Serono, Novartis and Teva. FV is an advisory board member for Teva Biogen Merck Serono and Novartis. PMC Nothing to disclose. CR received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck Serono and Bayer Schering. JLS accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen, Genzyme Sanofi, Merck Serono, Novartis and Teva. SH Unrestricted educational grant from Merck Serono and travel grants from Biogen Idec, Genzyme, Novartis and Sanofi. MLS Nothing to disclose. AL is a Bayer, Biogen, Genzyme, Merck Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. Her institution received research grants from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. MT received speaker honoraria from Biogen-Idec, BayerSchering, Sanofi, Merck-Serono, Teva, and Novartis; has received research grants for her Institution from Biogen-Idec, Merck-Serono, and Novartis. HB served on scientific advisory boards for Biogen, Novartis and Sanofi and has received conference travel support from Novartis, Biogen and Sanofi. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. We would also like to acknowledge the MSBase Foundation for its support of this project. The MSBase Foundation is an independent not for profit organisation which receives support in the form


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of grants from the National Health and Medical Research Council (NHMRC) Australia, Merck, Merck Serono, Biogen, Novartis, and Genzyme a Sanofi company.

studies should investigate if this subgroup might benefit from certain hormonal medication. Disclosure

P323 MS symptom worsening during menstrual period may be associated with disease severity later in life K.S. Kavak1, C.B. Vaughn1, B.E. Teter1, M. Nadeem1, K. Zakalik1, P. Coyle2, L. Krupp2, M. Hyland3, B. Jubelt4, M. Gottesman5, K. Edwards6, B. Weinstock-Guttman1, New York State Multiple Sclerosis Consortium 1Dept. of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Buffalo, 2Dept. of Neurology, SUNY Stony Brook School of Medicine, MS Comprehensive Care Center, Stony Brook, 3Dept. of Neurology, University of Rochester Medical Center, Rochester, 4Dept. of Neurology MS Clinic, SUNY Upstate Medical University, Syracuse, 5Winthrop Comprehensive MS Care Center, Mineola, 6MS Center of Northeastern New York, Latham, NY, United States Background: Multiple sclerosis (MS) is possibly mediated by sex hormones as evidenced by the apparent influence of gender on disease susceptibility and disease course, and the favourable effect of pregnancy on MS. The menstrual cycle has been found to have an influence on several autoimmune diseases. In MS, studies have reported MS symptom worsening during the menstrual period with percentages ranging from 43% to 82%. Objective: To investigate women reporting menstrual MS symptom worsening and to explore differences between women reporting symptom worsening and those that do not. Methods: Our sample is comprised of a sub-group of 477 women with MS registered with the New York State MS Consortium (NYSMSC) who completed an extensive questionnaire inquiring on reproductive events. Demographic and clinical characteristics were compared between women who indicated that their menstrual period negatively affected their MS symptoms and those who reported it did not. All results were adjusted for age and disease duration using logistic regression. Results: Of the 443 women who responded to the question, 74 (16.7%) reported that their menstrual periods negatively affected MS symptoms. Those affected were younger at symptom onset (25.4±8.4 vs 30.5±10.1, p=.001), more likely to use an assistive device (47.2% vs. 36.0%, p=.03) and were younger when first starting to use a cane (40.0±9.7 vs 46.4±10.8, p=.04). Furthermore, in a subgroup of menopausal women, patients who reported having had worse MS symptoms during their menstrual period were also more likely to report feeling worse after menopause (30.6% vs 16.9%, p=.002). There were no differences in contraceptive use or disease duration. Conclusion: 16.7% of women in our sample reported complaints of MS symptom deterioration during their menstrual period, a percentage lower than found in other studies. Individual susceptibility to cyclic sex hormone changes which in turn can influence the immune system may explain why some report symptom worsening. The fact that the group reporting menses-related worsening of MS symptoms had significantly lower age at disease onset and higher use of an assistive device may indicate that this is a unique at-risk subset of patients. Although we did not find a difference in (hormone-based) contraceptive use between the groups, future

Katelyn Kavak: nothing to disclose. Caila Vaughn: nothing to disclose. Barbara Teter: received grant and/or research support from Biogen Idec, Teva Neuroscience, EMD Serono, Avanir, Genzyme and Novartis Muhammad Nadeem: nothing to disclose. Karen Zakalik: nothing to disclose. Patricia Coyle: receives consulting fees from AbbVie, Accordant, Acorda, Bayer, Biogen, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, and Teva. She also receives research support from Actelion, Genentech/Roche, NINDS, Novartis, and Opexa. Lauren Krupp: received either consulting fees, honoraria, or royalty payments from the following: Biogen, Pfizer, Teva Neurosciences, EMD Serono, Janseen, Biogen, Novartis, Abbvie. Megan Hyland: Dr. Hyland´s employer, the University of Rochester, has received research support from Novartis and Chugai. Burk Jubelt: received Clinical Trial Grants from: Sanofi-Aventis (Relapsing MS/Teriflunomide), Genzyme (MS/Alemtuzumab), Novartis (Secondary Progressive MS/Fingolimod/Siponimod), Grifols (Post Polio Syndrome/Flebogamma), Receptos (MS/ RPC1063), NY Stem Cell Program (Secondary Progressive MS), NIH/NINDS (SUNY Next Clinical Site), Clinical Studies: BiogenIdec, Continuing Medical Education Speaker:CMEducation Resources LLC,Prime Education, Inc., Patient Education Speaker: National Multiple Sclerosis Society, Multiple Sclerosis Resources of Central New York. Malcolm Gottesman: has served as a consultant for Biogen, Teva, and Genzyme. Keith Edwards: Consulting services: Biogen, Genzyme. Speaker bureaus: Biogen, Genzyme. Research support: Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/ Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis, Pfizer, Vaccinex. Bianca Weinstock-Guttman: has received personal compensation for consulting, speaking and serving on a scientific advisory board for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Questcor and Genzyme& Sanofi and has received financial support for research activities from NMSS, NIH (not for the present study), ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Genzyme. P324 Pregnancy decision-making and related outcomes among women with MS enrolled in the New York State Multiple Sclerosis Consortium C.B. Vaughn1,2,3, K. Kavak2,3, M. Nadeem1, K. Zakalik1,2,3, B. Teter1, P. Coyle3,4, L. Krupp3,5, M. Hyland6, B. Jubelt3,7, M. Gottesman3,8, K. Edwards3,9, B. Weinstock-Guttman1,2,3, New York State Multiple Sclerosis Consortium 1Neurology, University at Buffalo, State University of New York, 2Jacobs Comprehensive MS Treatment and Research Center, 3New York State Multiple Sclerosis Consortium, Buffalo, 4Neurology, Stony Brook University Medical Center, Stony


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Poster Session 1, 22(S3) Brook, 5NYU Langone Medical Center, New York, 6Neurology, University of Rochester Medical Center, Rochester, 7Neurology, SUNY Upstate Medical University, Syracuse, 8Winthrop Comprehensive MS Care Center, Mineola, 9MS Center of Northeastern New York, Latham, NY, United States Background: Pregnancy is a period of relative disease quiescence for a majority of women with multiple sclerosis (MS). Though the use of disease modifying therapies (DMTs) is discouraged during pregnancy, specific recommendations with respect to breastfeeding or timing of cessation of DMT use as well as reinitiation of DMT postpartum are often unclear. Objective: Our primary objective is to examine the pregnancymaking decisions of women with MS enrolled in the New York State MS Consortium (NYSMSC) and the associations with clinical outcomes. Methods: 800 women enrolled in the NYSMSC were mailed a questionnaire inquiring on reproductive history and reproductive decision-making. Longitudinally collected information including demographics, disease characteristics (MS type, relapses), EDSS, DMT history, and patient-reported outcomes are available from the 20-year ongoing prospective NYSMSC registry. Results: To date, 477 questionnaires have been received. Of the 365 women who responded to specific pregnancy questions, 97 (26.6%) reported at least one pregnancy or pregnancy attempt after diagnosis of MS. Of those who attempted pregnancy postMS diagnosis, 64 (66%) reported at least one successful pregnancy, while 21 (21.7%) reported that they were unable to conceive, and several were still trying. The majority of women (61.1%) resumed the same DMT they had been taking before their pregnancy, and 65.4% resumed DMT use within 6 months of delivery. Ten women (10.3%) reported relapses during pregnancy. There were no significant differences in age or DMT use between women who reported relapses and women who did not. Women who reported relapses during pregnancy were also more likely to report relapses in the 12 months prior to the pregnancy (p=0.020). Sixteen women reported a relapse in the 12 months before pregnancy; of those, 11 (68.8%) also reported relapses in the 12 months after pregnancy. Of the 55 women who did not have a relapse in the 12 months before pregnancy; 15 (29.1%) reported having a relapse in the 12 months after pregnancy. The difference between the two groups was significant (p-value=0.004). Conclusion: A substantial portion of women with MS will intend to become pregnant after their MS diagnosis. As such, it is essential that evidence-based information is available to young women with MS. Additional analyses will be presented in a larger sample with respect to the effect and type of DMT used before and after pregnancy on relapses. Disclosure Caila Vaughn: Nothing to disclose. Katelyn Kavak: Nothing to disclose. Muhammad Nadeem: Nothing to disclose. Karen Zakalik: Nothing to disclose. Barbara Teter has received grant and/or research support from Biogen Idec, Teva Neuroscience, EMD Serono, Avanir, Genzyme and Novartis. Patricia Coyle receives consulting fees from AbbVie, Accordant, Acorda, Bayer, Biogen, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, and Teva and she also receives

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research support from Actelion, Genentech/Roche, NINDS, Novartis, and Opexa. Lauren Krupp has received either consulting fees, honoraria, or royalty payments from Biogen, Pfizer, Teva Neurosciences, EMD Serono, Janseen, Novartis and Abbvie, and has received research funding from Novartis, Teva Neurosciences, the National Multiple Sclerosis Society, the Department of Defense, the national Institutes of Health and the Lourie Foundation. Megan Hyland´s employer, the University of Rochester, has received research support from Novartis and Chugai. Burk Jubelt has received compensation for patient education speaking for the National Multiple Sclerosis Society and Multiple Sclerosis Resources of Central New York, he has performed CME for CMEducation Resources LLC and Prime Education, Inc. and has received research support from Sanofi-Aventis, Genzyme, Novartis, Grifols, Receptos, Biogen-Idec, NY Stem Cell Program and Nih/NINDS. Malcolm Gottesman has served as a consultand for Biogen, Teva and Genzyme. Keith Edwards has received fees for consulting servies from Biogen and Genzyme, has performed in speaker bureaus for Biogen and Genzyme and has received research support from Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/Sanofi, Hoffman-La Roche, Merz Pharmaceuticals, Novartis, Pfizer and Vaccinex. Bianca Weinstock-Guttman has received personal compensation for consulting, speaking and serving on a scientific advisory board for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Questcor and Genzyme& Sanofi and has received financial support for research activities from NMSS, NIH (not for the present study), ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Genzyme. This study has been funded by Teva Pharmaceuticals. P325 Later age of menarche is associated with inflammatory and neurodegenerative changes in female multiple sclerosis patients D. Jakimovski1, B. Weinstock-Guttman2, C. Kolb2, D.P. Ramasamy1, N. Bergsland1,3, D. Hojnacki2, R. Zivadinov1,4 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States, 3IRCCS ‘S.Maria Nascente’, Don Gnocchi Foundation, Milan, Italy, 4MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). During the last decades, the prevalence ratio of women to men has notably increased (2-3:1). This may be attributed to hormonal, genetic and lifestyle differences between genders. Female life span is marked by several hormonal changes starting from menarche, through child bearing years, ending with menopause. The effect of hormonal changes on MRI outcome measures in MS patients is still poorly understood.


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Objective: To investigate the effect of different age of menarche on MS inflammatory and neurodegenerative MRI outcome measures. Methods: This study utilized data from an ongoing prospective Cardiovascular, Environmental, Genetic (CEG) study. 276 female MS patients who underwent full clinical examination, MRI assessment on 3T MRI scanner and completed an epidemiological questionnaire regarding reproductive history were selected. Grey matter (GM) volume, white matter (WM) volume, cortical volume and ventricular cerebrospinal fluid (vCSF) volume were calculated using SIENAX cross-sectional software. Volumes of total deep grey matter, thalamus, caudate nucleus, putamen, globus pallidus and hippocampus were measured using fMRIB’s Integrated Registration and Segmentation Tool (FIRST) software. T2-, T1and gadolinium- (Gd) lesion volumes (LV) and lesion numbers (LN) were calculated using a reliable semi-automated edge detection contouring-thresholding technique. Partial correlation analysis controlling for age and age of MS onset was used to assess the relationship between age of menarche and MRI measures. Results were considered statistically significant at p< 0.05. Results: The mean age of the group was 47.3 years (SD=10.9), median Expanded Disability Status Scale (EDSS) of 3 (IQR=25.5), mean disease duration of 15.2 years (SD=10.1) and mean menarche age of 12.7 years (SD=1.7). Later menarche onset showed significant correlation with increased T1-LV (r=0.13, p=0.035) and T1-LN (r=0.16, p=0.009). Later menarche onset also correlated with larger vCSF volume (r=0.15, p=0.012) and with smaller caudate (r= -0.15, p=0.01), globus pallidus (r= -0.13, p=0.032) and total deep GM (r= -0.13, p=0.037) volumes. Age at menarche onset was not associated with EDSS. Conclusion: Later age of menarche is associated with worse neurodegenerative MRI outcomes. Hormonal factors may influence disease progression and further studies need to corroborate our findings. Disclosure Dejan Jakimovski, Deepa P. Ramasamy and Niels Bergsland have nothing to disclose. Bianca Weinstock-Guttman received honoraria as a speaker and as a consultant for Biogen Idec,Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr WeinstockGuttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus and IMS Health.

P326 Early menarche is associated with increased risk of multiple sclerosis and earlier age at onset of multiple sclerosis in Danish patients A.B. Oturai1, J.H. Laursen2, N. Koch-Henriksen3, F. Sellebjerg2, L.W. Thørner4, H. Ullum4, H.B. Søndergaard2 1Department of Neurology, 2Neurology, Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen

University, Rigshospitalet, 3Danish Multiple Sclerosis Registry, Copenhagen University, Rigshospitalet, 4Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark Background: Time of menarche has declined over the last century. It has been suggested that this may contribute to the increasing incidence of multiple sclerosis (MS) among women. Previous studies have shown conflicting results regarding the influence on age at MS onset. Objectives: To study time of menarche and risk of MS in a casecontrol design in ethnic Danish individuals, and further to evaluate the influence on time at MS onset. Methods: Data from a comprehensive environmental/lifestyle questionnaire were collected from Danish MS patients and controls. MS patients were recruited among 2775 individuals from the Danish MS Biobank, 2058 (74%) responded. The control group consisted of blood donors, recruited from five major donor locations, where only two places were able to calculate the response rate which was 75 and 90%. In total we have questionnaire data from 7289 individuals (2058 cases and 5231 controls). Of these, 529 (7%) were excluded due to other etnicity than Danish and other 248 (3%) for age corrections. Thus, we included 6512 individuals (1827 patients and 4685 controls). 3408 (96%) women (1295 patients, 2113 controls) had completed data sets for the investigated parameters and were included in the analyses. Information on age at onset was obtained from the Danish MS Registry. A logistic regression model was used to investigate the association between menarche and the risk of MS. The risk was adjusted for year of birth. Univariate regression analysis was used to evaluate the association between time of menarche and age at disease onset. Results: Mean (SD) age at menarche was lower in patients compared to controls, 13.1 (1.5) vs 13.3 (1.4), p=0.01. For each additional year of menarche the risk of MS decreased by 5% (Odds ratio = 0.95 (95% confidence interval (CI) 0.905-0.997, p < 0.04)). Additionally, we found a positive association between age at menarche and age at MS onset (p < 0.001), with an effect size of 0.67, meaning that age at onset decreases 0.67 years as age of menarche decreases by one year. Conclusions: We found an association between earlier age at menarche and increased risk of MS. In addition, we found an association between earlier age at menarche and earlier age at onset of MS. Disclosure Annette Bang Oturai has served on scientific advisory boards for Biogen Idec and Genzyme; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, Teva, Biogen, Novartis and Genzyme. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, SanofiAventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Genzyme (Sanofi-aventis) and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough. His laboratory


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Poster Session 1, 22(S3) has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis and Novartis. Nils-Koch Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis. Helle Bach Søndergaard has received support for congress participation from TEVA and Genzyme. Julie Hejgaard Laursen has received honoraria for lecturing from Merck Serono and has had travel expenses reimbursed by Teva, Almirall and Merck Serono. Henrik Ullum has received honoraria for lecturing from Roche. Lise Wegner Thørner has nothing to disclouse.

P327 Disease course during pregnancy in patients with highly active multiple sclerosis I. Meinl, R. Hohlfeld, T. Kuempfel Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet Muenchen, Munich, Germany Background: Counselling of pregnant women who have an active disease course of multiple sclerosis (MS) is important. Objective: to evaluate the disease course during and up to 6 months after pregnancy in patients with active MS. Methods: We collected data and assessed the disease course of 23 women with 27 pregnancies prior, during and after pregnancy. Results: 19 women with 23 pregnancies were treated with natalizumab (NAT) and 4 with fingolimod (FTY) prior to pregnancy. Overall, 29 relapses were recorded, 19 during pregnancy and 10 postpartum. 15 patients stopped NAT at the beginning of their pregnancy and three (20%) remained stable throughout pregnancy without recurrence of disease activity. 10 (67%) experienced relapses during pregnancy 7 (+/- 3) months after cessation of NAT. One resumed NAT during the 30th week of gestation due to ongoing disease activity and remained stable thereafter. 7/15 (47%) had postpartal relapses, 5 (33%) showed disease activity at during pregnancy as well as postpartum. In three pregnancies NAT treatment was stopped at 12 weeks of gestation; in two of them relapses occurred during the third trimester. Continuous use of NAT in five women during pregnancy as well as postpartum was accompanied by an entirely stable disease course in all of them. 9 women who stopped NAT during pregnancy restarted NAT early after delivery and remained stable thereafter. All four patients who were treated with FTY prior to pregnancy experienced relapses during pregnancy. Discontinuation of FTY two months prior to pregnancy resulted in severe relapses during the first trimester in three patients, and in one relapse postpartum in one of them. One woman who accidentally took FTY until early pregnancy experienced a relapse during the third trimester. So far, 25 deliveries have been recorded, and 23 healthy babies were born, two pregnancies are ongoing. One baby exposed to NAT as well as valproic acid for epilepsy was born with a congenital heart defect, and the baby who was exposed to NAT since the 30th week of gestation was born with anal atresia. Conclusions: Women who stop FTY or NAT prior to, or during the first trimester of pregnancy have a high risk for increased disease activity during pregnancy and/or postpartum compared to

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women who continue NAT therapy during pregnancy. Continuous use of NAT throughout pregnancy can be an option for women with active MS and should be considered as an individual option in selected cases. Disclosure RH has received grant support from Bayer, Biogen, GenzymeSanofi, Merck-Serono, Novartis, Teva and personal fees from Actelion, Bayer, Biogen, Genzyme-Sanofi, Medday, MerckSerono, Novartis, Roche, and Teva. TK has received travel expenses and personal compensations for from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis Pharma, Sanofi-Aventis/Genzyme and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis Pharma. IM has received travel expense compensation from Teva and Biogen-Idec

MS symptoms P328 Impact of MS symptoms and symptom clusters on quality of life: a cross-sectional study of a large community cohort C. Chen1, T. Stuchiner1, L. Lucas1, E. Baraban1, S. Cohan2 1Providence Brain & Spine Institute, 2Providence Multiple Sclerosis Center, Providence Health & Services, Portland, OR, United States Background: Multiple Sclerosis (MS) is a chronic disease of the central nervous system in which damage resulting from repeated inflammatory insults and neurodegeneration leads to varying types and degrees of symptoms and impairment causing profound adverse impact on quality of life (QOL). Objective: To study the prevalence of MS symptoms and which symptoms and symptom clusters affect QOL. Method: This is a cross-sectional study using survey data on patient characteristics, MS symptoms, Patient Determined Disease Steps (PDDS) and Multiple Sclerosis Impact Scale (MSIS) from the Pacific Northwest MS Registry. Maximum Likelihood Exploratory Factor Analysis was used to summarize twenty symptoms into four factor groupings. Multiple linear regression was used to determine the correlation between the factor groups and the physical and psychological dimensions of MSIS, controlling for gender and disease duration. Results: Data from 2,092 registry participants with mean age of 59.8 (±11.5) years, mean disease duration of 19.4 (±10.4) years, median PDDS of 3, and median MSIS physical and psychological scores (scaled 0-100) of 33.3 [IQR: 13.3, 58.3] and 33.3 [IQR: 14.8, 48.2] respectively were included in the analyses; 81.4% were female and 62.0% had relapsing MS. Among the 20 symptoms studied, fatigue (68.5%), numbness and/or tingling (60.5%), heat sensitivity (59.1%), difficulty walking or maintaining balance (53.7%), and stiffness, spasms, or tremors in limbs (50.9%) were the most prevalent symptoms. Through factor analysis the symptom data were reduced to 4 factors: (a) immobility and bladder/bowel dysfunction, (b) pain and fatigue, (c) dysphasia and speech problem, and (d) cognitive and psychological impairment. Regression results suggested that difficulty walking, often occurring in association with bladder and bowel dysfunction, had the strongest correlation with the physical impact score (Relative Risk (RR) = 10.51, p< .01). In contrast, the pain and fatigue factor


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had the strongest association with the psychological impact score (RR=7.89, p< .001). Conclusion: This study identified co-occurring MS symptoms and their differing correlation to the physical and psychological dimensions of QOL as measured by the MSIS. Future studies will investigate the symptoms that are inter-related and seek underlying etiological relationships to assist in development of effective strategies for the detection and management of these complex and clinically significant MS symptoms. Disclosure Chiayi Chen, Tamela Stuchiner, Lindsay Lucas, and Elizabeth Baraban have nothing to disclose. Stanley Cohan serves on steering committees and advisory boards for Biogen, Novartis, Sanofi-Genzyme, Genentech and Mallinckrodt, receives research support from Biogen, Novartis, Sanofi-Genzyme, Roche, Opexa, and Mallinckrodt, receives speaking honoraria from Biogen, Novartis, Sanofi-Genzyme and Acorda; received support for air travel, lodging and meals from Biogen, Novartis, and Sanofi-Genzyme. P329 Progressive multiple sclerosis and incontinence: what do we know? N. Cotterill1, C. Copestake2, I. Weir3, M. Drake1, C. Norton4, A. Wilkins2 1Bristol Urological Institute, 2North Bristol NHS Trust, 3University of the West of England, Bristol, 4King’s College London, London, United Kingdom Background and goals: Approximately 107,000 people in the UK have a diagnosis of Multiple Sclerosis (MS) and associated bladder and bowel problems are common. Accurate data regarding severity of MS and incontinence is lacking due to the use of varied definitions and measurement methods. Methods: IMPAQTS is a survey study conducted at eight UK sites, requesting patients with progressive MS (PMS) and urinary (UI) and/or anal incontinence (AI - incontinence of flatus, liquid or solid stool) to complete validated patient reported questionnaires to evaluate MS status (Functional Assessment of MS - FAMS) and Incontinence (International Consultation on Incontinence modular Questionnaires - ICIQ). Results: 200 individuals (153 females, 47 males) participated. Mean FAMS score was 86.0 (SD 29.5, observed score range 25-165 of possible 0-176) indicating moderate impact of MS on daily function. Specific domain mean scores were calculated with higher scores indicating increased presence of the characteristic: Mobility 7.9 (5.6, 0-26) mean (SD, observed range) Symptoms 17.0 (6.1, 2-28) Emotional well-being 15.5 (7.2, 0-28) General contentment 12.7 (6.2, 1-28) Thinking/fatigue 13.9 (9.0, 0-35) Family/Social well-being 17.7 (6.4, 0-28) 92% reported UI, which was deemed severe or very severe by 41%, and 97% reported AI; 79% if flatus incontinence excluded. 53% reported frequent urinary incontinence, 65% reported frequent flatus incontinence. Frequent leakage of liquid and solid stool were less prevalent (42% and 31% respectively). Urinary and anal incontinence in combination occurred in 81% of the

population, with males and females being affected near equally, female and male data detailed respectively: Urinary incontinence 56%:44% Flatus incontinence 67%:60% Liquid stool incontinence 45%:36% Solid stool incontinence 32%:28% There was no evidence of correlation between the FAMS domain scores and incontinence scores (ICC 0.02-0.25). Conclusions: Among individuals with PMS and incontinence, varying severity of MS symptoms was reported with moderate impact of symptoms on daily function, in particular in the areas of symptoms, emotional well-being and family/social well-being. Incontinence levels are reportedly high and affect both men and women in similar proportions. Both bladder and bowel problems often occur in combination. It is recommended that clinicians treating individuals with PMS should actively enquire about all incontinence regardless of disease severity or gender. Disclosure Nikki Cotterill is supported by a Junior Fellowship from the MS Society. Carole Copestake: nothing to disclose. Iain Weir: nothing to disclose. Marcus Drake is a speaker, advisory board member and conducts research supported by Allergan, Astellas and Ferring. Christine Norton: nothing to disclose. Alastair Wilkins: nothing to disclose. P330 Multi-dimensional assessment of symptom severity in matched NMO and MS patients R. Green1, J. Nathanson2, I. Kister1 1NYU Langone Medical Center, 2Yeshiva University, New York, NY, United States Objectives: To compare self-reported symptom severity in patients with NMO and gender-, race-, age- and disease durationmatched MS controls using symptoMScreen, an in-house developed tool for multi-dimensional symptom assessment. Background: NMO and MS are distinct neuro-inflammatory disorders with overlapping symptomatology. SymptoMScreen is a validated battery of 7-point Likert scales for assessing symptom severity in 12 neurologic domains: mobility, dexterity, spasticity, body pain, sensation, bladder function, vision, fatigue, vision, dizziness, cognition, depression, and anxiety. SymptoMScreen has been validated for MS populations, but not for NMO. Methods: NMO and MS patients seen in NYU MS Care Center (New York) completed the symptoMScreen at each clinic visit. Every NMO patient was matched 1:2 with MS patients on age (+/1 year), gender, race, and disease duration (+/- 1 year), except for 1 NMO patient who only yielded one MS match. Symptom severity in each of the 12 symptoMScreen domains was compared using matched-samples t-tests; p< 0.05 was considered significant. Results: There were 43 NMO patients in our cohort, with mean age 51 +/- 14.4 years and mean disease duration of 11.1 +/- 8.8 years. The matching 85 MS patients had very similar mean age (51.2 +/- 14.7 years) and mean disease duration (11.2 +/- 8.1 years). In both groups, gender was 97% female and racial distribution was: 46% African-American, 33% Hispanic-American, 15%


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Poster Session 1, 22(S3) White-American, 5% Asian and 1% other. Of the 12 symptoMScreen domains, significant differences between NMO and MS were observed in only 4 domains. Vision and bladder symptoms were significantly worse in NMO as compared to MS (p=0.03 for both domains), while cognition (p< .001) and anxiety (p=0.03) were significantly worse in MS patients. No significant differences were observed in the remaining 8 domains, though there were trends for worse spasticity and pain in NMO (p=0.06) and worse depression in MS (p=0.07). Conclusions: SymptoMScreen is a useful screening tool to assess symptom severity in NMO as in MS, and identifies relevant clinical differences between the two diseases. Worse selfreported vision in NMO compared to MS is an expected finding, and worse bladder function likely reflects more severe cord damage in NMO than MS, which may also explain trends for worse spasticity and pain in NMO. Better cognition and anxiety scores in NMO may be due to the relative sparing of cerebrum in this disease relative to MS. Disclosure The authors have no disclosures to report as the research was carried out using authors own resources. P331 Systematic assessment and characterization of chronic pain in multiple sclerosis patients D. Plantone1, D. Ferraro2, A.M. Simone2, F. Morselli2, G. Dallari3, F. Vitetta2, P. Sola2, G. Primiano1, V. Nociti1, M. Pardini4, M. Mirabella1, C. Vollono1 1Catholic University, Rome, 2University of Modena and Reggio Emilia, 3Nuovo Ospedale Civile Sant’Agostino/Estense, Modena, 4University of Genoa, Genoa, Italy Background: Chronic pain is defined by the International Association for the Study of Pain as constant or intermittent daily pain, persisting for more than three months, without apparent biologic value. Many studies have assessed the prevalence of pain in Multiple Sclerosis (MS), reporting a wide variability (29%-92%). Aim: We aimed to describe the prevalence and characteristics of chronic pain in a cohort of MS patients, using validated tools. Methods: MS patients underwent a neurological examination and were asked to fill out questionnaires including the DN4 (where a score of at least 4 indicates the presence of neuropathic pain), the Neuropathic Pain Symptom Inventory, the Brief Pain Inventory, and the McGill Pain Questionnaire. We analyzed data using MannWhitney’s test, Spearman statistics, and logistic regression. Results: We enrolled 374 patients (age: 46.7±12.5 years, 120 males) including 301 (80.5%) with relapsing-remitting and 73 (19.5%) with progressive MS. The overall prevalence of chronic pain was 52.1%, most frequently affecting the lower limbs (36.9%). Neuropathic pain was the most frequent type of chronic pain (89/195; 45.6%). Patients with chronic pain had significantly higher EDSS scores (2.7 versus 2.3; p=0.025), while the two groups did not differ in terms of age or disease duration. A significant positive correlation was found between EDSS e DN4 scores (p=0.0002). Sensory, pyramidal, cerebellar and bowel and bladder EDSS functional system scores positively correlated with the total DN4 score. At univariate logistic regression, EDSS and sensory, pyramidal and bowel/bladder functional system involvement

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increased the risk of neuropathic pain, though at multivariable analysis, only a sensory involvement maintained a statistical significance (OR:1.7; p= 0.001). There was no association between neuropathic pain and age, sex or disease duration. Conclusions: More than half of patients fulfilled criteria for chronic pain, the most frequent type being neuropathic pain. There was a significant correlation between EDSS and DN4 scores, and a sensory involvement was predictive of neuropathic pain. The present study supports the routine assessment of neuropathic pain in MS patients with high disability and with sensory functional system involvement, in order to avoid underdiagnosing and under-treating a potentially invalidating condition. Disclosure Domenico Plantone has nothing to disclose. Diana Ferraro has nothing to disclose. Anna Maria Simone has nothing to disclose. Franca Morselli has nothing to disclose. Giulia Dallari has nothing to disclose. Francesca Vitetta has nothing to disclose. Patrizia Sola has nothing to disclose. Guido Primiano has nothing to disclose. Viviana Nociti has nothing to disclose. Matteo Pardini has nothing to disclose. Massimiliano Mirabella has nothing to disclose. Catello Vollono has nothing to disclose. P332 Multiple sclerosis broke my heart G. Androdias1, E. Bernard2, D. Biotti3, N. Collongues4, F. Durand-Dubief2, C. Delmas3, J. Ninet5, R. Marignier2, S. Vukusic2 1Réseau Rhône Alpes Sclérose en plaques, 2Hopital Neurologique de Lyon, Lyon, 3Centre Hospitalier Universitaire, Toulouse, 4Centre Hospitalier Régional Universitaire, Strasbourg, 5Hopital Edouard Herriot, Lyon, France Objectives: To describe 5 cases of transient left ventricular dysfunction related to multiple sclerosis (MS) relapses and discuss pathophysiological processes. Methods: Retrospective case series of 5 consecutive patients referred for acute heart failure associated with MS exacerbation in two French university hospitals. Results: Transient cardiomyopathy developed in 5 MS patients (2 men and 3 women, aged 16 to 27) during a relapse that was inaugural in and led to the diagnosis of MS in 3 cases. Clinical signs of brainstem dysfunction preceded by a few days cardiac symptoms in 4 cases and were concomitant in one. Heart failure was severe in all patients, requiring intensive care management. Echocardiography showed left ventricular hypokinesis which was global in 2 patients and basal in 3. No other cause of acute heart failure has been found despite a comprehensive work-up. All patients had developed a new medullary lesion on brain MRI. Rapid and complete recovery of ventricular function was observed in all patients after intravenous corticosteroids and symptomatic cardiac treatment. We concluded to a takotsubo phenomenon. Conclusion: Physicians should be aware that MS relapse is a rare but possible cause of takotsubo cardiomyopathy. Cardiologists in particular have to look for neurological symptoms in case of acute


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heart failure of unknown origin. In our series, all cases were associated with a new lesion of the medulla oblongata underlining the role of the brain-heart axis in this cardiomyopathy of incompletely understood pathogenesis. Disclosure Dr Géraldine Androdias has received lecturing fees, travel grants and research support from Almirall, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi and Teva Pharma Dr Emilien Bernard has nothing to disclose Dr Damien Biotti has nothing to disclose Dr Nicolas Collongues has nothing to disclose Dr Françoise Durand-Dubief has received lecturing fees, travel grants and research support from Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi and Teva Pharma Dr Clément Delmas has nothing to disclose Dr Jacques Ninet has nothing to disclose Dr Romain Marignier has received lecturing fees, travel grants and research support from Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi and Teva Pharma Dr Sandra Vukusic has received lecturing fees, travel grants and research support from Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi and Teva Pharma P333 Protective personality traits: high openness and low neuroticism are linked to better memory in MS V.M. Leavitt1, J.F. Sumowski2 1Neurology, Columbia University, 2Neurology, Mount Sinai School of Medicine, New York, NY, United States Memory impairment occurs early in the disease course of persons with multiple sclerosis (MS), though it is variable and our understanding of its causes is poor. In healthy adults, personality factors are related to memory function and protection from memory decline: high openness and conscientiousness are linked to better memory, and high neuroticism is linked to worse memory. Here, we comprehensively examined personality factors and memory/ non-memory function in MS patients. Methods: 70 MS patients (56 female, age 50.7±9.6 years, education 15.5±2.3 years, disease duration 14.2±7.9 years, phenotype: 54 relapsing-remitting, 11 secondary progressive, 5 primary progressive) completed the NEO Five-Factor Inventory, a 60-item scale yielding scores for 5 personality factors: openness, neuroticism, agreeableness, extraversion, conscientiousness. Cognitive measures: Memory composite included verbal and visual memory measures (age-adjusted norm-referenced mean t-score= 45.5±11.9). Non-memory measures: processing speed, working memory/attention, executive functions, language functions, visuospatial functions, and motor. Premorbid intelligence (IQ): Wechsler Test of Adult Reading (mean: 109.5±12.1). Partial correlations were run for 5 factors and cognitive measures, controlling for education and IQ. Linear regression was run to determine the independent contribution of personality to predict cognitive function: education and IQ were entered in block 1, personality factors entered in block 2 (stepwise, entry p=.05, removal =.10). Results: Memory was the only cognitive function associated with personality. Controlling for education and IQ, high openness and low neuroticism were associated with better memory. Stepwise

regression: The full model predicting memory was significant, R2=.397, p< .001. Openness and neuroticism independently contributed to memory function over and above IQ and education (ΔR2=.190; p< .001). Summary: This is the most comprehensive investigation of the relationship of personality factors to cognitive function in MS to date. Our findings reveal a link between high openness/low neuroticism and better memory function in persons with MS, consistent with findings in healthy adults. This is the first study in any population controlling for education and IQ, thereby isolating the independent contribution of personality to memory for the first time. Consideration of personality factors may help explain/predict differential memory impairment in MS. Disclosure Victoria M. Leavitt: Nothing to disclose. James F. Sumowski: Nothing to disclose. P334 Profiling cognitive deficits of patients with remitting relapsing multiple sclerosis (RRMS) in initial and later disease stages M. Stumpfe1, E. Redelstein2, K.-O. Sigel3, J. Fischer4, U. Kausch5, E. Scholz6, S. Gierer7, G. Reifschneider8, W. Hofmann9, E. Schlegel10, M. Plaschke11, S. SchlmilchPaschen12, S. Schmidt13, J. Kunz14, M. Ernst15, K. Gehring16, B. Elias17, W. Elias17, A. Bergmann18, M. Lang19, H. Schreiber19 1Universität Ulm, 2University of Ulm, Ulm, 3NTD Study Group on MS, Munich, 4NTD Study Group on MS, Regensburg, 5NTD Study Group on MS, Bogen, 6NTD Study Group on MS, Böblingen, 7NTD Study Group on MS, Dillingen, 8NTD Study Group on MS, Erbach, 9NTD Study Group on MS, Aschaffenburg, 10Neurological Practice Center, Siegen, 11NTD Study Group on MS, Aibach, 12Neurological Practice Center, Kandel, 13NTD Study Group on MS, Bonn, 14NTD Study Group on MS, Ravensburg, 15NTD Study Group on MS, Sinsheim, 16NTD Study Group on MS, Itzehoe, 17NTD Study Group on MS, Hamburg, 18NTD Study Group on MS, Neuburg, 19NTD Study Group on MS, Ulm, Germany Backround: Cognitive dysfunction, besides fatigue and depression, is one of the most important non-motor deficits of MS representing an essential prediction factor for MS-associated the quality of life. Objective: Baseline analysis of cognitive profiles of 200 RRMS patients starting therapy with dimethylfumarate (Tecfidera®) or switching from other MS medications and participating in a longitudinal follow-up of 24 months. Questions: (1) Is the cognitive profile of the total RRMS sample different from that of healthy controls? (2) Do cognitive profile and performance distinguish RRMS patients without premedication (de-novo) from those switching to DMF (switchers)? (3) What are the covariate influences on cognitive variables? Methods: Baseline analysis of a prospective, non-interventional, multicenter (15 practice centers) study of 24 months with assessments at baseline/T0 and after 6,12 and 24 months follow-up (T6, T12, T24). Inclusion: 18-60 yr, RRMS/Mc


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Poster Session 1, 22(S3) Donald, EDSS: 0,5-5. Group: 159 RRMS patients compared to 29 healthy controls, among them 111 switchers and 48 de-novo patients. Assessments: clinical (EDSS, ambulation index, functional status), behavioral (CGI, fatigue/FSS/FSMC, daytime sleepiness/ESS, self-rated attention/FEDA, depression/BDI, quality of life/EQ5D) and cognitive domains (executive function: verbal and non-verbal fluency/RWT,RFFT, interference control/ Stroop; working memory: WMSr-BS/ZS, information processing:SDMT, and learning & memory: non-verbal/BVMT, verbal/CVLT). Results: (1) When comparing total RRMS vs. controls, significant cognitive deficits were shown for patients in the domains of executive function and memory (verbal and non-verbal domains, respectively) (2) When comparing de-novo MS vs. switchers, highly significant deficits were shown for the switchers concerning depression, verbal working memory (WMSr-ZS) and EDSS. (3) A significant covariate influence on cognition was found for time on disease with respect to visual learning (BVMT), information processing (SDMT), fatigue (FSMC), interference control (Stroop) und all clinical parameters (EDSS, CGI, AI). Conclusion: (1) the early MS disease process seems to primarily affect aspects of executive functions and verbal/non-verbal learning and memory (2) switchers are more affected by working memory deficits and depression suggesting that these areas may be particulary vulnerable in case of medication failure and longer disease duration. Disclosure Nothing to disclose P335 Balancing the demands of two tasks: an investigation of cognitive-motor dual-tasking in relapsing remitting multiple sclerosis E. Butchard-MacDonald, L. Paul, J. Evans University of Glasgow, Glasgow, United Kingdom Backgound: People with relapsing remitting MS (PwRRMS) have been shown to suffer disproportionate decrements in gait performance under dual-task conditions, when walking is combined with a cognitive task. There has been much less investigation of the impact of cognitive demands on balance. The aims of this study were to investigate whether: (1) PwRRMS show disproportionate decrements in postural stability under dual-task conditions compared to healthy controls; (2) dual-task decrements are associated with everyday dualtasking difficulties; (3) mood and fatigue are associated with level of dual task decrement. Methods: 34 PwRRMS and 34 matched controls completed cognitive (digit span) and balance (movement of centre of pressure on a Biosway, on stable and unstable surfaces) tasks under single and

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dual-task conditions. Everyday dual-tasking was measured using the Divided Attention (DiVA) Questionnaire. Mood was measured by the Hospital Anxiety and Depression Scale (HADS). Fatigue was measured via the Modified Fatigue Index Scale (MFIS). Results: There were no differences in age, gender, years of education, estimated pre-morbid IQ or baseline digit span between the groups. In comparison to healthy controls, PwRRMS showed a significantly greater decrement in postural stability under dualtask conditions on an unstable surface (p=.007), but not a stable surface (p=.679). PwRRMS reported higher levels of everyday dual-tasking difficulties (p< .001). Balance decrement scores were not correlated with everyday dual-tasking difficulties, or with fatigue. Stable surface balance decrement scores were significantly associated with levels of anxiety (rho=.527, p=.001) and depression (rho=.451, p=.007). Conclusion: RRMS causes difficulties with dual tasking, impacting balance, particularly under challenging conditions, which may contribute to an increased risk of gait difficulties and falls. The striking relationship between anxiety/depression and dual-task decrement suggests that worry may be contributing to dual-task difficulties, and raises the possibility that therapeutic interventions aimed at managing worry may improve cognitive-motor dual-tasking. Disclosure Emma Butchard-MacDonald: Nothing to disclose Lorna Paul: Nothing to disclose Jonathan Evans: Nothing to disclose P336 Patient reported symptoms associated with activities of daily living in upper limb impairment for people with multiple sclerosis T. Street1, I. Swain2,3, P. Taylor1,3 1Salisbury NHS Foundation Trust, Salisbury, 2Bournemouth University, Bournemouth, 3Odstock Medical Ltd, Salisbury, United Kingdom Background: Multiple Sclerosis (MS) upper limb sensorimotor impairment is experienced by 66% of people with MS.1,2 Upper limb impairment has a large impact on the ability to perform activities of daily living such as eating and dressing. Interventions for impairment in the upper limb are lacking in the literature. The current pilot study sought to gain a greater understanding of the symptoms that people with MS experience as having the most impact on activities of daily living. Methodology: A convenience sample of 21 people with MS (EDSS level 4.5-8) completed the activities of daily life self-questionnaire (ADL-SQ) and then identified which MS related symptoms caused them difficulty in completing the items on the ADL-SQ. Symptoms included pain, dexterity, stiffness/spasticity, tremor, weakness, muscle fatigue and abnormal sensations. Participants were also questioned on the frequency and intensity of these symptoms. They were further questioned on specific tasks they would like to achieve or maintain with treatment. Participants completed the questionnaire independently or with support due to MS related symptoms. Results: Dexterity (95%) was the most frequently self-reported associated problem with activities of daily living followed by


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weakness (86%). Nearly half of participants experienced problems with dexterity and weakness all the time (48%), closely followed by experiencing abnormal sensations all the time. The most frequently identified goal involved maintaining or developing better dexterity (42%). Conclusions: The preliminary findings from this small pilot questionnaire suggests the two most common MS related symptoms to be dexterity and weakness. Further development of the questionnaire may be useful in targeting future interventions for the upper limb in people with MS. The questionnaire could also potentially be developed as a clinical tool alongside other assessments to identify which symptoms to target, changes as a result of intervention and clinically meaningful changes.

Conclusion: Symptoms consistent with NP are common in MS, and in the current study almost two-thirds of respondents reported some such symptoms. Strong gradients of NP were observed across many clinical attributes, as well as for work status. 1. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 1997;48(2):332-8. 2. Foley PL, Vesterinen HM, Laird BJ, Sena ES et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain 2013;154(5):632-42. 3. Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 2007;68(15):1178-82.

Disclosure Tamsyn Street: has received a grant from the Salisbury Charitable Trust to complete this work. Ian Swain: Ian Swain is Professor of Clinical Engineering at Bournemouth University and is also Clinical Director and a shareholder in Odstock Medical Limited who manufacture the equipment and provide the clinical treatment that is the subject of this research. Paul Taylor: holds shares in OML, the manufacture of the device used in this study. P337 Neuropathic pain in multiple sclerosis C.A. Young1,2, R.J. Mills3, A. Tennant4, TONiC Study Group 1Walton Centre NHS Trust, 2University of Liverpool, Liverpool, 3Royal Preston Hospital, Preston, United Kingdom, 4Swiss Paraplegic Research, Nottwil, Switzerland Introduction: Neuropathic pain (NP) refers to pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [1]. Its prevalence in Multiple Sclerosis has been reported as over 28% [2]. It has been shown to have considerable impact upon the various domains of health status [3]. Methods: 722 people with MS were recruited into the early stages of the longitudinal TONiC study. Each completed a questionnaire booklet with a range of scales, including the Neuropathic Pain Scale (NPS) [1]. Results: Mean age was 48.9 years (SD 11.6) with mean disease duration of 11.5 years (SD 9.1). Just under a third (32.1%) had a progressive form of MS. Almost two thirds (62%) had an EDSS of 4.5 or greater. 65.9% reported some aspect of NP (i.e. NPS>0). No difference was found in the NPS by age (Kruskal Wallis; p>0.642) or by gender (Mann Whitney p=>0.584). However, a significant difference was found for duration, incorporating a u-shaped curve, such that with those whose duration was less than 5 years, and those exceeding 17 years experienced the highest NP (Kruskal Wallis p=0.045). A significant gradient was also observed for disease subtype, where those with Secondary Progressive MS (SP) showed the highest levels of NP (Kruskal Wallis; p < 0.001). This may account for the u-shaped pattern to duration, as those with SP have the longest duration (F 55.3; p=< 0.001). A strong gradient was also observed for EDSS (Kruskal Wallis; p < 0.001). Significantly higher levels of NP were also reported for those not working (Mann Whitney U; p= 0.001). For those with an NPS score in the upper third of its range, the odds of being in work, adjusted for age, was reduced by 3.8 times.

Disclosure Carolyn Young has received honoraria and travel expenses for scientific meetings and advisory boards, or grants from Bayer, Biogen Idec, Merck Serono, Genzyme, Motor Neurone Disease Association, MS Trust, National Institute for Health Research, Novartis, Roche, Teva, and Wellcome Trust. Roger Mills has received conference expenses from Biogen Idec and Teva. Alan Tennant : nothing to disclose. P339 Restless leg syndrome (RLS) in patients with multiple sclerosis (MS): evaluation of risk factors and clinical impact L. Lebrato Hernandez, M. Diaz Sanchez, M. Prieto Leon, N.A. Cerda Fuertes, J.L. Casado Chocan, A.J. Ucles Sanchez Neurology, Virgen del Rocío Hospital, Seville, Spain Background: RLS is a sensorimotor disorder characterised by a distressing urge to move the legs usually associated with uncomfortable sensation. We aim to examine the prevalence of RLS symptoms in MS patients, as the fulfillment of at least 2 of the 4 essential requirements included in the diagnostic criteria for RLS (Allen RP, 2003). We also evaluate the possible risk factors and clinical implications. Material and methods: We enrolled consecutive, unrelated MS patients diagnosed according to the McDonaldcriteria-2010. We excluded patients with other neurologic diseases or conditions associated with an increased risk of RLS (iron deficiency, renal failure, etc.). We used validated questionnaires to analyse the presence of RLS, its severity, possible risk factors and clinical impact (demographic variables, clinical forms of MS, EDSS, insomnia, fatigue, sleepiness, anxiety, depression, quality of life). Results: We included 120 MS patients (65.8% women), with a mean age of 39 years and a mean follow-up of 83 months. Thirty-four patients (28.33%) met at least two of the requirements of the RLS diagnostic criteria, all of them with a moderate to severe severity. Anxiety (p< 0.001), depression (p = 0.001), pain (p = 0.002), a relapse in the previous three months (p< 0.001) and disease duration (p=0.001) were associated with RLS in MS patients in univariate analyses. Multivariate logistical regression model showed that a recent relapse (p=0.012, OR 7.51 [IC:1.51-36.30]) and a shorter disease duration (p = 0.004, OR 0.98 [IC:0.97-0.99]) were associated with RLS symptoms.


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Poster Session 1, 22(S3) Finally, RLS symptoms may cause insomnia (p = 0.001), sleepiness (p = 0.01), cognitive impairment (p = 0.038) and poor quality of life (p = 0.037) in MS patients. Conclusions: The appearance of symptoms of RLS is common in patients with MS, usually with moderate-severe degree, causing an important comorbidity. Early identification and treatment of this sleep disorder may improve quality of life in MS patients. Disclosure L. Lebrato Hernández: nothing to disclose. M. Díaz Sánchez: nothing to disclose. M. Prieto León: nothing to disclose. N. Cerdá Fuertes: nothing to disclose. JL. Casado Chocán: nothing to disclose. AJ. Uclés Sánchez: nothing to disclose.

Disclosure Glen Doniger is an employee of NeuroTrax Corporation

P340 Multiple sclerosis and EDSS: the imprint of depression and subjective cognitive fatigue on cognitive function D. Golan1,2, J. Underwood3, M. Gudesblatt3, K. Wissemann3, M. Zarif3, B. Bumstead3, L. Fafard3, M. Buhse3,4, K. Blitz3, C. Sullivan5,6, J. Wilken6,7, G. Doniger8 1Department of Neurology, Carmel Medical Center, 2Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, 3South Shore Neurologic Associates, Patchogue, 4Stony Brook University, Stony Brook, 5Neuropsychological Associates, Fairfax, NY, 6Georgetown University Hospital, Department of Neurology and Washington Neuropsychology Research Group, Washington, DC, 7Neuropsychological Associates, Fairfax, VA, 8NeuroTrax Corporation, Bellaire, TX, United States Background: Multiple Sclerosis impacts cognition and is associated with fatigue and depression. However the association between subjective cognitive fatigue and objective cognitive dysfunction in people with MS (PwMS) is complicated and independent analyses of this relationship provide conflicting results. A major difficulty is that subjective fatigue seems strongly correlated with depression, which might also impair cognition. Objective: To explore the association between cognitive fatigue, depression, and cognitive function in a large PwMS cohort. Methods: PwMS completed a standardized computerized cognitive assessment battery (NeuroTrax) while cognitive fatigue impact (cognitive subscale of the Modified Fatigue Impact Scale) and depression (Beck Depression Inventory Questionnaires) were evaluated respectively, in the course of routine care. Results: 672 PwMS [Female: 506 (75%), EDSS 2.6±2, Education years: 14.6±2.7]. Both subjective cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: memory, executive function, attention, information processing and motor function. Therefore, a fatigue and depression sensitive global cognitive score (FDS-GCS) was defined as the average of these sub-scores. A significant interaction was identified between disease stage [low disability (EDSS 0-3.5) vs high disability (EDSS 4-8)] and depression on cognitive function [F(1,668)=4.1, P=0.05]. For patients with low physical disability (n=551), Linear regression modeling revealed significant independent correlations only between depression and

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FDS-GCS (β=-0.3, P=< 0.0001), while subjective cognitive fatigue had no independent correlation with objective cognitive function. Depression and subjective cognitive fatigue accounted for 12% of the variance in FDS-GCS. In highly disabled PwMS (n=121), neither fatigue nor depression were correlated with objective cognitive function. Conclusion: Cognitive function in PwMS with low physical disability is associated with depression, but is not independently associated with subjective cognitive fatigue. These factors explain only a small portion of the variance in computerized cognitive scores in PwMS.

Clinical assessment tools P341 Correlation between static and dynamic balance in people with multiple sclerosis: quantitative assessment using inertial sensor and force platform M. Pau, S. Caggiari, A. Mura, B. Leban, F. Corona, G. Coghe, M.G. Marrosu, E. Cocco University of Cagliari, Cagliari, Italy Background: Timed Up and Go test (TUG) is frequently used to assess balance and physical mobility, in people with MS (pwMS). In particular TUG summarizes the ability of an individual to change posture (from sitting to standing) and turn, as well as basic walking performance. This test is simple to administer, characterized by high reproducibility and reliability and is clinically relevant. However, its main limitation is that only the overall time needed to perform is considered. In recent times, inertial sensors have been used in TUG tests for neurological diseases. This approach represents a good option to objectively assess dynamic balance and mobility in a clinical setting. Aim: The study aims to assess the feasibility of use of inertial sensors to assess TUG performance in pwMS. Also, we want to correlate the TUG results with static balance abilities of the participants, quantitatively assessed using stabilometry. Methods: Fifty pwMS (EDSS range 2-6.5) were enrolled for the study. They were tested using a wearable inertial sensor attached at the lower lumbar level. Participants were asked to perform a TUG test, by standing up from a standard chair without arm-rest, walking for 3 m, performing a 180° turning, returning to the chair and sitting on it. The following parameters were investigated: sit to stand (and viceversa) time, intermediate and final turning time. In the same day, a stabilometric test was also carried out. On the basis of the center of pressure (COP) time-series acquired for a 30 s bipedal test, we calculated the following sway parameters: sway area, COP Path Length, COP displacements and velocities in anteroposterior (AP) and mediolateral (ML) direction. Pearson product-moment correlation coefficient was calculated to analyze correlation between TUG and stabilometric parameters. Results: Among the set of TUG parameters, only the duration of the first 180° turning was found significantly correlated with sway parameters (r=0.441 p=0.001 for ML displacement, r=0.491 p
0.7, >0.7, and < -0.6 were hypothesized, respectively. Responsiveness of Sagas was assessed by anchoring with a ⩾3-point change on the RMI scale and by calculating receiver operator characteristic curves (ROCs). Predictive validity was assessed by correlation of SaGAS scores with an decrease ⩾3 in RMI in the following 2 years. Results: 251 patients with MS were included (median EDSS 6, range 2-9; median age 56, median years since diagnosis 17, median stay duration 20 days). Before and after score differences were 1.49 units (95% CI 1.49-1.5) for RMI, 17.5 meters (14.5-20.5) for 2MWD, 0.75 units (0.6-0.9) for SaGAS 10. All measured correlation coefficients for SaGAS 10 exceeded hypothesized values: 0.76 for RMI, 0.84 for 2MWD, and -0.67 for EDSS. Responsiveness was moderate with an AUC of 0.60 (95% CI 0.48-0.72). Also a Spearman correlation of 0.33 was found between SaGAS 10 and the occurrence of an decrease of ⩾3 in RMI in the following 2 years. Conclusions: These results indicate that SaGAS 10 is a valid measure for effectiveness of rehabilitation. It is more sensitive to changes over the time span of an intervention than EDSS and easier to administer than MSFC. Being exclusively based on timed performance tests, SaGAS 10 is also less subjective than the EDSS. Its usage can therefore be recommended for routine rehabilitation assessment. Disclosure nothing to disclose P346 Cognitive-motor interference and cerebellar involvement in patients with multiple sclerosis O. Argento, B. Spanò, V. Pisani, C. Incerti, M. Bozzali, C. Caltagirone, U. Nocentini

IRCCS S. Lucia Foundation, Rome, Italy Background: Gait and cognitive impairments are two relevant clinical features of Multiple Sclerosis (MS). The separate assessment of both is important to address therapeutic approaches, but taking into account the interaction of them (cognitive-motor interference-CMI) could allow to compute the real disabling impact of the pathology. CMI correlates have been widely investigated in MS with sometimes different results due to neuroimaging methods, CMI procedures, and the involvement of different samples (Leone,2014). Cerebellum has recently shown to play an important role not only in balance control and coordination of voluntary movements but also in cognitive functions (Jacobi, 2015). Goal: Aim of this study is to clarify the characteristics of CMI in MS and the role of cerebellar lobules into this interfering process. Method: 20 MS and 18 matched controls (HC) underwent clinical assessments, Dual-Task procedure (DTp) and 3T-MRI. For each participant, a high-resolution T1-weighted magnetisation prepared rapid gradient echo sequence was acquired. DTp was composed by three 2-minutes trials in which subjects were asked to walk fast along a route. In trial-N subjects only had to walk, in trial-C they should add a backward counting task, in trial-W they should add a semantic Word List Generation task. Meters covered (Mt) and correct scores (CS) were collected for all subjects. Results: Both groups evidenced a decreased motor performance in both interfering conditions (trial-C and -W) but the effect of Trial-W in MS was significantly greater since involved the cognitive task too (p=.039). MS were then divided into high- and low-performers (HP>1SD; LP< 1SD) by using the HC’s z-score of trial-W’s CS. An ANOVA between HP, LP and HC’s grey matter volumes of all cerebellar lobules corrected for total volume showed a significant difference in Vermis lobules VIIIA (p=.015) and IX (p=.034). In particular HP showed a significant increased GM volume compared to HC for both lobules (p=.016; p=.034). Conclusions: The influence of a cognitive task on walking performance also exists in HC, but is significantly more evident in MS. Trial-W has showed to be the most suitable interfering DTp to detect CMI. We can speculate the existence of an initial cerebellar compensatory mechanism consequent to higher control request of supra-tentorial circuits in MS patients who maintain high cognitive performance. Then cerebellar GM loss leads to a more evident expression of motor CMI symptoms. Disclosure U. Nocentini has participated in an advisory board for Biogen. M. Bozzali took part in advisory boards for Roche and Lilly Pharmaceuticals. He is also involved in Clinical trials for TEVA Pharmaceutical. C. Caltagirone took part in an advisory board for Epitech. O. Argento, B. Spanò, C. Incerti and V. Pisani have nothing to disclose. P347 Elastography: a new diagnostic tool for the evaluation and quantification of multiple sclerosis spasticity


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Poster Session 1, 22(S3) G. Illomei Studio Radiologico del Corso, Cagliari University, Cagliari, Italy Purpose: The purpose of the study was to investigate the use of ultrasound (US) based elastography in evaluating the muscle fibers status and its changes after multiple sclerosis (MS) antispasticity treatment in order to assess its interest as a new imaging tool for the evaluation of spasticity. Methods and materials: Two groups of patient were enrolled: GROUP A, 110 MS patients. In all these patients spasticity examination was performed with the modif. Ashworth scale by a neurologist. All patients also underwent US elastography tests in their both legs quadriceps muscle fibers and images scored with the 0-5 RTHE scale. GROUP B, 50 MS patients starting Nabiximols (THC:CBD oromucosal spray) treatment for their resistant MS spasticity according to medical judgment and the Italian drugs agency (AIFA) criteria. All patients were non-responders to previous spasticity treatments. For each patient spasticity was evaluated by the 0-10 NRS scale at baseline and after 1 month (trial period). Participants’ both legs quadriceps muscle fibers were examined through US elastography and images scored with the 0-5 RTHE scale. The study was approved by the local Ethics committee. Results: GROUP A: there was full concordance between the Ashworth scale evaluation scores and the US elastography scores. However, patients classified as score “0” in the Ashworth scale could be further split by US elastography into “0a” (total normality of muscle fibers elasticity) and “0b” (initial compromising of muscle fibers elasticity). GROUP B: Initial responders to Nabiximols (pre-defined as an improvement ⩾20% in their 0-10 NRS spasticity score vs. baseline) after the 1 month trial period were 65% of sample. They had a mean -1.88 NRS score reduction and also a -1.95 change in their US elastography 0-5 mean RTHE score, while the 35% of patients not reaching the 20% NRS clinical initial response threshold improved their mean NRS score by -0.55 and their mean RTHE score by a -0.95, showing a correlation between these subjective and objective scales changes. Conclusion: US elastography could be the new objective gold standard to evaluate MS muscle spasticity, in early or late periods and also to evaluate the efficacy of antispasticity therapy. Disclosure Nothing to disclose P348 National Finnish Treatment Register for MS patients - first results M. Soilu-Hänninen1, P. Hartikainen2, A. Remes2, R. Vanninen2, M.-L. Sumelahti3, M. Ukkonen3, J. Kriuger4, S. Atula5, P. Tienari5, K. Koivisto6, N. Oksala7, J. Ruutiainen8, I. Elovaara3 1Division of Clinical Neurosciences, Turku University Hospital, Turku, 2University of Eastern Finland, Kuopio, 3University of Tampere, Tampere, 4University of Oulu, Oulu, 5University of Helsinki, Helsinki, 6Seinäjoki Central Hospital, Seinäjoki,

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Technology Development Project, Turku, 8Finnish Neuro Society, Masku, Finland Background: The incidence and prevalence of MS in Finland are high and the structure of the Finnish health care system with publicly funded health care program is ideal for data basing of health administrative data. However, Finland has been the only Scandinavian country without a national MS register. To meet this need, Finnish Neurological Association assigned a steering board to develop an MS-registry in Finland in January 2011. Methods: A registry software was developed with a private company, StellarQ. Each hospital joining the registry makes a contract with StellarQ and forms a closed registry of their own. National register data is obtained by combining anonymized data from each closed hospital registry. Results: By April 2016 all 5 university hospitals and 6 central hospitals have joined the register. An initially internet based registry software service has been integrated into the electronic patients files during 2016 in most participating hospitals. Date of birth, gender and date of MS diagnosis (ICD-code G35) have been registered from altogether 6304 MS patients and 548 patients with a clinically isolated syndrome, CIS (ICD-code G37.9). A total of 71 % of the MS patients and 64 of CIS patients are female. Complete retrospective data sets of EDSS evolution, relapses, corticosteroid pulses and medication side effects and reasons for medications discontinuations are presented from approximately 400 patients from Turku University Hospital, that was the first one to start using the registry in August 2014. A method to import predefined structured brain and spinal cord MRI data into the registry has been piloted in the Kuopio University Hospital. A patient application for patients to import data of their symptoms and wellbeing into the closed hospital register to assist their doctor in therapy decision making will be piloted in Turku University Hospital during autumn 2016. Conclusions: The Finnish MS registry has been successfully launched in all university hospitals and most central hospitals in Finland. Integration of the register into the electronic patient files will provide a unique avenue for automated structured data capture of MS in Finnish health care system in near future. Disclosure Niku Oksala is an employee of StellarQ. The other authors have been nominated into the steering board by the Finnish Neurological Association and have nothing to disclose. The development of the registry software has been financially supported by Biogen Idec, Genzyme, Novartis, Roche, Teva and the Finnish Funding Agency for Technology and Innovation (Tekes). P349 Efficient fine-grained video-based rating of motor dysfunction using setwise comparison S. Steinheimer1, J. Dorn2, C. Morrison3, A. Sarkar3, M. D’Souza4, J. Boisvert2, R. Bedi2, J. Burggraaff5, P. Kontschieder3, F. Dahlke2, A. Sellen3, B. Uitdehaag5, L. Kappos6, C.P. Kamm1


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Inselspital, Bern University Hospital and University of Bern, Bern, 2Novartis Pharma AG, Basel, Switzerland, 3Microsoft Research, Cambridge, United Kingdom, 4University Hospital Basel, Basel, Switzerland, 5Neurology, VU University Medical Center, Amsterdam, The Netherlands, 6Neurology, University Hospital Basel, Basel, Switzerland Objective: To establish video-based setwise comparison as a more efficient way than pairwise comparison to rate severity of motor dysfunction, while maintaining comparable levels of reliability and validity. Background: To train machine learning algorithms, high-quality ground truth data is needed. In the context of developing Assess MS, motor dysfunction has to be rated in a large number of patient videos in an efficient and consistent way. We have previously shown that video-based pairwise comparison of videos enables more reliable and fine-grained rating of motor dysfunction than established ordinal scales like the Expanded Disability Status Scale (EDSS). However, it is too time consuming for large data sets. Setwise comparison was developed to address this problem. Setwise comparison asks neurologists to rank sets of eight videos from least to most disabled using an optimized touch interface. A subset of videos appear in multiple sets enabling a complete ranking of all patient videos using the Trueskill scoring algorithm. This approach scales linearly (tenfold increase in the number of videos leads to a tenfold increase in sets), making it more efficient than pairwise comparison, which scales quadratically (tenfold increase in the number of videos leads to a hundredfold increase in pairs). Methods: Eight neurologists rated a set of 40 multiple sclerosis (MS) patient videos of the finger-to-nose test using both pairwise and setwise comparison techniques. Reliability was assessed by the intra-class correlation coefficient (ICC). Validity was assessed by Pearson correlation to EDSS upper-extremity subscores and the Nine-hole-peg-test (9HPT). Efficiency was assessed by comparing the time needed for ratings. Results: ICC was 0.7 for pairwise and 0.83 for setwise comparison. Correlation to tremor/dysmetria score of the Neurostatus was 0.79±0.08 (pairwise) and 0.83±0.06 (setwise) and correlation to the 9HPT was 0.63±0.10 (pairwise) and 0.73±0.07 (setwise). The time needed to rate 40 videos was 78±15 minutes (pairwise) and 24±8 minutes (setwise). Conclusions: Setwise comparison is substantially more efficient than pairwise comparison, with comparable validity and higher interrater reliability. It reflects fine-grained clinical judgement and is efficient enough even with larger data sets to be used in clinical research beyond validating clinical scales. Disclosure S. Steinheimer: received travel support from Bayer AG and Merck and has received honoraria for consulting from Teva and Merck. M. D’Souza: received travel support from Bayer AG, Teva and Genzyme and research support from the University of Basel. J. Dorn: employee of Novartis Pharma AG. C. Morrison: employee of Microsoft Research. A. Sarkar: employee of Microsoft research. R. Bedi: employee of Novartis Pharma AG. J. Burggraaff: Novartis Pharma AG (Basel, CH) for one research project.

F. Dahlke: employee of Novartis Pharma AG. P. Kontschieder: employee of Microsoft Research. A. Criminisi: employee of Microsoft Research. A. Sellen: employee of Microsoft research. B. Uitdehaag: received personal compensation for consulting, serving on a scientific advisory board from: Biogen Idec, Novartis, EMD Serono, Teva Pharmaceuticals, Genzyme and Roche. L. Kappos: My institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for my activities as principal investigator and member or, chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech,, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva. I have received grants from the Swiss MS Society, Swiss, National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. C. P. Kamm: has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Bayer Schweiz AG, Teva, Merck, Genzyme, Roche and the Swiss MS Society (SMSG). P350 Validity of mobility measures in multiple sclerosis, according disability level: a European RIMS multi-center study I. Baert1, C. Keytsman1, K. Rasova2, A. Heric-Mansrud3, R. Ehling4, I. Ellorriagia5, U. Nedeljkovic6, D. Backus7, A. Kalron8, A. Tacchino9, B. Gebara10, H. Vandenbroek11, G. Stachowiak12, T. Smedal13, K. Gusowski14, D. Cattaneo15, M. Nijs16, J. Hebert17, P. Feys1 1University Hasselt, Diepenbeek, Belgium, 2Charles University and General Faculty Hospital, Prague, Czech Republic, 3Multiple Sclerosis Center, Hakadal AS, Hakadal, Norway, 4Reha Zentrum Münster Gröben, Gröben, Austria, 5Eugenia Epalza Rehabiltation Center Bilbao, Bilbao, Spain, 6Clinical Center in Belgrado, Belgrado, Serbia, 7Shepherd Center in Atlanta, Atlanta, GA, United States, 8Sheba Medical Center, Tel Hashomer, Israel, 9FISM Scientific Research (AISM), Genova, Italy, 10National Multiple Sclerosis Center Melsbroek, Melsbroek, 11AZ Klina, Campus De Mick, Rehabilitation, Brasschaat, Belgium, 12John Paul II Rehabilitation Centre for People with Multiple Sclerosis, Borne Solinowo, Poland, 13Haukeland University Hospital (Norwegian Multiple Sclerosis Competence Centre and Department of Physiotherapy), Bergen, Norway, 14Neurological Rehabilitation Centre Quellenhof, Bad Wildbad, Germany, 15Don Gnocchi Foundation Milano, Milan, Italy, 16Rehabilitation and MS Center Overpelt, Overpelt, Belgium, 17University of Colorado - Anschutz Medical Campus, Aurora, CO, United States Background: Mobility difficulties (including walking and balance) are common and important for persons with multiple sclerosis (pwMS). In order to properly evaluate disability, disease progression or treatment efficacy, it is necessary to consider psychometric properties of measures. Aim: To investigate convergent validity of mobility measures in pwMS, according disability level.


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Poster Session 1, 22(S3) Methods: A convenience sample of 231 pwMS from 17 centers across Europe and US were measured on 10 clinical scales (CLINROs) and 4 self-reported questionnaires (PROs). Disability subgroups were made according EDSS-level: mild (EDSS 2-4), moderate (EDSS 4.5-5.5), severe (EDSS 6) and very severe (EDSS ⩾6.5). Spearman’s rank and Pearson correlation coefficients were calculated, as appropriate. Results: Participants are representative of the MS population (65% female, mean age±SD of 40.1±10.3 years , mean time±SD since diagnosis of 12.1±8.2 years, median EDSS score of 4.5 (IQR 3.5-6) and type of MS of 54% relapsing remitting, 26% secondary progressive, 17% primary progressive, 3% unknown). Overall, good to excellent correlations were found between timed measures (Timed 25 foot walk, Timed Up and Go, Timed Up and Go cognitive, 2 minutes walk test, Four Square Step Test). Correlations were mostly moderate between Berg Balance Scale, Dynamic Gait Index, 5 times Sit-to-Stand, modified 5STS and other CLINROs. Between CLINROs and PROs correlations were fair to moderate and between mutual PROs fair to good. According disability, highest correlations were found in the mild disability group, especially between mutual CLINROs, and between mutual PROs. Correlations between CLINROs and PROs were generally lower than between mutual CLINROs, especially in the severe disability group. Validity between mutual PROs varied strongly between disability groups. All disability groups showed high correlations between timed measures, and between MS walking scale-12 and MS impact scale-29 physical. Discussion: CLINROs measuring performance do not fully reflect PROs measuring patients perception and behavioral consequences of mobility deficits on the impact of daily life. This is surely true in the more disabled pwMS. Although different CLINROs imply diverse components of mobility (walking, stepping, turning, transfers, … ) mutual correlations were moderate to good in the whole group and in the mild disability group. Patients’ disability level has an influence on the choice of mobility measures.

relapsing forms of MS (RMS). TSQM measurement performance has yet to be evaluated in routine RMS clinical practice. Objective(s): To evaluate the measurement performance of the TSQM (version 1.4), using traditional psychometric methods and Teri-PRO (NCT01895335) study data. Methods: Teri-PRO included patients with RMS (n=1000) starting treatment with teriflunomide 7 mg or 14 mg as per local labelling. TSQM data were collected at baseline and Week 48/end of treatment (EOT); data for Week 48/EOT were used. Aspects of 5 measurement properties were examined: data completeness (item-level missing data); scaling assumptions (item means, variances and item-total correlations corrected for overlap, exploratory factor analysis [EFA]); scale-to-sample targeting (score distributions: floor=lowest/ceiling=highest satisfaction); internal consistency reliability (Cronbach’s α, homogeneity coefficients); construct validity (within-scale/with other variables). Results: Item-level missing data were low (< 1%). Domain scores were computable for ⩾88% of patients. Scaling assumptions were satisfied (similar item means and variances; item-domain correlations 0.63-0.90; EFA supported item groupings). Scale-to-sample targeting was adequate overall: domain scores exceeded scale midpoints, floor scores noted in ⩽3% of patients. However, ceiling effects were 57% for Convenience and 58% for Side Effects. Internal consistency reliability was high (Cronbach’s α ⩾0.86, homogeneity coefficients ⩾0.67) and standard errors of measurement were small (5.49-7.02). Construct validity was supported by the characteristics of between-domain correlations (0.17-0.69). Scores were not biased by sample characteristics (correlations -0.23-0.013). Conclusions: This analysis of TSQM performance, using TeriPRO “real-world” data, complements our prior analysis in TENERE, and gives similar findings: good overall measurement properties with the potential to improve scale-to-sample targeting. Together, our analyses support the TSQM as a useful measure of treatment satisfaction in patients with RMS. Disclosure

Disclosure All authors have nothing to disclose. P351 Measuring treatment satisfaction in patients with RMS in the real world: is the TSQM fit for purpose? An evaluation using Teri-PRO study data J. Hobart1, K. Thangavelu2, S. Hass2, S. Chowdhury3, P. Rufi4 1Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom, 2Sanofi Genzyme, Cambridge, MA, United States, 3Cytel, Pune, India, 4Sanofi Genzyme, Chilly-Mazarin, France Background: The Treatment Satisfaction Questionnaire for Medication (TSQM) has 14 items and generates 4 domain scores: Effectiveness (3 items); Side Effects (5 items); Convenience (3 items); Global Satisfaction (4 items). Although not developed specifically for use in MS, the TSQM demonstrated good measurement performance in an MS clinical trial setting, the TENERE phase 3 trial of teriflunomide (NCT00883337) in patients with

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Study supported by Sanofi Genzyme. JH: Honoraria, consulting fees (Acorda, Biogen Idec, Critical Path Institute, LORA group, MAPI Research Institute, Sanofi Genzyme); license fee payments or royalty payments (Plymouth University receives fees for the use of rating scales developed as part of author’s research); research support (Biogen Idec, Novartis, Merck Serono). KT: Employee of Sanofi Genzyme. SH: Employee of Sanofi Genzyme. SC: Nothing to disclose. PR: Employee of Sanofi Genzyme. P352 Multivariate analysis of time and frequency domain parameters of baroreceptor sensitivity, heart rate and blood pressure variability in multiple sclerosis compared to age and sex matched controls - a non-invasive autonomic function analysis E. Barin1, F. Shirbani1, Y.-C. Lee2, A. Fontes-Villalba2, K. Ng2, M. Butlin3, A. Avolio3, J.D.E. Parratt2


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Macquarie University Health Sciences Centre, Sydney, 2Neurology, Royal North Shore Hospital, St Leonards, 3Biomedical Sciences, Macquarie University, Sydney, NSW, Australia Background: The mechanism whereby cardiac autonomic dysfunction relates to prognosis and extent of disease in Multiple Sclerosis (MS) is unclear. Measures of baroreceptor sensitivity (BRS) provide a means to quantify cardiovascular control mediated by autonomic tone. Aims: To assess differences in short-term beat-to-beat non-invasive BRS, as well as heart rate variability (HRV) and systolic blood pressure (SBP) variability, in MS subjects compared with age and sex matched controls. Methods and results: 46 subjects (23 MS, 23 controls) were studied using a finger cuff pressure device (Edwards Nextfin®). 5 minute recordings of heart rate and blood pressure (BP) were obtained and BRS curves derived by sequence techniques and spectral methods. Vasomotor parameters, HRV, biometrics, electrocardiograms, time-based HRV and power spectral analysis (PSA) of HRV at very low frequencies (VLF< 0.04 Hz), low frequencies (LF 0.04 - 0.15 Hz) and high frequencies (HF 0.15 - 0.4 Hz) were measured. BRS by frequency technique is calculated by the square root of power spectral density of HRV/ power spectral density of SBP variability which is termed Modulus. The average of this Modulus in each frequency band is termed the alpha index. Coherence between SBP variability and HRV was measured and the average calculated for each frequency band. The average age in the MS group was 38±12 years, 15 were females, and average disease duration was 10±8 years. The average age in the control group was 38±12 years (15 females). For a combined set of 65 variables and autonomic function parameters, the Mann-Whitney U Test was used to compare inter-group differences, and Chi-squared for comparison of proportions, with significance set at p< 0.05. Multinominal Logistic Regression (MATLAB) was applied to 10 parameters identified to be significantly different between the groups on univariate analysis. After multivariate analysis, two independent variables emerge: BRS spectral frequency by ⩾0.5 coherence (p=0.04) and mean Modulus of HF frequency variability of systolic BP (p=0.04). Conclusions: Systemic autonomic function analysis demonstrates that spectral BRS and spectral SBP distinguish MS patients from age and sex matched controls. These results suggest that BRS and BP analysis by PSA techniques provide a potential method to monitor patients with MS. Disclosure E Barin: nothing to disclose. F Shirbani: nothing to disclose. YC Lee: nothing to disclose. A Fontes-Villalba: has received educational sponsorship from Merck Serono and Genzyme.. K Ng: nothing to disclose. JDE Parratt: nothing to disclose M Butlin: nothing to disclose. A Avolio: nothing to disclose.

P353 The expanded timed up-and-go (ETUG) is a sensitive measure for predicting falls in multiple sclerosis patients C.B. Vaughn1,2,3, K. Kavak2,3, S. Gandhi4, A. Sanai3, D. Jakimovski4, S.E. Bennett1,3,5, M. Ramanathan1,6, R.H.B. Benedict1, R. Zivadinov1,4, B. Weinstock-Guttman1,2,3 1Neurology, University at Buffalo, State University of New York, 2New York State Multiple Sclerosis Consortium, 3Jacobs Comprehensive MS Treatment and Research Center, 4Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 5Rehabilitation Science, 6Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States Background: Falls are extremely prevalent occurrences among multiple sclerosis (MS) patients. Approximately 40-60% of MS patients will report a fall in any given year and at least half of those falls will result in an injury. It is important, therefore, to identify measures that can better assess patients’ risk for falling and provide timely appropriate preventive therapies. Objective: Our objective was to determine whether the Expanded Timed Up-and-Go (ETUG) and/or its individual components can be used to predict whether individuals are at risk for falling. Methods: Participants for our study are part of a larger, ongoing Cardiovascular, Environmental and Genetic (CEG) study that aims to enroll 350 patients with MS or clinically isolated syndrome (CIS) and 150 healthy controls (HC). Our present analyses include 66 participants; 49 MS/CIS patients and 17 HC subjects. Participants were evaluated with Kurtzke Expanded Disability Status Scale (EDSS), the Timed 25-Foot walk (T25FW) and the ETUG. Subjects who reported falls during the past year were compared to subjects who did not with regards to demographic information, mobility and disability measures. Receiver operating characteristic (ROC) analyses were carried out to establish cutoff scores maximising sensitivity and specificity that were later used to determine whether ETUG and/or its timed components were of value in predicting which participants had reported falls. Results: The average age for MS/CIS patients was 55.9 years (SD=12.0) and 51.0 (SD=17.5) years for HC. Both groups were predominantly female (81.6% in the MS/CIS group and 70.6% in the HC). For MS/CIS patients who took longer than 17.89 seconds to complete the ETUG, they were 13.87 times as likely to fall compared to those who took less time (p-value=0.001). Each of the 6 component mobility measures of the ETUG was able to significantly differentiate fallers from non-fallers in MS/CIS patients (all p-values ⩽0.005). Four HC reported falls (23.5%), however the only component of the ETUG that was able to distinguish fallers from non-fallers in HCs at almost significant levels was the second walk (p=0.057). Conclusion: The ETUG and its subsidiary components are sensitive measures for predicting which patients reported a fall in the past year. Though additional studies are needed to confirm our findings, the ETUG is an easy-to-administer, objective measure that may be able to predict falls in at-risk MS patients. Disclosure Caila Vaughn: Nothing to disclose. Katelyn Kavak: Nothing to disclose.


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Poster Session 1, 22(S3) Sirin Gandhi: Nothing to disclose. Ahmed Sanai: Nothing to disclose. Dejan Jakimovski: Nothing to disclose. Susan Bennett has participated in speakers´ bureaus and on advisory boards for Acorda Therapeutics. Murali Ramanathan has received research funding from the National Multiple Sclerosis Society and the National Science Foundation. He receives royalty income from a self-published textbook. Ralph Benedict received research support from Biogen, Novartis, Genzyme, Acorda and Mallinckrodt and provides consultation for Biogen, Genetech, Teva, Novartis, and Sanofi, and conducts CME for EMD Serono. Robert Zivadinov has received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees and has received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Bianca Weinstock-Guttman has received personal compensation for consulting, speaking and serving on a scientific advisory board for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Questcor and Genzyme& Sanofi and has received financial support for research activities from NMSS, NIH (not for the present study), ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Genzyme. P354 Expanded timed up-and-go (ETUG) test is associated with development of central atrophy over 5 years in multiple sclerosis patients D. Jakimovski1, B. Weinstock-Guttman2, N. Bergsland1,3, S. Gandhi1, A. Sanai2, C. Kolb2, R. Benedict2, R. Zivadinov1,4 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States, 3IRCCS ‘S.Maria Nascente’, Don Gnocchi Foundation, Milan, Italy, 4MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: Walking difficulties are among most limiting manifestations of multiple sclerosis (MS). Assessment tools that can evaluate walking disability are essential in management of MS patients. The Expanded Timed Up-and-Go (ETUG) test has been proposed as being more sensitive and clinically useful in assessing mobility. The relationship between walking impairment and brain MRI outcomes still remains unclear. Objective: To determine if ETUG and/or its subcomponents are associated with changes in longitudinal MRI outcome measures over 5 years in MS patients. To compare ETUG association with MRI measures vs. other widely used ambulatory assessments. Methods: The subjects are part of a prospective, ongoing Cardiovascular, Environmental and Genetic (CEG) study. We

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included 37 MS patients who were assessed at baseline and at follow-up using 3T MRI scanner that did not undergo major hardware or software upgrades. At both time points, an experienced neurologist applied Expanded Disability Status Scale (EDSS) and Timed 25-Foot Walk (T25FW) test as part of full clinical examination. The ETUG test was introduced at the follow-up clinical visit. Correlation coefficients were calculated by Spearman’s rank order correlation. Results were considered statistically significant at P < 0.05. Results: Three out of six individual components and total ETUG test showed a significant association with change in ventricular cerebrospinal fluid (vCSF) volume over the 5-year follow-up. These included: turn around (r=0.43, p=0.008), total ETUG (r=0.4, p=0.013), gait initiation (r=0.4, p=0.013) and second walk (r=0.35, p=0.034). ETUG demonstrated concurrent validity with T25FW and EDSS (p< 0.001). ETUG (p=0.013) showed a more significant relationship with change in vCSF volume over 5-years compared to T25FW test (p=0.024) and EDSS (p=0.08). Conclusion: ETUG and its subcomponents showed greater associations with development of central atrophy compared to T25FW test and EDSS. ETUG should be added into the clinical routine to complement the assessment of MS patients. Larger sample size is needed to confirm our preliminary results. Disclosure Dejan Jakimovski, Sirin Gandhi and Ahmed Sanai have nothing to disclose. Bianca Weinstock-Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Channa Kolb has received personal compensation for activities with Teva Neuroscience, Biogen Idec and EMD Serono as a speaker and scientific advisory board member Ralph Benedict has acted as a consultant or scientific advisory board member for Bayer, Biogen Idec, Actelion, and Novartis. He receives royalties from Psychological Assessment Resources, Inc. He has received financial support for research activities from Shire Pharmaceuticals, Accorda and Biogen Idec Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus and IMS Health. P355 Internal construct validity and reliability of the neuropathic pain scale in multiple sclerosis: a rasch analysis C.A. Young1,2, R.J. Mills3, A. Tennant4, TONiC Study Group 1Walton Centre NHS Trust, 2University of Liverpool, Liverpool, 3Royal Preston Hospital, Preston, United Kingdom, 4Swiss Paraplegic Research, Nottwil, Switzerland Introduction: Neuropathic pain (NP) refers to pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [1]. It may manifest in different ways, for example as


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tingling or burning. It is important to have confidence in the assessment of such pain, particularly where Patient Reported Outcome Measures (PROM’s) are used for such a purpose. One widely used PROM is the Neuropathic Pain Scale (NPS) [1]. It consists of 10 Numeric Rating Scale (NRS) responses, as well as additional questions asking the patient to describe aspects of the pain. Previously, classical test theory approaches have been used to demonstrate the reliability and validity of the NPS in MS [2]. The current study examines the scale from a modern (Rasch) psychometric perspective. Methods: 722 people with MS completed a questionnaire booklet including the NPS. Data from this scale were fit to the Rasch model to ascertain if the NPS is compliant with modern standards for measurement, including transformation to interval scaling. Results: Initial fit of the NPS to the Rasch model among those reporting pain was poor (Chi Square 355 (df(90); p=< 0.001). However, several pairs of items breached the local independence assumption (for example intensity and sharpness), indicating some redundancy in the scale. Consequently, the items were grouped into two testlets (to absorb the dependency) and fit to the model was then good (Chi-Square 21.8 (df 18); p= 0.24). The unidimensionality test showed a significant difference of 5.19% (95%CI: 3.6-6.8%) in the estimates derived from the two sets, supporting unidimensionality. The latent estimate derived from the procedure accounted for 93% of the total variance. Reliability (α) was 0.83. Conclusion: The NPS showed good internal construct validity and reliability when its data were fit to the Rasch model. This analysis provides an interval scaled latent estimate which can be used to examine the relation of neuropathic pain to other disease factors, such as disease type and severity, and in models exploring the relationship of neuropathic pain to quality of life. 1. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology. 1997;48(2):332-8. 2. Rog DJ, Nurmikko TJ, Friede T, Young CA. Validation and reliability of the Neuropathic Pain Scale (NPS) in multiple sclerosis. Clin J Pain. 2007;23(6):473-81. Disclosure Carolyn Young has received honoraria and travel expenses for scientific meetings and advisory boards, or grants from Bayer, Biogen Idec, Merck Serono, Genzyme, Motor Neurone Disease Association, MS Trust, National Institute for Health Research, Novartis, Roche, Teva, and Wellcome Trust. Roger Mills has received conference expenses from Biogen Idec and Teva. Alan Tennant: nothing to disclose. P356 A pilot study comparing the MSFC score to the DAM application, a self-assessment solution for MS patients S. Medjebar1, C. Louapre2,3, R. Debs2, C. Peczynski1, E. Maillart2,4 1Ad Scientiam, 2Department of Neurology, Pitié Salpêtrière Hospital, APHP, 3CIC_1422, ICM - Institut du Cerveau et de la Moelle épinière, 4WP11, IHU-A-ICM, Paris, France

Background: Multiple Sclerosis Functional Composite score (MSFC) is one of the gold standard for multiple sclerosis (MS) patient clinical evaluation. However, its practical implementation is not always optimal as it can prove to be very time consuming. Moreover, it often constrains the range of tests used and is not a particularly good marker for patient real life disability status. A mobile application called Digital Self-Assessment for Multiple Sclerosis (DAM) was developed in order to replicate each of MSFC tests available in order to assess MS progression in the patient environment. Objective: To establish a correlation between application DAM and MSFC. Methodology: DAM was created using the Apple open source Research Kit. An ongoing pilot study is currently recruiting 30 patients with an established diagnosis of MS. Patients are selected during a consultation at the Neurology department of the PitiéSalpêtrière Hospital (France). Each patient is given access to DAM on their own or a provided iPhone. During the enrolment visit, patients have to complete a MSFC and DAM evaluation (V0). Through a push-notification on their phone, patients are reminded to perform two DAM evaluations at home at days 30 (V1) and 60 (V2). At day 90 (V3), they have to come back to hospital for a second MSFC and DAM evaluation. Interim analyses were performed in April 2016 using correlation tests after 24 V0 and 12 V1 were completed. A comparison between each test of DAM and MSFC was done in order to evaluate the reproducibility and robustness of DAM tests. Results: Reproducibility of MSFC on smartphone seems to be excellent (correlation between MSFC V0 and DAM V0 Z-scores, r=0.79, p< 10-5). Timed 25-Foot Walk (T25-FW, r=0.68, p< 10-3) and Paced Auditory Serial Addition Test (PASAT, r=0.65, p< 10-3) have the best reproducibility. Robustness of DAM seems to be good (correlation between DAM V0 and V1 at day 30, r= 0.68, p< 0.05), particularly for the 9HPT (r=0.77, p< 10-2) and PASAT (r=0.67, p< 0.05). Conclusions: These results reinforce the idea that a smartphone application would be a good self-assessment tool for patients with MS. A new version of the application taking into accounts these interim results is under development. Qualitative insights from patients and clinicians will also be used to enhance usability and clinical relevance with updated or new tests. Further validation will also be required using a larger sample size to improve the confidence level. Disclosure S Medjebar: affiliate of Ad Scientiam C Louapre: travel grant from Genzyme and Novartis R Debs: nothing to disclose C Peczynski: affiliate of Ad Scientiam E Maillart: conference fees from Teva, Biogen, Genzyme, Merck and Novartis / travel Grant from Teva, Biogen, Novartis and Genzyme Ad Scientiam: privately held research company which received a research grant from Roche France for the conduct of this study P357 Validating a participant-led computerised cognitive battery in people with multiple sclerosis L. Connell, R. Daws, A. Hampshire, R. Nicholas, J. Raffel Imperial College London, London, United Kingdom


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Poster Session 1, 22(S3) Introduction: The majority of people with MS (pwMS) experience cognitive impairment (CI), which can result in a major impact on their life goals and achievements. While CI is an important outcome measure, it is insufficiently tested in both a clinical and research environment mainly because traditional neuropsychological batteries are expensive in time and resources to administer. There is a need for validated participant-led computerised tools to measure CI in pwMS at repeated time points from the research, clinical, and home environment. The Cambridge Brain Sciences (CBS) computerised cognitive battery consists of 12 cognitive tasks based on standard neurological tests, optimised to perform equally regardless of computer specifications. It has been validated in a ~100,000 cohort of the general population. Aims: To determine whether CI in pwMS can be reliably assessed using a participant-led computerised cognitive battery by validating the CBS battery against traditional face-to-face cognitive testing. To determine whether the CBS computerised battery can detect longitudinal fluctuations in CI related to monthly natalizumab infusions. Methodology: Both the Minimal Assessment of Cognitive Function in MS (MACFIMS) and the CBS battery were administered in lab to over 60 pwMS and 30 healthy controls. Study participants then undertook the CBS battery at pre-determined intervals from the home environment. Results: CI measured by the CBS computerised battery correlates well with CI measured by MACFIMS. Correlations between specific domains of CI are present between batteries. Longitudinal results will be presented, to determine whether CBS can detect fluctuations in CI related to the timing of monthly infusions of natalizumab treatment. Conclusion: The CBS computerised battery can measure CI in pwMS, and correlates with traditional face to face testing. It has the capability to measure CI at repeated time points with minimal resources required, and should be further developed as a participant-led tool for use in the research, clinical, and home environment. Disclosure Laura Connell: nothing to disclose Richard Daws: nothing to disclose Adam Hampshire: nothing to disclose Richard Nicholas: Bayer, Biogen, Genzyme, Merck Serono, Roche - honorarium for speaking, advisory boards. Biogen, Genzyme, Novartis - funds for organising education, staff. Biogen, Novartis - Principal investigator. Joel Raffel: nothing to disclose P358 The associations between commonly used walking measures and physical and psychosocial outcomes in persons with multiple sclerosis S. Ozakbas, T. Kahraman, H. Limoncu, P. Yigit, O. Ertekin, Z. Mehdiyev Dokuz Eylül University, Izmir, Turkey Walking disturbance is one of the most common complaints of persons with multiple sclerosis (MS). Regular walking assessment is an important component of patient management and requires instruments that are appropriate from the clinician’s and

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the patient’s perspectives. The MS Walking Scale-12 (MSWS-12) measures walking ability from the patients´ perspective and the Timed 25-Foot Walk (T25FW) is the best-characterized objective walking test from the clinician’s perspective. Although these two measures are very commonly used in research and clinical practice in persons with MS, there is a lack of evidence about their associations with physical and psychosocial outcomes. This study examined the associations between MSWS-12, T25FW and cognitive function, upper limb function, health-related quality of life (HRQoL), depression, sleep quality, and fatigue. In total, 194 persons with MS (122 female) participated in this cross-sectional study. Disability level was assessed with the Expanded Disability Status Scale (EDSS). The cognitive function was examined with the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-2 (CVLT2), Brief Visuospatial Memory Test-Revised (BVMT-R), Paced Auditory Serial Addition Test (PASAT), and MS Neuropsychological Questionnaire-patient and informant (MSNQ-P, MSNQ-I). The upper limb function, depression, sleep quality, fatigue, and HRQoL were assessed with the Nine-Hole Peg Test (9HPT), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), Fatigue Impact Scale (FIS), and Short Form-36 (SF-36), respectively. The MSWS-12 was significantly correlated with the number of relapses (r=.278), EDSS (r=.590), 9HPT (r=.475), SDMT (r=.437), CVLT2 (r=.230), BVMT-R (r=.232), PASAT (r=.293), MSNQ-P (r=.499), FIS (r=.543), physical and mental component scores of SF-36 (r=.759 and .394), ESS (r=.431), and BDI (r=.413) (all p< 0.05). The T25FW was significantly correlated with the number of relapses (r=.355), EDSS (r=.214), 9HPT (r=.259), SDMT (r=.203), CVLT2 (r=.179), PASAT (r=.210), physical component score of SF-36 (r=.199) (all p< 0.05). However, there was no significant correlation between the T25FW and BVMT-R, MSNQ-P and MSNQ-I, FIS, mental component score of SF-36, ESS and BDI (p>0.05). This study suggests that the MSWS-12 was more informative measure because of its high number of associations with physical and psychosocial outcomes compared to the T25FW. Additionally, the MSWS-12 was a powerful indicator of HRQoL. Disclosure Serkan Ozakbas: nothing to disclose Turhan Kahraman: nothing to disclose Hatice Limoncu: nothing to disclose Pinar Yigit: nothing to disclose Ozge Ertekin: nothing to disclose Zaur Mehdiyev: nothing to disclose P359 Timed 25-foot walk instead of EDSS: does it make difference defining NEDA? J. Martins1, R. Samões1, I. Moreira1,2, A. Bettencourt3,4, E. Santos1,4, A. Martins Silva1,2,4 1Neurology Department, 2Laboratory of Neurobiology of Human Behavior, Centro Hospitalar do Porto - Hospital de Santo António, 3Immunogenetics Laboratory, 4Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal


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Introduction: With increasingly effective therapies for the treatment of relapsing remitting multiple sclerosis (RRMS), status of “no evidence of disease activity” (NEDA) has become the main goal. Whether EDSS is sensible enough to reflect disease progression has been a topic of discussion. Objective: The aim of this study was to determine if the timed 25-foot walk (T25FW), the 9-hole peg test (9HPT) or the symbol digit modalities test (SDMT) change the classification of disease activity comparing to EDSS. Methods: Patients with RRMS were evaluated using the same battery test, in two different moments. Disease activity between the evaluations was revised and patients were classified as “stable” or “unstable” using relapse rate (>1), brain MRI (⩾2 Gd-enhancing or new lesions), EDSS (>1 point), T25FW (worsening >20%), 9HPT (worsening >20% in one side) and SDMT (worsening >40%). The Rio Score was calculated and compared to three adapted versions of Rio Score using T25FW, 9HPT and SDMT instead of EDSS. Results: A total of 144 patients were included in this study: mean age=42±11 years, mean years of education=14±6, mean disease duration=12±7 years; at first evaluation mean EDSS= 2.3±1.8 and 73% under disease modifying treatment (DMT); mean time between evaluations=12±6 months. 74.3% of patients were considered NEDA (Rio score=0) with EDSS, 77.6% with SDMT (p>0.05), 70.2% with 9HPT (p>0.05) and 61.1% with T25FW (p=0.017, corresponding to 25 patients). None of these patients switched DMT because of disease progression. There is no significant difference between patients who maintained NEDA and patients who scored 1 with T25FW, concerning age, disease duration, interval of evaluations and the other tests. Conclusion: Almost a quarter of patients considered NEDA with EDSS were not stable with T25FW. However, it had no impact on treatment decision. More studies are needed to validate this tool as a marker of disease activity. Disclosure Joana Martins: nothing to disclose Raquel Samões: nothing to disclose Inês Moreira: nothing to disclose Andreia Bettencourt: nothing to disclose Ernestina Santos: nothing to disclose Ana Martins Silva: nothing to disclose P360 ‘Exploring dual task cost in people with multiple sclerosis; the relationship to falls status and cognitive function’ G. Quinn1,2, S. Coote1, C. McGuigan2, R. Galvin1, L. Comber1 1Clinical Therapies, University of Limerick, Limerick, 2St. Vincent’s University Hospital, Dublin, Ireland Background: Both walking and cognition are commonly impaired in people with Multiple Sclerosis (MS). Simultaneous execution of motor and cognitive tasks can lead to deterioration in one or both of the tasks; this interference is quantified as the dual task cost (DTC). Previous research has shown DTC to be associated with increased fall risk in MS. Objectives: The objective of this analysis is to examine the difference in DTC between fallers and non-fallers and to

determine if there is any correlation with prospective falls status and cognition. Methods: Consecutive patients with MS attending the Neurology service in a tertiary hospital were recruited. Data collected included the Expanded Disability Status Scale score (EDSS), Symbol Digit Modalities Test (SDMT) score to assess cognitive function, time since diagnosis, type of MS and walking aid(s) used. Consenting participants completed a questionnaire of falls risk factors and the timed up and go test (TUG) under single and dual task conditions. Falls were prospectively recorded for 3 months using falls diaries. Results: Falls status was available for 94 participants and total falls recorded for 88 participants. Mean age was 52.2 (SD 10.8) and 66% were female. EDSS score ranged from 3 to 6.5 with a mean of 5.3 (SD 1.1) and a mean time since diagnosis of 14.3 (SD 9.4) years. 72.3% of the sample had progressive MS with 73% using a mobility aid. There was no difference in DTC score between fallers and non-fallers (p=0.87). Binary logistic regression on DTC ability to predict fall status was not significant (OR=1.002, 95% CI, p=0.32). DTC explained only 3% of the variance in falls status. There was a weak correlation (rho=0.23) between DTC and SDMT score. DTC was not correlated to the total number of falls (rho=0.03). Conclusion: In this sample with mean EDSS of 5.3 and predominantly secondary progressive MS, DTC alone did not correlate with falls status or number of falls. DTC in isolation should not be used to predict fallers. Analysis of DTC in combination with other variables to develop a falls risk algorithm is ongoing. Disclosure Ms. Gillian Quinn: has received research stipend from MS Ireland. Dr. Susan Coote: has received consultancy fees from Novartis and research funding from MS Ireland, the Health Research Board and the Irish Research Council Dr. Rose Galvin: nothing to disclose Dr. Chris McGuigan: has received research grants from Biogen, Genzyme, Novartis and Bayer, honoraria as a consultant from Biogen, Genzyme, Novartis and Roche. Ms. Laura Comber: has received research stipend from MS Ireland. P361 Unipedal stance test evaluation in progressive multiple sclerosis C. Pinto1, B. Soler2, T. Labbe1, M. Vasquez1, A. Reyes1, E. Vergara1, D. Weaver1, P. Feliu1, R. Uribe-San-Martin2, E. Ciampi2, C. Carcamo2 1Pontificia Universidad Catolica de Chile, 2Neurology, Pontificia Universidad Catolica de Chile, Santiago, Chile Background: Disability outcome measures in Multiple Sclerosis (MS) may be too difficult or too long to be performed in the setting of daily clinical practice. Unipedal Stance Test (UST) is a one-minute per leg task that has been validated in elder population and other neurological conditions such as Parkinson´s disease (e.g. risk of falling), and has the advantage of being reliable and easy to perform, with normal population values already available.


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Poster Session 1, 22(S3) Its association with MS disability outcomes has been poorly described. Goals: To explore the association of UST and disability in a cohort of patients with Progressive Multiple Sclerosis (PrMS). Methods: A prospective cohort of PrMS patients was explored. The average time (right leg UST + left leg UST in seconds divided by 2) was recorded. Demographical and clinical variables including Expanded Disability Status Score (EDSS), Timed 25 Foot Walk Test (T25FWT), Multiple Sclerosis Functional Composite (MSFC), quality of life (Multiple Sclerosis Impact Scale 29-MSIS29), depression (Beck Depression Inventory-BDI) and Fatigue Severity Scale (FSS) were also collected. Results: Thirty nine (39) PrMS were recruited (21 primary progressive, 18 secondary progressive), mean age 56.2 years, 24 women, mean disease duration 15.5 years, median EDSS 6. Mean UST was 0.82s (range 0 - 4.98) and it was correlated with EDSS (Rho -0.57, p< 0.001), T25WT (r=-0.42, p=0.026) and MSIS29 (r=-0.43, p=0.007), although after adjusting for EDSS, depression and fatigue, correlation with MSIS29 was no longer significant (rp=-0.253, p=0.22). No associations were found between UST and age, gender, primary/secondary progression, disease duration, MSFC, depression or fatigue. Conclusions: Unipedal Stance Test is a quick and easy to perform task that correlates with disability in PrMS. Although this is an small exploratory study in a highly disabled population, a validation cohort including larger sample size with relapsing remitting MS patients and longitudinal evaluations is needed to asses the utility of including this measure routinely in the daily practice. Disclosure Carmen Pinto declare no conflict of interest Bernardita Soler declare no conflict of interest Tomás Labbe declare no conflict of interest Macarena Vasquez declare no conflict of interest Ana Reyes declare no conflict of interest Elizabeth Vergara declare no conflict of interest Daniella Weaver declare no conflict of interest Patricia Feliu declare no conflict of interest Reinaldo Uribe declare no conflict of interest Ethel Ciampi declare no conflict of interest Claudia Carcamo declare no conflict of interest

walking-motor function, is insensitive to many important factors including cognitive function. Activities of daily living (ADL) ability can impact QoL. EDSS scores intended to reflect a homogenous disease burden, but ADL skills ability might vary within EDSS groups and ADL decline might impact QoL and reflect disease progression but not be reflected by EDSS changes. Objective: Investigate the relationship between EDSS and ADL ability by use of the physical self-maintenance scale (PSMS), and explore the impact of cognition on PSMS independent of EDSS. Methods: Retrospective review of PwMS who underwent standardized computerized cognitive testing (NeuroTrax, NT) during routine clinical care and completed PRO-PSMS, and Likert QoL. PwMS EDSS was grouped: 0-2.5(A), 3-4.5(B), and ⩾5.0(C). Results: 191 PwMS (average age 45.3 +/- 10.8, 72.1% female). PwMS-PSMS scores track with EDSS (p< .0001, r=.48,). However, PwMS-PSMS variability within the 3 EDSS groups was: 11%(A), 12%(B), and 23%(C) respectively, but PwMSPSMS scores overlap between EDSS groups: 52% (A-B) and 31% (B-C) respectively. PwMS-PSMS scores correlated with: QoL (p< .001, r=.225); NT scores: memory (p=.004, r=.207), executive function (p=.001, r=.325), attention (p=.001, r=.295), global cognitive summary score (p< .001, r=.275) and the number of cognitive domains (CD) impaired >1 standard deviation (p< .001, r=.252). Conclusions: PwMS-PSMS correlates with EDSS and QoL, but there is considerable variability of PSMS within higher EDSS, and different EDSS scores might reflect similar PSMS ability. Cognitive function impacts PSMS ability, whereas EDSS is insensitive to cognitive function. Physical self-maintenance is not solely dependent upon physical ability. Analysis of PwMS disease impact and treatment needs requires information beyond the EDSS. Disclosure Glen Doniger is an employee of NeuroTrax Corporation

P362 Multiple Sclerosis, EDSS and physical self maintenance ability: cognitive impairment impacts self care ability beyond the physical ability C. Davis1, S. Zarif1, K. Wissemann1, M. Zarif1, B. Bumstead1, L. Fafard1, M. Buhse1, C. Sullivan2, J. Wilken2, G. Doniger3, M. Gudesblatt1 1South Shore Neurologic Associates, Patchogue, NY, 2Neuropsychological Associates, Fairfax, VA, 3NeuroTrax Corporation, Bellaire, TX, United States

P363 Multiple sclerosis and cognitive fatigue: relationship to visual evoked potential latency J. Srinivasan1, D. Nemirov1, K. Wissemann1, M. Gudesblatt1, M. Zarif1, B. Bumstead1, L. Fafard1, M. Buhse1,2, K. Blitz1, C. Sullivan3,4, J. Wilken3,5, D. Golan6,7, G. Doniger8 1South Shore Neurologic Associates, Patchogue, 2Stony Brook University, Stony Brook, NY, 3Neuropsychological Associates, Fairfax, VA, 4Georgetown University Hospital, Department of Neurology and Washington Neuropsychology Research Group, Washington, DC, 5Georgetown University Hospital, Department of Neurology and Washington Neuropsychology Research Group, Washington, NY, United States, 6Department of Neurology, Carmel Medical Center, 7Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, 8NeuroTrax Corporation, Bellaire, TX, United States

Background: Multiple Sclerosis (MS) is a disease impacting more than EDSS, relapse and MRI changes. People with MS (PwMS) experience reduced Quality of Life (QoL) from: physical and cognitive impairment, fatigue, depression, and loss of independence/employment. EDSS, a scale that primarily reflects

Background: People with Multiple Sclerosis (PwMS) frequently report fatigue that can be disabling and impact quality of life (QoL) and employment. PwMS-fatigue is related to: physical disability, medication, sleep disorders, and depression. Effective PwMS-fatigue treatment is problematic. The role/degree

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cognitive fatigue plays in PwMS patient reported outcome (PRO) fatigue is unknown. Objective: Explore the relationship PRO-fatigue and depression in PwMS and Visual Evoked Potential latency (VEP-L), one objective neurophysiological measure of central demyelination. Methods: Retrospective review of PwMS who underwent VEP and completed PRO Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), and Beck´s Depression Inventory (BDI) during routine clinical care. PRO-MFIS sub-score scales reportedly identify and differentiate between physical, cognitive, and psychosocial subtypes of fatigue, whereas PRO-FSS does not allow such differentiation. Results: 60 PwMS (average age 45 +/-10.4 years, 72% female) were identified. VEP-L correlated with PRO-sub-scale cognitive fatigue scores in PwMS: both right (r=0.27, p=0.03) and left (r=0.31, p=0.02) eyes, MFIS-global, MFIS-physical, and MFISpsychosocial fatigue sub-scale scores and FSS-global score did not significantly correlate with VEP-L in either eye. VEP-L also correlated with PwMS PRO-MFIS-cognitive fatigue Raschcorrected analysis scores for both right (r=0.26, p=0.04) and left (r=0.27 p=0.04) eyes, whereas scores of MFIS-global and MFISphysical PRO-sub-scale and global-FSS did not correlate with VEP-L in either eye. BDI scores did not significantly correlate with any latency outcomes. Conclusion: VEP-Latency, an objective neurophysiological proxy marker reflecting CNS demyelination along the visual pathway, correlates with PwMS PRO-MFIS-cognitive fatigue. PwMS PRO-Fatigue is not unidimensional, and fatigue subtypes should be measured independently to produce a better understanding of individual PwMS PRO-fatigue. PRO-fatigue subtypes in PwMS may have different physiologic underpinnings, as indicated by the specific correlation between PRO-MFIScognitive fatigue and VEP-L independent of other PRO-fatigue subtypes. Future studies of PRO-fatigue in PwMS should investigate which aspects PRO-fatigue and PRO-cognitive fatigue may be reflective of the degree of demyelination as measured independently by objective measures. Disclosure Glen Doniger is an employee of NeuroTrax Corporation P364 The feasibility of computerized cognitive monitoring in the clinic and community in people with MS: initial results of the msreactor study A. van der Walt1,2, D. Merlo3,4, J. Haartsen3, H. Butzkueven2,5, D. Darby3,5,6 1University of Melbourne, 2Neurology, Royal Melbourne Hospital, 3Eastern Health Research Unit, Monash University, 4Melbourne Brain Centre, University of Melbourne, 5Neurology, Box Hill Hospital, 6Behavioural Neuroscience, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia Background: Cognitive impairment (CI) affects 40-65% of MS patients. Memory, attention, and processing speed are commonly involved. Mild CI is difficult to detect, even for experienced clinicians. Compared to neuropsychological tests, computerized

cognitive batteries (CCB) can be self-administered, have standardized presentations and accurate, automated scoring. Aim: Establish the feasibility of a computerized cognitive monitoring tool in the MS clinic and home. Methods: We established a CCB using three cognitive tasks from the NeurabilityTM system, on a secure, purpose-built website, www.msreactor.com. We implemented testing in two tertiary MS clinics, screening for processing speed, attention and working memory. Participants confirm the appearance of a ball (Simple Reaction Test, (SRT)), react correctly to the colour of the ball (Choice Reaction Test (CRT)) and detect if consecutive cards are identical (One Back Test (OBT)). Self-administered testing takes under 15 minutes. Scores are immediately uploaded, processed, and graphically displayed. Participants are offered clinic (6 monthly) or home-based testing (1-3 monthly). Clinic-based testing includes electronic versions of the Penn State Worry Questionnaire (PSWQ-15), Patient Health Questionnaire (PHQ-9), and an Acceptability Questionnaire (adapted 10 point Likert scale) and the MusiQol Quality of Life score. Results: We recruited 68 patients (n=41 female) with predominantly RRMS (n=61) over 5-weeks who agreed to clinic and home testing. The median EDSS was 2.7 (Std deviation=1.9) and disease duration 13.2 years (9.7). SRT (r=-0.31, p=0.014), CRT (r=-0.25, p = 0.06) and OBT (r=-0.36, p=0.003) correlated with MusiQol scores. No correlations were observed (p>0.05) between depression (PHQ), anxiety (PSWQ) and msreactor tests. Acceptability was high with 55.4% “not anxious at all” during the test, and 96.4% finding test duration “about right”. 64.7% found tasks “very enjoyable” and only 4.6% were “very unhappy” to repeat tasks. Interest in the tasks rated “high” or “about right” in 76.9%. Conclusion: CCBs may fill the cognitive monitoring gap, allowing physicians to detect neurocognitive changes in real-time, potentially informing treatment decisions. The rapid recruitment rate and acceptability of the msreactor platform demonstrates its feasibility in both clinic and community environments. Given ongoing recruitment rates, we plan to present uploaded baseline data on >150 participants at ECTRIMS. Disclosure A van der Walt served on scientific advisory boards for Biogen, Novartis and Merck. She received conference travel support from Novartis, Biogen, Merck and Teva. D Merlo has nothing to disclose. J Haartsen has nothing to disclose. H Butzkueven served on scientific advisory boards for Biogen, Novartis and Sanofi and has received conference travel support from Novartis, Biogen and Sanofi. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. D Darby acted as a consultant for the creators of the cognitve testing software, Neurability. P365 Multiple sclerosis, EDSS, and objective cognitive function: a walking scale with no apparent brains and limited thought


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Poster Session 1, 22(S3) M. Gudesblatt1, K. Wissemann1, M. Zarif1, B. Bumstead1, L. Fafard1, K. Blitz1, M. Buhse1,2, C. Sullivan3,4, J. Wilken3,4, G. Doniger5 1South Shore Neurologic Associates, Patchogue, 2Stony Brook University, Stony Brook, NY, 3Neuropsychological Associates, Fairfax, VA, 4Georgetown University Hospital, Department of Neurology and Washington Neuropsychology Research Group, Washington, DC, 5NeuroTrax Corporation, Bellaire, TX, United States Background: Multiple Sclerosis (MS) is measured by MRI, relapse rates and EDSS. EDSS scale primarily driven by motorwalking impairment. Cognitive impairment, independent of EDSS, in people with MS (PwMS) impacts: employment, driving, fall risk, Quality of Life (QoL). EDSS is universally accepted to measure treatment efficacy but cognitive function does not impact EDSS. Cognitive function varies independently of walking ability and is an important aspect of PwMS disease impact. Objective: Investigate the sensitivity of EDSS impairment reflecting PwMS cognitive ability. Methods: PwMS completed a computerized cognitive assessment battery (NeuroTrax) with analysis of 7 cognitive domains (CD) and a global cognitive score (GCS) reflecting an average of these domain scores. The number of CD impaired (greater than one standard deviation from age- and education-matched norms) were also explored for each CD. EDSS-groups were defined: lowEDSS (0-2.5), moderate-EDSS (3-4.5), high-EDSS (5-6.5) and severe-EDSS (>7). Percent overlap of NeuroTrax cognitive scores across both adjacent EDSS-groups and extreme EDSS groups (low & severe) were calculated. Results: 258 PwMS (72.5% female, average age = 46.2±10.2). PwMS-GCS had an average overlap: 65.0% across adjacent EDSS-groups, and 42.4% across extreme EDSS-groups. The overlap of the adjacent and extreme cognitive domain scores were respectively: memory (65.3% and 65.3%), executive function (65.1 % and 35.1%), attention (60.3% and 38.1%), information processing speed (58.0% and 42.5%), visual spatial (65.6% and 63.2%), verbal function (70.1% and 66.4%), and motor skills (55.2% and 32.3%). The overlap of the number of CD scores impaired >1SD was: 72.2% across adjacent groups, and 38.1% across extreme EDSS-groups. Conclusions: EDSS is insensitive to assess individual PwMS cognitive ability and does not predict accumulated cognitive disability. Cognitive impairment in PwMS, independently of EDSS, correlates with many important milestones. EDSS use as a solitary gold standard in measuring unique accumulated PwMS disability should be reconsidered. Disclosure Glen Doniger is an employee of NeuroTrax Corporation P366 Multiple sclerosis & patient-derived disease steps (PDDS): a walking scale with no hands M. Gudesblatt1, K. Wissemann1, B. Bumstead1, M. Zarif1, L. Fafard1, S. Thotam1, C. Sullivan2,3, J. Wilken2,3, M. Buhse1,4, D. Golan5,6

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Shore Neurologic Associates, Patchogue, NY, Associates, Fairfax, VA, 3Georgetown University Hospital, Department of Neurology and Washington Neuropsychology Research Group, Washington, DC, 4Stony Brook University, Stony Brook, NY, United States, 5Department of Neurology, Carmel Medical Center, 6Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2Neuropsychological

Background: Multiple Sclerosis (MS) is a disease evaluated by EDSS. Critical EDSS changes/thresholds are primarily driven by walking/motor ability in people with MS (PwMS). Functional ability/independence separate from walking is critical when evaluating PwMS disease burden. Although EDSS is primarily a walking scale, hand function represents an independent factor impacting functional ability and independence. EDSS scores strongly correlate with the patient reported outcome patient-reported disease progression (PRO-PDDS). Objective: To investigate the relationship between in PwMS PRO-PDDS and PRO-hand function and PRO-tremor/coordination and evaluate how these PRO correlate to self-reported quality of life (QoL). Methods: PwMS completed standardized PRO questionnaires for hand function, tremor/coordination, and Likert QoL during routine care. Regression analyses to investigate: relationship between hand function and tremor/coordination, PRO-PDDS and PRO-QoL; and multivariate regression to investigate: the relationship of hand function and tremor/coordination with PRO-QoL. PDDS scores were grouped: mild-PDDS (0-1), moderate-PDDS (2-4), severe-PDDS (>4). Percent variability of PRO-hand function and PRO-tremor/coordination were analyzed within each PRO-PDDS group, and % overlap of hand function and tremor/coordination was analyzed across PROPDDS groups. Results: 783 PwMS (73.7% female, average age = 49.3±11.2). PRO-hand function and PRO-tremor/coordination correlated (r=0.59, p=< 0.01) and both PRO-Hand function and PRO-tremor/coordination correlated with QoL (r=0.38, p=< 0.01). PDDS correlated with QoL (r=0.38, p=< 0.01). However, PRO-hand function scores showed great variability: >100% (low-PDDS), 71.3% (moderate-PDDS), and 72.6% (severePDDS); average overlap of 55.7% between adjacent PDDSgroups, and 33.9% overlap between extreme PDDS-groups. PRO-Tremor/coordination scores also demonstrated >100% variability (low-PDDS), 66.5% (moderate-PDDS), and 68.1% (severe-PDDS), average overlap of 52.3% between adjacent PDDS-groups, and 32.1% overlap between extreme PDDSgroups. Conclusions: Hand function, tremor/coordination and PDDS are all factors that significantly relate to self-reported QoL. However, PRO-PDDS is a scale that is insensitive to PRO-hand function and PRO-tremor/coordination. The use PRO-PDDS as an important measure of global disability in PwMS should be reconsidered. Disclosure All: nothing to disclose


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P367 Validation of the tremor biomechanics analysis laboratory (TREMBAL) software in MS tremor A. Van der Walt1,2, F.M.C. Boonstra3, S.A.C. Yohanandan4,5, A.P. Vogel6,7, S.C. Kolbe3, J. Ly1, G. Noffs7, H. Butzkueven2,8,9, A.H. Evans2,10, T. Perera4,11 1Melbourne Brain Centre, Department of Medicine, University of Melbourne, Parkville, 2Neurology, Royal Melbourne Hospital, 3Neuroimaging group, Melbourne Brain Centre, University of Melbourne, Melbourne, 4The Bionics Institute, East Melbourne, 5School of Computer Science and Information Technology, RMIT University, 6Audiology and Speech Pathology, 7Centre for Neuroscience for Speech, 8Melbourne Brain Centre, University of Melbourne, 9Eastern Health Research Unit, Monash University, 10University of Melbourne, 11Medical Bionics Department, University of Melbourne, Melbourne, VIC, Australia Background: Tremor in MS (MST) is difficult to treat and the development of new interventions is limited by the absence of universal measuring systems. At present, therapeutic outcomes are measured by a variety of clinical rating scales that are subjective and lack sufficient sensitivity. With increasing use of interventional treatments such as Botulinum toxin injections or Deep Brain Stimulation for MST, it has become critical to develop precise measurement instruments. Objective: To clinically validate the TREMBAL software in MST. Methods: TREMBAL (Bionics Institute, Melbourne, Australia) utilises an electromagnetic motion tracker (Ascension, Vermont, US) to acquire absolute displacements and rotations of a tremulous body part. Tremor was recorded bilaterally from four locations (second phalanx of the middle finger, wrist dorsum, forearm and upper arm) in five positions (hands resting on lap, arms outstretched in front, finger-nose, batwing static and batwing action). Tremor exercises were video recorded (GoPro Hero3, GoPro Inc., San Mateo, California) and rated by two experts using the 5-point Unified Tremor Rating Assessment (UTRA) scale where 0=no tremor and 4=severe. TREMBAL tremor displacements (measured in units of millimetres) were averaged and log transformed to match the distribution of clinical ratings. Data were pooled across exercises. Congruence between TREMBAL measures and mean clinical ratings was explored using regression analysis and Pearson´s correlation. Results: We assessed ten MST patients over 6 months and rated 200 videos. The median pooled UTRA score was 0.5 (interquartile range 0, 1.5). The average TREMBAL recorded tremor displacement was 1.65 mm (standard deviation 2.1). A strong correlation between UTRA scores and log transformed TREMBAL displacement was found, r = 0.749, p< 0.001. Conclusions: TREMBAL measurements are highly accurate when compared to clinical measurements. While other objective tremor measures exist, only a few have been benchmarked specifically against MST clinical ratings. The validation of an objective, 3 dimensional tremor measurement system provides real-time tremor severity measurements for clinicians and can be applied in clinical trials of putative therapies for MST.

Disclosure A. van der Walt served on scientific advisory boards for Novartis, Biogen and Merck. She received conference travel support from Biogen, Novartis, Merck and Teva. F.M.C. Boonstra has nothing to disclose. S.A.C. Yohanandan has nothing to disclose. A.P. Vogel has nothing to disclose. S.C. Kolbe has nothing to disclose. J. Ly has nothing to disclose. G. Noffs has nothing to disclose. H. Butzkueven served on advisory boards for Biogen, Novartis and Sanofi and has received conference travel support from Novartis, Biogen and Sanofi. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. A. Evans has received honoraria from Novartis for giving presentations and providing consultancy services. He has participated in scientific advisory board meetings for Novartis, UCB Pharma, Allergan, and Boehringer Ingelheim. T Perera has nothing to disclose.

Economic burden P368 The expenditure for treating multiple sclerosis and the 10-year risk of disease progression M. Moccia1, R. Palladino2, R. Lanzillo3, A. Carotenuto3, M. Triassi3, V. Brescia Morra3 1Department of Neuroscience, Federico II University, Napoli, Italy, 2Imperial College London, London, United Kingdom, 3Federico II University, Napoli, Italy Background: Soaring costs for Disease Modifying Treatments (DMTs) have received much attention for their long-term financial impact in relation to Multiple Sclerosis (MS) clinical evolution. In view of this, the present retrospective cohort study aims to explore the relationships between costs sustained for DMT administration and management, and the evolution of MS. Methods: 544 newly diagnosed, drug naïve Relapsing Remitting MS (RRMS) patients, were included and followed up for 10.1±3.3 years. Costs for DMT administration and management were referred to each year of observation (annual costs), in order to obtain annual costs before study endpoints were reached. Following clinical endpoints were recorded: occurrence of the first relapse, annualised relapse rate (ARR), 1-point EDSS progression, reaching of EDSS 4.0, reaching of EDSS 6.0, and conversion to secondary progressive MS (SP). Age, gender, disease duration and EDSS were recorded at the time of diagnosis, and utilized as covariates for statistical analyses. Results: At time varying Cox regression models, increasing annual costs before the specific endpoint was reached, were negatively associated with the 1-point EDSS progression (HR=0.897; p=0.018), with the reaching of EDSS 6.0 (HR=0.925; p=0.030), and with the conversion to SP (HR=0.902; p=0.006), but not with the occurrence of the first relapse (HR=0.993; p=0.913), and with


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Poster Session 1, 22(S3) the reaching of EDSS 4.0 (HR=0.929; p=0.070). At Poisson regression analysis, overall annual costs were positively associated with the ARR (Coef=2.183; p=0.016). Conclusion: A higher expenditure for treating more aggressive MS has been associated with a relatively milder disease evolution after 10 years. Therefore, in spite of the short-term resource utilization, the early initiation of the most appropriate DMT might cause long-term direct and indirect cost savings. Disclosure Authros have nothing to disclose. P369 Comparison of cost, feasibility and satisfaction of telemedicine versus in-person visits for multiple sclerosis patients: a randomised cross-over study J.F. Robb, M.H. Hyland, A.D. Goodman University of Rochester, Rochester, NY, United States Background: Telemedicine, the provision of healthcare using an audio-visual connection, is increasingly used to enhance access to medical care for patients with geographic or mobility limitations. The virtual house call--conducting a clinical visit remotely with a patient located at home--has been used successfully in other neurologic disorders but has not been systematically assessed in multiple sclerosis (MS) patients. Goals: 1) Assess feasibility and satisfaction of virtual house calls for MS patients. 2) Determine differences in cost and visit duration between telemedicine and in-person visits. Methods: MS patients of a university-affiliated clinic were recruited to participate in two follow-up visits with their treating neurologists, at three and six months after the baseline visit. Randomisation determined which type of visit occurred first for each subject (MS clinic versus virtual house call). Subjects completed surveys providing demographics, MS-related information and opinions on both types of clinical encounter. Feasibility was determined using the percentage of each visit type completed within the scheduled time window. Key questions on subjectcompleted surveys were used to determine subject’s satisfaction, time spent, and costs. Results: 42 subjects were randomised, 37 of whom completed both the in-person and virtual house call visits. Twenty-five of the 37 (67.6%) telemedicine visits were completed within the specified time frame as compared with 28 of the 38 (73.7%) inperson visits (difference 6.1%, p=0.75). Nearly all subjects (97.1%) reported that they would recommend virtual house call visits to a peer, similar to 97.4% of subjects who would recommend an in-person visit. A telemedicine visit saved subjects an average of $55 as compared with an in-person visit. An in-person visit required an average of 92 minutes longer to complete compared with a telemedicine visit while a significantly greater percentage of the telemedicine visit was spent with the physician (79.0% vs 25.7%, p< 0.01). Subjects’ unscripted survey comments expressed satisfaction with the virtual house calls, with frequently mentioned themes of convenience and equivalence with in-person visits.

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Conclusions: This study demonstrates that virtual house calls are feasible and well-liked by a sample of MS patients. The cost effectiveness and time-savings make this form of telemedicine an attractive method for increasing access to neurologic care for MS patients. Disclosure Dr. Robb: nothing to disclose Dr. Hyland´s employer, the University of Rochester, received research support from Novartis and Chugai. Dr. Goodman received personal compensation for consulting from the following commercial entities: Abbvie, Acorda Therapeutics, Atara, Bayer, Biogen Idec, Genentech, Sanofi Genzyme, Novartis, Purdue, Teva; Dr. Goodman´s employer, the University of Rochester, received research support for conducting clinical trials from the following commercial entities: Acorda Therapeutics, Avanir, Biogen-Idec, EMD-Serono, Novartis, Ono, Roche, Sanofi Genzyme, Sun Pharma, Teva. P370 Healthcare resource utilisation and costs in patients with active relapsing-remitting multiple sclerosis treated with alemtuzumab vs. SC IFNB-1a (CARE-MS II) A. Smith, L. Hashemi, on behalf of the CARE-MS II Investigators Sanofi Genzyme, Cambridge, MA, United States Background: CARE-MS II (NCT00548405) was a 2-year, phase 3, head-to-head trial of alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS) and an inadequate response (⩾1 relapse) to prior therapy at baseline.1 Compared with SC IFNB-1a, alemtuzumab demonstrated greater improvements in clinical and MRI outcomes, and significantly more alemtuzumab-treated patients achieved no evidence of disease activity. Goal: To evaluate healthcare resource utilisation and direct costs (US dollars) over the 2-year trial period for RRMS patients randomised to either alemtuzumab or SC IFNB-1a. Methods: Healthcare resource utilisation was a tertiary endpoint of the CARE-MS II trial. Patients’ use of healthcare resources was assessed at scheduled study visits (every 3 months) utilising the Health Resource Utilisation Questionnaire (HRUQ), a patient self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilisation was collected in the following areas: admissions and stays in the hospital, rehabilitation centres, nursing homes, consultations with specialists, general practitioners, or other healthcare professionals. Direct costs in US dollars (adjusted to US 2016 medical inflation) are reported for the alemtuzumab and SC IFNB-1a treatment arms. Results: At baseline, resource utilisation and costs were similar in the alemtuzumab and SC IFNB-1a treatment arms. At 2-years, a statistically significant difference in resource use was observed in favour of alemtuzumab, with the SC IFNB-1a arm having a higher mean number of hospital stays and days in hospital, rehabilitation centre stays and outpatient visits, and nursing home stays and outpatient visits. Higher total direct healthcare costs were observed for SC IFNB-1a versus alemtuzumab 12 mg


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($18,995 vs $10,963 respectively, P=0.0256). No differences were seen with regard to visits with specialists and other healthcare professionals. Conclusion: Direct healthcare resource utilisation and costs as measured by HRUQ in the CARE-MS II trial were decreased with alemtuzumab treatment versus SC IFNB-1a.

of instruments that were developed to properly assess employment-related difficulties in MS patients. With these instruments, specific rehabilitation programs could be tailored towards the needs of MS patients in order to keep them as long as possible in the work process. Disclosure

Reference 1. Coles AJ, Twyman CL, Arnold DL, et al. Lancet 2012;380: 1829-39. Disclosure Study support: Sanofi Genzyme. AS and LH: Employees of Sanofi Genzyme.

P371 Employment in MS: validation of a set of assessment instruments in German MS patients P. Flachenecker, C. Sterz, H. Meissner, K. Gusowski Neurological Rehabilitation Center Quellenhof, Bad Wildbad, Germany Background: Multiple Sclerosis (MS) has a major impact on work ability and employment status. Objective: We aimed to validate a recently developed set of instruments assessing predictive factors for employment that consist of standardized questionnaires and objective performance tests. Methods: For the current study we included 102 employed MS patients (mean age 44.7 years, 64 % females, median EDSS 4.0), all admitted to inpatient rehabilitation, and administered the following patient-reported instruments: Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ), Würzburger Screening (WüScr), and subjective dimensions of mood (CES-D), pain (BPI), vision (NEI-VFQ), mobility/balance (MSWS-12), fear of falling (FES-I), fatigue (WEIMuS), cognitive complaints (MSNQ) and quality of life (MSIS-29). Objective performance tests were 2 min walking test, 10 m walking test, timed-get-up-and-go, Tinetti score, comprehensive neuropsychological testing, and visual testing. Six months after rehabilitation, patients were re-contacted via questionnaires to gather information about their current employment situation. Results: The questionnaire was returned by 76 patients (75%). Of these, 62 patients (82%) were still employed, and 9 patients (12%) were prematurely retired; the remaining 5 patients were still in sick leave and/or uncertain about their future situation. According to WüScr, 8/9 patients (89%) of the retirees had stated high burden with regard to employment already when admitted to rehabilitation, and according to MSWDQ, 7/9 (78%) had planned to withdraw work. The proportions of patients with abnormal test results were higher in retired compared to employed patients for mood (CES-D 67% vs 29%), physical fatigue (WEIMUS 56% vs 42%), cognitive difficulties (MSNQ 89% vs 44%) and pain (78% vs 55%); these results reached significance for MSNQ (p< 0.02). MSIS-29 scores were also significantly impaired in retired patients (54.0±18.9 vs. 38.0±14.9, p< 0.005). MSWS-12 and objective test results for mobility were not significantly different between both groups. Conclusion: The results of our study underline the high impact of “hidden” symptoms in MS on employment and validated the set

This work is funded by a research grant from the German Pension Insurance (“Deutsche Rentenversicherung Baden-Württemberg”). Peter Flachenecker has received speaker’s fees and honoraria for advisory boards from Almirall, Bayer, Biogen, Genzyme, Novartis, Merck-Serono, Roche and Teva. He has participated in pharmaceutical company sponsored trials by Almirall, Biogen and Novartis. None resulted in a conflict of interest. Christiane Sterz: nothing to disclosure Heike Meissner: nothing to disclosure Klaus Gusowski: nothing to disclosure P372 Social economic costs, quality of life and experience in multiple sclerosis patients and their caregivers: the IMPrESS (International MultiPlE SclerosiS) survey M. Tinelli1, P. Kanavos1, J. Mossman2 1London School of Economics, London, United Kingdom, 2European Brain Council, Brussels, Belgium Background: Multiple-sclerosis (MS) is the most common cause of disability among central-nervous-system (CNS) diseases. The available data provide limited information on the impact and burden of MS as experienced by people living with MS (PwMS)/ caregivers. If decisions on MS management and treatment availability are to reflect patient needs, international evidence to capture the full picture of the multiple domains of MS burden is needed. Objectives: To assess and compare the costs, health-related-quality-of-life (HRQoL), and experience reported by people living with MS/caregivers across international settings. Methods: Information from patients/caregivers will be collected through an anonymous online survey. Participation is open to adult MS/caregivers. The study will be available in fifteen countries in Europe and overseas. Individuals will be enrolled through MS-societies and clinics. The survey will capture data on direct and indirect costs, patients’ and caregivers’ HRQoL (EuroQol-5D), patients’ disability (Barthel-Index), burden among caregivers (Zarit-Burden-Interview), participants’ experience, as well as demographic variables, and disease information. The societal, HRQoL and economic impact of MS management will be evaluated across countries. Results: PWMS already replied from France (n=97), USA (n=70), Romania (n=44), UK (n=25) and Germany (n=10). Total average annual PWMS costs were €40,313; €20,631 were associated with direct medical costs (medicines, consultations, hospitalisations), followed by indirect costs (loos of productivity, €16,061) and direct non-medical costs (caregiver costs, €2,127). The proportion of indirect costs became more significant as the level of disability increased. The average utility value reported was 0.60 (60% of perfect health), with a loss of 25% compared with the general population. Cost and utilities varied across healthcare systems and types of MS. 22% (12/54) of the responses already available from


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Poster Session 1, 22(S3) the caregivers were suitable for preliminary analysis. Caregiver costs related to productivity losses (€31,000) were about double the cost reported by PWMS, whereas they reported better utility compared with PWMS (70% vs. 60% of perfect health). Both PWMS/caregivers reported a mild level of discomfort/disability. Their experience of MS care varied across healthcare systems. Conclusion: Results will identify the impact of MS as experienced by PwMS/caregivers and may be used to inform the development of future services. Disclosure The project was funded by an unrestricted educational grant from Roche. Dr Michela Tinelli is assistant professorial research fellow, London School of Economics (LSE) and associate researcher LSE Consulting. Dr Panos Kanavos is Reader in International Health Policy in the Department of Social Policy, LSE and Programme Director of the Medical Technology Research Group (MTRG) at LSE Health. MS Jean Mossman is a healthcare consultant with an honorary role at the LSE, a volunteer with the European Brain Council, and working with patient organisations; she currently consults for the following pharma companies: Bayer, Celgene, Novartis and Roche in relation to patient priorities in a number of disease areas. P373 Societal costs of multiple sclerosis in Ireland: study results C. Mc Guigan1,2, K. O ‘Rourke2,3, A. Larkin4, D. O ‘Boyle5, P. Carney2,6 1St. Vincent’s University Hospital, 2University College Dublin, 3Mater Misericordiae Hospital, 4MS Society of Ireland, Dublin, 5National University of Ireland, Galway, 6Novartis Ireland, Dublin, Ireland Objective: To measure the economic impact of MS on the individual and on society in Ireland using a nationally representative sample of people with MS. Most EU countries have previously studied the full economic impact of MS; this research aims to provide the Irish experience— in directly comparable terms— to the wider EU picture. Methods: A comprehensive questionnaire was designed with careful reference to similar studies from around Europe, and a number of directly comparable instruments were included. As well as direct and indirect economic costs, well-being was measured using EQ-5D to estimate the ‘intangible cost’ aspect. The survey was made available online and in paper form. Recruitment was via the MS Society of Ireland mailing list and social media platforms, as well as in print media. Our costing followed a ‘prevalence-based’ methodology for the year 2015. For estimation of non-market costs we used a human capital approach and values consistent with the literature. Results: Our final sample (n=595) had characteristics indicating national representativeness on geographic measures, and typical demographic features associated with MS - in terms of age and gender representation. We find that total costs escalate with disease and disability progression from mild (€34,942) through moderate (€57,857) to severe (€100,554). The self-reported relapses component of relapsing-remitting MS disease activity (62.9% of our sample) was estimated to be associated with an incremental annual cost of €7,261 per relapse and €12,588 per year.

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At an average cost of €47,683 per annum and an Irish MS population of 9000, the total societal costs of MS amounted to €429m with 30% being accounted for by direct costs, 50% indirect, and 20% intangible or reduced QoL costs. Conclusions: Non-direct costs associated with MS represented up to 70% of the total societal costs associated with MS. These less salient or hidden costs increase with disease progression and are primarily driven by early and permanent workforce withdrawal. The ubiquity with which MS severity and relapse activity is a predictor of total costs in this study—as in the international literature—highlights the economic importance of reducing and delaying disease progression. Disclosure C. McGuigan has received research grants from Biogen, Genzyme, Novartis and Bayer, honoraria as a consultant from Biogen, Genzyme, Novartis and Roche. K. O’Rourke has received honoraria from Novartis. D. O’Boyle has received a fee from Novartis for data consultancy and writing services. A. Larkin is an employee of MS Ireland. MS Ireland received a research grant from Novartis Ireland in support of this study. P. Carney is an employee of Novartis Ireland. Ethical approval for the study was provided by UCD (LS-14-59). P374 A retrospective claims analysis: compliance and discontinuation rates among canadian MS patients treated with disease-modifying therapies - Canadian real world experience P. Duquette1, D. Rivest2, D. Selchen3, V. Devonshire4, V. Bhan5, M. Yeung6, R. Schecter7, P. Haddad7 1Notre-Dame Hospital, Université de Montréal, Montreal, 2Hôtel-Dieu de Lévis, Quebec, QC, 3St Michael’s Hospital MS Clinic, Mississauga, ON, 4University of British Columbia MS Clinic, Vancouver, BC, 5Dalhousie Multiple Sclerosis Research Unit, Halifax, NS, 6University of Calgary Multiple Sclerosis Clinic, Calgary, AB, 7Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada Background: Pharmacological management of relapsing-remitting multiple sclerosis (RRMS) includes the use of oral, injectable, or infusible Disease Modifying Therapies (DMTs). Optimal treatment in MS requires adherence to medication administration schedule. Objective: To assess compliance and discontinuation rates with DMTs in Canadian patients with RRMS. Methods: In this Canadian retrospective claims analysis based on IMS Rx Dynamics® database, patients had ⩾1 prescription filled for each DMT (oral: fingolimod, dimethyl fumarate (DMF), teriflunomide; injectable (BRACE): interferon beta-1a, interferon beta-1b, glatiramer acetate; infusible: natalizumab). Patients were considered compliant if the medication possession ratio (MPR) was ⩾80%. Discontinuation rates were calculated based on patients who stopped therapy (60 day window) or who were switched to another DMT. Compliance and discontinuation rates were collected for a 6-month period and discontinuation for 12 and 24-month periods (cohorts from 2012-2015, rolling 36 months total).


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Results: Compliance data was collected for 11448 patients (fingolimod, n=1476; DMF, n=2900; teriflunomide, n=1113; natalizumab, n=589; BRACE, n=5370). The percentage of patients deemed compliant after 6 months across Canada was higher for fingolimod (77%), compared to natalizumab (69%), DMF (62%), and BRACE (55%) and comparable to teriflunomide (77%). Patients on fingolimod had the lowest discontinuation rate after 6, 12 and 24-month periods (24%, 21%, 26% respectively) compared to: BRACE (48%, 42%, and 58%); natalizumab (34%, 30%, and 53%) and DMF (27%, 29% and 36%); and similar to teriflunomide at 6 and 12-month periods (24% and 23%), 24-month data was not available. Conclusions: The percentage of patients deemed compliant and treated with fingolimod was similar to teriflunomide, but higher than for other DMTs. The discontinuation rate was similar to teriflunomide, but lower compared to other DMTs over the short-term. Unlike other DMTs, the discontinuation rate with fingolimod did not significantly increase over the 24-month period. These findings may inform MS management strategies which may lead to improved clinical and economic outcomes. Findings based in part on data licensed from IMS Health Canada Inc. All Rights Reserved. Disclosure Pierre Duquette - Has received honoraria for advisory boards, for CMEs from Novartis, Biogen-Idec, Genzyme, EMD Serono and Teva Neurosience. He has taken part in Investigator-initiated trials funded by Novartis, Biogen-Idec, Genzyme and EMD Serono and has received funding from peer-reviewed agencies such as the Canadian Institutes for Health Research (CIHR) and the MS Society of Canada. Donald Rivest - Has received honoraria for consulting and advisory board participation from Biogen-Idec, Bayer, Novartis, Genzyme, EMD Serono and Teva Innovation. He has acted as site principal investigator for clinical trials for Biogen, EMD Serono and Novartis. Virginia Devonshire - Has received honoraria for advisory meetings and speaker honorarium from EMD Serono, Biogen-Idec, Teva Neurosciences, Novartis, Allergan and Genzyme. UBC has received payments for clinical trials in which Dr. Devonshire was the Principal Investigator from Novartis, Serono, and Genzyme. Virender Bhan - Has received honoraria for speaking, consulting, and advisory board participation from Biogen-Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience. He has acted as site principal investigator for clinical trials for Biogen-Idec, EMD Serono, Novartis, Sanofi-Aventis and Teva Neuroscience. Daniel Selchen - Has received honoraria for speaking, consulting and advisory board participation from Teva Innovation, Merck Serono, Genzyme, Novartis, Biogen-Idec, Bristol-Myers Squibb and Boehringer Ingelheim. Michael Yeung - Has received consultation fees from EMD Serono, Genzyme and Novartis, the Canadian Agency for Drugs and Technologies in Health (CADTH)/Health Canada, and research support from Biogen-Idec, Genzyme, Hoffmann-La Roche, Novartis, and Teva Canada Innovation. Robyn Schecter - Employee of Novartis Pharmaceuticals Canada Inc. Paola Haddad - Employee of Novartis Pharmaceuticals Canada Inc.

P375 Treatment discontinuation and clinic resource utilization among patients treated with fingolimod and dimethyl fumarate in the real-world setting P. Repovic1, Y. Park2, V. Herrera3 1Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, WA, 2University of Maryland School of Pharmacy, Baltimore, MD, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Fingolimod (FTY) and dimethyl fumarate (DMF) are two commonly used oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). While clinical trials have established the efficacy and safety of both agents, less is known about their performance and resource utilization in the real-world setting. Objective: To compare the real-world performance and resource utilization of FTY and DMF among patients with relapsing MS. Methods: Consecutive patients treated with FTY or DMF with available 12-month follow-up were retrospectively identified from the Swedish MS Center in Seattle, Washington. Patient demographic and MS characteristics were extracted from the medical record. Primary outcome was the discontinuation of index therapy. Secondary outcomes included time to and reason for discontinuation, as well as clinic resource utilization, defined as the number of clinic visits, phone calls, and lab tests. Chisquare, t-test, and Cox proportional hazard model were used to assess differences between two cohorts. Results: A total of 338 patients prescribed FTY (n=169) and DMF (n=169) were included in this study. At baseline, FTY cohort had longer MS disease duration (10.7 vs. 7.3 years; p=0.003) and slower timed 25-foot walk (6.7 vs. 5.5 sec; p=0.014); they were more likely to be treatment-experienced (94% vs. 83%; p=0.001) and stop prior DMT due to disease activity (39% vs. 25%; p=0.001) compared to DMF cohort. Overall discontinuation rate was low (13%, or 44 patients). Patients on DMF had numerically higher rate of treatment discontinuation (15% vs. 11%; p=0.196), but significantly greater number of phone calls (annualized mean+/-SD: 4.3+/-5.7 vs 3.4+/-3.8, p< 0.001), mostly due to greater number of clinic-initiated calls (1.3+/-1.5 vs. 1.0+/-1.9; p< 0.001). The leading reason for treatment discontinuation was tolerability in both groups; tolerability issue was reported more commonly in patients on DMF (13%) compared to patients on FTY (7%; p=0.044). Conclusions: Our study suggests that patients on FTY in realworld setting have more advanced MS at treatment initiation compared to patients on DMF. In contrast to other single-center studies we did not find the difference in discontinuation rates between FTY and DMF, possibly because of the overall low discontinuation rate. In keeping with previous studies, our results suggest better tolerability profile of FTY compared to DMF in the real-world setting. Disclosure P. Repovic: received compensation as consultant and/or speaker from Acorda, Biogen, EMD Serono, Genzyme, and Teva. Y. Park: employee of University of Maryland. V. Herrera: employee of Novartis. Source of funding: Novartis.


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Neuro-ophthalmology P376 Macular combined ganglion cell and inner plexiform layers (mGCIPL) thinning in the unaffected eye of patients at optic neuritis onset S. Collorone1,2, N. Cawley1, D.H. Milller1, A. Toosy1, O. Ciccarelli1,3 1NMR Research Unit, Queen Square MS Centre, Institute of Neurology, University College of London, London, United Kingdom, 2Sapienza University, Rome, Italy, 3NIHR University College London Hospitals Biomedical Research Centre, University College of London, London, United Kingdom Background: Optical Coherence Tomography (OCT) is emerging as a useful tool to monitor neurodegeneration during the progression of multiple sclerosis (MS). Monitoring the thickness of the retinal layers by OCT may help to predict disability worsening in patients with MS. Objectives: We aimed to compare specific retinal layers between patients at the onset of optic neuritis and healthy controls and assess correlations between retinal layers, brain volumes and clinical scores. Methods: We recruited 18 subjects (10F, mean [SD] age 33.5 yrs [±7.27]) with optic neuritis (ON), within 3 months of symptoms onset, and 12 healthy controls (HC) (8F, mean [SD] age 34.20 yrs [±7.07]. All subjects underwent a MRI protocol at 3T. Brain tissue segmentation was performed to obtain brain white matter and grey matter (GM) volumes. Spectralis OCT was used to quantify the peripapillary retinal nerve fibre layer (pRFNL) and the macular combined ganglion cell and inner plexiform layers (mGCIPL). Patients were assessed with Expanded Disability Status Scale (EDSS), MS Functional Composite score, (MSFC) and the Brief Cognitive Assessment for MS (BICAMS). Linear regression models were used to compare differences between groups adjusting for age and sex. In patients, Pearson’s correlation was used to explore the association between OCT parameters, brain volumes and clinical outcomes. Results: Patients with optic neuritis had a median EDSS of 1.0 (range 0 - 2.5) and were cognitively intact. Patients showed lower pRFNL and mGCIPL in the affected eye (AE) than HC (88.18±21 vs. 97.41±13 and 73.53±11 vs. 96.69± 7.6) (all p values< 0.02). They also had lower mGCIPL in the unaffected eye compared to HCs (88.61± 6.4 vs. 96.69±7.6, p< 0.02). Patients did not show significant differences in brain GM and WM volumes compared to HC. OCT parameters did not correlate with MRI measures and clinical scores. Conclusion: Previous studies in MS have shown that mGCIPL is a more sensitive and specific index of axonal loss than pRNFL, independent of ON history. Therefore, we extended these findings by reporting a thinning of mGCIPL not only in the affected, but also in the unaffected eye at the onset of ON. Our results suggest that measuring the mGCIPL thickness may provide early assessment of neurodegeneration. The next step is to investigate the relationship between early mGCIPL thinning in the unaffected eye, brain volume changes and clinical outcomes over time. Disclosure S Collorone 2016 AAN meeting expenses paid by Novartis N Cawley nothing to disclose

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D. H. Miller received grants from UCL/UCLH Biomedical Research Centre, during the conduct of the study; has received grants from Biogen, GlaxoSmithKline, the National Institute for Health Research, Novartis, and Apitope; has board membership with Biogen Idec, GlaxoSmithKline, Bayer Schering Pharma, and Mitsubishi Pharma Europe; has been a consultant for Merck and Chugai; and has received personal fees from McAlpine’s Multiple Sclerosis, 4th edition. A. Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation, Bayer and meeting expenses from Biogen Idec. O. Ciccarelli is an Associate Editor of Neurology and serves as a consultant for GE Healthcare, Novartis, Roche, Biogen, Genzyme and Teva. P377 Clinical and radiological characteristics of optic neuritis in demyelinating disorder with serum anti-MOG antibody I. Nakashima1, T. Akaishi1, T. Takeshita2, D.K. Sato1, K. Kaneko1, T. Nakazawa2, M. Aoki1, K. Fujihara3 1Neurology, 2Ophthalmology, Tohoku University, Sendai, 3Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan Background: The most common clinical manifestation in demyelinating disorder with serum anti-myelin oligodendrocyte glycoprotein (MOG) autoantibody has been revealed to be optic neuritis (ON). However, its characteristics in optic MRI and visual prognosis, compared to optic neuritis in other demyelinating disorders like multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), are not fully known. Methods: We retrospectively collected 69 MS patients with ON history (MS-ON; 75 ON-eyes), 23 NMOSD patients with ON history (NMOSD-ON; 27 ON-eyes), and 17 anti-MOG-Ab (+) patients with ON history (MOG-ON; 24 ON-eyes), all of whom visited and were followed up in Tohoku University Hospital between 2005 and 2015. The following information was collected: sex, onset age of ON, distribution of ON-lesions, ON-lesion length, nadir of visual acuity (VA) in the acute phase, and the latest VA in the chronic phase. Results: The onset age of ON was higher in NMOSD-ON. ON-lesion lengths in the acute phase were not significantly different among the three subtypes, though MOG-ON showed slightly longer ON-lesions. Intra-orbital lesions were the most frequent in MS-ON and NMOSD-ON, but intra-cranial lesions without chiasmal lesions were the most frequent in MOG-ON. The appearance of ON-lesions in the acute phase was the longest and most prominent in MOG-ON with severe swelling and meandering. Nadirs of VA in the acute phase were not significantly different among the three subtypes, but the latest VA in the chronic phase was significantly better in MOG-ON with almost full-recoveries. The visual prognosis in NMOSD-ON was slightly worse than that in MS-ON. Conclusions: Though the ON-lesions were the longest and most prominent in MOG-ON, visual prognoses were much better with almost full recovery in them. Disclosure All of the authors has nothing to disclose for this presentation.


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P378 Optical coherence tomography (OCT) pattern in myelinoligodendrocyte-glycoprotein (MOG) autoantibodies positive patients: characterised by severe optic neuritis and subclinical retinal axonal degeneration J. Havla1, T. Kümpfel1, R. Schinner2, M. Spadaro1, E. Schuh1, E. Meinl1, R. Hohlfeld1, O. Outteryck3 1Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet Muenchen, 2Institute of Clinical Radiology, Ludwig-Maximilians Universitaet Muenchen, Munich, Germany, 3University of Lille, Department of Neurology, Roger Salengro Hospital, Lille, France Objectives: Myelin-oligodendrocyte-glycoprotein (MOG) autoantibodies are present in subgroups of neuromyelitis optica spectrum disorder (NMOSD), recurrent unilateral or bilateral optic neuritis (rON), childhood or adult multiple sclerosis (MS), and - rarely - anti-NMDAR encephalitis, but the clinical significance and pathogenetic relevance of MOG abs remains to be further defined. It is well known that ON can occur in patients with MOG-abs, but in contrast to MS and AQP-4 associated NMOSD, characteristic OCT phenotype patterns have not been reported. We and others showed, that MOG-abs-positive patients might have severe retinal damage. Using optical coherence tomography (OCT), a non-invasive, high-resolution technique using lowcoherence interferometry to obtain cross-sectional images of the retina, we assessed whether MOG-abs might serve as potential marker of retinal axonal degeneration. Patients and methods: In this ongoing study we investigate a clinically heterogeneous cohort of MOG-abs-positive patients (N=13). As controls, we study age, sex and ON episode(s)matched MOG-abs-negative MS patients and healthy controls (HC). In addition, we investigate 19 unmatched aquaporin-4-abspositive NMOSD subjects. Results: Considering all eyes in a first analysis, global pRNFL (in µm, mean [sd]) was significantly reduced in MOG-abs-positive patients (72.56 [22.71]) compared to MOG-abs-negative MS (80.81 [13.55], p=0.0128), HCs (103.54 [8.529], p=0.0014) and NMOSD (88.32 [18.43], p=0.0353). Non-ON (NON) eyes from MOG-abs-positive subjects showed significant subclinical atrophy of temporal pRNFL quadrants. Microcystic macular edema (MME) was observed only in eyes of MOG-abs-positive (24%) and aquaporin-4-positive NMOSD (5.6%), but not in MOG-absnegative MS or HC (p< 0.01). Conclusions: We show further evidence that MOG-abs may serve as potential markers of retinal degeneration. Specifically, MOGabs-related OCT features a) show atrophy that predominates in temporal pRNFL quadrants (resembling the MS retinal pattern), b) differ from the retinal pattern of NMOSD, c) indicate subclinical pathology in NON eyes, and d) may be associated with MME.

Sanofi-Aventis, and Biogen as well as grant support from BayerSchering AG and Novartis. RS has nothing to disclose. MS has nothing to disclose. ES has nothing to disclose. EM has received grant support from Novartis and personal compensations from Roche. RH is supported by the Deutsche Forschungsgemeinschaft, Munich Cluster for Systems Neurology (SYNERGY) and the KKNMS and has received personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Biogen, Novartis Pharma, Sanofi-Aventis and Genzyme. OO reports grant for research from Novartis; grants and personal fees from Biogen, Genzyme-Sanofi, Merck-Serono, Novartis and Teva Pharmaceuticals Industries, outside the submitted work. P379 RIsk of multiple sclerosis after optic neuritis in patients with normal baseline MRI H.D. Hambardzumyan, H.M. Manvelyan Neurology, Yerevan State Medical University, Yerevan, Armenia Introduction: Optic Neuritis (ON) is the initial presentation of multiple sclerosis (MS) in approximately 20% of patients. Although abnormal baseline brain MRI is the strongest conversion predictor, patients with normal MRI can also develop MS. In these patients predictors of conversion are still to be determined. Our objective is to estimate MS risk and identify conversion predictors in ON patients with normal baseline MRI. Methods: Retrospective chart review of patients with idiopathic ON and normal MRI, presenting to our hospital between 2005 and 2015. Demographic, clinical, paraclinical and treatment data were collected and analyzed. Results: 44 patients were included. 10 patients converted to MS, seven during the first 2 years and the remaining during the next 3 years. 5-year MS conversion rate was 25.8%. A statistically significant increase in MS conversion rate was associated with retrobulbar ON (p=0.024), a history of previous symptoms suggestive of demyelination (p=0.002), positive oligoclonal bands in CSF (p=0.004) and incomplete recovery (p=0.002). Age, sex, ON laterality, other neurological exam abnormalities, abnormal visual evoked potentials, corticosteroid treatment or ON recurrence were not associated with a significant increase in MS conversion rates. Conclusion: A considerable proportion of patients with ON and normal baseline brain MRI will develop MS. The risk of conversion appears to be higher during the first 2 years, so follow up, at least during this period, is advisable. Early immunomodulatory treatment may be considered individually, especially in patients with multiple factors associated with increased MS conversion risk

Disclosure

Disclosure

JH received speaker honoraria, travel expenses, and personal compensations from Merck Serono, Bayer Healthcare, Sanofi Genzyme and Novartis Pharma. TK has received travel expenses and speaking honoraria from Bayer Healthcare, Genzyme, Teva Pharma, Merck-Serono, Novartis,

nothing to disclose P380 The value of visual parameters which evaluated overt or subclinical optical neuritis in multipl sclerosis by various methods


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Poster Session 1, 22(S3) Ö. Öcek1, M. Gedizlioğlu1, A. Köşkderelioğlu1, P. Kurceren Ortan1, B. Yüksel2, M. Türe3, F. Gediz2 1Neurology, 2Ophthalmology, Izmir Bozyaka Training and Reseach Hospital, 3Ophthalmology, Atagöz Ophthalmological Diseses Hospital, Izmir, Turkey Objective: In this study we aimed to analyze the relationship of the visual function tests with the disability scales and to investigate their value in detecting overt or subclinical optical neuritis (ON) in MS. Material and method: 66 MS patients were included. Of these, 59(89,4%) had relapsing-remitting, and 7(10,6%) secondary progressive. Patients were divided into two groups as those who have ON and who have not. EDSS, MSFC scores were calculated. The examinations carried out were as follows: visual field test, visual acuity(VA) with high contrast(100%) and low-contrast(2,5% and 1,25%) cards, Snellen scale, visual evoked potential(VEP) and optic coherence tomography(OCT). The National Eye Institute 25-item Visual Function Questionnaire(NEI-VFQ-25) which measures the influence of visual disability and visual symptoms on generic health domains, was applied. Results: 132 eyes of 66 MS patients, 48 females(72,7%) and 18 males(27,3%) with ages ranging from 18 to 49(36,8±7,3), were included. Significantly more visual affection was detected in the ON group with low-contrast VA cards compared to high contrast VA cards and Snellen scale(p=0,007). Average peripapillary retinal nerve fiber layer(pRNFL), ganglion cell layer(GCL), macular RNFL(mRNFL) thickness and total macular volume were found significantly less in 65 eyes with ON history compared to those who had no such previous history(p< 0,0001; p=0,028; p=0,002; p=0,025). When homologous quadrants of visual fields and pRNFL thickness in OCT were compared; OCT revealed more and statistically different abnormalities(p< 0,001). Correlations of pRNFL with VEP latency and low-contrast VA charts were found significant(p< 0,001). Whereas a significant correlation between low-contrast VA cards and VEP abnormalities was found. Significant relationships were detected between low-contrast VA cards and NEI-VFQ-25 test, also disability scales (EDSS, MSFC)(p< 0,0001). Conclusion: Low-contrast VA test that is superior in displaying alterations of visual activity. Combined with VEP and OCT, lowcontrast VA test applied at certain intervals can detect subclinical optic abnormality with high accuracy. Disclosure no financial disclosure nothing to disclosure P381 Optic neuritis in anti aquaporine 4 and myelin oligodendrocyte glycoprotein autoantibody: a comparative study K. Lecouturier, R. Deschamps, J. Savatovsky, A. Lecler, C. Vignal, J. Aboab, O. Gout Fondation Rothschild, Paris, France Studies using cell-based immunoassays have demonstrated the presence of antibodies (Abs) targeting aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) in some patients with optic neuritis (ON) not related to multiple sclerosis.

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Objective: To compare the characteristics of ON in two populations, AQP4 positive and MOG positive. Methods: We retrospectively reviewed the medical records of all the patients admitted in our institution with ON associated with AQP4 or MOG Abs. Demographic characteristics, clinical neurologic and ophthalmic findings, cerebrospinal fluid (CSF), brain and orbital MRI and OCT features, treatments, and course of disease were studied. Results: 24 AQP4+ patients (leading to 62 ON episodes; 87.5% women) and 12 MOG+ patients (28 ON; 58.3%) were analyzed. We found no significant differences concerning age of onset, annual rate of inflammatory events, and time before relapses. Patients with MOG Abs had significantly more bilateral ON (p=0.0059) and better initial visual acuity (p=0.033), mean deviation of the visual field (p=0.009), and final visual acuity (p=0.046). Area postrema syndrome, oligoclonal bands in CSF and posterior visual pathway involvement on MRI were not observed in our MOG population. Conclusion: Our study confirm that ON with MOG-Abs have distinctive features than AQP4+ patients, in particular better visual prognosis, but the risk of relapse isn’t different. Disclosure Karen Lecouturier: Nothing to disclose P382 Prevalence of internuclear ophthalmoplegia in multiple sclerosis: a prospective infrared oculography study J.A. Nij Bijvank1,2, L. Balk1, H.S. Tan2, B.M.J. Uitdehaag1, L.J. van Rijn2, A. Petzold1,3 1Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, 2Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands, 3Moorfields Eye Hospital, London, United Kingdom Background: Demyelinisation is a key pathologic feature in multiple sclerosis which causes a plethora of symptoms. One very specific symptom is gaze evoked diplopia due to internuclear ophthalmoplegia (INO), caused by a demyelinating lesion in the medial longitudinal fasciculus (MLF). Clinically it is not always straightforward to recognise the adduction delay. With infrared oculography however, even a mild INO can readily be detected. This study aimed to describe the prevalence of INO and vision related quality of life in patients with multiple sclerosis. Methods: A prospective, single-centre, infrared oculography study. We developed and validated a standardised protocol suitable for a multicenter setting, the DEMONS-protocol. For the prosaccade task, the versional dysconjugacy index, (VDI, describing the ratio between abducting and adducting eye), for peak velocity was calculated. The repeatability of this VDI is very high (intraclass correlation coefficient of 0.90-0.95). A z-score of 1.96 of the VDI values of the healthy controls was taken as a threshold for detecting INO. Patient characteristics and vision-related quality of life, determined by the Visual Function Questionnaire (VFQ-25), were compared between MS patients with and without an INO, taking a history of MS associated optic neuritis (MSON) into account. Results: 47 MS patients and 13 healthy controls were included. The mean VDI of the healthy controls was 1.07 (SD 0.09). A


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z-score of 1.96 corresponded to a VDI of 1.24. Consequently, all MS patients with a VDI to the left or right above the cut-off of 1.24 were considered having an INO. This resulted in 11 (23%) patients with an INO, of which 6 bilateral. Compared to the nonINO group, the INO group tended to be older (mean of 55 vs. 51 years), to have a longer disease duration (mean of 18 vs. 16 years), a higher EDSS (median of 3.5 vs. 3.0), and more frequently secondary progressive disease (36% vs. 14%). The VFQ-25 mean score in the INO group was 82, minimally worse compared to the non-INO group (mean score of 87, p>0.05). The rate of MSON was slightly higher in the INO group (55%) compared to the nonINO group (50%, p>0.05). Conclusion: We found an INO in 23% of the MS patients, which was clinically documented in 1 patient (9%) only, despite another 6 patients mentioning visual problems due to diplopia. These data suggest that about a quarter of patients with MS suffer from INO, which is recognised clinically only in a minority.

INO), was normal in her case (right eye 271 degr/s, left eye 302 degr/s). The VDI (versional dysconjugacy index) for peak velocity, more clearly illustrated the discrepancy between ab- and adduction with the former been delayed in both eyes (VDI to the right 0.81, to the left 0.73). There was no abduction paresis. MR imaging showed a T2 hyperintense lesion in the posterior pons involving the medial longitudinal fasciculus (MLF) and right nucleus prepositus hypoglossi. In addition she fulfilled the radiological criteria for dissemination in space (>2 periventricular, juxtacortical, infratentorial and spinal lesions) and on subsequent MRI dissemination in time with a new contrast enhancing lesion in the cerebellum. She is diagnosed of having posterior INO of Lutz, first described by the German ophthalmologist Anton Lutz in 1923. This clinically succinct diagnosis is rarely described in literature, and only a few cases caused by multiple sclerosis have been reported. Disclosure

Disclosure J.A. Nij Bijvank: nothing to disclose L. Balk: the VUmc MS Centre received research support from TEVA H.S. Tan: nothing to disclose B.M.J Uitdehaag: has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. L.J. van Rijn : nothing to disclose A. Petzold: is member of the steering committee for the OCTiMS study (Novartis), no consulting fees. Performs OCT QC for the Passos study (Novartis), receives consulting fees. P383 A rare variant of INO in multiple sclerosis: posterior INO of Lutz J.A. Nij Bijvank1,2, L. Balk1, H.S. Tan2, B.M.J. Uitdehaag1, L.J. van Rijn2, A. Petzold1,3 1Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, 2Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands, 3Moorfields Eye Hospital, London, United Kingdom Internuclear opthalmoplegia (INO) is a common eye movement disorder in multiple sclerosis (MS). We describe a patient who showed an unusual variant, called posterior or reverse INO of Lutz. Our 22 year old patients was recently diagnosed with MS. One year earlier she experienced a left Bell´s palsy associated with nausea and vertigo. After recovering, she transiently suffered from left hemisensory symptoms in her limbs and a second Bell´s palsy occurred, this time on the right. She was treated with corticosteroids and made a full recovery. Importantly, she describes a number of problems with her visual function. First, cycling in a busy Dutch environment she has difficulties focusing when she turns her head. The same is the case in a busy shopping mall, or when she is doing computer work for an extended period of time. She also describes episodes of short lasting gaze evoked binocular horizontal diplopia. Suspecting an INO we performed infrared-oculography (Eyelink 1000 plus). The recordings of the pro-saccades did show a minimal delay in abduction for both eyes (right eye 221 degr/s, left eye 220 degr/s). In contrast, adduction,(typically delayed in

J.A. Nij Bijvank: nothing to disclose L. Balk: the VUmc MS Centre received research support from TEVA H.S. Tan: nothing to disclose B.M.J Uitdehaag: has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. L.J. van Rijn: nothing to disclose A. Petzold: is member of the steering committee for the OCTiMS study (Novartis), no consulting fees. Performs OCT QC for the Passos study (Novartis), receives consulting fees.

Pathology P384 Systemic vascular disease burden in multiple sclerosis: a post mortem case - control study R. Geraldes1, M. Esiri2, J. Palace1, G. De Luca2 1Clinical Neurosciences Department, 2Neuropathology Department, Oxford University Hospitals, Oxford, United Kingdom Introduction: Vascular disease burden may contribute to Multiple Sclerosis (MS) progression and reduced life expectancy. Few in vivo studies assessed markers of atherosclerosis with no post mortem study to date having systematically evaluated vascular burden in MS. We aim to obtain a reliable systemic vascular disease score determined by autopsy and to compare it in MS versus non-MS cases. Materials and methods: MS and non-MS cases older than 35 were selected from the Oxford Brain Bank (1971-2001). The following variables were obtained by two independent raters from autopsy reports: gender, age at death, cause of death, aorta and coronary arteries atheroma; cardiac weight; renal hypertensive disease (RH); myocardial infarction (MI); and stroke. A total systemic vascular disease score (SVDs) was computed from individual variables. Results: 71 MS cases (mean age 60.9±12.2, 57.7% females and 40 controls (mean age 62.1±13.3, 55.5 % females) were included, with no significant differences in age or gender between groups. In terms of causes of death, infections were more common in MS


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Poster Session 1, 22(S3) compared to controls, while cancer and stroke/MI were more common in controls. No significant differences between individual scores of arterial atheroma, RD, MI or stroke were found between groups. Heart weight and ischemic stroke were greater in controls compared to MS, but this difference was no longer significant after excluding cases with stroke/MI deaths from both groups. However even excluding these cases total SVDs was lower in MS cases when compared with controls. Conclusion: In our cohort, we found lower total SVDs in MS cases when compared with controls. This is the first study to combine detailed systemic autopsy findings related to vascular disease in MS cases and sets the stage for systematic interrogation of the interaction of vascular disease and MS pathology. Disclosure Nothing to disclose P385 Immunohistochemical characterization of mesenchymal perivascular stem/stromal cells in multiple sclerosis and healthy brain tissue E. Iacobaeus1,2, R.V. Sugars3, A.A. Törnqvist1, J.J. Alm1, K. Alkass4, H. Druid4, M. Röyttä5, K. Le Blanc1 1Clinical Research Centre, Department of Laboratory Medicine, 2Department of Clinical Neurology, 3Oral Facial Diagnostics and Surgery, Department of Dental Medicine, 4KI Donatum, Department of Forensic Medicine, Karolinska Institute, Stockholm, Sweden, 5Department of Pathology, University of Turku, Turku, Finland Perivascular tissues of multiple human adult organs were recently found to harbor mesenchymal stem/stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. MSCs display potent immunoregulatory and regenerative properties and are currently evaluated as cellular therapy for different disease’s, including Multiple Sclerosis, (MS). Although well defined in vitro, the true in vivo identity and function of MSCs is poorly investigated. In this study the presence, distribution and proliferative activity of a cell population termed “mesenchymal perivascular stromal cells” (MPCs) was identified and assessed in MS and healthy brain tissue. Serial sections of post-mortem brain tissue blocks from progressive MS (n=11) and healthy persons (n=5) were used for immunohistochemical analyses of MSC and pericyte markers. The MS tissue included active lesions (n=9), chronic active lesions (n=18), inactive lesions (n=5) and normal appearing white matter (n=7). Cells co-expressing MSC/perictye markers were exclusively found in the perivascular tissue of both healthy and MS brain tissue. Two distinct MPCs subtypes were identified by marker expression and localization, including a CD146+PDGFRbeta+ population in the tunica media and a CD73+CD271+PDGFRbeta+cell population in the adventitia. Active and chronic active demyelinating MS lesions possessed increased number of vessels with significantly increased localization of MPCs, most prominently found in the adventitial layer (p< 0.0001). Both MPC subpopulations displayed proliferative activity, as demonstrated with positive KI67 staining in both MS and healthy brain vessels. The CD146+PDGFRbeta+ population in chronic active lesions displayed increased proliferative activity compared to healthy tissues (p< 0.0001). Our data provide further

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evidence for the vascular niche as an origin for MSCs. In addition our results suggest that cerebral vessels contain mesenchymal progenitor cells that respond to disease processes in MS. Disclosure The authors have nothing to disclose. P386 Pro-inflammatory cytokine elevation in MOG-Ab+, AQP4-Ab+ disorder and MS K. Kaneko1, D.K. Sato1,2,3, R. Ogawa1, T. Akaishi1, Y. Takai1, S. Nishiyama1, T. Takahashi1,4, T. Misu1,5, H. Kuroda1, S. Tanaka6, I. Nakashima1, K. Nomura6, D. Callegaro2, K. Fujihara5,7, M. Aoki1 1Department of Neurology, Tohoku University, Sendai, Japan, 2São Paulo University, São Paulo, 3Brain Institute and Hospital Sao Lucas Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil, 4Department of Neurology, NHO Yonezawa Hospital, Yonazawa, 5Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, 6Department of Neurology, Saitama Medical Center, Kawagoe, 7Department of Neurology, Fukushima Medical University, Fukushima, Japan Objective: To examine acute phase cerebrospinal fluid(CSF) cytokine levels in myelin oligodendrocyte glycoprotein(MOG)Ab+ cases, compare the result with the clinical and laboratory findings, and then compare the results with those in aquaporin4(AQP4)-Ab+ cases, multiple sclerosis (MS), and noninflammatory cases. Methods: We measured 27 cytokine/chemokines by multiplex fluorescent bead-based immunoassays, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) level by commercially available ELISA assays in the CSF of 26 MOGAb+(>18yo: n=13, < 18yo: n=13), AQP4-Ab+(n=19), MS(n=12), non-inflammatory neurological diseases (n=16). In patients with MOG-Ab+ and AQP4-Ab+, antibody status was examined both in serum and CSF using cell-based assays. Samples were collected in acute phase (< 30 days from onset) before treatment except for non-inflammatory cases. Results were analyzed with clinical information, antibody titer, and CSF routine examination. Results: IL-6,IP-10, and IFN-1ra were significantly elevated in MOG-Ab+ and AQP4-Ab+ cases as compare with MS. IL-10 and IL-15 were higher in MOG-Ab+ cases than in MS. G-CSF was significantly higher in MOG-Ab+ cases than in AQP4-Ab+ cases and MS while GM-CSF was much higher in MS than in MOG-Ab+ and AQP4-Ab+ cases. Cytokines levels were not different in various clinical phenotypes (ADEM, NMOSD, myelitis, and optic neuritis) of MOG-Ab+ cases. In comparison of adult and pediatric cases, IL17A was significantly elevated in adult group. Unlike significant association between AQP4-Ab titers/IL-6 and GFAP in AQP4-Ab+ cases, there was only mild associations between serum/CSF MOG-Ab titers, cytokine orroutine CSF findings and CSF-MBP level in MOG-Ab+ cases. Conclusion: In MOG-Ab+ cases, cytokine profile including significantly elevated IL-6 was largely similar to AQP4-Ab+ cases but was different from MS. However, considering the relatively mild correlation between MOG-Ab titers/IL-6 and MBP level as compared with AQP4-Ab+ cases, in addition to MOG-Ab, other


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pathogenetic factors, such as T, B and other immune cells, may be needed in the lesion development in MOG-Ab+ diseases. Disclosure Kimihiko Kaneko: no discloser Douglas Kazutoshi Sato: a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brasil (CSF-PAJT—88887.091277/ 201400) and speaker honoraria from Novartis Ryo Ogawa: nothing to disclos Yoshiki Takai: nothing to disclose Shuei Nishiyama: nothing todisclose Toshiyuki Takahashi: nothing to disclose Tatsuro Misu: speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co, and Astellas Pharma Inc, and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co, The Chemo-SeroTherapeutic Research Institute, Teva Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan Hiroshi Kuroda: grants from the Ministry of Education, Culture, Sports,　Science and Technology of Japan Satoru Tanaka: nothing to disclose Ichiro Nakashima: grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and from Ministry of Health, Labour and Welfare of Japan, personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd, and grants from LSI Medience Corporation; SN JSPS KAKENHI Grant (Grant-in-Aid for Young Scientists(B)) Number 26860656; RM serves on the scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen Idec, Merck Serono,Novartis, Sanofi-Genzyme and Teva Kyoichi Nomura: personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Astellas Pharma Inc, personal fees from Chemo-Sero-Therapeutic Research Institute and personal fees from Teijin Pharma Dagoberto Callegaro: nothing to disclose Kazuo Fujihara: scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc, Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co, Daiichi Sankyo and Nihon Pharmaceutical; serves as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and is an advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical and Genzyme Japan; and

is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigatorby the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Masashi Aoki: nothing to disclose P387 Temporal changes of pathological features in NMO spectrum disorders with aquaporin4 antibody Y. Takai1, T. Misu2, I. Nakashima1, H. Kuroda1, T. Takahashi3, S. Nishiyama1, K. Kaneko1, T. Akaishi1, R. Ogawa1, K. Fujihara4, M. Aoki1 1Neurology, Tohoku University, 2Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, 3Department of Neurology, Yonezawa National Hospital, Yonezawa, 4Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan Background: Neuromyelitis optica spectrum disorders (NMOSD) is pathologically characterized by massive astrocyte destruction, and NMOSD-specific aquaporin 4 (AQP4) antibody probably plays a pathogenetic role in damaging AQP4-expressing astrocytes. However, detailed neuropathological analyses have revealed the diversity of lesion types including predominantly demyelinating lesions as well as astocytopathic ones. It is unclear whether the different lesion types are associated with the clinical stage of NMO patients under the definite diagnosis with AQP4 antibody. Objective: To clarify the temporal pathological changes in the lesions of NMOSD seropositive for AQP4 antibody (AQP4Ab+NMOSD). Material and method: We analyzed seven autopsied cases of AQP4Ab+NMOSD (Three with the acute lesions [AL, autopsied within 3 months of last relapse] and four with the chronic lesions [CL, no relapse for more than a year]). Brain and spinal cord lesions were evaluated by neuropathological and immunohistochemical techniques with specific markers of astrocytes, oligodendrocytes, myelin sheaths, axons, complements and inflammatory cells. We measured the areas of demyelinating, astrocytopathic and neuronopathic lesions and the combined areas of the lesions in each case, and calculated the percentage of area of each lesion type relative to all lesion areas. Inflammatory changes in clinical stages were also evaluated. Result: Disease durations were 0.3±0.3 years in cases with AL and 15.8±5.1years in ones with CL. Large loss of AQP4 staining regardless of astrocyte destruction was seen in most AL (91.2±9.5%) but less common in CL(30.5±25.5%, P< 0.05). Astrocyte destructive lesions were also a major pathology in AL (82.7±24.0% vs 7.4±13.4% in CL, P< 0.05). Meanwhile, gliosis with or without AQP4 staining was extensive in CL (60.8±24.8% vs 6.7±11.5% in AL, P< 0.05), and demyelinating lesions with preserved axons and gliosis were widespread in CL, too (50.0±35.5% vs AL 3.9±6.7% , P< 0.05). Lesions with macrophage infiltrations were frequently seen in AL (54.4±15.9% vs 4.2±7.2% in CL). Perivascular complement deposits were distinct between AL and CL (C9 (activated); AL 3/3 cases vs CL 0/4 cases, C3d (degraded); AL 1/3 vs CL 3/4). Conclusion: Extensive astrocyte destruction with active inflammation is a feature of AL in AQP4Ab+NMOSD, while gliosis and demyelinating lesions spread in CL. These temporal


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Poster Session 1, 22(S3) changes should be carefully considered in making the pathological diagnosis. Disclosure Dr. Takai Y has received research support from a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr. Misu T has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Dr. Nakashima I has received funding for travel and received speaker honoraria from Tanabe Mitsubishi Pharma Corporation and has received research funding from LSI Medience Corporation and the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr. Kuroda H has received research support from a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr. Takahashi T reports no disclosures. Dr. Shuhei Nishiyama has received research support from a grantin-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr. Kaneko K reports no disclosures. Dr. Akaishi T reports no disclosures. Dr. Ogawa K reports no disclosures. Prof. Fujihara K serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and an advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#22229008, 2010-2015；#26293205, 2014-2016) and by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Prof. Aoki M has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan.

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Inflammation and tissue damage P388 Claudin-4 is required for astrocytic tight junction formation and protects against inflammatory lesion size and severity in the central nervous system C. Chapouly, S. Horng, A. Therattil, A. Tadesse Argaw, G.R. John Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States Objective: To characterize molecular mechanisms that mediate the protective function of reactive astrocytes against inflammatory Central Nervous System (CNS) lesion size and severity. Background: A protective barrier restricts the passage of lymphocytes and soluble proteins from the bloodstream into the CNS parenchyma. This barrier termed the blood brain barrier (BBB), has been characterized as a single layer consisting of tight-junction (TJ) bonds between CNS microvascular endothelial cells. However, recent work deleting the layer of astrocytes encircling the BBB has revealed a protective role for this additional layer, termed the glia limitans (GL), in delimiting lesion size and severity. We hypothesized that astrocytes form TJs themselves at the GL under conditions of inflammation, thereby representing a second line of defense distal to the BBB. Design and methods: We screened for changes in TJ molecule expression in primary human astrocytes under control and inflammatory conditions, a model of reactive astrogliosis, and positively identified three molecules : claudin-1, claudin-4 and JAM-A. Immunohistochemistry and immune-EM of two in vivo mouse models of inflammatory CNS disease revealed that all three proteins localized to TJ between astrocytic endfeet at the GL. In vitro co-culture assays of reactive astrocytes, in which these genes were silenced using siRNA, and CD3+ T cells, demonstrated that all three proteins regulate the capacity of reactive astrocytes to limit migration of inflammatory cells. An astrocyte-specific claudin-4 knock out mouse was used to characterize lesion pathology and was found to have increased lesion size and severity as well as significantly exacerbated clinical disability in experimental autoimmune encephalomyelitis (EAE). Results: We report the presence of a second TJ barrier between the blood and the CNS, at the GL, composed of claudin-1, claudin-4 and JAM-A, which are dynamically upregulated in response to inflammatory stimuli. In vitro, claudin-4 knock-down in reactive astrocytes limits their ability to restrict leukocyte dispersion. In vivo, astrocytespecific loss of claudin-4 leads to increased lesion size in inflammatory models, and worsened clinical disability in EAE. Conclusions: reactive astrocytes upregulate claudin-1, claudin-4 and JAM-A, leading to the formation of TJs and a second barrier distal to the classical BBB at the GL, which protects against the size and severity of inflammatory CNS lesions. Disclosure Candice Chapouly: nothing to disclosure P389 High prolactin serum level predicts low inflammatory damage during INF-beta treatment in patients with MS L. De Giglio1, F. Marinelli2, V.T. Barletta2, L. Prosperini1, F. Gurreri2, V. Tomassini3, P. Pantano1, C. Pozzilli1


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and Psychiatry, Sapienza University, 2MS Centre, Sant’Andrea Hospital, Rome, Italy, 3Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, United Kingdom Background: The relationship between prolactin (PRL) serum levels and white matter volume in patients with multiple sclerosis (MS) supports a role of PRL in promoting myelin repair. In experimental models, PRL shows beneficial effects on clinical signs of disease when administered in combination with Interferon beta (IFN beta). Here, we test the hypothesis that PRL serum levels predict the development of inflammatory damage during the treatment with IFN beta. Methods: Blood samples for the assessment of PRL serum level were obtained in relapsing-remitting MS (RRMS) patients who were randomly assigned in a 1:1:1 ratio to receive subcutaneous IFN beta only or IFN beta in association with two different doses of estroprogestins. Patients underwent brain MRI scan and clinical evaluation at baseline and after 1 and 2 years of treatment. We quantified white matter hyperintense lesion volume on T2-weighted images (T2LL) and hypointense lesion volume on T1-weighted pre- and post-contrast images (T1LL and Gd+LL). We also calculated the number of combined unique active (CUA) lesions, defined as new T2 lesions or gadolinium enhancing (Gd+) lesions without double counting. Baseline predictors of CUA number during IFN beta treatment were assessed with a Poisson regression model. Results: We included 99 women with MS with a mean (SD) age of 30 (7) years, mean MS duration of 3.5 (3.8) years, median EDSS of 1.5 (range 0-4.5); mean PRL level was 13.8 (7.7) ng/ml. No correlation was found between PRL levels and demographic or clinical baseline data. PRL level showed a negative correlation with baseline T2LL and T1LL (rho=-0.245, p=0.014 and rho=0.236 p=0.018, respectively), but not with Gd+LL. Mean number of CUA was 1.9 (2.6) at year 1 and 1.4 (3.17) at year 2. We found a negative correlation between CUA number at 2 year and baseline PRL level (rho=-0.221, p=0.02). Lower CUA number at year 2 was predicted by higher EDSS score (HR 0.373, 95%CI 0.2820.494, p< 0.001), higher PRL levels (HR 0.557, 95% CI 0.4350.713 p>0.001) and the absence of Gd+ lesions (HR 3.506, 95%CI 2.318-5.304, p< 0,001) at baseline. Conclusion: The association between higher baseline levels of PRL and lower inflammatory damage at follow-up suggests that PRL is an independent predictor of tissue damage development during treatment with IFN beta. Disclosure LDG has nothing to disclose FM has nothing to disclose VTB has nothing to disclose LP has received consulting and/or lecture fees and travel grant from Bayer Schering, Biogen Idec, Genzyme, Biogen Idec, Novartis and Teva FG has nothing to disclose VT has nothing to disclose PP has received founding for travel from Novartis, Genzyme and Bracco and speaker honoraria from Byogen CP has received consulting and lecture fees from Bayer Schering, Biogen, Merck-Serono, Novartis, and Sanofi-Aventis; has received research funding from Bayer Schering, Merck Serono, Novartis, and Sanofi-Aventis.

P390 Th17 induced neuronal injury is initiated by KV1.3-mediated glutamate release K. Birkner1, D. Luchtman1, T. Ruck2, S.G. Meuth2, F. Zipp1, S. Bittner1 1Neurology, University Medical Center of the Johannes Gutenberg University, Mainz, 2Neurology, University of Muenster, Muenster, Germany Ion channels are increasingly recognized as pivotal regulators of (patho-) physiological immune cell responses (Bittner and Meuth, Ther Adv Neurol Disord 2010). The voltage-gated potassium channel KV1.3 (KCNA3) has been reported to play a role in the regulation of T cell-mediated autoimmune disorders and high levels of KV1.3 (KCNA3) are expressed by autoreactive T cells isolated from patients with multiple sclerosis (MS). We have previously characterized critical steps in direct T cell-mediated neuronal damage by intravital two-photon microscopy of EAE lesions in the brainstem (Siffrin et al., Immunity 2010). Infiltrating Th17 cells in EAE lesions induce severe, localized, and partially reversible fluctuation in neuronal intracellular Ca2+ concentration as an early sign of neuronal damage. However, the underlying pathways are still only partially understood. Here, we investigate the role of KV1.3 channels in pathogenic Th17 cells for T cell-neuron interaction (Liblau et al., Trends Neurosci 2013) using intravital two-photon microscopy (2PM). Intracellular Ca2+ influx following T cell receptor stimulation was decreased in differentiated Th17 cells after treatment with selective channel blockers. KV1.3 blockade significantly reduced the immediate glutamate release in Th17 cells, but not in neurons lacking KV1.3 in vitro. We also made use of a transgenic neuronal Ca2+ indicator for assessing neuronal responses in a Th17mediated adoptive transfer EAE model in vivo. Local application of KV1.3 blockers leads to significantly decreased intracellular Ca2+ levels in neuronal soma in the presence of Th17 cells. In summary, our results characterize a novel KV1.3-controlled pathway of acute T-cell mediated neuronal damage in autoimmune neuroinflammation and point towards a control of Ca2+mediated vesicular glutamate release by KV1.3 in Th17 cells as a novel effector pathway. Disclosure All authors declare no conflict of interest. P391 The neuroprotective protein ARNT2 as a mediator of neuronal health and disease progression in models of MS T. Rahim, A. Yu, J. Quandt Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada The process of axonal degeneration and neuronal loss has been described as the major cause of irreversible clinical disability in multiple sclerosis (MS). Preliminary work shows aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2), a transcription factor with neuroprotective properties, changes over the course of experimental autoimmune encephalomyelitis (EAE) correlating with disease progression and recovery. We hypothesized that alterations in ARNT2 are relevant to neuronal health and disability in


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Poster Session 1, 22(S3) MS. ARNT2 expression was characterized in chronic EAE and also in primary neuronal, astrocyte and microglial populations in response to inflammatory mediators for its relevance to cell viability and function. In healthy spinal cord, ARNT2 expression is largely limited to neuronal cell bodies of the tracts and cells of the grey matter, with some staining in in 20-30% of astrocytes in white matter. At acute and chronic stages of the disease, ARNT2 increases, particularly within astrocytes in lesioned/inflamed areas. ARNT2 % positivity and expression increases 1.6 and 2.7 fold in GFAP positive astrocytes within the white matter of EAE mouse spinal cords (p< 0.05). Whereas GFAP+ astrocytes are typically absent from healthy grey matter, EAE cords show numerous reactive astrocytes with nearly 100% of cells staining intensely for ARNT2. Examination of individual neurons in vitro reveals that most cells demonstrate low-medium ARNT2 expression under steady-state conditions. Exposing neurons to apoptotic stimuli and hydrogen peroxide to mimic oxidative stress rapidly increases ARNT2. Primary cultures of astrocytes and microglia express low and negligible ARNT2 respectively but expression increases in microglia with lipopolysaccharide and interferon-γ exposure in vitro. Studies are ongoing to examine the functional relevance of ARNT2 expression in neuronal and glial populations in addition to examining ARNT2 expression in MS lesions compared to healthy tissues and other neurodegenerative disorder cases. This work uniquely demonstrates temporal regulation of ARNT2 follows disease onset and progression in models of MS, and that stressors including inflammatory mediators are able to alter ARNT2 expression throughout the CNS. Given known and as yet uncharacterized neuroprotective roles for ARNT2 in the CNS, our studies highlight ARNT2 as a plausible target for the modulation of inflammatory and neurodegenerative processes that contribute to MS. Disclosure Tissa Rahim: nothing to disclose P392 IFNγ reduces expression of connexin43 in astrocytes via activation of microglia M. Watanabe1, K. Masaki1, R. Yamasaki1, J. Kawanokuchi2, H. Takeuchi2,3, A. Suzumura2, J.-I. Kira1 1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 2Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 3Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan Objective: We previously reported extensive loss of astrocytic connexins (Cxs) in multiple sclerosis (MS) lesions. Because it is widely accepted that autoimmune T cells cause MS lesions, we hypothesized that inflammatory T cells would affect Cxs expression in astrocytes and contribute to MS lesion formation. We assessed whether interferon (IFN)γ, interleukin (IL)-4, or IL-17, which is produced by Th1, Th2, or Th17 cells, respectively, reduced Cx43 expression in astrocytes. Methods: Primary mixed glial cell cultures mainly composed of astrocytes and microglia were prepared from the brains of

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newborn C57BL/6 mice. Microglia were separated from these cultures by anti-CD11b antibody-conjugated magnetic beads. Then, astrocyte-rich cultures and astrocyte and microglia-mixed cultures were reconstituted. These cultures were treated with IFNγ, IL-4, or IL-17 for 24 h. Cx43 expression was evaluated by Western blotting, immunocytochemistry, and quantitative realtime PCR. Results: Treatment of primary mixed glial cell cultures with IFNγ, IL-4, or IL-17 showed that only INFγ-treatment reduced Cx43 expression in a concentration-dependent manner. Treatment of astrocyte-rich cultures or astrocyte and microglia-mixed cultures with IFNγ exhibited that Cx43 expression was downregulated only in astrocyte and microglia-mixed cultures. IFNγ-treated microglia conditioned medium induced significant downregulation of Cx43 expression in astrocyte-rich cultures. We found that IFNγ concentration-dependently increased IL-1β and tumor necrosis factor (TNF)α in microglia conditioned medium. Furthermore, treatment with IL-1β and TNFα reduced Cx43 expression in astrocyte-rich cultures. Finally, we treated primary mixed glial cell cultures with conditioned media of Th1, Th17 and regulatory T cells differentiated from naïve T cells in vitro. Only Th1 cell conditioned medium significantly reduced Cx43 expression in astrocytes. Conclusions: These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β and TNFα, which reduce Cx43 expression in astrocytes. Thus, Th1-dominant inflammatory states can disrupt astrocytic intercellular communication and may exacerbate MS. Disclosure Mitsuru Watanabe is funded by a research grant from Japan Society for the Promotion of Science, Japan; Katsuhisa Masaki: nothing to disclose; Ryo Yamasaki: nothing to disclose; Jun Kawanokuchi: nothing to disclose; Hideyuki Takeuchi: nothing to disclose; Akio Suzumura: nothing to disclose; Jun-ichi Kira is a consultant for Biogen Idec Japan and Medical Review. He has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical and Medical Review. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan. Source of funding: This study was supported by “Glial assembly” Grant-in-Aid for Scientific Research on Innovative Areas (Grant Number 25117012) from the Ministry of Education, Culture, Sports, Science and Technology, and Grant-in-Aid for Young Scientists (Grant Number 15K19489) from Japan Society for the Promotion of Science, Japan. P393 Anti-lipid serum antibodies in MS patients: predominant recognition of cholesterol A. Jurewicz1, M. Domowicz1, A. Ewiak-Paszynska1, G. Galazka1, C.S. Raine2, K. Selmaj1 1Department of Neurology, Medical University of Lodz, Lodz, Poland, 2AlbertcEinstein College of Medicine, New York, NY, United States


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Background: Recent data indicate that lipids might represent important targets of serum antibodies (Abs) in multiple sclerosis (MS) patients. In this study, we have assessed serum Abs binding to lipids isolated from post-mortem MS brain tissue. Methods: Lipid fractions were isolated by the Folch procedure from MS and non-MS brains and characterized by thin layer chromatography (TLC). Nine endogenous lipid fractions with defined lipid composition were used for binding with serum from relapsingremitting MS (n=10) and control patients (n=10) using an ELISA assay. In a confirmatory set of experiments, serum immunoreactivity with synthetic lipids: sulfatides, L-α-lysophophatidylcholine, cholesterol, galactocerebrosides, β2-glycoprotein 1 (β2-GP1) and cardiolipin, was assessed. To confirm specific binding of serum immunoglobulins, IgG and IgM were purified by affinity chromatography (IgG) or dialysis and size-exclusion chromatography (IgM), and digested with pepsin to obtain F(ab)2 and Fc fragments before ELISA assessment. Results: As defined by TLC, in MS brains, neutral lipids dominated and all nine lipid fractions contained cholesterol or cholesterol esters. In contrast, in control brains, dominated phospholipids and cholesterol esters were present in smaller quantities. The pattern of MS patient serum binding to endogenous lipid fractions suggested predominant binding to fractions containing cholesterol and cholesterol esters. F(ab)2 fragments of IgG and IgM showed a high affinity for lipid fractions, in contrast to Fc fragments, confirming a specific antibody type of binding. To confirm cholesterol binding by MS serum, synthetic lipids were used as antigens in ELISA assays in an independent set of experiments and showed that cholesterol-bound IgG and IgM of MS serum had high efficacy. In addition, preabsorption of MS serum with cholesterol significantly decreased subsequent IgG and IgM binding of lipid fractions, thus confirming specific cholesterol recognition by the serum of MS patients. Conclusion: These results indicate for the first time that IgG and IgM of MS serum specifically and predominantly recognize native cholesterol and cholesterol esters isolated form the brain tissue of MS patients. Disclosure Anna Jurewicz has nothing to disclose. Malgorzata Domowicz has nothing to disclose. Alicja Ewiak-Paszynska has nothing to disclose. Grazyna Galazka has nothing to disclose. Cedric S. Raine has nothing to disclose. Krzysztof Selmaj has nothing to disclose. P394 CD14 expression in CSF, meningeal infiltrates and cortical lesions is associated with less severe and slower progression in multiple sclerosis R. Magliozzi1,2, S. Rossi1,3, C. Senatore3, C. Cruciani1, O. Howell4, P.G. Righetti5, S. Monaco1, F. Facchiano3, R. Reynolds2, M. Calabrese1 1University of Verona, Verona, Italy, 2Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom, 3Istituto Superiore di Sanità, Rome, Italy, 4Swansea University, Swansea, United Kingdom, 5Politecnico di Milano, Milano, Italy Introduction: Increased meningeal inflammation and cortical microglia activation have been proposed to be strictly associated

with cerebral grey matter (GM) pathology. Our preliminary proteomic analysis of CSF samples from MS patients at disease onset revealed altered protein levels of the monocyte marker CD14 associated with different level of GM demyelination, as assessed by advanced MRI. Aims: In order to better understand whether/how CD14 may represent a link between intrathecal inflammation and cortical pathology, detailed analysis of immunolocalization and gene expression of CD14, and its associated TLR4 innate-immunity pathway, has been performed in paired meningeal and GM samples from 20 post-mortem SPMS and 10 control cases. Furthermore, by using Western blot, ELISA and Bioplex analysis, the levels of sCD14 and sCD163 proteins, as indicators of monocytes and their activation, have been examined in the CSF samples from 40 MS patients at disease onset and 10 controls. Results: By using immunohistochemistry and immunofluorescence in 10 non-neurological control brains, CD14 was found normally expressed only by perivascular-, ventricle- and meningeal-macrophages, but not by resting parenchymal microglia. Increased expression of CD14 in meningeal macrophages and cortical microglia was found in 10 out of the 20 post-mortem SPMS cases, characterized by lower GM pathology and less rapid disease progression. The expression of CD14 gene and its associated TLR4 pathway was also found significantly upregulated in the GM lesions of the same 10 SPMS cases with less rapid disease progression compared to the 10 SPMS cases rapidly progressive. Furthermore, we found significantly increased levels of sCD14 protein only in the CSF of MS patients with a lower GM lesion load (volume and number), as revealed by double inversion recovery 3T MRI, and more favourable disease outcome; on the contrary, sCD163, marker of activated monocytes, was found overexpressed in rapidly progressive MS patients with a higher GM lesion load. Conclusions: Different CD14 levels in the meninges, CSF and GM of MS patients, either progressive or at disease onset, may indicate altered monocyte profile and activation that may be specifically associated with different GM injury and MS outcome. CD14 may therefore represent a potential marker of intrathecal inflammation associated to cortical pathology useful to predict and monitor MS evolution. Disclosure M.Calabrese: Payment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer-Schering; Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA P395 Severely exacerbated neuromyelitis optica rat model with extensive tissue damage including astrocytopathy and axonal damage by high affinity anti-aquaporin-4 monoclonal antibody K. Kurosawa1, T. Misu1,2, Y. Takai1, D.K. Sato2,3,4, T. Takahashi5, Y. Abe6,7, H. Iwanari8, R. Ogawa1, I. Nakashima1, K. Fujihara2, T. Hamakubo8, M. Yasui6,7, M. Aoki1 1Neurology, 2Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan, 3Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, 4Neurology, University of Sao Paulo, Sao


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Poster Session 1, 22(S3) Pablo, Brazil, 5Yonezawa National Hospital, Yamagata, 6Keio Advanced Research Center for Water Biology and Medicine, 7Pharmacology, Keio University, 8Quantitative Biology and Medicine, University of Tokyo, Tokyo, Japan Results: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A). Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage with axonal swelling. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO. Conclusions: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. Disclosure Dr. Kazuhiro Kurosawa has no disclosure to report. Dr. Tatsuro Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan (No. 24591247). Dr. Yoshiki Takai has no disclosure to report. Dr. Douglas Kazutoshi Sato has received scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15 K19472), research support from CAPES/Brasil (CSF-PAJT 88887.091277/2014-00) and speaker honoraria from Novartis. Dr. Toshiyuki Takahashi has nothing to disclose. Dr. Yoichiro Abe has nothing to disclose. Dr. Hiroko Iwanari has nothing to disclose. Dr. Ryo Ogawa has nothing to disclose. Dr. Ichiro Nakashima has received funding for travel and received speaker honoraria from Bayer Schering Pharma and Biogen Idec and has received research funding from Mitsubishi Chemical Medicine Corporation and the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan. Prof. Kazuo Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono

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Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and an advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan (#22229008, 2010-2015;#26293205, 2014-2016) and by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Prof. Takao Hamakubo serves on an outside board member for Perseus Proteomics. Inc. and has supported by Grants-in Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan. Prof. Masato Yasui has nothing to disclose. Prof. Masashi Aoki has received research support from Grants-inAid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. P396 Dynamic changes of hippocampal subfields in CIS patients: a 3-month MRI longitudinal study L. Cacciaguerra1, E. Pagani2, S. Mesaros3, J. Dackovic3, T. Stosic-Opincal4, J. Drulovic3, M. Filippi2, M.A. Rocca2 1San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience,, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, 3Neurology Clinic, Clinical Centre of Serbia, School of Medicine, 4Radiology Clinic, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia Background: Lesional and atrophy data support the evidence of grey matter (GM) involvement in patients with clinically isolated syndrome (CIS) suggestive of MS. The hippocampus is affected early in MS, with characteristic subregional patterns of involvement at different stages of the disease. The subgranular layer of the dentate gyrus (DG) supports neurogenesis and there is evidence of its in-vivo expansion in relapsing-remitting (RR) MS patients. Aims: To evaluate short-term patterns of regional hippocampal volume variations in CIS patients early in the course of the disease. Methods: Brain dual-echo and 3D T1-weighted scans were acquired from 20 CIS patients within 2 months from clinical onset and after 3 months. Ten healthy controls (HC) were also studied. Manual hippocampal segmentation was performed according to a standardized procedure, and global volumes were derived. Radial atrophy distribution was assessed using 3D parametric surface mesh models.


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Results: At baseline, CIS patients had a reduced radial distance (RD) (p< 0.05) involving the lateral CA1 subfield of both the right and left hippocampal tail and of the right hippocampal head. In the right hippocampus, RD was negatively correlated with T2, T1 and GD-lesion load (LL) (p< 0.05, R>-0.5). At 3 months, an expansion of the right hippocampus DG subfield was observed (p< 0.01), associated with homolateral CA1 and subiculum volume loss in the tail (p< 0.01) and a partial volume recovery in the head. Interestingly, in the left hippocampal tail, only a CA1 RD increase was found, with no DG expansion. Considering the radial variation between the timepoints in the right hippocampus, a volume increase in DG and a volume loss in CA1 region emerged. DG increase correlated positively with baseline T2, T1 and GD LL (p< 0.05) (R>0.5). Conclusions: Regional hippocampal volume abnormalities occur in CIS patients, with higher susceptibility to damage of CA1 and subiculum. After an acute inflammatory event, hippocampal volume abnormalities are dynamic and modulated by the burden of inflammation, as suggested by the correlation between DG expansion and lesional measures. The lateralization of our data, predominantly in the right side, might be explained by an higher vulnerability to damage of this hemisphere. These is in agreement with previous works reporting a more marked volume loss of the right hippocampus with aging and in MS patients. Disclosure Drs Cacciaguerra, Pagani, Dackovic, and Stosic-Opincal have nothing to disclose. Dr Mesaros has received funding for travelling and honoraria for speaking from Merck Serono, Novartis, Bayer Schering, Medis. Dr Drulovic has served on scientific advisory boards for Merck Serono, Novartis, and Bayer Schering; has received funding for travelling and honoraria for speaking from Merck Serono, Teva, Novartis, Bayer Schering, Medis. She is the principal investigator in clinical trials for Merck Serono, Teva, Biogen Idec, Roche, Genzyme, a Sanofi Company, Receptos. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.

Experimental models P397 c-Myc activity controls encephalitogenic T helper cells development M.P. Mycko1, M. Cichalewska1, H. Cwiklinska1, A. Wilson2, H.R. MacDonald2, K.W. Selmaj1 1Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland, 2Developmental Immunology Group, Ludwig Center for Cancer Research of the University of Lausanne, Lausanne, Switzerland

c-Myc is a transcription factor that functions as a major mediator of the cell development, differentiation and survival. c-Myc has been shown to play a critical role in development of NK T cells, intraepithelial lymphocytes and memory CD8 T cell. However, c-Myc involvement in major T helper (Th) cell populations and generation of autoimmune reactions have not been investigated so far. To analyze the role of c-Myc in Th cell development and induction of autoimmune demyelination we used conditional knockout mice (cKO) that lack c-Myc expression in T cells. Furthermore we have used c-myc-GFP transgenic mice to track c-Myc presence in Th cells during multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In lck-cre c-myc cKO T cell development was arrested, and only a few pre-T cells passed through the DN3 and DN4 checkpoint, mostly in the absence of division. CD4-cre c-myc cKO mice demonstrated that once past this critical checkpoint, further intrathymic development of mature CD4 and CD8 T cells appears to be independent of c-Myc. Activation of peripheral Th cells by T cell receptor stimulation resulted in normal upregulation of CD69 and downregulation of CD62L in c-Myc deficient as well as control mice. In contrast profound inhibition of proliferation was observed in c-Myc deficient peripheral T cells, in particular in naïve T helper cells. In EAE animals c-Myc presence has been found to be particularly highly expressed in the brain infiltrating myelin reactive cells with c-Myc presence correlating with IL-17 expression in Th cells. Accordingly, CD4-cre c-Myc cKO mice were completely resistant, both clinically and histologically, to EAE. Our results demonstrate a previously unrecognized role of c-Myc in development and differentiation of peripheral Th with particular role in generation of Th17 cells and development of autoimmune demyelination. Disclosure All authors have nothing to nothing to disclose. P398 Monitoring optic nerve damage in an animal model of multiple sclerosis by multiparametric MRI L. Chaabane1, C. Chirizzi1, D. De Battista1, R. Chang2, U. Boschert2, G. Comi1, L. Leocani1 1INSPE, San Raffaele Hospital, Milan, Italy, 2Research & Development Institute, EMD Serono, Inc., Boston, MA, United States Optic neuritis (ON) is a frequent and early sign of multiple sclerosis (MS). For the success of neuroprotective therapies, it is essential to define the time window for potential protection. Therefore, a sensitive diagnostic tool as MRI that could define the degree of damage is required. To investigate new therapies, Experimental autoimmune encephalomyelitis (EAE) is a model widely used with myelin loss and axonal degeneration mainly observed in the spinal cord and also in optic nerves. In the present study, we optimized an MRI protocol to monitor and characterize optic nerve damage during EAE progression. MRI protocol included T2 with and without fluid attenuation, magnetization transfer (MT) and also diffusion tensor imaging (DTI). MRI was conducted in vivo on a 7-Tesla scanner with animals kept under gas anesthesia. EAE has been induced in dark agouti rats with a mix of a MOG with complete Freund’s adjuvant.


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Poster Session 1, 22(S3) Disease score and body weight were daily monitored. Longitudinal MRI was performed after the acute phase, starting from day 21 to 55 post immunization (pi). Initial optic nerve damage was clearly found at 21 days pi with MT contrast which was reduced and at 35 days pi, fractional anisotropy was reduced in 21% of the EAE-rats. Overtime, MT and DTI reduction was progressively worsening and more frequent (58% of case). Furthermore, the occurrence of optic nerve damage did not correlate with disability and disease severity. Interestingly, fractional anisotropy reduction has been also reported in MS patients. Furthermore, EAE have the same clinicoradiological paradox seen in MS, where MRI lesions does not always correspond to the common clinical disability evaluations, mostly based on locomotion. Our results suggest that MRI could be a relevant tool to define the window of opportunity to initiate therapy with a neuroprotective agent in this model.

and eosin staining) and axonal sparing (staining for phosphorylated neurofilament). Results: Mice treated with DMF initiated after the onset of disease (late treatment group) showed a significant reduction in clinical scores compared to vehicle treated mice. However, DMF initiated prior to disease onset (early- and mid-treatment groups) yielded no clinical improvement compared to vehicle. Histological analyses at 26 weeks showed significant reductions in demyelination, inflammation and axonal loss in the late treatment group compared to vehicle. The early- and mid-treatment groups showed little or no significant improvement in these parameters at 5, 9 or 26 weeks compared to vehicle. This lack of response could be due to increased viral load (judged by qPCR analyses of viral VP2 transcripts). Conclusions: These results indicate that oral DMF treatment can mitigate neurodegenerative disease in the TMEV-IDD model of MS after the onset of clinical disease symptoms.

Disclosure

Disclosure

L. Chaabane, C. Chirizzi, D. DeBattista, R. Chang, U. Boschert: nothing to disclose. Pr. L. Leocani is part of the Biogen (Advisory Board); and has received financial support (travel and research) from Almirall, Novartis, Biogen and Merck Serono. Pr. G. Comi has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma AG, Serono Symposia International Foundation, Merck Serono International, Teva, Sanofi Aventis, and Biogen Dompe. The study was funded by EMD Serono.

This study was funded by an investigator initiated grant from Biogen. Noel Carlson: received funding from Biogen. Linda Schmidt: nothing to disclose. Blair Wood: nothing to disclose. Crystal Clendennen: nothing to disclose. Lauren M Weber: nothing to disclose. Mateo Paz Soldan: received funding from Biogen. John Rose: received funding form Biogen.

P399 Therapeutic effects of oral dimethyl fumarate in the Theiler’s murine encephalomyelitis virus model of multiple sclerosis N.G. Carlson1, L.A. Schmidt1, B. Wood1, C. Clendennen1, L.M. Weber1, M. Paz Soldan2, J.W. Rose3 1GRECC, 2Neurology, VA Salt Lake City Health Care System, 3Neurology, University of Utah, Salt Lake City, UT, United States Background: There have been many advances in therapies for multiple sclerosis (MS), but none of the current treatments completely halt the processes of demyelination, oligodendrocyte (OL) loss, axonal injury and neuronal death. A formulation of dimethyl fumarate (DMF), BG-12 (TecfideraTM), is a promising new oral therapy that has both potent immunomodulatory and anti-neurodegenerative effects. Objective: Our goal was to examine whether treatment with DMF mitigates neurodegenerative disease in the Theiler´s murine encephalomyelitis virus-induced demyelinating disease (TMEVIDD) model of MS that features inflammation, demyelination, loss of axons and a progressive disease course. Methods: SJL/J mice received intracerebral injections of TMEV followed by oral treatment with DMF (100 mgs/kg per day) or vehicle initiated at 2 days (early treatment), 3 weeks (mid treatment) or 9 weeks (late treatment) after TMEV injection and continued until the mice were sacrificed at 5, 9 or 26 weeks. Mice were monitored twice a week using the righting response; signs of disease began to appear 9 weeks after injection. Brains and spinal cords were histologically analyzed for inflammation, demyelination (using Luxol fast blue combined with hematoxylin

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P400 Acute axonal damage in three different murine models of multiple sclerosis T. Hochstrasser1, K.M. Höflich2, M. Kipp1 1Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, Munich, 2Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany Axonal damage has been identified as a significant contributor of permanent clinical disability in multiple sclerosis. In the context of demyelinating disorders, this destructive event could be the result of inflammation, demyelination and/or the activation of innate defense cells such as microglia or monocytes. The relative contribution of each of these variables to acute axonal injury is, however, unknown. In the present study, we compared the extent of acute axonal damage in three different murine demyelination models using anti-amyloid precursor protein (APP) immunohistochemistry. T-cell dependent (MOG35-55-induced experimental autoimmune encephalomyelitis (EAE)) as well as T-cell independent demyelination models (cuprizone- and lysolecithin-induced demyelination) have been included. APP-positive spheroids were present in all three experimental demyelination models. The number of APP-positive spheroids was greatest within lysolecithin-induced lesions. Equal amounts were found in the spinal cord of EAE animals and the corpus callosum of cuprizone-intoxicated animals. Moreover, we detected increased immunoreactivity of another pre-synaptic protein, i.e. vesicular glutamate transporter 1 (VGlut1) in demyelinated foci. VGlut1-staining revealed long stretched, ovoid-like structures, which colocalized with APP.


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In summary, we were able to show that acute axonal damage is evident under various experimental demyelination paradigms. Furthermore, disturbed axonal transport, which is responsible for intra-axonal APP-accumulation, is not only restricted to APP but also to other synaptic proteins. These results indicate that despite differences in their characteristics, all three models may serve as a good model for investigating responsible mechanisms of axonal damage and potential protective strategies. Disclosure Tanja Hochstrasser: nothing to disclose Katharina Marie Höflich: nothing to disclose Markus Kipp: nothing to disclose This research project was supported by the Doktor Robert Pfleger - Foundation. P401 Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity C. Huck1, V. Wegert1, C. Schmid1, B. Dunn2, P. Smith1 1Novartis Institutes for BioMedical Research, Basel, Switzerland, 2Novartis Institute for Functional Genomics, Inc., San Diego, CA, United States Background: Anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) have consistently shown significant clinical efficacy in relapsing-remitting multiple sclerosis (RRMS) patients. Rituximab and ocrelizumab are administered as high-dose intravenous infusions, whereas ofatumumab is a relatively low-dose subcutaneous formulation. During RRMS, lymph node-resident B cells act as antigen-presenting cells, thereby facilitating autoimmune T-cell activation. Objective: Using a rodent anti-CD20-depleting antibody, we characterised the impact of dose (high/low) and administration route (subcutaneous / intravenous) on B-cell subset frequencies in blood and lymphoid tissues. The treatment regimens were subsequently evaluated in a B cell-dependent neuroinflammation model for efficacy. Lastly, we investigated the kinetics of B-cell repletion upon treatment cessation. Methods: Mice were treated with a depleting anti-CD20 monoclonal antibody or isotype control using two different regimens: low-dose subcutaneous or high-dose intravenous administration. B cell-dependent, experimental autoimmune encephalomyelitis (EAE) was induced via immunisation with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in an adjuvant. Lymph nodes, spleens and blood were analysed for B-cell subsets and T-cell populations by flow cytometry. Results: Maximum depletion of circulating blood B cells was similar irrespective of anti-CD20 dose and administration route; however, the time to nadir occurred slightly later with the subcutaneous treatment. Lymph node B-cell depletion was slightly enhanced following the subcutaneous treatment, whereas splenic B-cell numbers were consistent between the treatment regimens. Follicular (FO) and Marginal Zone (MZ) B-cell subsets rapidly depleted, whereas Germinal Centre (GC) populations were relatively unchanged. Low-dose subcutaneous anti-CD20 therapy delayed EAE disease onset and significantly inhibited neurological deficits; no additional efficacy was observed in the high-dose intravenous treated group.

Conclusions: Low-dose, subcutaneous anti-CD20 therapy is highly effective in depleting B cells within lymph nodes and blood, resulting in amelioration of CNS autoimmune inflammation. No superiority was observed with the high-dose intravenous anti-CD20 therapy. Disclosure This abstract is supported by Novartis Pharma AG, Basel, Switzerland. All the authors are employees of Novartis. P402 An alternatively activated phenotype in mouse microglia promotes phagocytosis and may be beneficial in the clearance of myelin debris L. Nicol, G. Rosignoli, P. Thornton, J. Stockley, B.G. Perez-Nievas, J. Nys, M. Sleeman, C. Jones MedImmune, Cambridge, United Kingdom Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. In rodent models of de/remyelination the removal of myelin debris via phagocytosis facilitates axonal regeneration and re-modelling and creates an environment that is permissive for remyelination and repair. It is generally believed that the prime suspects for carrying out this phagocytosis are microglia and infiltrating peripheral macrophages. Therefore modulating functional polarity of these cells to enhance phagocytic efficacy may present a promising strategy in the treatment of MS. Utilising pHrodo® technology we set up a high throughput in vitro assay to quantitatively measure and compare myelin phagocytosis in unstimulated “M0”, pro-inflammatory “M1” (48h interferon-gamma (IFN-γ) and lipopolysaccharide (LPS) stimulation) and anti-inflammatory “M2” (48h interleukin (IL)-4 and IL-13 stimulation) polarised mouse microglia. In addition we used flow cytometry to study the impact of myelin on cell polarity based on the expression of cell surface markers: cluster of differentiation (CD) -86, major histocompatibility complex class II (MHCII) and CD206. We examined a range of myelin doses (1, 5, 10 and 15µg/well) and found that myelin exposure induced a dose-dependent cell death, which was potentiated in M1 polarised cells. Based on these data we screened the effects of myelin on microglial phenotype using the lowest dose of myelin (5µg/ well) that showed reduced impact on cell survival. We report that myelin induced changes in the expression of cell surface markers of M0 microglia and up-regulated CD206, a marker associated with an alternative M2 phenotype. The expression profile in M2 polarised cells was similar to that of M0 cells, whereas M1 cells sustained their pro-inflammatory phenotype and showed greater expression of MHCII compared to M0 and M2 cells. We also demonstrated that M2 polarised microglia exhibited a 3-4 fold greater capacity to phagocytose myelin debris at 24-30 hours than compared to M1 polarised cells. In conclusion, we have established a plate based assay enabling the quantification of myelin phagocytosis in primary murine microglia and have shown that an alternatively activated phenotype may be necessary for the effective clearance of myelin debris. Phenotypic profiling indicates that myelin exposure also induces an M2 switch, which may be inhibited in a pro-inflammatory environment.


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Poster Session 1, 22(S3) Disclosure

Disclosure

Louise Nicol: Nothing to disclose Guglielmo Rosignoli: Nothing to disclose Peter Thornton: Nothing to disclose John Stockley: Nothing to disclose Beatriz Gomez Perez-Nievas: Nothing to disclose Josquin Nys: Nothing to disclose Matthew Sleeman: Nothing to disclose Clare Jones: Nothing to disclose

Haindl M: nothing to disclose. Köck U: nothing to disclose Zeitelhofer-Adzemovic M: nothing to disclose Storch MK: nothing to disclose Fazekas F: nothing to disclose Hochmeister S: nothing to disclose We did not receive any specific funding for this work.

P403 Investigation of remyelination facilitating factors produced by astrocytes in an animal model of multiple sclerosis M. Haindl1, U. Köck2, M. Zeitelhofer-Adzemovic3, M.K. Storch1, F. Fazekas1, S. Hochmeister1 1Dept. of Neurology, Medical University Graz, Graz, 2Center for Brain Research, Medical University Vienna, Vienna, Austria, 3Dept. of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institute, Stockholm, Sweden The role of astrocytes in Multiple Sclerosis (MS) is discussed controversially with contradicting data available. Depending on their immediate plaque milieu, astrocytes appear to have functions in driving inflammation as well as in facilitating remyelination through mediators which they produce. BDNF (brain-derived neurotrophic factor) has been suggested to have neuroprotective functions and to promote regeneration of neurons. FGF2 (fibroblast growth factor) is proposed to favour effective remyelination and enhances the recruitment of oligodendrocyte progenitor cells (OGPs). Semaphorin 3A is a guidance molecule, active in controlling OGP cell migration. On the other hand astrocytes are still often believed to act as a barrier for remyelination because of the glial scar (GS) formation. We investigated the astrocytic reaction in experimental autoimmune encephalomyelitis, induced by active immunization with Myelin Oligodendrocyte Glycoprotein in Dark Agouti rats. This animal model allows examination of lesion evolution over the full course from active demyelination up to a successfully completed repair. We correlated the astroglial reaction by immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP) to the remyelination capacity by in situ hybridisation for mRNA of proteolipid protein. Quantitative evaluation and statistical analysis were performed for all lesion stages in a total of over 400 lesions. More than 250 lesions were used for IHC-doublestaining of GFAP and BDNF, FGF2 and SemA respectively. The amount of GFAP positive astrocytes increased during lesion evolution and reached its peak in shadow plaques. The highest number of OGPs was detected in the state of early remyelination. BDNF and FGF2 reached their peaks in early remyelination with a mean of 15%±5.0 BDNF+ and 17%±5.6 FGF2+ astrocytes. In contrast, SemA+ cells peaked early with 61%±31.3 in active lesions and then decreased with remyelination. The SemA peak might confirm the relation of SemA OGP guidance with the inflammatory process. BDNF and FGF2 are both closely related with remyelination explaining their presence in early remyelinating lesions. All factors however could be detected in all lesion stages and were even expressed by astrocytes forming a GS. These data support the beneficial role of astrocytes and suggest that even an abundant GS reaction does not prohibit remyelination in this animal model of MS.

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P404 Apolipoprotein E modulates abcg2 transporter expression and function in the context of teriflunomide-therapy of experimental autoimmune encephalomyelitis L. Schrewe1,2, D. Meyer1, A. Böhme1, S.M. Pittlik1, S. Demir1, S. Faissner1,3, N. Hagemann4, D. Schmidt5, D.M. Hermann4, F. Lühder6, A. Chan2 1Dept. Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany, 2Dept. of Neurology, Inselspital, Bern University Hospital, Bern, Switzerland, 3Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada, 4Dept. Vascular Nerology and Dementia, University of Duisburg-Essen, Essen, 5Sanofi-Aventis Deutschland GmbH, Frankfurt, 6Dept. of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany Background: Different immunotherapies for MS, e.g. teriflunomide (teri) and mitoxantrone, are ABC-transporter substrates. Modulators of ABC-transporter activity could have potential therapeutic implications. Apolipoprotein E (ApoE) modulates transporter activity in experimental stroke, but effects on ABC-transporters in chronic autoimmune neuroinflammatory disease are unknown. Objective: To investigate influence of apoE on abcg2-transporter expression and function in vitro and during experimental autoimmune encephalomyelitis (EAE) using abcg2-substrate teri. Methods: abcg2-mRNA expression (spinal cord (sc), spleen/ splenic T-cells) from wildtype (wt) and apoE-deficient (apoE-/-)mice were analyzed by qRT-PCR. Stimulated T-cells (anti-CD3, 10µg/ml; anti-CD28, 10ng/ml; 24h/48h) were treated with teri (12.5-100µM) +/-abcg2-inhibitor fumitremorginC (10µM; FTC). T-cell death (annexinV/PI) and proliferation (CSFE) were analyzed by flow cytometry. Intracellular teri-concentration was analyzed by HPLC. Chronic EAE was induced by active immunization with MOG35-55 in wt and abcg2-/--mice. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. Results: apoE-/--mice exhibited 1.8-fold higher abcg2-mRNA expression in splenic T-cells than wt (p=0.003). During acute EAE, abcg2-mRNA decreased 5-fold in wt (p=0.05) and 7-fold in apoE-/--mice (p=0.004) in sc. In vitro, teri-induced inhibition of T-cell proliferation was stronger in cells from wt than from apoE-/-mice (difference of inhibition: 7-8%, 12.5-100µM teri, 48h). FTC increased teri-induced inhibition by 20% in wt and 24% in apoE/--mice (both genotypes: p< 0.05, 100µM teri, 48h). Teri-induced T-cell apoptosis was 11% higher in wt than in apoE-/--mice (p=0.02, 100µM teri, 24h). After 48h, intracellular teri-concentration tended to be higher in apoE-/--mice than in wt (p=0.06, 25µM teri). Teri-treatment ameliorated clinical EAE-course more pronounced in abcg2-/--mice (teri, n=2 vs. vehicle, n=3; p< 0.001) than in wt (teri, n=5 vs. vehicle, n=5; p=0.003).


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Conclusions: apoE-deficiency is accompanied by increased abcg2-expression specifically in peripheral immune organs/Tcells. Functional relevance is indicated by decreased teri-induced inhibition of T-cell proliferation and apoptosis in apoE-deficient cells and by a stronger therapeutic effect in abcg2-/--mice than in wt. Functional relevance of abcg2 on teri in vitro and in vivo is supported by further investigation in abcg2-/--mice.

exhibited activation of macrophages/ microglia with very few neutrophils. Conclusion: Systemic inflammation exacerbates neuroinflammation and neurodegeneration in the cortical lesion independently of BBB integrity. Disclosure There is no conflict of interest of these authors for this work

Disclosure This study is sponsored by Genzyme. LS received travel grant from Novartis. SF received travels grants from Biogen and Genzyme. DS is an employee of Sanofi-Aventis. FL received research grants from Teva and Genzyme. AC has received personal compensation for activities with Bayer, Biogen, Merck, Novartis, Roche and Teva Neuroscience, research support from Biogen, Genzyme and Novartis. All other authors report no disclosures. P405 Role of blood-brain barrier in an animal model of cortical progressive multiple sclerosis B.A. Silva1,2, M.C. Leal1, M.I. Farias1, F.J. Pitossi1, C.C. Ferrari1,2 1Leloir Institute Foundation, 2ICBME, Buenos Aires, Argentina Background: Cortical demyelinated and neurodegenerative lesions represent a hallmark of Progressive forms of Multiple Sclerosis (PFMS). Pathological studies suggested that the inflammation and neurodegeneration remained trapped into a closed blood brain barrier (BBB) in PFMS. However, several studies reported increased immune cell activation in peripheral blood of progressive MS patients. Additionally, animal studies suggested that a leaky BBB is required for the entrance of immune cells within the Central Nervous System (CNS). Objectives: To study the role of the BBB on cortical neuroinflammation and neurodegeneration after peripheral stimulation in a focal animal model of PFMS. Methods: Chronic central lesions were induced in adult rats by the long term expression of interleukin 1 beta (IL-1b) in the cerebral cortex using an adenovector expressing either human IL-1b (Ad-IL1b) or betagalactosidase (Adbgal) as control. Systemic inflammation was induced by peripheral injection of either Ad-IL1b or Adbgal. We performed histological and inmmunohistochemical analysis and peripheral blood cells counting to check the systemic stimulation. Results: The long term expression of IL-1b in the cortex induces inflammation characterized by BBB breakdown, macrophages and neutrophil recruitment, demyelination, meningeal inflammation, astroglia and microglia activation peaked at 15-21 days post injection (dpi). The peripheral stimulation with Ad-IL1b at this time point, when BBB is opened, exacerbates cortical inflammation (mainly composed of neutrophils and macrophages/microglia) and neurodegeneration. At 56 dpi, the BBB is restored and the central lesion exhibited less inflammation, forming a scar composed mostly of macrophages/microglia . Interestingly, even though the BBB is restored, the peripheral stimulation induced exacerbation of the cortical neurodegenerative lesion with significant meningeal inflammation. The exacerbated cortical lesion

P406 Oligodendrocyte apoptosis triggers peripheral immune cell recruitment into the forebrain U. Chrzanowski, S. Bhattarai, M. Kipp Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, Munich, Germany Background: Brain-intrinsic degenerative cascades, such as oligodendrocyte apoptosis with concomitant microglia activation, have been proposed to be an initial factor driving inflammatory lesion formation in multiple sclerosis (MS). Experimental models recapitulating this sequel of events are, however, missing. Objectives: To identify primary oligodendrocyte apoptosis as a potent trigger for peripheral immune cell recruitment into the mouse forebrain and, thus, the formation of new inflammatory, demyelinating lesions. Methods: Female C57BL/6 mice were fed cuprizone for one week followed by subsequent immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). While cuprizone feeding induces primary oligodendrocyte apoptosis, MOG immunization results in the formation of myelin autoreactive T-cells in peripheral lymphoid organs. Brains were histochemically evaluated for the presence and spatial distribution of perivascular inflammatory infiltrates. Furthermore, such infiltrates were characterized in detail by immunohistochemistry. Results: While inflammatory infiltrates were virtually absent in the forebrain of MOG-immunized animals (i.e. active experimental autoimmune encephalomyelitis), widespread perivascular foci were found in the forebrains of animals subjected to cuprizone prior to MOG-immunization. Peripheral immune cell recruitment induced microglia activation, astrocyte dysfunction, demyelination, and oligodendrocyte loss. Furthermore, acute axonal damage (determined by anti-APP staining) was clearly evident in these inflamed regions. White matter areas without overt demyelination (i.e. normal appearing white matter) showed as well moderate microglia activation. Conclusion: This study clearly illustrates the significance of brain-intrinsic degenerative cascades (i.e. primary oligodendrocyte apoptosis) for immune cell recruitment and MS lesion formation. Further studies have to address the signalling cascades and mechanistic processes which form the top-down communication between the affected brain area, neurovascular unit and peripheral immune cells. Disclosure Uta Chrzanowski: nothing to disclose Sudip Bhattarai: nothing to disclose Markus Kipp: nothing to disclose This study was supported by the Doktor Robert-Pfleger Foundation.


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Poster Session 1, 22(S3) P407 The transcription factor Ddit3/Chop as a regulator of neuroinflammation M. Gottschling1, M. Scheld2, S.-O. Rohr1, T. Clarner2, M. Kipp1 1Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, Munich, 2Institute of Neuroanatomy, RWTH Aachen University, Aachen, Germany The general dogma suggests that the formation of new lesions in Multiple sclerosis begins with an immune dysregulation, with the consequence that the immune system targets the brain compartment, resulting in active demyelinating foci. Other studies, however, have proposed that brain-intrinsic degenerative cascades are the initial factors driving Multiple sclerosis lesion formation, including oligodendrocyte death, focal microglia activation, or axonal damage. We recently provided experimental evidence for the latter hypothesis recruitment (see Scheld et al and Kipp; J Neurosci. 2016 Jan 27;36(4):1410-5). There, we were clearly able to show that neurodegeneration is a potent trigger for peripheral immune cell recruitment into the forebrain. In this work we demonstrate that the amelioration of oligodendrocyte and neuronal degeneration results in lower, secondary immune-cell infiltration in this novel Multiple sclerosis animal model. We identified by genome-wide array analyses Ddit3/Chop as an early regulator of oligodendrocyte apoptosis. Ddit3 is exclusively expressed in oligodendrocytes during initial cuprizoneinduced cytodegeneration, and early oligodendrocyte apoptosis is reduced in Ddit3-deficient mice. This initial protection is paralleled at later stages by less severe demyelination, microgliosis and axonal damage. Furthermore, Ddit3-deficient mice show reduced forebrain peripheral immune cell recruitment after subsequent MOG-immunization. This study clearly illustrates the importance of brain-intrinsic degenerative cascades for immune-cell recruitment and thus Multiple sclerosis lesion formation. Dampening of cytodegenerative signaling cascades results in less severe immune cell recruitment. A better understanding of involved factors would allow for the first time an effective hand-in-hand intervention against both, degenerative and inflammatory aspects of the disease.

Cortical demyelination is a common finding in patients with chronic multiple sclerosis (MS) and is thought to contribute to disease progression and overall disability. The exact pathomechanism of the cortical lesions is so far not clear. Recent studies of local traumatic injection of proinflammatory cytokines directly into the cortex (Merkler et al., 2006) and into the subarachnoidal space (Gardner et al., 2013) of rats subclinically preimmunized with Myelin Oligodendrocyte Glycoprotein ( MOG) produced a short lived cortical demyelination in the injected hemisphere, which was completely resolved within a few days. In our experiment we implanted a catheter into the cortex of 11 weeks old male Dark Agouti rats. After a healing period of 14 days the rats were subclinically immunized with MOG dissolved in incomplete Freund’s Adjuvant. After building a stable anti-MOG antibody titer the animals received an injection of the proinflammatory cytokines TNF- alpha and IFN- gamma through the catheter. This avoided any additional mechanical trauma. Clinically, the animals showed a slightly slow behavior without any motor symptoms between day 9-15, which totally resolved after day 15. Rotarod performances dropped slightly between d3 and d15 and went back to preinjected values on d30. Animals were sacrificed at days 1, 3, 15 and 30 after cytokine injection. Tissues were embedded in paraffin and immunohistochemically stained for macrophages, T cells and proteolipid protein (PLP) to detect myelin. On day 1 we found some invading macrophages directly around the catheter site containing early myelin degradation products in luxol fast blue staining and some demyelinating activity. On day 3 already a marked demyelination around the catheter implantation site spreading towards the upper cortex area is visible, while only minor cellular infiltrates are detectable. On day 15 we see a marked demyelination with near absence of PLP immunoreactivity (PLPIR) affecting not only the immediate catheter area, but extending over large parts of the cortex of both hemispheres. On day 30 animals still show patches of demyelinated cortex areas with loss of PLP-IR along with areas of partially restored PLP-IR. No spinal cord pathology was detected in any animal. In our study we show that widespread demyelination of the cortex of both hemispheres can be induced in rats. This model might help to investigate the pathogenesis of cortical lesions in MS.

Disclosure

Disclosure

Malin Gottschling: nothing to disclose Miriam Scheld: nothing to disclose Sven-Olaf Rohr: nothing to disclose Tim Clarner: nothing to disclose Markus Kipp: nothing to disclose This study was supported by the Doktor Robert-Pfleger Fundation.

Hochmeister S: nothing to disclose Ücal M : nothing to disclose Haindl M : nothing to disclose Theisl L: nothing to disclose Zeitelhofer-Adzemovic M : nothing to disclose Strasser J: nothing to disclose Ropele S: nothing to disclose Schäfer U: nothing to disclose Fazekas F: nothing to disclose We did not receive any specific funding for this work.

P408 Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG- immunized rats S. Hochmeister1, M. Ücal2, M. Haindl1, M. ZeitelhoferAdzemovic3, L. Theisl1, J. Strasser1, S. Ropele1, U. Schäfer2, F. Fazekas1 1Dept. of Neurology, 2Dept. Neurotraumatology, Medical University Graz, Graz, Austria, 3Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden

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Genetics/Epigenetics and Pharmacogenetics P409 Identification of glatiramer acetate B lymphocytes targets in multiple sclerosis


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C. Criscuolo1, A. Cianflone1, C. La Rocca2, G. Matarese3,4, R. Lanzillo1, D. Carrella5, D. Di Bernardo6,7, V. Brescia Morra1 1Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, 2Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, 3Dipartimento di Medicina e Chirurgia, Facoltà di Medicina e Chirurgia, Università di Salerno, Baronissi, Salerno, 4IRCCS-MultiMedica, Milan, 5Telethon Institute of Genetics and Medicine, Napoli, 6Telethon Institute of Genetics and Medicine, 7Department of Electrical Engineering and Information Technology, Federico II University, Naples, Italy Background: Glatiramer acetate (GA) is one of the first line therapy for relapsing-remitting multiple sclerosis (RRMS) treatment, although its targets on B cells are unknown. Mode of Action by NeTwoRk Analysis (MANTRA) identifies the drug’s molecular targets by building a “network of drugs” in which two compounds are connected if they elicit similar transcriptional responses. The smaller the drug distance (DD), the more similar the two compounds are. Drugs are partitioned into groups of interconnected compounds (communities) significantly enriched for drugs with similar mode of action (MoA). Objectives: To identify B cells GA targets in RRMS patients using an integrated experimental and computational approach. Methods: We enrolled 7 women treatment-naïve patients with RRMS according to Mc Donald criteria. All the patients didn’t receive corticosteroid treatment in the 30 days before the enrolment. B cells were isolated at baseline (in vitro) and after 6 months treatment (in vivo). At baseline, B cells were treated or not with 100µg/mL GA for 6h. B cells gene expression profiles of both in vitro and in vivo treatments were analyzed with MANTRA for MoA identification and with Gene Set Enrichment Analysis (GSEA) for the functional characterization of the genes. Results: At baseline, MANTRA identified 7 communities when treated B cells were compared with non-treated B cells. All the communities were significantly associated to GA response (DD range 0.68-0.79). The compound with the smallest DD to GA (DD 0.68) was Ambroxol, a mucolytic agent that acts by blocking Na2+ channels and by reducing nitric oxide levels. GSEA results showed a significant down regulation of genes involved in ion channel activity in treated cells vs non treated cells (p< 0.001). After 6 months treatment, MANTRA identified 8 communities when in vivo GA treated cells were compared to non-treated cells, and 18 communities when compared to in vitro GA treated cells. In both cases, the smallest DDs were between GA and communities n.89, 90, 13, 14 and 61. The most enriched MoAs were CDK2 inhibitors (i.e. H-7 Dihydrochloride), topoisomerase II inhibitor (i.e. mitoxantrone) and inhibitor of potassium channels (i.e. gliclazide). Conclusions: GA targets B cells in RRMS. Our data suggest a role for GA in inhibiting B cells activation and/or maturation by blocking ion channels, known to be essential for cell proliferation. Further analysis are needed to confirm the data. Disclosure Chiara Criscuolo: nothing to disclose Alessandra Cianflone: nothing to disclose Claudia La Rocca: nothing to disclose Giuseppe Matarese: nothing to disclose Diego Carella: nothing to disclose

Diego Di Bernardo: nothing to disclose Roberta Lanzillo: nothing to disclose Vincenzo Brescia Morra: nothing to disclose P410 Circulating microRNAs as biomarkers for rituximab therapy, in neuromyelitis optica (NMO) A. Vaknin Dembinsky, H. Charbit, L. Brill, O. Abramsky, D. Wahnon, I. Ben-Dov, I. Lavon Hadassah University Hospital, Ein Kerem, Jerusalem, Israel Background: Neuromyelitis optica (NMO) is a chronic autoimmune disease of the central nervous system (CNS). The main immunological feature of the disease is the presence of autoantibodies to Aquaporin 4 (AQP4+), identified in about 82% of cases. Currently, there are no reliable biomarkers for monitoring treatment response in patients with NMO. In an effort to identify biomarkers we analyzed micro RNAs (miRNAs) in the blood of rituximab-treated NMO patients before and after therapy. Methods: Total RNA extracted from whole blood of 9 rituximabresponsive NMO patients before, and 6 months following treatment was subjected to small RNAseq analysis. The study included also an additional group of 7 untreated AQP4+ seropositive NMO patients and 15 healthy controls (HCs). Results: 14 miRNA were up regulated and 32 were down regulated significantly in the blood of NMO patients following effective therapy with rituximab (all p< 0.05). Furthermore, we show that expression of 17 miRNAs was significantly higher and of 25 miRNAs was significantly lower in untreated NMO patients compared with HCs (all p< 0.05). Following rituximab treatment, the expression levels of 10 of the 17 miRNAs that show increased expression in NMO reverted to the levels seen in HCs. Six of these “normalized” miRNAs are known as brain specific/enriched miRNAs. Conclusions: Specific miRNA signatures in whole blood of patients with NMO might serve as biomarkers for therapy response. Furthermore, monitoring the levels of brain specific/ enriched miRNAs in the blood might reflect the degree of disease activity in the CNS of inflammatory demyelinating disorders. Disclosure Adi Vaknin Dembinsky: nothing to disclose Hanna Charbit: nothing to disclose Livnat Brill: nothing to disclose Oded Abramsky: nothing to disclose Devorah Wahnon: nothing to disclose Iddo Z. Ben-Dov: nothing to disclose Iris Lavon: nothing to disclose

P411 Defining a robust disease severity phenotype for use in genetic association studies V.G. Jokubaitis1,2, T. Kalincik1,2, D. Horakova3, E. Havrdova3, P. Kleinova3, K. Kucerova3, G. Izquierdo4, F. Matesanz5, A. Lugaresi6,7, T.J. Kilpatrick2,8, J. Lechner-Scott9,10, M. Slee11, M. Barnett12, S. Vucic13, D. Booth13, A. Manouchehrinia14, B. Taylor15, J. Hillert14, P. de Jager16, H. Butzkueven1,2,17 1Department of Medicine (RMH), University of Melbourne, 2Deparment of Neurology, Royal Melbourne Hospital, Parkville,


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Poster Session 1, 22(S3) VIC, Australia, 3Department of Neurology and Center for Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 4Hospital Universitario Virgen Macarena, Sevilla, 5Instituto de Parasitologia y Biomedicina Lopez Neyra, CSIC, Grenada, Spain, 6DIBINEM, Universita di Bologna, 7IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy, 8Melbourne Neuroscience Institute, University of Melbourne, Parkville, VIC, 9Department of Neurology, John Hunter Hospital, 10School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, 11Flinders University and Medical Centre, Adelaide, SA, 12Brain and Mind Centre, 13Westmead Institute, University of Sydney, Sydney, NSW, Australia, 14Karolinska Institutet, Stockholm, Sweden, 15Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia, 16Brigham and Women’s Hospital,Harvard Medical School, Boston, MA, United States, 17Department of Neurology, Box Hill Hospital, Monash University, Box Hill, VIC, Australia Background: To-date efforts to identify genetic associations with MS phenotype have been largely unrewarding. One possible explanation for this is that past genotype-phenotype association studies have relied on cross-sectional definitions of disease severity. Objective: To define a robust relapse-onset MS (RMS) disease severity phenotype based on longitudinally acquired outcomes data for use in genetic association studies. Methods: Using data obtained from MSBase, we identified all RMS patients from collaborating centres with minimum disease duration of 5 years, 5 years minimum prospective follow-up, and minimum 3 EDSS scores recorded in the absence of a relapse. Collaborating physicians nominated mild and severe RMS patients from their centres that served to define cut-offs for phenotypic outcomes of interest. Area under the EDSS-time curve was calculated for each individual and adjusted for follow-up. Using pre-defined EDSS-time cut-offs we created an algorithm that identified patients at the clinician-defined extremes of RMS outcome. Our algorithm was relapse, MRI and treatment agnostic. We validated algorithm calls by assessment of median MSSS over the entire observation period. Results: We identified 5,075 individuals meeting minimum inclusion criteria. Median cohort follow-up in MSBase was 8.8 years (interquartile range (IQR): 6.7y, 12.5y), with a median 16 (IQR: 9, 27) EDSS scores available for assessment. Median symptom duration at most recent visit was 15.2 years, and median MSSS over the entire observation period was 3.49 (IQR: 2.06, 5.51). The mild RMS cohort as selected by our algorithm (25.9% of the total population) had a median symptom duration of 11.6 years (IQR: 8.2, 16.5), 14 EDSS scores assessed (IQR: 8,25), and a median observation follow-up MSSS of 1.50 (IQR: 0.88, 2.25). The severe RMS cohort constituted 18.4% of the total population. Severe RMS cohort characteristics included: median symptom duration of 19.0 years (IQR: 13.5, 25.9), 15 EDSS scores assessed (IQR: 9, 24), and a median observation follow-up MSSS of 7.21 (6.15, 8.27). Conclusion: We have successfully defined a robust RMS phenotype using longitudinal, prospectively acquired clinical outcomes data validated against the MSSS. We are now actively recruiting patients identified using this definition of disease severity to perform a de novo genome-wide association study aiming to identify markers of relapse-onset MS severity.

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Disclosure This study is supported by grants from The Royal Melbourne Hospital [MH2013-055]; The MSBase Foundation; CharityWorks for MS/MS Research Australia [MSRA12-062], and an NHMRC Centre for Research Excellence Grant [Grant ID 1001216]. The MSBase Foundation is an independent not for profit organisation which receives support in the form of grants from the National Health and Medical Research Council (NHMRC) Australia, Merck, Merck Serono, Biogen, Novartis, and Genzyme a Sanofi company. The Authors report no disclosures with regards to this study. VGJ: Nothing to disclose; TK: Nothing to disclose; DH: Nothing to disclose; EH: Nothing to disclose; PK: Nothing to disclose; KK: Nothing to disclose; GI: Nothing to disclose; FM: Nothing to disclose; AL: Nothing to disclose; TJK: Nothing to disclose; JLS: Nothing to disclose; MS: Nothing to disclose; SV: Nothing to disclose; DB: Nothing to disclose; AM: Nothing to disclose; BT: Nothing to disclose; JH: Nothing to disclose; PDJ: Nothing to disclose; HB Nothing to disclose. P412 Genetic factors associated with clinical phenotypes of multiple sclerosis in the Japanese T. Matsushita1, S. Sato1, K. Yamamoto2, J. Zhuang1, Y. Nakamura1, J.-I. Kira1, the Japanese Multiple Sclerosis Genetics Consortium 1Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 2Department of Medical Chemistry, School of Medicine, Kurume University, Kurume, Japan Background: Susceptibility to multiple sclerosis (MS) is thought to be influenced by both environmental and genetic factors. With the notable exception of the human leukocyte antigen (HLA) system, genetic factors associated with clinical phenotype have not been yet identified. Objective: To clarify genetic factors associated with clinical phenotypes of multiple sclerosis (MS) in Japanese population whose genetic background is relatively homogeneous. Method: Genome-wide 600,000 SNPs were genotyped in Japanese MS. Allelic effects for age at onset, MS severity score (MSSS) and positivity of IgG oligoclonal bands (OCB) were calculated based on a linear or logistic regression model. Individual non-MHC MS genetic burden (MSGB) was calculated based on risk variants and the odds ratio of European patients with MS and the associations with clinical phenotypes were tested. Results: 553 cases were available for the analyses. rs13202636 (lipoprotein(a)) in chromosome 6 and rs4731427 (leptin) in chromosome 7 were associated with MSSS (p = 3.04e-7 and 2.074e-6 respectively). Lipoprotein(a) (LPA) and leptin were measured in 182 samples from case subjects that had been genotyped in this analysis. The number of the risk allele of rs13202636 was negatively correlated with concentrations of LPA. rs2808707 (Neurotrophic Tyrosine Kinase, Receptor, Type 2 gene, receptor for brain derived neurotrophic factor (BDNF)), was associated with age at onset (p = 2.37e-7). MSGB score was not associated with age at onset or MSSS. Several SNPs in MHC region were also associated with the positivity of OCB and MSGB was higher in patients with OCB than in OCB negative patients (p = 0.0476).


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The OCB positivity was negatively and positively correlated with HLA-DRB1*04:05 and DRB1*15:01 respectively in multivariate analysis. Conclusion: Several genetic loci relating to lipid metabolisms were associated with disability progression of Japanese patients with MS. BDNF may influence age at onset of MS. CSF IgG abnormality was associated with MHC variants in Japanese patients with MS as in people with MS of European descent. HLA-DRB1 alleles were associated with the positivity of OCB and aggregation of risk variants for MS in people of European descent weakly influences OCB positivity. Disclosure Takuya Matsushita has received honoraria from Bayer Schering Pharma, Biogen Idec, Takeda Pharmaceutical Company and Mitsubishi Tanabe Pharma. Shinya Sato: nothing to disclose Ken Yamamoto: nothing to disclose Jingcong Zhuang: nothing to disclose Yuri Nakamura: nothing to disclose Jun-ichi Kira is a consultant for Biogen Idec Japan and Medical Review and has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical and Medical Review. P413 Similarities and differences in the gene expression profiles of glatopa and copaxone S. Kolitz1, D. Laifenfeld2, K. Fowler1, T. Hasson2, A. Konya2, S. Bakshi2, B. Zeskind1, I. Grossman2, M.R. Hayden2 1Immuneering Corporation, Cambridge, MA, United States, 2Teva Pharmaceutical Industries, Petach Tikva, Israel Background: Copaxone (glatiramer acetate) has provided a safe, effective treatment option for multiple sclerosis (MS) patients for decades. Copaxone is thought to act through complex immune mechanisms related to its antigenic nature. Recently, a differently manufactured glatiramoid, Glatopa, was launched in the US. Since genome-wide expression profiling measures biological impact across many pathways, this unbiased method was applied to characterize both glatiramoids. Objectives: To characterize biological effects of Copaxone and Glatopa in a mouse interchangeability model, and in a human monocyte cell line. Methods: Gene expression profiles induced by Copaxone and Glatopa were measured in two model systems: 1) ex-vivo exposure of Copaxone/Glatopa stimulated splenocytes (mouse) and 2) in vitro stimulation of THP-1 cells. Results: Copaxone significantly modulated thousands of genes and dozens of pathways in mouse splenocytes, many of which exhibit immunogenic functionality. Copaxone upregulated key anti-inflammatory cytokine IL-10 (FC=1.54, adj p< 1.8e-16), and the cytokine-cytokine receptor interaction pathway was enriched among top upregulated genes (adj p< 5e-6). These findings are concordant with previously reported effects of Copaxone. Glatopa also upregulated IL-10 (FC=1.46, adj p< 9.9e-12), among thousands of genes modulated similarly by Glatopa and Copaxone. Alongside these similarities, hundreds of genes (FC range -1.6 to 1.5) enriching for multiple biological pathways were significantly

differentially expressed between Copaxone and Glatopa. Observed differences included higher expression with Glatopa of genes and pathways such as TH17 related genes IL-6 and IL-1b, and the cytokine-cytokine receptor interaction pathway (adj p< 2e-4). Enrichment of this pathway was confirmed in studies comparing Glatopa to Copaxone in THP-1 cells (Gene Set Enrichment Analysis, p< 0.001). This pathway among others was differentially expressed in prior studies comparing Copaxone with glatiramoids Polimunol (Hasson et al, 2016) and Probioglat (Kolitz et al, 2015). Conclusions: Gene expression studies in different models identify many genes as similarly modulated by Copaxone and Glatopa, alongside a subset of immune-related genes and pathways that demonstrate significant differences. These functional differences, coupled with observed physicochemical differences between the two glatiramoids, warrant further investigation to ensure the safety of MS patients. Disclosure SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries to perform studies included in this report. DL, TH, SB, IG and MRH performed studies in this report and are employees of Teva Pharmaceutical Industries. P414 Lymphoid somatic mutations in multiple sclerosis M. Valori1, L. Jansson2, A. Kiviharju1, K. Porkka3, P. Ellonen4, S. Mustjoki5, P. Tienari6 1Research Programs Unit, Molecular Neurology, University of Helsinki, 2Department of Neurology and Research Programs Unit, Molecular Neurology, Helsinki University Hospital and University of Helsinki, 3Hematology Research Unit and Department of Hematology, University of Helsinki and Helsinki University Hospital, 4Finnish Institute of Molecular Medicine (FIMM), University of Helsinki, 5Hematology Research Unit and Dept of Hematology, University of Helsinki and Helsinki University Hospital, 6Department Neurology and Research Programs Unit, Molecular Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland Background: Genetic and environmental risk factors and treatment paradigms overlap in multiple sclerosis (MS) and hematological malignancies. Somatic mutations have a central role in cancer but their role in MS is not known. Moreover, the general features of somatic mutations in non-cancerous cells are unclear such as mutation frequencies, clonal size (allelic fraction) and mutational hot-spots. Aims: In this pilot study we addressed the following questions: Are somatic mutations detectable in MS patients’ blood and what is their allelic fraction within a specific cell population? Are there mutational hot-spots? Do the mutations preferentially occur in a particular cell population? Methods: We extracted peripheral blood mononuclear cells from 16 relapsing MS patients, and separated them into CD4+ T-lymphocytes, CD8+ T-lymphocytes, CD19+ B-lymphocytes and CD4/CD8/CD19 negative populations (antibody MicroBeads, Miltenyi Biotec). From these separated cell populations, we performed next-generation DNA sequencing targeting coding regions


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Poster Session 1, 22(S3) of a panel of immunologically relevant genes with a sequencing depth of 1000x (target capture by SeqCap, Roche Nimblegen; sequencing with Illumina HiSeq 2500). This depth allows the detection of somatic mutations with low allelic fractions. Potential mutations in the discovery phase were confirmed by another sequencing method (amplicon-based sequencing, Illumina MiSeq). Results: It was possible to detect and confirm somatic mutations in MS patients´ peripheral blood. More than half of the MS patients had non-synonymous somatic mutations. The allelic fractions of the mutations within each of the cell populations were under 5%. The mutations were significantly enriched into the CD8+ T-lymphocytes (85% of mutations). There were no mutational hot-spots, each patient had a unique mutational profile. Most of the mutations were novel, while a few were previously reported in cancer databases. Conclusions: We have outlined an approach by which next-generation sequencing can be used for screening low-frequency somatic mutations in blood. These results are among the first views into the landscape of somatic mutations in non-cancerous setting. More than half of the MS patients had somatic mutations, and the mutations were enriched in the CD8+ T-lymphocytes. Although the significance of somatic mutations in MS is presently unclear, their possible role as drivers of autoimmunity warrants further research. Disclosure This study has been funded by research grants from the Finnish Academy, Helsinki University Hospital, Finnish Multiple Sclerosis Foundation, University of Helsinki and Biogen Finland. Pentti Tienari has made consultations for Bayer, Biogen, Genzyme, Merck, Novartis and Teva, Others have nothing to disclose. P415 No association of the SLC9A9 gene variant rs2800 and disease activity in MS patients before and during treatment with interferon-beta H. Bach Søndergaard1, A.B. Oturai1, N. Koch-Henriksen2,3, P.S. Sørensen1, F. Sellebjerg1 1Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, 2The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, 3Clinical Institute, Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Background: Recently, a single nucleotide polymorphism (SNP) rs9828519 in the SLC9A9 gene, a NA+-H+- exchanger, was found to be associated with less treatment response to interferon-beta (IFN-β) in MS patients. In that study more disease activity was reported for carriers of the rs9828519G allele. Objective: Our aim was to investigate the association of a SLC9A9 gene variant, rs2800, which is in complete linkage disequilibrium with rs9828519, with disease activity in two cohorts of patients treated with IFN-β. Methods: The two cohorts of IFN-β treated patients had relapsing-remitting MS (RRMS) and began treatment with IFN-β in the years 1995-2008 and 1996-2012, respectively. Samples from the first cohort were obtained for a previously published study,

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and samples from the second cohort were collected subsequently. Clinical data were obtained from the Danish MS Treatment Registry. Only patients without neutralizing antibodies to IFN-β were included. SNP rs2800 was genotyped in the first cohort using TaqMan allelic discrimination (Life Technologies) and in the second cohort on the MS replication chip designed and conducted by the International MS Genetics Consortium. In the first cohort the relationship between the SLC9A9 rs2800G/A SNP and time to first relapse and time to EDSS progression was analysed by a Kaplan-Meier and Mantel-Cox analysis in 563 IFN-β treated patients. In the second cohort the relationship between the SLC9A9 rs2800G/A SNP and relapse number the two years before treatment (n=756) and during IFN-β therapy (n=682) was analysed by Poisson regression and negative binomial models. Age and sex were included as covariates in the primary analyses. Results: The minor allele frequency of rs2800G was 0.27 and 0.30 in the two cohorts, respectively. In the first cohort there was no relationship between the genotype of the SLC9A9 SNP and the time to first relapse or time to sustained EDSS progression during two to five years of treatment with IFN-β, respectively. In the second cohort no significant association was observed between number of relapses 2 years prior treatment and the rs2800 SNP genotypes (incidence rate ratio (IRR)GG= 0.97; 95% CI: 0.811.17; p=0.79). Likewise, relapses during treatment with IFN-β were not associated with the rs2800 SNP (IRRGG= 1.28; 95% CI: 0.92-1.79; p=0.14). Conclusion: The SNP rs2800 in the SLC9A9 gene is not associated with relapse risk or disease progression in Danish MS patients treated with interferon-beta. Disclosure Helle Bach Søndergaard has received support for congress participation from Biogen Idec, Genzyme and Teva. Annette Bang Oturai has served on scientific advisory boards for Novartis, and served as consultant for Biogen Idec; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from, Biogen Idec, Novartis, and Sanofi-Aventis. Nils Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis for the Danish MS Treatment Register. P. S. Sørensen has received personal compensation for serving on scientific advisory boards, steering committees or independent data monitoring boards for Biogen Idec, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, medDay Pharmaceuticals and Forward Pharma and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme, and Novartis. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough.


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P416 Multiple sclerosis risk variant PLEK C. Larochelle1,2, M. Paterka2, N. Hoppmann2, C.S. Abrams3, V. Siffrin2, C.M. Lill4, F. Zipp2 1Neurosciences, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada, 2University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany, 3University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States, 4University of Lübeck, Lübeck, Germany Background: Understanding the link between genetic risk factors for multiple sclerosis (MS) and mechanisms of neuroinflammation is a major step towards unraveling the pathogenesis of MS. PLEK single nucleotide polymorphisms (SNPs) are associated with MS susceptibility and have recently been shown to influence mRNA expression specifically in the CD4 T cell subset. In line with this, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, a striking upregulation of Plek mRNA is found in CD4 Th17 cells that have infiltrated the central nervous system (CNS). How pleckstrin, the protein encoded by PLEK, can contribute to CNS inflammatory processes is however still unknown. Goals: To identify the role of PLEK/pleckstrin in neuroinflammatory processes such as MS and EAE. Methods: We characterized the expression of pleckstrin and Plek in human and murine samples using Western Blot and qPCR. We used a PLEK knock out (KO) transgenic animal to study the role of pleckstrin in immune cell populations ex vivo and in vitro, and in EAE in vivo. Results: Pleckstrin is upregulated upon activation in murine CD4 T cells. PLEK KO animals show a normal proportion of immune cell populations, but a slight increase in the absolute number of peripheral immune cells. Moreover, PLEK KO CD4 T cells show a higher ratio of Tbet/GATA3 mRNA ex vivo as compared to littermates, suggesting a skew towards a pro-inflammatory phenotype. While the course of active EAE is not significantly altered in PLEK KO versus littermates, when isolating the role of PLEK in CD4 using reconstitution or transfer, EAE reproducibly started earlier and showed a more severe course in the recipients of PLEK KO CD4 T cells. In addition, expression of TNF was higher in CNS-infiltrating PLEK KO CD4 T cells as compared to wild-type CD4 T cells. Finally, while the expression of pleckstrin in human CD4 T cells is not significantly correlated with age or sex, it is significantly lower in CD4 isolated from untreated MS patients, as compared to controls or treated MS patients ex vivo. Conclusions: Our results show that pleckstrin -which SNPs are risk variants for MS- exhibits a beneficial role in neuroinflammation, as indicated by a lower expression in CD4 T cells from untreated MS patients, and a more severe EAE course upon deletion of PLEK in CD4 T cells. We will further provide novel data on PLEK SNPs association with the conformation of DNA and expression of natural antisense in human CD4 T cells. Disclosure Catherine Larochelle has nothing to disclose in relation with this project and holds a fellowship from the Canadian Institutes of Health Research. Magdalena Paterka has nothing to disclose in relation with this project.

Nicola Hoppmann has nothing to disclose in relation with this project. Charles S Abrams has nothing to disclose in relation with this project. Volker Siffrin has nothing to disclose in relation with this project. Christina Maria Lill has nothing to disclose in relation with this project. Frauke Zipp has nothing to disclose in relation with this project. Underlying original work was supported by the German Research Council (DFG; CRC-TR 128 to F.Z.) and by the German Competence Network Multiple Sclerosis (KKNMS), which is funded by the German Federal Ministry of Education and Research (BMBF to F.Z.). P417 miRNAs in CSF allow the prediction of multiple sclerosis patients likely to have a severe course E. Quintana1,2, F.J. Ortega3, R. Robles-Cedeño1,2,4, L.M. Villar2,5, M. Buxó6, J.M. Mercader7, N. Pueyo1, H. Perkal1, J.-M. Fernández-Real3,8, L. Ramió-Torrentà1,2,4 1Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, 2Red Española de Esclerosis Múltiple (REEM), Barcelona, 3Nutrition, Eumetabolism and Health Research Group, Girona Biomedical Research Institute (IDIBGI), 4Neuroimmunology and Multiple Sclerosis Unit (UNIEM), Department of Neurology, Dr. Josep Trueta University Hospital, Girona, 5Immunology Department, Ramón y Cajal Hospital, Madrid, 6Girona Biomedical Research Institute (IDIBGI), Girona, 7Joint BSC-CRG-IRB Research Program in Computational Biology, Supercomputing Centre, Barcelona, 8Diabetes, Endocrinology and Nutrition Department, Dr. Josep Trueta University Hospital, Girona, Spain Objective: MicroRNAs (miRNAs) are non-coding RNAs that regulate cellular processes by controlling protein translation and mRNA degradation. We aimed to explore the miRNA signature present in the CSF of MS patients and particularly in those with lipid-specific oligoclonal IgM bands in CSF (LS_OCMB), which have been associated with a severe disease course. Methods: An extensive profile of 754 miRNAs was evaluated in the CSF of 14 women (9 MS and 5 controls) using TaqMan LowDensity Arrays. Differentially expressed miRNAs together with others previously identified in the literature were validated in an extended sample of 86 MS patients (39 LS_OCMB+) and 55 controls. Results: Three miRNAs (miR-328, miR-30a-5p and miR-645) were up-regulated in MS patients compared to controls while five miRNAs (miR-21, miR-199a-3p, miR-191, miR-365, miR-106a and miR-146a) showed down-regulated expression. Taking into account two types of MS patients, LS_OCMB+ patients showed up-regulation of miR-30a-5p and miR-645 and down-regulation of miR-191 compared to controls. Furthermore, LS_OCMBpatients showed down regulation of miR-199a-3p and miR-106a compared to controls. Conclusion: An association is found between some miRNAs in CSF (miR-21, miR-199a-3p, miR-191, miR-365, miR-328, miR30a-5p, miR-106a, miR-146a and miR-645) and MS. These miRNAs provide an insight into proliferation and apoptosis as key


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Poster Session 1, 22(S3) processes to understand MS physiopathology. This study highlights the potential utility of miRNAs in CSF as biomarkers for MS. Disclosure E. Quintana: nothing to disclose FJ. Ortega: nothing to disclose R. Robles-Cedeño: nothing to disclose Luisa M Villar has received payment for lectures, grants or support for attendance to scientific meetings from Biogen, Merck Serono, Novartis, Teva, Bayer and Sanofi-Genzyme. M. Buxó: nothing to disclose JM. Mercader: nothing to disclose N. Pueyo: nothing to disclose H. Perkal: nothing to disclose JM. Fernández-Real: nothing to disclose Ll. Ramió-Torrentà has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. Funding: Spanish Ministry of Economy and Competitiveness Grant (PI13/01782). P418 A candidate gene study testing the role of sphingosine pathway genes on response to fingolimod in a cohort of Italian relapsing-remitting multiple sclerosis patients F. Esposito1,2, F. Clarelli2, L. Ferre’1,2, E. Mascia2, G. Sferruzza1,2, M. Radaelli1, F. Sangalli1, M. Rodegher1, L. Moiola1, B. Colombo1, V. Martinelli1, M.A. Rocca1,3, M. Filippi1,3, G. Comi1,2, F. Martinelli Boneschi1,2 1Department of Neurology, San Raffaele Scientific Institute, 2Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit & INSPE, San Raffaele Scientific Institute, 3Neuroimaging Research Unit, INSPE, San Raffaele Scientific Institute, Milan, Italy Background: A substantial heterogeneity in treatment response is observed across multiple sclerosis (MS) patients. MS is a typical condition where a more personalized intervention would be highly beneficial, favorably impacting long-term clinical outcomes and optimizing treatment costs. Aims: To investigate the genetic factors associated to interindividual differences in the response to fingolimod (FTY) therapy by applying a candidate-gene approach and exploring the sphingolipid signaling pathway. Methods: A cohort of 216 Italian relapsing-remitting MS patients treated with FTY, followed prospectively for 2 years and with available array genetic data were evaluated. Treatment response was assessed evaluating the proportion of patients with no evidence of clinical and MRI activity and no clinical progression (NEDA-3 criterion). The time to first relapse was also considered as additional outcome. A knowledge-driven candidate-gene approach was adopted, by investigating genes belonging to “Sphingolipid signaling pathway” (n=120) as available in KEGG database and additional genes selected from manual literature screening (n=63). PLINK, VEGAS and SKAT tools were used for testing gene-based associations. The selected genes were also tested for evidence of expression modulation by putative SNPs

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(eSNPs) using different public databases (SNPExpress, SCAN, and Braineac). Results: The DEGS1 gene was consistently replicated across outcomes and different tools (p-value=0.001 with VEGAS). It encodes a member of the fatty acid desaturase family and is expressed in both central nervous system and immune system. Additional genes were selected when considering 2 out of the 3 tested tools. Among them there is the TRAF6 gene, a member of the TNF receptor associated factor protein family, which functions as a signal transducer in the NF-KappaB pathway. We then assessed the presence of eSNPs in brain and peripheral blood mononuclear cell (PBMC) tissues. We observed a statistically significant association for the rs11784259 (p-value=3x10-4), which modulates ROCK2, CASP5 and PRKCE in PBMCs. This eSNP maps to the SLC7A13 gene, an anionic amino acid transporter. Conclusions: These preliminary data suggest a possible involvement of the sphingosine pathway genes in influencing response to FTY in MS patients. Epistatic analysis is ongoing to detect possible gene-gene interactions within the pathway. Additional analyses are planned to replicate these data in a larger cohort. Disclosure F. Esposito received honoraria from TEVA and Merck. L. Moiola received honoraria for speaking at meetings or for attending to advisory board from Sanofi-Genzyme, Biogen-Idec, Novartis and TEVA. B. Colombo received travel grant from Biogen-Idec, Merck, Bayer, Genzyme. V. Martinelli has received honoraria for consulting and speaking activities from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis and Excemed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. M. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). G. Comi has received compensation for consulting services with the following companies: Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma and compensation for speaking activities from Novartis, Teva, Sanofi, Genzyme, Merk, Biogen, Excemed, Roche. F. Martinelli Boneschi has received compensation for activities with Teva Neuroscienze as speaker and/or advisor. F. Clarelli: nothing to disclose. L. Ferre’: nothing to disclose. E. Mascia: nothing to disclose. G. Sferruzza: nothing to disclose. M. Radaelli: nothing to disclose. F. Sangalli: nothing to disclose.


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M. Rodegher: nothing to disclose. This study is supported by the “Fondazione Italiana Sclerosi Multipla”, project 2013/R/13 P419 Familial risk of childhood- versus late-onset multiple sclerosis: a nation-wide cohort study J. Song, H. Westerlind, C. Almqvist, J. Hillert, A. Manouchehrinia Karolinska Institutet, Stockholm, Sweden Background: Individuals with a family member affected by multiple sclerosis (MS) are at higher risk of developing the disease. The familial risk of MS in relation to the age at the disease onset has not been investigated and may disentangle the interplay of gene and environment in development of MS. Goals: To estimate and compare the relative risks (RRs) of childhood- (onset age ⩽16 years) and late-onset MS (onset age ⩾50 years) for individuals with a relative diagnosed with MS. Methods: We used three nationwide registers in Sweden; the National Patient Register (NPR) to identify MS cases and controls, the Multigenerational register for familial relations and the Swedish MS register to obtain MS onset age. RRs of childhood-, adolescent- (onset age between 10-16 years) and late-onset MS in individuals with a relative diagnosed with MS were calculated in a matched case-control design. Results: We identified 457 childhood-onset and 1,149 late-onset MS patients and included 2,981,645 randomly selected matched controls. The RRs of developing childhood-onset MS in individuals with a first and second degree relative diagnosed with MS were 7.02 (95% Confidence Intervals (CI): 4.47 to 11.04) and 2.64 (95%CI: 1.54 to 4.51), respectively. The RRs of late-onset MS in individuals with a first and second degree relative diagnosed with MS were 6.81(95%CI: 5.28 to 8.78) and 2.30 (95%CI: 1.49 to 3.54). The RRs of adolescent-onset MS (n=371) in individuals with a first and second degree relative diagnosed with MS were 7.95 (95%CI: 4.71 to 13.42) and 2.71 (95%CI: 1.50 to 4.90), respectively. Conclusions: Familial recurrence risk of MS, which to large extent represents genetic susceptibility to the disease, was significantly increased and was remarkably comparable in patients at the two ends of MS onset age distribution. These findings may indicate that age at development of MS is more influenced by environmental factor(s) than genetics. Disclosure Funding: The Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare JS, HW, CA and AM: nothing to disclose. JH has received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, MerckSerono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme and Novartis.

E. Quintana1,2, G. Reverter1, F.J. Ortega3, R. Robles-Cedeño1,2,4, L.M. Villar2,5, N. Pueyo1, H. Perkal1, J.-M. Fernández-Real3,6, L. Ramió-Torrentà1,2,4 1Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, 2Red Española de Esclerosis Múltiple (REEM), Barcelona, 3Nutrition, Eumetabolism and Health Research Group, Girona Biomedical Research Institute (IDIBGI), 4Neuroimmunology and Multiple Sclerosis Unit (UNIEM), Department of Neurology, Dr. Josep Trueta University Hospital, Girona, 5Immunology Department, Ramón y Cajal Hospital, Madrid, 6Diabetes, Endocrinology and Nutrition Department, Dr. Josep Trueta University Hospital, Girona, Spain Background: MicroRNAs (miRNAs) are non-coding RNAs that regulate cellular processes by controlling protein translation and mRNA degradation. In a previous study, Junker et al. in 2009 established miRNA profiles from active multiple sclerosis (MS) lesions by analysing white matter from brain tissue blocks, comparing sections with active lesions and white matter control tissue. The authors described a list of up-regulated miRNAs in active lesions. Objective: Our aim was to test the presence of some up-regulated miRNAs in the CSF of MS patients, and assess whether they are up-regulated in patients with active lesions in the MRI. Methods: Fifty patients (mean age: XXXX; 72% of females) with MS that fulfilled McDonald 2010 criteria were included in the study. All patients were submitted to an MRI with gadolinium as a contrast within a month before or after the date of the lumbar puncture. Fifty five per cent of the patients presented gadolinium positive lesions in the MRI. miRNA extraction from CSF was performed using a mirVana PARIS® Isolation kit, after which retrotranscription and preamplification was performed using Megaplex® RT assays. Individual TaqMan hydrolysis probes were used to study the presence of circulating miRNA candidates in samples. The non-parametric U- Mann Whitney test was used for comparisons. Results: After quantifying the expression of the eight most upregulated miRNAs in active MS lesions (miR-650, miR-155, miR-326, miR-142-3p, miR-146a, miR-146b, miR-34a and miR21), we could not detect the presence of miR-650, miR-326 and miR-142-3p circulating in the CSF. Three other miRNAs are upregulated in the CSF of patients with gadolinium positive lesions in the MRI: miR-146a (Gd-: median=0.0580, Gd+: median=0.1244; p=0.019), miR-146b (Gd-: median=0.0074, Gd+: median=0.0206; p=0.024) and miR-21 (Gd-: median=0.0145, Gd+: median=0.0288; p=0.023). We assessed the expression of the significant miRNAs for the number of T2 lesions in the MRI but no differential expression was found. Conclusion: Three miRNAs previously described as up-regulated in active MS lesions, also presented up-regulation in the CSF. The detection and quantification of miRNAs in the CSF could be useful as a biomarker of disease progression. Disclosure

P420 Up-regulation of miR-146a, miR-146b and miR-21 in CSF were found in patients with active MS lesions

E. Quintana: nothing to disclose G. Reverter: nothing to disclose FJ. Ortega: nothing to disclose


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Poster Session 1, 22(S3) R. Robles-Cedeño: nothing to disclose LM. Villar has received payment for lectures, grants or support for attendance to scientific meetings from Biogen, Merck Serono, Novartis, Teva, Bayer and Sanofi-Genzyme. N. Pueyo: nothing to disclose H. Perkal: nothing to disclose JM. Fernández-Real: nothing to disclose Ll. Ramió-Torrentà has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. Funding: Becas Investigación Esclerosis Múltiple, Fundación Genzyme 2014. P421 Differential DNA methylation patterns of neural gene promoters in neural precursor cells (NPCs) after cytokoine stimulation K.N. Poulatsidou1, R. Lagoudaki1, O. Touloumi1, E. Kesidou1, E. Chartomatsidou2, M. Grigoriou3, K. Chlichlia3, N. Grigoriadis1 12nd Neurology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, 2Institute of Applied Biosciences (INAB), Thessaloniki, 3Department of Molecular biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece Background: NPCs are characterized by their ability to differentiate towards neurons and glia and thus may provide a valuable tool in stem cell-based therapies for neurodegenerative diseases. However, the inflammatory environment of the CNS seems to affect important biological processes of endogenous or transplanted NPCs. Epigenetic modifications constitute a major intracellular mechanism that controls gene expression in response to extracellular cues. In this context, we aimed to investigate the effects of cytokines, the main inflammatory mediators, on expression levels of differentiation-related genes and also on DNA methylation patterns of the corresponding promoter regions. Methods: NPCs from postnatal C57bl/6J mice were cultured as free-floating neurospheres. Cells were treated with pro- or antiinflammatory cytokines (IFNγ, TNFα and TGFβ) or vehicle, as control. Total RNA was isolated and reversely transcribed into cDNA. Real time PCR was used to evaluate mRNA expression levels of neural and glial genes. Also, genomic DNA was isolated from each group and was treated with bisulfite. PCR was used for the amplification of selected gene promoter regions. Finally, PCR products were cloned into pCR2.1 plasmids and analyzed with Sanger sequencing. Results: IFNγ increased the expression of Neurogenin1 (Ngn1) (p< 0.05, 3.96-fold), Olig2 (p< 0.05, 2.5-fold), Tubb3 (p< 0.0001, 4.6-fold). TNFα induced expression of NeuroD1 (p< 0.005, 2.8fold), Ngn1 (p< 0.005, 6.4-fold), Math1 (p< 0.05, 2.75-fold) and DCX (p< 0.0001, 3.5-fold). TGFβ increased mRNA levels of NeuroD1 (p< 0.005, 3.2-fold), Ngn1 (p< 0.05, 2-fold), Math1 (p< 0.005, 6.8-fold), Olig2 (p< 0.005, 2.9-fold) and reduced DCX (p< 0.005, 0.4-fold), NG2 (p< 0.005, 0.17-fold) and S100b (p< 0.005, 0.22-fold). Ngn1 (total methylation: ctrl-5%, IFNγ-4.2%,

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TNFα-3.05%, TGFβ-4.1%) and Tubb3 (total methylation: ctrl88.3%, IFNγ- 92.3%) presented differential methylation pattern between cytokine-treated groups. Conclusions: Pro-inflammatory cytokines seem to induce neuronal differentiation of NPCs, while TGFβ represses both neuronal and glial differentiation. Our results indicate that the induction of neural gene expression could be regulated via DNA methylation. Disclosure This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund. Conflicts of interest: none Kyriaki Nefeli Poulatsidou: Nothing to disclosure Roza Lagoudaki: Nothing to disclosure Olga Touloumi: Nothing to disclosure Evangelia Kesidou: Nothing to disclosure Elisavet Chartomatsidou: Nothing to disclosure Maria Grigoriou: Nothing to disclosure Katerina Chlichlia: Nothing to disclosure Nikolaos Grigoriadis: Nothing to disclosure P422 Similarities and differences in the gene expression profiles of copaxone and polimunol D. Laifenfeld1, T. Hasson2, S.E. Kolitz3, K.D. Fowler3, A. Konya1, S. Bakshi2, B. Zeskind3, I. Grossman1, M.R. Hayden1 1Teva Pharmaceutical Industries, Petach Tikva, 2Teva Pharmaceutical Industries, Netanya, Israel, 3Immuneering Corporation, Cambridge, MA, United States Background: Copaxone (glatiramer acetate) has provided a safe, effective treatment option for multiple sclerosis (MS) patients for decades. Copaxone is thought to act through complex immune mechanisms related to its antigenic nature. Polimunol is a glatiramoid manufactured by a different manufacturer (Synthon) and authorized in Argentina. Recently Synthon obtained approval for their glatiramoid in Europe. Genome-wide expression profiling was used to characterize both glatiramoids in a mouse interchangeability model and a human monocyte (THP-1) cell line (Hasson et al, 2016). Here we show further analyses and study outcomes, including use of stricter fold change (FC) criteria. Objectives: To further explore the biological effects of Copaxone and Polimunol by applying multiple methodologies to data from a mouse model and THP-1 cells. Methods: Gene expression profiles induced by Copaxone and Polimunol were assessed in two model systems: 1) ex-vivo treatment of splenocytes from mice immunized with Copaxone or Polimunol and 2) in vitro stimulation of THP-1 cells. Results: Copaxone significantly modulated many genes and pathways in mouse splenocytes. Consistent with well-documented Copaxone mechanisms, these effects included key anti-inflammatory genes Il10 (FC=2.7, adj p< 2.3x10-24) and Foxp3 (FC=1.9, adj p< 3.4x10-23). Polimunol also upregulated Il10 (FC=3.0, adj


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p< 1.3x10-13) and Foxp3 (FC=2.0, adj p< 3.7x10-12) among thousands of genes modulated similarly by Polimunol and Copaxone. Using a strict threshold of FC ⩾1.4, differences were observed between Copaxone and Polimunol. 70 probesets were significantly differentially expressed (adj. p < 0.05) between Copaxone and Polimunol, and enriched for biologically relevant pathways including immune response (adj p< 6.8x10-9), response to virus (adj p< 2.3x10-8), RIG-I-like receptor signaling (adj p< 9.2x10-5), cytokine activity (adj p< 0.03), and cytokine-cytokine receptor interaction (adj p< 0.04). Cytokine-cytokine receptor interaction (adj p< 1.9x10-5) and immune response (adj p < 1.5-5) pathways were also enriched comparing Polimunol to Copaxone in THP-1 cells at a threshold of FC ⩾ 1.1. Conclusions: While the gene expression profiles of Copaxone and Polimunol share many similarities, Polimunol induces proinflammatory genes and pathways to a greater extent than Copaxone. These consistent and biologically relevant observations suggest a need for further study in the interest of MS patient safety. Disclosure DL, TH, AK, SB, IG and MRH are employees of Teva Pharmaceutical Industries, Israel. SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries, Israel. P423 A P2X7 - P2X4 haplotype with near absent P2X7 surface expression impairs phagocytosis in familial multiple sclerosis J.S. Wiley1, B.J. Gu1, X. Huang1, A. Ou1, A.D. Sadovnick2,3, A.L. Traboulsee3, C. Vilarino-Guell2 1The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia, 2Department of Medical Genetics, 3Department of Neurology, University of British Columbia, Vancouver, BC, Canada Much evidence implicates the P2X7 receptor and its “pore” function in promoting proinflammatory effects in the CNS including our recent genetic study showing a variant, Arg307Gln with loss of P2X7 pore function (but normal expression) was associated with two-fold protection against the risk of developing multiple sclerosis (MS) (Gu et al, Human Molecular Genetics, 2015). The P2X7 receptor however has a second function in the CNS as a scavenger receptor which recognizes and regulates the phagocytosis of apoptotic cells and foreign particles (such as beads) by cells of the monocyte-microglia lineage. We performed exome sequencing in five individuals from a single family affected with MS. Only a three variant P2RX7-P2RX4 haplotype (P2RX7 T205M N361S - P2RX4 G135S) was found in all five affected members, as well as in two obligate carriers and in one out of seven healthy relatives. Linkage analysis resulted in a LOD score of 3.07 for the whole family confirming co-segregation of the P2RX7-P2RX4 haplotype with disease. We then studied the functional effects on P2X7 function of each of the three variants separately and together as a haplotype. P2X7-induced “pore” formation was assessed by measuring ATP-induced ethidium uptake into HEK293 cells transfected with P2X7 and/or P2X4 constructs

either wildtype or containing mutations to resemble the haplotype. The P2X7 205M-361S P2X4 135S constructs together conferred >95% inhibition of P2X7 “pore” function. Most but not all of the functional loss was associated with 205M alone. Surface expression of the P2X7 receptor was measured in transfected HEK293 cells by the binding of FITC conjugated monoclonal antibody specific for the extracellular domain of P2X7. The P2X7 205M-361S P2X4 135S constructs expressed together conferred >95% impairment of surface P2X7 expression. Finally we measured the phagocytosis of non-opsonized 1.0 um YO fluorescent beads by the transfected HEK293 cells. Cells transfected with wildtype P2X7 showed brisk uptake of beads while cells expressing P2X7 205M-361S P2X4 135S constructs showed major impairment of bead uptake. Our data show that variants with near total loss of surface expression of P2X7 receptors not only inhibit P2X7 “pore” function but also block the phagocytic function of this receptor. Loss of phagocytic function is a significant risk factor for developing MS. Disclosure Funded by the ARC and NHMRC of Australia. A.L.T declares consultancy for Novartis, Genzyme and Roche. Other co-authors declare no conflict of interest.

Immunology P424 The effect of fingolimod treatment on natural killer cells N.P. Acar1, R. Karabudak2, D. Ozkazanc3, G. Sayat-Gurel2, G. Esendagli3, A. Tuncer2 1Neurology, Ankara Atatürk Training and Research Hospital, 2Neurology, Hacettepe University Faculty of Medicine, 3Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey Objective: The aim of this study is to evaluate the effects of fingolimod on the natural killer (NK) cells, in relapsing remitting multiple sclerosis (RRMS) patients during fingolimod treatment. Background: Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells. Fingolimod may also modulate peripheral effector and regulatory T cells in MS patients.There are few studies about the effect of fingolimod theraphy on NK cells. Methods: Age and sex matched healthy volunteers (HV, n=16) and RRMS patients receiving other immunomodulatory drugs (MS-IMT, n=23) were taken as the control group; RRMS patients under fingolimod treatment were divided into three groups according to the duration of the treatment (1 month (n=15), 3-6 months (n=16), 12-24 months (n=15)). Leukocytes were isolated and expression of T and NK cell markers (CD3, CD16, CD56, CCR7, NKG2D, NKp46) were analyzed with multi-color flow cytometry. Additionally, leukocytes were co-cultured with K562 cell line to evaluate the activation of NK cells. IFN-gamma production and degranulation of NK cells were also assessed. Results: After fingolimod treatment, beginning from the first month, lymphocyte number; percentage and number of T lymphocytes and CCR7 expression were decreased. The percentage of NK cells were significantly higher in the fingolimod treatment groups than MS-IMT controls (p=0,001; p=0,000; p=0,024).


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Poster Session 1, 22(S3) CCR7 expression was also decreased on these NK cells in the first six months of fingolimod compared with HV (p=0,004). The percentage of CD56bright NK sub-population and NKp46, NKG2D cytotoxicity markers did not change significantly during the treatment. On the other hand, CD107a expression indicating degranulation activity of NK cells was higher in the 12 - 24 months of the fingolimod treatment compared with earlier months and MS-IMT (p=0,038; p=0,009, respectively). Patient-derived NK cells retained capacity to highly degranulate and produce IFN-g upon stimulation with K562 target cells. Conclusion: Even though the number of NK cells was also affected by treatment with fingolimod, these cells did not lose their functional capacity. Our results may indicate the importance of NK cells for immune competency in the absence of T lymphocytes in RRMS patients under fingolimod therapy.

Before the initiation of therapy, a larger fraction of CD8+ cells specific for EBV latent antigens showed the phenotype of terminally differentiated and senescent cells compared to healthy individuals; the frequency of these cells did not change following treatment with Copaxone. Interestingly, exhausted PD-1+ EBVspecific CD8 cells decreased significantly after Copaxone therapy. These data suggest that at least two mechanisms are influencing the immune response to EBV in MS patients: on one hand, EBV-specific cells progress through terminally differentiated and functionally impaired and senescent cells, likely due to chronic viral stimulation, and this is an irreversible process; secondly, we find that some EBV-specific T cells are exhausted and express PD-1. This state is reversible, and treatment with Copaxone reduces their frequency.How Copaxone achieves these effects is not clear, and future studies will address this issue.

Disclosure

Disclosure

Nazire Pınar Acar: nothing to disclose Didem Özkazanç: nothing to disclose Güneş Esendağlı: nothing to disclose Güliz Sayat: nothing to disclose Rana Karabudak: nothing to disclose Aslı Tuncer: nothing to disclose

This study was supported by a grant from TEVA Pharmaceutical Industries Angelini DF: nothing to disclose Guerrera G: nothing to disclose Ruggieri S: nothing to disclose Gargano F: nothing to disclose Placido R: nothing to disclose Borsellino G: nothing to disclose Battistini L received honoraria for speaking or consultation fees from Teva, Baxter, and Genzyme. He also received grants from TEVA. Gasperini C has received compensation for consulting from Bayer HealthCare Pharmaceuticals and Biogen Idec and as a speaker for lectures from Biogen Idec, Bayer HealthCare Pharmaceuticals, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries. JP reports personal fees from Biogen Idec, Teva Pharmaceutical Industries, Merck Serono, Bayer Schering, Novartis, Chugai Pharma,Ono Pharmaceuticals Co, and CI consulting, and grants from Merck Serono, Bayer Schering, and Novartis.

P425 EBV-specific CD8+ T cells are exhausted and senescent in multiple sclerosis patients D.F. Angelini1, G. Guerrera1, S. Ruggieri2,3, F. Gargano1, R. Placido1, G. Borsellino1, L. Battistini1, C. Gasperini2 1Neuroimmunology Unit, Fondazione Santa Lucia, 2Department of Neuroscience, A.O. S. Camillo Forlanini, 3Department of Neurology and Psichiatry, University of Rome ‘Sapienza’, Rome, Italy Multiple sclerosis (MS) is thought to be caused by a complex interaction between genetic and environmental factors. EpsteinBarr virus (EBV) shows the strongest association with the disease based on robust sera-epidemiologic data, including increased EBV sera prevalence and higher titres of antibodies to EBV antigens in MS patients compared to the general population, a low risk of MS among EBV sera negative individuals, a correlation between serum antibody titres to EBNA-1 and risk of developing MS, and an increase in MS risk following infectious mononucleosis. MS patients also have higher EBV-specific CD4 T cells. In order to characterize the CD8 T cell response to EBV in MS, and to investigate on the effect of Copaxone on the immune response to EBV, we designed a set of pentamers coupled with EBV peptides derived from antigens of the lytic and latent phase, and we measured the frequency of CD8+ pentamer+ cells in MS patients before and at selected time points after therapy. Moreover, CD8+pentamer+ cells were characterized to evaluate their functional state. We measured expression of molecules associated with memory differentiation and immune senescence, such as KLRG1 (Killer cell lectin-like receptor G1), in combination with PD-1 (Programmed cell Death protein 1, a negative regulator of immune responses and marker or cell exhaustion), CD127 (the receptor for Interleukin 7), and chemokine receptor CXCR3. Differential expression of these molecules enables the definition of the differentiation/functional status of CD8 cells.

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P426 The role of dopamine in regulating interactions of the immune and nervous system in multiple sclerosis A. Boyko1, M. Melnikov1, M. Pashenkov2 1Pirogov Russian National Research Medical University, 2Institute of Immunology, Moscow, Russian Federation Introduction: Multiple sclerosis (MS) - chronic autoimmune disease of the CNS predominantly mediated by T-cells. Dopamine (DA) can participate in MS pathogenesis modulating immune cells activity and cytokine production. Objective: To study the relationship between clinical impairment, DA concentration in the serum, quantitative characteristics of Тh17-cells, and to clarify the influence of DA on the function of Th17 cells. Materials and methods: Data from 43 patients with relapsingremitting MS and 20 healthy controls were included. Fourteen patients were examined during relapses, 29 during clinical remission. The DA concentration in the serum was measured by ELISA. Circulating Th17-cells were determined by flow cytometry (CD4+CD26+CD161+CD196+). The levels of interleukin-17


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(IL-17) and interferon-gamma (IFN-γ) were studied by ELISA in supernatants of peripheral blood mononuclear cells (PBMC) stimulated with microbeads coated with anti-CD3 and anti-CD28 antibodies in the absence and in the presence of DA and antagonists of DA-receptors at a concentration of 10-5 M. Results: The level of DA was lower in MS patients during relapse than in patients during remission and in healthy subjects (p< 0.05). The percentages of Th17-cells and production of IL-17 and IFN-γ by PBMC were higher in patients in relapse compared to patients in remission or to the control group (p< 0.01). DA reduced IL-17 and IFN-γ production in all groups (p< 0.05). Blockade of D1-like receptors enhanced the inhibitory effect of DA on IL-17 production (p< 0.05) while blockade of D2-like receptors abolished the suppressive effect of DA in all groups. Blockade of D1-like receptors without the subsequent addition of DA reduced the production of IL-17 (p< 0.05) while blockade of D2-like receptors stimulated production of IL-17 in all groups (p< 0.05). Conclusion: These data suggest an anti-inflammatory role for DA in MS which is mediated by D2-receptors. Disclosure There is nothing to disclose. P427 Epitope specificity of human MOG antibodies and their pathogenic effect in neuroinflammatory demyelinating diseases P. Peschl1, K. Schanda1, R. Höftberger2, A. Saiz3, M. Bradl4, B. Zeka4, K. Rostasy5, A. Lutterotti6, T. Berger1, M. Reindl1 1Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, 2Medical University of Vienna/ Institute of Neurology, Vienna, Austria, 3Service of Neurology, Hospital Clinic and Institut dÍnvestigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 4Department for Neuroimmunology, Medical University Vienna, Center for Brain Research, Vienna, Austria, 5Department of Pediatric Neurology, Children´s Hospital Datteln, University Witten/Herdecke, Datteln, Germany, 6Klinik für Neurologie, UniversitätsSpital Zürich, Zurich, Switzerland Introduction: The myelin oligodendrocyte glycoprotein (MOG) is an important target of autoantibodies associated with atypical inflammatory demyelinating diseases like acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and monophasic or recurrent clinically isolated demyelination. Although experimental studies suggest that antibodies (Ab) against MOG can augment demyelination in rodents and primates, the pathogenic role of human MOG (hMOG) Abs under inflammatory conditions is still unclear. Potential reasons might be that only a subset of hMOG-Abs is also reactive with rodent MOG or a differential binding to MOG epitopes. Methods: 100 hMOG seropositive samples from 73 patients (27 follow-ups from 25 patients) were screened for their reactivity to rat (rMOG) and mouse MOG (mMOG) with a cell-based assay (CBA). A selection of 40 hMOG positive patients (16 reactive against rMOG and mMOG, 0 against rMOG only, 13 against mMOG only and 11 negative for both) and 18 hMOG seronegative controls were screened for their reactivity on mildly fixed, snap frozen human cerebellum and mouse/rat brain slices via

immunohistochemistry (IHC). To test whether this binding was specific we preabsorbed samples with hMOG transfected cells. The effect of purified IgG from three MOG positive patients (one reactive against rMOG) was also investigated in an experimental rat model. Results: Our present data show that hMOG-Abs are not necessarily reactive to mMOG (72/100, 72%) or rMOG (26/100, 26%) transfected HEK293A cells. Follow-ups did not change their reactivity to rodent MOG. 11/29 mMOG reactive samples and 9/16 rMOG reactive samples showed a positive staining in mouse/rat brain tissue. These samples had significant higher Ab-titre to rMOG/mMOG compared to samples with negative staining. However, we could not detect any association with clinical parameters. Moreover, 25/40 hMOG positive patients had a specific binding in the IHC on human cerebellar slices. Three MOG-IgG preparations were transferred to a rat model of experimental autoimmune encephalitis but none of them induced severe pathological changes. Conclusion: These data show that not all of the hMOG Ab-positive serum samples are also reactive to rodent MOG. Sera with a higher titre to rodent MOG have a better binding efficiency on rat and mouse brain tissue. With this finding we are now able to further investigate potential pathogenic effects of selected MOG positive serum samples in a suitable animal model. Disclosure Patrick Peschl is enrolled in the graduate program W1206 SPIN funded by the Austrian Science Funds and has no conflict of interest. Kathrin Schanda: nothing to disclose Romana Höftberger is funded by Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien, Project 15022 and declares no conflicts of interest. Albert Saiz is funded by Marató de TV3 (20141830) and has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, SanofiAventis, Teva Pharmaceutical Industries Ltd and Novartis. Monika Bradl is funded by the Austrian Science Funds, project P28476-B30, and has no conflict of interest. Bleranda Zeka: nothing to disclose. Kevin Rostasy is funded by project No.14158 from the Jubilaeumsfonds of the Austrian National Bank and has no conflict of interest. Andreas Lutterotti: nothing to disclose Thomas Berger: nothing to disclose Markus Reindl is funded by the graduate program W1206 SPIN funded by the Austrian Science Funds and project BIG WIG MS from the Austrian Federal Ministery of Science, Research and Economy and has no conflict of interest. P428 CNS-transmigration of distinct B-cell subsets through the choroid plexus in patients with multiple sclerosis B. Wildemann1, H. Rudolph2, S. Libicher1, S. Faller1, A. Schwarz1, M. Korporal-Kuhnke1, S. Jarius1, T. Tenenbaum2, C. Stump-Guthier2, C. Schwerk2, H. Schroten2, J. Haas1 1Dept. of Neurology, University Hospital of Heidelberg, Heidelberg, 2Dept. of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany


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Poster Session 1, 22(S3) Background: The role of B lymphocytes in MS immunopathogenesis is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby antigen-experienced memory B-cells accumulate in the CSF. While trafficking of B cells across the blood-brain barrier has been intensively investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood. Objectives: To investigate the interaction of B cells with the choroid plexus to transmigrate into the CSF. Methods: We isolated B cells and B-cell subsets from peripheral blood samples of healthy donors (HC) and MS patients, utilized an inverted transwell culture system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of distinct B-cell subsets, and immunofluorescence microscopy to analyze their migration route through the epithelial barrier. Experiments were completed by cytokine assays and RT-PCR to determine cytokines/chemokines mediating B-cell transmigration. Results: Transmigration rates of both HC- and MS-derived B cells across HIBCPP were initially low, significantly increased in response to B-cell specific chemokines (including CXCL-12, -13), and were further enhanced following pre-activation (CPGODN, CD40/IgM). Migrated cells predominantly exhibited a CD27+ memory phenotype. Interestingly, chemotactic activities of MS-derived memory B cells were higher when compared with HC-derived cells. Exposure of HIBCPP to pro-inflammatory stimuli induced distinct changes in their cytokine/chemokine profiles and permeability during B-cell transmigration. Conclusions: Our findings provide new information on how antigen-experienced B-cell phenotypes and the BCSFB act together to facilitate aberrant B-cell accumulation in the CSF of MS patients. Disclosure Supported by grants the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), “Understand MS” and Research Consortium 3: “Prognostic and Treatment markers”) and the Klaus Tschira Foundation. Funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the abstract for publication. HR, SL, SF, KT, AS, SJ, TT, CG, CS, HS, and JH have nothing to disclose. BW has received honoraria for speaking/consulting and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Genzyme, a Sanofi Company Novartis Pharmaceuticals, Teva Pharma GmbH, and research grants from Biogen Idec, MerckSerono, Novartis Pharmaceuticals, Teva Pharma GmbH, the German Ministry of Education and Research, the Dietmar Hopp Foundation, and the Klaus Tschira Foundation. P429 Mucosal biopsy reveals immunologic changes of the colon in patients with early multiple sclerosis W. Spindelboeck, A.M. Moser, H. Strohmaier, C. Enzinger, T. Gattringer, S. Fuchs, F. Fazekas, G. Gorkiewicz, P. Wurm, C. Högenauer, M. Khalil Medical University of Graz, Graz, Austria

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Objective: Data from animal models, epidemiologic and metabolomics studies suggest a role of the gastrointestinal tract in multiple sclerosis (MS). We wanted to substantiate this assumption by directly investigating the immune cells of the colonic mucosa in treatment-naïve patients with a clinically isolated syndrome (CIS) or early relapsing MS and to assess a possible association with the faecal content in short-chain fatty acids (SCFA). Methods: We obtained mucosal specimen during ileocolonoscopy from fifteen CIS /MS patients and ten controls. Mucosal immune cells were analyzed by Fluorescence-activated cell sorting (FACS) and gas chromatography-mass spectrometry (GC-MS) measurements of stool samples served to determine SCFA. Results: The number of total dendritic cells (DC), CD103+ tolerogenic DCs and CD4+CD25+127- regulatory T-cells (Tregs) was significantly reduced in the left-sided colon of CIS/ MS compared to controls while we found no differences on the right side. The patients’ faecal samples also showed a substantially lower content of SFCA and especially lower levels of butyrate and acetate. Interpretation: Our findings indicate a disturbed homeostasis of colonic DCs and Tregs in MS patients which could be associated to colonic SCFA depletion. While not implying causality these findings strengthen a role of the gut in MS and warrant further research if modulation of the colonic SCFA profile or the colonic Treg pool can serve to modify the course of MS. Disclosure Dr. Spindelboeck: nothing to disclose Dr. Moser: nothing to disclose Dr. Strohmaier: nothing to disclose Dr. Enzinger: nothing to disclose Dr. Gattringer: nothing to disclose Dr. Fuchs: nothing to disclose Dr. Fazekas: nothing to disclose Dr. Gorkiewicz: nothing to disclose Mr. Wurm, Msc: nothing to disclose Dr. Högenauer: nothing to disclose Dr. Khalil: nothing to disclose P430 Dimethyl fumarate selectively affects memory and helper T cells in multiple sclerosis patients Y. Mao-Draayer, Q. Wu, Q. Wang, C. Dowling, M. Guangmei, S. Lundy University of Michigan, Ann Arbor, MI, United States Background: Dimethyl fumarate (DMF; also known as BG-12, trade name TecfideraTM) is an oral formulation of the fumaric acid ester FDA-approved for treating relapsing-remitting multiple sclerosis (RRMS). Objectves: To better understand the therapeutic effects of Tecfidera, as well as the recently-implicated and devastating sideeffect of progressive multifocal leukoencephalopathy (PML). Methods: we conducted comprehensive immunophenotyping of Tecfidera-treated RRMS patients cross-sectionally and longitudinally. Circulating immune cell subsets, including CD4 and CD8 memory


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T cells and T helper cell functional markers were analyzed using multi-color flow cytometry. Results: Significantly decreased absolute numbers of both CD4 and CD8 T cells were observed in the blood of DMF-treated patients compared to pre-treatment levels (median=0.40×106/mL) in both short-term (4-6 month, median=0.22×106/mL) and longterm (>18 month, median=0.17×106/mL) treatment groups. More significant reductions were seen with CD8+ T cells compared with CD4+ T cells resulting in a significant increase of the CD4/CD8 ratio after >18 months of treatment with DMF from median 3.9 to 6.3. Among T lymphocytes, memory T cells, particularly, effector memory T cells (Tem) were reduced in treated patients. In addition, the T helper 17/1 (Th17/Th1) subset was most significantly reduced, while the Th2 subset increased significantly after DMF treatment. Furthermore, T cell activation was reduced with DMF treatment, especially among Tem and effector memory RA (Temra) T cells. Culture of peripheral blood mononuclear cells with DMF in vitro led to increased T cell apoptosis and decreased proliferation. An increase in IL4, and decreases in IFNγ and IL17, as well as a decrease in CCR7 expression were also induced by DMF treatment. Conclusions: Our results suggest that DMF may specifically target memory T cells by affecting their survival, proliferation, activation and cytokine production. Monitoring these subsets could be important for determining the efficacy as well as risk stratification for PML during DMF treatment. Disclosure No commercial funding was received to support this work. The study was funded with institutional support from the University of Michigan Medical School. Drs. Wu, Wang, Dowling and Mao have no funding disclosures to report. Dr. Lundy was supported by grants from NIH NIAID: R03-AI105029, R21-AI115117 and Autoimmune Center of Excellence grant: UM1-AI110557; and has received additional research support from the Edward T. and Ellen K. Dryer Foundation. Dr. Mao-Draayer has served as a consultant and/or received grant support from: Acorda, Bayer Pharmaceutical, Biogen Idec, EMD Serono, Genzyme, Novartis, Questor, and Teva Neuroscience. Dr. Mao-Draayer is currently supported by grants from NIH NIAID Autoimmune Center of Excellence: UM1-AI110557; NIH NINDS R01-NS080821 and the University of Michigan Neurology Department.

P431 A multicenter study on the diagnostic significance of a single cerebrospinal fluid IgG band D. Ferraro1, A.M. Simone1, E. Cocco2, M. Santangelo3, P. Immovilli4, M. Calabrese5, M. Di Filippo6, R. Orlandi1, R. Bedin1, F. Vitetta1, A. Gallina6, C. Solaro7, C. Gasperini8, M.E. Rodegher9, P. Sola1 1University of Modena and Reggio Emilia, Modena, 2University of Cagliari, Cagliari, 3Ospedale B. Ramazzini, Carpi, 4Ospedale G. da Saliceto, Piacenza, 5University of Verona, Verona, 6University of Perugia, Perugia, 7Ospedale PA Micone, Genova, 8Ospedale San Camillo Forlanini, Rome, 9IRCSS - Policlinico San Donato, Milano, Italy

Introduction: The finding of a single cerebrospinal fluid (CSF) Immunoglobulin G (IgG) band is rare and only few studies have explored its frequency and diagnostic significance. Objective: To establish 1) the diagnoses associated with the finding of a single CSF IgG band, 2) the proportion of patients with a single IgG band who will be diagnosed with Multiple Sclerosis (MS) within the following 2 years and 3) whether there are differences in the CSF characteristics of patients subsequently diagnosed with MS compared to those with alternative diagnoses, in a multicenter study. Methods: We collected clinical and CSF data of patients who showed a single CSF-restricted IgG band, with or without an associated “mirror pattern”, at CSF isoelectric focusing (IEF) analysis, carried out for any reason, from 2005 onwards. Results: Out of 8156 CSF IEF analyses, 113 showed a single CSF IgG band (1.4%). In another cohort of 500 CSF analyses carried out for suspected MS, only 2 showed a single CSF IgG band (0.4%). A definite diagnosis was established in 98 patients. MS was diagnosed in 26 (27%) patients, other central nervous system (CNS) demyelinating diseases in 20 (20%), CNS infections in 7 (7%), inflammatory peripheral nervous system (PNS) diseases in 6 (6%), CNS autoimmune/paraneoplastic diseases in 5 (5%), cerebral tumours in 3 (3%), and other diagnoses in 31 (32%), including CNS/PNS degenerative diseases (6%), spondylomyelopathy (3%), idiopathic intracranial hypertension (2%), headache (2%), Tolosa-Hunt syndrome, reversible cerebral vasoconstriction syndrome, hereditary spastic paraparesis, DYT1-positive dystonia and cerebral venous thrombosis. Patients who acquired a diagnosis of MS were significantly younger (38±13 versus 46±18 years; p=0.03) than those with other diagnoses. There were no differences in CSF data (cell number and type, proteins, Link’s Index, CSF/serum albumin ratio, presence of additional “mirror pattern”) between the two groups. Conclusion: MS was the single most frequent diagnosis in patients with a single CSF IgG band. Nevertheless, the majority of patients with a single CSF IgG band have neurological diseases other than MS or CNS demyelinating diseases, the most frequent being CNS infections, inflammatory PNS diseases, CNS autoimmune/paraneoplastic diseases and cerebral tumours. Patients with a subsequent diagnosis of MS are significantly younger than those with other neurological diseases. Disclosure Ferraro D has nothing to disclose. Simone AM has nothing to disclose Cocco E has nothing to disclose Santangelo M has nothing to disclose Immovilli P has nothing to disclose Calabrese M has nothing to disclose Di Filippo M has nothing to disclose Orlandi R has nothing to disclose Bedin R has nothing to disclose Vitetta F has nothing to disclose Gallina A has nothing to disclose Solaro C has nothing to disclose Gasperini C has nothing to disclose Rodegher ME has nothing to disclose Sola P has nothing to disclose


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Poster Session 1, 22(S3) P432 The international MS microbiome study (iMSMS): investigating the role of gut microbiota in multiple sclerosis through open collaboration S.E. Baranzini, for the iMSMS Neurology, UCSF, San Francisco, CA, United States The human microbiome is emerging as a major driver of multiple pathologic conditions from metabolic, to neurological to immune disorders, including MS. In particular the gut microbiome has been associated with critical regulatory functions over both innate and adaptive immune responses and its dependence on diet and environmental influences make this an attractive venue to modulate and potentially cure these conditions. However, with the exception of diseases affecting the gastrointestinal tract (colitis, inflammatory bowel disease, etc) the magnitude of the observed effects are modest. This underscores the need for large, collaborative studies that use standardized protocols and analytical methods to maximize their usefulness and relevance. The international MS microbiome study (iMSMS; www. imsms.org) is a collaborative effort that includes research teams across three continents with the goal of characterizing the gut microbiome in MS and its potential consequences on the disease pathogenesis. The ultimate goal of iMSMS is to set up the stage for therapeutic interventions through modification of the gut microbiota via probiotics, prebiotics, antibiotics, fecal transplants or a defined combination of the above. The inaugural iMSMS team is composed by translational MS research teams at UCSF (San Francisco, CA), Mount Sinai (New York, NY), Brigham and Women’s (Boston, MA), University of Edinburgh (Edinburgh, UK), and FLENI (Buenos Aires, Argentina). In addition basic research teams with expertise in the microbiome include Caltech (Pasadena, CA), UCSD (San Diego, CA), Harvard (Cambridge, MA) and the Max Planck Institute (Munich, Germany). The iMSMS has the goal of recruiting and analyzing stool and DNA samples from 2000 subjects with MS and 2000 matched healthy controls. All disease subtypes are being recruited and a significant proportion of the patients are off therapy or never received disease modifying treatment. In addition to 16S ribosomal DNA gene sequencing, full genome host DNA variation and HLA typing are being investigated. Immunoprofiling and fecal microbiota transfer into germ-free mice are being conducted to investigate the potential mechanisms of disease pathogenesis induced by gut dysbiosis. The iMSMS follows an open and collegial collaborative model and encourages independent research with potential to advance the field for MS and other complex diseases. Disclosure Sergio Baranzini has received funding from the NMSS, NIH, Department of Defense, and the Valhalla Charitable Foundation. P433 M1/M2 macrophages’ balance is altered in multiple sclerosis V. Chiurchiu1,2, A. Leuti1,2, M. Albanese3, L. Battistini4, D. Centonze3,5, M. Maccarrone1,2 1Neurochemistry of Lipids, IRCCS Fondazione Santa Lucia, 2Department of Medicine, Campus Bio-Medico University of

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Rome, 3Tor Vergata University, 4Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Roma, 5IRCCS Istituto Neurologico Mediterraneo Neuromed Pozzilli, Isernia, Italy Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Several studies demonstrated that MS lesions contain multiple leukocytes including adaptive and innate immune cells, all of which are believed to contribute to lesion formation and progression. Among these, macrophages have been identified as major effectors of inflammation and demyelination in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the activation and heterogeneity of macrophages in MS has not been studied in detail yet. Thus, we evaluated M1 and M2 macrophages’ immunophenotype from treatment-free relapsing remitting (RR-MS) patients compared to healthy subjects through polychromatic flow cytometry and ELISA assay. Our investigation showed that M1 macrophages of MS patients possessed a higher proinflammatory profile, since they expressed higher levels of activation/co-stimulatory markers (iNOS, CD25, CD80/CD86, PD-L1 and CCR7) and cytokines/chemokines (IL-6, IL-12, CXCL9, CXCL10); whereas M2 lost their M2-like phenotype by showing decreased expression of their signature markers CD206, CD200R, CD36, IL-10 and a concomitant upregulation of M1-like markers iNOS, CD25, CD80/ CD86, IL-6 and IL-12. Overall, our data seem to delineate a immunophenotypic alteration of M1/M2 macrophage balance during MS, with M1 being hyperactive and more pro-inflammatory and M2 being less protective, which can be of crucial importance not only for a better understanding of the immunopathology of this neurodegenerative disease but also to potentially develop new macrophage-centered therapeutic strategies. Disclosure nothing to disclose This work was funded by Italian Foundation of Multiple sclerosis (FISM) to V.C. P434 Increased inflammatory activities of monocytes from neuromyelitis optica spectrum disorder patients B.S. Kong, G.Y. Kim, Y.S. Kim, H.J. Kim Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea Background: A series of evidence suggested that B cells play a fundamental role in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, there are still gaps left to be answered in NMOSD pathogenesis that is not fully understood without describing roles of other immune cells, such as T cells and monocytes. Methods: CD14+ monocytes separated from peripheral blood mononuclear cells (PBMC) of 10 NMOSD, 10 multiple sclerosis (MS) patients and 10 healthy controls (HC) were used in this study. Using flow cytometry, the surface expression levels of major CD14+ monocyte molecules (CD80, CD86, HLA-DR, and CD54) were examined in condition either untreated or treated with CD40L (1.0 µg/ml) and/or IFNγ (100 ng/ml) for 24 hours. Various cytokines (TNFα, IL-6, IL-10, and IL-1β) was measured from the same condition by ELISA.


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Results: Untreated monocytes of NMOSD showed higher mean fluorescent intensity (MFI) levels of CD80, CD86, HLA-DR and CD54 than those of MS and HC[a1] . Treatment with IFNγ and/or CD40L led to increase in MFI levels of surface molecules in the order of HC, MS, and NMOSD, but the increase was far greater in NMOSD monocytes than MS or HC. IFNγ treatment in NMOSD monocytes showed greater increase of CD80, CD86, HLA-DR and CD54 than other groups. Likewise, CD40L treatment in NMOSD monocytes showed higher MFI levels of CD80, HLA-DR, and CD54 than other groups. Co-treatment of CD40L and IFNγ synergistically increased MFI levels of inflammatory markers. Similar patterns were observed in the cytokines measured from the supernatants of monocytes. Both untreated and treated monocytes with IFNγ or CD40L produced significantly higher levels of proinflammatory cytokines, TNFα and IL-1β, in NMOSD than other groups. Differences between groups were more evident when CD40L and IFNγ were co-treated. On the other hand, IL-10, an anti-inflammatory cytokine, showed reciprocal result compared to TNFα and IL-1β production. IL-10 production of NMOSD monocytes was significantly lower compared to other groups particularly in CD40L treated condition, which suggests an impaired production of IL-10 in NMOSD monocytes. IL-6 production was higher in both NMOSD and MS than HC. Conclusion: Our finding suggests that activation levels and inflammatory responses of monocytes appear to be higher, whereas anti-inflammatory response in NMOSD was lower than MS or HC. Disclosure This study was supported by the Bio& Medical Technology Development Program (M3A9B6069339) through the Ministry of Science, ICT & Future Planning P435 In silico prediction analysis of immunoglobulin-driven T-B cell collaboration in multiple sclerosis R.A. Høglund1,2, A. Lossius2,3,4, J. Johansen3, H. Robins5, R.D. Bremel6, T. Holmøy1,2 1Department of Neurology, Akershus University Hospital, Lørenskog, 2Institute of Clinical Medicine, University of Oslo, 3Department of Immunology and Transfusion Medicine, 4Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway, 5Adaptive Biotechnologies, Seattle, WA, 6EigenBio LLC, Madison, WI, United States Introduction: Intrathecally synthesized IgG of multiple sclerosis (MS) patients carry somatic mutations compatible with an antigen-driven and T cell mediated immune response, but the target antigens remain unknown. Based on proof-of-principle experiments we have postulated that mutated fragments of immunoglobulin molecules are presented as antigens to the T cells, and thereby sustain the immune response. The immense diversity of the IgG repertoire has so far precluded further studies. The complete immunoglobulin heavy-chain variable (IGHV) transcriptome can now be established by next generation sequencing (NGS), and the ability of the immunoglobulins to stimulate T cells can be predicted based on their amino acid sequences and the human leukocyte antigen (HLA) makeup of each patient.

Methods: IGVH transcriptomes (complementarity determining region 3 (CDR3) and framework region 3) from blood and CSF of 11 MS patients and 6 controls with other neurological diseases (OIND) were identified by high throughput sequencing. The binding affinities of deduced IgG peptides to HLA class II molecules, the likelihood of protease (cathepsin S) cleavage, and the stimulating potential of their T cell exposed motifs (TCEM) were calculated in silico. Results: Among the 2,151,776 recovered transcripts, we discovered two distinct patterns of TCEM utilization in blood vs CSF when computing pairwise correlations. Moreover, IGVH transcripts from CSF exhibited two different TCEM patterns in MS vs OIND patients. This suggests a selection of different TCEM in CSF of patients with MS compared to OIND. Further we found an IGHV4 predominance in the CNS of MS patients that was associated with a significantly higher likelihood of cleavage with cathepsin S than the other IGVH classes (p< 0,05, Tukey-Kramer HSD). Reiterative mutation resulting in a high recurrence of TCEM that otherwise only appears elsewhere in the IGHV occurs in the CDR3 region of both MS and OIND patients. Conclusion: Bioinformatic prediction analysis suggests that intrathecally synthesized IgG carry hypervariable regions which can be presented on HLA class II and stimulate T cells, and that cathepsin S cleavage contributes to a preferential use of IGVH4 in CSF of MS patients. Disclosure Rune A. Høglund: nothing to disclose. Robert D.Bremel holds equity in EigenBio LLC, responsible for the biostatistics algorithms used in this project. Trygve Holmøy has received speakers honoraria from Biogen, Genzyme, Novartis and Merck-Serono. Andreas Lossius has received speaker honoraria from Genzyme and Fisher Scientific. Jorunn Johansen: nothing to disclose. Harlan Robins: nothing to disclose. P436 Multiple sclerosis and Hashimoto´s thyroiditis: differences and similarities in the immune regulation S. Perga1, F. Montarolo1, S. Martire1, M. Spadaro1, G. Bono1, I. Giordano2, F. Orlandi2, A. Bertolotto1 1Neurobiology Unit, Neurologia 2 - CReSM (Regional Referring Center of Multiple Sclerosis), Neuroscience Institute Cavalieri Ottolenghi (NICO) University of Turin & AOU San Luigi Gonzaga, Orbassano, 2Division of Internal Medicine, Department of Medical Sciences, Gradenigo Hospital, University of Turin, Turin, Italy Multiple sclerosis (MS) is an autoimmune inflammatory disease frequently associated with other autoimmune conditions such as Hashimoto’s thyroiditis (HT). The pathogenetic mechanism underlying these associations is unknown but genetic, environmental and immune defects may have a role in the poliautoimmunity. In particular, several evidences indicated altered serum levels of vitamin D metabolites and the deregulation of regulatory T cells (Tregs) in both the diseases.


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Poster Session 1, 22(S3) With the aim of highlighting common immune deregulated mechanisms shared by MS and HT, we investigate the levels of Tregs and the expression of important Treg differentiation genes (i.e. FoxP3, BACH2, NR4A family and PDCD5) in healthy controls (HC) and treatment-naïve patients affected by MS, HT or both the pathologies. We also evaluated the expression of the TNFAIP3 gene, a key negative regulator of inflammation involved in several autoimmune conditions and recently genetically associated to MS. Finally, we assessed the serum level of vitamin D, a key modulator of immune cell lineages including Tregs that plays a critical role in the prevention of autoimmune diseases. We demonstrated a significant reduction of Tregs in both MS and HT patients compared to HC. Notably, the Tregs number was significantly lower in MS compared to HT, consistently with a more profound immune deregulation in this disorder. Surprisingly, the number of Tregs in patients affected by both diseases was similar to HT patients and significantly higher respect to MS patients, suggesting a “protective” role of HT against autoimmune aggression in MS. Similarly, we observed differences in gene expression between groups: the level of the anti-inflammatory and Treg differentiation genes TNFAIP3, NR4As and BACH2 were lower in MS patients, supporting a more severe immune deregulation. Conversely, HT patients displayed an over expression of the PDCD5 gene, which is important in the induction of apoptosis, a dominant phenomenon in the HT pathogenesis. Finally, our data demonstrated very low circulating levels of 25-OH vitamin D compared to the reference values in all groups. Among these, MS patients showed the lowest levels. In conclusion, our study suggests that MS and HT share some common pathogenetic mechanisms able to support the epidemiological observation of their frequent association, but also they present deep differences, as evidenced by the different clinical evolution and prognostic impact of the two diseases.

Toll-like receptor 2 (TLR2) is an important innate immune receptor that can sense a broad spectrum of microbial as well as endogenous ligands due to its ability to heterodimerise with either TLR1 or TLR6. Multiple Sclerosis (MS) is an immune-mediated, inflammatory demyelinating disease of the central nervous system, in which pro-inflammatory Th17 cells appear to prevail over anti-inflammatory regulatory T cells (Tregs). Our lab has previously shown that TLR2 stimulation on human Tregs reduces their suppressive functions and can drive their differentiation towards a Th17-like phenotype and function. In addition, Tregs from relapsing-remitting MS (RRMS) patients are more susceptible to such TLR2-induced effects than those from healthy controls (HC). We are now expanding these studies to see whether these mechanisms are relevant in vivo. In the HEK-293 transfection system and Dual luciferase reporter (DLR) assay, we identified some infectious stimuli including Helicobacter pylori, E. coli, S. aureus, S. epidermis, K. pneumoniae, P. aeruginosa, P. vulgaris as strong stimulants for TLR2, which could be associated with MS. We also tested the potential of urine and serum samples from MS patients and HC in the HEK-293 system to stimulate TLR2. Urine samples from MS patients in relapse contain higher TLR2-stimulating activity than HC; however, pilot paired samples from relapse and remission do not show significant differences. Besides, we are assessing the level of soluble TLR2 (sTLR2) as a potential biomarker of inflammation during MS relapses, measured both in serum and in urine by ELISA. In MS patients, sTLR2 levels are higher in urine during relapses than in remission, while in serum no significant differences were observed. We have collected paired relapse and remission samples from 25 RRMS patients to compare Treg and Th1/Th17 parameters by flow cytometry upon TLR2 stimulation in vitro in PBMCs and CD4+ T cells. Disclosure

Disclosure Perga Simona: nothing di disclose Montarolo Francesca: nothing di disclose Martire Serena: nothing di disclose Spadaro Michela: nothing di disclose Giordano Ilaria: nothing di disclose Orlandi Fabio: nothing di disclose Bertolotto Antonio: nothing di disclose The study was supported thanks grants from the Fondazione Italiana Sclerosi Multipla (FISM - Grant number 2010/R/7) from the Italian Ministry of Health (Bando Giovani Ricercatori 2010Grant agreement GR-2010-2315964) and the European Community´s Health Seventh Framework Programme (FP7/20072013 under grant agreement 259867) P437 Role of Toll-like receptor 2 in mediating infection and inflammation in multiple sclerosis M.J. Hossain1, E. Morandi1, R. Tanasescu1, T.A. Faraj2, C. Erridge2, B. Gran1 1Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Queen’s Medical Centre, Nottingham, 2Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom

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Conflict of interest statements: Md Jakir Hossain: I am being supported by a McDonald Fellowship from Multiple Sclerosis International Federation (MSIF). Elena Morandi: Nothing to disclose Radu Tanasescu: Nothing to disclose Clett Erridge: Noting to disclose Tola A. Faraz: Nothing to disclose Bruno Gran: I received research grant for this project from Italian Multiple Sclerosis Society (FISM Grant 2013/R/14) P438 ALCAM regulates B cells migration across the barriers of the central nervous system L. Michel1, C. Grasmuck2, E. Peelen2, M. Charabati2, M.-A. Lécuyer2, L. Bourbonnière2, S. Larouche2, P. Duquette2, A. Bar-Or3, J. Gommerman4, A. Prat2 1Neurologie, CHU de Nantes, Nantes, France, 2CRCHUM, 3McGill University, Montréal, 4University of Toronto, Toronto, QC, Canada Background: Multiple Sclerosis (MS) is classically considered as a T lymphocyte- mediated autoimmune disease. However, the efficacy of therapies targeting B cells and the presence of inflammatory cell aggregates within the meninges of patients, plead for


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an important role of B lymphocytes. ALCAM (Activated Leukocyte Cell Adhesion Molecule) has been identified in our lab as a major adhesion molecule involved in monocytes trafficking inside the CNS. Objective: To analyze the phenotype and the function of ALCAM+ B cells in vitro in both humans and mice, and also in vivo in active EAE model. Methods: Phenotype of ALCAM+ B cells was first determined by flow cytometry and immunohistofluorescence in healthy volunteers. Then, transmigration of B lymphocytes (with or without blocking Abs against ALCAM) was assessed in primary cultures of parenchymal and meningeal endothelial cells that replicate in vitro the Blood Brain Barrier (BBB) and Blood Meningeal Barrier (BMB). Adhesion and velocity of B cells from KO ALCAM mice or WT mice on Brain Murine Endothelial Cells (BMECs) was analyzed using flow assays. Lastly, the effects of anti-ALCAM Abs was assessed in active rhMOG EAE model. Results: Ex vivo human B lymphocytes express ALCAM (40%). These ALCAM+ B lymphocytes contain significantly more CD19+CD27+/CD24hiCD38- memory B lymphocytes. They are also significantly enriched in markers of activation as compared to ALCAMneg B cells and secrete significantly more pro-inflammatory cytokines (such as IL-6, TNFα and GM-CSF). ALCAM significantly mediates migration of human B cells in vitro across the BBB and BMB with a 30% migration inhibition using the blocking Ab. Moreover, using flow assays, we found that the adhesion on BMECs and the velocity of B cells are significantly reduced using B cells from ALCAM KO animals compared to those from WT animals. In active rhMOG EAE, ALCAM+ B cells significantly infiltrate the CNS at the peak of the disease compared to the chronic phase. Finally, treatment of active rhMOG EAE mice with anti-ALCAM Ab between Day 7 to Day 20 reduced the severity of the disease. Conclusion: ALCAM+ B cells are memory pro-inflammatory B cells. Moreover, ALCAM plays an important role in B cell migration across CNS barriers and anti-ALCAM Ab reduces the severity of disease in active rhMOG EAE. Targeting this molecule on B cells could represent a major and innovative advance in the therapeutic. Disclosure CG, EP, MC, MAL, LB, SL, PD, JG and AP have nothing to disclose LM received consultant honoraria from Biogen and Novartis. ABO has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc, Roche, and Merck/EMD Serono. P439 T and B lymphocyte subsets of anti myelin oligodendrocyte glycoprotein-related disorder and anti-aquaporin 4 antibodypositive neuromyelitis optica spectrum disorder in remission S. Tanaka1, A. Kubota1, M. Kojima1, S. Izaki1, T. Dembo1, H. Fukaura1, K. Kaneko2, D.K. Sato2, I. Nakashima2, K. Nomura1 1Neurology, Saitama Medical Center, Kawagoe, 2Tohoku University, Sendai, Japan

Objective: We study the subsets of T and B lymphocytes present in the active and remission phases of anti-myelin oligodendrocyte glycoprotein (MOG)-related disorder (MOG-RD) and anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD). In this study, the subsets of T and B cells in peripheral blood were compared in patients in remission. Patients and methods: Peripheral blood was collected from 5 and 12 patients who had been treated for acute MOG-RD and AQP4-NMOSD, respectively, ⩾1 month earlier and were presently in remission. The levels of anti-MOG and anti-AQP4 antibodies was measured by the Department of Neurology, Tohoku University School of Medicine. Without removing red blood cells, 2 ml peripheral blood was subjected to staining of various T- and B-cell surface markers and flow cytometry using BD FACSCanto II (Becton, Dickinson and Company). T cells examined in this study were CD8+ CD11b− cytotoxic T cells, activated CD4 (CD4+ HLA+) T cells, activated CD8 (CD8+ HLA+) T cells, CD4+ CD25high regulatory T cells, and CD3− CD16/56+ natural killer cells. B cells examined were CD19+ CD27+ CD38high CD180− plasmablasts, CD19+ CD27+ memory B cells, CD19+ CD27− naive B cells, and CD19+ CD24high CD38high transitional B cells. Results: No significant difference in T cell subsets was observed between the two disorders. As for B cell subsets, the level of plasmablasts was significantly higher in patients with AQP4-NMOSD (1.9±1.72) than in those with MOG-RD (0.74±0.62), whereas no significant difference was observed in transitional, naive, and memory B cells. Conclusion: Plasmablasts might be involved in the pathology of AQP4-NMOSD, but not MOG-RD, even in the remission phase. Disclosure nothing P440 Transforming growth factor-β1-producing regulatory B cells limit the induction phase of autoimmune neuroinflammation N. Molnarfi1, K. Bjarnadóttir1, M. Benkhoucha1, D. Merkler1,2, M.S. Weber3,4, N.L. Payne5, C.C. Bernard5, P.H. Lalive1,6,7 1Department of Pathology and Immunology, University of Geneva, Faculty of Medicine, 2Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland, 3Department of Neuropathology, 4Department of Neurology, University Medical Center, Georg August University, Göttingen, Germany, 5Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia, 6Division of Neurology, Department of Clinical Neurosciences, University of Geneva, Faculty of Medicine, 7Division of Laboratory Medicine, Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland Objective: The efficacy of B cell depleting therapy in Multiple Sclerosis (MS) has renewed interest in the function of B cells in this disease. We tested the importance of B cell-derived expression of transforming growth factor (TGF)-β1, a regulatory cytokine with pleiotropic functions in control of T cell responses, in autoimmune neuroinflammation. Background: Evidence suggests that some B cell subsets may have an important role in immune regulation of central nervous system (CNS) autoimmunity. While data indicate a role for TGF-β1


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Poster Session 1, 22(S3) expression in regulatory B cell (Breg) functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Design and methods: Transgenic mice that cannot express TGFβ1 in B cells (B-TGF-β1-/-) were tested in experimental autoimmune encephalomyelitis (EAE) induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG), a B and T cellmediated mouse model of MS. Results: In this EAE model, B-TGF-β1-/- mice showed an earlier onset of neurologic impairment and markedly increased cumulative disease severity compared to their control littermates. Exacerbated EAE susceptibility in B-TGF-β1-/- mice was associated with augmented encephalitogenic autoimmune T helper (Th)1/17 responses in the peripheral immune compartment and the CNS. Moreover, selective B cell TGF-β1-deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-β1 can constrain Th1/17 responses through inhibition of APC activity. Conclusion and relevance: Collectively our data suggest that B cells can down-regulate function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-β1, findings which may be relevant to B cell-targeted therapies. Disclosure K. Bjarnadóttir reports no disclosures. M. Benkhoucha reports no disclosures. M.S. Weber is an academic editor for PLoS One and is supported by grants from the National Multiple Sclerosis Society (NMSS; PP 1660), the DFG (WE 3547/4-1), and the ProFutura Programm of the Universitätsmedizin Göttingen. D. Merkler reports no disclosures. N. Payne reports no disclosures. C.C. Bernard reports no disclosures. N. Molnarfi reports no disclosures and received grant support for this work from the Swiss MS Society (SMSS) and from an advanced researcher exchange 2011 fellowship from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Foundation. P.H. Lalive is on the scientific advisory board for Biogen-Idec and Novartis and received travel funding and/or speaker honoraria from Biogen-Idec, Teva, and Merck Serono. Supported by grants to P.H. Lalive from the Swiss National Science Foundation (310030-153164) and the SMSS. P441 IL-6/IL-10 producing B cells in patients with clinically isolated syndrome: association with radiological/clinical evolution T. Guerrier1,2,3, H. Zéphir1,2,3, O. Outteryck1,2,3, C. Lee-Chang2,3, L. Mars2, E. Duhin1, C. Hauspie1,2,3, G. Lefèvre1,2,3, D. Launay1,2,3, M. Labalette1,2,3, P. Vermersch1,2,3, S. Dubucquoi1,2,3 1CHRU, 2Inserm UMR 995, 3Universté Lille 2, Lille, France Introduction: Recent evidence, particularly the efficacy of B cell-depleting therapies, has underlined the role of B cells in multiple sclerosis (MS) pathophysiology. Nevertheless, B cell involvement in the early onset of MS, especially in clinically isolated syndrome (CIS), is not precisely understood. Moreover, at

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this CIS phase, biomarkers with predictive value that could influence early therapeutic decisions are still missing. Objectives: The objectives of this work were: a. to compare pro-inflammatory and anti-inflammatory functional properties of circulating B cells of CIS patients with healthy subjects, b. to evaluate whether these B cell functional properties, analyzed at the time of patient inclusion, correlate with the future radiological/clinical evolution. Patients, materials and methods: Analyses were performed before any initiation of immunomodifying treatments and at least one month after corticoid flashes. Enrolled CIS patients had suffered the symptomatic events within less than 6 months and were radiologically/clinically followed. The proportions of IL-6 producing B cells and of IL-10 producing B cells, evaluated using a cytometric approach after polyclonal stimulation, were used to assess pro-inflammatory and anti-inflammatory functional properties of peripheral blood B cells, respectively. Results: 46 CIS patients and 38 healthy controls were enrolled. During the study (follow-up for 12+/-6 months), 17 CIS didn’t evolve and 29 converted in Relapsing-Remittent MS (RR MS) after 9+/-6 months of follow-up. We didn’t observe quantitative changes of IL-10/IL-6-producing B cells between CIS patients and healthy subjects. However, our results showed that CIS patients who will evolve toward RR MS had, at enrollment, an increased IL-6+ B cell/IL-10+ B cell ratio in comparison with CIS patients that won’t. Conclusion: The association between a high IL-6/IL-10 producing B cell ratio and the evolution of CIS patients toward RR MS suggests a skew of B cells toward pro-inflammatory properties that could be implicated in the early disease history of MS progression. Disclosure Thomas Guerrier: Research grant and fellowship from Université Lille 2, fellowship from ARSEP foundation Hélène Zéphir: nothing to disclose Olivier Outteryck: nothing to disclose Catalina Lee-Chang: Research grant and fellowship from Novartis Lennart Mars: nothing to disclose Emeline Duhin: nothing to disclose Carine Hauspie: nothing to disclose Guillaume Lefèvre: nothing to disclose David Launay: nothing to disclose Myriam Labalette: nothing to disclose Patrick Vermersch: Honoraria and consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Teva, Merck-Serono, GSK and Almirall. Research supports from Biogen, Bayer, Novartis, Sanofi-Genzyme and Merck-Serono Sylvain Dubucquoi: nothing to disclose P442 Synergistic effect of vitamin D on methylprednisoloneinduced T-cell apoptosis M. Pistor1, L. Schrewe1, K. Schanzmann1,2, A. Salmen3, A. Chan3, R. Hoepner1 1Dept. Neurology, St. Josef Hospital, Ruhr University, Bochum, 2Biogen, Ismaning, Germany, 3Dept. Neurology, Inselspital, Bern University Hospital, Bern, Switzerland


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Background: Methylprednisolone (MPS) pulse therapy is the first-line therapy of MS-relapses. Nevertheless, some patients do not adequately respond to treatment. Strategies to improve glucocorticoid (GC) efficacy, especially in GC-resistant MS patients, are thus needed. Vitamin D (VD) deficiency is a risk factor for MS. In this context, we investigated the effects of 1,25(OH)2D3 (VD) on MPS-induced apoptosis in T-cells, one presumed mechanism of GC action in MS. Methods: The influence of VD (100nM, 1µM) on MPS-induced apoptosis (MPS 2.5mM) was investigated in vitro in steroid resistant Jurkat cells (T-cell leukemia; n=5). C57BL/6 mice were treated in vivo with VD (20ng/d for 3 days) or vehicle control. Splenic T-cells were isolated and incubated in vitro with MPS for 24 hours (6nM, 60nM and 600nM; n=5). Blood samples from 7 MS patients with steroid responsive and 4 MS patients with steroid resistant relapses with indication for plasma exchange were collected after MPS pulse therapy. T-cells were incubated in vitro for 72 hours with VD (10nM) and MPS (75µM). In all experiments apoptosis was measured by flow cytometry using Annexin V/PI staining. Results: In Jurkat cells, VD monotherapy did not induce apoptosis (percentage of apoptosis: 6.9% (control, SD 1.0); 6.3% (VD 100nM, SD 1.5); 6.1% (VD 1µM, SD 1.5) however VD augmented MPS-induced apoptosis (percentage of apoptosis: 42.3% (MPS 2.5mM, SD 11.2); 57.0% (MPS 2.5mM+VD 100nM, SD 14.4, p>0.05); 81.1% (MPS2.5mM+VD 1µM, SD 10.9, p< 0.05)). The synergistic effect of VD and MPS was also present in mice pre-treated with VD in vivo (x-fold increase of T-cell apoptosis: VD20ng+MPS 6nM (1.8-fold, p< 0.05), VD20ng+60nM (1.7fold, p< 0.05), VD20ng+600nM (1.2-fold, p>0.05). In MS patients with GC-responsive relapses MPS-induced T-cell apoptosis in vitro was 48.5% (SD 17.8), p>0.05). Further VD did not lead to any additional effect on MPS-induced T-cell apoptosis (p>0.05) in GC-responsive patients. In contrast, patients without sufficient MPS response during MS relapse showed an increase of MPSinduced T-cell apoptosis in vitro from 36.9% (SD 2.5) to 40.5% (SD 0.8) by co-incubation with VD (p=0.068). Conclusion: This study showed an effect of VD on MPS-induced apoptosis in Jurkat cells, murine and human T-cells of GC-resistant MS patients. This may indicate approaches to enhance efficacy of MPS-treatment in MS patients with steroid-resistant relapses. Disclosure M Pistor reports no disclosures. L Schrewe received travel grant from Novartis. K Schanzmann is part time employee of Biogen. A Salmen received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. A Chan received personal compensation as a speaker or consultant for Bayer, Biogen, Genzyme, Merck, Sanofi, Roche and Teva Neuroscience. A. Chan received research support from Biogen, Genzyme and Novartis. R Hoepner received research and travel grants from Biogen and Novartis. P443 Cerebrospinal fluid antibody-secreting cells, but not memory B cells, are dominated by IgG in multiple sclerosis J. Curnow1, E. Rathbone1, D. Lindsay1, M.R. Douglas1,2,3 1Institute of Inflammation and Ageing, University of Birmingham, 2School of Life and Health Sciences, Aston

University, 3Deaprtment of Neurology, Dudley Group NHS Foundation Trust, Birmingham, United Kingdom A characteristic feature of multiple sclerosis (MS) is the presence of oligoclonal bands in the cerebrospinal fluid (CSF), some of which are restricted to the CSF and not detectable in the blood. In addition, clonally expanded, hypermutated B cells are found in many compartments of the MS brain including the CSF. The presence of ectopic meningeal B cell follicles in late disease suggests a sustained immunopathological B cell response; however the relative contributions of recently recruited peripheral B cells versus locally expanded B cells remains unclear. We investigated the phenotype of B cells and antibody-secreting cells in the blood and CSF of MS patients using flow cytometry, recruiting patients with a clinically isolated syndrome, relapsing-remitting MS, MS patients ceasing chronic natalizumab (anti-alpha4) treatment and control patients with other neurological diseases. We demonstrated that both B cells and antibody-secreting cells display a more activated phenotype in the CSF versus those in the blood and were more prevalent in MS patients than controls. Antibodysecreting cells in the CSF almost exclusively expressed IgG, compared to the predominant IgA expression seen in the blood, whereas memory B cells displayed similar immunoglobulin expression profiles in both compartments. Furthermore, antibodysecreting cells in the CSF of MS patients demonstrated a higher degree of kappa light chain restriction compared to B cells. These data suggest that in the CSF of MS patients, the majority of B cells result from non-specific inflammatory recruitment of peripheral memory B cells, whereas antibody-secreting cells are involved in a local and persistent antigen-driven immune response and are more likely to be involved in disease pathogenesis. Disclosure This work was funded by the Medical Research Council U.K. S. John Curnow: Consultant for Celentyx Ltd. E. Rathbone: nothing to disclose L. Durant: nothing to disclose M.R. Douglas: Received funds from Genzyme to attend a conference in 2015

MS and infections P444 Altered humoral immunity to Mycobacterium paratuberculosis epitopes in Japanese multiple sclerosis patients D. Cossu, K. Yokoyama, Y. Hoshino, Y. Tomizawa, N. Hattori Department of Neurology, Juntendo University, Tokyo, Japan Objective: Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen which can infect both animals and humans. MAP has recently been associated with multiple sclerosis (MS) in patients from Italy. We aimed to study the serology of MAP in a population characterized by a different ethnic and genetic background such as Japan, looking at several markers of MAP presence. Methods: A total of 50 MS patients free-therapy compared to 50 sex-and age-matched healthy controls, all from Japan, were tested by indirect ELISA for the presence of antibodies (Abs) toward the


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Poster Session 1, 22(S3) following epitopes: MAP_0106c121-132 and the human homologues MBP85-98, MAP_402718-32 and humanhomologues IRFF5424-432, and MAP_2694295-303. Results: Amongst all the peptides, only Abs against MAP_2694295-303 epitope, which share homology with human gamma delta T cell receptor, were significantly recognize in MS patients (30%) compared to controls (2%) (p = 0.0004). Conclusions: These findings support the view that MAP could act as risk factor or a triggering agent of MS also in some Japanese patients with a genetic susceptibility to the mycobacterium. On the other side, the lack of humoral response against several epitopes suggested that the association of a specific environmental pathogen with causation/progression of a disease such as MS can be population dependent, and the immune response directed against multiple epitopes depends on different genetic and nongenetic factors. Disclosure Cossu Davide: nothing to disclose Yokoyama Kazumasa: nothing to disclose Hoshino Yasunobu: nothing to disclose Tomizawa Yuji: nothing to disclose Hattori Nobutaka: nothing to disclose P445 Late Epstein-Barr virus infection and a second virus are linked to multiple sclerosis risk M. Biström1, R. Gustafsson2,3, E. Engdahl4, I.L. Bomfim4, J. Huang4, D. Jons5, O. Andersen5, M. Hortlund6, L. AlonsoMagdalena7, T. Waterboer8, I. Kockum4, T. Olsson4, A. FogdellHahn4, P. Sundström1 1Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 2University Laboratory, Karolinska University Hospital, 3Department of Clinical Neuroscience, 4Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, 5Section of Clinical Neuroscience, Institution of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, 6Department of Laboratory Medicine, Karolinska Institutet, Stockholm, 7Neurology Department, Skåne University Hospital, Malmö, Sweden, 8Infection and Cancer Program, German Cancer Research Center (DKFZ), Heidelberg, Germany Different infectious agents have been considered in multiple sclerosis (MS) aetiology. Foremost among them are viruses, particularly those belonging to the herpesviridae family, with the Epstein-Barr virus (EBV) as the prime candidate. One hypothesis is that late EBV infection increases the risk for MS, supported by the link between infectious mononucleosis and MS risk. In this project the intention was to identify biobank samples drawn at a younger age compared to previous prospective MS biobank studies - with the aim to study risk factors in samples drawn at the pathophysiological onset of MS, which presumably is during childhood-adolescence. In this study we had access to serum samples drawn before the age of 40 from 488 cases that later developed MS with relapsing onset, and 488 matched controls. The presence of antibodies (seropositivity) against several viruses was determined using a Luminex assay. Based on age at sample draw, the study population was

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divided into three age strata: 0-20 (n=188), 20-25 (n=294) and above 25 years (n=494). Odds ratio (OR) was calculated using matched logistic regression analysis in SPSS. Seropositivity against EBV was associated with a decreased risk for MS (OR=0.48; 95% CI: 0.23-0.98) in the 0-20 year category. Seropositivity against another virus was associated with an increased risk for MS (OR=2.5; 95% CI: 1.3-4.7 and OR=2.6; 95% CI: 1.6-4.3 in the 0-20 and 20-25 year categories). Viral serologies analysed in presymptomatic samples drawn during the presumed pathophysiological onset of MS reveal a new pattern for EBV, showing that MS is associated with late EBV infection. Also shown was that MS is strongly associated with another virus, previously not established in MS pathogenesis, the name of which will be disclosed at the meeting. Disclosure Martin Biström: nothing to disclose. Peter Sundström: has received honoraria from BiogenIdec for serving as a member of a stipend committee. Oluf Andersen: nothing to disclose Maria Hortlund: nothing to disclose Daniel Jons: nothing to disclose Lucia Alonso-Magdalena: has received unrestricted grant from Novartis and speaking fees from Biogen, Merck Serono. Served on advisory board for Biogen, Merck Serono. Izaura Lima Bomfim: nothing to disclose Jesse Huang: nothing to disclose Ingrid Kockum: has received honoraria for lecture from Merck Serono. Tomas Olsson: has received compensation for lectures and /or advisory boards, or unrestricted MS research grants from Biogen, Allmiral, Novartis, Genzyme, Astrazeneca and Merck. Tim Waterboer: nothing to disclose Rasmus Gustafson: nothing to disclose Elin Engdahl: nothing to disclose Anna Fogdell-Hahn: has received funding and speaking honoraria from Biogen Idec and Pfizer. P446 Epstein-Barr virus and immune gene expression analysis of laser microdissected immune infiltrates from the multiple sclerosis brain C. Veroni1, B. Serafini1, B. Rosicarelli1, C. Fagnani2, F. Aloisi1 1Department of Cell Biology and Neuroscience, 2National Centre of Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanità, Rome, Italy Epstein-Barr virus (EBV) is widely recognized as a major environmental risk factor for multiple sclerosis (MS) but the mechanisms linking this ubiquitous virus to chronic central nervous system (CNS) inflammation are debated. One of the current hypotheses proposes that immune responses primarily directed toward EBV-infected B cells, the preferred cellular reservoir of the virus, cause bystander damage in the CNS. The goal of this study has been to explore further the hypothesized link between EBV deregulation and immune activation in the MS brain. Immunohistochemistry, laser capture microdissection and advanced polymerase chain reaction (PCR) methods were combined to study gene expression of well characterized immune


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infiltrates isolated from post-mortem brain tissue of persons with secondary progressive (SP) MS. Brain tissue was provided by the UK MS Tissue Bank. White matter perivascular cuffs (n=39) and meningeal infiltrates (n=36), including ectopic B-cell follicles, were isolated from brain sections of 11 SPMS cases and analyzed for expression of 78 immune-related genes and 6 EBV genes. EBV transcripts were detected in CNS immune infiltrates from 9 of 11 SPMS cases, more frequently in meningeal infiltrates and with a pattern consistent with profound viral deregulation (latency disruption and entry into the lytic cycle). As to cellular genes, transcripts associated with type 1 immunity (mediated by Th1/ Tc1/NK cells) predominated over transcripts associated with type 2 and type 3 immunity in both meningeal and white matter infiltrates. RNA signals related to B-cell growth/differentiation (BCMA, BAFF), lymphoid tissue formation (CCL19, CCL21), cell proliferation (Ki76), antigen presentation (CD1a), myeloid cell recruitment (CCL2) and type 1 immunity (IFN-gamma) were also significantly higher in meningeal than in white matter infiltrates. A strong association was found in the meninges between EBV transcripts indicative of viral latency disruption (latency II and III programmes) and cellular genes involved in pathogen recognition (TLR9, RIG-1), B-cell growth/differentiation (IL6, CD138), type-1 IFN pathway (IRF7, MxA), antigen presentation (CD1a, MHC class II), immunoregulation (p35/EBI3, FoxP3) and cytotoxic cell recruitment and expansion (CD8, Tbet, IL2, CXCL10, CXCR3). These findings strengthen the link between EBV deregulation, B-cell activation/formation of ectopic B-cell follicles and antiviral immunity in the MS brain. Disclosure Caterina Veroni: nothing to disclose Barbara Serafini: nothing to disclose Barbara Rosicarelli: nothing to disclose Corrado Fagnani: nothing to disclose Francesca Aloisi: nothing to disclose This study is funded by Italian Multiple Sclerosis Foundation (grant 2013/R/22 to BS) and Italian Ministry of Health (grant RF 2011-02347228 to FA). P447 Phase 2 baseline versus treatment clinical trial of the HIV drug raltegravir in patients with active relapsing remitting multiple sclerosis: the INSPIRE study results M. Marta1, D. MacManus2, T. Yousry2, D. Miller2, D.R. Altmann3, U.C. Meier1, T. Christensen4, H. Maruszak5, D. Holden1, L. Bianchi1, R. Adiutori1, K. Schmierer1, B. Turner1, G. Giovannoni1, J. Gold1,5 1Neuroscience and Trauma, Blizard Institute, Queen Mary University London, Barts and the London School of Medicine and Dentistry, 2Institute of Neurology, University College Hospital, 3Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, United Kingdom, 4Department of Biomedicine, Aarhus University, Aarhus, Denmark, 5The Albion Centre, Prince of Wales Hospital, Sydney, NSW, Australia Background: Although the aetiology of Multiple Sclerosis (MS) remains elusive, it is clear that Epstein Barr Virus (EBV) and

possibly other viruses have a role in the pathogenesis of MS. Laboratory evidence suggests that a Human Endogenous Retrovirus (HERV) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting a HERV or retroelements that could be implicated in MS. Objectives: To systematically investigate the effects of an HIV integrase inhibitor, raltegravir, on the number of gadolinium (Gd)enhanced MRI lesions in people with active relapsing MS. Methods: This is a Phase 2b clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results: All patients completed the six months trial period. The primary outcome indicated raltegravir had no significant effect on MS disease activity as measured by either the number or rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in either disability or quality-of-life measures that could reasonably be attributed to the intervention. Conclusions: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of anti-retroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Disclosure M. Calado Marta Nothing to disclose D. MacManus Nothing to disclose T. Yousry Nothing to disclose D. Miller Nothing to disclose D. R. Altmann Nothing to disclose U. C. Meier Nothing to disclose T. Christensen Nothing to disclose D. H. Maruszak Nothing to disclose D. Holden Nothing to disclose L. Bianchi Nothing to disclose R. Adiutori Nothing to disclose R. K. Schmierer Nothing to disclose B. Turner Nothing to disclose G. Giovannoni Nothing to disclose J. Gold Nothing to disclose This study was funded by Merck Sharpe and Dohme. P448 Phase 2 baseline versus treatment clinical trial of the HIV drug raltegravir in patients with active relapsing remitting multiple sclerosis: the INSPIRE study biomarker outcome results J. Gold1,2, M. Calado Marta1, U.C. Meier1, T. Christensen3, D. Miller4, D. Altmann5, D. Holden1, L. Bianchi1, R. Adiutori1, D. MacManus4, T. Yousry4, K. Schmierer1, B. Turner1, G. Giovannoni1


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and Trauma, Blizard Institute, Queen Mary University London, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 2The Albion Centre, Prince of Wales Hospital, Sydney, NSW, Australia, 3Department of Biomedicine, Aarhus University, Aarhus, Denmark, 4Institute of Neurology, University College Hospital, 5Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, United Kingdom Background: INSPIRE was a Phase 2b clinical trial, 3 month baseline followed by 3 months treatment, to investigate the effect of the HIV integrase inhibitor, raltegravir 400mg twice a day, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active RRMS. The primary outcome was negative. Objectives and methods: The 20 participants enrolled were monitored monthly with saliva collection for EBV shedding, blood collection for safety monitoring, virology, including Human Endogenous RetroViral expression (HERVs); measurement of immunological and inflammatory markers, as well as Gd-enhanced MRI and clinical measurements, throughout duration of the trial. Results: Statistically significant positive correlation was detected between HERV-W or Multiple Sclerosis Related Virus (MSRV) Gag Flix B cells and the number of Gd-enhanced lesions (r = -0.54; p = 0.012), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions, but there was a borderline significant association between EBV shedding and the number of total lesions (OR 0.79 per lesion; p = 0.08), which may be due to the development of new lesions or inflammatory activity. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by Raltegravir. Conclusion: Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found. Disclosure M. Calado Marta Nothing to disclose D. MacManus Nothing to disclose T.Yousry Nothing to disclose D. Miller Nothing to disclose D. R. Altmann Nothing to disclose U. C. Meier Nothing to disclose T. Christensen Nothing to disclose D. H.Maruszak Nothing to disclose D. Holden Nothing to disclose L. Bianchi Nothing to disclose R. Adiutori Nothing to disclose K. Schmierer Nothing to disclose B.Turner Nothing to disclose G. Giovannoni Nothing to disclose J. Gold Nothing to disclose This study was funded by Merck Sharpe and Dohme

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P449 Antibodies against Helicobacter pylori-specific antigens differentiate relapsing remitting from secondary progressive multiple sclerosis Z. Tsouris1,2, G. Efthymiou1,2,3, C. Liaskos1,3, E. Marou1,3, M. Sokratous2, A. Michalopoulou2, V. Tsimourtou2, G. Tsivgoulis4, T. Scheper5, W. Meyer5, L.I. Sakkas3, G. Hadjigeorgiou2, D.P. Bogdanos1,3, E. Dardiotis2 1Cellular Immunotherapy & Molecular Immunodiagnostics, Biomedical Section, Centre for Research and Technology-Hellas (CERTH) - Institute for Research and Technology -Thessaly (IRETETH), 2Department of Neurology, 3Department of Rheumatology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 4Second Department of Neurology, ‘Attikon’ Hospital, School of Medicine, University of Athens, Athens, Greece, 5Institute of Immunology, EUROIMMUN, Lübeck, Germany Background: Helicobacter pylori (Hp) has been considered an infectious trigger of MS, but detailed antigen specificity of antiHp antibodies (abs) in MS patients with RRMS or SPMS is still lacking. Aim: To systematically investigate ab reactivity against individual Hp antigens and to assess their clinical relevance. Material and methods: Sera from 129 MS (102 RRMS and 27 SPMS) and 63 matched healthy controls (HCs) were tested. IgG anti-Hp (whole extract) abs were tested by ELISA (Euroimmun). IgG abs to individual CagA, VacA, p120-CagA, p95-VacA, p67FSH, p66-UreB, p54, flagelin, p50, p30-OMP, p29-UreA, p19OMP were tested by immunobloting. Results: Anti-Hp abs (whole extract) were present in 55 (42.6%) MS patients (40.2% RRMS-51.8% SPMS, p=ns) compared to 42 (66.6 %) HCs (MSvsHC, p=0.002). Within anti-Hp positive MS, anti-VacA abs were more prevalent in MS than HCs (29.1vs9.5% HCs, p=0.023), while anti-CagA did not differ (72.7vs 85.7%). Anti-UreB abs were comparable in MS and HCs (63.3vs76.2%) and in RRMSvsSPMS (63.4vs 64.3%). Anti-p50 and anti-UreA antibodies differed between RRMS and SPMS (39vs85.7%, p=0.004, and 31.7vs71.4%, p=0.013, respectively). No differences were observed for p30 and p19 OMPs. Anti-FSH presented in 52.7 MSvs76.2% HCs, p=0.093. Anti-flagelin were significantly lower in MS than HCs (16.4vs35.7%; p=0.035; HCsvsRRMS, p=0.008; RRMSvsSPMS, p=0.037). The magnitude of anti-CagA was higher in MS compared to HCs (p=0.003) but that of antiflagelin was lower in MS compared to HCs (p=0.023). AntiUreA ab concentrations were lower in MS than HCs (p=0.013). While reactivity to the whole Hp extract by ELISA was not associated with clinical features, reactivity to individual antigens revealed that anti-UreA ab responses were associated with EDSS (p=0.01) and number of relapses (p=0.02); responses to p-30 OMP were associated with age at onset (p=0.03) and anti-p-19 OMP tended to be associated with EDSS (p=0.09). Conclusions: Anti-Hp abs against the whole extract (Hp ELISA) are more frequent in healthy individuals than in MS patients from Central Greece. Significant differences in the prevalence and magnitude of responses against Hp antigens is evident between MS and healthy individuals, as well as between RRMS and SPMS, indicating association with this bacterium. Clinical correlations involving responses to anti-UreA may suggest the pathophysiological importance of this antigen in MS.


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Disclosure No conflict of interest Funding: Research Committee, University of Thessaly Z. Tsouris: Nothing to disclose G. Efthymiou: Nothing to disclose C. Liaskos: Nothing to disclose E. Marou: Nothing to disclose M. Sokratous: Nothing to disclose A. Michalopoulou: Nothing to disclose V. Tsimourtou: Nothing to disclose G. Tsivgoulis: Nothing to disclose T. Scheper: Nothing to disclose W. Meyer: Nothing to disclose L.I. Sakkas: Nothing to disclose G. Hadjigeorgiou: Nothing to disclose D.P. Bogdanos: Nothing to disclose E. Dardiotis: Nothing to disclose

Environmental risk factors P450 Intestinal microbiota in multiple sclerosis: influence of treatment with interferon β-1b F. Castillo Álvarez1, P. Pérez Matute2, S. Colina Lizuain1, A. Erdocia Goñi1, C. Iglesias Gutiérrez Cecchini1, M. Gómez Eguilaz1, M.Á. López Pérez1, E. Marzo Sola1 1Neurology, Hospital San Pedro, 2CIBIR (Centro de Investigación Biomédica de La Rioja), Logroño, Spain Objectives: Describe and compare the relative composition in bacterial taxa and archaea of the gut microbiota between patients with multiple sclerosis (MS) untreated and treated with interferon β-1b compared with healthy controls, in terms of phyla and more frequent taxa. Background: The gut microbiota plays an important role in the development of experimental autoimmune encephalomyelitis; however, its role in MS is not yet defined. Design and methods: Single centre descriptive study. Participants included 30 MS patients (half of whom had been treated with interferon β-1b for at least 9 months) and 14 otherwise healthy controls. A metagenomic study of faecal microbiota was conducted in stool samples collected for all the participants. Results: The most common phyla across all 3 study groups included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. The differences relating to the abundance of Firmicutes, Actinobacteria, Proteobacteria and Lentisphaerae between patients, untreated and treated with interferon β-1b, and controls were found to be statistically significant. Firmicutes, Actinobacteria and Lentisphaerae differed between untreated MS patients, who tend to rebalance their microbiota after treatment, and controls. The differences between MS patients and controls regarding bacterial abundance for 12 different species, including Prevotella copri DSM 18205, were found to be statistically significant; following treatment with interferon β-1b, these bacteria tend to achieve similar levels to those found in healthy subjects. Patients with MS showed lower abundance of Archaea than healthy controls. Conclusions: Our findings suggest that the gut microbiota is significantly altered in patients suffering from MS compared to healthy subjects.

Interferon β-1b tends to be effective at rebalancing the gut microbiota of patients affected with this condition, being this particularly evident for Prevotella copri. DSM 18205 These preliminary results support the need for further studies on the potential role of microbial dysbiosis for preventing and treating MS. Disclosure Federico Castillo-Álvarez: nothing to disclose Patricia Pérez Matute: nothing to disclose Sandra Colina Lizuain: nothing to disclose Amaia Erdocia Goñi: nothing to disclose Carmen Iglesias Gutiérrez Cecchini: nothing to disclose Eugenia Marzo Sola: nothing to disclose

P451 Adipokines modulate immune response in obese multiple sclerosis patients affecting different cell populations J. Correale, M.F. Farez, L. Negrotto Neurology, Institute for Neurological Research Dr. Raul Carrea, FLENI, Buenos Aires, Argentina Background and goals: Increased prevalence of both autoimmune diseases and obesity has led to a search for common mechanisms linking both conditions. Indeed, recent evidence suggests obesity in childhood and adolescence may influence MS development. Fat tissue produces a variety of soluble factors involved in immunity and inflammation regulation. These mediators, known as adipokines are secreted both by adipocytes and by different immune cells, and participate in a wide range of biological functions strengthening possible ties between immune function, metabolism and nutritional state. Our aim was to study whether obesity altered immune tolerance in MS patients. Methods: We studied fifty obese relapsing-remitting MS patients (body mass index (BMI) > 30 kg/m2), 50 non-obese MS patients and 50 age- and gender-matched healthy controls (HCs). Leptin, adiponectin, resistin and visfatin were measured by ELISA, and IL-1α, IL-1b, IL-2, IL-4, IL-6, IL-10, IL-15, IL-21, TNF-α, and IFN-g production were evaluated using ELISPOT . CD4+CD25+FoxP3+ Treg cells were assessed using flow cytometry. Results: Obese MS patients showed higher relapse rates and disability scores as well as increased radiological activity, compared to non-obese MS individuals. Serum levels of leptin, resistin, and visfatin, were significantly higher in obese MS patients compared to non-obese patients and healthy controls, and correlated with BMI. In contrast, adiponectin serum levels were lower in obese MS patients, inversely correlating with BMI. Obese MS patients showed higher number of IL-1α, IL-1b, IL-2, IL-6, IL-15, IL-17, TNF-α, and IFN-g producing cells, and lower number of CD4+CD25+FoxP3+ Treg cells, compared to non obese MS subjects. All these effects were reversed by leptin neutralization or inhibition of its receptor. Moreover, leptin dampened CD4+CD25+FoxP3+ Treg cell response. Interestingly, resistin inhibition only affected monocytes, reducing IL-6 and TNF-α production. Meanwhile, visfatin inhibition significantly reduced monocyte and B cell production of IL-1b, IL-6, and TNF-α. Conclusions: Adipokines have different effects on T cells, monocytes, B cells and regulatory T cells, mainly promoting


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Poster Session 1, 22(S3) inflammatory responses, thus pointing indicating a potential link between obesity and autoimmunity in MS. Disclosure JC is a board member of Merck-Serono Argentina, Novartis Argentina, Genzyme LATAM,Genzyem global, Biogen-Idec LATAM, and Merck-Serono LATAM. Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, Genzyme Argentina, Novartis Argentina, Novartis LATAM, Novartis Global, and TEVA Argentina as well as professional travel/accommodations stipends. MFF has received professional travel/accommodations stipends from Merck-Serono Argentina and Novartis Argentina LN has nothing to disclose P452 Mendelian randomization provides evidence for a causal effect of low vitamin D on multiple sclerosis risk in two independent populations B. Rhead1, M. Bäärnhielm2, M. Gianfrancesco3, A. Mok3, X. Shao3, H. Quach3, L. Shen4, C. Schaefer4,5, J. Link6, A. Gyllenberg6, A.K. Hedström2, T. Olsson6, J. Hillert6, I. Kockum6, M.M. Glymour7, L. Alfredsson2,8, L.F. Barcellos3,4 1Computational Biology Graduate Group, University of California, Berkeley, CA, United States, 2Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, 3Divison of Epidemiology, School of Public Health, University of California, Berkeley, 4Kaiser Permanente Division of Research, 5Research Program on Genes, Environment and Health, Kaiser Permanente, Oakland, CA, United States, 6Department of Clinical Neuroscience and Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden, 7Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States, 8Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden Background: Low serum levels of 25-hydroxyvitamin D (25(OH) D) are associated with a higher risk of multiple sclerosis (MS) and with greater MS activity and disease progression. However, a causal relationship between 25(OH)D and MS has not been firmly established. Methods: We conducted Mendelian randomization analyses using three single nucleotide polymorphisms found to be associated with serum 25(OH)D level in a genome-wide association study (Ahn et al., 2010) to estimate the causal effect of low 25(OH)D on MS susceptibility. We constructed the instrumental variable (IV) by computing a weighted genetic score for variants associated with increasing 25(OH)D levels in serum, using the estimated effect of each risk variant: rs2282679-C, in an intron of GC; rs2060793-G, upstream of CYP2R1; and rs3829251-A, in an intron of NADSYN1. We analyzed the effect of the IV on MS susceptibility in two separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, ancestry, self-reported body mass index at age 18-20, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles, the strongest genetic risk factor for MS.

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Results: The genetic score for increasing levels of 25(OH)D was associated with a decreased risk of MS in both populations. In White, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the causal odds ratio (OR) was 0.79 (p=0.04, 95% CI: 0.64-0.99). In members of a Swedish population from the EIMS and GEMS MS case-control studies (6,335 cases and 5,762 controls), the causal OR was 0.86 (p=0.03, 95% CI: 0.76-0.98). A meta-analysis of the two populations gave a combined causal OR of 0.85 (p=0.003, 95% CI: 0.76-0.94). Conclusion: These results provide evidence that low serum 25(OH)D concentrations are a cause, rather than a result, of MS, independent of established risk factors. *These authors contributed equally. Disclosure B. Rhead: nothing to disclose M. Bäärnhielm: nothing to disclose M. Gianfrancesco: nothing to disclose A. Mok: nothing to disclose X. Shao: nothing to disclose H. Quach: nothing to disclose L. Shen: nothing to disclose C. Schaefer: nothing to disclose J. Link has received research support from Neuro Sweden. A. Gyllenberg has received funding from the Swedish NEURO foundation 2014-2015. A.K. Hedström: nothing to disclose T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grant support from Biogen, Novartis, Genzyme and Merck. He has received academic grant support from the Swedish research Council, the AFA foundation, the Knut and Alice Wallenberg foundation and the Swedish Brain foundation. J. Hillert has received honoraria for serving on advisory boards for BiogenIdec and Novartis and speaker’s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis, and has served as principle investigator for projects, or received unrestricted research support from, BiogenIdec, Merck-Serono, TEVA, Sanofi-Aventis, Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council. I. Kockum has received speaker honoraria from Merck. Has received research support from the “100års fonden”, NHR foundation and Swedish childhood diabetes foundation. L. Alfredsson receives research support from the Swedish Medical Research Council (521-2012-2917) and Swedish Research Council for Health, Working Life and Welfare (2012-0325 and 2015-00195) and the Swedish Brain Foundation; received speaker honoraria from Teva. L.F. Barcellos: nothing to disclose P453 Gene-environment interaction study in multiple sclerosis using a “candidate-interactome” approach R. Mechelli1, R. Umeton1, - Imsgc-Wtccc2, G. Ristori1, M. Salvetti1 1Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University, Rome, Italy, 2The International Multiple Sclerosis Consortium & the Wellcome Trust Case Control, Oxford, United Kingdom


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We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with a given environmental or cellular factor) analysis of genome-wide association data in MS to highlight possible factors that may participate to disease etiology interacting with predisposing genetic variants. For this study we considered interactomes representative of factors and biological processes known to be or not involved in MS. Twenty candidate interactomes were obtained from the literature: 9 viruses, 1 bacterium, 10 cellular factors (9 proteins and 1 noncoding RNAs target repository). Among these, 6 were manually curated (EpsteinBarr virus, Hepatitis B virus, Cytomegalovirus, HHV8 Kaposi sarcoma, JC virus, Inflammasome), 7 were obtained from databases of molecular interactions (Autoimmune regulator, Vitamin D receptor, Aryl hydrocarbon receptor, Sirtuin 1, Sirtuin 7, Polyomavirus, Human-microRNA targets), 7 were obtained from the literature from a unique source (proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species, Human immunodeficiency virus, Hepatitis C virus, human innate immunity interactome for type I interferon, H1N1-influenza, histone deacetylases, Chlamydia). The genome wide association data were obtained from the latest published GWAS in MS: a) the first data set published in 2011; b) Immunochip data, published in 2013, in which were studied SNPs selected from autoimmune associated loci. To evaluate globally the contribution of all the SNPs analysed in both the datasets, we constructed METACHIP1: a combination of the former two where GWAS 2011 data was given preference in case of overlap (eg, if both chips had a SNP in the same position, the GWAS-2011 p-value was preferred) and METACHIP2 where Immunochip data was given preference. Association LIst Go AnnoTatOR (ALIGATOR) program was used to search for statistical enrichment of associations between interactome’s genes and genome-wide association data (considering all the SNPs with a p-value< 0.05 of association with MS). The results showed that some environmental factors may be associated with MS through their genetic autoimmune component. Among others, herpes viruses reached statistical relevance respect to MS and Epstein-Barr virus seems to be confirmed as the most associated virus. Disclosure The study was funded by Italian Multiple Sclerosis Foundation grant (2007/R/12). Rosella Mechelli: nothing to disclose Renato Umeton: nothing to disclose IMSGC and WTCCC2: nothing to disclose Giovanni Ristori: nothing to disclose Marco Salvetti: received lecture fees from BiogenDompé, research support from BayerSchering, BiogenDompé, MerckSerono, SanofiAventis

P454 Body mass index is causally associated with pediatric and adult multiple sclerosis onset: a study of over 20,000 individuals using Mendelian Randomization L.F. Barcellos1, M. Gianfrancesco1, X. Shao1, B. Rhead1, J. Graves2, A. Waldman3, T. Lotze4, T. Schreiner5, A. Belman6, B. Greenberg7, B. Weinstock-Guttman8, G. Aaen9, J.M. Tillema10, J. Hart2, J. Ness11, Y. Harris11, J. Rubin12, M. Candee13, L. Krupp6, M. Gorman14, L. Benson14,

M. Rodrigue10, T. Chitnis15, S. Mar16, I. Kahn17, J. Rose13, S. Roalstad13, T.C. Casper13, L. Shen18, H. Quach1, C. Metayer1, M. Glymour2, S. Walter2, A. Hubbard1, I. Jónsdóttir19, K. Stefansson19, P. Strid20, J. Hillert20, A. Hedstrom20, T. Olsson20, I. Kockum20, C. Schaefer18, E. Waubant2, L. Alfredsson21 1University of California, Berkeley, 2University of California, San Francisco, CA, 3Children’s Hospital of Philadelphia, Philadelphia, PA, 4Texas Children’s Hospital, Houston, TX, 5University of Colorado School of Medicine, Aurora, CO, 6SUNY Stony Brook, Stony Brook, NY, 7University of Texas Southwestern, Dallas, TX, 8SUNY Buffalo, Buffalo, NY, 9Loma Linda University, Loma Linda, CA, 10Mayo Clinic, Rochester, MN, 11University of Alabama at Birmingham, Brimingham, AL, 12Ann & Robert Lurie Children’s Hospital of Chicago, Chicago, IL, 13University of Utah, Salt Lake City, UT, 14Boston Children’s Hospital, 15Brigham and Women’s Hospital, Boston, MA, 16Washington University St. Louis, St. Louis, MO, 17Children’s National Medical Center, Washington, DC, 18Kaiser Permanente Division of Research, Oakland, CA, United States, 19deCODE Genetics, Reykjavík, Iceland, 20Karolinska Institutet, 21Centre for Occupational and Environmental Medicine, Stockholm, Sweden Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We utilized separate-sample Mendelian Randomization (MR) to estimate the causal effect of body mass index (BMI) on MS susceptibility. For non-Hispanic Caucasian members of Kaiser Permanente, Northern California (1,104 MS cases and 10,536 controls) and a replication dataset from Sweden (5,133 MS cases and 4,718 controls), a weighted genetic risk score (GRS) was constructed using 97 variants previously established to predict BMI. Models were adjusted for birth year, sex, education, smoking, ancestry, and genetic predictors of MS including HLA-DRB1*15:01 and 110 non-HLA variants. We also examined this relationship in non-Hispanic white pediatric MS cases and controls from over 15 sites across the U.S. (total sample size: 394 MS cases, 10,875 controls). Adjusted MR estimates suggested higher genetically induced BMI predicted greater MS susceptibility in adult KPNC and Swedish datasets (odds ratio [OR] = 1.13, 95% CI 1.04, 1.22 and OR=1.09, 95% CI 1.03, 1.15, respectively). A significant causal association between BMI GRS and pediatric MS was also demonstrated (OR = 1.20, 95% CI 1.06, 1.36; p=0.004) after adjusting for sex, ancestry, HLADRB1*15:01, and 110 non-HLA MS risk variants. Although the mechanism remains unclear, these findings support a causal effect of increased BMI on MS and suggest a role for inflammatory pathways. Disclosure L.F. Barcellos: nothing to disclose M. Gianfrancesco: nothing to disclose X. Shao: nothing to disclose B. Rhead: nothing to disclose J. Graves is supported by grants from the NMSS, Race to Erase MS, Biogen and Genentech. A. Waldman: is supported by grants from the NIH (K23NS069806) and Biogen Idec.


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Poster Session 1, 22(S3) T. Lotze: nothing to disclose T. Schreiner: nothing to disclose A. Belman: nothing to disclose B. Greenberg: nothing to disclose B. Weinstock-Guttman: nothing to disclose G. Aaen: nothing to disclose J.M. Tillema: nothing to disclose J. Hart: nothing to disclose J. Ness: nothing to disclose Y. Harris: nothing to disclose J. Rubin: nothing to disclose M. Candee: nothing to disclose L. Krupp: nothing to disclose M. Gorman: nothing to disclose L. Benson: nothing to disclose M. Rodrigue: nothing to disclose T. Chitnis: nothing to disclose S. Mar: nothing to disclose I. Kahn: nothing to disclose J. Rose has research support from VA, NMSS, Guthy Jackson Charitable Foundation, Arrien Pharmaceuticals, Teva Neuroscience, Biogen and AbbVie. S. Roalstad: nothing to disclose T.C. Casper: nothing to disclose L. Shen: nothing to disclose H. Quach: nothing to disclose C. Metayer: nothing to disclose M. Glymour: nothing to disclose S. Walter: nothing to disclose A. Hubbard: nothing to disclose I. Jónsdóttir: nothing to disclose K. Stefansson: nothing to disclose P. Strid: nothing to disclose J. Hillert has received honoraria for serving on advisory boards for BiogenIdec and Novartis and speaker’s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis, and has served as principle investigator for projects, or received unrestricted research support from, BiogenIdec, Merck-Serono, TEVA, Sanofi-Aventis, Novartis and Bayer-Schering and his MS research is funded by the Swedish Research Council. A. Hedstrom: nothing to disclose T. Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis , Allmiral and Genzyme. I. Kockum has received honoraria for lecture from Merck Serono. C. Schaefer: nothing to disclose E. Waubant: nothing to disclose L. Alfredsson: nothing to disclose

P455 Body mass index during adolescence, rather than childhood, is critical in determining multiple sclerosis risk L. Alfredsson, A.K. Hedström, T. Olsson Karolinska Institutet, Stockholm, Sweden Objective: Obesity in childhood and during adolescence has repeatedly been associated with increased risk of developing multiple sclerosis (MS). We aimed to investigate whether the most critical period occurs during childhood or later, during adolescence.

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Methods: Using a population-based case-control study (1586 cases and 2800 controls), subjects with different body sizes at age 10 and different body mass indices at age 20 were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. Potential interactions between HLA-DRB1*15 and absence of HLA-A*02, respectively, and both childhood and adolescent obesity were evaluated by calculating the attributable proportion due to interaction. Results: Regardless of body size at age 10, subjects with adolescent obesity had a 90% increased risk of MS. Among subjects who were not obese at age 20, no association was observed between body size at age 10 and subsequent MS risk. An interaction was observed between the HLA MS risk genes and adolescent, but not childhood, obesity. Conclusions: Our results suggest that BMI during adolescence, rather than childhood, is critical in determining MS risk. Disclosure Dr. Hedström reports no disclosures. Dr. Olsson received compensation for scientific advisory boards or lectures for Biogen and Genzyme, unrestricted MS resarch grants from Biogen, Bovartis, Genzyme, Allmiral and AstraZeneca, the Swedish Research Council (07488), EU fp7 Neurinox, Knut and Alice Wallenberg Foundation, Margareta af Ugglas Stiftelse, the Afa Foundation and the Swedish Brain Foundation. Dr. Alfredsson receives research support from the Swedish Medical Research Council (K2013-69X-14973-10-4) and Swedish Council for Working life and Social Research (Dnr 2012-0325). Source of funding: The study was supported by grants from the Swedish Medical Research Council; from the Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, the AFA foundation, the Swedish Brain Foundation and the Swedish Association for Persons with Neurological Disabilities.

Neurobiology P456 Relationship between microvesicles and free radicals in multiple sclerosis patients M.A. Gironi1,2, G. Dalla Costa1, A. Finardi1, V. Martinelli1, G. Comi1, R. Furlan1 1Università’ Vita Salute, OSR, INSPE, Milano, 2CAM-SYNLAB, Monza, Italy Background: Myeloid cells act as “double edged sword” in the pathogenesis of MS. They play a neuro-destructive role by secreting ROS and free or microvesicles (MVs)-embedded proinflammatory cytokines (classically activated microglia) or neuroprotective functions through the production of anti-inflammatory cytokines and neurotrophic factors (alternatively activated microglia). Recent data suggests that oxidative stress may trigger the release of MVs and, in turn, MVs may generate free radicals by activation of the oxidative stress machinery. Objective: Preliminary investigation of the relationship between oxidative stress markers and MVs release by myeloid cells in MS patients. Design and methods: We measured Glutathione levels (GSH, GSSG, GSH/GSSG ratio), slow and fast plasma antioxidant power


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(PAO), radical oxidative species (ROS), malondialdheide (MDA), Anti-oxidized Low density lipoprotein antibodies (Anti-OxLDL), Coenzyme Q10 (Coq10) levels as well as PBMC derived MVs in peripheral blood of age-and-sex matched Health controls (HC) and patients with relapsing remitting and progressive forms of MS. Results: Using K-means clustering alghoritms, two cluster patterns of oxidative stress measures were detected : cluster A with prevailing anti-oxidative markers and cluster B with more prooxidative stress markers. No differences between HC and MS patients in cluster patterns of oxidative stress were observed. Female patients produced much more MVs than males regardless of the oxidative status. Young patients with high oxidative stress released statistically significant more MVs than young patients with low oxidative stress, while for older patients the relationship is reversed. According to covariance analysis, upon ATP stimulation, patients with prevailing anti-oxidative markers have significantly higher levels of MVs than patients with pro-oxidative stress markers (p 0.01). Conclusion: A dual relationship between myeloid MVs and oxidative stress markers has been found by these preliminary results, with a positive relationship between the two variable in young patients and the reverse in older patients. In either cases, oxidative stress reduces MVs release after ATP stimulation

K2p-1 deficient oligodendrocytes revealed potentially novel interaction partners of the channel. Taken together, our results indicate a so far unknown and a versatile modulation of precursor as well as differentiating oligodendroglial cell functions by distinct K2P channels, which may contribute to novel therapeutic opportunities for the treatment of MS.

Disclosure

P458 Dual functions of oligodendrocyte-encoded potassium channel Kir4.1 during development and remyelination L. Schirmer1, L.R. Shiow2,3, L. Ben Haim1, K.W. Kelley1, J. Wright1, S. Chang1, K. Sabeur1, R.J. Franklin4, C. Zhao4, D.H. Rowitch2,3,5 1Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, 2Department of Pediatrics, 3Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, United States, 4Cambridge Stem Cell Institute & Dept of Clinical Neuroscience, 5Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom

M Gironi, G Dalla Costa, A Finardi, V Martinelli, G Comi and R Furlan have non potential conflict of interest and didn´t receive any special grant for this study P457 K2P channels: novel regulators of oligodendroglial cell functions S. Albrecht1, S. Korr1,2, V. Narayanan2, F. Stortz1, M. Araúzo-Bravo3, S.G. Meuth2, P. Ehling2, T. Kuhlmann1 1University Hospital Muenster, Institut of Neuropathology, 2Department of Neurology, Institute for Translational Neurology, University Hospital Muenster, Muenster, Germany, 3Biodonostia Health Research Institute, Institute of Computational Biology and Systems Biomedicine, San Sebastian, Spain In multiple sclerosis (MS) decreased numbers of myelin forming oligodendrocytes and reduced differentiation of oligodendrocyte precursor cells (OPC) are key aspects hampering remyelination. Previous studies linked potassium channels to myelination, as unspecific channel blockers suppress maturation as well as proliferation of OPCs in mice. Based on electrophysiological and molecular biological characterization, our study demonstrates for the first time an important role of a distinct member of the two pore domain potassium channel family, K2P-1, in the proliferation and maturation of murine oligodendrocytes. K2P-1 deficient OPCs exhibited a reduced proliferation capacity together with a marked earlier onset of differentiation in vitro. This differentiation promoting effect was corroborated in vivo, as K2P-1 deficiency resulted in earlier developmental myelination in mice. Furthermore, the accelerated maturation of K2P-1 deficient oligodendrocytes also promoted remyelination in a mouse model of toxic demyelination. Regarding molecular mechanisms underlying these K2P-1 mediated phenotypes, gene expression profiling of

Disclosure Albrecht S.: nothing to disclose Korr S.: nothing to disclose Narayanan V.: nothing to disclose Storz F.: nothing to disclose Araúzo-Bravo M.J.: nothing to disclose Meuth S.G. SGM received honoraria for lecturing and travel expenses for attending meetings and financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Omniamed, Novo Nordisk, SanofiAventis and Teva. Ehling P.: nothing to disclose Kuhlmann T.: TK received speaker honoraria from Novartis, Biogen Idec Canada,and Teva; she received compensation as a consultant from Genzyme.

Kir4.1 (KCNJ10) is the main inward rectifying K+ channel in astrocytes and oligodendrocytes (OL). Mutations of KCNJ10 are associated with EAST/SeSAME syndrome, and altered expression in glial cells has been reported in a subset of multiple sclerosis (MS) lesions. However, the role of Kir4.1 in OL development and remyelination remains unclear. Using a multifaceted approach applying in-vivo, ex-vivo and invitro experiments, we aimed to understand Kir4.1 function during OPC differentiation and remyelination. Therefore, we specifically removed Kir4.1 from OPCs using Olig2-cre and Sox10-cre lines. During early postnatal development we found lower proliferation rates in immunopanned OPCs and in white matter tissue from Kir4.1 cKO mice as compared to controls. Ablation of Kir4.1 from OPCs resulted in expedited OPC differentiation in vitro and precocious myelination along white matter tracts in vivo. With aging, we observed aberrant myelin compactness and features of axonal degeneration that accompanied clinical deficits in Kir4.1 cKO animals. Early remyelination after lysolecithin-induced spinal cord injury appeared to be more robust in Kir4.1 cKO animals. Our findings suggest that Kir4.1 plays a key regulatory role during myelination and OPC differentiation. We speculate that loss of Kir4.1 in OPCs results in precocious cell cycle exit that


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Poster Session 1, 22(S3) expedites OPC differentiation in early development, but leads to progressive white matter pathology during aging pointing towards maladaptive mechanisms that may take place in progressive MS. Disclosure Lucas Schirmer: has received travel support from Genzyme. Lawrence R. Shiow: nothing to disclose. Lucile Ben Haim: nothing to disclose. Kevin W. Kelley: nothing to disclose. Jackie Wright: nothing to disclose. Sandra Chang: nothing to disclose. Khalida Sabeur: nothing to disclose. Robin J. Franklin: nothing to disclose. Chao Zhao: nothing to disclose. David H. Rowitch: nothing to disclose. P459 c-Fos reporter analyses of astrocytic activity modulated by S1P signaling in experimental autoimmune encephalomyelitis (EAE) J. Chun Molecular & Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, United States Background: Fingolimod (FTY720; Gilenya), when phosphorylated, is an S1P analog that has high affinity interactions with four of five S1P receptor (S1PR) subtypes, S1P1,3-5. It has been proposed to work by sequestration of pathogenic lymphocyte subsets in secondary lymphoid organs. However, it also enters the CNS where it can bind to multiple S1PR subtypes on cells from neural and non-neural lineages. In particular, astrocytes show internalization and functional S1P1 loss during fingolimod exposure, which is in part responsible for its efficacy in experimental autoimmune encephalomyelitis (EAE). The present goal was to better understand the astrocyte effects of S1P signaling modulation. Methods and results: A transgenic mouse line with a tetracyclinesuppressible cis element (tTA) and a c-Fos driven nuclear GFPhistone fusion protein was crossed with an astrocyte specific, conditional S1P1-null mouse line. Monophasic EAE was induced, then tTA activated upon onset of EAE signs, allowing c-Fos activated cells to express a semi-permanent GFP signal. Activated astrocytes were visualized in the intact lower spinal cord using tissue clearance techniques that identified columnar structures in the cord’s long axis, particularly in the periphery. Astrocytes were the predominantly activated cell-type. The extent of activation correlated with disease severity as demonstrated by flow cytometry. Fingolimod administration or astrocyte targeted S1P1 removal reduced the number of activated astrocytes. GFP-positive EAEactivated astrocytes were isolated by FACS and processed for RNAseq, revealing differential transcriptional changes. Conclusions: Astrocyte activation correlates with clinical severity; both are reduced by genetic or pharmacological S1P1 signaling loss in murine EAE. Examination of the lower spinal cord by using tissue clearance technologies during the course of EAE development identified increases in activated astrocytes within lesions that produced discrete 3-dimensional geometries in the spinal cord. Distinct transcriptional changes in isolated astrocytes processed by FACS and RNAseq during EAE were identified and will be discussed.

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Disclosure JC has received compensation for serving as a consultant or speaker, or having received research funds from AbbVie, Amira Pharmaceuticals, Arena, Biogen Idec, Cellular Bioengineering Inc., GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Ono Pharmaceuticals, and Taisho Pharmaceutical Corporation. P460 EGFL7: a novel player in multiple sclerosis implicated in CNS infiltration C. Larochelle1,2, T. Uphaus2, B. Broux1,3, M. Paterka2, E. Gowing1, L. Michel1,4, M. Schmidt2, A. Prat1, F. Zipp2 1Neurosciences, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada, 2University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany, 3Research Foundation Flanders - FWO, Antwerp, Belgium, 4Centre Hospitalier Universitaire de Nantes, Nantes, France Background: Multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), is characterized by multiple foci of perivascular immune cell infiltration, in the presence of a dysfunctional blood-brain barrier (BBB). Extracellular matrix (ECM) proteins secreted by BBB endothelial cells (ECs) are implicated in the regulation of cell trafficking through interaction with integrins. While laminins have been shown to modulate leukocyte transmigration, the contribution of other ECM proteins to the recruitment and polarization of integrin-bearing leucocytes in the CNS of neuroinflammatory disorders such as multiple sclerosis is still unknown. Goals: The goal of this study was to assess the expression and function of epidermal growth factor-like protein 7 (EGFL7), an ECM protein which binds to alphavbeta3 integrin and can promote neuronal differentiation, in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Methods: Ex vivo, in vitro and in situ approaches were used to characterize the expression of EGFL7 in the CNS and peripheral immune system of MS, EAE, and controls. In vivo EAE experiments were performed using EGFL7 knock-out (KO) animals and administration of recombinant EGFL7 to define the role of EGFL7 in neuroinflammation. Results: EGFL7 is expressed by human BBB-ECs in primary culture in vitro, but no significant expression was detected in human and murine leucocytes. In MS lesions, the pattern of EGFL7 expression by BBB-ECs is disturbed as compared to non-inflammatory controls. Moreover, preliminary results suggest that treatment of human BBB-ECS with recombinant EGFL7 tightens the BBB in vitro. The ligand of EGFL7 is expressed by human T lymphocytes, which adhere to EGFL7. In vivo, EGFL7 KO is associated with a significantly earlier onset of EAE, and a heavier immune cell infiltration of the CNS as compared to littermates. Finally, injection of recombinant EGFL7 protein in vivo is associated with a significant delay of EAE onset, along with a decrease of CNS infiltration by inflammatory leukocytes, supporting a beneficial role of EGFL7 in neuroinflammation. Conclusions: The ECM protein EGFL7 plays a role in neuroinflammatory conditions such as MS and EAE, and its modulation could prove of therapeutic interest.


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Disclosure Catherine Larochelle has nothing to disclose in relation with this project and holds a fellowship from the Canadian Institutes of Health Research. Timo Uphaus has nothing to disclose in relation with this project. Bieke Broux has nothing to disclose in relation with this project and holds a fellowship from FWO-Flanders. Magdalena Paterka has nothing to disclose in relation with this project. Elizabeth Gowing has nothing to disclose in relation with this project. Laure Michel has nothing to disclose in relation with this project and holds a fellowship from the Canadian Institutes of Health Research. Mirko Schmidt has nothing to disclose in relation with this project. Alexandre Prat has nothing to disclose in relation with this project and holds a senior Canada Research Chair in Multiple Sclerosis. Frauke Zipp has nothing to disclose in relation with this project. Underlying original work was supported by the German Research Council (DFG; CRC-TR 128 to F.Z.) and by the German Competence Network Multiple Sclerosis (KKNMS), which is funded by the German Federal Ministry of Education and Research (BMBF to F.Z.). P461 Investigation of microtubule and actin integrity in the optic nerve during autoimmune optic neuritis J. Bojcevski, A. Stojic, S.K. Williams, R. Diem, R. Fairless Neurology, University Clinic Heidelberg, Heidelberg, Germany Background and objectives: Optic neuritis is a common first manifestation of multiple sclerosis. It can be modelled using a variant of experimental autoimmune encephalomyelitis, immunization of Brown Norway rats with myelin oligodendrocyte glycoprotein. In this model, degeneration of retinal ganglion cells (RGCs) starts during the induction phase of autoimmune optic neuritis (iAON) prior to lymphocyte infiltration and inflammatory demyelination in optic nerves. This preclinical RGC degeneration is timed with increases in retinal calcium and activation of the calcium-activated protease, calpain. Since calpain is known to target structural components involved in axonal transport and cytoskeletal integrity, we wished to determine if such changes occur and how they might fit into the calcium-activated cascades potentially involved in RGC degeneration. Methods and results: In order to assess axonal transport deficits, longitudinal optic nerve sections from different time points during AON were immunostained with antibodies against the molecular motor of axonal transport (kinesin) and against the transported proteins synaptophysin and APP. Accumulation of these markers was observed with the onset of the clinical phase of AON (cAON), but only around inflammatory lesions. This was similarly observed following intravitreal injection of cholera toxin β - Alexa488 conjugate, whose transport is known to be dependent upon intact microtubules. In addition to the microtubule system, integrity of the actin cytoskeleton network was also investigated by Western blot evaluation of the ratio between globular and filamentous actin. The G/F-actin ratio was increased two-fold in iAON and three-fold in cAON animals compared to healthy controls. Similar

increases were also observed in a model of primary retinal injury induced by intravitreal injection of glutamate. Furthermore, after intravitreal injection of the NMDA receptor blocker MK-801 during iAON, which reduces early RGC degeneration in the optic neuritis model, the optic nerve G/F-actin ratio was restored to values comparable to those in healthy animals. Conclusion: Disruption of microtubule-associated axonal transport was not seen during the time frame of preclinical RGC degeneration being observed only following onset of cAON in the vicinity of inflammatory lesions. However, actin network stability was compromised during the early disease stages and appears to be connected to glutamate receptor-mediated RGC degeneration. Disclosure The authors have nothing to disclose. This study was funded by the German Research Foundation (FOR2289).

Progressive MS P462 The CSF-profile of patients with primary progressive multiple sclerosis (PPMS) in a large multicentric cohort A. Abdelhak1, T. Hottenrott2, C. Mayer3, U. Zettl4, O. Stich2, H. Tumani1 1Department of Neurology, University Hospital Ulm, Ulm, 2Department of Neurology, University Hospital Freiburg, Freiburg, 3Department of Neurology, University Hospital Frankfurt, Frankfurt, 4Department of Neurology, University Hospital Rostock, Rostock, Germany Introduction: Cerebrospinal fluid (CSF) analysis remains an important part to establish the diagnosis in patients with primary progressive multiple sclerosis (PPMS). Most of previous studies regarding CSF data of PPMS patients suffer from small samples size. Methods: We retrospectively evaluated CSF data obtained from PPMS patients (McDonald criteria 2010) seen between 2009 and 2014 in four tertiary hospitals in Germany (Ulm, Frankfurt, Freiburg and Rostock). The basic CSF parameters (cell count, lactate, albumin CSF/serum quotient (QALB), immunoglobulin indices and oligoclonal bands (OCB)) were analyzed in correlation with the Expanded Disability Status Scale (EDSS) at time of first LP (EDSSLP) as well as the progression rate. Results: A total of 254 patients were included. The median EDSSLP was 4.0. The median cell count was within normal range. The QALB was elevated in 29.6 %. Intrathecal OCB were detectable in 91.1 %. The median index for IgG, IgM and IgA were 0.8, 0.06 and 0.3, respectively. We found no statistically significant correlation between the markers of immunoglobulin synthesis in CSF and the clinical parameters. Median CSF-lactate was within reference range. However, it showed a statistically significant positive correlation with the disease progression rate (spearman correlation =0.3, p= 0.02 ). Discussion: To our knowledge, this cohort of PPMS-patients with complete CSF data represents one of the largest published. The high incidence of intrathecal IgG production could highlight the inflammatory nature of the PPMS, which may explain the success of B cell depleting therapies in PPMS. Apart from CSF-lactate we found no correlation between the CSF parameters and clinical severity of the disease.


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Disclosure

No conflict of interest

Alma Mikkola: nothing to disclose Aku Ojanen: nothing to disclose Juha Hartikainen: nothing to disclose Anne M. Remes: nothing to disclose Sakari Simula: nothing to disclose

P463 Deterioration of cardiac repolarization is different during primary progressive and relapsing-remitting multiple sclerosis A. Mikkola1, A. Ojanen2, J. Hartikainen3, A.M. Remes1, S. Simula4 1Department of Neurology, Kuopio University Hospital and Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, 2Department of Clinical Physiology and Nuclear Medicine, Mikkeli Central Hospital, Mikkeli, 3Heart Center Kuopio University Hospital and Institute of Clinical Medicine - Medicine, University of Eastern Finland, Kuopio, 4Department of Neurology, Mikkeli Central Hospital, Mikkeli, Finland Background: Cardiac repolarization is controlled by central autonomic network (CAN) and has been reported to be longer in patients with multiple sclerosis (MS) than in healthy subjects. The location of demyelinating lesions has not fully explained the presence of cardiac autonomic dysfunction in MS patients. Accordingly, other explaining factors may also exist. Despite the distinct characteristics in pathogenesis, possible differences in cardiac repolarization during the course of primary progressive MS (PPMS) and relapsing-remitting MS (RRMS) are not known. Objective: To compare the effects of PPMS and RRMS on cardiac repolarization during the disease course. Methods: Eight PPMS patients with a 12-lead electrocardiogram (ECG) recorded at the time of diagnosis of PPMS (ECG1) and 61 RRMS patients with a 12-lead ECG recorded at the time of the initial symptom leading to the diagnosis of RRMS (ECG1) were retrospectively identified from the patient records. Every patient had a 12-lead ECG recorded at the later course of disease (ECG2) for comparison. QT interval was assessed by automatic analysis and defined as the interval between the start of QRS-complex and the end of T-wave. QT interval is influenced by heart rate (HR) and thus, HR corrected QT intervals were calculated using the Bazett equation (QTcBaz) and the Karjalainen formula (QTcKar). Results: The time interval between ECG1 and ECG2 was similar between PPMS patients (11.5±7.1 y) and RRMS patients (8.5±5.8 y). QTcBaz and QTcKar did not differ in ECG1 between PPMS and RRMS patients. However, during follow-up, a significant prolongation in QTcBaz (24±18 ms vs 5±25 ms; p< 0.05) and in QTcKar (23±30 ms vs 1±20 ms; p< 0.05) was observed in patients with PPMS as compared to patients with RRMS, respectively. In ECG2, QTcBaz (447±37 ms vs 414±23 ms; p=0.001) and QTcKar (432±38 ms vs 402±16 ms; p=0.06) were longer in PPMS patients than in RRMS patients, respectively. The difference in QTc prolongation between PPMS and RRMS showed no relation with age, duration of follow-up, comorbidities or concomitant medication. Conclusions: Cardiac repolarization becomes prolonged during the disease course in PPMS patients but not in RRMS patients. This may reflect differences in disease activity targeted towards CAN between PPMS and RRMS. Consequently, patients with PPMS may be at higher risk for unfavorable cardiovascular outcome.

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P464 Early relapses and cortical damage predict the risk of developing secondary progressive MS A. Scalfari1, C. Romualdi2, M. Mattoscio1, P. Muraro1, R. Nicholas1, M. Calabrese3 1Imperial College London, London, United Kingdom, 2Padova University, Padova, 3Verona University Hospital, Verona, Italy Introduction: Among relapsing remitting (RR) MS patients, a larger number of early attacks predicts faster disease evolution. We set out to elucidate the relationship between early relapses and grey matter pathological changes, and to explore baseline factors, affecting the long-term prognosis. Methods: By using 3D Double Inversion Recovery, 3D T1 weighted imaging and Freesurfer analysis, we assessed the number and volume of cortical lesions (CLs), and the rate of cortical thinning, among RR MS patients with 1 (n = 116), 2 (n = 53) and ⩾3 (n = 50) relapses during the first 2 years, followed for a mean of 7 years. The multivariate cox regression model estimated the risk of conversion to secondary progressive (SP) MS, according to early clinical and MRI features. Results: During the observation period, patients with high early relapses frequency entered the SP phase in larger percentage (⩾ 3 attacks = 54.0%, 2 attacks = 30.2%, 1 attack = 13.8%; p< 0.001) and in shorter time (⩾ 3 attacks = 68.0, 2 attacks = 80.5, 1 attack = 79.0 median months; p< 0.001). At clinical onset, the 3 groups had similar global cortical thickness, but patients with higher number of early attacks were distinguished by a larger volume of CLs (mean mm3 volume: ⩾3 attacks = 544.0; 2 attacks = 379.5; 1 attack = 181.6; p< 0.001). In addition, they accrued in the long term significantly higher volume of cortical lesions (mean mm3 increase: ⩾3 attacks = 790.5; 2 attacks = 138.8; 1 attack = 118.8; p< 0.001) and more severe global cortical atrophy (global cortical thickness: ⩾ 3 attacks = 2.26; 2 attacks = 2.36; 1 attack = 2.38 mean mm; p< 0.001). Among all RR MS patients, larger volume of baseline CLs predicted shorter time to reach the SP phase (84.5, 103.5, 136.1 mean months in the group with large, intermediate and small volume, respectively; p< 0.001). The multivariate model estimated that the risk of experiencing a progressive course was significantly higher, among patients older at onset (HR=2.02; p< 0.001), with a larger volume of baseline cortical lesions (HR = 2.06; p=0.008) and with ⩾3 early relapses (HR= 6.38; p< 0.001). Conclusions: Patients with frequent early relapses develop more prominent focal and diffuse cortical damage over time, accounting for their faster disease evolution. The number of early attacks and the extent of baseline focal cortical damage can be used for selecting groups at high risk of progression, who may potentially benefit from early aggressive treatment.


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Disclosure

Disclosure

Dr Scalfari received honoraria for speaking from Teva and Genzyme and travel support from Teva, Biogen and Genzyme. Dr Romualdi: nothing to disclose Dr Mattoscio received financial support for travel, accommodation and scientific meeting expenses from Biogen Idec, Genzyme, Novartis and Teva. Dr Muraro received honoraria for speaking and travel support from Merck Serono, Biogen, Bayer and Novartis. Dr Nicholas received honoraria for speaking from Bayer, Biogen, Genzyme, Merck Serono, Roche, and funds from Biogen, Genzyme, Novartis. Dr Calabrese received payment for development of educational presentations from Biogen, Genzyme, Teva, Bayer-Schering, and support for travel from Novartis, Genzyme, Biogen, Merck Serono, Bayer-Schering, Teva

Project funded by a NMSS pilot grant.

P465 The gut microbiome affects the progression of disease in a murine model of secondary progressive MS J. Ochoa-Reparaz1, E. Kasper2, S. Colpitts2, L. Kasper2 1Biology, Eastern Washington University, Cheney, WA, 2Microbiology/Immunology, Dartmouth Medical School, Hanover, NH, United States Background and objective: Recent findings reveal the importance of gut microbes in the development of experimental models of CNS inflammatory demyelination. We demonstrated that gut microbes and in particular the symbiont factor polysaccharide-A (PSA) produced by Bacteroides fragilis significantly influence gut immune responses and drive protection in relapsing-remitting EAE. Furthermore, in mice with EAE, onset of disease promotes significant changes in the intestinal permeability due to molecular modifications in the epithelial tight junctions, and changes in gut microbial abundances have been observed in MS patients when compared with healthy individuals. These observations suggest that the host-microbiota interaction is bi-directional. We propose that immunological changes that occur during disease modify the composition of the gut microbiome. Methods: We hypothesized that the gut microbiota relative abundances differ between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive MS (SP-EAE). We compared the gut microbiome in the EAE model of Non-Obese Diabetic (NOD) mice with non-EAE mice. The NOD model shows a bi-phasic pattern of disease that more closely resembles the human condition (RR-MS transitioning to SP-MS). In addition, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics and the treatment with PSA would modify the outcome of the progressive stage of EAE in NOD mice. Results: Results showed that the trend of the mortality and the clinical scores of mice treated with antibiotics, as well as with oral treatment with PSA, were reduced when compared to untreated EAE NOD mice. Conclusions: Results obtained in this work support the hypothesis that there is a reciprocal effect of experimental CNS inflammatory demyelination on the modification of the microbiome. Our studies provide the foundation to determine whether therapeutic intervention in the gut might be beneficial in terms of disease progression.

P466 Cerebellar volume as an outcome measure in therapeutic trials of primary progressive multiple sclerosis M. Inglese1, M. Petracca1, C. Saiote1, S. Ruggieri1, M. Fabian1, J. Howard2, C. Riley3, S. Krieger1, A. Miller1, F. Lublin1, M.P. Sormani4 1Icahn School of Medicine at Mount Sinai, 2New York University Langone Medical Center, 3Columbia University Medical Center, New York, NY, United States, 4Università di Genova, Genoa, Italy Background: Count of Gadolinium-enhancing and new T2 lesions are useful outcomes to monitor response to immunomodulatory agents in patients with relapsing-remitting MS. However, they are insensitive to changes in patients with primary-progressive MS (PP-MS) where the underlying pathology is dominated by diffuse brain gray and white matter damage (GM and WM), and worsening of tissue damage within existing lesions rather than by accumulation of new brain WM lesions. Objectives: To identify imaging measures with a significant change after one year follow-up, to be considered as potential outcome measures in therapeutic trials for PP-MS. Methods: We recruited 26 patients (14 F) with PPMS, (mean age 50.92±10.30 years, median EDSS 4.0 (range 1.5-6.0), mean 9HPT 33.89±15.33 sec and 25FWT 7.34±2.16 sec) and 20 healthy controls (11 F), mean age 51.05±9.80 years. The 3T magnetic resonance imaging (MRI) protocol included a) brain and cervical spinal cord T2-weighted Turbo-Spin-Echo; b) brain and spinal cord T1-weighted 3D Fast-Field-Echo; c) brain PSIR at both time points. WM T2 and T1 lesion volumes were measured using JIM 6.0; normalized brain, white and gray matter volumes (NBV, WMV and GMV) using SIENAX; normalized cerebellar cortex volume (CCV) and WM volume (CWMV) using Freesurfer; normalized cervical cord cross sectional area (CSA) at C2-C3 level (CSAnC2C3), and from C2 to C5 (CSAnC2C5) using Jim 6.0. Variables that significantly changed over 1 year were screened by non-parametric Wilcoxon test. Those who had a significant change were tested for their correlation with disability worsening by a logistic regression. Sample sizes for given treatment effects and power were calculated using parameters estimated from the sample. Results: Over one year, significant changes were detected in brain T1 lesion volume, CCV, CWMV, CSAnC2C3, CSAnC2C5 and T2 spine lesion number (p< 0.05). However, only CCV percentage change was significantly reduced in clinically progressed patients when compared to non-progressed patients (p< 0.01; AUC of 0.87). For a 12-month treatment trial, the minimum sample size per arm required to detect a 50% treatment effect on CCV, at 80% power was 130. Conclusions: Our study suggests that measures of cerebellar volume are feasible and sensitive to tissue changes over 1-year and should be considered as a primary outcome measure for therapeutic trials in PP-MS. Disclosure This study was supported in part by Novartis Pharmaceuticals (CFTY20DUSNC15T), National Multiple Sclerosis Society (NMSS RG 5120A3/1) and the Noto Foundation to MI and by a


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Poster Session 1, 22(S3) research fellowship from Fondazione Italiana Sclerosi Multipla (2013/B/7) to MP M Inglese, Dr. Matilde Inglese has received research grants from NIH, NMSS, Novartis Pharmaceuticals Corp., Teva Neuroscience Maria Petracca has received a research fellowship from Fondazione Italiana Sclerosi Multipla Catarina Saiote has nothing to disclose Serena Ruggieri has nothing to disclose Michelle Fabian has nothing to disclose Jonathan Howard has nothing to disclose Claire Riley has served as a consultant and/or participant in advisory board meetings for Genzye/Sanofi, Biogen Idec, Novartis, and Teva. She has received research support from NMSS Stephen Krieger has served as a consultant for Acorda Therapeutics; Bayer; Biogen Idec; EMD Serono; Genentech; Genzyme Corporation; Novartis; Questcor Pharmaceuticals; Teva Pharmaceutical Industries. He has participated in IndustrySponsored Non-Promotional, Non-Marketing Lectures for Genzyme Corporation; Biogen Idec Aaron Miller has served as a consultant and/or participant in advisory board meetings for Genzyme/sanofi-aventis, Biogen Idec, Glaxo Smith Kline, EMD Serono (Merck Serono), Novartis, ONO, Acorda, Nuron Biotech,Teva, Questcor and Accordant Health Services. He has received research support from Acorda, Novartis, Genentech, Genzyme/sanofi-aventis, Biogen Idec, Roche, and Questcor. He has served as Editor of Continuum, a continuing medical education publication of the AAN and currently serves as Editor of Continuum Audio. He is a member of the editorial board of Multiple Sclerosis and Related Disorders. He occasionally performs expert reviews of medical records or serves as an expert witness in medical malpractice cases. Fred Lublin Sources of Funding for Research: Acorda Therapeutics, Inc.; Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi; Celgene; NIH; NMSS; Consulting Agreements/Advisory Boards/DSMB: Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Teva Neuroscience; Actelion; Sanofi-Aventis; Acorda; Questcor; Roche, Genentech; Celgene; Johnson & Johnson; Revalesio; Coronado Bioscience, Genzyme, MedImmune; Bristol-Myers Squibb, Xenoport, Receptos; Forward Pharma; Co-Chief Editor: Multiple Sclerosis and Related Diseases; Stock Ownership: Cognition Pharmaceuticals, Inc. Maria Pia Sormani has received consultation fees from TEVA, Novartis, Biogen, Roche, Genzyme, Merck and Vertex.

P467 Disease trajectory in secondary progressive multiple sclerosis: a ten years follow-up study E. D’Amico, A. Zanghì, S. Lo Fermo, M. Zappia, F. Patti Department G. F. Ingrassia, Section of Neurosciences, University of Catania, Catania, Italy Background: Secondary progressive multiple sclerosis (SPMS) can occur after a variable time of relapsing remitting phase and, it is usually characterized by a progressive decline of neurologic functions with disability accrual. However, patients with SPMS (pwSPMS) can experience clinical relapses and new MRI gadolinium enhancing lesions. Scarce evidence are described about the long term disease trajectory in SPMS in the real life and, whether

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pwSPMS experiencing inflammatory activity are more prone to disability accrual than no active pwSPMS. Objectives: To compare the disability accrual fashion in two groups of pwSPMS who experienced or not relapse and/or radiological activity after entering the progressive phase. Methods: pwSPMS were divided in “active” or “non active” groups, basing on the presence or not of clinical relapses and gadolinium T1 lesions on magnetic resonance imaging (MRI) of brain. Demographical, clinical and radiological data were collected. Disability was assessed by Expanded Disability Status Scale (EDSS). Survival analysis were conducted to compare any difference in time to reach the disability milestone of EDSS 6.0; a Cox model was run to explore the relationship between the survival of patients and several explanatory variables. Results: Out of 282 pwSPMS, 164 (58.1%) had active course. Active pwSPMS were younger, had shorter disease duration, lower baseline EDSS, higher number of relapse prior progression and stayed for a longer time on therapy after progression (p< 0.005 for all). The comparison of survival curves (Breslow-Wilcoxon test) showed higher probability to reach the event EDSS 6.0 for pwSPMS who experienced “more than 1 treatment switch prior progression” [χ2 (1) = 3,898, p < 0.005]. The independent variables retained in the Cox model were: the number of T1 MRI gadolinium lesions at last neurological evaluation [Exp (b) value of 1,297, CI 1,004-1,675 (p< 0.005)] and withdrawal of therapy post progression [Exp (b) value of 1,542, CI 1,037-2,293 (p< 0.005]. Conclusions: In a real word setting, active pwSPMS showed a more aggressive fashion of disability accrual than no active pwSPMS. In pwSPMS the withdrawal and/or the switch choice of MS therapy should be weighted carefully. Disclosure Dr Emanuele DÁmico has received funding for travel by Teva, Biogen, Merck Serono, Bayer-Schering, Genzyme/Sanofi and Novartis. Dr Aurora Zanghì: nothing to disclose Dr Salvatore Lo Fermo: nothing to disclose Dr Mario Zappia has served on scientific advisory boards and received honoraria from UCB-Union Chimique Belge and Lundbeck, and has received scientific grants from the Italian Medicines Agency (AIFA) and Novartis. Dr Francesco Patti has served on scientific advisory boards for Teva, Biogen-Idec, Bayer-Schering and Novartis, and has received honoraria as a speaker for Teva, Biogen, Merck Serono, Bayer-Schering, Genzyme/ Sanofi and Novartis. P468 Could fampridine change gait kinematics to improve walking speed in primary progressive multiple sclerosis? I. González-Suárez1, D. Gómez-Andrés2, A. Montero-Atalaya3, I. Pulido-Valdeolivas2, I. Rodríguez-Andonaegui3, J.A. Martín-Gonzalo3, A. Orviz-Garcia4, V. López de Velasco4, E. Rausell2, C. Oreja-Guevara4 1Neurology, Hospital Alvaro Cunqueiro, Vigo, 2Universidad Autónoma de Madrid, 3School of Physiotherapy ONCE-UAM, 4Hospital Clínico San Carlos, Madrid, Spain


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Introduction: Primary progressive MS (PPMS) is a MS variant without treatment at the date in which the gait alterations represent the main source of disability. Fampridine was approved based on the improvement in walking speed as measured by 25FWT for MS patients. We hypothesize that fampridine would produce changes in a number of angular joint movements during gait cycle to allow improvement in translation capacity and balance. Objectives: To analyze the response to Fampridine in PPMS patients by evaluating the spatio-temporal changes measured by instrumental gait analysis (IGA). Material and methods: 10 PPMS patients were analyzed by IGA and 12 speed standard spatial parameters in both right (R) and left (L) leg were recorded: normalized speed according leg length(VN), cadence (C), total time support (% TTA) -% of gait cycle and its distribution among one leg (AM) and first (% 1FS) and second double support (% 2DS). Results were compared to 12 healthy controls matched by age. Improvement was defined as approximate values to normal and was measured by the difference between the absolute values of Z-score pre-treatment and those obtained after 15 days of starting treatment with fampridine. The confidence interval was calculated at 95% average improvement bootstrap accelerated corrected for bias. Results: After 15 days of daily treatment with fampridine most of the Z-score of all spatial variables improved statistically significantly except % 1FS (R) and % AM (R). The improvement is 0.69(L) / 0.41(R) VN, 1.21(L) / 0.83 (R) for C, 1.30 (L) / 1.34 (R) % TTA, 0.61(L) / 0.68(R)% 1FS, 0.32 (L) / 0.13 (R)% AM, and 0.19 (L) / 0,13 (R) for% 2DS. Conclusions: Treatment with Fampridinedemonstrates a statically improvement in cadence, total time support and 2nd double support in both legs, and first double support time in left leg. These changes imply greater stability and balance during the stay and gait after treatment administration. Disclosure Gonzalez Suárez I has received funding form Novartis, Biogen and Genzyme. Pulido-VAldeolivas I: nothing to disclosure Gomez-Andrés D: nothing to disclosure Orviz-Garcia A: has received funding from Novartis Montero-Atalaya A: nothing to disclosure Martin-Gonzalo JA: nothing to disclosure Rodríguez-Andonaegui I: nothing to disclosure López de Velasco V has received funding form Genzyme Rausell-tamayo E: nothing to disclosure Oreja-Guevara C: has received fundings form Novartis, Genzyme, Biogen, Roche, Merck

P469 Residual intrathecal inflammation after natalizumab and methylprednisolone treatment in progressive multiple sclerosis correlates with axonal damage J. Romme Christensen1, M. Komori2, M.R. von Essen1, R. Ratzer1, L. Börnsen1, B. Bielekova2, F. Sellebjerg1 1Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Copenhagen, Denmark, 2Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, NIH, Bethesda, MD, United States

Background: The understanding of the pathogenesis of progressive multiple sclerosis (MS) is challenged by the lack of biomarkers reflecting the complex pathology. Cerebrospinal fluid (CSF) biomarker studies have demonstrated high sensitivity for intrathecal inflammation by soluble CD27 (sCD27, a marker of T cell inflammation) and markers of B cells (sCD21) and microglia/ macrophage inflammation (sCD14 and sCD163). We investigated the effects of treatment with natalizumab (NTZ) and methylprednisolone (MP) on these soluble biomarkers and other candidate CSF biomarkers of inflammation in progressive MS. Methods: Baseline and week 60 follow-up CSF samples from progressive MS patients from two open-label trials of NTZ or MP treatment were included. CSF concentrations of soluble surface markers, a panel of chemokines and cytokines, and neurofilament light chain (NFL, a marker of axonal damage) and myelin basic protein (MBP, a marker of demyelination) were analysed by electrochemiluminescent assay and ELISA assays. Results: NTZ treatment significantly reduced CSF concentrations of sCD21, sCD27, IL10, IL12p40, TNF-alpha and CXCL10, while IL5 and IL7 concentrations increased. MP treatment significantly reduced sCD21, sCD27 and IL12p40 and increased sCD163, IL5, IL7, IL15 and CCL2 concentrations. For both treatments, CSF sCD27 and sCD21 showed the most significant decreases and superior signal-to-noise ratios for change after treatment, but remained above reference levels for healthy donors. Correlation analysis of baseline concentrations (N=52) of CSF markers of inflammation and axonal damage (NFL) demonstrated significant positive correlations between NFL and sCD14, sCD21, sCD27, sCD163, CHI3L1, IL8, IL10, TNF-a, VEGF, CCL11, CCL22 and CXCL10, while MBP concentrations correlated with sCD14 and sCD163. Correlation analyses of CSF concentrations after 60 weeks of NTZ (N=17) or MP (N=23) treatment showed sCD27 to be the only marker of intrathecal inflammation consistently correlating with NFL. Conclusions: Treatment of progressive MS with NTZ or MP results in significant decreases of CSF markers of intrathecal inflammation which correlate with axonal damage, but still substantial residual T- and B-cell inflammation remains after treatment. CSF biomarkers of T- and B-cell inflammation, sCD27 and sCD21, demonstrated consistent responsiveness and low signalto-noise ratios during both treatments, supporting their potential use in future progressive MS clinical trials. Disclosure JRC has received speaker honoraria from Novartis and TEVA, consultant honoraria from Biogen Idec and TEVA, and has had travel expenses reimbursed by Biogen Idec. MK declares no conflict of interest. MRvE declares no conflict of interest. RR has had travel expenses reimbursed by BiogenIdec and Genzyme. LB has received support for conference participation from Genzyme and Novartis and has received research grants from the Danish Multiple Sclerosis Society. BB is a co-inventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH. FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva.


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Repairing mechanisms P470 Prickle1 as positive regulator of oligodendrocyte differentiation R. Zilkha-Falb1, M. Gurevich1, E. Hanael1, A. Achiron1,2 1Multiple Sclerosis Center, Sheba Medical Center, Ramat Gan, 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Spontaneous neural repair from endogenous neural stem cells (NSCs) niches occurs in response to central nervous system (CNS) injuries to only a limited extent. Uncovering the mechanisms that control neural repair and can be further manipulated to promote NSCs towards oligodendrocyte progenitors cells (OPCs) and myelinating oligodendrocytes is a major objective. In the current study, we describe high throughput transcriptional changes in adult mouse subventricular zone (SVZ)-NSCs during differentiation in vitro. In order to identify myelin specific transcriptional regulators amongst large transcriptional changes associated with differentiation we have focused on transcripts encoding transcription factors and regulators showing expression profile that is highly correlated with expression of myelin encoding genes. We have revealed previously undescribed effect of Prickle1 and Nfe2l3 transcriptional regulators that are positively correlated (r=0.92, p=2.8x10-10 and r=0.88, p=7.8x10-9, respectively) with expression of myelin basic protein (MBP). Using Prickle1 and Nfe2l3 silencing and immunocytochemistry approaches we demonstrated that silencing of Prickle1 dramatically decreases differentiation to NG2+OPCs by 90.6% (p< 0.002) while Nfe2l3 moderately decreases by 31.9% (p< 0.04) as compared with control siRNA. Moreover, silencing of Prickle1 also decreases maturation of OPCs to MBP+oligodendrocytes by 77.4% (p< 0.002). This inhibitory effect of Prickle1 silencing was also evident at different time points of NSCs differentiation to NG2+OPCs and CNPase+ or MBP+oligodendrocytes. Our findings demonstrate the role of Prickle1 in positive regulation of differentiation and maturation of oligodendrocytes suggesting that targeting Prickle1 in CNS injuries and particularly in demyelinating disease could promote generation of myelinating oligodendrocytes from endogenous niches to replenish damaged oligodendrocytes. Disclosure Rina Zilkha-Falb: nothing to disclose Michael Gurevich: nothing to disclose Erez Hanael: nothing to disclose Anat Achiron: nothing to disclose P471 Inhibition of hyaluronidase activity by modified flavonoids promotes functional remyelination L.S. Sherman1, W. Su1, S. Matsumoto1, S. Back2, P. Weigel3, K. Girish4 1Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, 2Pediatrics, Oregon Health & Science University, Portland, OR, 3University of Oklahoma, Oklahoma City, OK, United States, 4Tumkur University, Tumkur, India The mechanisms underlying remyelination failure in demyelinating diseases are unclear. We previously demonstrated that the

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glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions from patients with multiple sclerosis (MS). The presence of HA in these lesions coincides with reactive astrogliosis and accumulation of oligodendrocyte progenitor cells (OPCs) that fail to become myelinating oligodendrocytes. The addition of HA to OPCs grown in vitro, in white matter slice cultures, or in lysolecithin-induced demyelinating lesions blocks OPC maturation and leads to remyelination failure. Interestingly, low molecular weight HA products accumulate in MS lesions. We recently reported that OPCs and reactive astrocytes within demyelinating lesions express a hyaluronidase, called PH20, that generates specific sizes of HA digestion products that inhibit OPC maturation. Blocking hyaluronidase activity promotes OPC maturation and remyelination, and restores fast conduction velocities in axons within demyelinating lesions as assessed by compound action potential recordings. Specific HA digestion products generated by PH20 block remyelination through signaling cascades shared by other inhibitors of remyelination. We screened a number of compounds for their effects on hyaluronidase activity and have identified several novel modified flavonoids that selectively block PH20 activity and promote OPC maturation and functional remyelination of lysolecithin-induced lesions. These compounds are well tolerated in mice with experimentally induced demyelinating diseases and lead to reduced inflammatory demyelination in mice with experimental autoimmune encephalomyelitis. These compounds are currently being tested for their safety and efficacy in both rodent models and in a novel, spontaneous non-human primate model of MS, Japanese macaque encephalomyelitis, that mimics the immunological and neurohistopathological characteristics of MS in humans. All together, our data indicate that digestion products generated by hyaluronidase activity in MS lesions contribute to remyelination failure through signaling cascades shared by other mechanisms that prevent OPC maturation. Blocking hyaluronidase activity may be an effective approach to promoting functional remyelination in patients with MS. Disclosure Larry S. Sherman: nothing to declare Weiping Su: nothing to declare Steven Matsumoto: nothing to declare Paul Weigel: nothing to declare Stephen Back: nothing to declare Kesturu Girish: nothing to declare This work was supported by grant RG 4843A5/1 from the multiple sclerosis society

P472 Longitudinal assessment of large-scale brain functional networks in patients with multiple sclerosis: relationship with clinical disability and cognitive impairment M.A. Rocca1, P. Valsasina2, A. Colombi2, F. Pirro2, E. Pagani2, E. De Meo2, B. Colombo3, P. Preziosa2, V. Martinelli3, G. Comi3, A. Falini4, M. Filippi2 1Ospedale San Raffaele - Vita-Salute San Raffaele UniversityDivision of Neuroscience, 2Neuroimaging Research Unit, INSPE, San Raffaele Scientific Institute, 3Dept. of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, 4Dept. of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, Milan, Italy


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Aims: We investigated the temporal evolution of resting state (RS) functional connectivity (FC) in patients with multiple sclerosis (MS) and its correlation with clinical and cognitive worsening. Methods: Diffusion tensor and RS fMRI scans, clinical and neuropsychological evaluations were obtained from 56 MS patients and 24 healthy controls (HC) at baseline and follow-up (median time=3.6 years). Seed-voxel RS FC was performed with seven major cortical/subcortical seeds. Fractional anisotropy between regions of each functional network was also measured. RS FC longitudinal changes were compared between HC, clinically stable and worsened MS patients. Multivariable logistic models investigated the predictive role of clinical and RS FC variables on neurological/cognitive deterioration. Results: At follow-up, 11 MS patients (20%) were clinically worsened and 6 developed cognitive impairment. Global functional and structural connectivity was lower in HC vs MS, and in worsened vs stable MS patients at both timepoints. RS FC remained stable over time in HC. Clinically stable MS patients showed increased (or stable) RS FC over time, while decreased RS FC was found in clinically worsened patients. Structural connectivity decreased over time in both MS subgroups. A lower baseline thalamic and default-mode network RS FC predicted neurological deterioration at follow-up (p=range 0.004-0.04). Decreased RS FC in the same networks was associated with a worse cognitive performance at follow-up. Conclusions: Longitudinal modifications of RS FC occur in MS patients and differ from those of HC. Increased RS FC over time plays an adaptive role in delaying disability accrual and cognitive deterioration. Disclosure This study has been partially supported by a grant from FISM 2014/R/7. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. P. Valsasina has nothing to disclose. A. Colombi has nothing to disclose F. Pirro has nothing to disclose. E. Pagani has nothing to disclose. E. De Meo has nothing to disclose. B. Colombo has nothing to disclose. P. Preziosa has nothing to disclose. V. Martinelli has received honoraria and travel reimbursement for lectures at Meetings and Congresses from Teva Pharma, Bayer, Genzyme, Biogen Idec, Novartis and Merck Serono; he has received research support from Merck Serono and has served as a member in Advisory Board for Bayer, Genzyme, Biogen Idec, Novartis and Merck Serono. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. A. Falini has nothing to disclose. M. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from

Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). P473 pH and KV channel conductance are not central to damage of demyelinated axons in the cuprizone mouse model V. Schultz1, F. Paap2, U. Scheidt2, C. Stadelmann2, W. Brück2, A. Junker3 1University of Glasgow, Institute of Infection, Immunity and Inflammation, Glasgow, United Kingdom, 2University Medical Center Göttingen, Institute of Neuropathology, Göttingen, 3University Hospital Essen/ Institute of Neuropathology, Essen, Germany Hallmarks of MS lesions are demyelination and axonal pathology, which occurs early after disease onset and is associated with disease progression and persistent disability in MS. Demyelination, which leads to a loss of support by oligodendrocytes, increased energy demand of the axon and/ or increased impact of toxins, is considered as the major cause for axonal damage and degeneration. The establishment of a new myelin sheath, i.e. remyelination, has been known as a mechanism of repair and axonal protection. However, the interrelation of the axon and the myelin sheath in regards of axonal damage and remyelination is unknown. Demyelination and remyelination cause a rearrangement of many transmembrane proteins, such as voltage gated potassium (KV) channels, which might result in an increased vulnerability of the axon to axonal damage due to pH shifts and ion disbalance. To shed light onto the interrelationship of axons and the myelin sheath during de-/ and remyelination, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the density of acutely damaged and preserved axons. We observed more damaged axons in late stage demyelinated MS lesions than in late stage remyelinated MS lesions. To investigate the relation of demyelination, remyelination and axonal damage in more detail, we employed a toxic model of cuprizone-induced demyelination and performed tight time course experiments assessing the evolution of remyelination and acute axonal damage. We found neither an evidence for increased vulnerability of axons to axonal damage due to early remyelination nor that pH shifts and alteration of KV channel conductance were involved in axonal damage in the absence of an adaptive immune response. Disclosure V. Schultz, F. Paap, U Scheidt, A. Junker: nothing to disclose C. Stadelmann received honoraria for speaking and travel reimbursement from Novartis Pharma GmbH, Teva Pharmaceutical Industries Ltd., Biogen, and Bayer Health Care. She served on scientific advisory boards of Novartis and Teva. She receives research support from Teva. She is a member of the editoral board of the Multiple Sclerosis Journal and Neurology: Neuroimmunology & Neuroinflammation. W. Brück has received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received


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Poster Session 1, 22(S3) funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. W. Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders.

Imaging P474 Establishing a reference population for individualized brain volume assessment in multiple sclerosis: toward clinical use of brain volume tools P. Beauchemin1,2, R. Carruthers1, R. White3, A. Riddehough4, D. Li5, A. Traboulsee1, R. Tam6 1Neurology, University of British Columbia, Vancouver, 2Neurologie, Université Laval, Ville de Québec, 3Statistical Consulting and Research Laboratory, 4University of British Columbia, 5Radiology, 6Radiology and Neurology, University of British Columbia, Vancouver, BC, Canada Background: Brain Volume Loss (BVL) is increasingly considered a component of the assessment of brain health in individuals with Multiple Sclerosis (MS). The next frontier is to translate BVL measurements into clinical practice and individual patient care. To appraise BVL measurements, clinicians need to know what to expect from their individualized MS patients, relative to gender and age. This will further provide clinical usefulness of BVL in individualized MS patient care. Goal: To establish a normative cross-sectional and longitudinal Brain Volume reference range. Methods: A model was developed from a reference population of 1213 subjects with multiple observation points (total of 3665 MRIs). BVL was assessed by Brain Parenchymal Fraction (BPF) using an in-house method based on the segmentation of combined T2 and PD. The model adjusts for repeated measurements on each patient and estimates the effect of age, gender and disease duration on a patient’s baseline BPF in addition to the rate of change in each patient’s BPF over time. The model estimates the level of variation associated with BPF measurements both within and between patients. Results: Age, gender and disease duration at baseline each had a significant impact on BPF. Female BPF is 2.6% larger than Male BPF on average given the same age and disease duration. A 10 year increase in age is associated with a 1% decrease in BPF on average. A 10 year increase in duration is associated with a 2% decrease in BPF on average. Subjects showed a consistent decrease in BPF over time. Using age or disease duration give similar results in our model. Disease duration is often difficult to determine, so age is more reliable. Based on the model, the BPF of a typical patient can be predicted given their gender, age and disease duration. By predicting the BPF at different times, the typical change in BPF can also be predicted. The level of variation estimated by the model is used to provide a range of plausible values for each prediction. Conclusion: By modeling a large population of MS patients, we can provide a meaningful context in which clinicians can interpret BVL in an individualized patient, both in term of brain volume (BPF) at one point in time and of BVL(ΔBPF) between two different assessments. It can determine brain volume trajectory in individual patients. Real world usefulness of Brain Volume Loss measurements is still to be determined. Our model is a steppingstone toward this ultimate goal.

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Disclosure Philippe Beauchemin: Consulting fees: Novartis, EMD Serono. Robert Carruthers: Grants/Research Support: Site PI for studies funded by MedImmune, Teva and Guthy Jackson; Speakers Bureau/Honoraria: Speaking fees for unbranded lectures from Biogen, Genzyme and Teva; Consulting Fees: Novartis, EMD Serono, Genzyme. Roger Tam: nothing to disclose. Andrew Riddehough: nothing to disclose. David Li: has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada. He is the Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Novartis, Perceptives, Roche and Sanofi-Aventis. The UBC MS/MRI Research Group has also received grant support for investigator-initiated independent studies from Genzyme, Merck-Serono, Novartis and Roche. He has acted as a consultant to Vertex Pharmaceuticals and served on the Data and Safety Advisory Board for Opexa Therapeutics and Scientific Advisory Boards for Adelphi Group, Novartis and Roche. He has also given lectures which have been supported by non-restricted education grants from Novartis and Biogen. Rick White: nothing to disclose. Anthony Traboulsee: is a consultant for Novartis, Genzyme, Roche and a principal investigator on clinical trials with Biogen, Genzyme, Roche, and Chugai.

P475 Influence of edema on MRI measures of white matter: a quantitative assessment of in vivo MTR, DTI and post-mortem quantitative immunohistochemistry in a mouse model of inflammatory, vasogenic edema R. Rajagovindan1, S.P. Zehntner2, A.P. Zijdenbos2, J.D. Beaver1 1AbbVie, North Chicago, IL, United States, 2Biospective Inc., Montreal, QC, Canada Background: Magnetization Transfer (MT) imaging and Diffusion Tensor Imaging (DTI) are increasingly utilized in clinical trials of novel multiple sclerosis therapies. While measures derived from these techniques are sensitive to changes in white matter pathophysiology, they are also believed to be influenced by confounding factors such as changes in edema, typical in MS lesions, and thus limited in specificity. We investigated the sensitivity of in vivo MT ratio (MTR) and DTI measures to quantitative changes in myelin and edema derived from immunohistochemistry (IHC). Methods: Experimental edema was induced in C57BL/6 mice (n=16) using stereotactic injection of mouse recombinant VEGF-A protein (2µL, 1000ng) into the corpus callosum. 3D DTI (140x140x360 µm, b~1000 s/mm2, 20 directions) and MTR (140x140x140 µm, 9.6 µT Gaussian RF pulse, 3 kHz off-resonance) on a 7T MRI scanner were acquired in three cross-sectional cohorts of animals at days 3, 4, 5/6 following VEGF-A injection, and sacrificed immediately following image acquisition. Fractional anisotropy (FA), axial (AD), radial (RD), mean diffusivity (MD), and MTR maps were derived from the MR images. Brains were serially-sectioned and stained to assess myelin density (MBP) and edema (IgG). The IHC sections were digitized, reconstructed into


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3D quantitative IHC volumes, and spatially normalized to the MRI data using Biospective’s PERMITS™ software. Univariate and multivariate analysis were performed on MRI and IHC measures derived from lesion and extra-lesion regions-of-interest (ROIs). Results: Focal lesions were detected in all animals. Edema was highest at Day 3 followed by reduction over the next 3 days, thereby recapitulating the evolution of edema within an acute MS lesion. In healthy extra-lesional corpus callosum, the MTR, RD and T2 signal intensity correlated best with myelin (r=0.51, -0.36, -0.46, respectively; p< 0.05). Within edematous lesions defined on IgG IHC, diffusivity measures (MD, AD, RD) were most associated with edema (r~0.4-0.5; p< 0.1) and edema had marginal influence on MTR and FA (p>0.6). MTR and FA were the only variables associated with myelin (r>0.5, p< 0.05) with and without accounting for edema as a covariate within lesions. Conclusions: The findings provide improved understanding of the pathophysiological sensitivity and specificity of MRI measures, aiding in the choice of optimal measures and their precise interpretation in clinical trials of remyelinating agents.

(Iba1) and edema (IgG). Quantitative endpoints were derived from lesions manually delineated on MRI and IHC. Results: Focal lesions were detected in all animals. Myelin and axonal pathology were highest at 14 dpi followed by spontaneous repair evidenced by improvement in MBP and NF1 staining (p< 0.05) by 56 dpi. In line with the IHC findings, increase in MTR, FA and reduction in MD, RD and T2 were observed 56 dpi relative to 14 and 28 dpi (p< 0.05). MTR and FA increased by 3 and 30%; MD, RD and T2 decreased by 4, 10 and 17% at 56 dpi relative to 14 dpi. The outcome of univariate and multivariate analysis to elucidate the magnitude of influence each underlying aspect of pathophysiology (myelin, axon, inflammation and edema) had on each MRI outcome measure will be reported along with strategies to minimize the influence of confounding factors in the interpretation of MRI outcome measures. Conclusions: The findings provide improved understanding of the pathophysiological sensitivity and specificity of MRI measures, aiding in the choice of optimal measures and their precise interpretation in clinical trials of remyelinating agents.

Disclosure

Disclosure

RR and JDB are employees of AbbVie. SPZ and APZ are employees of Biospective. Biospective received research funding from AbbVie for the conduct of this study and analysis. AbbVie participated in the design, analysis, interpretation of data, review, and approval of the publication.

Authors are employees of AbbVie. The study was sponsored by AbbVie. AbbVie conducted the study, interpretation of data, review, and approval of the publication.

P476 Sensitivity of MRI measures to axonal and/or myelin repair in the presence of inflammation: a quantitative assessment of in vivo MTR, DTI and post-mortem immunohistochemistry in a rodent model of spontaneous remyelination R. Rajagovindan, B. Hooker, M. Voorbach, C. Schroeder, J. Beaver AbbVie, North Chicago, IL, United States Background: Magnetization Transfer (MT) imaging and Diffusion Tensor Imaging (DTI) are increasingly utilized in clinical trials of novel multiple sclerosis therapies. While measures derived from these techniques are sensitive to changes in white matter pathophysiology, they are also believed to be influenced by confounding factors such as changes in edema, typical in MS lesions, and thus limited in specificity. We investigated the sensitivity and specificity of in vivo MT ratio (MTR) and DTI measures to quantitative changes in myelin and axonal density in the presence of inflammation and edema assessed by immunohistochemistry (IHC). Methods: Focal demyelination was induced in Sprague Dawley rats (n=24) using stereotactic injection of 3uL of 1% lysophosphotidylcholine into the corpus callosum. DTI (380x380x500 µm, b~700 s/mm2, 30 directions) and MTR (250x250x500 µm, 9 µT Gaussian RF pulse, 2 kHz off-resonance) at 4.7T were acquired in three cross-sectional cohorts of animals at 14, 28, 56 days post injection (dpi), and sacrificed following image acquisition. Fractional anisotropy (FA), axial (AD), radial (RD), mean diffusivity (MD), T2 signal intensity and MTR maps were derived from the MR images. Brains were serially-sectioned and stained to assess myelin density (MBP), axonal density (NF1), inflammation

P477 Convergent effects of a functional C3 polymorphism on cognitive impairment, brain atrophy and demyelination in multiple sclerosis T. Roostaei1,2, S. Sadaghiani2, R. Mashhadi3, M. Falahatian2, E. Mohammadi2, A. Nazeri2,4, R. Doosti2, A. Naser Moghadasi2, M. Owji2, A.P. Hashemi Taheri5, A. Shakouri Rad5, A. Azimi2, A. Nazeri1,2, M.A. Sahraian2 1Kimel Family Translational Imaging-Genetics Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada, 2Multiple Sclerosis Research Center, 3Urology Research Center, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran, 4Bioimaging Program, Boston University School of Medicine, Boston, MA, United States, 5Department of Radiology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran The complement system is a key component of the innate immune system that has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Complement component 3 (C3) is a central element in the activation of complement cascades. Rs2230199 is a common coding variant in the C3 gene that affects the activity of C3 and is an established genetic risk factor for age-related macular degeneration. Here we assessed the effect of rs2230199 on disease severity in 155 relapsing-remitting MS patients (agerange:18-57, F/M:121/34, EDSS⩽6, in-remission) using clinical, cognitive and imaging outcomes. Clinical disability was assessed using EDSS and MSFC. Cognitive function was indexed by averaging the standardized scores of Paced Auditory Serial Addition Test, Symbol-Digit Modalities Test and California Verbal Learning Test. Imaging was conducted at two sites using 1.5T MRI scanners. General linear models were used to assess the effect of rs2230199 on clinical and cognitive measures. Wholebrain gray matter voxel-based morphometry (using T1-weighted


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Poster Session 1, 22(S3) images), tract-based spatial statistics (using diffusion-tensor images), and white matter voxel-based analysis (using magnetization transfer ratio images) were performed using permutation testing and threshold-free cluster enhancement approach. Voxels with familywise error corrected p< 0.05 were considered significant. All analyses were performed while controlling for the effects of age, sex, and disease duration (and also imaging site in the imaging analyses). While the C3 genetic variant showed no significant effect on clinical severity, rs2230199 minor-allele dosage was associated with worse cognitive performance (t= -2.19, p=0.03). Moreover, the variant was associated with lower brain parenchymal fraction (t=-2.96, p=0.003). Voxel-wise analyses showed significant inverse relation between rs2230199 minor-allele dosage and regional gray matter volume in subcortical structures and insular cortex (n=155), fractional anisotropy in white matter skeleton of corpus callosum, corona radiata and cingulum (n=105) and magnetization transfer ratio in right periventricular white matter and corona radiata (n=90). We found converging evidence that carrying the C3 functional variant which is linked to enhanced complement activity is associated with greater cognitive impairment and white matter and gray matter damage in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.

Material and method: This is a retrospective cross sectional study of 163 patients with MS (42 men and 121 women, aged 20-68 years). The ratio of T1 intensity in the dentate nuclei versus the pons (DNP ratio) was calculated. We noted the number of administrations, type and amount of GBCA. Results: The patients received an average number of 5.37 GBCA administrations each over 0-17 years (mean 5.23). The accumulated dose of GBCA per patient ranged between 0-275 ml (mean 72.7 ml). Of the total number of administrations (N=873), 74 % were the macrocyclic agents. We found a significant correlation between the DNP ratio and the number of gadolinium administrations (r=0.22, p=0.006), as well as between the DNP ratio and the accumulated dose (r=0.23, p=0.004) and mean dose (r=0.17, p=0.035) per patient. There was not a significant correlation of the DNP ratio with number of administrations (r=0.14, p=0.28) or total doses (r=0.155, p=0.242) for the subgroup of patients who had received only macrocyclic agents (N= 59). Conclusion: Our study supports observations by other research groups that the use of GBCAs can result in neural tissue deposition. We found a correlation of increased DNP ratio both with the total dose, and with the number of administered GBCA doses. Further and larger studies are needed to identify the clinical impact of this observation.

Disclosure TR, SS, RM, MF, EM, AN, RD, ANM, MO, APHT, ASR, AA, AN and MAS declare no conflict of interest. TR and AN are recipients of Jacqueline Du Pré grant (2011) provided by the Multiple Sclerosis International Federation. P478 T1 hyperintensity in the dentate nuclei of multiple sclerosis patients correlates with number of administrations and total dose of gadolinium based contrast agent E.S. Lindland1,2, S. Nabi3, D. Biernat4, E.G. Celius5,6, P. Sowa3,4, H.F. Harbo5,7, M.K. Beyer4,8 1Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, 2Sorlandet Hospital, Arendal, 3University of Oslo, 4Radiolgy and Nuclear Medicine, 5Department of Neurology, Oslo University Hospital, 6Institute of Health and Society University of Oslo, 7Clinical Medicine, University of Oslo, 8Department of Life Sciences and Health, Oslo and Akershus University College of Applied Sciences, Oslo, Norway Background: (2272/349) Gadolinium based contrast agents (GBCAs) are extensively used for MRI examinations. In order to eliminate the toxicity of free gadolinium the various agents have different chelate molecules. The structure of this ligand can be linear or macrocyclic. Macrocyclic agents are considered more stable. In the past few years there have been several reports observing T1 hyperintensity in specific brain structures in patients with multiple contrast enhanced MRI examinations. Recent animal and post mortem studies give evidence of gadolinium deposition in neural tissue. The physiological and clinical significance of such deposition is not known. Objective: We aimed to provide supportive or contradictive evidence of hyperintensity in the dentate nuclei in patients with multiple sclerosis (MS) in relation to previous GBCA administration, and to study any differences for the various gadolinium chelates.

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Disclosure Elisabeth G. Celius received funding for travel and speaker’s fees from Almirall, Biogen Idec, Genzyme, Novartis, Sanofi-Aventis and Teva, and received unrestricted research grants from Biogen Idec, Genzyme and Novartis outside the submitted work. Dr. Hanne F Harbo received an unrestricted research grant from Novartis, and support for travelling and speaking honoraria from Biogen Idec, Novartis, Sanofi-Aventis and Teva outside the submitted work. Dr.Mona K Beyer has nothing to disclose Dr Elisabeth Lindland has nothing to disclose Dr Donata Biernat has nothing to disclose Dr Piotr Sowa received honoraria for lectures from Novartis, Genzyme and Biogen Idec. Sehrish Nabi has nothing to disclose P479 Cognitive decline in multiple sclerosis is linear and associated with lesion accumulation and corpus callosal atrophy: results of an 18-year longitudinal study G. Bergendal1,2, R. Ouellette3,4, S. Shams1,5, J. Martola1,5, C. Mainero3,6, M. Kristoffersen-Wiberg1,5, S. Fredrikson2,7, T. Granberg1,3,5 1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, 2Department of Neurology, Karolinska University Hospital, Stockohlm, Sweden, 3Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, 4Department of Radiology, Harvard Medical School, Cambridge, MA, United States, 5Department of Radiology, Karolinska University Hospital, Stockholm, Sweden, 6Harvard Medical School, Cambridge, MA, United States, 7Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden


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Background: Cognitive impairment is common in multiple sclerosis (MS) and an important aspect of the disease. Understanding the progression and underlying mechanisms of cognitive dysfunction is important to be able to counteract cognitive decline. Objective: To describe the long-term progression and neuroanatomical correlates of cognitive dysfunction in MS. Methods: A cohort of 37 MS-patients, reflecting five decades of disease duration and all MS subtypes, was recruited at the Department of Neurology, Karolinska University Hospital, and followed neuropsychologically over 18 years: baseline, 9- and 18-year follow-up. A cognitive index was calculated using principal component analysis to reflect global cognitive function. During the last 9 years of the study (the two later time points), brain MRI was performed to analyze normalized volumetrics of three global tissue compartments (white matter and grey matter, lesions) and strategic regions (corpus callosum, thalamus, hippocampus). Age- and sex-matched controls were recruited for the last follow-up. The local ethical review board approved the study and informed consent was obtained from all participants. Results: Cognitive impairment developed linearly, accompanied by linear lesion accumulation and atrophy on a group level. Cognitive index partly correlated with Expanded Disability Status Scale (Spearman ρ -0.47, p < 0.001) and was mainly associated with the lesion fraction (standardized β -0.48, p < 0.001) and corpus callosal fraction (standardized β 0.39, p 0.002) in multiple linear regression analysis. Symbol Digit Modalities Test revealed the highest proportion of dysfunction (40%) while Rey-Osterrieth Complex Figure Test showed a more pronounced decline over the disease course. Conclusions: Cognitive impairment in MS develops linearly in a long-term perspective, associated with linear atrophy and lesion accumulation, suggesting that interventions could be beneficial at all disease stages. Wide-spread cognitive functions are more profoundly affected, associated with lesions and corpus callosal atrophy, supporting the idea of an underlying disconnection mechanism for cognitive decline in MS. Disclosure Professor Fredrikson has received honoraria for lectures or educational activities from Allergan, Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva. All other authors report no disclosures. Assistant professor Mainero has received research support from EMD Merck Serono and speaker fees from Biogen. This study was supported by grants provided by the Stockholm County Council (ALF project). P480 Late MS is not associated with increased β-amyloid deposition B. Zeydan1, V. Lowe2, C.G. Schwarz2, S.A. Przybelski3, T.G. Lesnick3, M.L. Senjem4, C.R. Jack Jr2, R.C. Petersen1, O.H. Kantarci1, K. Kantarci2 1Neurology, 2Radiology, 3Health Sciences Research, 4Information Technology, Mayo Clinic College of Medicine, Rochester, MN, United States Background: Cognitive difficulties in older adults are commonly associated with cortical atrophy and β-amyloid (Aβ) deposition. Cognitive difficulties observed in late MS could also be associated

with Aβ deposition. [11C]-Pittsburgh compound B (PiB) is a tracer that binds to fibrillar-Aβ with high affinity, helpful in quantifying cortical amyloid plaques. We studied the Aβ load measured by PiB-positron emission tomography (PET), cortical thickness, thalamic volume and cognitive function in patients with late MS compared to controls. Methods: From 4869 adult participants in the Mayo Clinic Study of Aging (MCSA) (a prospective population-based study of older adults) evaluated between 2004 & 2015, 24 patients were confirmed to have an MS diagnosis, concordant with the prevalence of MS in the same population. 16 patients underwent brain MRI and 12 underwent PiB-PET scanning. MS patients were age- and sex-matched 1:5 to clinically normal controls from the same cohort. All quantitative image analyses were performed using both automated and semi-automated image processing pipelines. Results: Mean age at imaging was 66.1±10.9 (controls) and 66.0±11.2 (MS); 42% were men. Patients with MS had lower cognitive z-scores for memory (p=0.03) and language domains (p=0.02) when compared to controls. Patients with MS when compared to controls also had greater thalamic (p=0.03) and cortical gray matter (frontal p=0.03; temporal p=0.006) atrophy after adjusting for white matter hyperintensity volume. However, we found no difference in global PiB-standardized uptake value ratios (SUVR) between patients with MS (SUVR=1.28) and controls (SUVR=1.35; p=0.49) adjusted for white matter hyperintensity volume. Conclusion: In late MS, despite the expected decrease in cognitive function, cortical as well as thalamic gray matter atrophy, we did not observe an increase in Aβ deposition. Disclosure B. Zeydan: Received support from the Turkish Neurological Society. V. Lowe: Consultant for Bayer Schering Pharma, Piramal Imaging Inc, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), the Elsie and Marvin Dekelboum Family Foundation, the Liston Family Foundation, and the MN Partnership for Biotechnology and Medical Genomics. CG. Schwarz: Nothing to disclose SA. Przybelski: Nothing to disclose TG. Lesnick: Nothing to disclose ML. Senjem: Equity/options ownership in medical companies: Gilead Sciences, Inc., Inovio Pharmaceuticals, Medtronic, and PAREXEL International Corporation. CR. Jack Jr: Serves as a consultant for Eli Lily and receives research support from the NIH. RC. Petersen: Serves on scientific advisory boards for Elan Pharmaceuticals, Wyeth Pharmaceuticals, and GE Healthcare and receives research support from the NIH. OH. Kantarci: Received support from the European Regional Developmental Fund - Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123); Gave and organized scientific presentations at meetings supported by Novartis Pharmaceuticals, but has received no personal compensation; Presented as an invited professor in Biogen Pharmaceuticals, but received no personal compensation. K. Kantarci: Serves on the Data Safety Monitoring Boards for Takeda Global Research & Development Center, Inc., Pfizer and Janssen Alzheimer Immunotherapy; she is funded by the NIH.


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Poster Session 1, 22(S3) P481 Quantitative susceptibility mapping and iron-related single nucleotide polymorphisms: an association with multiple sclerosis J. Hagemeier1, M. Ramanathan2, F. Schweser1,3, M.G. Dwyer1, F. Lin1, N. Bergsland1,4, B. Weinstock-Guttman5, R. Zivadinov1,3 1Buffalo Neuroimaging Analysis Center, Department of Neurology, University at Buffalo, 2Department of Pharmaceutical Sciences, State University of New York Buffalo, 3MRI Clinical Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 4IRCCS Don Gnocchi Foundation, Milan, Italy, 5Department of Neurology, University at Buffalo, Buffalo, NY, United States Background: The disturbance of brain iron levels among multiple sclerosis (MS) patients has been well documented in recent years. However, little is known about the association of MS related iron disturbance and genetic predisposition to iron overload. Important iron single nucleotide polymorphism (SNPs) include: rs1800562 (Cys282Tyr; hemochromatosis), rs1799945 (His63Asp; iron uptake dysregulation), and rs1049296 (transferrin C1/C2; iron transport disruption). Objective: Investigate the association of iron-related SNPs with a novel iron sensitive imaging technique in MS and healthy controls (HCs). Associations with clinical measures of MS disease progression was also assessed. Methods: The study included 261 relapsing remitting MS, 139 progressive MS, and 150 HCs. DNA was obtained from peripheral blood mononuclear cells. Participants underwent 3T MRI with quantitative susceptibility mapping (QSM) and genotyping for SNPs associated with iron regulating genes: rs1800562 (risk allele A), rs1799945 (risk allele G), and rs1049296 (risk allele T). Susceptibility was determined for the deep gray matter, with higher values representing increased iron content. Voxelwise associations with SNPs were investigated. Age adjusted regression analyses (α< .05) with main effects of disease, MS type, sex, SNPs and interaction effects between predictors were investigated. Results: There were more rs1049296 T allele carriers among MS patients than HCs (29.8% v. 17.8%, p=.014). rs1799945 was significantly associated with putamen susceptibility (beta=.190, p< .05), regardless of study group. MS rs1800562 A allele carriers had reduced putamen susceptibility (p< .05). Additional interaction effects were found between men and women: male rs1800562 A allele carriers had higher hippocampal susceptibility; and male rs1049296 T allele carriers had lower putamen susceptibility (p< .05). Voxelwise analysis confirmed the increased susceptibility in the putamen of MS rs1800562 carriers. EDSS was significantly associated with rs1800562 allele status (p=.027), but only among progressive MS patients. Discussion: The rs1800562 polymorphism, a SNP associated with hemochromatosis and iron regulation, appears to have MS-specific effects in its association with putamen iron concentration. Significant sex interactions highlight that iron-associated genes have diverging effects on brain susceptibility among men and women. Further research will have to corroborate these disease and sex effects.

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Disclosure Jesper Hagemeier: nothing to disclose Murali Ramanathan: received research funding from the National Multiple Sclerosis Society and the National Science Foundation. He receives royalty income from a self-published textbook. Ferdinand Schweser: nothing to disclose. Michael G Dwyer: received research grant support from Novartis and consultant fees from Claret Medical and EMD Serono. Fuchun Lin: nothing to disclose Niels Bergsland: nothing to disclose Bianca Weinstock-Guttman: received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Robert Zivadinov: received personal compensation from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Novartis, Claret Medical and Genzyme for speaking and consultant fees. Dr Zivadinov received financial support for research activities from Biogen Idec, Teva Pharmacuticals, EMD Serono, Novartis, Claret Medical and Genzyme. Dr Zivadinov serves on the editorial board of Journal of Alzheimer’s Disease, BMC Medicine, BMC Neurology, Veins and Lymphatics and Clinical CNS Drugs. He is Treasurer of the International Society for Neurovascular Disease. P482 Resting functional connectivity does not mirror task functional connectivity in multiple sclerosis A.A.S. Alahmadi1,2, C. Tur1, M. Pardini1,3, R.S. Samson1, P. Zeidman4, E. D’Angelo5,6, K. Friston4, A.T. Toosy1, C.A.M. Gandini Wheeler-Kingshott1,5,6 1NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom, 2Department of Diagnostic Radiology, Faculty of Applied Medical Science, KAU, Jeddah, Saudi Arabia, 3Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa, Italy, 4Wellcome Centre for Imaging Neuroscience, UCL, Institute of Neurology, London, United Kingdom, 5Brain Connectivity Centre, C. Mondino National Neurological Institute, 6Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy Background: Abnormal functional connectivity patterns have been observed in multiple sclerosis (MS) patients compared to healthy subjects (HS) using resting state fMRI (rsfMRI); in particular the sensorimotor network shows increased connectivity in MS. Here we explore how these resting functional abnormalities relate to task activations and task-based connectivity. Methods: 26 Right-handed (RH) subjects (10 HS: 5F; aged 31 (3.85) and 16 relapsing-remitting (RR) MS: 11F; aged 34 (3.23); median (range) EDSS =3.0 (1.5, 6.5)) were recruited. The 3T fMRI protocol consisted of: 1) A visuomotor event-related power-grip RH task and 2) rsfMRI. We investigated: Task related functional segregation (activations); Task related functional integration - effective connectivity (using Psychophysiological Interaction (PPI));


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Functional integration - functional connectivity at rest (using rsfMRI); Correlations of the aforementioned measures with clinical scores. The contralateral M1 was used as a seed in the PPI analysis. The resultant task connectivity PPI network was then used to investigate its rsfMRI connectivity. Group statistics were calculated (P< 0.05 FWE, corrected). Results: Task fMRI: Greater functional activation was seen in MS compared to HS, especially in the ipsilateral hemisphere, including sensorimotor, associative and sub-cortical areas. Positive correlations with clinical scores were observed (P< 0.001); Task Connectivity: PPI of M1 to the rest of the brain was preserved contralaterally in MS patients, compared to HS, but was completely lost in the ipsilateral hemisphere; rsfMRI: Conversely, higher rsfMRI connectivity was observed in the same regions that showed loss of task-based connectivity in MS; The most indicative positive correlations with clinical scores (P< 0.001) were found between increased rsfMRI functional connectivity and EDSS. On the other hand, contralateral task-based connectivity was decreased with increasing EDSS. Conclusion: Given the increased functional activations in MS, the reduced task-based connectivity, the increased rsfMRI connectivity and their relationship with clinical scores (EDSS), we question whether increased activations and rsfMRI connectivity in MS always reflect a compensatory mechanism or may actually herald a maladaptive process. We speculate that MS could be characterised by a frequency specific (task related) functional disconnection that could also represent reduced myelination mediating task related connectivity. Disclosure Adnan Alahmadi, Matteo Pardini, Rebecca Samson, Peter Zeidman, Egidio DÁngelo and Karl Friston have nothing to disclose. Carmen Tur has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Bayer-Schering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. Ahmed Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation, Bayer and meeting expenses from Biogen Idec. Claudia GWK is on the editorial board of Functional Neurology and receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. P483 FLAIR2 improves automatic lesion segmentation over FLAIR in MS patients M. Le, A. Rauscher, T. Brosch, Y. Yoo, L. Tang, M. Jarrett, A. Traboulsee, D.K.B. Li, R. Tam MS/MRI Research Group, University of British Columbia, Vancouver, BC, Canada Goal: This study is to assess the performance of FLAIR vs. FLAIR2 magnetic resonance (MR) images in their ability to identify lesions in multiple sclerosis (MS) patients using an autosegmentation technique.

Methods: MR images, including 2D FLAIR and 2D T2w, from a randomly selected group of 50 relapsing-remitting MS patients were included. FLAIR2 images were created by multiplying coregistered FLAIR and T2 images using fslmaths. Lesion volumes for FLAIR and FLAIR2 were obtained using LesionTOADs. Lesions identified by a neuro-radiologist were used as the Gold Standard (GS). Performance indices relative to the GS, including DICE coefficient (reflecting both lesion location accuracy and size accuracy), Sensitivity (SEN) (reflecting the ability to identify GS lesions), Relative Lesion Load Volume (VOL) (relative volume difference to GS), and Symmetric Surface Distance (SSD) (distance between the GS lesions and auto-segmented lesions), were calculated for FLAIR and FLAIR2. Mean (meandiff) and corresponding 95% confidence interval (CI) were obtained for (FLAIR2 - FLAIR) differences. The Wilcoxson signed-rank test was used to statistically assess the differences. Relative improvement score (meandiff/meanFLAIR) for each index was calculated. Results: Lesion loads could not be obtained for 3 out of the 50 patients due to running errors by LesionTOADs; these were excluded in subsequent calculations. Characteristics of the Gold Standard lesion volumes include mean=11,150 voxels, median=8,149 voxels, range: 139-48,706 voxels. SDD for one patient was undefined since no volume was identified by FLAIR. Overall, FLAIR2 had statistically significant and higher scores than FLAIR in all 4 indices; DICE: meandiff = 0.050 (95%CI: 0.013-0.087; p value = 0.022) with a relative improvement of 14%; SEN: meandiff = 0.069 (95%CI: 0.040-0.098; p value < 0.001) with a relative improvement of 25%; VOL meandiff = -0.202 (95%CI: -0.352 - -0.049; p value < 0.001) with a relative improvement of 31%; SSD: meandiff = -3.43mm (95%CI: -6.66mm - -0.20mm; p value = 0.018) with a relative improvement of 23%. Conclusion: FLAIR2 outperforms FLAIR in its ability to provide lesion segmentation accuracy in MS patients. FLAIR2 can be easily calculated when T2 and FLAIR are available. FLAIR2 is a very simple way to increase overall segmentation performance with little additional effort when using LesionTOADs. Disclosure Megan Le: nothing to disclose Alexander Rauscher: nothing to disclose Tom Brosch: nothing to disclose Youngjin Yoo: nothing to disclose Lisa Tang: nothing to disclose Mike Jarrett: nothing to disclose Anthony Traboulsee has received personal compensation (honorarium) consulting for Genzyme, Roche, Teva, and Biogen and research support (PI on clinical trials) from Genzyme, Roche, Chugai, and Biogen David Li has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada. He is the Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Novartis, Perceptives, Roche and Sanofi-Aventis. The UBC MS/MRI Research Group has also received grant support for investigator-initiated independent studies from Genzyme, Merck-Serono, Novartis and Roche. He has acted as a consultant to Vertex Pharmaceuticals and served on the Data and Safety Advisory Board for Opexa Therapeutics and Scientific Advisory Boards for Adelphi Group, Novartis and


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Poster Session 1, 22(S3) Roche. He has also given lectures which have been supported by non-restricted education grants from Novartis and Biogen. Roger Tam: nothing to disclose P484 Impaired retinal microcirculation related to ganglion cell layer thickness in multiple sclerosis H. Jiang1,2, Y. Yang1,3, S. Delgado2, J. Wang1 1Bascom Palmer Eye Institute, 2Department of Neurology, University of Miami, Miami, FL, United States, 3School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, China Objective: The impaired retinal microcirculation in patients with relapsing and remitting multiple sclerosis (RRMS) was reported (Jiang et al. MSJ 2006). The thinning of the combination of ganglion cell layer and inner plexiform layer (GCIP) is regarded as a biomarker of neurodegeneration. The goal was to determine the relationship between retinal blood flow velocity and GCIP thickness in RRMS. Methods: Twenty nine eyes of 29 RRMS patients (7 males and 22 females, age 37.4 ± 11.4 years) were imaged using retinal function imager (RFI, Optical Imaging Ltd) to measure the retinal blood flow velocities in arterioles and venules. None of the eyes had a history of optic neuritis. GCIP was imaged using Zeiss Cirrus optical coherence tomography. The relationships among vascular measurements, GCIP thickness, and clinical manifestations were analyzed. Results: The GCL thickness was 76.6 ± 8.4 µm. The blood flow velocities of retinal arterioles (3.66 ± 0.82 mm/s) and venules (2.81 ± 0.64 mm/s) were significantly lower in MS patients compared to age- and gender-matched normal controls (arteriole: 4.16 ± 0.78 mm/s; venule: 3.19 ± 0.57 mm/s, paired t-test: P = 0.02). The velocity in arterioles was significantly related to GCIP thickness (r = 0.40, P < 0.05), but not with EDSS or disease duration (r ranged from -0.03 to 0.20, P > 0.05). Conclusion: This is the first study to establish the relationship between impaired microcirculation and GCIP, indicating that impaired microcirculation may have a role in retinal neurodegeneration in MS. A longitudinal study may determine that the altered microcirculation is a primary vasculopathy or the consequence of neurodegeneration in MS. Disclosure Dr. Jianhua Wang is a member of scientific advisory board of Optical Imaging Ltd. All other authors have no proprietary interest in any materials or methods. P485 Retinal nerve fiber layer birefringence alteration in multiple sclerosis J. Wang1, W. Chen2, S. Delgado3, C. Liu1, H. Jiang1,3 1Bascom Palmer Eye Institue, University of Miami, Miami, FL, United States, 2Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China, 3Department of Neurology, University of Miami, Miami, FL, United States Introduction: Retinal nerve fiber layer (RNFL) thinning is established as an ocular biomarker of neurodegeneration in multiple

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sclerosis (MS). RNFL is also known to exhibit tissue birefringence alteration, which is often associated with disease onset and progression. Polarization sensitive optical coherence tomography (PS-OCT) can assess the depth-resolved polarization properties of RNFL that represent tissue microstructural integrity. The goal was to determine RNFL birefringence in patients with MS using PS-OCT. Methods: A custom built PS-OCT was used to measure the birefringence of peripapillary RNFL in one eye of each subject. To test the reproducibility of our PS-OCT system, 11 healthy volunteers were repeatedly measured in one eye. 26 RRMS patients (averaged age 40.4 ± 11.7 yrs old, 18 females and 8 males) without history of optic neuritis were also imaged in one eye. In addition, 26 eyes from 26 age- (± 5 yrs) and gender-matched healthy controls were imaged. The peripapillary RNFL thickness of MS patients was measured using Zeiss Cirrus OCT. Results: The coefficient of repeatability for the birefringence of the peripapillary RNFL was 13.0%. The birefringence in MS eyes was 0.05 ± 0.03 o/µm, which was significantly lower than that obtained in normal controls (0.08 ± 0.03 o/µm, P = 0.001). In comparison to that of the controls, the birefringence alteration in MS was mainly located at the temporal and superior quadrants (P < 0.01). The birefringence in MS was not correlated to EDSS, disease duration, or RNFL thickness (r ranged from -0.13 to 0.26, P > 0.05). The RNFL thickness was 94.7 ± 7.4 µm. Conclusion: This is the first study using PS-OCT to study the RNFL birefringence in MS patients. It appeared that the alteration of RNFL birefringence occurs prior to the thinning of RNFL. PS-OCT is a useful tool in studying MS pathophysiology. Disclosure nothing to disclose P486 The neural basis of fatigue in Multiple Sclerosis: a multimodal MRI approach S. Batista1,2, A.M. Novo1, C. Alves3, O.C. d’Almeida3,4,5, I.B. Marques6, C. Macário1, L. Sousa1,2, M. Castelo-Branco3,4,5, I. Santana1,2,5, L. Cunha1,2 1Neurology, Centro Hospitalar e Universitário de Coimbra, 2Faculty of Medicine, University of Coimbra, 3Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, 4Visual Neuroscience Laboratory, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 5Centre for Neuroscience and Cell Biology (CNC).IBILI, University of Coimbra, Coimbra, 6Neurology, Hospital da Luz, Lisboa, Portugal Introduction: Fatigue affects between 50% and 80% of patients with multiple sclerosis (MS). Despite its clinical significance, the pathophysiology of fatigue is still not completely understood. Objectives: To explore the underlying neural basis of fatigue in patients with MS. Methods: We enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, gender, and education. Fatigue was assessed using the Portuguese version of Modified Fatigue Impact Scale (MFIS). All participants underwent 3Tesla brain MRI including conventional and diffusion tensor imaging (DTI) sequences. White matter (WM) focal lesions were identified and


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T1 and T2 lesion volume were computed. Tract-based spatial statistics (TBSS) were applied for voxel-wise analysis of DTI metrics fractional anisotropy (FA) and mean diffusivity (MD) on normal-appearing WM (NAWM). Using Freesurfer software, total and regional volumes of cortical and subcortical gray matter (GM) were calculated. Results: Compared to HC, patients with MS scored significantly higher on MFIS (33.8±19.7 vs. 16.5±15.1, p< 0.001). Patients with MS presented a multifocal pattern of GM atrophy and an extensive NAWM damage. The total T1 lesion and the T2 lesion volumes were 12.9±5.3 ml and 16.8±15.8 ml, respectively. MFIS scores were not significantly correlated with T1/T2 lesion volumes, total GM volume, or with any regional volume of cortical and subcortical GM. Regarding TBSS analysis, significant correlations (p< 0.05 corrected for multiple testing by family-wise error rates) were found between global scores of MFIS and DTIderived measures (FA decrease and/or MD increase) of the NAWM skeleton, including: corona radiata, internal capsule, external capsule, corticospinal tract, cingulum, corpus callosum, fornix, superior longitudinal fasciculus, superior fronto-occipital fasciculus, sagittal stratum, posterior thalamic radiation, cerebral peduncle and uncinate fasciculus. Conclusions: Fatigue was associated with a widespread NAWM damage but not with lesion load or GM atrophy. This finding supports the theory that functional disconnection, caused by diffuse microstructural WM damage, might be the main neural basis of fatigue in MS. Disclosure This research was supported by a grant from Biogen. The sponsor did not participate in any aspect of the design or performance of the study, including the data collection, management, analysis, and interpretation or preparation of the work. S. Batista has received honoraria for serving on scientific advisory boards of Biogen and Novartis Pharma, and for speaking in scientific meetings of Teva, Merck Serono, Biogen, and Novartis Pharma. C. Macário and L. Sousa have received honoraria for serving on scientific advisory boards or speaking in scientific meetings of Teva, Merck Serono, Bayer, Genzyme, Biogen, and Novartis Pharma. AM Novo, C. Alves, O. C. d’Almeida, II.B. Marques, M. CasteloBranco, I. Santana and L. Cunha have nothing to disclose. P487 PREVAIL: predicting pecovery through estimation and visualization of active and incident lesions J.D. Dworkin1, E.M. Sweeney2, M.K. Schindler3, S. Chahin4, D.S. Reich3, R.T. Shinohara1 1Department of Biostatistics and Epidemiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 2Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, 3Translational Neuroradiology Unit, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disease and Stroke, National Institute of Health, Bethesda, MD, 4Multiple Sclerosis Division of the Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States

Objective: The goal of this study was to develop a model that integrates imaging and clinical information observed at lesion incidence for predicting the recovery of white matter lesions in multiple sclerosis (MS) patients. Methods: Demographic, clinical, and magnetic resonance imaging (MRI) data were obtained from 32 subjects with MS participating in research studies at the National Institutes of Health. A total of 401 lesions met the inclusion criteria and were used in the study. Imaging features were extracted from intensity-normalized T1-weighted (T1w) and T2-weighted as well as magnetization transfer ratio (MTR) sequences acquired at lesion incidence. T1w and MTR signatures were also extracted from images acquired 1-year post-incidence. Imaging features were integrated with clinical and demographic data observed at lesion incidence to create statistical prediction models for long-term damage in each lesion. Validation: The performance of the T1w and MTR predictions was assessed in two ways: first, the predictive accuracy was measured quantitatively using leave-one-lesion-out cross-validated (CV) mean-squared predictive error. Then, to assess the prediction performance from the perspective of a clinical expert, three board-certified MS clinicians were asked to individually score how similar the CV model-predicted 1-year appearance was to the true 1-year appearance for a random sample of 100 lesions. Results: The cross-validated root-mean-square predictive error was 0.95 standard-deviation units for normalized T1w and 0.064 for MTR, compared to the estimated measurement errors of 0.48 and 0.078 respectively. The three expert raters agreed that T1w and MTR predictions closely resembled the true 1-year follow-up appearance of the lesions in both degree and pattern of recovery within lesions. Conclusion: This study demonstrates that using only information from a single visit at incidence, an accurate prediction of how a new lesion will recover can be obtained using relatively simple statistical techniques. The potential to visualize the likely course of recovery has implications for clinical decision-making, as well as trial enrichment. Disclosure Jordan D. Dworkin: nothing to disclose Elizabeth M. Sweeney: nothing to disclose Matthew K. Schindler: nothing to disclose Salim Chahin: nothing to disclose Daniel S. Reich: nothing to disclose Russell T. Shinohara: nothing to disclose P488 Thalamic magnetic resonance spectroscopy in highly active multiple sclerosis L. Peress, I. Ribeiro Violante, G. Scott, K. Zimmerman, D. Sharp, R. Nicholas, J. Raffel Imperial College London, London, United Kingdom Background: Magnetic resonance spectroscopy (MRS) is a noninvasive imaging technique used to measure changes in the concentration of metabolites in a specific, predefined area of the brain that might appear otherwise normal using conventional MRI. The thalamus is a deep grey matter structure in the brain, and is highly connected with both white matter tracts and cortical grey matter. We postulate that thalamic MRS may be a biomarker of global


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Poster Session 1, 22(S3) pathology in the MS central nervous system, and may be responsive to changes in metabolite levels after treatment with disease modifying therapy. Objective: To compare the concentration of metabolites in the thalamus of patients with highly active MS and healthy controls using MRS and to quantify the changes in metabolite concentration after natalizumab treatment. Methods: Thalamic MRS was performed on 17 patients with highly active MS, all of whom were scheduled to initiate natalizumab treatment, and 12 age-matched healthy controls. Thalamic MRS was repeated after 3 months and 13 months of natalizumab treatment, and clinical data collected. Results: Concentration of glutamate (Glu), a marker of glutamatergic neurotransmission and glutamatergic metabolic functions, was lower in the thalami of MS patients compared to healthy controls (p< 0.05), and was strongly negatively correlated with total lesion volume (r=-0.80, p< 0.01). After 3 months and 13 months of natalizumab treatment concentration of glutamate did not change, but concentration of creatine-phosphocreatine (Cr-PCr), a marker of metabolic activity, decreased significantly (p< 0.05). Correlations between changes in metabolites and clinical response to treatment will be reported. Conclusions: MRS of thalamic glutamate may be a good surrogate for global MS pathology which is not influenced by current disease modifying therapy. Thalamic creatine-phosphocreatine may respond to metabolic changes caused by treatment effects. Further research is warranted to investigate whether thalamic MRS can predict long-term prognosis, and long-term response to disease modifying treatment in MS. Disclosure Luisa Peress: nothing to disclose. Ines Ribeiro Violante: nothing to disclose. Gregory Scott: nothing to disclose. Karl Zimmerman: nothing to disclose. David Sharp: nothing to disclose. Richard Nicholas: Bayer, Biogen, Genzyme, Merck Serono, Roche - honorarium for speaking, advisory boards. Biogen, Genzyme, Novartis - funds for organising education, staff. Biogen, Novartis Principal investigator. Joel Raffel: nothing to disclose. P489 T2* at 3T detects a higher proportion of white matter lesions with central veins compared to FLAIR-SWI in patients with MS A.P.R. Samaraweera1, O. Mougin2, M. Clarke1, R.A. Dineen3, P.S. Morgan4, N. Evangelou1 1Clinical Neurology, Division of Clinical Neuroscience, 2School of Physics and Astronomy, Sir Peter Mansfield Imaging Centre, 3Division of Radiological and Imaging Sciences, University of Nottingham, 4Department of Medical Physics, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Background: White matter lesion (WML) central veins seen on MRI maybe a specific imaging biomarker for multiple sclerosis (MS). T2*-weighted sequences best delineate WML central veins, but susceptibility weighted imaging (SWI) is commonly used in clinical practice to investigate other diseases. Comparisons of

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each sequence are lacking which would help future clinical adoption, especially for smaller hospitals. In clinical practice a proportion of WMLs with central veins could be used for the diagnosis of MS. Objectives: To determine if the proportion of WMLs with central veins is different when using T2* compared to a fusion of fluid attenuated inversion recovery (FLAIR) and SWI (FLAIR-SWI) at 3T. Method: 20 patients with RRMS were scanned on a 3T Philips Achieva MR scanner. T2* with a high EPI factor and FLAIR imaging were acquired for each patient. SWI was produced by combination of a phase mask and magnitude image. FLAIR-SWI was produced by fusion of FLAIR and SWI. Total WML numbers, WML central vein numbers and the proportion of WMLs with central veins were counted using T2* and FLAIR-SWI by one rater. A one way repeated analysis of variance (ANOVA) and Friedman’s test were used to determine any significant differences between T2* and FLAIR-SWI. Results: One rater analysed all scans. T2* median WML numbers= 33.5, interquartile range (IQR) (20.3 - 54.8), FLAIR-SWI= 47 (IQR 30 - 70.8). Pairwise comparison p=0.168. T2* median WML central vein numbers= 23 (IQR 9.25-44.5), FLAIR-SWI= 22 (IQR 11.25-36). Pairwise comparison p=1.0. T2* mean proportion of WMLs with central veins 66.9% ± 19.2% (2 standard deviations, SD), FLAIR-SWI 43.4% ± 15.9%. Mean difference in proportions between T2* and FLAIR-SWI= 23.4% (95% CI 12.9 - 34%), p< 0.0005. Conclusions: T2* allowed a greater proportion of WMLs with central veins to be identified than FLAIR-SWI. This difference could be due to the lack of contrast agent or the fusion of SWI with FLAIR which may not produce ideal central vein visibility compared to the already known FLAIR* imaging. For future clinical adoption T2* maybe suitable for hospitals without the expertise to produce FLAIR-SWI. Disclosure AP Samaraweera: nothing to disclose, O Mougin: nothing to disclose, M Clarke: nothing to disclose, RA Dineen: nothing to disclose, PS Morgan: nothing to disclose, N Evangelou: nothing to disclose. P490 Impact of 3 Tesla MRI on diagnosis in clinically isolated syndrome: a MAGNIMS multicentre study M.H.J. Hagens1, J. Burggraaff1, I.D. Kilsdonk2, S. Ruggieri3,4, S. Collorone3,5, R. Cortese5,6, N. Cawley5, E. Sbardella3, M. Andelova7, M. Amann7,8,9, J.M. Lieb9, P. Pantano3, B.I. Witte10, J. Killestein1, C. Oreja-Guevara11, J. Wuerfel8, O. Ciccarelli5, C. Gasperini3, C. Lukas12, A. Rovira13, M.P. Wattjes2, F. Barkhof2 1Neurology, MS Center Amsterdam, 2Radiology and Nuclear Medicine, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, 3Neurology and Psychiatry, Sapienza University of Rome, 4Neurosciences, San Camillo-Forlanini Hospital, Rome, Italy, 5NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of


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Neurology, London, United Kingdom, 6Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy, 7Neurology, University Hospital Basel, 8Medical Image Analysis Centre (MIAC), 9Radiology, Division of Neuroradiology, University of Basel, Basel, Switzerland, 10Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands, 11Neurology, Hospital Clínico San Carlos, Madrid, Spain, 12Diagnostic and Interventional Radiology and Nuclear Medicine, St. Josef Hospital, Ruhr University, Bochum, Germany, 13Radiology, Hospital Universitari Vall d’Hebron, Barcelona, Spain Introduction: High field strength 3 Tesla (T) MRI improves image resolution and signal-to-noise ratio, but its clinical relevance in clinically isolated syndrome (CIS) remains uncertain. We studied whether 3T MRI improves lesion detection in CIS patients in a multicentre setting, and whether this leads to an earlier MS diagnosis and improved inter-rater agreement. Methods: We selected 30 patients and 10 controls from our prospective cohort of 67 CIS patients and 27 healthy controls from 6 different European centres. All subjects received baseline 1.5T and 3T brain and spinal cord scan at baseline; patients also followup brain MRI after 3 to 6 months. Four experienced neuroradiologists and four less-experienced raters (PhD-students or radiology residents) scored the number of lesions by anatomical region (juxtacortical, periventricular, infratenorial, spinal cord) and subsequently determined dissemination in space and time (DIS and DIT) and diagnosis of MS according to McDonald 2010 criteria. Differences in lesion load between 1.5T and 3T scans were determined using generalized estimating equations. Kappa scores were calculated to assess inter-rater agreement. Results: In healthy controls we saw a significant increase in overall number of lesions (mean per rater per subject, 3T vs 1.5T: 0.38 vs 0.05 lesions, p=0.005). However, in the MS group there was no significant difference between field strengths in overall number of lesions (4.40 vs 4.18, p=0.657) or by region. At baseline there was no significant difference in number of cases with DIS, DIT or diagnosis of MS. At follow-up, the number of cases with DIT tended to be higher at 3T (mean per rater: 9.75 vs 8.13, p=0.067), with a significantly more frequent diagnosis of MS (6.38 vs 4.63, p=0.032).Inter-rater agreement for DIS, DIT and diagnosis of MS at baseline was reasonable to good, varying from 0.51 to 0.83. At follow-up, 3T slightly improved the interrater agreement for the experienced raters (DIS 0.51 to 0.55; DIT 0.77 to 0.81; MS 0.61 to 0.75), while the agreement between less-experienced raters slightly decreased (DIS 0.64 to 0.59; DIT 0.65 to 0.63; MS 0.73 to 0.67). Conclusion: High field MRI had a modest effect on lesion detection in both controls and CIS patients, leading to an increased frequency of diagnosis of MS at follow-up. Experienced readers seemed to benefit more from 3T imaging than less experienced ones, underlining the need for additional training in reading higher field strength images. Disclosure Marloes Hagens has nothing to disclose. Jessica Burggraaff has nothing to disclose. Iris Kilsdonk had nothing to disclose. Serena Ruggieri has nothing to disclose. Sara Collorone received meeting compensations from Novartis.

Rosa Cortese has nothing to disclose. Niamh Cawley has nothing to disclose. Emilia Sbardella has nothing to disclose. Michaele Andelova has nothing to disclose. Michael Amann has nothing to disclose. Johanna Lieb has nothing to disclose. Patrizia Pantano has received founding for travel from Novartis, Genzyme and Bracco and speaker honoraria from Biogen. Birgit Witte has nothing to disclose. Joep Killestein has accepted speaker and consultancy fees from Merck-Serono, Teva, Biogen, Genzyme, Roche and Novartis. Celia Oreja-Guevara received honoraria as speaker from BiogenIdec, Bayer-Schering, Merck-Serono, Teva, Genzyme and Novartis. Jens Wuerfel received research grants from Novartis and Biogen, speaker honoraria from Bayer, Novartis, Teva, and Biogen, and he served for advisory boards for Novartis and Biogen. Olga Cicarelli is an Associate Editor of Neurology, and she serves as consultant for Novartis, Roche, Genzyme, and Teva and payments are made to the institution. Claudio Gasperini received fees as speaker for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen, Teva, Novartis and Merck Serono, and received a grant for research by Teva. Carsten Lukas holds an endowed professorship supported by the Novartis foundation, has received consulting and speaker’s honoraria from BiogenIdec, Bayer Schering, Novartis, Sanofi, Genzyme and TEVA, and has received research scientific grant support from MerckSerono. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, Stendhal, Novartis and Biogen Idec, and has research agreements with Siemens AG. Mike Wattjes serves on the editorial boards of Neuroradiology, Journal of Neuroimaging, European Radiology, Frontiers of Neurology, and serves as a consultant for Roche, Novartis and Biogen. Frederik Barkhof serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen, Teva, Novartis, Roche, Synthon BV and Jansen Research. P491 Apparent fiber density: A novel method to detect axonal degeneration in patients with MS S. Gajamange1, D. Raffelt2, T. Dhollander2, A. Shelton3, O. White4, T. Kilpatrick1,2, A. Connelly2,5, J. Fielding3,6, S. Kolbe1 1Department of Anatomy and Neuroscience, University of Melbourne, 2The Florey Institute of Neuroscience and Mental Health, 3School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, 4Department of Radiology, Royal Melbourne Hospital, 5The Florey Department of Neuroscience and Mental Health, 6Department of Medicine, University of Melbourne, Melbourne, VIC, Australia Background: Axonal degeneration is a key pathological driver of disability in MS. Diffusion-weighted MRI can non-invasively


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Poster Session 1, 22(S3) detect microstructural changes in white matter that are associated with axonal loss. A novel diffusion-weighted MRI measure, “apparent fiber density” (AFD) can be obtained from the fiber orientation distributions (FODs) computed by spherical deconvolution techniques. Using this approach it is possible to estimate differences in both Fiber Density (FD) and Fiber Cross-section (FC), for each fiber element (termed ‘fixel’) in each voxel (Raffelt et al. 2012). Objective: We sought to determine whether FD and/or FC differences exist specifically in the visual pathways in patients with a history of acute optic neuritis compared to healthy controls. Methods: Diffusion-weighted scans were acquired for 17 patients with historical optic neuritis (disease duration: 4.48 ± 0.61 years) and 14 healthy controls with the following parameters: TR/TE=7800/112ms; voxel size=2.5x2.5x2.5mm3, b=3000s/ mm2, 7 non-diffusion and 60 diffusion encoded scans. For fixelspecific measures, a population-average FOD template was generated from subject specific FOD images obtained by a novel method that accounts for non-white matter tissues (Dhollander et al. 2016). Each subject’s FOD image was then registered to the template, allowing for whole-brain fixel-based comparison between patients and controls. The statistical analysis was performed using connectivity fixel enhancement (5000 permutations) to identify regions of reduced FD and FC (Raffelt et al. 2015). All results were family wise error (FWER) corrected for multiple comparisons. Results: Optic neuritis patients showed significantly lower FD bilaterally in the inferior fronto-occipital fasciculus compared with heathy controls (FWER corrected p< 0.05). A significant FC difference was not detected. Conclusion: AFD is sensitive to trans-synaptic axonal degeneration in the visual pathways of patients with historical optic neuritis. Fixel-specific markers of axonal degeneration could be used as markers in early therapeutic trials or to monitor disease progression. References Raffelt, D., et al, NeuroImage, (2012). 59(4): p. 3976-3994 Raffelt, D., et al, Neuroimage, (2015). 117: p. 40-55 Dhollander, T., Connelly, A., Proc. ISMRM (2016). 24: p. 3010 Disclosure Sanuji Gajamange: nothing to disclose David Raffelt: nothing to disclose Thijs Dhollander: nothing to disclose Annie Shelton: nothing to disclose Owen White: receives research support from Novartis and Biogen Idec Trevor Kilpatrick: nothing to disclose Alan Connelly: nothing to disclose Joanne Fielding: receives research support from Novartis and Biogen Idec Scott Kolbe: receives honoraria from Novartis P492 Quantitative susceptibility mapping of multiple sclerosis lesions in a longitudinal cohort using magnetic resonance imaging

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K. Subramanian1, D. Utriainen1, D.P. Ramasamy2, J. Beaver3, S. Sethi1, F. Schweser2, M. Fawaz1, J. Hagemeier2, R. Rajagovindan3, R. Zivadinov2, E.M. Haacke1 1Magnetic Resonance Innovations Inc., Detroit, MI, 2The Buffalo Neuroimaging Analysis Center, Buffalo, NY, 3AbbVie, North Chicago, IL, United States Background: Increased paramagnetic susceptibility in Multiple Sclerosis (MS) lesions occurs in roughly one-third of MS lesions. This is believed to be due to one or more of the following factors: increased iron content in macrophages, reduction in diamagnetism due to loss of myelin, presence of blood products and changes in perfusion. This work aims to quantitatively assess changes in susceptibility in lesions over time using quantitative susceptibility mapping (QSM). Methods: The study included 50 MS patients (40 RRMS, 8 SPMS, 2 PPMS: 19 male, 31 female) aged 45.8+/-11 years. Patients were imaged at baseline and 2 years later with susceptibility weighted imaging (SWI) and conventional MRI at 3T. Disease duration was 12.8+/-9 years and Expanded Disability Status Scale (EDSS) was 3.0+/-2 for baseline and 3.1+/-2 for follow-up. Iron-laden lesions were identified in the QSM images and then compared to T1WI and T2 FLAIR. Iron lesions were classified as: (1) stable between scans, (2) absent from baseline and present in follow-up, (3) present in baseline but shrinking in follow-up, (4) present in baseline but absent in follow-up, or (5) growing between baseline and follow-up. Count, volume and susceptibility of the lesions were estimated and its association with EDSS was assessed. Results: Iron-laden lesions were present in 31 subjects (62%) with a total of 107 QSM lesions. The susceptibilities at baseline and follow up for the different categories of lesions were: (1) 82 lesions with 48.6+/-18.2ppb and 43.9+/-21ppb; (2) 4 lesions with 21.1+/-3.2ppb and 45+/-16.2ppb; (3) 9 lesions with 46.6+/20.8ppb and 27.9+/-13.6ppb; (4) 9 lesions with 32.1+/-15.1ppb and 10.5+/-9.4ppb; (5) 1 lesion with 59.4ppb and 57.5ppb. In 2 QSM lesions no corresponding signal was seen in T1 or T2 FLAIR, their susceptibilities were 19.9+/-9.3ppb and 10.2+/4.7ppb respectively. EDSS was not associated with the presence or change in QSM detected lesion (p>0.05). Conclusions: SWI and QSM both provide a means to visualize iron-laden lesions and quantitatively assess susceptibility changes longitudinally. Many of the lesions had susceptibilities comparable to gray matter (~50ppb) suggesting local demyelination. Not all QSM lesions were associated with signal changes on T1 or FLAIR images and thus susceptibility changes may potentially represent a more sensitive index of the underlying pathophysiological process that warrants further investigation. Disclosure Karthikeyan Subramanian: Full time employee of MR Innovations Inc. David Utriainen: Full time employee of MR Innovations Inc. Deepa P Ramasamy: Nothing to disclose. John Beaver: Full time employee of AbbVie. This research was sponsored by AbbVie. Participated in the design, interpretation of data, preparation, and approval of the publication.


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Sean Sethi: Full time employee of MR Innovations Inc. Ferdinand Schweser: Nothing to disclose Miller Fawaz: Full time employee of MR Innovations Inc. Jesper Hagemeier: Nothing to disclose. Rajasimhan Rajagovindan: Full time employee of AbbVie. This research was sponsored by AbbVie. Participated in the design, interpretation of data, preparation, and approval of the publication. Robert Zivadinov: Received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Ewart Mark Haacke: President of MR Innovations, research support was provided by AbbVie. P493 Outer and inner cortical MTR abnormalities in clinically isolated syndromes R.S. Samson1, W.J. Brownlee1, M.J. Cardoso2,3, J.W.L. Brown1,4, M. Pardini1,5, F. Prados Carracos1,2, S. Ourselin2,3, C.A.M. Gandini Wheeler-Kingshott1,6,7, D.H. Miller1,8, D.T. Chard1,8 1NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, 2Centre for Medical Image Computing, UCL Department of Computer Sciences, 3Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, 4Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, 5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 6Brain MRI 3T Center, C. Mondino National Neurological Institute, 7Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy, 8National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, United Kingdom Background: Substantial pathology occurs in cortical grey matter (CGM) in MS, with lesions and neuroaxonal loss occurring preferentially in outer (subpial) CGM. In relapse-onset MS, cortical magnetization transfer ratio (cMTR) is abnormal, and more so in the outer compared with deeper cortical layers. It is not known whether a similar gradient in cMTR changes occurs soon after the first symptoms of MS, or is only a feature of more long-standing MS. Objective: To investigate inner and outer cMTR changes in people soon after a clinically isolated syndrome (CIS) suggestive of MS, and compare cMTR abnormalities in those who remained CIS and those who developed MS within 15 years. Methods: Seventy-two people with optic neuritis (ON) underwent MRI scanning within 6 months of onset (mean age 33.4 years, 51 F) and were followed up 15 years later. Thirty-six healthy controls (HC; mean age 34.0, 24 F) were also scanned. Using a 1.5T GE Signa scanner, proton-density/T2-weighted, T1-weighted images, and MTR data were acquired. Segmentation of lesion filled T1-weighted images was performed using the Geodesical Informational Flows algorithm, and the cortex was subdivided into inner and outer bands by calculating the midharmonic location using the Laplace equation-based cortical

thickness framework. Inner and outer cortical bands were coregistered to MTR data using NiftyReg, and a 90% threshold was applied to CGM probability maps to limit potential partial volume effects. Between-group differences were examined using SPSS with one-way ANCOVA tests, adjusted for age, gender and brain parenchymal fraction. Results: The ON group had significantly lower outer and inner cMTR compared with HC, and the outer-to-inner cMTR ratio was also significantly lower in ON (all p< 0.001). In the ON group, compared with HC, inner and outer cMTR were lower both in those who developed clinically definite MS after 15 years (n=56, p< 0.001) and in those that remained CIS (n=16, p< 0.05). Compared with HC, the cMTR ratio was also significantly lower in MS (p< 0.001) but not the CIS group. The outer cMTR and cMTR ratio were both reduced in MS compared to the CIS group (p< 0.05). Conclusions: Gradients in cMTR abnormalities - with greater disease effects towards the surface of the brain - are seen soon after a clinically isolated ON, and appear to be related to the subsequent risk of developing MS. This suggests that outer cortex abnormalities are already present early in the course of MS. Disclosure Rebecca Samson receives grant support from the MS Society of the UK. Wallace Brownlee: Nothing to disclose. Manuel Cardoso: Nothing to disclose. J.William Brown is funded through a Next Generation Fellowship funded by the Grant Charity of the Freemason’s and has received meeting expenses from Novartis, Biogen Idec and Genzyme. Matteo Pardini is supported by the non-profit Karol Wojtila Association (Lavagna, Italy) and has received research support from Novartis. Ferran Prados Carracos: Nothing to disclose. Sebastian Ourselin: Nothing to disclose. Claudia Gandini Wheeler-Kingshott s on the editorial board of Functional Neurology and receives research grants (PI and coapplicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. David Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe & Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. Declan Chard has received honoraria (paid to his employer) from Ismar Healthcare NV, Swiss MS Society, Excemed (previously Serono Symposia International Foundation), Merck, Bayer and Teva for faculty-led education work; Teva for advisory board work; meeting expenses from Merck, Teva, Novartis, the MS Trust and National MS Society; and has previously held stock in GlaxoSmithKline. P494 Reproducible quantitative cervical spinal cord MRI for progressive MS


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Poster Session 1, 22(S3) J.-W. Kim1, M. Inglese1, C. Dula2, S. Lancia2, C. Alfonso1, P. Sun2, S.-K. Song2, R.T. Naismith2, J. Xu1 1Icahn School of Medicine at Mount Sinai, New York, NY, 2Washington University, St. Louis, MO, United States

Junqian Xu was supported by Radiological Society of North America (RSNA) research scholar grant RSCH1328 and International Progressive Multiple Sclerosis Alliance (IPMSA) infrastructure award PA0097

Purpose: Accurate and reliable imaging biomarkers of axonal degeneration and demyelination are crucial to develop therapies for multiple sclerosis (MS) through clinical trials. Feasibility of multicentre clinical studies must be a key component of imaging development so that enough progressive MS patients may be recruited for the required statistical power. Recent developments in quantitative cervical spinal cord (CSC) magnetic resonance imaging (MRI) offers encouraging imaging biomarkers to inform decision making in clinical trials of progressive MS patients. In this two-site pilot study, we assessed both intra- and inter-site reproducibility of MRI measurements of CSC area and microstructural integrity at 3 tesla (3T). Methods: Three healthy volunteers and three progressive MS patients were recruited at each of the two sites. Intra-site short (n=12) and long (n=6) term, as well as inter-site short (effective n=9) and long (n=3) term, reproducibility was evaluated by repeated scans including traveling subjects. The quantitative CSC MRI protocol, harmonized between sites (Siemens scanners), included structural imaging (0.9 mm isotropic T2-weighted (T2w) and 0.8 mm × 0.8 mm × 3 mm phase sensitive inversion recovery (PSIR)), axial 0.9 mm × 0.9 mm × 5 mm cardiac gated diffusion MRI (dMRI) and 0.75 mm × 0.75 mm × 5 mm magnetic transfer (MT) imaging. The dMRI protocol incorporated the latest multiband sequence and image reconstruction development with extensive piloting. The MT on and off images were co-registered before calculating MT ratio (MTR) image. The dMRI images were aligned using an updated 2-dimentional registration scheme before calculating the diffusion tensor maps. Results: Preliminary data analysis indicated good intra- and intersite reproducibility, both short and long term, with small variations. For example: standard deviation < 2 mm2 for vertebral-level-wise spinal cord area from C3 to L1 measured from T2w image and reliable grey-matter-to-white-matter contrast-to-noise ratio (> 2) from PSIR image; Kolmogorov-Smirnov test statistics < 0.2 for the difference in the distributions of MTR and DTI maps. Full data analysis is ongoing to quantify reproducibility and inter-site biases. Conclusions: Reproducible quantitative cervical spinal cord MRI is achievable from multiple sites (single MRI scanner vendor) with careful acquisition protocol harmonization and centralized data analysis.

P495 Detection of new multiple sclerosis lesions on longitudinal brain MRI M. Cabezas1, D. Pareto2, A. Oliver1, J.F. Corral2, C. Auger2, X. Aymerich2, J. Sastre-Garriga3, M. Tintoré3, X. Montalban3, X. Lladó1, A. Rovira2 1Vicorob Institute, University of Girona, Girona, 2Magnetic Resonance Unit, Radiology Department, 3Department of Neurology-Neuroimmunology and Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Disclosure Joo-won Kim: nothing to disclose Dr. Matilde Inglese has received research grants from NIH, NMSS, Novartis Pharmaceuticals Corp., Teva Neuroscience. Courtney Dula: nothing to disclose Samantha Lancia: nothing to disclose Christina Alfonso: nothing to disclose Peng Sun: nothing to disclose Sheng-Kwei Song is supported by grants from NIH, NMSS, and DOD. Robert T Naismith has received fees for consulting from: Alkermes, Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, EMD Serono, Novartis, Pfizer, Teva

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Background: Determining the presence/absence of new T2 lesions is an accepted biomarker and a key factor to evaluate treatment efficacy in MS. However, this is commonly done visually or semi-automatically being time-consuming and prone to observer errors. Objective: To compare a set of recent automated methods to detect new T2 MS lesions on serial brain (baseline and one-year follow-up) MRI scans of patients presenting a clinically isolated syndrome (CIS). Materials and methods: The cohort included 60 patients that were scanned with a 3T magnet, including transverse T2-FLAIR, PD-w, T2-w and T1-w images. 37 of these patients (61.7%) presented new T2 lesions that were visually and semi-automatically annotated by expert neuroradiologists (using the Jim tool). The mean number of new T2 lesions was 6.17 (SD=9.9) and the mean new T2 lesion volume was 203.18 (SD=404.5) mm3. The performance of three different methods was compared with respect to the experts’ annotations. The first one, being an automated pipeline based on subtraction and deformation fields computed using Demons non-rigid registration, while the second and third pipelines were based on the LST toolbox for SPM, which incorporates two different approaches to segment lesions in a given time point (LGA and LPA) and a strategy to compare the segmentations between time points of these approaches to provide a longitudinal analysis for each. Results: The first pipeline obtained a 71.8% true positive fraction (TPF) in terms of detection and a 63.3% TPF in terms of segmentation. Using the LGA and LPA methods, these values decreased to 45.2% and 28.7% for detection and to 35.7% and 16.0% for segmentation. Regarding false positive fraction, the first method obtained values of 20.4% and 33.3% for detection and segmentation respectively compared to 37.7% and 54.5% for the LGA and 70.3% and 86.01% for the LPA method. The Dice similarity coefficient and the average surface distance were also better with the first approach. Regarding the patients without new lesions, the first method found false positives in 21.7% of the cases compared to 43.5% and 91.3% for the LGA and LPA respectively. Conclusion: The automated method based on subtraction and deformation fields outperformed the pipelines implemented on the LST toolbox for the given cohort. These results show that subtraction approaches are preferred for automated lesion detection than approaches based on comparing independent segmentations for each time point.


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Disclosure M. Cabezas:nothing to disclose. D. Pareto: has received speaking honoraria from Novartis and Genzyme. A. Oliver: nothing to disclose. J. Corral: has nothing to disclose. C. Auger: has received speaking honoraria from Biogen, Stendhal and Novartis. F. X. Aymerich: has nothing to disclose J. Sastre-Garriga: has received compensation in the last 12 months for speaking or participation in advisory boards from Novartis, Biogen and Merck and grants from Genzyme. M. Tintoré: has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, MerckSerono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Novartis, Almirall, Genzyme, and Roche. X. Montalban: has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva Pharmaceutical. X. Lladó: nothing to disclose. A. Rovira: serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec, and has research agreements with Siemens AG. P496 The two cytoarchitectonic divisions of BA 4 show distinguishable BOLD-force profiles in multiple sclerosis A.A.S. Alahmadi1,2, M. Pardini1,3, R.S. Samson1, E. D’Angelo4,5, K. Friston6, A.T. Toosy1, C.A.M. Gandini Wheeler-Kingshott1,4,5 1NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom, 2Department of Diagnostic Radiology, Faculty of Applied Medical Science, KAU, Jeddah, Saudi Arabia, 3Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa, 4Brain Connectivity Centre, C. Mondino National Neurological Institute, 5Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy, 6Wellcome Centre for Imaging Neuroscience, UCL, Institute of Neurology, London, United Kingdom Background: The primary motor cortex - Brodmann area 4 (BA4) - has two cytoarchitectonically distinct sub-regions: anterior (BA4a) and posterior (BA4p). Recently, in healthy subjects (HS), it has been shown that these two sub-regions possess unique BOLD-grip-force (GF) relationships during a grip task. Here, we aimed to assess whether, in multiple sclerosis (MS), the BOLD-GF relationship is altered in BA4 and shows regional differences between BA4a and BA4p. Methods: 14 right-handed (RH) HS (9F; aged 31 (±4.64) years) and 14 RH relapsing-remitting (RR) MS patients (10F; aged 35 (±5.36) years; median (range) EDSS 3.5 (1.5-6.5)) were assessed with a 3T fMRI whilst performing a visuomotor power-grip task

using a squeezeball with their RH. The paradigm comprised 75 trials divided into 5 GFs (20, 30, 40, 50, and 60% of maximum strength). Signal changes were fitted with higher-order polynomial expansions using a parametric design to assess linear and non-linear BOLD-GF effects. Significant voxels were defined using P< 0.05, corrected (FWE). In addition, to better understand the effect of disability, we divided the MS group based on their EDSS score into two sub-groups of low (EDSS⩽3) and high (EDSS>3) disability. Results: We report four major findings: 1) Main effect of movement: RRMS patients showed increased and greater activation extent compared with HS in both BA4a and BA4p (P=0.0001). RRMS patients also showed increased activations as their EDSS increased within BA4p only (P=0.001); 2) Mean BOLD-GF in BA4p: In patients with low EDSS, the BOLD-GF relationship was very similar to HS, whereas at higher EDSS, the regression of BOLD on GF deviated from the HS pattern or patients with low disability; 3) Mean BOLD-GF in BA4a: No differences were detected between MS subjects and HS; 4) Response profile comparison at subject level: The profile was very similar across subjects, when comparing responses of subjects at similar stages of the disease. Conclusion: We have shown altered relationships in BA4 between BOLD and GF in patients with MS. The observation that the BOLD response to GF in patients with low EDSS was similar to that of HS, while it was consistently altered at higher EDSS (within BA4p but not BA4a) poses interesting mechanistic questions, suggesting differences not only in cytoarchitecture but also in myeloarchitecture of these two sub-regions, translating into differences in susceptibility and adaptive responses to MS pathology. Disclosure Adnan Alahmadi, Matteo Pardini, Rebecca Samson, Egidio DÁngelo and Karl Friston have nothing to disclose. Ahmed Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation, Bayer and meeting expenses from Biogen Idec. Claudia GWK is on the editorial board of Functional Neurology and receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. P497 Cladribine effect on brain volume loss and its correlation with disability progression in patients with relapsing multiple sclerosis N. de Stefano1, A. Giorgio1, M. Battaglini1, A. De Leucio1, G. Giovannoni2, C. Hicking3, F. Dangond4, M.P. Sormani5 1Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy, 2Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 3Merck KGaA, Darmstadt, Germany, 4EMD Serono, Inc., Billerica, MA, United States, 5Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy


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Poster Session 1, 22(S3) Background: In the CLAdRIbine Tablets treating multiple sclerosis orallY (CLARITY) study, treatment of patients with relapsing multiple sclerosis (RMS) with cladribine tablets (3.5 and 5.25mg/kg, cumulative) significantly reduced relapse rates, magnetic resonance imaging (MRI) measures and slowed disability progression vs placebo. Recent MS studies have shown that MRI-derived measures of brain volume loss can provide clinically meaningful estimates of brain tissue damage and that this might be slowed down during therapy. Objectives: To assess the treatment effect on brain volume of therapy with cladribine tablets in patients who participated in the CLARITY study, and to investigate its correlation with disability progression. Methods: Exploratory analyses were undertaken to measure MRI-derived percentage brain volume change (PBVC) between 6 and 24 months (excluding the first 6 months of treatment to avoid pseudoatrophy), and to assess the correlation of PBVC with 3-month confirmed EDSS progression (3m-CDP). Efficacy objectives were classed as exploratory; all determinations of significance should be regarded as nominal. Results: The mean annualised PBVC rate (month 6 to 24) was greater in patients treated with placebo (-0.70%, SD 0.787, n=338) than those who received cladribine tablets 3.5 and 5.25mg/kg (-0.56%, SD 0.676, n=336 and -0.57%, SD 0.717, n=351, respectively). Furthermore, PBVC (month 6 to 24) was less in patients treated with cladribine tablets 3.5mg/kg (p=0.019) and 5.25mg/kg (p=0.018) than placebo. After adjusting for treatment group, PBVC (month 6 to 24) in all patients showed a significant correlation with the cumulative probability of 3m-CDP (hazard ratio [HR] 0.753, 95% confidence interval [CI] 0.670-0.846; p< 0.001). Compared with placebo, the risk of disability progression was significantly lower with cladribine tablets 3.5mg/kg (p=0.009) and 5.25mg/kg (p=0.003). Sub-division of patients into PBVC tertiles showed that the highest proportion of patients free from disability progression at 24 months was in the tertile with the lowest PBVC and the smallest proportion of progression-free patients was in the tertile that showed the greatest PBVC. Conclusions: In the CLARITY study, patients treated with cladribine tablets showed significantly less brain atrophy rates over 2 years than placebo recipients. Interestingly, patients with the least brain atrophy rates showed the highest probability of remaining free from disability progression. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Nicola de Stefano has received honoraria from Schering, BiogenIdec, Teva, Novartis, Genzyme, and Merck for consulting services, speaking and travel support. He serves on advisory boards for Merck and Novartis. He has received research grant support from the Italian MS Society. Antonio Giorgio has no conflicts of interest to declare. Marco Battaglini has no conflicts of interest to declare. Alessandro De Leucio has no conflicts of interest to declare. Gavin Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc,

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Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Christine Hicking is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. Maria Pia Sormani has received personal compensation for consulting services and for speaking activities from Genzyme, Merck, Teva, Synthon, Actelion, Novartis and Biogen Idec. P498 Fatigue in multiple sclerosis: the contribution of resting-state functional connectivity reorganization A. Bisecco1,2, F. Di Nardo2, R. Docimo1, G. Caiazzo2, A. d’Ambrosio1, R. Sacco1, S. Bonavita1,2, M. Cirillo2,3, F. Esposito2,4, G. Tedeschi1,2, A. Gallo1,2 1Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, 2MRI Center ‘SUN-FISM’, Second University of Naples and Institute of Diagnosis and Care “Hermitage-Capodimonte”, 3Neuroradiology Service, Department of Radiology, Second University of Naples, Naples, 4Department of Medicine and Surgery, University of Salerno, Baronissi, Italy Background: Fatigue affects a large proportion of patients with multiple sclerosis (MS). Despite its relevance and frequency in MS, the pathophysiology of MS-related fatigue is still poorly understood and controversial. Objectives: To investigate resting-state functional connectivity (RS-FC) of the default mode network (DMN) and of sensorimotor network (SMN) in MS patients with (F) and without (NF) fatigue. Methods: Sixty not-depressed relapsing remitting (RR) MS patients and 30 sex, age and education-matched healthy controls (HC) underwent a 3T magnetic resonance imaging (MRI) protocol including structural and resting-state fMRI (RS-fMRI) sequences. MS patients were evaluated by a neurological examination and the Fatigue Severity Scale (FSS). Functional connectivity of the DMN and SMN was evaluated by independent component analysis (ICA). Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). Results: Thirty RRMS patients were fatigued (F-MS). Compared to HC: 1) NF-MS patients showed a stronger RS-FC in the posterior cingulate cortex (PCC) of the DMN and a reduced RS-FC in the pre-central gyrus of the SMN; 2) F-MS patients showed a stronger RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN. F-MS patients, compared to NF-MS patients, revealed: 1) an increased RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN and 2) an increased RS-FC in the precentral gyrus and in the supplementary motor area of the SMN. All detected RS-FC changes did not co-localize with regional gray matter atrophy. Conclusions: Fatigue in RRMS is associated to relevant RS-FC changes, including an antero-posterior reorganization of the DMN and a strengthening of the SMN. These results further supports the hypothesis that fatigue in MS is mostly subtended by a functional rearrangement of frontal networks.


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Disclosure Alvino Bisecco: nothing to disclose. Federica Di Nardo: nothing to disclose. Renato Docimo: nothing to disclose. Giuseppina Caiazzo: nothing to disclose. Alessandro dÁmbrosio: nothing to disclose. Rosaria Sacco: nothing to disclose. Mario Cirillo: nothing to disclose. Fabrizio Esposito: nothing to disclose. Simona Bonavita received speakers honoraria from Biogen Idec, Novartis, and Merck-Serono. Gioacchino Tedeschi has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck Serono, and Fondazione Italiana Sclerosi Multipla. Antonio Galloreceived honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Genzyme, Teva, Bayer-Schering and Novartis.

P499 Predicting gadolinium enhancement using non-enhanced FLAIR MRI imaging in relapsing-remitting multiple sclerosis M. Guranda, M. Essig, A. Poulin, R. Vosoughi University of Manitoba, Winnipeg, MB, Canada Background: Magnetic resonance imaging (MRI) with gadolinium is considered a “gold standard” diagnostic test in relapsingremitting multiple sclerosis (RRMS); however, certain contraindications exist. This study is based on our personal observation that in RRMS patients, demyelinating lesions of outstanding brightness (“ultrabright”) on non-contrast axial Fluid Attenuation Inversion Recovery (FLAIR) MRI are more likely to enhance with gadolinium. Here, we attempted to qualitatively and quantitatively identify the “ultrabright” lesions using axial FLAIR and explore their association with gadolinium enhancement. Methods: The MRI scans of patients with RRMS from 2010-2015 were pre-reviewed for presence of potentially “ultrabright” lesions. The scan data was extracted as anonymized DICOM images (FLAIR, pre- and post-gadolinium T1). Two radiologists independently identified “ultrabright” lesions on FLAIR sequences. The signal-to-noise ratio (SNR) of each “ultrabright” lesion was calculated as follows: SNR = Mean lesion signal intensity / Air signal standard deviation. One of the radiologists also reviewed the T1 pre- and post-gadolinium images to identify the enhancing lesions (study subject identification numbers were recoded). Results: A total of 107 lesions was included in the analysis. Seventy seven lesions were identified by both radiologists as “ultrabright” (72%). Kappa statistic of inter-rater reliability was not significant. The lesions that were identified by both radiologists as “ultrabright” demonstrated a strong association with gadolinium enhancement (χ2(1) = 8.863, p = .003). For quantitative method, the odds of the lesion being enhanced increased by 1.02 with every 1.0 increment in signal-to-noise ratio (OR 1.02, 95% CI [1.01-1.03], p < .001). Positive predictive value of “ultrabright” lesions of visually identified by both radiologists was 88%, 95% CI (78-94%); positive predictive value of 100% was achieved using cutoff signal-to-noise ratio of 345.

Conclusions: Both qualitatively and quantitatively identified “ultrabright” FLAIR lesions are associated with gadolinium enhancement. Quantitative measurement of lesions SNR provides unequivocal cutoff value for “ultrabright” lesions and acts as a more reliable predictor of gadolinium enhancement with lower numbers of false positives compared to visual identification. Disclosure The authors declare no conflict of interests. The study has not been funded. P500 Detection of cortical lesions by 3D-double inversion recovery imaging in Japanese patients with multiple sclerosis and neuromyelitis optica spectrum disorder K. Shinoda1, T. Matsushita1, Y. Nakamura1, K. Masaki1, A. Hiwatashi2, J.-I. Kira1 1Department of Neurology, Graduate School of Medical Sciences, Kyushu University, 2Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Background: Cortical lesions (CLs) are frequently found in Caucasian patients with multiple sclerosis (MS) and contribute to disability. Three-dimensional double inversion recovery (3DDIR) imaging has facilitated detection of CLs. However, there are currently no reports on 3D-DIR imaging of CLs in Asian patients with MS or neuromyelitis optica spectrum disorder (NMOSD). Objective: To elucidate the frequency and clinical significance of CLs in Japanese patients with MS and NMOSD. Methods: The study enrolled 67 patients with MS (55 with relapsing-remitting MS [RRMS], 12 with secondary progressive MS [SPMS]) and 12 patients with NMOSD, who visited the MS clinic at Kyushu University Hospital from May 1, 2015 to April 13, 2016. All images were obtained using 3T MRI. Two examiners blinded to the diagnoses investigated CLs and classified them into intracortical or leucocortical lesions by consensus. Results: CLs were detected in 44.8% of MS and 0% of NMOSD patients. The frequency and number of CLs were higher in SPMS patients than in RRMS patients (75.0% vs. 38.2%, 5.67 ± 5.18 vs. 0.80 ± 1.79, p = 0.0008). MS patients with CLs had significantly higher Kurtzke Expanded Disability Status Scale (EDSS) scores than those without CLs (3.35 ± 2.11 vs 1.79 ± 1.76, p = 0.0006), whereas there were no significant differences in gender, disease duration or positivity for oligoclonal IgG bands (OBs). The number of CLs showed a significant positive correlation with EDSS score (Rs = 0.4512, p = 0.0001), but not disease duration or age at examination. HLA-DRB1*15:01 carriers had a significantly higher frequency and number of intracortical lesions than HLA-DRB1*15:01 non-carriers. Conclusions: Although the frequency of CLs in Japanese patients was relatively low in MS and zero in NMOSD, CLs were associated with secondary progression, greater disability, and HLADRB1*15:01,but not with gender, age at examination, or positivity for OBs. Disclosure Jun-ichi Kira is a consultant for Biogen Idec Japan and Medical Review. He has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical


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Poster Session 1, 22(S3) and Medical Review. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan. Takuya Matsushita has received honoraria from Bayer Schering Pharma, Biogen Idec Japan, Takeda Pharmaceutical Company and Mitsubishi Tanabe Pharma. Koji Shinoda, Yuri Nakamura and Katsuhisa Masaki have nothing to declare.

P501 Cerebral microbleeds in multiple sclerosis evaluated on susceptibility-weighted imaging and quantitative susceptibility mapping are associated with more severe cognitive and physical outcomes R. Zivadinov1,2, R.R.H. Benedict3, D.P. Ramasamy1, P. Polak1, J. Hagemeier1, C. Magnano1,2,4, M.G. Dwyer1, N. Bergsland1,5, N. Bertolino1, B. Weinstock-Guttman3, C. Kolb3, D. Hojnacki3, D. Utriainen6, E.M. Haacke7,8,9, F. Schweser1,2 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 4GE Healthcare, Waukesha, WI, United States, 5Magnetic Resonance Laboratory, IRCCS Don Gnocchi Foundation, Milan, Italy, 6Magnetic Resonance Innovations, Inc, 7Department of Radiology, Wayne State University, Detroit, MI, United States, 8School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada, 9Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai, China Background: Cerebral microbleeds (CMBs) are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established in the multiple sclerosis (MS) literature. Objective: To assess CMB prevalence in MS and clinically isolated syndrome (CIS) patients, and explore their association with clinical outcomes. Methods: 445 MS patients (266 relapsing-remitting, 138 secondary-progressive and 41 primary-progressive), 45 CIS patients, 51 patients with other neurologic diseases and 177 healthy controls (HCs) were assessed by 3T MRI and clinical examinations. A subset of 168 MS patients and 50 HCs underwent neuropsychological testing. CMB number was assessed on susceptibility-weighted minimum intensity projections using the Microbleed Anatomical Rating Scale, while volume was calculated using quantitative susceptibility maps. Differences between the groups were analyzed using the chi-square, Fisher’s exact test, Student’s t-test and analysis of variance, while the associations of CMBs with clinical and other MRI outcomes were explored using correlation and regression analyses. Because frequency of CMBs increases with age, we investigated their prevalence separately in subjects ⩾50 or < 50 years old.

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Results: In a correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory/verbal learning and memory (p=0.006), and visual information-processing speed trending (p=0.049) in MS patients. In regression analysis, adjusted for age, hypertension and normalized brain volume, an increased number of CMBs was significantly associated with increased physical disability in MS population (R2=0.23, p< 0.0001). Significantly more MS patients had CMBs compared to HCs (19.8% vs. 7.4%, p=0.01) in ⩾50 years old age group. A trend for greater presence of CMBs was found in MS patients (p=0.016), and in CIS patients < 50 years old (p=0.039), compared to HCs. Conclusions: Monitoring CMBs may be relevant in MS and CIS patients at higher risk for developing cognitive and physical disability. Disclosure Funding statement: This study was funded with internal resources of the Buffalo Neuroimaging Analysis Center. In addition, we received support from the Jacquemin Family Foundation. Collective disclosure statement: Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus and IMS Health. Deepa P. Ramasamay, Paul Polak, Jesper Hagemeier, Christopher Magnano, Niels Bergsland, Nicola Bertolino, David Utrianen and Ferdinand Schweser have nothing to disclose. Michael G. Dwyer has received consultant fees from Claret Medical and EMD Serono. Bianca Weinstock- Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. Ralph RH.. Benedict has acted as a consultant or scientific advisory board member for Bayer, Biogen Idec, Actelion, and Novartis. He receives royalties from Psychological Assessment Resources, Inc. He has received financial support for research activities from Shire Pharmaceuticals, Accorda and Biogen Idec. David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis. E. Mark Haacke is the president of Magnetic Resonance Innovations, Inc. P502 Continuous short-term structural network reorganisation beyond atrophy in patients with RRMS V. Fleischer1, N. Koirala1, A. Droby1, R.-M. Gracien2, R. Deichmann2, S. Meuth3, U. Ziemann4, M. Muthuraman1, F. Zipp1, S. Groppa1 1Department of Neurology and Neuroimaging Center (NIC) of the Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg-University,


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Mainz, 2Brain Imaging Center, Goethe University, Frankfurt, 3University of Muenster, Department of Neurology, Muenster, 4Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany Background and aim: Longitudinal assessment of structural brain changes is important to track the clinical course of multiple sclerosis (MS), but an exact quantification of the diffuse tissue damage is highly challenging. We aimed to identify short-term structural dynamics by measuring grey matter (GM) network connectivity patterns and comparing these with established morphological measures of GM integrity. Methods: For our prospectively designed study, we collected data from January 2013 through December 2014. In total, forty-five structural MRI datasets from relapsing-remitting MS patients in the relapse free phase of the disease (mean age: 42 ± 12.1 years; median EDSS 1.5 (0 - 2.5); mean disease duration 3.5 ± 6.5 years) were acquired using 3T MRI. Each patient was followed up every 8 weeks for 8 months and all patients were enrolled at two German university hospitals. Longitudinal brain atrophy was analyzed using SIENA (part of FSL), while FreeSurfer was used to investigate cortical thickness changes over time. GM connectivity patterns were reconstructed from cortical thickness correlation matrix between anatomical regions, as derived from the AAL atlas, and a network analysis was conducted using graph theoretical approaches. Results: Our study shows a significant longitudinal structural network reorganisation in the absence of cortical thinning and brain atrophy already over a period of 4 months. We demonstrate an increased local (clustering coefficient (F(4,41) = 3.547, p < 0.001), local efficiency (F(4,41) = 3.0874, p < 0.01)) and modular connectivity pattern (modularity (F(4,41) =2.612, p < 0.01)). Conversely a concomitant break-down of long-range connectivity occurred (assortativity (F(4,41) = 3.0654, p < 0.01) and smallworld index (F(4,41) = 3.687, p < 0.001)). No regional or global atrophy signs were detected in the applied morphometric analysis. Conclusions and relevance: Our GM network analysis demonstrates a short-term increase in local connectivity and a decrease in long-range paths in MS patients in the relapse free state of the disease, in the absence of atrophy or clinical progression. Structural reorganisation patterns with co-occurrence of detrimental and adaptive reorganisation processes might be important sensitive measurable fingerprints of the disease that can be used in clinical practice. Disclosure All listed authors have nothing to disclose. P503 Correlations of volumetric and R2*-defined microstructural abnormalities in hippocampus and amygdala with cognition in MS J. Wen1, D.A. Yablonskiy1, A.H. Cross2 1Radiology, 2Neurology, Washington University School of Medicine, St. Louis, MO, United States Background: Despite their abundance in multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) techniques often miss grey matter (GM) lesions. We previously demonstrated

that the transverse relaxation (R2*) of gradient echo MRI signal is sensitive to GM injury in MS. Our prior study of relapsing-remitting (RRMS), secondary-progressive (SPMS) and primary progressive (PPMS) patients analyzed regional R2* values in cortical GM, finding R2* values to correlate better with cognition than cortical volumes. Here, we analyzed quantitative R2* in two deep GM structures involved in memory. Objective: We hypothesized that R2* of the hippocampus and amygdala would correlate with cognitive tests. Hippocampus was examined due to its importance for memory and amygdala because of its physical and neural connections to hippocampus. Methods: Human studies committee approval was obtained. All subjects gave informed consent. 26 RRMS, 12 PPMS, 25 SPMS and 26 healthy controls (HC) underwent MRI to calculate quantitative R2* parameters. Paced auditory addition task (PASAT - auditory working memory) and symbol digit modalities test (SDMT - visual working memory) were done the same day. All volumes and R2* values were age-corrected. Volume was normalized to skull size. Due to known gender differences in the amygdala, its volume and R2* were compared between MS and HC stratified by sex. Results: Hippocampal R2* (p< .03) and volume (p< .04) were lower in MS than HC. In amygdala, MS females had lower R2* than female HC in left amygdala (p=.02), whereas R2* on the right and amygdala volumes were not different between MS and HC. In all patients, amygdala and hippocampus volumes correlated with one another (r=.54 for left hemisphere, r=.69 for right), whereas R2* of hippocampus and amygdala were mildly correlated only in right hemisphere (r=.35). In RRMS, hippocampus (r=.4) and amygdala (r=.4) volumes correlated with SDMT, but not with PASAT. R2* did not correlate with SDMT or PASAT in either structure in RRMS. In SPMS, R2* of hippocampus and amygdala significantly correlated with PASAT and SDMT (r= 0.4 for all). Volumes did not correlate with test scores in SPMS. Conclusions: Hippocampal R2* and volume were reduced in MS vs. HC. Hippocampus and amygdala volumes correlated with SDMT in RRMS, while R2* in hippocampus and amygdala correlated with both SDMT and PASAT in SPMS. These data suggest that R2* reflects injury in hippocampus and amygdala in SPMS patients. Disclosure Jie Wen has nothing to disclose. Anne H. Cross has done consulting for AbbVie, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, and Teva. Dmitriy A. Yablonskiy has nothing to disclose. Funding: Funded by the National MS Society USA and the Conrad N. Hilton Foundation. Jie Wen was a post-doctoral fellow of the NMSS during these studies. P504 High resolution, quantitative magnetic susceptibility and phase mapping MRI techniques show increased iron deposition in patients with multiple sclerosis M.S. Hbahbih1, I. Athamneh2, H.A. Alabadi2, A.A. Hazzaá3, N.S. Hijjawi3, A.M. Al-Radaideh3 1Neurology, 2Radiology, King Hussein Medical Centre, Amman, 3Hashemite University, Zarqa, Jordan


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Poster Session 1, 22(S3) Introduction: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system leading to demyelination and axonal loss. Oligodendrocytes and myelin are rich in iron and neurodegeneration in MS might be expected to cause an accumulation of iron in deep grey matter (dGM) structures which have extensive expression of the transferrin receptor and the ferrous iron transporter. The change in magnetic susceptibility due to iron accumulation causes local field shifts which can be detected on phase images particularly at high field MRI, which can be inverted to produce maps of the distribution of magnetic susceptibility. The aim of this study is to measure the magnetic susceptibility and phase values of dGm structures in patients with relapsing-remitting MS (RRMS) patients and correlate them with the T2 lesion load, Extended Disability Status Scale (EDSS), number of relapses, and disease duration. Methods: Subjects: 30 RRMS patients were recruited from the neurology clinic at King Hussein Medical Centre, Jordan along with 30 age and sex matched healthy controls. All participants were consented. Clinical and EDSS assessments were carried out a senior neurologist. MR Imaging: Scanning was performed on a 3T Siemens Trio MR system. High resolution 3D T2*-weighted gradient echo and T2-weighted Fluid-Attenuated Inversion Recovery (FLAIR) sequences were obtained. Both magnitude and phase images of the T2* sequence were reconstructed for further analysis. Post Processing and Analysis: Phase images were converted into susceptibility maps on which different regions-of-interest (ROIs) were drawn to cover the caudate nucleus (CN), putamen (PT), globus pallidus (GP) and thalamus (TH). The posterior horn of internal capsule was used as a normal reference value. T2-weighted FLAIR images were used to calculate the lesion load. Results: For the RRMS patients, significant moderate correlation (p< 0.05) was found between the EDSS and the susceptibility in both CN (r=0.522) and PT (r=0.532). Significant differences (p< 0.05) in magnetic susceptibility were found between RRMS and HC subjects for the PT, GP and TH. Furthermore, significant differences (p< 0.05) in phase values were found between RRMS and HC subjects for the CN, PT, GP, and TH. Conclusion: High resolution susceptibility and phase mapping techniques were found to be sensitive to changes in iron deposition, and showed increased iron deposition in RRMS patients compared to HCs. Disclosure Majed Hbahbih: nothing to disclose Imad Athamneh:nothing to disclose Hadeel A. Alabbadinothing to disclose: Abeer A. Hazza’a:nothing to disclose Nawal S. Hijjawi:nothing to disclose Ali M. Al-Radaideh:nothing to disclose

Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, 2Translational Imaging Group, Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, UCL, 3NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom Background: Increased total sodium concentration has been demonstrated in the brains of patients with relapsing remitting, secondary progressive and primary progressive multiple sclerosis (MS). It is thought that this may reflect neuroaxonal pathology. However, it is still unknown if increased sodium is seen in subjects presenting with a clinically isolated syndrome (CIS). Objective: The aim of this study is to estimate the total sodium concentration in the normal appearing white matter, cortical grey matter, deep grey matter and T2 lesions in patients presenting with a CIS. Methods: We recruited 20 CIS subjects (10F:10M), with a mean age 35.6 (±8.6) years within 3 months from symptom onset and 11 healthy controls (7F:4M), with a mean age 35.2 (±7.5) years. Patients had a median EDSS of 1.0 (range 0-2.5), with the majority of subjects presenting with an optic neuritis (N=17). 11 of the CIS subjects had an abnormal MRI scan with asymptomatic, nonenhancing T2 lesions at baseline (mean T2 lesion volume = 6.20 (±5.5) ml). Subjects underwent two protocols in the same session using a 3T scanner: 1) PD/T2 and 3D T1 images; and 2) quantitative total sodium MRI. After lesion filling the 3D T1 images, probabilistic tissue brain segmentations were performed using GIF. Tissue masks were registered and resampled to the sodium space using NiftyReg. Linear regression models compared differences between groups adjusting for age, gender and grey or white matter tissue fraction. Results: Increased sodium concentration was seen in the asymptomatic brain T2 lesions compared with normal appearing white matter in CIS subjects (49.98±7.77mM versus 33.16±3.7mM, p=0.005). There were no differences in sodium concentration for normal appearing white matter (33.16±3.7mM versus 31.4±2.3mM), cortical grey matter (41.8±3.2mM versus 41.1±2.6mM) and deep grey matter (35.5±3.3mM versus 34.4±2.5mM) in CIS patients when compared to controls. Conclusion: This study extends the findings of increased sodium concentration in MS to patients presenting with a CIS. Increased total sodium levels in the T2 lesions could reflect the underlying oedema, associated with an inflammatory event; additionally, this could reflect neuroaxonal dysfunction and/or loss occurring at the onset of a first demyelinating event. Sodium imaging may have a role as an outcome measure in clinical trials that target the sodium pathway of the neurons. Disclosure

P505 Increased total sodium concentration in asymptomatic T2 lesions in clinically isolated syndrome N. Cawley1, B.S. Solanky1, F. Prados1,2, S. Collorone1, B. Kanber2, S. Ourselin2, C.A.M. Gandini Wheeler-Kingshott1, D.H. Miller1,3, A.J. Thompson1,3, A. Toosy1, O. Ciccarelli1,3

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Niamh Cawley - nothing to disclose Bhavana S. Solanky - nothing to disclose Ferran Prados - nothing to disclose Sara Collorone - nothing to disclose Baris Kanber - nothing to disclose Sebastian Ourselin - nothing to disclose CAM Gandini Wheeler Kingshott - serves as a consultant for Biogen and receives research support from the UK MS Society, UCL/UCLH NIHR BRC, EPSRC, ISRT, Wings for Life, New Zealand Brain Research Centre, Novartis, and Biogen.


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David H. Miller - received grants from UCL/UCLH Biomedical Research Centre, during the conduct of the study; has received grants from Biogen, GlaxoSmithKline, the National Institute for Health Research, Novartis, and Apitope; has board membership with Biogen Idec, GlaxoSmithKline, Bayer Schering Pharma, and Mitsubishi Pharma Europe; has been a consultant for Merck and Chugai; and has received personal fees from McAlpine’s Multiple Sclerosis, 4th edition. Alan Thompson - has received honoraria and support for travel for consultancy from Biogen Idec, Eisai, Genzyme, Novartis and Medday, and for speaking from EXCEMED, Novartis, Remedica and Teva. He receives an honorarium from Sage Publications as Editor-in-Chief of Multiple Sclerosis Journal. Ahmed Toosy - Meeting expenses ECTRIMS conference 2015 paid by Biogen Idec. Olga Ciccarelli - serves as a consultant for Biogen, GE Healthcare and Novartis, and payments are made to the institution; she receives an honorarium as Associate Editor of Neurology. P506 A multicentre study of quantitative susceptibility mapping in sub-cortical deep gray matter structures in relapsing multiple sclerosis R. Zivadinov1,2, F. Schweser1,2, C. Dawes3, J. Hagemeier1, L. Ly3, C. Wang3, N. Bergsland1,4, H. Beadnall3, E. Carl1, B. Weinstock-Guttman5, R.R.H. Benedict5, M. Barnett3 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States, 3Sydney Neuroimaging Analysis Centre, Brain & Mind Centre, University of Sydney, Sydney, NSW, Australia, 4IRCCS ‘S.Maria Nascente’, Don Gnocchi Foundation, Milan, Italy, 5Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: Gray matter (GM) damage is present in multiple sclerosis (MS) patients, and involves both the cortical GM and sub-cortical deep GM (SDGM) structures. No multicentre studies have investigated differences in quantitative susceptibility mapping (QSM) of the SDGM structures between healthy controls (HC) and patients with relapsing multiple sclerosis (MS). Objective: To investigate associations between QSM and clinical outcomes of disease severity in a multicentre study. Methods: This is an ongoing, Phase IV, prospective, MRI-readerblinded, longitudinal, two centres (USA and Australia) study that enrolled 44 MS patients and 34 age- and sex-matched HCs. The clinical and MRI assessments were performed at baseline, and are collected at 6, 12 and 24 months after initiation of the fingolimod treatment. The MRI is obtained at 3T MRI with standardized protocol between the two centres. The QSM images were reconstructed by unwrapping phase images with a best-path algorithm, background-field correction with V-SHARP and conversion to QSM using HEIDI. The volume of brain SDGM structures was also calculated.

Results: When adjusted for age, sex and centre, MS patients showed increased susceptibility in caudate (p=0.001) and decreased susceptibility in thalamus (p=0.003), and decreased thalamus (p=0.008) and putamen (p=0.02) volumes. In correlation analysis, increased disability in MS patients, as measured by Expanded Disability Status Scale (EDSS), was associated with increased susceptibility in the globus pallidus (r=0.63, p< 0.001), putamen (r=0.54, p< 0.001), total SDGM (r=0.55, p< 0.001) and caudate (r=0.34, p=0.032). The associations between the increased EDSS and decreased SDGM volumes were: globus pallidus (r=0.48, p< 0.001), total SDGM (r=-0.37, p=0.015), putamen (r=0.33, p=0.032) and caudate (r=-0.32, p=0.037). In regression analyses, using susceptibility and volumetric variables as the independent- and disability as dependent- measure, while adjusting for age and sex, increased susceptibility in the globus pallidus (Beta=0.5, p=0.004) and putamen (Beta=0.37, p=0.031) were the only variables associated with increased disability. Conclusions: The measurement of QSM is feasible in a multicentre study. QSM is a novel MRI outcome that is better associated with increased disability than volumetric SDGM measures. Disclosure Funding statement: This study was funded by the research grant from Novartis. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health, and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus, and IMS Health. Ferdinand Schweser, Caitlin Dawes, Jesper Hagemeier, Tim Wang, Niels Bergsland, Heidi Beadnall, Ellen Carl have nothing to disclose. Bianca Weinstock- Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Ralph RH. Benedict has acted as a consultant or scientific advisory board member for Bayer, Biogen Idec, Actelion, and Novartis. He receives royalties from Psychological Assessment Resources, Inc. He has received financial support for research activities from Shire Pharmaceuticals, Accorda and Biogen Idec. Michael Barnett has received institutional support for research, speaking and consulting activities from Biogen, Genzyme, Novartis, Teva and Roche; and travel support from Novartis and Biogen. P507 An abnormal periventricular gradient in magnetisation transfer ratio occurs early in multiple sclerosis J.W.L. Brown1,2, M. Pardini1,3, W.J. Brownlee1, K. Fernando4, R. Samson1, C. Gandini Wheeler-Kingshott1,5, D.H. Miller1,6, D.T. Chard1,6 1Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, 2University of Cambridge, Cambridge, United Kingdom, 3Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and IRCCS AOU San Martino-IST, University of Genoa, Genoa,


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Poster Session 1, 22(S3) Italy, 4Department of Neurology, Royal Free Hospital, London, United Kingdom, 5Brain MRI 3T Center, Mondino National Neurological Institute of Pavia, Pavia, Italy, 6National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, United Kingdom Background and goals: In multiple sclerosis (MS), tissue abnormality - as assessed using magnetisation transfer ratio (MTR) increases close to the lateral ventricles. We aimed to determine whether or not they: i) are present from the earliest clinical stages of MS; ii) occur independently of white matter lesions; iii) are associated with conversion to clinically definite MS and disability following a clinically isolated syndrome. Methods: Seventy-one people had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (ON, 49 females, mean age 33.5 years) and were followed up clinically two and five years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter (NAWM), MTR gradients were measured 1-5mm and 6-10mm from the lateral ventricles. Results: The MTR gradient over 1-5mm differed significantly between the ON and control groups (+0.059 percentage units/mm (pu/mm) vs -0.033 pu/mm, p=0.010). The MTR gradient was not significantly affected by the presence of brain lesions (T2 lesions (p=0.918), periventricular T2 lesions (p=0.580) or gadoliniumenhancing T1 lesions (p=0.724)). It was significantly steeper in those developing clinically definite MS within two years compared to those who did not (0.132 pu/mm vs 0.016 pu/mm, p=0.020). In multivariate binary logistic regression the MTR gradient was independently associated with the development of clinically definite MS within two years (MTR gradient odds ratio (OR) 61.708, p=0.023; presence of T2 lesions OR 8.500, p=0.071). At five years, lesional measures overtook MTR gradients as significant predictors of conversion to MS. The MTR gradient also correlated with Expanded Disability Status Scale (EDSS) score five years later (Spearman r=0.313, p=0.027). Conclusions: A gradient in periventricular MTR abnormality occurs early in MS, is at least partly independent of lesion formation, and is associated with the development of MS and disability following a clinically isolated syndrome. Disclosure Funding: The Queen Square MS centre is supported by the MS Society of Great Britain and Northern Ireland. J.W.L.B is funded through a Next Generation Fellowship funded by the Grant Charity of the Freemason’s. M.P. is supported by the non-profit Karol Wojtila Association (Lavagna, Italy). Potential conflicts of interest: J.W.L.B is in funded through a Next Generation Fellowship funded by the Grant Charity of the Freemason’s and has received travel expenses from Novartis, Sanofi-Genzyme and Biogen-Idec. M.P. is supported by the non-profit Karol Wojtila Association (Lavagna, Italy) and has received research support from Novartis. R.S. has nothing to disclose. C.G.W-K. was on the advisory board for

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BG12 (Biogen) and is editor of Functional Neurology. D.H.M has received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support for undertaking MRI analysis in multiple sclerosis trials sponsored by GlaxoSmithKline, Biogen Idec and Novartis. D.T.C. has received honoraria (paid to his employer) from Ismar Healthcare NV, Swiss MS Society, Excemed (previously Serono Symposia International Foundation), Merck, Bayer and Teva for faculty-led education work; Teva for advisory board work; meeting expenses from Merck, Teva, Novartis, the MS Trust and National MS Society; and has previously held stock in GlaxoSmithKline. P508 Brain functional MRI changes in multiple sclerosis patients treated with Tetrahydrocannabinol:Cannabidiol (THC:CBD) oromucosal spray for spasticity A. Gajofatto1, N. Cardobi2, F. Gobbin1, M. Calabrese1, M. Barillari3, M. Turatti4, M.D. Benedetti4 1Department of Neuroscience, Biomedicine, and Movement Sciences, 2Section of Radiology, University of Verona, 3Radiology Unit, 4Neurology Unit B, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy Background: THC:CBD is a second-line agent for the treatment of spasticity in MS with partial efficacy. Although THC:CBD mechanism of action is not completely understood, it may involve modulation of nociceptive as well as corticospinal pathways. Goals: Aim of this study is to investigate brain networks connectivity changes on resting state (RS) functional MRI (fMRI) of MS patients treated with THC:CBD. Methods: Based on statistical power calculation, we planned to include at least 12 MS patients eligible for treatment with THC:CBD oromucosal spray and followed at Verona University Hospital MS Center. Patients were evaluated at baseline before treatment start (T0) and after ⩾4 weeks of THC:CBD treatment at a stable dose (T1). Clinical variables included the EDSS and the Numerical Rating Scale (NRS) for spasticity scores. THC:CBD response was defined as a ⩾20% reduction on the NRS score at T1 compared to T0. Brain MRI was performed at T0 and T1 on a 1.5 T scanner, acquiring RS fMRI with a T2-weighted EPI sequence (TR=3000 ms, TE=50 ms, slice thickness=4 mm, ETL=57, 30 slices, 80 dynamics, time=240 s). Connectivity changes were compared before and after treatment in the whole group and according to response status, using functional connectivity toolbox (CONN, version 15.h). Each exam was first preprocessed using default CONN pipeline, then a second level group analysis step was applied. ROI-to-ROI and seed-to-voxel connectivity were evaluated. Results: Between January and September 2014, 15 consecutive patients were enrolled in the study. Of these, 12 (7 males, 5 females) completed all the assessments and entered data analysis. Median age was 51 years (36-73), disease duration 21.5 years (1037), EDSS score 6.0 (4.5-8.0), and baseline NRS score 8 (5-9).


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The clinical course was relapsing-remitting in 2 and secondary progressive in 10 patients. Seven patients (58.3%) resulted THC:CBD responders at T1. On fMRI analysis, we observed a significant association between THC:CBD therapy and global brain connectivity increase, decreased connectivity of motor areas, and bidirectional connectivity changes of the left cerebellum with a number of cortical areas. Connectivity increase at T1 was greater in responders than non-responders. Conclusions: THC:CBD administration appears to increase overall brain connectivity of MS patients with spasticity, particularly in responders. Modulation of motor areas and cerebellum connectivity seems to play a prominent role in THC:CBD effect. Disclosure Gajofatto Alberto: nothing to disclose. Cordobi Nicolò: nothing to disclose. Gobbin Francesca: nothing to disclose. Calabrese Massimiliano: Advisory Board membership: BayerShering, Genzyme, Biogen Idec. Payment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer Schering, Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA. Barillari Marco: nothing to disclose. Turatti Marco:nothing to disclose. Benedetti Maria Donata: nothing to disclose P509 Subclinical optic nerve involvement in CIS patients demonstrated by MRI is associated with McDonald MS 2010 criteria F. London, H. Zéphir, N. Hadhoum, P. Vermersch, O. Outteryck Centre Hospitalier Régional Universitaire de Lille, Lille, France Background: As spinal cord lesions, subclinical involvement of the optic nerve is frequent in relapsing remitting multiple sclerosis patients (RRMS) but is not considered in spatial dissemination of MS lesions. Objective: To evaluate frequency of subclinical optic nerve involvement in clinically isolated syndrome (CIS) and to measure its relationship with dissemination in space and/or time according to McDonald 2010 criteria. Material and methods: We prospectively included 49 patients presenting a CIS between November 2013 and March 2016. Each patient underwent a brain MRI at 3 months after CIS. Brain MRI (Philips Achieva 3T, 32 array coils) included 3D-sequences (T1, FLAIR, Double Inversion Recovery, T1-gadolinium). Subclinical optic nerve T2 hypersignal were investigated with 3D-DIR and 3D-FLAIR. For each patient, we collected MRI data fullfilling or not the DIS and DIT criteria according to McDonald 2010 criteria. Results: Among CIS patients, 35 were women (71.4%). Mean age was 30.6 ± 7 years. Monofocal presentation was predominant (93.9%). We recruited 20 patients with optic neuritis (40.8%), 18 patients with spinal cord syndrome (36.7%), 8 patients with brainstem syndrome (16.3%) and 5 patients with other symptoms (10.2%). We highlighted subclinical optic nerve involvement in 19 patients (38.8%; 21 optic nerves). Subclinical optic nerve involvement was not significantly associated with presence of DIS (p=0.3) or DIT (p=0.08) but was significantly associated with

MS defined according to MS McDonald 2010 criteria (p=0.04; presence of DIS and DIT). Conclusion: Subclinical optic nerve involvement is very frequent at the earliest clinical stage of RRMS and is associated with the diagnosis of RRMS according to McDonald 2010 criteria. As MAGNIMS 2016 recommendations, we suggest to systematically include an optic nerve MRI analysis at the CIS occurrence and to evaluate the predictive value of optic nerve involvement for CDMS occurrence. Disclosure FL reports grant from Biogen and funding fro travel from Genzyme. HZ reports personal fees and funding for travel from Biogen-Idec, Bayer, Novartis, Genzyme-Sanofi and Teva Pharmaceutical Industries, funding for travel from Merck-Serono. NH reports funding for travel from Teva Phamaceutical Industries and Biogen. PV reports grant for research from Novartis; grants and personal fees from Merck-Serono and Bayer, personal fees from BiogenIdec, Almirall, Genzyme-Sanofi and Teva Pharmaceutical Inductries. OO reports grant for research from Novartis; grants and personal fees from Biogen-Idec, funding for travel from Biogen-Idec, Genzyme-Sanofi, Merck-Serono, Novartis and Teva Pharmaceutical Industries. P510 Grey matter hypoperfusion and subsequent brain atrophy in MS: a longitudinal MRI study with pseudo-continuous arterial spin labeling L. Freeman1, J.A. Lincoln1, P.A. Narayana2, J.S. Wolinsky1 1Department of Neurology, 2Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Background: Perfusion is reduced in the grey matter (GM) of MS patients. It remains unclear to what extent this reduction in cerebral blood flow (CBF) is a pathological process that negatively impacts an already precarious energy balance in MS tissues, or a physiological response to reduced metabolic activity. Objective: To investigate whether changes in CBF are pathologyrelated in MS by comparing regional perfusion patterns between healthy controls (HC) and patients, and between patients with subsequent high vs low rates of brain atrophy. Methods: 31 MS patients and 19 HC underwent brain MRI at 3T with pseudo-continuous arterial spin labeling (pCASL) to quantify CBF and 3D-MPRAGE for volumetric assessment. Longitudinal volumetric data was available for 21 relapsingremitting MS patients (mean follow-up=25 months). FreeSurfer was used for segmentation, cortical surface reconstruction and quantification of annual rates of brain volume loss. CBF maps were obtained after quantification, calibration and partial volume effect correction of pCASL images. Patients were classified as having minimal brain atrophy if their annual rate of brain volume loss was less than 0.6% per year (n=10, mean=-0.24% per year) or as moderate to severe if the rate was greater than 0.8% per year (n=11, mean=-1.14% per year). Region-of-interest


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Poster Session 1, 22(S3) (ROI) and surface-based analyses (corrected for multiple comparisons) were performed to compare baseline CBF values in deep GM and cortical structures in patients vs HC, and in patients with high vs low rates of subsequent brain atrophy. Results: Patients showed significant decreases in CBF in all subcortical and most lobar ROI tested when compared to HC. Cortical mapping of inter-group differences found widespread areas of decreased CBF in fronto-temporal cortices in MS. We identified several regions of decreased baseline CBF in patients with subsequent moderate to severe brain atrophy when compared to patients with only minimal atrophy. These clusters involved the left postcentral, right lateralorbitofrontal and right cingulate cortices and were not associated with significant differences in cortical thickness at baseline. ROI analyses also showed a trend to lower perfusion in total cortical and subcortical GM ROI. Conclusion: The results of our pilot study suggest that hypoperfusion is widespread in the cortical and subcortical GM of MS patients and that it could be a determining factor in subsequent tissue damage. Disclosure Leorah Freeman receives research funding from the National Multiple Sclerosis Society through the University of Texas Health Science Center at Houston (UTHSCH). John Lincoln in the last 3 years has received compensation for promotional presentations for Acorda Pharmaceuticals, Biogen Idec, Genzyme-Sanofi, Novartis and Teva and have participated as an advisory board member for Genzyme-Sanofi and Novartis. Ponnada Narayana receives research funding from the NIH and Sunovion/ Sanbio, Inc. Jerry Wolinsky in the last 3 years has received compensation for service on steering committees or data monitoring boards for F. Hoffmann-La Roche Ltd., Medday Pharmaceuticals, Novartis, Sanofi Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, EMD Serono, Forward Pharma, Genentech, Inc., F. Hoffmann-La Roche Ltd., Novartis, Sanofi Genzyme, Takeda, Teva, and XenoPort; research support from, Sanofi Genzyme, the NIH and the NMSS through the University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH. P511 The cerebello-thalamic tract as a neural correlate for tremor in multiple sclerosis F. Boonstra1, G. Florescu2, C. Steward2, A. Evans3, H. Butzkueven4, P. Mitchell2, S. Kolbe1, A. Van Der Walt4 1Anatomy & Neuroscience, University of Melbourne, 2Radiology, 3Neurology, Royal Melbourne Hospital, 4Medicine, University of Melbourne, Melbourne, VIC, Australia Introduction: Tremor is a prominent and debilitating feature of Multiple Sclerosis (MS) whose pathophysiology is not fully established. Recent studies suggest that MS-tremor may be dystonic and caused by injury to subcortical grey matter structures and the cerebello-thalamic tract. Our aim was to determine the correlation between clinical tremor severity and magnetic resonance imaging (MRI) based volumetric measures of structures within the cerebello-thalamic tract.

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Methods: Eleven patients (54.1±11.4yrs) with right-sided, unilateral MS-related upper limb tremor underwent 3T MRI (high resolution T1, T2 and FLAIR) and a clinical tremor assessment by a movement disorder neurologist. Tremor severity was quantified using the Bain score (0 to 10) for overall severity, writing and drawing of an Archimedes spiral. Thalamic volumes were calculated using FreeSurfer (5.7). Superior Cerebellar Peduncle (SCP) cross-sectional areas were manually labeled and calculated as the average of two independent raters (intraclass correlation=0.729). Thalamic and SCP measures were compared interhemispherically using paired t-tests. Tests for correlations between volumetric (with and without correction for intracranial volume [ICV]) and clinical parameters employed two-tailed Spearman tests. Results: Patients’ right hemisphere thalamic volumes (6058±917mm3) were significantly lower than left hemisphere (6865±1267mm3; t=-4.522, p=0.001). There was no significant difference between the right SCP (22.3±3.34mm3) and the left SCP (22.4±2.66mm3). Left thalamic volume significantly correlated with right-side Bain tremor severity score (uncorrected for ICV: r=-0.750, p=0.008; corrected for ICV: r=-0.677, p=0.022). Right SCP cross-sectional area significantly correlated with rightsided Bain writing (r=-0.688, p=0.019) and Archimedes spiral scores (r=-0.731, p=0.011). Conclusions: Our study demonstrates that contralateral thalamic and ipsilateral SCP atrophy correlate with MS tremor severity. As both structures are part of the same cerebello-thalamic tract, these findings support the hypothesis that damage to this tract has a central role in tremor pathophysiology in MS. Further study in a larger cohort is needed to elucidate this further. Disclosure F. Boonstra has nothing to declare G. Florescu has nothing to declare C. Steward has nothing to declare A. Evans has received honoraria from Novartis for giving presentations and providing consultancy services. He has participated in scientific advisory board meetings for Novartis, UCB Pharma, Allergan, and Boehringer Ingelheim. He has received conference travel support from Boehringer Ingelheim. H. Butzkeuven has received consulting fees from Genzyme, Biogen, Novartis, Merck and Oxford PharmaGenesis and grant/ research support from Biogen, Novartis, Merck and Genzyme P. Mitchell has nothing to declare S. Kolbe receives grant income from the National Health and Medical Research Council of Australia and has received honoraria from Novartis A van der Walt has received travel support from Biogen Idec, Novartis, Teva, Merck and serves on several advisory boards P512 Microstructural white matter correlates of motor fatigue in multiple sclerosis - a diffusion weighted imaging study C. Bauer1,2, K.W. Andersen1, O. Svolgaard1, K.H. Madsen1, T.B. Dyrby1, F. Sellebjerg3, H.R. Siebner1,4 1Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, 2Department of Technology, Metropolitan University College, 3Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University,


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Rigshospitalet, 4Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark Introduction: Fatigue is one of the most common symptoms in multiple sclerosis (MS). It contributes significantly to reduced quality of life. Some studies suggest that fatigue is a consequence of microstructural disease alterations in specific white matter (WM) tracts - e.g., right anterior thalamic radiation (rATR) (Bester 2013, Gobbi 2014). However, others have not been able to find any associations between WM changes and fatigue. Consequently, the role of microstructural WM changes in the pathophysiology of fatigue remains unclear. The aim of this study was to evaluate the relation between WM microstructural brain pathology and motor fatigue in MS. Methods: We included 50 mildly disabled relapsing remitting MS patients from the Danish Multiple Sclerosis Centre and 25 age -and sex-matched healthy controls (HC). Fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMC). Additionally, all participants underwent a standard MS test-battery and a Magnetic Resonance Imaging (MRI) examination including conventional scans and Diffusion Weighted Imaging (DWI). i) The local microstructural brain structures were assessed with fractional anisotropy (FA) for detecting the voxelwise indicating indices of WM abnormalities compared to HC. ii) The disruption of neural fibres connecting specific brain areas was assessed with anatomical connectivity mapping (ACM), which reflects the strength of connectedness of each WM voxel to the entire brain (Lyksborg 2014). iii) We also assessed the correlation between fatigue scores and MS-related WM pathology. Results: Relative to HC, MS patients showed reduced FA and ACM in the body of the corpus callosum (CC) containing motor fibres (p< 0.001 and p=0.022 respectively, FWE corrected at the cluster level). We did not find statistically significant correlations between motor fatigue and microstructural disease alterations in rATR (p>0.900) (extracted with the JHU White-Matter Tractography Atlas) or using a whole brain white-matter mask (p>0.706). Conclusion: The microstructure in the body of CC, including the transcallosal motor fibres, was significantly altered in the MS group relative to HC. This suggests that individuals with MS have a changed interhemispheric connectivity in the commissural motor fibres. Since we found no association between regional WM microstructure and fatigue, our data do not support the notion that a local structural WM change may be critical for the emergence of fatigue in MS. Disclosure Christian Bauer: nothing to disclose Kasper Winther Andersen: Partly funded by the Danish Multiple Sclerosis Society (DMSS) Olivia Svolgaard: Funded by the Danish Multiple Sclerosis Society (DMSS), recieved travel funding from Biogen Idec and DMSS. Kristoffer H. Madsen: nothing to disclose Tim B. Dyrby: nothing to disclose Finn Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker

honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva. Hartwig R. Siebner has served on a scientific advisory board for Lundbeck A/S, Valby Denmark, and has received honoraria as speaker from Biogen Idec, Denmark A/S, Genzyme, Denmark and MerckSerono, Denmark, has received honoraria as editor from Elsevier Publishers, Amsterdam, The Netherlands and Springer Publishing, Stuttgart, Germany, has received travel support from MagVenture, Denmark, and has received a research fund from Biogen-idec. P513 Heterogeneity of cortical lesions susceptibility map in multiple sclerosis and its neuropathological interpretation M. Castellaro1,2, R. Magliozzi2,3, A. Palombit1, S. Montemezzi4, A. Bertoldo1, R. Reynolds3, S. Monaco2, M. Calabrese2 1Department of Information Engineering, University of Padova, Padova, 2Neurology B, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona, Italy, 3Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom, 4Radiology Units, Department of Diagnostics and Pathology, Verona University Hospital, Verona, Italy Background: Cortical lesions (CLs) in multiple sclerosis (MS) are a frequent and early phenomenon having significant impact on physical and cognitive disability progression. Susceptibility Weighted Imaging (SWI) and Quantitative Susceptibility Mapping (QSM) have previously been used to characterize iron and myelin alterations in deep grey matter of MS patients. The aim of this study is to characterize the susceptibility map of CLs in MS patients and to compare the in vivo neuroimaging characterization with neuropathological observations. Methods: The pattern of microglial/macrophage activation was studied in post-mortem brain tissue from 16 secondary progressive (SP) MS cases characterized by the presence of widespread cortical demyelination and from 5 age-matched normal controls. 29 MS patients underwent 3T MRI, which included isotropic high resolution 3D double inversion recovery (DIR) (1x1x1mm3) and 3D-EPI SWI (0.55x0.55x0.55mm3). The susceptibility maps were obtained with a novel Total Generalized Variation algorithm. Intracortical and leukocortical CLs were identified on DIR sequences. The QSM map, corresponding to each CL, was then evaluated. Results: The neuropathological analysis on post-mortem SPMS brains revealed the preponderance of chronic active CLs and the presence of an intense band of microglia activation in the external cortical layers close to the pial membrane in subpial CLs, or at the WM border of leukocortical CLs. The QSM analysis revealed a total of 178 CLs; 104 CLs were classified as hyperintense, 28 as isointense, and 45 as hypointense. Sixteen patients showed at least two QSM-subtypes of CLs and four patients showed all QSMsubtypes of CLs at the same time. In relapsing remitting (RR) MS, 71.5% of CLs were hyperintense and 16.4% hypointense, whereas in SPMS 39% of CLs were hyperintense and 43.0% were hypointense (p< 0.00001). QSM hyperintensity edge found in proximity of the pial surface or at the WM/GM interface in some of the QSM-hyperintense CLs, accurately mirrors the microglia activation observed in the neuropathology analysis.


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Poster Session 1, 22(S3) Conclusions: The susceptibility maps of CLs are highly heterogeneous among MS patients, even at the individual level. QSM hyperintense CLs are more frequent in RRMS patients. QSM hyperintensity edge found in proximity to the pial surface in some of the QSM-hyperintense CLs might be due to the subpial gradient of microglial/macrophage activation. Disclosure Dr. Massimiliano Calabrese has the following disclosure Advisory Board membership: Bayer-Shering, Genzyme, Biogen IdecPayment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer-Schering, Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA The other authors have nothing to disclose. P514 Neurite orientation dispersion and density imaging (NODDI) reflects early microstructural brain tissue changes in clinically isolated syndrome (CIS) S. Collorone1,2, N. Cawley1, F. Prados1,3, C. Tur1, F. Grussu1, B. Kanber1,3, S. Ourselin3, C.A.M. Gandini WheelerKingshott1,4,5, D.H. Milller1,6, A. Thompson6, A. Toosy1, O. Ciccarelli1,6 1NMR Research Unit, Queen Square MS Centre, Institute of Neurology, University College of London, London, United Kingdom, 2Sapienza University, Rome, Italy, 3Medical Physics and Bioengineering, University College of London, London, United Kingdom, 4Brain MRI 3T Research Center, C. Mondino National Neurological Institute, 5Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy, 6NIHR University College London Hospitals Biomedical Research Centre, University College of London, London, United Kingdom Background: Diffusion tensor imaging (DTI) has been applied in clinically isolated syndrome (CIS), and demonstrated the presence of pathological abnormalities in the normal-appearing white matter (NAWM). However, DTI indices have a low pathological specificity. Neurite Orientation Dispersion and Density Imaging (NODDI) is a new diffusion weighted multi-compartment model, which reflects neuronal morphology, like the density and the dispersion of the neurites (axons and dendrites). Preliminary applications to patients with relapsing-remitting multiple sclerosis have shown abnormal NODDI parameters in the NAWM and grey matter (GM). Objective: The aims of this study were to: (i) compare the NODDI parameters between CIS patients and healthy controls (HCs) (ii) determine in CIS patients the relationship between NODDI measures and clinical scores. Methods: We recruited: 21 CIS subjects within 3 months from symptom onset (10 females), mean age 34.25 years (SD8.57) and 12 HC (8 females), mean age 33.73 years (SD7.18). The brain MRI protocol performed at 3T included T2-images, volumetric images and NODDI. 14/20 patients had asymptomatic T2 WM lesions. Brain tissue segmentation was performed to obtain white matter (WM) and GM tissue volumes (after lesion filling). Using

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the NODDI matlab toolbox we obtained: orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (isoVF); they were calculated in WM, GM and T2 lesions. The Expanded Disability Status Scale (EDSS), MS Functional Composite score, (MSFC) and the Brief Cognitive Assessment for MS (BICAMS) were scored in the patient group. Linear regression models were used to compare the differences in MRI measures between groups adjusting for age, gender and brain volume fractions. Results: Patients had a median EDSS of 1.0 (range 0 - 2.5) and were cognitively intact. Patients showed a higher orientation dispersion index (ODI) in NAWM than WM of HCs (0.26 ±0.1 vs 0.25±0.05 p< 0.023). The other NODDI parameters did not differ between CIS and HCs. The NAWM ODI did not correlate with clinical scores. Conclusion: Our results suggest a reduced alignment of axons that become more dispersed and less oriented when compared to those of the normal WM. These results now need to be confirmed in a larger sample (recruitment is ongoing). Disclosure S. Collorone Meeting expenses AAN conference 2016 paid by Novartis. N. Cawley Nothing to disclose F. Prados Nothing to disclose C. Tur has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Bayer-Schering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare F. Grussu is funded by the H2020-EU.3.1 CDS-QUAMRI grant (ref.: 634541) and received support from the UCL Grand Challenge Studentships scheme. B. Kanber Nothing to disclose S. Ourselin Nothing to disclose CAM Gandini Wheeler-Kingshott is on the editorial board of Functional Neurology and receives research grants (PI and coapplicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. D.H Miller received grants from UCL/UCLH Biomedical Research Centre, during the conduct of the study; has received grants from Biogen, GlaxoSmithKline, the National Institute for Health Research, Novartis, and Apitope; has board membership with Biogen Idec, GlaxoSmithKline, Bayer Schering Pharma, and Mitsubishi Pharma Europe; has been a consultant for Merck and Chugai; and has received personal fees from McAlpine’s Multiple Sclerosis, 4th edition. A. Thompson Received honorarium from SAGE Publishers as Editor-in-Chief for Multiple Sclerosis Journal. Free subscription from Elsevier as member of Editorial Board for The Lancet Neurology . Received personal compensation for consulting, serving on a scientific advisory board and speaking from Biogen, MedDay, Novartis and Teva. A.Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation, Bayer and meeting expenses from Biogen Idec. O. Ciccarelli is an Associate Editor of Neurology and serves as a consultant for GE Healthcare, Novartis, Roche, Biogen, Genzyme and Teva.


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P515 Corpus callosum in clinically isolated syndromes: lesion distribution, atrophy and predictor value to conversion D. Pareto1, J. Sastre-Garriga2, C. Auger1, J.F. Corral1, M. Tintoré2, X. Montalban2, À. Rovira1 1Radiology, 2Neurology and Neuroimmunology and Multiple Sclerosis of Catalonia, University Hospital Vall d’Hebron, Barcelona, Spain Background: In multiple sclerosis (MS) patients, the corpus callosum (CC) is a structure affected by demyelination and axonal loss. It has been also associated with brain atrophy, cognitive impairment and as a predictor of long-term disability. The role of the cc in clinically isolated syndrome (CIS) patients has not been deeply studied so far. Objective: To evaluate the presence and the spatial distribution of lesions in the CC, as well as the role of the CC atrophy in predicting conversion to MS of CIS patients. Material and methods: 87 patients with a mean age of 34.4 years (SD 7.9) underwent a brain 3T MRI within the first 5 months after symptoms onset (baseline) and at one year. Time to conversion using McDonald 2010 criteria was recorded. Barkhof criteria were scored for all patients and fulfilment coded as 0-1-2 versus 3-4. In the baseline MRI, lesions in the CC were identified and outlined semiautomatically over a T2-FLAIR image with the JIM (Xynapse Systems) software. With the generated lesion mask, a lesion-filling procedure was applied over the structural images before segmenting it with FreeSurfer. CC volumes (anterior, mid anterior, central, mid posterior and posterior) were normalized to the total intracranial volume. The corresponding lesion probability map (LPM) was also generated with Statistical Parametric Mapping (SPM8). Cox regression analysis was applied to explore the relationship between CC atrophy and conversion to MS. Results: CC lesions were identified in 68% of the patients. The LPM distribution was quite homogeneous along the CC (at least 84% of the cc portions were covered by a lesion), with the maximum incidence located in areas of the anterior portion. A 71% of patients converted to MS (either clinically or by MRI) in the follow-up period. Cox regression indicated that normalized volume of the mid anterior portion of the CC was associated with conversion to MS (HR: 1.703; IC95%: 1.028-2.822; p=0.039); however, this association was not significant after adjusting by Barkhof criteria fulfilment. Conclusions: The anterior portion of the CC showed the highest incidence of lesions. Volume of the mid anterior part of the CC was associated with conversion to MS, but did not improve prediction over Barkhof criteria although the sample size might have been too small. Disclosure D Pareto has received speaking honoraria from Novartis and Genzyme. J Sastre-Garriga has received compensation in the last 12 months for speaking or participation in advisory boards from Novartis, Biogen and Merck and grants from Genzyme. C Auger has received speaking honoraria from Biogen, Stendhal and Novartis JF Corral has nothing to disclose.

M Tintoré has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck-Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Novartis, Almirall, Genzyme, and Roche X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Amirall, Bayer, Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva Pharmaceutical. A Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer, Genzyme, SanofiAventis, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, Stendhal, Novartis and Biogen Idec, and has research agreements with Siemens AG. P516 Cortical and deep grey matter network changes in secondary progressive multiple sclerosis K.A. Meijer, A.J.C. Eijlers, J.J.G. Geurts, M.M. Schoonheim Department of Anatomy and Neurosciences, VUmc MS centre Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands Background: Atrophy of the deep grey matter (DGM) is a common and early finding in MS, while cortical atrophy seems to be more frequent in later phases. It is currently unknown, however, how functional connectivity of the cortex and DGM changes in the different stages of MS and how this relates to cognition. Aim: To investigate changes in functional connections within and between cortical and DGM areas in early relapsing remitting (RR), late RR and secondary progressive (SP) MS. Method: A cohort of 243 RRMS patients, 53 SPMS patients and 96 healthy controls underwent resting state functional MRI and extensive neuropsychological testing. Using a median split on disease duration, 121 RRMS patients were classified as early (mean disease duration 7 (5-10) years) and 122 as late RRMS (mean disease duration 20 (10-38) years). The groups were compared by looking at (1) the averaged within-DGM connectivity, (2) the averaged within-cortex connectivity and (3) the averaged DGMcortex connectivity. Connectivity values were corrected for individual means and standard deviations in order to specifically look at network balance changes (i.e. relative connectivity) and compared between groups using general linear models with sex and education as covariates (p< 0.05, Bonferroni corrected). In order to assess the additive value of connectivity beyond structural measures, forced-entry linear regression models were used for each network measure to predict the most severely affected cognitive domain in SPMS. Results: SPMS patients showed decreased within-cortex connectivity and increased within-DGM connectivity compared to early RRMS. Late RRMS showed increased within-DGM connectivity compared to early RRMS, with no change in within-cortex connectivity. The connections between cortical and DGM regions were stronger in SPMS and late RRMS compared to early RRMS and HC. In SPMS, increased within-DGM connectivity (β=0.270) and decreased normalised DGM volume (β=0.540) were


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Poster Session 1, 22(S3) the only significant predictors for information processing speed (IPS) dysfunction (R2=0.37). Conclusion: In late RRMS and SPMS, increased connectivity within the DGM and between the DGM and the cortex was observed compared to early RRMS. These connectivity changes were associated with IPS. Decreased within-cortex connectivity was unique to SPMS. These findings indicate that a specific shift in network balance occurs throughout the disease course, which needs to be confirmed in future longitudinal studies. Disclosure KA Meijer: nothing to disclose and receives funding from a Biogen research grant AJC Eijlers: nothing to disclose and receives research support from the Dutch MS Research Foundation, grant 14-358e JJG Geurts: nothing to disclose MM Schoonheim: nothing to disclose and receives research support from the Dutch MS Research Foundation, grant 13-820 P517 Correlation between brain volume change and T2 relaxation time in patients with clinically isolated syndrome F.X. Aymerich1,2, C. Auger1, M. Alberich1, D. Pareto1, J. Sastre-Garriga3, M. Tintoré3, X. Montalban3, A. Rovira1 1Unitat RM Vall d’Hebron (IDI), Hospital Vall d’Hebron, 2Automatic Control Department, Universitat Politècnica de Catalunya, 3CEMCAT, Hospital Vall d’Hebron, Barcelona, Spain Background and objective: Regional volumetric studies have suggested that reversible brain volume changes (pseudoatrophy) are mostly confined to the white matter, where inflammatory infiltrates, glial activation and vasogenic oedema are more prominent compared to grey matter. The aim of this study is to correlate pseudo-T2 values (a measure of brain hidratation status) with brain volume changes in patients with clinically isolated syndrome (CIS). Materials and methods: 96 patients with CIS were included (62 women; median age, 33 years; age range, [19, 49]; EDSS mean, 2; EDSS range, [0, 4.5]; mean disease duration, 3.78 months). Baseline and 12 months proton density (PD), T2-weighted, and 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequences were acquired on a 3.0T. The dual-echo sequence was used to produce pseudo-T2 maps [pT2=(TE2-TE1)/ln(S1/S2)], where S1 and S2 were the measured image intensities at each echo time, TE1 and TE2. Pseudo-T2 values, which are a simple measure that reflects brain water content, were evaluated in regions of normal appearing white matter drawn on PD-weighted images using Jim 6.0 software. The images acquired with the MPRAGE sequence were used to obtain white and grey matter fractions using SIENAX (FSL). Changes between month 12 and baseline studies in pT2, white and grey matter fractions were then evaluated. Statistical analysis include Spearman rank correlation test to evaluate the relation between changes in pT2 and changes in white and grey matter fractions. Results: A significant, although weak positive correlation (r=0.276, p=0.006) between changes in pT2 and changes in white matter was found. Changes in grey matter did not correlate with changes in pT2 (r=-0.002, p=0.982).

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Conclusions: The results obtained support the concept that white matter volume changes in patients with multiple sclerosis can be partially explained by fluctuations in brain water. Our results also support the value of pseudo-T2 measures to assess white matter water changes, and its potential role in distinguishing reversible from irreversible brain tissue loss (atrophy). Disclosure F. X. Aymerich has nothing to disclose C. Auger has received speaking honoraria from Biogen, Stendhal and Novartis M. Alberich has nothing to disclose D. Pareto has received speaking honoraria from Novartis and Genzyme J. Sastre-Garriga has received compensation in the last 12 months for speaking or participation in advisory boards from Novartis, Biogen and Merck and grants from Genzyme. M. Tintore has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, MerckSerono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Novartis, Almirall, Genzyme, and Roche. X. Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva Pharmaceutical A. Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec, and has research agreements with Siemens AG. P518 An integrated imaging informatics software platform to improve the analysis of clinical trials and research data in MS B. Kanber1, F. Prados1,2, N. Cawley2, A. Eshaghi2, S. Collorone2, C.A.M. Wheeler-Kingshott2,3, F. Barkhof1,2, O. Ciccarelli2, S. Ourselin1,4 1Medical Physics and Biomedical Engineering, UCL, 2Department of Neuroinflammation, UCL Institute of Neurology, London, United Kingdom, 3Brain Connectivity Center, C. Mondino National Neurological Institute, Pavia, Italy, 4Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom Background: There is an increasing number of MRI analysis methods in MS to calculate brain volume, cortical thickness, lesion characteristics and other imaging parameters. Additionally, increasingly large data sets are acquired in clinical trials and research projects. It is difficult and cumbersome to manually (or semi-automatically) process such large datasets with different, although linked, post-processing methods. Variations between software versions and pipeline parameters can bias the results, and controlling for inter-operator variability requires time and effort. We developed an integral system that offers scalable, automated, and distributed processing of MS imaging data and tested it using a large research data set.


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Methods: We customized an open-source imaging informatics software platform (XNAT) that facilitates data management for neuroimaging into an integrated system that automatically carries out the required processing over a scalable cluster of computers. We tested the efficacy of the system in 2 different MS research data sets with a total number of 202 MRI sessions. The test system architecture was modest and comprised 3 processing nodes with a total number of 10 processing cores. Results: The following processes were completed by the presented system: 130 brain parcellations, 54 lesion fillings, 65 segmentations of hippocampi, 65 cortical thickness calculations, 117 brain sodium maps, 56 Diffusion Tensor Imaging (DTI) maps, and 129 instances of Neurite Orientation Dispersion and Density Imaging (NODDI). The processing was completed in less than 8 weeks without operator intervention. In our calculations of brain total sodium concentration, we obtained significantly lower coefficients of variation (p< 0.05), and more significant differences between patients and healthy controls (p=0.002 vs. 0.033 for the GM) using the presented system as compared with a manual method. Conclusions: Our newly developed fully automated system for the analysis of imaging data is a more time- and resource-efficient method than the manual/semi-automatic solutions currently in use. The introduction of this service will help to standardize results across studies (including audit-trail and storage), as the same processing pipelines, software versions and parameters will be used for all the processes. Other benefits of the proposed architecture include its cost effectiveness and potential to be extended to clinical trials, clinical setting and other research centres. Disclosure Baris Kanber: nothing to disclose Ferran Prados: nothing to disclose Niamh Cawley: nothing to disclose Arman Eshaghi: Arman Eshaghi has received MAGNIMS and Multiple Sclerosis International Federation McDonald fellowships (MSIF, www.msif.org). Sara Collorone: nothing to disclose Claudia A.M. Wheeler-Kingshott: Claudia A.M. Gandini Wheeler-Kingshott serves as a consultant for Biogen and receives research support from the UK MS Society, UCL/UCLH NIHR BRC, EPSRC, ISRT, Wings for Life, New Zealand Brain Research Centre, Novartis, and Biogen. Frederik Barkhof: nothing to disclose Olga Ciccarelli: Olga Ciccarelli is an Associate Editor of Neurology and serves as a consultant for GE Healthcare, Novartis, Roche, Biogen, Genzyme and Teva. Sebastien Ourselin: nothing to disclose P519 Multiple MRI measures to predict disability in MS patients: which works best? S. Ruggieri1,2, F. De Luca1, N. Petsas1, F. Tona1, L. De Giglio1, N. Upadhyay1, L. Prosperini1, C. Pozzilli1, P. Pantano1 1Department of Neurology and Psichiatry, University of Rome ‘Sapienza’, 2Department of Neuroscience, A.O. S. Camillo Forlanini, Rome, Italy Background: Motor deficit plays a major role in global clinical disability in multiple sclerosis (MS). Despite its high prevalence

and detrimental effects on patients’ daily life activities, its structural substrates have yet to be fully elucidated. Objectives: 1) To assess the influence of structural damage in different sites of the motor system in a cross-sectional evaluation on a cohort of patients with MS. 2) To longitudinally identify which MRI measures can predict the evolution of disability in the following years. Methods: 58 MS patients underwent clinical examination and 3T MRI [11 male; mean age 36.5 ±7.1 years; median Expanded Disability Status Scale (EDSS) 1.5, (range 0-6); mean 25-Foot Walking Test (25FWT) 5.9±1.6 sec, mean 9-Hole Peg Test Dominant Hand (9HPT-DH) 18.8±3.4 sec, Non Dominant Hand (NDH) 20.4±4.5 sec]. MRI protocol included: T2-W TSE, 3D T1-W and DTI. We calculated the following MRI measures: corticospinal tract (CST) and corpus corpus callosum (CC) fractional anisotropy (FA); deep grey matter (DGM) normalized volumes as thalamus (ThV), caudate (CaV), putamen (PuV), and pallidum (PaV); total and infratentorial lesion load (LL, LLit respectively); normalized spine volume at C2-C3 level (SV). Follow-up (FU) (median FU: 3, range 1-5 years) clinical evaluation was performed on 47 MS patients from the baseline cohort. We carried out univariate correlations of the aforementioned MRI measures with baseline scores and Cox regression analyses to identify MRI variables predictive of future disability. Results: Cross-sectional analyses showed correlations between EDSS score and ThV, CaV, PuV (0.001 < p < 0.05). Baseline 25FWT was associated with SV, ThV, CaV, (0.001 < p < 0.05). 9HPT-DH exhibited an inverse correlation with LL and all DGM structures (0.001< p0.05), while 9HPT-NDH with LL, LLit, ThV, PaV (0.001< p< 0.05). At FU 18 patients showed worsening exceeding 20% in at least one clinical measure or increasing 1 point in the EDSS score. Baseline volume of the thalamus and LLit were the best predictors of worsening in EDSS (HR: 0.99, p=0.06; HR: 1.01, p=0.02 respectively). CaV predicted worsening in 9HPT-NDH at FU (HR: 0.99, p=0.02). Conclusion: Our results confirm the fundamental role of subcortical grey matter structures in motor impairment. Thalamic volume appears a good predictor of future disability assessed by EDSS, as caudate volume may predict future limitation in manual dexterity. Disclosure Ruggieri S: nothing to disclose De Luca F: nothing to disclose Petsas N has received speaker fee from Biogen Idec-Portugal Tona F: nothing to disclose De Giglio L: nothing to disclose Upadhyay N: nothing to disclose Prosperini L has received speaker honoraria from Biogen, Genzyme, Novartis and Teva; consulting fees from Biogen and Novartis; research grant from Genzyme andAISM/FISM. Pozzilli C has received consulting and lecture fees from Bayer Schering, Biogen, Merck-Serono, Novartis, and Sanofi-Aventis; has received research funding from Bayer Schering, Merck Serono, Novartis, and Sanofi-Aventis. Pantano P has received founding for travel from Novartis, Genzyme and Bracco and speaker honoraria from Biogen.


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Poster Session 1, 22(S3) P520 Decreased susceptibility of the thalamus is associated with increased disability in patients with multiple sclerosis R. Zivadinov1,2, J. Hagemeier1, E. Carl1, C. Kolb3, F. Lin1, N. Bergsland1, D. Hojnacki3, M.G. Dwyer1, D.P. Ramasamy1, J. Durfee1, B. Weinstock-Guttman3, F. Schweser1 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: Quantitative susceptibility mapping (QSM) is a novel MRI technique that can provide increased specificity in iron detection or changes of myelin. Previous research using a variety of MRI iron and myelin sensitive methods has shown that multiple sclerosis (MS) patients tend to have more severe demyelination and iron deposition, especially in the deep gray matter (DGM) and thalamus, in particular. However, no previous studies explored association between QSM and disability in MS patients. Objective: We explored association of QSM in DGM and disability, as measured by Expanded Disability Status Scale (EDSS) in a large cohort of MS patients. Methods: 600 MS patients (relapsing-remitting (RR): 452, secondary-progressive: 148) and 250 age- and sex-matched healthy controls (HCs) were recruited for the present study. QSM magnetic susceptibility was determined for DGM structures with higher susceptibility representing increased iron levels and lower susceptibility representing decreased iron levels. Associations of QSM with clinical outcomes were explored using regression analysis in which susceptibility of DGM structures was used as dependent variable, age and sex, as covariates, MS course (RR vs. SP), EDSS and disease duration, as variables of interest, and interaction effect to test whether relationship between EDSS and disease duration with QSM measures varies between RR and SP. Results: MS patients showed increased susceptibility in the caudate, putamen and globus pallidus (p< 0.001) and total DGM (p=0.003) and decreased in thalamus (p< 0.001) compared to HCs. SPMS patients showed decreased susceptibility in thalamus compared to RRMS (p=0.007). Decreased susceptibility of thalamus was significantly associated with longer disease duration (p=0.001), increased disability (p=0.006) and SPMS course (p=0.024). The interaction effect between QSM and disease duration showed that longer disease duration in RRMS was associated with decreased susceptibility of the thalamus. Additional significant relationships were found between increased susceptibility in the globus pallidus (p=0.004) and hippocampus (p=0.017) and increased disability. Conclusions: These findings suggest that decreased susceptibility of the thalamus is strongly associated with more severe disability, longer disease duration and SPMS course. The QSM changes of the thalamus may be also related to structural changes of the myelin and should be investigated in longitudinal studies.

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Disclosure Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Jesper Hagemeier, Ellen Carl, Fuchun Li, Niels Bergsland, Deepa Ramasamy, Jacqueline Durfee and Ferdinand Schweser have nothing to disclose. Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. Michael G Dwyer received personal compensation from Novartis and Claret Medical for speaking and consultant fees. He received financial support for research activities from Novartis. David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis. Bianca Weinstock- Guttman has participated in speaker´s bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Mylan Inc., and Acorda Therapeutics, Inc. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence as well as Questcor Pharmaceuticals, Inc., and Shire. She serves in the editorial board for BMC Neurology, Journal of International MS, Journal of Multiple Sclerosis. P521 Impact of fingolimod on MRI brain measures in routine clinical practice: interim results from a longitudinal observational, multicenter real-world outcome study in multiple sclerosis patients R. Zivadinov1,2, N. Khan3, J. Medin4, J. Korn5, N. Bergsland1, P. Christoffersen3, E. Carl1, M.G. Dwyer1, J. Price3, I. Bonzani6, D. Silva4, B. Weinstock-Guttman7 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 2MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States, 3IMS Health, 4Novartis Pharmaceuticals AG, Basel, Switzerland, 5IMS Health, Burlington, MA, United States, 6IMS Health, London, United Kingdom, 7Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: While there is an increasing need to monitor the effect of disease-modifying treatment on individual patient level in real time, the assessment of brain atrophy is not part of standard clinical evaluation. Objective: The objective of this analysis was to evaluate brain volume changes and presence of new/enlarging T2, T1 and gadolinium positive brain lesions on MRI performed in routine clinical practice among patients with relapsing remitting multiple sclerosis (RRMS) initiating fingolimod treatment. Design and methods: This is an ongoing, multicenter, retrospective, chart review of RRMS patients. Clinical and brain MRI data are being collected from 600 patients over 48 months.


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Patients aged 18-65 who initiated fingolimod (index) and received at least 28 days of treatment are included. Patients had data collected at index (6 months prior to 1 month after index) and post-index (9-24 months after index); all patients included had MRI available at both times. Patients with prior use of natalizumab are excluded. Detailed methodology is being presented in a separate abstract. Global MRI atrophy measures include annualized percent change in whole brain (WB) volume assessed by the SIENA method on 2D-T1 and 3D-T1 scanners, and percent change in lateral ventricular volume (LVV) assessed by VIENA on 2D-T1 and 3d-T1 scanners and NeuroSTREAM on FLAIR. Lesion measures include T2- and T1- lesion volumes (LV), new/enlarging T2 and gadolinium-enhancing (Gd+) T1 lesions. Results: Here we present results from interim analysis (N=252). New/enlarging T2 lesions were absent in 76% of patients and Gd+ lesions were absent in 96% of patients. There was slight increase in T2- and T1-LV (1.74% and 5.08%, respectively). The annualized WB volume loss was 0.20%, 0.34%, and 0.29%, as measured on 2D-T1, 3D-T1 sequences, or combined (3D-T1 used, 2D-T1 if missing); annualized LVV increased by 1.26% and 0.55%, as measured on 2D-T1 and 3D-T1 sequences, by 0.85% on FLAIR sequence, and by 0.91% overall (FLAIR used, 3D-T1 and 2D-T1 if missing). Conclusions: These interim results show that routine scans can be used for MRI assessment. Fingolimod treatment effect on MRI lesion and brain volume measures is comparable to that obtained in pivotal clinical trials, and results are consistent across scan types. Results from full analysis of 600 patients will be presented to confirm these preliminary findings. Disclosure Study Supported by: Novartis Pharmaceuticals AG Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Nasreen Khan is an employee of IMS Health, Switzerland Jennie Medin is an employee of Novartis Pharmaceuticals AG, Switzerland Jon Korn is an employee of IMS Health, United States Niels Bergsland has nothing to disclose. Pia Christoffersen is an employee of IMS Health, Switzerland Ellen Carl have nothing to disclose. Michael G. Dwyer has received consultant fees from Claret Medical and EMD Serono. and research grant support from Novartis. Jennifer Price is an employee of IMS Health, Switzerland Ian Bonzani is an employee of IMS Health, United Kingdom Diego Silva is an employee of Novartis Pharmaceuticals AG, Switzerland Bianca Weinstock- Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr WeinstockGuttman received research funds from Biogen Idec, Teva Pharmaceuticals,, EMD Serono, Genzyme&Sanofi, Novartis, Acorda.

P522 The effect of intramuscular interferon beta-1a on spinal cord volume in relapsing-remitting multiple sclerosis S. Dupuy, F. Khalid, B.C. Healy, S. Bakshi, M. Neema, S. Tauhid, R. Bakshi Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Objective: To explore the therapeutic effect of interferon beta-1a (IFNβ-1a) on spinal cord atrophy in patients with relapsing-remitting (RR) multiple sclerosis (MS) over two years in a pilot study. Background: Spinal cord atrophy occurs early in MS and impacts disability. Assessing therapeutic effects on such atrophy may complement information on disease severity and treatment effects obtained from brain imaging. Design and methods: We retrospectively identified 16 consecutive patients receiving weekly intramuscular IFNβ-1a for two years [baseline age (mean±SD) 47.7±7.5 years, Expanded Disability Status Scale score 1.1±0.8, timed 25-foot walk 4.6±0.7 seconds; time on treatment 68.3±59.9 months] and 11 sex- and age-matched normal controls (NC). The spinal cord was imaged at baseline, one, and two years later with 3T MRI. C1-C5 spinal cord volume was measured by an active surface method, from which normalized spinal cord area (SCA) was calculated. Results: SCA showed no change in the MS or NC group over two years [annualized mean difference (95% CI) MS: -0.604 mm2 (-1.352, 0.144), p=0.106; NC: -0.360 mm2 (-1.576, 0.855), p=0.524]. Between group analysis indicated no differences in onstudy SCA change [MS vs. NC; year 1 vs. baseline, annualized mean difference (95% CI): 0.400 mm2 (-3.350, 2.549), p=0.780; year 2 vs. year 1: -1.196 mm2 (-0.875, 3.266), p=0.245; year 2 vs. baseline: -0.243 mm2 (-1.120, 1.607), p=0.712]. Conclusion: Established IFNβ-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over two years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation. Disclosure Dr. Healy received consulting fees from Biogen and grant support from Genzyme, Merck Serono and Novartis. Dr. Neema is an employee of Biogen. Dr. Bakshi received consulting fees from AbbVie, EMD Serono, Genentech, and Novartis. Dr. Bakshi has received research support from Biogen, EMD-Serono, Novartis, and Sanofi-Genzyme. Dr. Bakshi serves as Editor-in-Chief of the Journal of Neuroimaging. Sheena Dupuy: nothing to disclose Fariha Khalid: nothing to disclose Sonya Bakshi: nothing to disclose Shahamat Tauhid: nothing to disclose Study supported by: Biogen P523 Protective personality traits for memory are related to larger hippocampal volume in MS V.M. Leavitt1, J.F. Sumowski2


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Poster Session 1, 22(S3) 1Columbia

University, 2Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States Background: Personality traits predict memory: healthy adults with high openness (a trait comprising intellectual curiosity, aesthetic sensitivity, imagination) have better memory; persons with high neuroticism have worse memory. We recently demonstrated a relationship between this personality profile (high openness/low neuroticism) and better memory in persons with multiple sclerosis (MS). Here, we investigate the relationship of hippocampal volume to the openness/neuroticism personality profile in persons with MS. Methods: 37 MS patients (28 female, age 53.5±8.7 years, education 15.2±2.4 years, disease duration 15.5±7.9 years, phenotype: 29 RRMS, 6 SPMS, 2 PPMS) completed the NEO Five-Factor Inventory, a 60-item scale yielding 5 scores: openness, neuroticism, agreeableness, extraversion, conscientiousness. Memory composite included verbal and visual memory measures (ageadjusted norm-referenced mean t-score= 42.5±11.8). Premorbid intelligence (IQ) was measured with the Wechsler Test of Adult Reading (mean: 106.8±13.0). 3.0T MRIs (analyzed with Freesurfer) yielded normalized volume for the hippocampus. Partial correlations (controlling for demographics and IQ) examined the relationship of openness/neuroticism to memory. Then, we examined the relationship of hippocampal volume to openness/neuroticism. Results: Expression of this high openness/low neuroticism profile was related to better memory (rp=.386, p=.024), and larger hippocampal volume (rp=.353, p=.040). Conclusions: High openness and low neuroticism may predispose individuals to participate in stimulating activities that benefit/protect memory; these results suggest that this effect may be mediated by the hippocampus. Our prior research has shown a link between frequent engagement in cognitively enriching adulthood activities (i.e., reading/writing) and better memory / larger hippocampal volume in persons with MS. Here, we provide the first evidence for a neural basis of the protective impact of personality factors on memory function in persons with MS, and promote personality factors and hippocampal volume as risk factors/ treatment targets for understanding/predicting memory impairment in MS. Disclosure Victoria M Leavitt: nothing to disclose James F Sumowski: nothing to disclose P524 Prospective measurement of quantitative spinal cord MRI in radiologically isolated syndrome: baseline analysis P. Alcaide-Leon1, S. Sankar2, K. Cybulsky2, B. Ahn2, C. Casserly2, A. Martin3, M. Hohol2, D. Selchen2, A. Bharatha1, J. Oh2 1Medical Imaging, 2Division of Neurology, St Michael’s Hospital, 3Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada Background: Radiologically-isolated-syndrome (RIS) describes asymptomatic individuals presenting with incidental MRI abnormalities suggestive of multiple sclerosis (MS), with limited

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consensus on optimal clinical management. Quantitative spinal cord (SC) MRI, including diffusion-tensor-imaging (DTI) and magnetization-transfer-imaging derived metrics have demonstrated increased sensitivity to underlying microstructural changes relevant to disability in MS. Applying these techniques to RIS may provide insight into clinically-relevant pathophysiologic changes in the earliest detectable stage of MS. Objectives: To assess for differences in quantitative SC-MRI in RIS vs. healthy controls (HCs). Methods: 20 RIS subjects and 10 age- and sex-matched HCs underwent 3T cervical SC MRI. Regions-of-interest circumscribing SC cross-sections between C3-C4 were used to extract: SC-cross-sectional area (CSA), fractional anisotropy (FA), mean, perpendicular, and parallel diffusivity (MD, λ⊥, λ||) and magnetization-transfer ratio (MTR). Manual segmentation of SC lesions, SC-grey matter (GM) and SC-white matter (WM) area were also performed. Student’s t-tests assessed differences in SC-MRI measures in RIS vs. HCs. Results: 70% of RIS subjects had lesions in the cervical SC. SC MTR was lower in RIS vs. HCs (p=0.01), and this difference showed a trend towards persistence even when slices with obvious lesions were excluded (p=0.07). There were no significant differences in SC-DTI metrics, GM, WM, or CSA between RIS and HCs. Conclusion: This study is the first to assess quantitative SC-MRI in RIS and demonstrates that SC MTR alone is different between RIS and HCs. Although these observations require confirmation in larger studies, they suggest that microstructural changes likely representing demyelination and inflammation are already present in the SC in RIS even in the absence of clinical symptoms. Furthermore, amongst quantitative SC MRI measures, SC-MTR appears to be most sensitive in detecting microstructural changes in the earliest identifiable stage of MS. These findings complement prior studies in established MS that have demonstrated a spectrum of quantitative SC MRI abnormalities, and highlight the importance of utilizing these techniques to provide needed insight into the earliest stages of MS disease evolution. Longitudinal follow-up of these subjects is planned, and will describe the predictive value of quantitative SC MRI in the clinical management of RIS. Disclosure Dr. Alcaide-Leon has received funding for her fellowship from Novartis. Dr. Casserly has received personal compensation for consulting for EMD Serono and Genzyme, received a travel grant from EMD-Serono, and received funding for her fellowship from Biogen Idec. Dr. Bharatha has received honoraria for educational lectures from Biogen, Novartis, EMD Serono. Dr Selchen has received honoraria for speaking, consulting, and/ or advisory board participation from Bayer, Biogen, Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharmaceuticals. Dr. Hohol has received honoraria for speaking, consulting, and/or advisory board participation from Bayer, Biogen Idec, EMD Serono, Novartis, Roche, Sanofi-Genzyme, and Teva Pharmaceuticals. Dr. Oh holds the Multiple Sclerosis Society of Canada Decker Family Transitional Career Development Award; has received research funding from Sanofi-Genzyme and Biogen-Idec and has


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received personal compensation for consulting or speaking from EMD-Serono, Genzyme, Biogen-Idec, Novartis, Teva and Roche. Dr. Martin: nothing to disclose. Ms Cybulsky: nothing to disclose. Ms Sankar: nothing to disclose. Mr Ahn: nothing to disclose.

P525 A MRI-pharmacokinetic study of gadolinium deposition in the dentate nucleus in multiple sclerosis patients receiving serial triple-doses of Gd for 14 consecutive months L. Wolansky1, J. Mitra2, P.A. DiCamillo1, S. Cook3, D. Cadavid3, T. Richards1, R.T. Naismith4, S. Lancia4, P. Tiwari2 1Dept. of Neuroradiology, University Hospitals Case Medical Center, 2Dept. of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 3Dept. of Neurology and Neurosciences, Rutgers-New Jersey Medical School, Newark, NJ, 4Dept. of Neurology, Washington University School of Medicine, St. Louis, MO, United States Background: In the BECOME study 75 multiple sclerosis (MS) (61 relapsing-remitting and 14 clinically isolated syndromes) received monthly triple dose (3-dose) gadopentetate dimeglumine at a high, off-label, 0.3 mmol/kg dosage for up to 26 consecutive months. The clinical outcomes of the study have been reported. Recently, Kanda et al. (Radiology, 2014) and others have described a phenomenon of long-term Gadolinium (Gd) deposition in the dentate nucleus that manifest as hyperintensity on noncontrast T1 weighted (T1w) images, a poorly understood and possibly concerning phenomenon. To date, studies of Gd deposition had inconsistent dosing. Purpose: Our purpose was to study the “MRI pharmacokinetics” of Gd deposition in the dentate nucleus in a randomly selected cohort of 15 subjects with MS, each of whom had systematically received 14 consecutive monthly 3-doses of Gd. Methods: The precontrast T1w images of 15 randomly selected patients with MS scanned monthly before & after monthly 3-dose of Gadopentetate Dimeglumine for 14 consecutive months was analysed. Screening scans were obtained without 3-dose Gd, the Month 13 scans were obtained 1 month after the 13th monthly 3-doses (39 dose equivalents). Pre-contrast T1w images were acquired with consistent voxel size, TR, TE, & angulation. The screening and longitudinal T1w images were corrected for MRI coil induced intensity inhomogeneities. Automatic segmentation of the dentate nuclei was performed by non-rigidly registering a cerebellar atlas to the screening scans. The longitudinal T1 scans were spatially aligned to the screening scans using an affine registration method, and their intensities were also normalised to the screening scan using a histogram normalisation method. The mean T1 intensities within the dentate nuclei were used from each longitudinal scan for the Gd dose-dependent trend and correlation analysis using Spearman’s rank correlation. Results: The mean intensities in the 30 dentate nuclei showed a progressive increasing trend of hyperintensity on pre-contrast T1w images from screening to the fourteenth month. The dosedependent relationship between T1 hyperintensity and number of triple-doses showed a positive correlation (>0.6, p< 0.05). Conclusion: Monthly administration of triple-dose Gadopentetate Dimeglumine over fourteen months is associated with Gd deposition, which progressively increases with subsequent doses.

Disclosure The BECOME study was supported by a grant from Bayer Healthcare Pharmaceuticals, but was initiated by & the intellectual property of the investigators. Leo Wolansky: nothing to disclose. Jhimli Mitra: nothing to disclose. Paul A. DiCamillo: nothing to disclose Stuart Cook: nothing to disclose Diego Cadavid: nothing to disclose Tyler Richards: nothing to disclose Robert T Naismith: Consulting: Alkermes, Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, Pfizer, Teva. Speaking: Acorda, Biogen, Genzyme. Samantha Lancia: nothing to disclose Pallavi Tiwari: nothing to disclose P526 Ultra-high field and gradient strength MRI reveal neuroaxonal pathology in cortex and white matter in early MS T. Granberg1,2,3, Q. Fan1,2, C.A. Treaba1,2, R. Ouellette1,2, E. Herranz1,2, G. Mangeat1,4, C. Louapre1,2, E.C. Klawiter2,5, J.A. Sloane6, C. Mainero1,2 1Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, 2Harvard Medical School, Cambridge, MA, United States, 3Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden, 4Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada, 5Department of Neurology, Massachusetts General Hospital, Charlestown, 6Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States Background: Neuro-axonal pathology is a main determinant of disease progression in multiple sclerosis (MS) but its in vivo detection is limited by low sensitivity and spatial resolution of conventional MRI. Objective: To characterize in early-stage MS the extent and microstructural properties of pathology in the cortex and white matter (WM) using ultra-high field and gradient strength MRI. Methods: Twenty-five early MS patients (age 39±8 years; disease duration 1.6±0.9 years; median EDSS 1.5, range 0-4) and 13 controls (age 34±11 years) underwent acquisition of 7T T2*weighted images (0.33x0.33x1.0 mm) for segmenting intracortical and leukocortical lesions (ICL, LCL); 3T multi-shell diffusion imaging (Siemens Connectome scanner, 1.5 mm isotropic, b 1k and 5k, 64 and 128 directions) that were analyzed using Neurite Orientation Dispersion and Density Imaging (NODDI), 3D MEMPRAGE and FLAIR scans for Freesurfer reconstruction and WM lesion segmentation. Group differences were assessed by t-test. Results: Cortical lesions were identified in ~90% of patients. The mean global lesion volume was 161 (range 0-924) mm3 in the cortex (ICL 87, 0-248; LCL 74, 0-738) and 970 (range 100-5212) mm3 in WM. There were no differences in cortical thickness between MS and controls (2.40±0.08 vs. 2.44±0.08 mm, p=0.16). The intracellular tissue volume fraction (ICVF) was lower in cortical lesions than in contralateral non-lesioned cortex (0.40±0.043 vs.0.44±0.061, p=0.006), with no differences between ICL and


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Poster Session 1, 22(S3) LCL. In MS, normal-appearing cortex NODDI metrics were similar to controls’ cortex. The ICVF was lower in normal-appearing WM in patients than in controls’ WM (0.62±0.023 vs. 0.64±0.026, p=0.02), and in WM MS lesions compared to contralateral nonlesioned WM (0.48±0.058 vs. 0.66±0.062, p=2.7e-12). WM lesions were also characterized by increased orientation dispersion index (0.27±0.032 vs. 0.26±0.039, p< 0.001), indicating less coherent underlying fiber orientation suggestive of axonal fanning. Conclusions: In early-stage MS, microstructural degenerative pathology was present focally in the cortex and diffusively in WM. The consistent decrease in ICVF suggests an underlying loss of cells and/or cell volumes with additional neurite dispersion in WM lesions. In the cortex, the observed focal changes in lesions might precede the development of diffuse atrophy. The results suggest that NODDI is valuable for in vivo identifying neuroaxonal pathology in early MS. Disclosure This study was supported by the National Institute of Health (NIH R01NS078322-01-A1) and Karolinska Institutet (ALF grant). Dr. Mainero has received research support from EMD Merck Serono and speaker fees from Biogen. Dr. Klawiter has received research support for Atlas5d, Biogen, EMD Serono and Roche and received consulting fees from EMD Serono, Genentech and Shire.

did not change in the regions with increased DTI-AD. Increased non-restricted isotropic diffusion tensor components (interpreted as edema or loss of tissue structural integrity) was seen in SPMS WM tracts. Results revealed that the confounding effect of edema or tissue loss contributed to the observed increase in DTI-AD. The anisotropic diffusion tensor fraction, as determined by DBSI, was reduced in regions of corpus callosum in SPMS, suggesting axonal loss. Conclusions: Tract based DBSI analyses showed loss of anisotropic components, consistent with axon loss in SPMS WM tracts. This imaging method may be useful for monitoring progression in MS. Disclosure Anne H. Cross has performed consulting for: AbbVie, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Teva. Peng Sun has no disclosures. Ajit George has no disclosures. Sheng-Kwei Song has no disclosures. Robert T. Naismith has performed consulting for: Alkermes, Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, Pfizer, Teva. Funding: Supported by the U.S. National Institutes of Health P01 NS059560.

P527 Whole brain white matter alterations revealed by diffusion basis spectrum imaging (DBSI) in multiple sclerosis A.H. Cross1, P. Sun2, A. George2, R.T. Naismith1, S.-K. Song2 1Neurology, 2Radiology, Washington University School of Medicine, St. Louis, MO, United States

P528 Long-term change in magnetisation transfer ratio detects chronic active lesions in multiple sclerosis Y. Zheng1, K. Nakamura1, R. Rudick2, B.D. Trapp3, E. Fisher2 1Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 2Biogen, Cambridge, MA, 3Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States

Background: Axon injury and loss, demyelination, and inflammation are the primary pathologies in multiple sclerosis (MS). Despite the prevailing thought that axon loss is the substrate of clinical progression, the roles that these individual pathological processes play in MS progression are ill-defined. Goal: To investigate whole brain white matter (WM) changes with particular focus on axons, we compared secondary progressive (SPMS) patients to healthy controls (HC) using diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI, quantitatively distinguishes isotropic from anisotropic diffusion) and a tract-based spatial statistics (TBSS) method for analysis. Methods: Human studies committee approval was obtained. All subjects gave informed consent. Sixteen patients with established SPMS and eleven HC underwent diffusion weighted MRI using a multi-b value diffusion weighting scheme (99 directions, maximum b-value 1500 s/mm2) and a 32-channel head coil at 3T. Whole brain voxel-wise (2×2×2 mm3) DTI and DBSI analyses were performed. Group analyses were done with TBSS (part of FSL). DTI and DBSI indices were projected onto the TBSS skeleton for statistical analyses. Nonparametric permutation tests (5000) were used for voxelwise statistical comparisons between HC and SPMS, with significance threshold for group differences of P < 0.05. Results: Not unexpectedly, abnormal diffusion changes were widespread in SPMS WM tracts: decreased DTI-FA, and increased DTI-axial (AD) and radial (RD) diffusivity. DBSI-AD

Introduction: Magnetisation transfer ratio (MTR) is an MRI technique commonly used to assess tissue integrity. MTR in MS lesions correlates with demyelination and axonal damage. Longitudinally, changes in MTR suggest changes in myelin status, axonal health, and/or inflammatory activity. We hypothesised that changes in lesion MTR over long-term follow-up are associated with changes in chronic active lesions, whereas stable MTR within pre-existing lesions is indicative of chronic inactive lesions. We tested these hypotheses in post-mortem brain tissue from an MS patient who had participated in our longitudinal MRI study for 11 years. Methods: Brain tissue from a 51-year-old male with SPMS (disease duration=23 years; cause of death=acute myocardial infarction) was procured through the Cleveland Clinic MS rapid autopsy protocol. We used the last 4 years of annual imaging data to classify T2 white matter (WM) lesion voxels into 6 possible categories based on the initial MTR level (low or high) and the pattern of MTR change over 4 years (decreasing, increasing, or stable) using voxel-wise linear regression. Thresholds for initial MTR level and MTR change were based on concurrently acquired WM MTR values from 14 healthy controls. We identified 11 regions-of-interest (ROI) based on MRI/MTR including normal-appearing WM (NAWM) and 4 MTR lesion categories. Histopathologically, we evaluated myelin status, axonal diameter and loss and inflammatory activity in these ROIs.

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Results: NAWM was myelinated, with a mean axonal diameter of 0.74 um and axonal density of 23.4%. In comparison, high and stable MTR regions were myelinated, with no swollen axons and some axonal loss (density=16.1%). Two ROIs with low and stable MTR had swollen axons and intermediate axonal loss (density=19.9%) compared to NAWM: one was myelinated; the other was a demyelinated, chronic inactive lesion. Regions with low and changing MTR (increasing or decreasing) were demyelinated with many swollen axons and axonal loss (density=14.9%), corresponding to chronic active lesions. There were no remyelinating lesions in the identified ROIs. Conclusions: Longitudinal MTR-based classification of T2 lesions showed different pathologies on histology: chronic active demyelinated lesions, chronic inactive demyelinated lesions, and myelinated but axonal loss with or without swollen axons. Our approach may be useful to quantify the extent of specific types of tissue damage and help in understanding MS pathogenesis. Disclosure This study was supported by the NIH NINDS P01-NS38667 and the National Multiple Sclerosis Society RG-3099. Dr. Rudick and Dr. Fisher are employees and stockholders of Biogen. Yufan Zheng: nothing to disclose. Dr. Nakamura: Consultant (NeuroRx Research); Research support (Biogen, Sanofi Genzyme). Dr. Trapp: receives grant support from NIH, State of Ohio, ALS Association, Sanofi Genzyme, and the NMSS. He also receives speaking fees from EMD Serono, Genentech, Sanofi Genzyme, and Novartis. He is founder and Chief Scientific Officer of Renovo Neural. P529 Diffusion tensor imaging shows brain structural damage associated with verbal memory in subjects with multiple sclerosis J. Puig1, G. Blasco1, C. Biarnés1, J. Gich2,3, M. Rivero3, J. Salavedra3, P. Danius i Estadella4, S. Pedraza1, L. Ramió-Torrentà3,5 1Imaging Research Unit, Diagnostic Imaging Institiute (IDI), 2Neurology Department, Dr. Josep Trueta University Hospital, 3Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), 4Department of Computer Science, Applied Mathematics and Statistics, University of Girona, 5Neuroimmunology and Multiple Sclerosis Unit (UNIEM), Department of Neurology, Dr. Josep Trueta University Hospital, Girona, Spain Objective: We studied differences in diffusion tensor imaging metrics (DTI-metrics) of white matter structural integrity among cohorts of subjects with multiple sclerosis (MS) classified according to progression and their relation to verbal memory. Methods: We prospectively studied consecutive patients with radiologically or clinically isolated syndrome (n=23; 18 female; age 35±9.1 years), primary or secondary progressive (PP/PS) MS (n=35; 19 female; age 53.5±7.2 years), relapsing-remitting (RR) (n=24; 16 female; mean age 43.9±11.3 years) MS, and 30 healthy controls (18 female; age 41.4±10.9 years) on a 1.5T scanner. Imaging included DTI with 16 diffusion-sensitized gradients

applied along 15 noncollinear directions with b-value of 1000s/ mm2 and anatomic T1 turbo-field echo sequence. We used Olea Sphere 3.0 to map axial diffusivity (AD), radial diffusivity (RD), mean diffusivity, and fractional anisotropy (FA); FSL tools to normalize images; and Juelich’s Atlas to identify white matter tracts. We calculated total white and grey matter volumes. We estimated verbal memory by the Long Term Storage (LTS) Selective Reminding Test (SRT) subtests. We used analysis of variance to assess differences in SRT among groups and analysis of covariance (ANCOVA) including variables associated with cognitive scores (p< 0.01) to analyze relations between DTI-metrics and SRT among groups. To avoid confounding by age or schooling on SRT, ANCOVA used unstandardized residual values of the regression between SRT and these variables. Results: Groups differed on SRT-LTS (p< 0.001). The best ANCOVA model to explain SRT-LTS scores among groups (p=0.002) included right acoustic radiation AD (p=0.001), corpus callosum AD (p=0.004) and RD (p=0.005), left corticospinal tract AD and RD (both p=0.001), right corticospinal tract RD (p=0.006), left fornix FA (p=0.004), right optical radiation RD (p=0.028), right superior longitudinal fascicle RD (p=0.006), and total grey matter volume (p=0.006). Conclusion: Our preliminary results suggest structural white matter integrity measured by DTI is associated with verbal memory scores in MS according to progression. Disclosure Ll. Ramió-Torrentà has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. G. Blasco: nothing to disclose C. Biarnés: nothing to disclose J. Gich has received consulting fees from Novartis and speaking honoraria from Bayer Schering Pharma, Biogen, EMD Merck Serono, Novartis, Teva Phramaceuticals, Almirall. M. Rivero: nothing to disclose J. Salavedra: nothing to disclose P. Danius i Estadella: nothing to disclose S. Pedraza: nothing to disclose J. Puig: nothing to disclose Funding: Novartis P530 Physical activity levels are associated with hippocampal dentate gyrus volume of pediatric patients with acquired demyelinating syndromes G. Longoni1, B. Aubert-Broche2, R.A. Brown2, S.A. Grover1, H. Branson3, D. Hopkins4, A. Bar-Or5, R.A. Marrie6, R.W. Motl4, D.L. Arnold2, B. Banwell7, S. Narayanan2, L.D. Collins2, A.E. Yeh1, on behalf of The Canadian Pediatric Demyelinating Disease Network 1Department of Pediatrics, Division of Neurology, The Hospital for Sick Children, Toronto, 2McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, 3Department of Medical Imaging, Division of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada, 4Department of Kinesiology and Community Health,


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Poster Session 1, 22(S3) University of Illinois at Urbana-Champaign, Champaign, IL, United States, 5Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, ON, 6Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada, 7Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: Hippocampal injury and dysfunction are common in multiple sclerosis (MS) and other neuroinflammatory conditions. Physical activity (PA) may partially mitigate such injury via its pleotropic effects. In murine models, increased levels of PA have been associated with higher dentate gyrus (DG) volumes (DGv) of the hippocampus. Objective: To assess the relationship between the average number of minutes of moderate-to-vigorous PA per day (MVPA) and DGv in pediatric patients with acquired demyelinating syndromes (ADS) of the central nervous system. Methods: Standardized MRI was acquired from 28 (15 females) pediatric participants with ADS [10 MS, 18 monophasic ADS (monoADS)] within 30 days of a 7-day period of accelerometry wear (7164 Actigraph accelerometer). EDSS and depression scores (CES-DC) were concurrently assessed. Subjects who experienced a relapse or received corticosteroids in the previous 30 days were excluded. Ethics approval was obtained from the SickKids REB. MRI analysis: 3D-T1 images for each subject were linearly registered to the template space. The DG within the hippocampal body and tail was manually traced according to a standardized protocol, yielding DGv normalized by brain size. Brain lesion volume (LV) was measured according to established pipelines. Statistical analysis: The effects of MVPA, group (MS, monoADS), sex, age, LV, and the interaction between MVPA and group on DGv were assessed using a general linear model (GLM). We also refit the model with each of EDSS and depression scores replacing LV to assess the impact of these potentially correlated factors. Results: Mean (SD) DGv [cm3]: MS 0.339 (0.064), monoADS 0.396 (0.1), p=0.082. Mean (SD) MVPA [minutes]: MS 15.2 (17.1), monoADS 38.8 (28.8), p=0.061. The GLM statistically significantly predicted the DGv, F(5.117), p=0.002, R2=0.594, adj. R2=0.478. We found a surprisingly strong relationship between DGv and MVPA in the monoADS (0.002 cm3/minute of MVPA, p=0.001) but not in the MS group (-0.003 cm3/minute of MVPA, p=0.103), which was independent of age, sex, EDSS, depression, and LV. Discussion: We found a relationship between MVPA and DGv in monoADS patients, but not in MS patients. This may have resulted from generally low MVPA in MS patients with limited variation, or from an effect of MS on DGv that cannot be reversed by exercise. Randomized controlled studies are needed to confirm these findings and investigate their relationship to functional outcomes. Disclosure Dr. Longoni receives training and research support from the National Multiple Sclerosis Society (NMSS). Dr. Aubert-Broche: nothing to disclose. R. A. Brown has received personal compensation from NeuroRx Research for consulting services. S. Grover: nothing to disclose. Dr. Branson: nothing to disclose.

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D. Hopkins: nothing to disclose. Dr. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc, Roche, and Merck/EMD Serono. Dr. Marrie receives research funding from: Canadian Institutes of Health Research, Public Health Agency of Canada, Manitoba Health Research Council, Health Sciences Centre Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, and has conducted clinical trials funded by Sanofi-Aventis. Dr. Motl: nothing to disclose. Dr. Arnold reports personal fees for consulting from Acorda, Biogen, Hoffman LaRoche, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research which was the image analysis centre for the trial. Dr. Banwell serves as a consultant to Novartis, and as an advisor on clinical trials to Biogen Idec, Teva Neuroscience, and Sanofi. Dr. Narayanan has received personal compensation from NeuroRx Research for consulting activities, and a speaker’s honorarium from Novartis Canada. Dr. Collins receives funding from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. Dr. Collins also receives consulting from NeuroRx Research and has equity interest in True Positive Medical Devices. Dr. Yeh receives funding from NMSS, MS Foundation/MSSC, Mario Batali Foundation, Centre for Brain and Mental Health, OIRM. She has received speaker´s honoraria from Novartis. P531 Diffusion basis spectrum imaging in acute and remote optic neuritis R.T. Naismith1, J. Xu2, C. Dula3, S. Peng4, J.-W. Kim2, S. Lancia5, A.H. Cross5, S.-K. Song4 1Neurology, Washington University, Saint Louis, MO, 2Radiology, Mount Sinai School of Medicine, New York, NY, 3Washington University School of Medicine, 4Radiology, 5Neurology, Washington University School of Medicine, St. Louis, MO, United States Background: Diffusion basis spectrum imaging (DBSI) is a microstructural imaging method in which anisotropic and isotropic diffusion components are modeled to assess the different pathologies within MS lesion. Myelinated and unmyelinated axons are modeled as anisotropic diffusion tensors. Cells, edema, and increased extracellular space are modeled as isotropic diffusion tensors. By accounting for the proportion of inflammatory components within an imaging voxel, the anisotropic DBSI “fiber” fraction can be used to estimate the density of axons within that voxel. Reduction of DBSI axial diffusivity (AD) provides a surrogate of axon injury, whereas increased DBSI radial diffusivity (RD) suggests loss of myelin integrity. This ongoing study leverages our expertise in optic nerve diffusion MRI (dMRI) and clinical research setting of optic neuritis (ON) to translate the DBSI method to human. Methods: Participants included those with acute ON (within 30 days of onset), chronic optic neuropathy due to remote ON (last episode ⩾ 1 year prior), and healthy controls (HC). Axial optic


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nerve data were collected using an inner-volume-imaging diffusion sequence at 1.3 mm isotropic resolution (10 slices) with four averages of 25 unique diffusion encoding directions at linearly spaced b-values (40-1000 s/mm2) plus two b0s. The optic nerve dMRI data were first pre-processed with a non-linear registration method and then underwent DBSI analysis. Region of interest (ROI) analysis were performed in each optic nerve. Results: DBSI data from 6 patients with remote ON, and 3 with acute ON were compared to 6 HCs. Patients with remote ON had significantly decreased DBSI fractional anisotropy - FA (0.76±0.14 vs. 0.83±0.08, p< 0.05), decreased DBSI fiber fraction (0.42±0.16 vs. 0.62±0.15), and increased hindered isotropic diffusion tensor fraction (edema/extracellular fluid) (0.34±0.19 vs. 0.22±0.09). Patients with acute ON had similar changes with reduced DBSI FA and DBSI fiber fraction, and increased DBSI RD and hindered isotropic diffusion. In addition, optic nerves with acute ON showed reduced DBSI AD (injured axons) (1.62±0.51 vs. 1.93±0.25 mcm2/ms) and mildly increased restricted isotropic diffusion tensor fraction thought to represent cellularity (0.10±0.04 vs. 0.07±0.04). Conclusion: DBSI has potential to determine the underlying pathology in ON by measuring axon injury and loss while accounting for cellularity, edema and increased extracellular space. Disclosure RT Naismith has received fees for consulting from: Alkermes, Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, EMD Serono, Novartis, Pfizer, Teva J Xu has no disclosures. C Dula has no disclosures. S Peng has no disclosures. JW Kim has no disclosures. S Lancia has no disclosures. AH Cross has received fees for consulting from: AbbVie, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Teva. SK Song has no disclosures. Funding: NIH R21NS090910 (RTN/SKS), C06RR014513 (JSP) P532 Diffusion tensor imaging of normal appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis S.-H. Kim1, K. Kwak2, J.-W. Hyun1, I.H. Jeong1, H.-J. Jo1, A. Joung1, W. Kim3, S.-Y. Huh4, S.H. Lee5, J.-M. Lee2, H.J. Kim1 1Neurology, Institute and Hospital of National Cancer Center, Goyangsi, 2Biomedical Engineering, Hanyang University, 3Neurology, The Catholic University of Korea College of Medicine, Seoul, 4Neurology, Kosin University College of Medicine, Busan, 5Radiology, Institute and Hospital of National Cancer Center, Goyangsi, Republic of Korea Background: Recent imaging evidence suggests that there is an occult brain injury in patients with neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate and compare occult changes in normalappearing white matter (NAWM) among patients with NMOSD and multiple sclerosis (MS) using tract-based spatial statistics diffusion tensor imaging (DTI) analysis.

Methods: Ninety-seven patients with NMOSD, 55 patients with MS, and 43 healthy controls (HC) were enrolled. DTI was performed along 32 nonlinear directions using a 3.0T MRI scanner. DTI followed by tract-based spatial statistics analysis was used to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Results: Compared with HCs, the patients with NMOSD had significantly reduced average FA and increased MD and RD, but no significant difference in AD, in their NAWM. Patients with MS showed a significantly greater reduction of FA and increased MD, AD, and RD in NAWM, compared with those with NMOSD. Average MD and RD were positively correlated with disease duration (p=0.002 and 0.002, respectively) and EDSS (p=0.009 and p=0.008, respectively) among patients with NMOSD. In addition, there were positive correlations between disease duration and WM diffusion changes among MS patients. NMOSD patients without brain lesions (n=37) also had significantly reduced FA in diffuse white matter, increased MD in the corpus callosum, and increased RD in the corpus callosum, internal capsule, optic radiation, and cerebral peduncle compared with HC (corrected p < 0.05). Conclusion: The present study using DTI demonstrated widespread occult damage in NAWM of patients with NMOSD. However, NAWM is affected to a lesser degree in patients with NMOSD than in those with MS. Occult damage in NAWM appears to be related to demyelination with limited axonal injury in NMOSD, whereas diffuse abnormalities of NAWM in MS are associated with both myelin and axonal damage. Disclosure This work was funded by the National Research Foundation of Korea (grant no. 2013R1A1A2058612), the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (NRF-2014M3C7A1046050). Kim HJ has given talks, consulted and received honoraria from Bayer Schering Pharma, Biogen Idec, Genzyme,Merck Serono, Novartis, Teva-Handok and UCB and received research grants from Genzyme, Kael-Gem-Vax and Merck Serono. He serves on a steering committee for MedImmune and is an editorial board member for Multiple Sclerosis Journal Experimental,Translational and Clinical. P533 Left versus right regional volumes related to cognitive deficits in multiple sclerosis S. Belliston1, P. Adany2, P. Lee2, D. Denney3, A. Hughes4, I.-Y. Choi2, S. Lynch1 1Neurology, 2Hoglund Brain Imaging Center, University of Kansas Medical Center, 3Psychology, University of Kansas, Kansas City, KS, 4Rehabilitation Medicine, University of Washington, Seattle, WA, United States Background: Multiple sclerosis (MS) causes deficits in information processing speed and memory that have been related to brain atrophy - both overall and in specific regions such as the subcortical nuclei of the medial temporal lobe (MTL) and deep grey matter (DGM). Hemispheric specialization is a well-established attribute of the human brain, but little attention has been paid to


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Poster Session 1, 22(S3) hemispheric differences in these regional volumes and how they might relate to patients’ cognitive performance on tests differing in verbal vs visual-spatial demand. Methods: Patients with MS (N=66) were compared with healthy controls (N=31) in terms of their performance on computerized versions of the Symbol Digit Modalities Test, Rey Auditory Verbal Learning Test, and Brief Visual Memory Test; and their left and right volumes for several brain regions: MTL - including the hippocampus, amygdala, and nucleus accumbens; DGM - including the thalamus, pallidum, putamen, and caudate; cortical gray matter; cerebral white matter; and cerebellum. Patients and controls were right handed and were well matched in terms of age, gender, and education. The patient sample included individuals with relapsing (N=25), primary progressive (N=22), and secondary progressive MS (N=19). Length of diagnosis ranged from 1 to 33 year (M=10.7) and disability ratings from 1 to 8.5 (Md=4.75). Regional brain volumes were based on automated segmentation using FreeSurfer applied to MR scans at 3 T and normalized on the basis of intracranial volume. Results: Patients had significantly lower scores than controls on all cognitive measures and on all but three lateralized regional volumes (left thalamus, left and right hippocampus). Also, with only a few exceptions, patients’ performance on each cognitive measure was significantly correlated with both their left- and right-side regional volumes. However, closer examination of these correlations revealed the relationship was often stronger (DR2 ⩾ .05) for the right volume than for the corresponding left volume (chi2 = 6.1, df =2, p = .047), regardless of the cognitive test. This was especially true for the regions composing the MTL and DGM. Conclusion: This asymmetry may indicate a difference in the cognitively-relevant impact of MS on a variety of subcortical nuclei. Its occurrence across a variety of cognitive measures also suggests that the tests used to evaluate cognitive deficits in MS may be insufficiently sensitive to lateralized cognitive dysfunction. Disclosure This work was partially funded by grant RG 4495-A-4 from the National MS Society Scott Belliston, DO: has a fellowship grant from the National MS Society. Peter Adany, PhD: Nothing to disclose Phil Lee, PhD: Nothing to disclose Doug Denney, PhD: Nothing to disclose Abbey Hughes, PhD: Nothing to disclose In-Young Choi, PhD: Nothing to disclose Sharon Lynch, MD: has received grant/research support from Actelion, Bayer, Biogen Idec, Cephalon, Cognition, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono Pharma, Pfizer, Receptos, Genentech, Roche, Sanofi Aventis, Sun Pharma, and Teva Neuroscience.

P534 Cortical mantle thinning in pediatric MS: correlations with motor function R. Datta1, C. Till2, E. De Somma2, N. Akbar2, M. Lysenko2, A.E. Yeh3, J. O’Mahony3, D.L. Arnold4, B. Banwell1 1The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 2York University, 3Hospital for Sick Children, Toronto, ON, 4Montreal Neurological Institute, McGill University, Montreal, QC, Canada

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Background: Multiple Sclerosis (MS) is characterized by both white matter and cortical pathology. Little is known regarding the extent of cortical involvement, however, in pediatric-onset MS, nor whether early cortical involvement contributes to the cognitive impairment experienced by over 30% of pediatric MS patients. Methods: Forty-five pediatric-onset relapsing-remitting MS patients (mean age 18 yr, range 9-24, age at onset mean 13 yr, range 7-17 yr 11 months) and 61 healthy age- and sex-matched controls were imaged using Siemens 3T Tim Trio MRI scanners with a 32 channel coil at two sites. Cortical mantle thickness was measured on 1mm3 T1-weighted MPRAGE images using FreeSurfer. Thickness measures were mapped onto a standard template surface and smoothed using a smoothing kernel of 15 mm. The 9 hole peg test (9HPT) was completed by 23 MS patients and 22 controls. General linear models (adjusted for age and sex) determined if the groups differed in cortical thickness at each vertex, and identified specific regions of difference. Performance on the 9HPT was correlated with precentral cortical thickness. Results: The mean overall cortical thickness was reduced in MS patients compared with controls [2.67mm (SD 0.1) versus 2.74mm (SD 0.1), p = 0.001]. After thresholding (using a false discovery rate, p= 0.01, t[101df]=3.4), significant focal cortical thinning was observed in the MS group across the entire cortical mantle, bilaterally in the supramarginal, precentral, lateraloccipital, superiorfrontal regions and unilaterally in caudalmiddlefrontal, lingual, inferiortemporal, superiorparietal, superiortemporal regions in the right hemisphere and entorhinal, insula, precuneus, pericalcarine, postcentral, posteriorcingulate in the left hemisphere. A negative relationship between age and cortical thickness was observed for the combined subjects (peak effect t[101df]=-8.5), as expected given normal cortical pruning in late adolescence. Within the MS group, 9HPT scores correlated with the thickness of the pre-central cortex (r=0.39, p=0.037). Conclusions: Pediatric-onset MS is associated with cortical mantle thinning, implicating early involvement of cerebral gray matter. Focal thinning of the precentral cortex correlates with reduced performance in a timed motor task of fine motor dexterity. Further studies will evaluate whether other structure-performance relationships exist for motor, visual, and sensory function. Disclosure Funding Source: Multiple Sclerosis Society of Canada, Scottish Rite Charitable Foundation Ritobrato Datta: nothing to disclose Christine Till: nothing to disclose Elisea De Somma: nothing to disclose Nadine Akbar: nothing to disclose Magdalena Lysenko: nothing to disclose Ann Yeh: nothing to disclose Julia O’Mahony: nothing to disclose Douglas Arnold: Disclosure Dr. Arnold reports personal fees for consulting from Acorda, Biogen, Hoffman LaRoche, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research. Brenda Banwell: Dr. Banwell serves as an un-paid advisor on clinical trials for Biogen-IDEC, Novartis, TevaNeuroscience, and Sanofi; and as a central MRI reviewer for Novartis (remunerated).


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P535 Longitudinal study of MS lesions using multi-parametric ultra-high field (7Tesla) MRI I. Kister1, S. Chawla2, J.T. Wuerfel3, T. Sinnecker3, F. Paul4, Y. Ge1 1New York University School of Medicine, New York, NY, 2University of Pennsylvania, Philadelphia, PA, United States, 3Medical Image Analysis Center AG (MIAC), Basel, Switzerland, 4NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany

Tim Sinnecker:Friedemann Paul:nothing to disclose Yulin Ge:nothing to disclose P536 Quantifying lesion progression in multiple sclerosis: a novel magnetic resonance imaging pipeline C. Wang1,2, L. Ly1,2, A. Klistorner1,3,4, H. Beadnall2, J. Barton2, R. Oliver1,2, M.H. Barnett1,2 1Sydney Neuroimaging Analysis Centre, 2Brain and Mind Centre, University of Sydney, Camperdown, 3Department of Ophthalmology, University of Sydney, 4Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia

Background: We previously characterized microstructural features and iron content of MS lesions using multi-parametric ultrahigh field (7 Tesla) MRI in a cross-sectional study (Chawla, et al. AJNR 2016). Objective: To compare distribution, number, size, iron content and lesion-vessel relationship of MS lesions at baseline and on follow-up ultra-high field MRI. Methods: Nine patients with definite MS underwent MRI on a 7T whole body human MR system (Magnetom; Siemens) equipped with a 24-channel phased array coil (Nova Medical). The imaging protocol included high-resolution (230x230µm3) axial 2D-gradient-echo (GRE)- T2*-weighted imaging, high-resolution (230x230µm3) axial 3D-susceptibility weighted imaging (SWI) and FLAIR and T1-weighted imaging. Only supratentorial brain regions were covered while acquiring 2D-GRE-T2* and 3D-SWI to avoid susceptibility artifacts from air-tissue interfaces. An inhouse-developed algorithm was used to reconstruct quantitative susceptibility mapping (QSM) from SWI. Lesions on baseline and follow-up MRI were examined by two experienced observers and compared with respect to total count, location, size, lesion-vessel relationship and iron content. Lesions were classified as “ironladen” if they demonstrated hypointensity on T2*-weighted images and/or SWI and hyperintensity on QSM and “non-ironladen” if they were hyperintense on T2* and isointense or hyperintense on QSM. Results: Longitudinal data on 5 MS patients were analyzed so far. Mean duration of follow up was 36 ±10 months. Total number of lesions at baseline was 74 (average 14.8/scan) and at follow-up 86 (17.2/scan). Increase in lesion size was evident in 2 lesions (3%) and decrease - in 3 lesions (4%). At baseline, 65% lesions had a visible central venule on GRE-T2*images; at follow up - 66% lesion had a central venule. In only 2 lesions (3%), previously seen venule was no longer detectable at follow-up, and in 2 lesions (3%), a venule was visible on follow up, but not at baseline. Percentage of iron-containing lesions increased from 37% at baseline to 43% at follow-up. In one lesion, iron content was apparently lost over time and in another lesion iron content appeared to be redistributed from nodular to rim-like configuration. Conclusion: Multi-parametric ultra-high field MRI is a promising technique for monitoring morphological changes in lesional iron content and other microstructural characteristics in vivo. Data on full patient cohort will be presented.

Introduction: Longitudinal measurement of diffusivity and magnetisation transfer ratio (MTR) parameters within multiple sclerosis (MS) lesions has been identified as a potential biomarker for monitoring de/remyelination and axonal loss in vivo [1]. Longitudinal assessment of MS lesions is frequently confounded by structural changes relating to brain atrophy and MS lesion activity, head positioning and scan-rescan variability. Objective: To develop a reproducible quantitative neuroimaging analysis pipeline for the assessment of MS lesion progression within a particular white matter (WM) tract. Methods: Magnetic resonance imaging (MRI) data was acquired on a 3T GE scanner from 14 MS patients with chronic optic radiation (OR) lesions at baseline and 6 months; and 35 healthy controls (HC). Sequences included 64-directions DTI, IR-FSPGR, Gadolinium-T1-SE, FLAIR and MTR. DTI was motion, eddycurrent and EPI susceptibility distortion corrected, prior to tensorreconstruction and co-registration. A probability weighted OR atlas was constructed from the HC MRI datasets using probabilistic tractography [2], and projected nonlinearly to individual study patients. Only chronic (non-enhancing) T2-hyperintense OR lesions were analysed. An analogous normal-appearing white matter (NAWM) ‘mirror’ reference region (RR) was delineated in the contralateral OR. Longitudinal changes of diffusivity metrics were measured within chronic OR lesions and the contralateral OR NAWM RR. Results: Axial diffusivity (AD) within MS lesions increased between baseline and 6 months (p=0.001) but other diffusion metrics showed no significant change over this timeframe. Progression of AD was significantly greater (p =0.037) in MS lesions (+0.019 µm2/ms) compared with the analogous RRs (+0.002 µm2/ms). Conclusion: We describe a sensitive neuroimaging analysis pipeline for monitoring short term MS lesion progression within WM tracts delineated by a probability-weighted atlas derived from probabilistic tractography in a group of HCs. This method detected progression of lesional AD, relative to change in an analogous contralateral RR, within 6 months, suggesting continued axonal loss in chronic lesions.

Disclosure

References

This work was supported by a grant from the Guthy-Jackson Charitable Foundation and the National MS Society Ilya Kister: nothing to disclose Sanjeev Chawla:nothing to disclose Jens Thomas Wuerfel:nothing to disclose

1. Mallik S, et al. Imaging outcomes for trials of remyelination in multiple sclerosis. JNNP, 2014. 2. Sherbondy A, et.al. ConTrack: Finding the most likely pathways between brain regions using diffusion tractography. J Vis . 2005.


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Disclosure

Chenyu Wang: nothing to disclose Linda Ly: nothing to disclose Alexander Klistorner: nothing to disclose Heidi Beadnall: nothing to disclose Joshua Barton: nothing to disclose Ruth Oliver: nothing to disclose Michael Barnett: has received institutional support for researchactivities, speaking and consulting from Biogen, Genzyme, Novartis, Tevaand Roche; and travel support from Novartis and Biogen.

Zongqi Xia: a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology, research funding from NINDS (K08NS079493), research grant from DNAGenotek (not relevant to this abstract) Sonya Steele: nothing to disclose Anshika Bakshi: nothing to disclose Sarah Clarkson: nothing to disclose Matthew Schindler: nothing to disclose Blake Dewey: nothing to disclose Joan Ohayon: nothing to disclose Lori Chibnik: nothing to disclose Irene Cortese: nothing to disclose Philip De Jager: a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society, research funding from the National Multiple Sclerosis Society (RG5003A2), research grant from Biogen, Sanofi/Genzyme (none relevant to this abstract) Daniel Reich: research funding from Intramural Research Program of NINDS, Myelin Repair Foundation, and Vertex Pharmaceuticals (none relevant to this abstract)

P537 Investigating early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk first-degree family members Z. Xia1,2, S. Steele3, A. Bakshi3, S. Clarkson2, M. Schindler3, B. Dewey3, J. Ohayon3, L. Chibnik2, I. Cortese3, P. De Jager2, D. Reich3 1Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 2Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3NINDS, Bethesda, MD, United States Objective: To assess the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities consistent with demyelination and axonal loss in asymptomatic individuals at risk for multiple sclerosis (MS). Background: Subclinical inflammatory demyelination and neurodegeneration likely precede symptom onset in MS. Methods: The Genes and Environment in Multiple Sclerosis (GEMS) is a prospective cohort study of MS first-degree family members that investigates risk factors and the sequence of events leading to MS onset. We assessed each subject’s risk for MS susceptibility using a weighted genetic and environmental risk score (GERS). Subjects in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination (including disability scale, visual, cognitive, motor, and sensory testing) as well as qualitative and quantitative neuroimaging with 3-tesla brain MRI and optical coherence tomography. Results: This study includes 100 subjects from higher-risk (n=41, 98% female) and lower-risk (n=59, 42% women) subgroups, with a mean age of 35.1 years. Given the unequal sex distribution between the two groups, we restricted analyses to women (n=65). Five women (8%) met the primary neuroimaging outcome of having brain T2-hyperintense brain lesions consistent with the 2010 MRI criteria for dissemination in space (4 higher-risk women and 1 lower-risk woman, 4:1 ratio). Further, a subset of these MS firstdegree relatives harbor many different neuroimaging features that are associated with MS pathology, including perivenous T2 hyperintense lesions (22%) and focal leptomeningeal enhancement (6%), consistent with the idea that these individuals are at higher risk of developing MS than the general population. Interestingly, higher-risk women exhibited worse vibration sensitivity in distal lower extremities as detected by the Vibratron-II device (p=0.0082, after adjusting for age, smoking status, height, and testing date). Conclusions: Asymptomatic family members at higher risk for MS manifest impaired vibration sensitivity, which may constitute evidence of myelitis, abnormal myelin structure / function and/or neurodegeneration and underscores the importance of early detection in high-risk individuals.

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P538 Global and regional annual brain volume loss rates in physiological ageing R. Opfer1,2, P. Suppa2, L. Spies2, C. Egger1, H.-J. Huppertz3, S. Schippling1 1Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland, 2Jung Diagnostics GmbH, Hamburg, Germany, 3Swiss Epilepsy Centre, Zurich, Switzerland Background: Brain volume loss (or brain atrophy) is an increasingly recognized in vivo-measure of Multiple Sclerosis (MS) neurodegenerative pathology. Discerning pathological brain atrophy from physiological ageing is key in the interpretation of brain volume loss rates among patients with MS. Objectives: To estimate average global and regional percentage brain volume loss per year (BVL/year) of the physiologically ageing brain. Methods: Two independent, cross-sectional single scanner cohorts of healthy subjects were included. The first cohort was acquired at the Medical Prevention Center (MPCH) in Hamburg, Germany and consisted of 251 healthy individuals (mean age 58.7 ± 13.1 years, range 18.2-89 years). The second cohort was taken from the Open Access Series of Imaging Studies (OASIS, http://www.oasisbrains.org). 315 healthy individuals from the cross-sectional study (mean age 44.9 ± 23.9 years, range 18-94 years) were included. Brain parenchyma (BP), grey matter (GM), white matter (WM), corpus callosum (CC), and thalamus volumes were calculated deploying a previously described atlas based volumetry approach. A non-parametric local linear regression technique was applied to fit the resulting age-volume data (for each brain region and cohort, separately). For each year the BVL/year was derived from the agevolume curves by taking local differences (in percent). The resulting BVL/year curves were compared between the two cohorts. Results: Consistent BVL/year curves were obtained for the MPCH and the OASIS


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cohort. Mean absolute difference between both BVL/year curves across an age range of 30 to 75 years was 0.01% for BP, 0.06% for GM 0.04% for WM, 0.1% for CC, and 0.02% for the thalamus. For the MPCH cohort the BVL/year curves of the BP was a increasing function starting from 0.2% at the age of 30 years increasing to 0.48% at age of 75 years (corresponding values for WM ranged from 0.02 % to 0.44%, GM from 0.32% to 0.5%, CC from 0.08% to 0.45%, thalamus from 0.25% to 0.5%). Conclusion: Physiological BVL/year rates were remarkably consistent between the two cohorts and independent from the scanner applied. Average annual BVL were clearly age and region/compartment dependent. This needs to be taken into account when defining cutoff values for pathological annual brain volume loss.

(lobules I-V) (p=0.0003), whereas better cognitive performance correlated with higher cerebellar volumes, mostly (p< 0.0001) in the posterior-inferior region (lobules VI-X). No correlations were found between clinical/cognitive parameters and normalized cerebral (total brain, white and grey matter) volumes. Conclusions: Motor and cognitive performances in MS seem to be more influenced by cerebellar than cerebral volumes. Cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting a critical contribution of regional cerebellar damage to the clinical manifestations of MS. This study has been partially supported by a grant from FISM 2011/R/19 and Italian Ministry of Health (GR-2009-1529671).

Disclosure

Disclosure

S Schippling has received research grants from Biogen, Bayer Healthcare, Novartis and Sanofi Genzyme, and consulting/speaker fees as well as travel support from Bayer Healthcare, Biogen, Merck Serono, Novartis, Teva, and Sanofi-Genzyme.

Drs dÁmbrosio, Pagani, Riccitelli, Colombo, Rodegher, and Falini have nothing to disclose. Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed.

P539 Cerebellar contribution to motor and cognitive impairment in multiple sclerosis patients: an MRI sub-regional structural analysis A. d’Ambrosio1, M.A. Rocca2, E. Pagani2, G.C. Riccitelli2, B. Colombo3, M. Rodegher3, A. Falini4, G. Comi3, M. Filippi2 1San Raffaele Scientific Institute, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 3Department of Neurology, 4Department of Neuroradiology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Background: The cerebellum plays a role in a wide variety of complex behaviors. Many evidences support a topographic division into “motor” and “non-motor” regions localized in the anterior and posterior cerebellum, respectively. Aims: To assess the role of cerebellar sub-regions in determining motor and cognitive impairment in MS patients. To our knowledge, this is the first attempt to investigate motor and cognitive impact of structural cerebellar sub-regional involvement in a large MS cohort. Methods: Cerebellar segmentation and lobular parcellation were performed on the 3D-T1 brain images from 95 MS patients and 32 healthy controls (HC) using the SUIT tool from SPM12. For all subjects, we also obtained normalized cerebral volumes and scores of motor performance (Nine Hole Peg Test [9-HPT]). MS patients also underwent a cognitive evaluation (Symbol Digit Modalities Test [SDMT], Paced Auditory Serial Addition Test [PASAT]). A linear regression analysis was used to assess the correlations between MRI derived volumes and both motor and cognitive scores. All results were considered significant (p< 0.05) after correction for multiple comparisons. Results: Compared to HC, MS patients showed a significant lower total brain, white (WM) and grey matter (GM) volume. Only secondary progressive (SP) MS patients showed significant lower cerebellar volumes compared to HC. No significant differences in the cerebellar volumes were found between MS patients and HC. In MS patients, better 9-HPT performance correlated with higher cerebellar volumes, mostly in the anterior region

P540 Longitudinal evaluation of diffusion tensor imaging measures in patients meeting criteria for “No Evidence of Disease Activity” A. Harel1,2, C. Saiote1, C. Farrell3, D. Sperling4, I. Katz-Sand5, M. Inglese2,4,6 1Neurology, Mount Sinai Medical Center, 2Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, 3Neurology, Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, 4Icahn School of Medicine at Mount Sinai, New York, 5Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, New york, 6Mount Sinai Medical Center, New York, NY, United States Background: The concept of “no evidence of disease activity”(NEDA), defined by absence of clinical activity (relapses or worsening on the Expanded Disability Status Scale (EDSS)) and radiological activity (new/enlarging T2 or enhancing lesions), is the ultimate goal of therapy for relapsing-remitting (RR) multiple sclerosis (MS). However, conventional MRI measures correlate modestly with disability and do not detect diffuse damage in normal-appearing brain tissue (NABT). Diffusion tensor imaging


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Poster Session 1, 22(S3) (DTI) provides quantitative measures of white matter (WM) integrity that yield a better correlation with physical and cognitive impairment, and thus DTI may be a better biomarker for ongoing disease pathology. While changes in DTI can be detected over time in MS in general, this has never been studied in the NEDA population. Methods: We devised a retrospective study utilizing chart review to identify RRMS patients who visited our MS Center between November 1, 2015 and January 31, 2016, met NEDA criteria for ⩾2 years prior, and whose MRIs included DTI data. Patients who did not meet NEDA criteria served as controls (EDA group). Clinical data was obtained from chart documentation. In addition to T2-, T1- and FLAIR sequences, the MRI protocol included a single-shot echo-planar sequence for DTI. Fractional anisotropy (FA) and mean diffusivity (MD) maps were created using tractbased spatial statistics. Mean FA and MD were measured over the global WM and in the corpus callosum (CC), and annual rates of change were calculated. Results: Preliminary data was obtained from ten NEDA and ten EDA patients. Averaged across twenty patients analyzed, FA in WM and CC decreased significantly at annual rates of 0.64% (p=0.05) and 0.52% (p=0.04) respectively. Mean FA in the NEDA group decreased at a slower annual rate than in the EDA group (0.45% vs 0.83% in WM, 0.28% vs 0.76% in CC). However, 3 patients in the NEDA group exhibited yearly WM FA decline >1%. These patients were more likely to have cognitive complaints than those with yearly decline < 1% (67% vs 29%). Conclusions: This data demonstrates proof of concept that changes in DTI measures can be detected over time in the setting of NEDA. While patients meeting NEDA criteria changed at a lower rate than the EDA group, the NEDA subgroup that had high rates of decline were more likely to complain of subjective cognitive change that did not affect the EDSS. The analysis of the entire cohort is underway and will be presented. Disclosure Asaff Harel: nothing to disclose. Catarina Saiote: nothing to disclose. Colleen Farrell: nothing to disclose. Dylan Sperling: nothing to disclose. Ilana Katz-Sand has received research support from the National MS Society, US Department of Defense, and the Guthy Jackson Charitable Foundation. Matilde Inglese has received research support from the National Institutes of Health, National MS Society, Novartis Pharmaceuticals, and Teva Neuroscience.

P541 Signal abnormalities on magnetic resonance imaging in acute optic neuritis. A prospective study K. Soelberg1,2, H.P.B. Skejø3, J.M.J. Mehlsen4, J. Grauslund5, F. Paul6,7, T.J. Smith5,8, S.T. Lillevang9, B.G. Weinshenker10, N. Asgari1,2 1Department of Neurology, Vejle Hospital, Vejle, 2Department of Neurobiology, Institutes of Molecular Medicine, University of Southern Denmark, Odense, 3Department of Radiology, AlerisHamlet Hospital, Copenhagen, 4Department of Ophtalmology, Vejle Hospital, Vejle, 5Department of Ophthalmology, Odense University Hospital, Odense, Denmark, 6Clinical

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and Experimental Multiple Sclerosis Research Center and NeuroCure Clinical Research Center, Department of Neurology, Charite - Universitätsmedizin Berlin, 7Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany, 8Department of Ophthalmology and Visual, University of Michigan Medical School, Ann Arbor, MI, United States, 9Department of Clinical Immunology, Odense University Hospital, Odense, Denmark, 10Department of Neurology, Mayo Clinic, Rochester, MN, United States Background: Optic neuritis (ON) as an inflammatory optic neuropathy usually occurs as an early manifestation of multiple sclerosis (MS) and neuromyelitits optica. ON is often an acute, self-limited event that recovers over several weeks. However, visual symptoms persist in 40-60 % of patients. Optic magnetic resonance imaging (MRI) features in the acute phase of the first ON episode remain poorly characterized. Methods: A prospective cohort study of patients with idiopathic ON in the Region of Southern Denmark from 2014-2016 with a one year follow-up was performed including acute ON evaluation. Patients were seen in a coordinated diagnostic investigation including clinical examination, analysis of blood and cerebrospinal fluid, measurement of evoked potentials, optical coherence tomography and MRI with 1.5 Tesla scanner. MRI was performed within two months of presentation. These studies were evaluated by a neuroradiologist, masked to clinical and serological information. Results: Sixty-two patients were evaluated for ON and 54 were included in the study. Forty-three patients met the inclusion criteria for acute ON, and 24 had an MRI evaluation at a single episode of ON. Median time between onset of symptoms and MRI was 17.5 days (range 2-55 days). All except one were Caucasian; the female: male ratio was 2:1 and median age at onset was 33 years (range 16-52 years). Twenty-two patients had unilateral and 2 had bilateral ON. Bilateral signal abnormalities on optic nerves on MRI were seen in one patient with only unilateral clinical symptoms. All three with bilateral involvement of optic nerves were females. Signal abnormalities on optic nerve were demonstrated by MRI in 79 % (19/24). Of these 74 % (14/19) had brain MRI abnormalities, 42 % (8/19) of whom met the diagnostic criteria for MS (McDonald dissemination in space criteria) within the acute ON episode. Further studies are in progress. Conclusions: These preliminary data indicate that signal abnormalities of the optic nerve on MRI occur frequently in the acute phase of a single ON episode. The presence of brain MRI abnormalities at the time of the first acute ON seems to be a relative risk factor for MS. Disclosure K. Soelberg: Nothing to disclose. HBP. Skejø: Nothing to disclose. JMJ. Mehlsen: Nothing to disclose. J. Grauslund: Nothing to disclose. F. Paul: F. Paul is on the steering committee for Novartis OCTIMS Study and MedImmune; received speaker honoraria and travel grants from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/ Genzyme, and Merck Serono; is an academic editor for PLoS ONE; is an associate editor for Neurology®: Neuroimmunology & Neuroinflammation; has consulted for SanofiGenzyme, Biogen Idec, and MedImmune; and received research support from Bayer,


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Novartis,Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, GermanResearch Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation, and National Multiple SclerosisSociety of the USA. TJ. Smith: Received research support from River Vision, NIH, University of South Denmark, Bell Charitable Foundation, Research to Prevent Blindness Foundation; he is an advisor to the Guthy-Jackson Charitable Foundation. He is scientific and medical director of the Graves’ disease and Thyroid Foundation, has been a paid consultant for Lipothera, River Vision, Wyeth, Merck, and Novartis, and holds patents for anti-IGF-1 receptor monoclonal therapy in autoimmune diseases. ST. Lillevang: Nothing to disclose. BG. Weinshenker: Royalties related to patent for discovery of NMO-IgG; licensed to RSR, Ltd., Oxford University, Member DSMB; Biogen Idec (Chair), Novartis and Mitsubishi (Chair). Attack Adjudication Committee; MedImmune Pharmaceuticals. Miscellaneous consulting; Chugai Pharmaceuticals and Chord Pharmaceuticals N. Asgari: Nothing to disclose. Study funding: The Danish Multiple Sclerosis Society. The Region of Southern Denmark Research. The University of Southern Denmark. Engineer Bent Bøgh, wife Inge Bøghs Foundation. Manufacturer Einar Willumsens Memorial Grant. Foundation of Lægevidenskabens Fremme. Torben and Alice Frimodts Foundation. The Hospital of Lillebaelt Foundation. P542 Thalamic functional connectivity in multiple sclerosis: the role of temporal thalamic sub-region in maladaptation A. d’Ambrosio1, M. Hidalgo de la Cruz2, P. Valsasina2, E. Pagani2, B. Colombo3, M. Rodegher3, A. Falini4, G. Comi3, M. Filippi2, M.A. Rocca2 1San Raffaele Scientific Institute, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 3Department of Neurology, 4Department of Neuroradiology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Background: Despite the well-known importance of the thalamus in MS, only limited data on whole and sub-regional thalamic functional connectivity (FC) are available. Aims: To investigate sub-regional thalamic resting state (RS) FC in MS patients and to correlate RS FC abnormalities with clinical/ cognitive measures. Methods: Diffusion tensor (DT), 3D-T1 weighted and RS functional MRI data were acquired from 200 right-handed MS patients and 100 age- and sex-matched healthy controls (HC). MS patients were clinically and cognitively evaluated. DT MRI data were used to parcellate the thalamus into five sub-regions, according to their structural connectivity profile (frontal, motor, post-central, occipital and temporal regions). For each subregion, a seed based RS FC analysis was performed. Multiple regression models were run to assess correlations of thalamic FC with clinical/cognitive variables. Results: Both in MS patients and HC, each thalamic sub-region RS FC map resembled structural connections with cortical areas. Compared to HC, MS patients had a higher intra and inter

thalamic RS FC in most thalamic sub-regions. Conversely, the temporal thalamic sub-region showed reduced intra-thalamic RS FC and higher RS FC with frontal and hippocampal areas. Compared to cognitively preserved, cognitively impaired MS patients had lower RS FC between thalamic sub-regions and caudate nucleus, anterior cingulate cortex and supplementary motor area, as well as higher RS FC between the thalamic temporal subregion, inferior frontal areas and para-hippocampal gyrus. This latter finding was correlated with poor motor and cognitive performance. Conversely, higher RS FC between thalamic subregions and caudate and cingulate cortex was correlated with better motor and cognitive performance. Conclusions: In MS patients, the different behaviour of temporal thalamic sub-region, compared to other thalamic sub-regions, could contribute explaining the high variability of thalamic RS FC findings in previous studies. Except for the temporal sub-region, MS patients had higher intra- and inter-thalamic RS FC. The increased RS FC between temporal thalamic sub-region and temporal/frontal regions seen in MS patients compared to HC, as well as in cognitively impaired compared to preserved MS patients is likely to be a maladaptive mechanism, associated with clinical/ cognitive impairment. Partially supported by grants from FISM 2011/R/19 and Italian Ministry of Health (GR-2009-1529671). Disclosure Drs dÁmbrosio, Hidalgo, Valsasina, Pagani, Colombo, Rodegher, and Falini have nothing to disclose. Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. P543 Deep gray matter atrophy in neuromyelitis optica spectrum disorder and multiple sclerosis J.-W. Hyun1, S.-H. Kim1, K.S. Park2, K. Kwak2, I.H. Jeong1, H.-J. Jo1, A. Joung1, J.-H. Kim1, S.H. Lee1, S. Kim1, J.-M. Lee2, H.J. Kim1 1Research Institute and Hospital of National Cancer Center, Goyang, 2Hanyang University, Seoul, Republic of Korea Introduction: Deep gray matter abnormality in neuromyelitis optica spectrum disorder (NMOSD) has not been fully elucidated.


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Poster Session 1, 22(S3) In a large cohort of NMOSD, we aimed to investigate the changes of DGM volume and their relation to cognition and clinical factors in NMOSD, and to compare the results with those of multiple sclerosis (MS). Methods: Three-Tesla structural brain MRIs and clinical data were prospectively evaluated in 91 patients with NMOSD, 52 patients with MS, and 44 healthy controls (HC). The patient group was classified as cognitive impairment (CI) or cognitive preserved (CP), using a criterion of ⩽1.5 standard deviation on at least 3 cognitive domains. Using general linear model, differences in DGM volumes were compared, between the 1) NMOSD, MS and HC groups, 2) NMOSD/MS patients with CI, CP and HC groups, 3) NMOSD patients with/without brain lesions and HC groups. Linear regression was performed to investigate the relationship between DGM volumes and clinical factors and partial correlation between DGM and brain lesion volumes was analyzed. Results: Patients with NMOSD had significantly reduced right thalamic volume compared to the HC (p = 0.021), but revealed less severe atrophy than patients with MS (p< 0.001). DGM atrophy is restricted to right thalamus in NMOSD, but broadly distributed in MS. NMOSD patients with CI disclosed more severe right thalamic atrophy than those with CP (p = 0.039) and HC (p = 0.004), whereas MS patients with CI revealed DGM atrophy not only in thalamus, but also putamen, accumbens, caudate, right hippocampus, and amygdala, when compared to the HC. EDSS score was related to right thalamic atrophy in both NMOSD and MS patients (p = 0.012 and 0.005, respectively). NMOSD patients with brain lesions demonstrated more severe right thalamic atrophy than NMOSD patients without brain lesions and HC (p < 0.001, respectively). Right thalamic volumes were negatively correlated with the brain lesion volumes in NMOSD patients (pr = -0.433, p < 0.001). Conclusions: DGM atrophy was less in degree and more selectively distributed in NMOSD than MS. Thalamic atrophy was associated with the clinical disability including CI in both NMOSD and MS. Disclosure This work was funded by the National Research Foundation of Korea (Grant No.2013R1A1A2058612), the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2014M3C7A1046050). Hyun JW, Kim SH, Park KS, Kwak, Jeong IH, Jo HJ, Joung AR, Kim JH, Lee SH, Kim S, Lee JM report no financial disclosure. HJ Kim has received honoraria for speaking or consulting for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, MedImmune, and Teva-Handok and has received research grants from Genzyme, Merck Serono, and Kael-GemVax. He serves on a steering committee for MedImmune and serves as an editor for the Multiple Sclerosis Journal - Experimental, Translational and Clinical.

P544 Structural connectivity in multiple sclerosis and simulation of disconnection E. De Meo1, M.A. Rocca2, E. Pagani2, B. Colombo3, M. Rodegher3, P. Preziosa2, G. Comi3, A. Falini4, M. Filippi2

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1San

Raffaele Scientific Institute, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 3Department of Neurology, 4Department of Neuroradiology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Background and aims: Several functional magnetic resonance imaging (fMRI) studies demonstrated the presence of disconnection across brain networks in multiple sclerosis (MS) patients and its relationship with clinical manifestations. Starting from this backgroung the aim of our study is to quantify structural connectivity integrity in multiple sclerosis (MS) patients with different clinical phenotypes and to simulate a disconnection due to T2 visible lesions and to verify the effect of macroscopic tissue damage on network-based measures. Methods: Diffusion tensor (DT) and dual-echo MRI scans were obtained from 239 MS patients (12 with a clinically isolated syndrome [CIS], 111 relapsing-remitting [RR] MS, 45 benign MS and 71 secondary progressive [SP] MS) and 131 healthy controls (HC). Structural connectivity matrices were produced and then artificially disconnected based on T2 lesion distribution. Global and nodal network metrics were calculated for both cases. Results: Compared to HC, MS patients showed decreased (p< 0.001) strength, assortativity, transitivity, global efficiency and increased average path length of the whole network. Similar hubs were identified in patients and controls. The postcentral, superior parietal, precuneus and cerebellar crus 1 e 2 hubs had reduced strength in SPMS versus RRMS patients. The analysis of the disconnected matrices identified more nodes with decreased strength in SPMS compared to RRMS and BMS patients. Conclusions: Global measures of structural connectivity were significantly different in MS patients compared with HC, showing an extended disruption of structural integrity in MS. The pattern of hub distribution was preserved in MS patients, with a preserved architecture of brain structural networks but a reduced strength of connections of nodes identified as hubs. The simulation of disconnection allowed us to identify the role of lesions in determining abnormalities in structural connectivity in MS patients and to better characterize the main disease clinical phenotypes. This work has been partially supported by grants from Fondazione Italiana Sclerosi Multipla (FISM/2011/R/19) and Italian Ministry of Health (GR-2009-1529671). Disclosure Drs De Meo, Pagani, Colombo, Rodegher, Preziosa, and Falini have nothing to disclose. Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from


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Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

P545 Head motion during resting state fMRI acquisition significantly alter functional connectivity and it depends on patient disability E. Silvestri1, M. Tonietto1,2, M. Castellaro1,2, M. Calabrese2, A. Bertoldo1 1Department of Information Engineering, University of Padova, Padova, 2Department of Neurological and Movement Sciences, University of Verona, Verona, Italy Background: Resting state functional connectivity (FC) represents a potential biomarker for clinical disability and disease progression in multiple sclerosis (MS). A confounding factor not previously investigated in MS is head motion during acquisition, which has recently been found to systematically alter FC measures (Power, Neuroimage 2012). Objectives: The aim of this study was to investigate the effect of head motion as possible confound in MS FC studies. Methods: Resting state fMRI at 3T (10 min, TR=2.6s, voxel=1.8x1.8x4mm) was acquired in 25 healthy controls (HC), 119 Relapsing Remitting (RR) and 12 Secondary Progressive (SP) MS patients. Images were pre-processed using state of the arts algorithms including a 12 degree of freedom motion correction step from which the mean displacement (mD) over time was calculated and used as a proxy for subject motion. Subsequently, images were analysed with group independent component analysis with 100 components, from which 41 were identified as non-artefactual. The time courses of these components were then reconstructed for each subject. Additional postprocessing was performed to remove remaining noise source in the time courses. These included regression of the motion parameters, of white matter and CSF average time courses (and their derivatives), and removal of outliers (volumes affected by displacement greater than 0.2mm plus the previous and the 2 subsequent volumes). Finally, individual FC was calculated as cross-correlation between each pair of time course. Pearson correlation (ρ) was calculated between all the subjects mD and FC to determine if the latter depended on subject motion. Differences in mD between groups of subjects were determined with Wilcoxon rank sum test. Furthermore, correlations between mD and clinical variables (EDSS, disease duration, age) were assessed. Results: FC was significantly correlated with mD for 19% of connections (42% without outliers removal), with ρ ranging from -0.4 to 0.5. We found differences between mD of HC and MS (p=0.007) and between RR and SP (p=0.0037). Furthermore, mD was correlated with EDSS (ρ=0.30, p=0.0004). Conclusions: Consistently with the fMRI literature, FC was strongly affected by head motion, with some connections made stronger while other weakened. Moreover, the degree of head motion was dependent on the subject group (HC, RR or SP) and patient disability. We believe this dependency constitutes a serious (and overlooked) cofounding factor in FC studies in MS.

Disclosure ES, MT, M Castellaro, AB: nothing to disclose. M Calabrese: Advisory Board membership: Bayer-Shering, Genzyme, Biogen Idec; Payment for development of educational presentations including service on speakers bureaus: BiogenElan, Genzyme, TEVA, Bayer-Schering; Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA. P546 Differences in brain MRI features between japanese and caucasian patients with multiple sclerosis Y. Nakamura1, L. Gaetano2,3, T. Matsushita1, A. Altermatt2, T. Sprenger2,4, E.-W. Radue2, L. Bauer2,3, M. Amann2, J. Würfel2, T. Saida5,6, L. Kappos3, J.-I. Kira1 1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 2Medical Image Analysis Center AG (MIAC), 3Neurology, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 4Department of Neurology, DKD Helios Klinik Wiesbaden, Wiesbaden, Germany, 5Institute of Multiple Sclerosis therapeutics, 6Department of Neurology, Kyoto Min-Iren-Central Hospital, Kyoto, Japan Objective: Clinical features of multiple sclerosis (MS) in Asians have been reported to be different from those in Caucasians. To identify differences in brain MRI features between Japanese and Caucasian MS patients by analysing and comparing baseline data from phase II fingolimod (FTY) trials with comparable inclusion criteria in both populations. Methods: Data from ninety-five Japanese and 84 Caucasian patients with MS with Expanded Disability Status Scale (EDSS) score of 0 to 6 were included in this analysis. T2-weighted (T2w) cerebral MRI at study baseline was used to evaluate the number, volume, and distribution of MS lesions. Using SIENAx (FSL), normalized total brain (NBV), cortical gray matter (cGM), white matter (WM) and deep gray matter (dGM) volumes were also assessed in the70-mm central area of the brain (z-block: MNI152 z-coordinates -10, bottom, to +60 mm, top). Results: Japanese patients had a lower frequency of secondary progressive MS (2.1 % vs. 14.3 %, p = 0.004), lower EDSS score (mean 2.0 vs. 2.6, p = 0.009) and Multiple Sclerosis Severity Score (mean 3.26 vs. 4.09, p = 0.008) and higher frequency of disease modifying therapy (DMT) for MS (57.9 % vs. 34.5 %, p = 0.002) compared with Caucasian patients. After adjusting for sex, age, MS subtype, disease duration, and previous DMT exposure, Japanese patients had marginally fewer number of T2w-lesions (mean 62 vs. 79, p = 0.06) and significantly lower NBV (mean 942,018 mm³ vs. 969,824 mm³, p< 0.001) compared with Caucasian patients. In univariate analysis, Japanese patients had lower frequency of T2 lesions in cerebellum than Caucasian patients (44.9 % vs. 68.7 %, p= 0.006). Cortical gray matter volume (cGMV)/NBV ratio was significantly lower in Caucasian patients than Japanese patients (p= 0.0003). NBV and deep grey matter volume (dGMV) had a significant inverse correlation with EDSS in both Japanese and Caucasian patients (NBV: r = -0.32, p = 0.004; r = -0.64, p < 0.0001. dGMV: r = -0.48, p < 0.0001; r = -0.34, p = 0.008, Spearman rank coefficient).


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Poster Session 1, 22(S3) Conclusions: Japanese patients had numerically fewer T2w lesions and less cerebellar involvement compared with matched Caucasian patients, which may be related to milder disease severity and progression. Disclosure Yuri Nakamura: nothing to disclose Laura Gaetano: nothing to disclose Takuya Matsushita: He has received honoraria from Bayer Schering Pharma, Biogen Idec, Takeda Pharmaceutical Company and Mitsubishi Tanabe Pharma. Anna Altermatt: nothing to disclose Till Sprenger: author’s previous and current institutions have received payments for consulting and speaking activities (Actelion, Biogen Idec, Electrocore, Genzyme, Mitsubishi Pharma, Novartis); grants received (EFIC-Grünenthal, Novartis Pharmaceuticals Switzerland, Swiss MS Society, Swiss National Research Foundation). Ernst-Wilhelm Radue: nothing to disclose Lorena Bauer: nothing to disclose Michael Amann: nothing to disclose Jens Würfel: he is CEO of MIAC AG, Basel, Switzerland. He served for advisory boards of Biogen, Novartis, Genzyme, TEVA. Takahiko Saida: nothing to disclose Ludwig Kappos: Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee for and consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB and Xenoport; speaker fees: Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society and the Swiss National Research Foundation. Jun-ichi Kira: He is a consultant for Biogen Idec Japan and Medical Review. He has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical and Medical Review. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan. This independent academic research was supported by Novartis and Mitsubishi Tanabe Pharma Corporation who provided baseline demographic data for the patients analyzed. Novartis and Mitsubishi Tanabe Pharma Corporation played no role in the design, methods, data management or analysis of the study.

P547 Impact of lesion segmentation and filling on cortical thickness estimation A. Palombit1, M. Castellaro1,2, E. Grisan1, S. Montemezzi3, F.B. Pizzini3, M. Calabrese2, A. Bertoldo1 1Information Engineering, University of Padova, Padova, 2Neurological and Movement Sciences, University of Verona,

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Unit, Department of Diagnostic and Pathology, University Hospital Verona, Verona, Italy Background: Among the Multiple Sclerosis (MS) potential hallmarks, the Cortical Thickness (CTh) has recently become a fundamental atrophy biomarker [Narayana et al., 2013]. However, its estimation from magnetic resonance T1w images is sensitive to the presence of lesions, requiring a lesion correction to segment and fill the affected areas with normal appearing tissue intensities. Objectives: To assess the impact of different lesion filling methods on CTh estimation with a simulation study and to quantify CTh sensitivity to lesion segmentation on MS patients data. Methods: 15 MS patients (12 RR, 3 SP, age 43±5 y, range 36-54 y, M/F: 6/9) and 10 Healthy Subjects (HS) were scanned with a Philips Achieva 3TX, acquiring an isotropic 1 mm3 T1wMPRAGE image. Simulation study: 15 lesion masks were manually drawn on MS patients images and randomly imprinted on HS images generating 150 in-silico MS-like images with known lesion mask. Three open source tools (lesion_filling - FSL, Lesion Segmentation Tool - LST and SLF) were used to fill each in-silico image. CTh was estimated on each image (both in-silico filled and HS images) using a Diffeomorphic Registration-based method (DiReCT, ANTs). Patients study: In addition to manual segmentation, lesions on MS patients images were segmented and filled using two available automatic pipelines (LST, SLS and SLF). CTh was finally estimated on those corrected T1w images. All CTh estimates were averaged over 108 cortical Region of Interests (ROI) outlined by Multi-Atlas Label Fusion (MALF) routine. Both the analysis of correlation and of variance (ANOVA) were performed to assess CTh sensitivity to different correction methods at ROI-level. Results: In the simulation study, CTh estimations after the application of different fillers displayed a high agreement (r>0.86) and no significant differences (p< 0.001, Bonferroni Corrected) among methods in all ROIs. CTh from in-silico images highly agreed (r>0.81) with the corresponding HS one, but statistically differs in 5/108 ROIs (p< 0.001, BC), tough always for less than inter-subject variability. Patient’s data processing revealed in all ROIs a high CTh agreement (r>0.82) without any differences among correction pipelines applied. Conclusions: CTh estimation resulted stable to different lesion correction methods both at segmentation and filling phase; CTh highly agreed both among different pipelines and respect to the manual correction. Disclosure Palombit A: nothing to disclose Castellaro M: nothing to disclose Grisan E: nothing to disclose Montemezzi S: nothing to disclose Pizzini FB: nothing to disclose Calabrese M: Advisory Board membership: Bayer-Shering, Genzyme, Biogen Idec; Payment for development of educational presentations including service on speakers bureaus: BiogenElan, Genzyme, TEVA, Bayer-Schering; Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA Bertoldo A: nothing to disclose


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P548 Leptomeningeal contrast enhancement in patients with neuromyelitis optica spectrum disorder S.V. Okar1, A. TUNCER1, R. Gocmen2, E. YILMAZ1, İ. Isikay1, R. KARABUDAK1 1Hacettepe University Faculty of Medicine, Department of Neurology, 2Hacettepe University Faculty of Medicine, Department of Radiology, Ankara, Turkey Objective: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the CNS. It is well known that imaging findings in NMOSD are distinct from multiple sclerosis (MS). Recently some atypical imaging findings and contrast enhancement patterns have been described in NMOSD patients. Depending on the limited data on leptomeningeal involvement, we investigated leptomeningeal enhancement in our NMOSD patients during their follow-up in our tertiary center. Material and method: We evaluated for leptomeningeal contrast enhancement in post-gadolinium T1 weighted images in 46 patients with NMOSD. NMOSD was diagnosed with new diagnostic criteria of NMOSD. Results: We identified four patients with NMOSD who have leptomeningeal contrast enhancement in post-contrast T1-weighted images. Note that all MRI scans were acquired on admission and before lumbar puncture. The mean age of the patients was twenty nine, all patients were female, two patients experienced bilateral visual loss whereas the others had myelitis concomitant with the studies magnetic resonance imaging (MRI) scans. Aquaporin-4 (AQP4) antibody was positive in three patients, however one was seronegative. None of them experienced any systemic vasculitis. MRI revealed diffuse leptomeningeal contrast enhancement on T1-weighted images. All patients had typical NMOSD parenchymal lesions with contrast enhancement. One patient had contrast enhancement in left third cranial nerve and bilateral seventh cranial nerves. They were all treatment responsive initially and they are currently all in our follow up. Conclusion: Leptomeningeal contrast enhancement may be a neuroimaging feature of NMOSD. Leptomeningeal enhancement is probably a result of functional impairment of AQP4 water channels in the pial and subpial surfaces. Thus, these findings suggest that AQP4 channel dysfunction in NMOSD is not only located to typical parencyhmal structures and is more disseminated in the central nervous system. Our next step will be to search whether leptomeningeal enhancement might be a new biomarker indicating disease activity prospectively. Disclosure Serhat V. OKAR: Nothing to disclose P549 Changes in diffusion-based structural brain network in relapsing-remitting multiple sclerosis T. Charalambous1, C. Tur1, J.D. Clayden2, F. Prados3, S.H.P. van Pavert1, D. Chard1, D.H. Miller1, S. Ourselin3, C.A.M. Gandini Wheeler-Kingshott1, A.J. Thompson1, A.T. Toosy1 1Queen Square MS Centre, University College of London, UCL Institute of Neurology, 2Institute of Child Health, 3Translational Imaging Group, CMIC, London, United Kingdom

Introduction: Disability in multiple sclerosis (MS) is not closely associated with conventional magnetic resonance imaging (MRI) measures. Recent advances in diffusion MRI and tractography methods enable us to non-invasively reconstruct the human brain structural networks, which may provide clinically relevant biomarkers for disease prognosis. In this longitudinal study, we constructed structural brain networks and assessed 1) differences in network measures (NM) between healthy controls (HC) and relapsing-remitting MS (RRMS) at baseline, 2) changes in NM over 24 months in each group separately, 3) differences in NM changes over time between controls and RRMS. Methods: Twelve MS patients and 12 age- and gender-matched HC were assessed by MRI at baseline and 24 months. MRI sequences performed were 3D sagittal T1-weighted fast field echo scan and high angular resolution diffusion imaging scan. Cortical, subcortical and cerebellar grey matter structures were identified based on the geodesic information flow (GIF) pipeline. We used TractoR for preprocessing of the diffusion weighted images which includes eddy-current distortion correction and fitting of the diffusion tensor. Then, we modelled the orientations of white matter fiber bundles using FSL-BEDPOSTX. Subsequently, we seeded 50 streamlines from each white matter voxel, and identified subsets which connected each pair of gray matter regions together. Structural networks are described as graphs and various network measures are derived using graph theoretical analysis. For the statistical analyses we used linear regression (adjusting for age and gender) and paired t-tests. Results: We found no significant differences when the NM were compared between HC and RRMS groups at baseline. The longitudinal analysis showed some borderline evidence of changes in NM in RRMS over 24 months (a decrease in the number of edges (p=0.065), edge density (p=0.091), mean clustering coefficient (p=0.086), global efficiency (p=0.092) and an increase in the mean shortest path (p=0.088)) no change in HC and no significant difference between the RRMS and HC groups. Conclusions: These preliminary results, obtained from small groups (RRMS and HC n=12), suggest that there may be a detectable deterioration in brain network integrity over 2 years in people with RRMS which is not part of normal ageing. Further work is now warranted to confirm these findings in a larger cohort, and determine their clinical relevance. Disclosure Thalis Charalambous has nothing to disclose. Carmen Tur has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Bayer-Schering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. Jonathan D. Clayden has nothing to disclose. Ferran Prados has nothing to disclose. Steven H.P. van Pavert has received some compensation for an internship with Teva Declan Chard has received honoraria (paid to his employer) from Ismar Healthcare NV, Swiss MS Society, Excemed (previously Serono Symposia International Foundation), Merck, Bayer and Teva for faculty-led education work; Teva for advisory board work; meeting expenses from Merck, Teva, Novartis, the MS Trust and National MS Society; and has previously held stock in GlaxoSmithKline. He is a member of the MS Society of Great


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Poster Session 1, 22(S3) Britain and Northern Ireland’s Biomedical Grant Review Panel. He is a member of the Data Safety Monitoring Committee for the PROXIMUS study, which is funded by National Multiple Sclerosis Society and Novartis. Both of these roles are unpaid. David H. Miller has received honoraria, through payments to UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma and has received compensation through payments to UCL Institute of Neurology for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen, Novartis and Merck. Sebastien Ourselin has nothing to disclose. Claudia A.M. Gandini Wheeler-Kingshott is on the editorial board of Functional Neurology and receives research grants (PI and coapplicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis Alan J. Thompson received honoraria/support for travel for consultancy from Eisai, Excemed, MedDay, support for travel from the International Progressive MS Alliance and National MS Society (USA), and an honorarium from SAGE Publishers as Editor-in-Chief of MSJ. Ahmed T. Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation, Bayer and meeting expenses from Biogen Idec.

OCT P550 Retinal measures correlate with cognitive and physical disability in early multiple sclerosis N. El Ayoubi1, S. Ghassan1, M. Said1, J. Allam2, H. Darwish1, S.J. Khoury1 1Multiple Sclerosis Center, American University of Beirut and Medical Center, 2Faculty of Agriculture and Food Sciences, American University of Beirut, Beirut, Lebanon Objectives: To explore the relationship between retinal layers’ thickness measured through OCT and cognitive function as well as disability in patients with early RRMS. Methods: Participants in this cross-sectional study were adults with RRMS and disease duration of five years or less, stable on Interferon beta-1a or Fingolimod therapy, and without a history of optic neuritis (ON) in one or both eyes. Patients were evaluated as per standards of care, and additionally underwent a battery of cognitive tests and a retinal OCT scan. A parallel cohort of healthy age and gender matched controls underwent a retinal OCT scan for retinal measurements reference. Results: We studied 47 patients with RRMS, on Interferon beta1a (N=32) or Fingolimod (N=15), and 18 healthy controls. Participants were comparable regarding demographic and clinical characteristics. However, the mean (SD) pRNFL and GCIPL thickness in controls [99.5 (8.9) µm, 86.8 (4.2) µm] was greater than that in either Interferon [92.0 (8.7) µm, 79.9 (6.7) µm] or Fingolimod [87.2 (8.4) µm, 75.0 (6.6) µm]-treated patients (p< 0.001). Multivariate analyses controlling for age, gender, disease duration, education, and treatment, showed that pRNFL thickness correlated negatively with EDSS (standardized Beta= -0.35, p= 0.02) and 9HPT (standardized Beta= -0.52, p< 0.001), and positively with SDMT (standardized Beta= 0.42, p= 0.01). GCIPL

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thickness correlated negatively with 9HPT (standardized Beta= -0.34, p= 0.03). Conclusion: In patients with early RRMS without optic neuropathy, retinal thickness measures correlated with physical and cognitive disability, supporting their potential as biomarkers of axonal loss and neurodegeneration. Disclosure Nabil El Ayoubi: reports no disclosures Stephanie Ghassan: reports no disclosures Marianne Said: reports no disclosures Joelle Allam: reports no disclosures Hala Darwish: reports no disclosures Samia J. Khoury: reports no disclosures Study supported by an unrestricted grant from Novartis pharmaceuticals. P551 Retinal nerve fibre layer changes over 2 years correlate with brain volume and N-acetylaspartate in alemtuzumab treated multiple sclerosis patients A.-L. Nguyen1, S.H. Kolind1, A.P. Lange1, R. Tam1, A. Riddehough1, I.M. Vavasour1, R. White1, R. Carruthers1, A.L. MacKay1, D.K.B. Li1, A. Jacobs2, A. Traboulsee1, ICAMMS IST 1University of British Columbia, Vancouver, BC, Canada, 2Sanofi Genzyme, Cambridge, MA, United States Background: In multiple sclerosis (MS) patients, retinal nerve fibre layer (RNFL) thinning as measured by optical coherence tomography (OCT) has been shown to reflect global brain atrophy on MRI, as well as grey matter and white matter volume changes. We previously reported the first cohort of relapsing-remitting MS (RRMS) patients to demonstrate a measurable improvement in RNFL thickness over 2-years during alemtuzumab treatment. Further analyses were undertaken to investigate the hypothesis that the neuroprotective effects seen on OCT will also be present on MRI. Objectives: To measure the correlations between changes in RNFL thickness over 2 years with whole brain volume, cortical thickness and total N-acetylaspartate (tNAA) in RRMS patients treated with alemtuzumab. Methods: 26 RRMS subjects at a single centre were treated with 2 courses of alemtuzumab in a prospective open-label study. The Heidelberg Spectralis SD-OCT was used to obtain the RNFL thickness at baseline and 6-monthly intervals to 2 years. Subjects were imaged with 1mm isotropic 3D T1-weighted spoiled gradient echo (SPGR) sequence and magnetic resonance spectroscopy (MRS) annually. Normalised brain volume (brain parenchymal fraction, BPF) and percentage brain volume change (PBVC) were measured with in-house segmentation-based and registrationbased methods, respectively. Other MRI measurements included cortical thickness and concentrations of tNAA measured in a single large (~53ml) voxel of predominantly normal-appearing white matter (NAWM) placed above the ventricles. Spearman rank correlations assessed the association between change in RNFL over 2 years with month 24 MRI values, as well as change in RNFL with change in MRI measurements over 2 years. Results: There were significant positive correlations between change in RNFL over 2 years with BPF at month 24 (r=0.457, p=0.033); and between change in RNFL with PBVC over 2 years


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(r=0.520, p=0.016). No significant correlations were seen between change in RNFL and cortical thickness. A strong positive correlation was seen between change in RNFL and tNAA at month 24 (r=0.684, p< 0.001). Conclusions: Associations were found between RNFL and two different measures of whole brain volume in our RRMS cohort treated with alemtuzumab over a 2-year period. In addition, the strong correlation between RNFL and tNAA but not cortical thickness may reflect a preferential effect on white matter over grey matter post alemtuzumab.

Neurological Institute, 6Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy, 7Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, 8Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Warwick, 9Keele University Medical School, Royal Stoke University Hospital, Stoke-onTrent, 10Department of Neurology, Royal Hallamshire Hospital, Sheffield, 11Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, United Kingdom

Disclosure

Background: Secondary progressive multiple sclerosis (SPMS) is characterized by accumulation of irreversible disability due to neuroaxonal loss. Optical coherence tomography (OCT) is a promising technique to predict multiple sclerosis (MS) progression by evaluating changes in the retinal nerve fibre layer (RNFL), the macular volume (MV), and the retinal ganglion cell (RGC) layer. Aim: To report early descriptive data of the cross-sectional baseline OCT and clinical measures in a cohort of SPMS patients enrolled in the MS-SMART trial (ClinicalTrials.gov NCT01912059). The MS-SMART trial is an ongoing UK multicentre, multi-arm, double-blind, placebo-controlled phase IIB randomised controlled trial for 440 patients with worsening SPMS randomised 1:1:1:1 between placebo, amiloride, riluzole and fluoxetine. The primary endpoint is brain atrophy (percent brain volume change) on structural magnetic resonance imaging at 96 weeks. A planned sub-group of patients are being evaluated in 2 centres (London/Edinburgh) with OCT. Methods: In this analysis, for patients without a history of optic neuritis (ON), OCT measures were calculated as the means of the values for both eyes; for those with a history of ON, only the nonaffected eye was included. We examined baseline data for the following clinical variables: age, sex, MS duration, SPMS duration, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), Symbol Digit Modality Test (SDMT) and Sloan low contrast letter visual acuity (SLCVA) charts at 5%. Temporal RNFL thickness (µm), macular (full thickness) volume (mm³) and RGC layer volume (mm³) were evaluated using spectral-domain OCT (Spectralis, Heidelberg Engineering, Germany). Results: A total of 104 patients (69F) were evaluated. The mean [SD] baseline features were: age 55.1yrs [6.5], disease duration 23.6yrs [10.2], disease progression 8.2yrs [6.0]. The mean [SD] clinical disability measures were: EDSS 5.8 [SD 0.82, median 6], MSFC 0.11 [0.35], SDMT 44.9 [10.6], SLCVA 5% 33.4 [11.5]. 40% of the total number of patients had contralateral ON. The mean values [SD] for OCT measures were: temporal RNFL 56.1 [15.3], MV 8.2 [0.45], and RGC volume 0.9 [0.14]. Conclusion: The study population enrolled in the MS-SMART trial represents a large cohort of subjects in which OCT and disability measures will be followed longitudinally over the next 2 years.

AN: grant support from Novartis for fellowship; consulting for EMD Serono. SHK: personal compensation for advisory board participation from Genzyme, Roche, Vertex Pharmaceuticals; research support from Genzyme, Roche. APL: nothing to disclose. RT: nothing to disclose. AR: nothing to disclose. IMV: nothing to disclose. RW: nothing to disclose. RC: speaking fees for unbranded lectures from Biogen, Genzyme, Novartis, Teva; consulting for EMD Serono, Genzyme; PI on clinical trials with MedImmune, Seattle Genetics, Guthy Jackson. ALM: consulting for Vertex Pharmaceuticals. DKBL: research funding from Canadian Institute of Health Research and MS Society of Canada; consulting for Vertex Pharmaceuticals; served on Data and Safety Advisory Board for Opexa Therapeutics and Scientific Advisory Boards for Adelphi Group, Novartis and Roche; given lectures supported by nonrestricted education grants from Novartis and Biogen; Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Novartis, Perceptives, Roche and Sanofi-Aventis; the UBC MS/ MRI Research Group has received grant support from Genzyme, EMD Serono, Novartis and Roche. AJ: employee of Genzyme. AT: consulting for Novartis, Genzyme, Roche; PI on clinical trials with Biogen, Genzyme, Roche, Chugai. Source of funding: Sanofi Genzyme.

P552 Optical coherence tomography in secondary progressive multiple sclerosis: a baseline data report from the MS-SMART trial F. De Angelis1, J. Cameron2, P. Connick2, D. Miller1, S. Pavitt3, G. Giovannoni4, C. Gandini Wheeler-Kingshott1,5,6, D. Plantone1, A. Doshi1, C. Weir7, R. Parker7, N. Stallard8, C. Hawkins9, B. Sharrack10, G. Cranswick11, S. Chandran2, J. Chataway1, for the MS-SMART trialists 1Queen Square Multiple Sclerosis Centre, NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, 2Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, 3Leeds Institute of Health Sciences, University of Leeds, Leeds, 4Department of Neurology, Barts and The London NHS Trust, The Royal London Hospital, London, United Kingdom, 5Brain MRI 3T Research Center, C. Mondino National

Disclosure The MS-SMART trial is a project funded by Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. It is also supported by the UK Multiple Sclerosis Society, the University College London Hospitals/UCL Biomedical Research Centres funding scheme.


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Poster Session 1, 22(S3) Floriana De Angelis, Domenico Plantone, Anisha Doshi, James Cameroon, Richard Parker, Peter Connick, Christopher Weir, Nigel Stallard, Clive Hawkins, Gina Cranswick, Siddharthan Chandran, Sue Pavitt, Basil Sharrack have no conflict of interest relevant to the submitted work. Peter Connick is funded by The Wellcome Trust. Claudia Gandini Wheeler-Kingshott is on the editorial board of Functional Neurology and receives research grants (PI and coapplicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. Jeremy Chataway has support from the National Institute of Health Research (NIHR) University College London Hospitals/ UCL Biomedical Research Centres funding scheme. He has attended advisory boards for Roche and Merck. He is local principal investigator for trials in multiple sclerosis funded by Novartis, Biogen, and GSK. He has an investigator grant from Novartis outside this work. David Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe & Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The NMR Research Unit at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Gavin Giovannoni has received compensation for serving as a consultant from AbbVie, Bayer Schering Healthcare, Biogen, Canbex, Eisai, Elan, Five Prime Therapeutics, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, MerckSerono, Novartis, Pfizer, Roche, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals. No other disclosures were reported.

P553 Retinal nerve fiber layer and macular volume in familial and sporadic MS patients M. Siger1, M. Grudziecka2, K. Selmaj2 1Neurology, Medical University of Lodz, 2Medical University of Łódź, Lodz, Poland Goal: The aim of this study was to determine whether the retinal nerve fiber layer (RNFL) thickness and the macula volume (MV) measured by spectral- domain OCT (SD-OCT) differs in familial (fMS) and sporadic (sMS) multiple sclerosis patients. Background: . There is unresolved issue whether sMS differs from familial form of disease Optical coherence tomography (OCT) allows quantification of retinal structures, such as RNFL thickness and MV. RNFL thickness is considered as a marker of axonal loss and MV as a marker of neuronal integrity and global neurodegeneration. Patients and method: 72 RR MS patients (31 fMS, 41 sMS) and 27 healthy control (HC) subjects, age and gender matched, were included in the study. Familial MS was defined based on whether or not the probant case had a first-degree relatives with MS. Both MS groups were matched according to neurological status measured by EDSS, annual relapse rate in previous 2 years and disease duration. MS patients and HC subjects underwent SD- OCT examination

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(Spectralis, Heildelberg Engineering). Total RNFL thickness and MV were assessed in right and left eyes and were expressed as a mean value for each patients. Results: Mean RNFL thickness in fMS and sMS were significantly lower than in HC (96.14 ±11.8 vs 106.7.5±7.06; p=0.001, and 98.4±11.4 vs 106.7.5±7.06 p=0.03 respectively). Mean RNFL thickness in fMS was lower than in sMS but this difference was not significant (96.14±11.8 vs 98.4±11.4 p=0.4). Mean MV was significantly lower in fMS and sMS compared to HC (8.1±1.0 vs 8.8±0.3 p=0.003 and 8.4±0.3 vs 8.8±0.3 p=0.001) respectively. Mean MV was lower but not significantly in fMS compared to sMS (8.1±1.0 vs 8.4±0.3 p=0.08). Conclusion: Our results suggest that RNFL and MV in fMS and sMS patients are lower than in control group. Both OCT measures showed the trend for diminished values in familial MS. Disclosure nothing to disclose P554 Leptomeningeal contrast enhancement is associated with loss of retinal nerve fiber layer thickness and macular volume on optical coherence tomography in multiple sclerosis R. Zivadinov1,2, D.P. Ramasamy1, S. Gandhi1, J. Hagemeier1, D. Jakimovski1, C. Kolb3, I. Paunkoski1, E. Carl1, A. Sanai3, D. Hojnacki3, B. Weinstock-Guttman3 1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 2MR Imaging Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States Background: Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients, as potential in-vivo marker of cortical pathology. Optical coherence tomography (OCT) is utilized for early outcome detection of post-inflammatory optic nerve events as well as for assessing the progression of different central nervous system (CNS) pathologies by quantifying the Retinal Nerve Fiber Layer Thickness (RNFLT) and Total macular volume (TMV). We hypothesized that if the LM CE is a marker of neurodegeneration in MS, it would be associated with decrease in RNFLT and TMV as measured by OCT. Objective: To investigate the association of presence and frequency of LM CE and loss of RNFL thickness and TMV on OCT. Methods: 81 MS patients (relapsing-remitting (RR): 48, progressive (PMS): 33) were enrolled in the present study. Presence and number of LM CE foci were assessed using 3D fluid-attenuated inversion recovery MRI sequence obtained 10 min after single dose of gadolinium injection on 3T scanner. RNFLT in superior, inferior, nasal and temporal quadrants were obtained for both eyes using OCT (Spectralis, Heidelberg, Germany). The OCT differences between subjects with and without LM CE were evaluated.


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We also explored the association between number of LM CE foci and OCT measures. Results: Of the 81 MS patients participating in the study, 35 (43.2%) showed presence of LM CE. PMS patients (n=19, 57.6%) showed significantly higher prevalence of LM CE compared to RRMS (n=16, 33.3%, p=0.026). No age (p=0.362), sex (p=0.347) or disease duration (p=0.227) differences were found between subjects with and without LM CE. MS patients with LM CE showed significantly decreased RNFLT (81.7 vs. 88.4 µm, p=0.046) and decreased TMV (7.4 vs. 8.1 mm3, p=0.036) compared to subjects without LM CE. The most robust regional RNFLT differences between MS patients with and without LM CE were observed in superior and inferior temporal quadrants (p< 0.05). There were significant associations between increased number of LM CE foci, and decreased RNFLT (r=-0.3, p=0.025) and decreased TMV (r=-0.36, p=0.012), which were more robust in RRMS than PMS patients. Conclusions: These findings suggest that LM CE is associated with atrophy of the retina nerve layer and macula, suggesting that LM CE is a potential biomarker of neurodegeneration occurring in the CNS independent and/or coexisting with an ongoing inflammatory process. Disclosure Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Deepa Ramasamy, Sirin Gandhi, Jesper Hagemeier, Dejan Jakimovski, Ivo Paunkoski, Ellen Carl, Ahmed Sanai have nothing to disclose. Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis. Bianca Weinstock- Guttman has participated in speaker´s bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Mylan Inc., and Acorda Therapeutics, Inc. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence as well as Questcor Pharmaceuticals, Inc., and Shire. She serves in the editorial board for BMC Neurology, Journal of International MS, Journal of Multiple Sclerosis.

P555 Retinal Layers as measured by optical coherence tomography are associated with distinct parameters of disease activity in multiple sclerosis B. Knier1,2, P. Schmidt3, L. Aly2,3, D. Buck3, A. Berthele3, M. Muehlau3,4, B. Hemmer3,5, T. Korn2,3,5 1Department of Neurology, Technical University Munich, Klinikum rechts der Isar, München, 2Department of Experimental Neuroimmunology, 3Department of Neurology, Technical University Munich, Klinikum rechts der Isar, 4Munich Cluster of Systems Neurology (SyNergy), 5Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Optical coherence tomography (OCT) of the retina allows for the accurate quantification of different retinal layers. It has previously been shown that both the inner nuclear layer (INL) as well as the peripapillary retinal nerve fiber layer (pRNFL) may reflect disease activity during the course of multiple sclerosis (MS). Here, we measured the impact of different retinal layers on various parameters of disease activity in a prospective manner. To date, 300 patients with early stage relapsing remitting MS (disease duration ⩽ 2 years) underwent retinal OCT examination with analysis of the pRNFL and macula layer segmentation. Eyes with past optic neuritis were excluded, all OCT underwent strict quality controls. Primary endpoints consisted of annualized relapse rate (ARR) and progression in expanded disability status scale (EDSS) after 2 years. Secondary endpoints included an annualized increase in T2 lesion load and annualized numbers of Gadolinium enhancing (Gd+) lesions in the cerebral MRI as well as changes in the multiple sclerosis functional composite (MSFC) score, the multiple sclerosis inventory cognition (MUSIC) score and the fatigue scale for motor and cognitive functions (FSMC) after 2 years. In our preliminary results, INL volume at baseline correlated positively with subsequent ARR (p=0.03) and the annualized increase in T2 and Gd+ lesions in cerebral MRI (p< 0.001). pRNFL thickness correlated negatively with the annualized increase in T2 lesion load in cerebral MRI (p=0.02). Progression in EDSS scores after 2 years was by trend associated with lower pRNFL thicknesses (p=0.07). Analysis of the remaining endpoints are pending; more patients are scheduled to finish the study during the next three months. Taken together, our results confirm the role of retinal OCT as a potential prognostic marker in multiple sclerosis. Furthermore, different retinal layers seem to reflect different aspects of disease pathology during the course of MS. Disclosure Benjamin Knier is supported by the Kompetenznetz Multiple Sklerose KKNMS and receives intramural funding from the Technical University Munich. Paul Schmidt and Lilian Aly have nothing to disclose. Dorothea Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. Achim Berthele reports grants from Bayer Healthcare, personal fees from Biogen, Merck Serono, Teva, Novartis, and Genzyme, and compensations for clinical trials from Biogen, Novartis, Genzyme, Roche, and Alexion Pharmaceuticals - outside the submitted work. Mark Muehlau has received research support from Germany ministry for research and education, German Research Foundation, Hertie-Foundation, Merck-Serono, and Novartis. Bernhard Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, and Genzyme Corporation; he has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd.; he has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals, Roche and Novartis Thomas Korn is supported by the Deutsche Forschungsgemeinschaft DFG (SFB 1054 and TR 128) and by the European Research Council ERC.


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Poster Session 1, 22(S3) P556 Associations between optical coherence tomography measures and clinical visual outcomes in patients with multiple sclerosis A. Papadopoulou1,2, L. Gaetano1,2, A. Pfister1, S. Magon1,2, M. Hardmeier1, P. Fuhr1, L. Kappos1, T. Sprenger1,3 1Neurology, University Hospital Basel, 2Medical Image Analysis Center (MIAC AG), Basel, Switzerland, 3Neurology, DKD Helios Klinik Wiesbaden, Wiesbaden, Germany Background: Optical coherence tomography (OCT) can measure the retinal layers. In patients with multiple sclerosis (MS), various OCT measures have been correlated with different visual tests, however, it is unclear which measure associates best with clinical visual deficits. Objectives: To investigate the association between different OCT measures and visual tests in patients with MS. Methods: Thirty-four patients with RRMS (16 with previous optic neuritis) and 33 controls, matched for age and gender underwent OCT and a clinical visual assessment, including high- and low-contrast letter acuity as well as colour vision testing (Ishihara table and Hardy-Rand-Rittler, HRR, pseudoisochromatic test). Patients and controls were compared for their visual- and OCTparameters. Correlations between OCT-parameters (thickness of the retinal nerve fiber layer, RNFL; thickness of the papillomacular bundle, PMB; volume of the macula) and visual tests were assessed. Results: Although patients and controls did not differ significantly regarding their scores in high- and intermediate (2.5%) contrast vision, low (1.25%) contrast letter acuity was significantly lower in MS patients vs. controls (respectively, 23.4±7.6 vs. 29.2±6.6; p=0.002). The Ishihara score was not different between patients and controls, however, the HRR score was significantly lower in MS patients vs. controls (34.97±2.1 vs. 35.97±0.2; p=0.012). Peripapillary RNFL and PMB were significantly thinner in MS patients vs. controls (RNFL: 96.5 mm±10.8 in patients vs. 104 mm±9.25 in controls, p=0.004; PMB: 48.5 mm±9.5 in patients vs. 54.4 mm±6.5 in controls, p=0.005). Macular volume was by trend lower in MS patients (8.66 mm3±0.41 vs. 8.85 mm3±0.41, p=0.072). Among the three OCT measures (macular volume, RNFL- and PMB thickness), PMB thickness showed a moderate correlation to both low-contrast (1.25%) vision (r=0.51, p=0.002) and HRR colour vision (r=0.54, p=0.002). Peripapillary RNFL thickness correlated moderately with HRR (r=0.57, p=0.001), but only by trend with low-contrast (1.25%) vision, while macular volume did not show significant associations with the visual tests. Conclusions: In this RRMS cohort, atrophy of the papillomacular bundle was the OCT measure associated both with low-contrastand colour vision. Focus on the PMB thickness instead of using the entire RNFL thickness in MS could increase the sensitivity to detect clinically relevant damage. Disclosure Athina Papadopoulou has received travel Support from Bayer AG, Teva and UCB-Pharma AG and research grant by the University of Basel. Laura Gaetano was in advisory board of Novartis. Armanda Pfister has nothing to disclose. Stefano Magon has received travel support by Biogen.

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Martin Hardmeier is supported by the Swiss National Science Foundation (grant 33CM30-140338). Peter Fuhr has grants from the Parkinson Schweiz, the Jacques and Gloria Gossweiler Foundation, the Freiwillige Akademische Gesellschaft Basel, the Gottfried und Julia Bangerter-Rhyner Foundation, the Swiss National Science Foundation, the Swiss Multiple Sclerosis Society, the Camelia Botnar Foundation, the Hedwig Widmer Foundation and unrestricted grants from: UCB Pharma AG, Roche AG, Abbvie AG, General Electrics; Advisory Board: Biogen inc. Ludwig Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer Health Care Pharmaceuticals, CLC Behring, Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharma, Pfizer, Receptos, F. Hoffmann-La Roche Ltd., Sanofi-Aventis, Santhera, Siemens and Teva, UCB, Xenport; royalties from Neurostatus AG; research grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, Novartis Research Foundation and Roche Research foundation. The current (DKD Helios Klinik Wiesbaden) or previous (University Hospital Basel) institutions of Till Sprenger have received payments for speaking or consulting from: Biogen Idec, Eli Lilly, Allergan, Actelion, ATI, Mitsubishi Pharma, Novartis, Genzyme, and Teva. Dr. Sprenger received research grants from the Swiss MS Society, Novartis Pharmaceuticals Switzerland, EFIC-Grünenthal grant, and Swiss National Science foundation. P557 Selective thinning of the maculo-papillary bundle and inner ganglion cell layer in radiologically isolated syndrome R. Karabudak1, A. Vural1, P.N. Acar1, A.M. Tuncer1, G. Sayat Gurel1, S. Kadayifcioglu2 1Neurology, 2Ophtalmology, Hacettepe University Faculty of Medicine, Ankara, Turkey Background: Optical coherence tomography (OCT) is a promising tool for the prediction of prognosis in individuals with radiologically isolated syndrome (RIS). Global thickness of peripapillary retinal nerve fiber layer (pRNFL) and total macular volume (MV) was found to be similar in healthy controls and RIS individuals. However, it is known from previous studies that pRNFL thinning can be segmental, specifically temporal, in both non-ON and ON eyes of patients with MS. Additionally, a relation between loss of pRNFL fibers in the temporal quadrant and reduction in macular volume was detected in MS patients. Aim: To investigate whether segmental analysis of pRNFL and macula can provide additional information compared to global analysis, regarding axonal degeneration in individuals with RIS. Methods: Retinas of consecutive individuals fulfilling the Okuda criteria for RIS and age and gender matched healthy controls (30 eyes of 15 individuals from each group) were analyzed with OCT. Global and segmental measurements of pRNFL and macula were performed by spectral domain optical coherence tomography (SD-OCT). Individual layers of macula were further segmented and analyzed.


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Results: Average pRNFL thickness and total macular volume and thickness were similar between groups. However, thickness of pRNFL in temporal (64.17 ± 11.43 vs 72.43 ± 10.7, p=0.016) and inferotemporal (137.77 ± 18.07 vs 149.43 ± 16.58, p=0.028) segments were reduced in individuals with RIS compared to controls. Analysis of the individual layers of macula revealed that macular RNFL volume (mostly in the nasal segment) was lower and ganglion cell layer of the inner macula was thinner in RIS individuals. Conclusion: Our findings support the existence of neuro-axonal degeneration in the retina of individuals with RIS. However, routine global measurements of pRNFL and macula are not sensitive enough to detect this phenomenon. Anatomically, papillomacular bundle (nerve fibers between temporal region of optic nerve and nasal part of macula) and neurons in the inner macular GCL are affected more prominently in RIS, as in MS patients. Segmental, rather than global, analysis of the SD-OCT data may be more sensitive to detect the subtle neuro-axonal degeneration that occurs in the earlier stages of MS. Disclosure Source of funding: This study is supported by a research grant from Merck-Serono. Rana Karabudak: Nothing to disclose. Atay Vural: Nothing to disclose. Nazire Pınar Acar: Nothing to disclose. Meryem Aslı Tuncer: Nothing to disclose. Güliz Sayat: Nothing to disclose. Sibel Kadayıfçılar: Nothing to disclose. P558 Optic neuritis does not mask progression of neurodegeneration affecting the macula in multiple sclerosis: a longitudinal OCT study D. Coric1, A. Petzold1,2, J. Killestein1, B.M.J. Uitdehaag1, L.J. Balk1 1Department of Neurology, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, 2Moorfields Eye Hospital, London, United Kingdom Background: Cross-sectional studies have provided evidence that inner retinal layer (IRL) atrophy is a clinically meaningful measure for neurodegeneration in multiple sclerosis (MS). Importantly, the presence of MS associated optic neuritis (MSON) causes severe IRL atrophy which masks the relationship with disability measures. The aim of this study was to investigate whether a history of MSON also masks IRL thickness changes over time and the relationship between these changes and clinical parameters of disability, potentially indicating an important limitation of the method. Methods: In this longitudinal study 118 MS patients underwent spectral domain OCT scanning and clinical assessment at baseline and after two years of follow up. Clinical assessment consisted of history of MSON, Expanded Disability Status Scale (EDSS), symbol digit modalities test (SDMT), 9-hole peg test (9-HPT) and timed 25-foot walk test (T25-FWT). The macular ganglion cell inner plexiform layer (mGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness were quantified. Paired samples T-test, regression analyses and Pearson’s r were used to assess

longitudinal changes in IRL thickness and to test the relationship between OCT and clinical measures. Results: Patients had a mean disease duration of 20.31 years (± 7.04) at baseline and 66.9% was female. Thirty-five patients (29.7%) had a history of bilateral MSON and 83 patients (70.3%) never experienced an episode of MSON (MSNON). Overall, patients showed significant thinning of the mGCIPL (mean decrease 0.58 µm [95%CI 0.34 - 0.82, p < 0.001]) but not the pRNFL (mean decrease 0.27 µm [95%CI -0.57 - 1.11, p = 0.520]) over the two year period. Progressive atrophy of the mGCIPL was similar for MSNON and MSON patients (p = 0.302). Preliminary analyses showed no significant correlations between changes in mGCIPL thickness and changes in test scores on the SDMT (r = 0.134, p = 0.197), 9-HPT (r = -0.113, p = 0.274) or T25-FWT (r = 0.161, p = 0.112). Likewise, patients who had progressed on the EDSS did not show more atrophy of the mGCIPL over time compared to those who did not (p = 0.296). Conclusion: The data suggests that the mGCIPL is a robust measure for progressive neurodegeneration in MS even in the clinical context of a previous episode of MSON. Evidence for progressive neurodegeneration in the visual system could however not be related to disability progression of broader cognitive and physical functioning. Disclosure D. Coric: has nothing to disclose A. Petzold: is a member of the steering committee for the OCTiMS study (Novartis), no consulting fees; and performs OCT QC for the Passos study (Novartis), receives consulting fees. J. Killestein: has accepted speaker and consulting fees from Merck-Serono, Biogen Idec, TEVA, Genzyme and Novartis BMJ. Uitdehaag: has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and TEVA LJ. Balk: received research support from TEVA P559 Signal quality dependency of intra-retinal segmentation algorithms in macular optical coherence tomography T. Oberwahrenbrock1, R. Jost1, H. Zimmermann1, I. Beckers2, F. Paul1,3, A.U. Brandt1 1NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 2Optics Laboratory, Beuth University of Applied Sciences, 3Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and MaxDelbrück Center for Molecular Medicine, Berlin, Germany Background: Intra-retinal layer thickness measurements assessed by optical coherence tomography (OCT) are increasingly implemented as outcome parameters in clinical MS trials. Insufficient image quality might interfere with segmentation results and hamper detection of subtle intra-retinal changes in longitudinal clinical trials. Objective: To compare segmentation quality of current retinal layer segmentation algorithms in relation to signal quality. Methods: Macula volume scans of 12 healthy controls were acquired with Spectralis and Cirrus OCT devices applying different settings for focus and image averaging (Spectralis only) to simulate a broad variety of noise levels. A device-independent


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Poster Session 1, 22(S3) signal-to-noise ratio (SNR) parameter was established and used to classify scans as high (SNR >71dB), medium (71 - 46dB) and low (< 46dB) quality scans. Layer segmentation was performed with the device’s build-in algorithms (HEYEX and Cirrus software) and device-independent software (Iowa Reference Algorithm (IRA) and AUtomated Retinal Analysis (AURA) tools). Segmentation results were classified by an experienced rater and layer thicknesses were compared to scans with the highest quality. Correlation and repeatability of the algorithms were investigated in dependency of SNR levels. Results: On high and medium SNR scans, segmentation results for all algorithms were similarly good with only few exceptions, but low SNR images caused severe errors in all segmentation algorithms. The algorithms generally showed good repeatability in high and medium SNR scans for all layers (Intraclass correlation coefficient (ICC): 0.82 - 0.99) with exception of the outer plexiform layer (IRA ICC: 0.62, HEYEX ICC: 0.71). The ganglion cell layer, inner plexiform layer and the complex of both showed stable segmentation results between scans with high and medium SNR (mean deviation (MD) to best scan =3µm), while low SNR resulted in higher MD (=10µm). The smallest differences were detected for the inner nuclear layer (MD=2µm) with the exception of low SNR scans segmented with HEYEX (MD=8µm). Correlations between algorithms and devices were high and gradually decreased with lower SNR. Conclusions: The quality of OCT scans and the choice of suitable segmentation algorithms are crucial for generating reliable results in clinical MS trials. The presented device-independent SNR parameter and the analysis of current segmentation algorithms provide guidance to develop appropriate study designs. Disclosure Timm Oberwahrenbrock is supported by EXIST-Forschungstransfer (German Federal Ministry for Economic Affairs and Energy, 03EFEBE079) and has received speaker honorary from TEVA, Germany and Bayer, Germany. Rebecca Jost has nothing to disclose. Hanna Zimmermann has received speaker honorary from TEVA, Germany and Bayer, Germany Ingeborg Beckers has nothing to disclose. Friedemann Paul is supported by the Deutsche Forschungsgemeinschaft (DFG EXC257), the Bundesministerium für Bildung und Forschung (BMBF Competence Network Multiple Sclerosis) and the Guthy Jackson Charitable Foundation, he has received travel grants, research support and personal compensation for activities with Alexion, Bayer, MerckSerono, Teva, Sanofi Genzyme, MedImmune, Chugai, BiogenIdec and Novartis. Alexander U. Brandt received funding for research from Novartis, Biogen, BMWi, BMBF and consulting fees unrelated to this study from Biogen, Novartis, Teva, Nexus, and Motognosis.

Neurophysiology P560 MRI and neurophysiological correlates of upper limb function in multiple sclerosis M. Krbot Skoric1, T. Gabelic1, D. Petravic1, M. Lisak2, B. Barun1, L. Crnosija3, M. Habek1,3

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1Department

of Neurology, University Hospital Center Zagreb, Clinical Hospital Center ‘Sestre Milosrdnice’, 3School of Medicine, University of Zagreb, Zagreb, Croatia 2University

Background: The aim of this study was to explore correlation between upper extremity function measured with 9-Hole Peg Test (9HPT), brainstem and cervical spinal cord MRI lesions and somatosensory evoked potentials of the median nerve (mSSEP). Methods: One hundred and nine patients with clinically isolated syndrome (CIS) were included in this study (78 females), mean age of 32.4±8.7. All patients were right handed. Brain MRI, mSSEP and 9HPT were performed for each patient. Cervical spinal cord MRI was available for 82 patients. Results of 9HPT for dominant and non-dominant hand, presence of T2 lesions in the brainstem and cervical spinal cord and N13-N20 interlatency of the mSSEP for each hand were analyzed. Results: For the non-dominant hand there was statistically significant correlation between N13-N20 interlatency of the mSSEP and results of the 9HPT (r=0.216, p=0.025). For the dominant hand there was no statistically significant correlation between N13-N20 interlatency of the mSSEP and the 9HPT. Brainstem lesions were present in 46 patients (42.2%). When compared to patients without brainstem lesions, those with brainstem lesions had significantly prolonged average time to perform 9HPT for both dominant and nondominant hand (median 20.58 vs. 19.20 s, p=0.023 and 21.88 vs. 19.90 s, p=0.003, respectively). Furthermore, patients with brainstem lesions had significantly prolonged interlatency of the mSSEP for the nondominant hand (6.8 vs 6.2 ms, p=0.018). No changes were observed with regard to cervical spinal cord lesions. Conclusion: Both morphological (MRI) and functional (mSSEP) measures of MS disease burden influence upper extremity function. This influence seems to be restricted to the brainstem lesions. Disclosure Funding: Croatian Science Foundation grant HRZZ UIP-112013-2622 P561 Objective pupil perimetry and MS progression E.N. Ali1, T. Maddess1, A.C. James1, C.F. Carle1, C.J. Lueck2 1Department of Neuroscience, John Curtin School of Medical Research, Australian National University, 2Department of Neurology, Canberra Hospital, Australian National University Medical School, Canberra, ACT, Australia Background: Our previous publication1 indicates that Multifocal Objective Pupil Perimetry (mfPOP) may provide disease severity measures in Multiple Sclerosis (MS) patients. A new measure based on the asymmetry between mfPOP results for the two eyes appears to improve on the earlier result. Methods: 35 normal controls and 85 MS subjects (72 relapsing remitting MS (RR), 13 Progressive or Secondary MS patients (PoS)) were enrolled. MfPOP responses were obtained using the FDA cleared nuCoria® Field Analyser that concurrently tested 44 visual field regions in each of the two eyes. Each region was analysed for deviations from normal according to response time to peak. Patients were grouped into 3 cohorts: EDSS < 3 (N=25), EDSS > 3 and < =4 (N=30), and EDSS > 4 (N=30). (ON): 66 subjects had optic neuritis (ON) vs. 104 with no ON. Diagnostic


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power was assessed by percentage area under ROC curves (%AUC) based on per region response delays relative to normal. Results: By our published method where eyes were individually classified the %AUCs for the three EDSS groups were: 62.5, 74.7, and 77.2 (all < ± 5.1%): while asymmetry gave 78.3, 82.9, and 85.8% (all < ± 4.6%). For ON vs. no ON subjects the published per eye method gave %AUCs of 75.4 ± 3.84 and 75.7 ± 4.4 (mean ± SE), while asymmetry gave 81.3 ± 3.24 and 81.8 ± 3.83. For RR and PS patients with EDSS ⩾ 5 (means 5.29 and 5.90) the %AUCs were 91.5 and 94.8 respectively. Scores for each control and patient based the first principle component of: the mean delay, the mean of the worst 7/44 region delays, and the mean of the worst 7/44 asymmetries were entered into a bootstrap cross-validated ROC analysis (1000 repeats) yielded %AUCs for the three EDSSS categories of 98.6 ± 1.23, 99.9 ± 0.11 and 99.9 ± 0.05%. Conclusions: The mfPOP results seemed to depend more on disease progression than the history of acute optic neuritis. Asymmetry between delays at anatomically equivalent visual field regions across eyes gave improved %AUC values compared to delays within each eye. EN Ali et al. MS Journal 2014: 20(7), 854-861. Disclosure EN Ali, C.J Lueck, AC Jame: nothing to disclose C Carle: nuCoria Pty Ltd: equity, patent application made for mfPOP T Maddess: Carl Zeiss; Meditec: patents, royalties. EyeCo Ltd: consultant, equity. nuCoria Pty Ltd: consultants, equity, patents under license, patent application made for mfPOP P562 Interoception and theory of mind in multiple sclerosis S. Esteves, I. García-Cordero, S. Abrevaya, D. Bruno, F. Pagani, B. Couto, F. Adolfi, E. Mikulan, A. García, A. Ibanez, L. Sedeño, V. Sinay INECO, Buenos Aires, Argentina The Heart-Evoked Potential (HEP) is a negative event-related potential associated with the attention of internal bodily signals (named interoception). Its main neural basis are the insular, anterior cingulate (ACC) and somatosensory cortex. Interoception is related to emotional awareness as shown by its influence on socio-cognitive domains, and by the overlap of brain networks between processes. Regarding Multiple Sclerosis (MS), although several studies have described atrophy in the insular cortex and alterations in theory of mind, none of them have assessed whether interoceptive processing is affected in patients, neither its potential impact in social cognitive domains. Our objectives were: (i) to evaluate the HEP modulations and its cortical correlates in patients with MS and healthy controls; (ii) to assess the possible association between HEP modulation and patients performance in a theory of mind (ToM) task. Methods: Thirty three patients with MS and 40 controls -matched for age, gender and level of education- were asked to follow their own heartbeats without any external cues (interoceptive condition). During the task, neurophysiological and cardiac signals were recorded via a high density electroencephalography (EEG) and electrocardiography (ECG). Neural correlates were examined through structural imaging. ToM was evaluated via the Faux pas task.

Results: Regarding HEP, healthy controls showed a significant more negative modulation compared to MS. The atrophy pattern of patients showed damage extended throughout right ACC, bilateral insular cortex and basal ganglia. In the control group, HEP was associated with two interoceptive hubs: the ACC and the insular cortex. These association was absent in the MS patients. However, the somatosensory cortex, other area linked with the perception of body information, was related to HEP in the MS patients and not in the control sample. Regarding ToM, only the last group presented a positive correlation with the HEP. Discussion: Our findings suggest that MS patients may present deficits in interoceptive processing. This is support by their atrophy patter that involves interoceptive areas. In patients, only the somatosensory cortex was correlated with HEP, which indicates a possible compensatory role. Finally, the relationship between interoception and ToM supports the link between the sensing of body signals and social cognition. Disclosure Supported by CONICET, CONICYT/FONDECYTRegular(1130920), COLCIENCIAS(1115-545-31374 and 1115569-33858), FONCyT-PICT 2012-0412, FONCyT-PICT 2012-1309, Novartis-Argentina, FONDAP 15150012, and INECO Foundation. The authors declare no conflict of interest. P563 Linking neurotransmitters and functional connectivity: a multimodal study on relapsing-remitting and progressive MS J.C. Nantes1, S. Proulx1, J. Zhong1, S.A. Holmes1, S. Narayanan2, R.A. Brown2, L. Koski1 1McGill University, 2Montreal Neurological Institute, Montreal, QC, Canada Background: Functional reorganization of neural networks has been linked to clinical expression of multiple sclerosis (MS). Studies on the healthy human brain suggest that its predominant excitatory (glutamate) and inhibitory (γ-aminobutyric acid (GABA)) neurotransmitters may modulate functional connectivity (FC), although this has not been investigated in people with MS or related diseases. Thus, we assessed relationships between FC and non-invasive markers of neurotransmitter level and activity in the brains of people with relapsing-remitting (RR) and progressive forms of MS. Methods: Participants included 21 RR MS, 13 progressive MS (6 primary progressive, 7 secondary progressive) and 16 healthy individuals. Proton magnetic resonance spectroscopy measures of neurotransmitter levels in the left hemisphere primary sensorimotor region were obtained. Transcranial magnetic stimulation was performed to measure intracortical facilitation and intracortical inhibition, which have been linked to excitatory and inhibitory neurotransmitter activity, respectively. FC strength was measured within a network related to the left hemisphere primary sensorimotor region. Age and sex were covariates in all analyses. Results: Mean FC strength within the network (control: 0.40±0.03, RR-MS: 0.37±0.02, P-MS: 0.25±0.03) was significantly lower in the progressive MS group compared to the other groups (p < 0.01). Among all MS participants, FC was significantly negatively correlated with GABA level (partial r = -0.34, p = 0.048) and positively (though non-significantly) correlated with glutamate level


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Poster Session 1, 22(S3) (partial r = 0.25, p = 0.15). Adjusting for sensorimotor glutamate level, GABA level and FC were significantly negatively correlated among those with a progressive (p = 0.004), but not with a RR (p > 0.05), MS course. Glutamate level and FC (adjusted for GABA level) were significantly positively correlated among participants with RR MS (p = 0.006) but not progressive MS (p > 0.05). Results remained significant when additionally adjusting for brain volume (normalized to head size). Intracortical facilitation and intracortical inhibition were not related to FC (p > 0.05). Conclusion: Lower glutamate and higher GABA levels are linked to weaker FC in the brains of people with MS. However, the strength of these relationships may depend on clinical course. While causal evidence is needed, these findings may be relevant to the development of therapies aiming to treat MS-related disability. Disclosure Julia C. Nantes receives personal PhD funding support through a Vanier Canada Graduate Scholarship; she declares no conflict of interest relevant to this work. Sebastien Proulx received financial compensation from the operating grant for data analysis support and is supported by an Alexander Graham Bell Canada Scholarship; he declares no conflict of interest relevant to this work. Dr. Jidan Zhong: Nothing to disclose. Scott A. Holmes: Nothing to disclose. Dr. Robert A. Brown has received personal compensation from NeuroRx Research for consulting services. Dr. Sridar Narayanan has received personal compensation from NeuroRx Research for consulting activities, and a speaker’s honorarium from Novartis Canada. Dr. Lisa Koski: Nothing to disclose. Funding: This study was supported by an operating grant from the Canadian Institutes of Health Research [MOP-119428].

P564 Increased variability of temporal gait parameters among patient with MS at early stages of the disease A.-L. Dubessy1,2, B. Bodini1,2, D. Garcia2, E. Le Page3, R. Assouad1, M.-L. Welter1, C. Papeix1, G. Edan3, C. Lubetzki1,2, R. Depaz1 1Hôpital de la Salpêtrière, 2ICM - Institut du Cerveau et de la Moelle épinière, Paris, 3CHU Pontchaillou, Rennes, France Gait impairment represents one of the most common and disabling symptoms of multiple sclerosis (MS). Spatial and temporal parameters of the gait cycle of patients with MS (PwMS) can be altered, with lower walking speed, shorter steps and an increased coefficient of variability. There is a lack of data concerning gait cycle at the early stages of the disease. The main goal of this study was to investigate early, subclinical? modifications of the gait cycle among PwMS. Methods: 33 PwMS, with disease duration above 5 years and an Expanded Disability Status Scale < 2 for pyramidal, sensory, and cerebellar sub-scores were compared to 29 healthy controls (HC). They had no complaint of walking difficulty. (est ce vrai?) Temporal parameters of the gait cycle were recorded through electronic foot switches, in different conditions: « Normal Pace» (NP), « Brisk Pace» (BP), and under dual task conditions : Word

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List Generation at Normal Pace (WLGN), Word List Generation at Brisk Pace (WLGB) and Serial Subtraction at Normal Pace (SSN). Results: CoV of the Step and Stride time were higher among PwMS compared to HC: the difference was significant in every condition for the CoV Step time (p < 0,01; < 0,0001; 0,02; < 0,01 and < 0,0001; respectively for NP, BP, WLGN, SSN and WLGB), but only for the BP (p< 0,01), SSN (p=0,036) and WLGB (p=0,002) conditions for the CoV Stride time. Conversely, no difference was found when confronting mean values of the Step Time and the Stride Time. Walking speed was similar between both groups, as well as the amplitude of the double task effect on gait parameters. Interpretation and conclusion: This study is the first to identify a high variability of the Step Time and Stride Time among a homogenous population of PwMS without reported walking impairment and an EDSS score < 2. High temporal variability of the gait cycle could be an early indicator of future walking impairment. This hypothesis will be addressed on long-term follow. Disclosure AL Dubessy: nothing to disclose B. Bodini: nothing to disclose D. Garcia: nothing to disclose E. Lepage: nothing to disclose R Assouad: nothing to disclose ML Welter: nothing to disclose G. Edan: nothing to disclose C Lubetzki: nothing to disclose R. Depaz: nothing to disclose P565 Autonomic dysfunction in patients with neuromyelitis optica disorders Y.S. Kim1,2, J.M. Seok1,2, M. Choi1,2, E.B. Cho3, H.L. Lee4, S.-Y. Kang5, K.H. Lee1,2, B.J. Kim1,2, J.-H. Min1,2 1Department of Neurology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 2Neuroscience Center, Samsung Medical Center, Seoul, 3Department of Neurology, Gyeongsang National Universiy Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, 4Chungbuk National University Hospital, Chungbuk National University College of Medicine, Chungbuk, 5Department of Neurology, College of Medicine, Jeju National University, Jeju, Republic of Korea Background and objectives: Central nervous system (CNS) demyelinating diseases are common secondary causes of central origin of autonomic dysfunction. Autonomic dysfunction (AD) in MS is explained by lesions in regions responsible for autonomic regulation such as nuclei in the periventricular region of fourth ventricle in the brainstem as well as medullar lesions. However, there is little known for autonomic dysfunctions in patients with neuromyelitis optica (NMO). In this study, we report the profile of autonomic dysfunction in patients with NMO spectrum disorder (NMOSD). Methods: We prospectively performed autonomic function test (AFT) in NMOSD patients; sympathetic skin response (SSR), quantitative sudomotor axon reflex test (QSART) and cardiovascular


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tests which include heart rate response to deep breathing (HRdb), blood pressure and heart rate responses to Valsalva maneuver and head-up tilt. Demographic and radiological findings were reviewed. Results: A total of 14 patients (mean age, 47.5 ±16.3 years; F:M=11:3) were enrolled in this study and mean EDSS score was 3.3 ± 2.3. The duration from onset to AFT was 51±43.4 months and the number of attacks was 3.43 ± 2.5. Among them, 78.6% of enrolled patients-11 patients-had abnormal AFT results. The cardiovagal dysfunction was most commonly observed (7/11 patients, 63.6%), and 4 patients had abnormal results in SSR, 3 in QSART, 4 in adrenergic function. The patients with autonomic dysfunction showed severe neurologic deficit (EDSS score of 3.6 ± 2.5 vs. 2.0 ± 1.0, p = 0.296), and there was a significant negative correlation between number of attacks and Valsalva ratio (r = -0.586, p = 0.028). The patients with myelitis attacks had frequent autonomic dysfunction (8/9 patients, 88.9%), and the cardiovagal abnormalities were associated with myelitis attacks (p = 0.021). There was a tendency of an association between the length of spinal cord lesions and the presence of cardiovagal dysfunction (5.7 vs 2.5 vertebral segments, p = 0.333). Brainstem attacks were associated with cardiovagal abnormalities (p = 0.029). Conclusion: Our study suggests that autonomic dysfunction is common in patients with NMOSD. The preferential locations of brain and spinal cord lesions could affect the profile of autonomic dysfunction in NMOSD. Further large cohort studies are needed to evaluate the pathophysiological mechanism of autonomic dysfunction in patients with NMOSD. Disclosure Ye Sel Kim : nothing to disclosure Jin Myoung Seok: nothing to disclosure Misong Choi: nothing to disclosure Eun Bin Cho: nothing to disclosure Hye Lim Lee: nothing to disclosure Sa-Yoon Kang: nothing to disclosure Kwang Ho Lee: nothing to disclosure Byoung Joon Kim: nothing to disclosure Ju-Hong Min: nothing to disclosure P566 The VEMP score as a predictor of disability progression in patients with multiple sclerosis T. Gabelić1, M. Krbot Skoric1, I. Adamec1, M. Habek1,2 1University Hospital Center Zagreb, 2School of Medicine, University of Zagreb, Zagreb, Croatia Background: Vestibular evoked myogenic potentials (VEMP) have been recognized as a reliable method in detection of symptomatic and asymptomatic brainstem lesions in multiple sclerosis (MS). We have previously reported that VEMP score demonstrated significant correlation with Expanded Disability Status Scale (EDSS) in a cross-sectional study on MS patients. The aim of this study was to evaluate the VEMP score as a predictor of disability progression in long-term follow-up of MS patients. Methods: Complete baseline work-up at the study entry consisting of EDSS, brainstem functional system score (BSFS), presence of brainstem lesions on the brain MRI and ocular and cervical VEMPs was performed in 100 MS patients. Second complete

clinical and neuroradiological analysis was done three years after with additional data about clinical evidence of disease activity which included number of relapses and increase in EDSS, total number of new T2 lesions and new gadolinium enhancing lesions (Gd+), and was available for 81 patients. Results were correlated with the VEMP score value at the study entry. Results: EDSS at follow-up significantly correlated with values of the VEMP score and ocular VEMP score at the study entry (R=0.223, p=0.045 and R=0.227, p=0.042, respectively). Number of relapses during follow up period correlated significantly with baseline and follow up EDSS (R=0.295, p=0.008 and R=0.448, p< 0.001, respectively), as well as with number of new T2 lesions and new Gd+ lesions (R=0.349, p=0.001 and R=0.319, p=0.004, respectively) during follow up period. Conclusions: The VEMP score is a promising marker of future disability development in patients with relapsing-remitting MS. Disclosure Tereza Gabelić: nothing to disclose Magdalena Krbot Skoric: nothing to disclose Ivan Adamec: nothing to disclose Mario Habek nothing to disclose P567 Vestibular evoked myogenic potentials in evaluating brainstem lesions in multiple sclerosis N. Celebisoy, G. Kavasoglu, N. Yuceyar Department of Neurology, Ege University Medical School, Izmir, Turkey Background: Cervical vestibular evoked myogenic potentials (cVEMPs) are inhibitory electrical potentials generated after a sound stimulus, originated in the saccule and conducted by the lower portion of the vestibular nerve all the way to the central nervous system (CNS), generating inhibitory electrical responses picked up by electrodes placed on the sternocleidomastoid muscle. A normal middle ear, inferior vestibular nerve and nucleus, vestibulospinal tract, the spinal accessory nucleus and nerve are needed for response generation. The aim of the study was to evaluate the contribution of cVEMPs in detecting brainstem involvement in multiple sclerosis (MS) and to compare the results with auditory evoked potentials (AEPs) and MRI. Material and methods: 30 MS patients (18 women and 12 men with a mean age of 30years (range 18-45years) and 30 healthy controls (18 women and 12 men with a mean age of 30 years (range 19-48 years) were included in the study. The latencies of peaks p13 and n23, peak-to-peak amplitude of p13-n23 divided by a mean prestimulus EMG (amplitude ratio) recorded during cVEMP testing were measured. For the AEPs I-III and III-V interpeak latencies were taken into consideration. Latencies exceeding 2.5 standard deviations were accepted as abnormal. Results: Brainstem involvement on MRI was present in 13 patients (44%). For cVEMPs there were 9 patients (30%) with prolonged latencies. AEP abnormalities were detected in 4 patients (13%). None of the electrophysiological tests used showed statistically significant advantage in detecting brainstem lesions. Conclusion: Though cVEMPs are superior to AEPs in detecting brainstem involvement, MRI is the most sensitive method.


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Poster Session 1, 22(S3) Disclosure Gökçe Kavasoğlu: Nothing to disclose Nur Yüceyar: Nothing to disclose Neşe Çelebisoy: Nothing to disclose P568 Myelin loss alters cortical network functionality by mediating a reorganization of activity pattern of the cortical layers and triggering cognitive deficits in rodents M. Cerina1, V. Narayanan1, P. Meuth1, K. Göbel1, A. Herrmann1, E.J. Speckmann2, S. Graebenitz2, T. Daldrup2, T. Seidenbecher2, H. Wiendl3, H.-C. Pape2, T. Budde2, S.G. Meuth1 1Münster University Hospital - Institute of Translational Neurology, 2Münster University - Institute of Physiology I, 3Münster University Hospital - Department of Neurology, Münster, Germany Background: Pathophysiologic myelin loss is an event common to many neurodegenerative diseases like multiple sclerosis (MS). In many animal models of MS and patients such event was often associated to the appearance of cognitive deficits. Objectives: Since myelin loss alone could not mediate alteration of higher cortical functionality such as cognition and learning, we hypothesized that altered cortical neuronal network mechanisms could be altered following de- and remyelination. Methods: We investigated the auditory thalamocortical (TC) system as exemplary neuronal network composed of both white and grey matter regions. We used the cuprizone model of general demyelination to assess alterations of the primary auditory cortex (A1; n = 11). Taking advantage of the spontaneous remyelination occurring in this model upon suspending cuprizone administration we assessed the potential benefits of myelin re-gain by combining voltage sensitive dye imaging techniques, extracellular recordings and behavior. Results: Decreased neuronal network activation was observed following demyelination in all cortical layers (-65.8 % vs. control) accompanied by increased latency to response (8.9 ms vs. 12.4 ± 0.06 ms). Heat maps showed a transitory hyperexcitation during the early remyelination phase (7 days) associated to altered spreading of the incoming cortical information into A1. Further analysis of the hierarchical activation of the different cortical layers revealed that a delayed activation of the cortical interneurons in layer 4 (0.005 ms longer than control) could mediate the hyperexcitation and the altered spreading of activity. Demyelination was also associated with a permanent loss of the tonotopic cortical organization in vivo, and the inability to induce tone-frequency-dependent conditioned behaviors, a status persistent after full remyelination (25 days). Conclusions: Demyelination altered the functionality of auditory neuronal networks and the persistency of alterations would indicate that despite myelin re-growth was necessary but not sufficient to ameliorate an irreversibly compromised network. Moreover, the molecular mechanisms underlying the hyperexcitation observed during the early phase of remyelination should be further investigated given the effect of a prolonged higher excitability of neurons. Disclosure This study was supported by the DFG CRC TRG128 -B06 Manuela Cerina: nothing to disclose

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Venu Narayanan: nothing to disclose Patrick Meuth: nothing to disclose Kerstin Göbel: nothing to disclose Alexander M. Herrmann: nothing to disclose Stephanie Graebenitz: nothing to disclose Thiemo Daldrup: nothing to disclose Thomas Seidenbecher: nothing to disclose Heinz Wiendl: nothing to disclose Erwin J. Speckmann: nothing to disclose Hans-Christian Pape: nothing to disclose Sven G. Meuth: nothing to disclose Thomas Budde: nothing to disclose P569 Hyperstable EEG-vigilance in multiple sclerosis patients M.G. Stoppe1, M. Schlingmann1, K. Meyer1, S. Olbrich2, F. Then Bergh3 1Department of Neurology, University Hospital Leipzig, Leipzig, Germany, 2Department of Psychiatry, University Hospital Zürich, Zürich, Switzerland, 3Department of Neurology, University of Leipzig, Leipzig, Germany Introduction: Fatigue is common in multiple sclerosis (MS) patients, experienced as restrictive in daily routine and a cause for early occupational disability. One hypothesis postulates a lack of physiological reserves by compensation of physical deficits and mental stress. This is supported by the observed activation of the hypothalamo-pituitary-adrenal (HPA) axis in MS patients (Then Bergh 1999) that is more pronounced in fatigued patients (Gottschalk 2005). Comparable to depression, antidepressants normalize this upregulation (Then Bergh 2001). Fatigue could furthermore originate from vigilance dysregulation. Vigilance regulation is described as important biological marker for different neuropsychiatric diseases (Olbrich 2011, Hegerl 2009, Hegerl 2011) with hyperstable and unstable vigilance as two aberrations from a slowly declining pattern (Olbrich 2012, Hegerl 2012). Methods: MS patients with and without fatigue; clinical scales: EDSS, WEIMuS (Würzburg Fatigue Inventory for Multiple Sclerosis), BDI (Beck Depression Inventory); EEG-based analysis of vigilance regulation via Vigilance Algorithm Leipzig (VIGALL); regulation of HPA-axis: combined dexamethasonecorticotropin-releasing hormone test (Dex-CRH); Statistics: SPSS11. Results: 34 MS patient’s data sets analyzed to date showed dysregulation of EEG vigilance with a significantly increased proportion of EEG-segments classified to highest vigilance stage (“awake”, W/0 p< 0.001), significantly fewer segments in low vigilance stages (A3 and C: p< 0.001, B1: trend with p< 0.07) compared to healthy controls (n=141, Olbrich 2013; one-sample t-test). EEG vigilance regulation over time was classified for each patient into hyperstable, slowly declining or unstable vigilance. Hyperstable vigilance was significantly more frequent (74%, p< 0.001) and slowly declining vigilance appeared in only 9% with no correlation of frequency to fatigue (scales or subjective classification) or BDI (p=0.35). For Dex-CRH, ACTH/cortisol-ratio of the maximum concentration was significantly lower in both hyperstable and unstable vigilance compared to slowly declining vigilance (p=0.046, ANOVA).


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Discussion: This is, to our knowledge, the first description of pathologic vigilance regulation as a feature of multiple sclerosis. Neither depression nor activation of HPA correlated with vigilance dysregulation, thus owing a final conclusion. Detailed analyses of fatigue scales with further variables of EEG will be presented. Disclosure Unrestricted grant for this investigator-initiated Project through University of Leipzig from Novartis Pharma. All authors: No disclosures related to this project. P570 Episodic autobiographical memory retrieval characteristics in multiple sclerosis C. Harand1,2, A. Mondou1,2, P. Piolino3, B. Desgranges2, G. Defer1, N. Derache1,2 1Neurology Department, University Hospital Center of Caen, 2U 1077 INSERM Unit, Caen, 3U 894 INSERM Unit, Paris, France Background: Episodic autobiographical memory (EAM) allows us to retrieve specific, detailed, meaningful personal events. Emotional experiences are further critical characteristics of AM as emotional memories are generally better retrieved than neutral ones. In multiple sclerosis (MS), several elements suggest that EAM retrieval may be impaired or, at least, manifests differently. Objective: In this study we investigated how emotion influences EAM retrieval in relapsing-remitting (RR) MS patients. Methods: Using a fine-grained EAM assessment known as the TEMPau task, we examined the retrieval of strictly EAMs according to their valence (positive, negative, neutral) in 20 RR patients (mean age ± SD: 45± 8.7 y) and 20 matched healthy-controls (mean age ± SD: 46.2± 8.3 y). In addition, we assessed factual, temporal, spatial and phenomenological characteristics for each emotional valence in our two groups. Exploratory correlational analyses were further conducted between EAM characteristics scores and measures on mood scales (depression, anxiety and alexithymia). Results: Autobiographical memory was impaired in MS (p< 0.01). More specifically, we demonstrated that patients retrieved fewer emotional negative EAMs than controls (p< 0.01). No differences were observed for positive ones (p=0.51). Focusing on negative valence, we also showed that patient’s negative EAMs were associated with less temporal (p< 0.001) and phenomenological (p< 0.001) characteristics compared to healthy subjects. Correlational analyses did not provided any significant results suggesting that mood alone cannot explain entirely this profile of performances. Discussion: These data provide evidence of distinct EAM retrieval profile in MS. Interestingly, we showed that difficulties to access phenomenological details possibly hampers retrieval of specific negative AM in patients, independently of any mood symptoms. In light with theories of coping, we propose that MS patients recalled negative events in a less specific way in order to prevent the emotional impact of painful memories and to deal more effectively with the disease. Disclosure Nothing to disclose

P571 Baseline cognition in those undergoing mesenchymal stem cell transplant: is there an opportunity to detect a repair signal? M. Abu-AlHawa1,2, M.S. Freedman2,3, H. Atkins2,3, C. Hilliker2, L.A.S. Walker1,2,4 1Cognitive Science, Carleton University, 2Neuroscience, Ottawa Hospital Research Institute, 3Medicine, 4Psychology, University of Ottawa, Ottawa, ON, Canada Background: Cell-based therapies for multiple sclerosis (MS) are receiving increasing interest. The Ottawa Hospital MS Clinic is at the forefront of this initiative. We reported positive outcomes up to 10 years post immunoablation and hematopoietic stem cell transplant (IA-HSCT). A unique contribution to this emerging literature is our finding on effects of cell-based treatment on cognition. Preliminary reports suggest no lasting negative cognitive impact of IA-HSCT despite early changes related to chemotoxicity. Mesenchymal stem cell transplant (MSCT) could possibly have similar benefits without chemotoxicity and has the potential for neural repair. Enrollment in the Mesenchymal Stem Cell Therapy for Canadian MS Patients (MESCAMS) trial has begun and several have completed baseline cognitive testing. Objective: Preliminary baseline cognition in MESCAMS participants is examined to determine if there is evidence of cognitive impairment. The presence of cognitive dysfunction could serve as a therapeutic target that could potentially lead to a marker of repair if cognition improves following treatment. Methods: MESCAMS participants completed a neuropsychological battery of attention/processing speed, working memory, language, visuospatial, learning/memory and executive function. Results: Cognitive impairment (at least 1.5 standard deviations below the mean) was noted as a group on tests of attention/processing speed, working memory and verbal memory. When examining results from individual participants working memory and delayed recall were most often affected. Conclusions: Preliminary MESCAMS data suggests that at baseline participants are more likely to demonstrate impairment on tests of attention/processing speed, working memory and delayed recall. Each of these areas is commonly impacted in individuals with MS. If change in cognition following mesenchymal stem cell transplant is to be detected, it would appear that these areas are most likely to yield markers of repair. Disclosure Maha Abu-AlHawa: nothing to disclose Mark Freedman: Honoraria or consultation fees from Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva Canada Innovation, and advisory or boards of Actelion, Bayer Healthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis, as well as speaker´s bureau for Genzyme. Harold Atkins: nothing to disclose Catherine Hilliker: nothing to disclose Lisa Walker: Honoraria or consultation fees from Serono Canada & Novartis


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Poster Session 1, 22(S3) P572 Brain perfusion SPECT with Brodmann areas mapping and neurocognition in multiple sclerosis L. Messinis1, D. Apostolopoulos2, G. Nasios3, S. Tsiouris4, T. Spiridonis2, A. Fotopoulos4, M.H. Kosmidis5, P. Zampakis6, P. Papathanasopowulos1 1Department of Neurology, 2Department of Nuclear Medicine, University of Patras Medical School, Patras, 3Department of Speech and Language Therapy, Technological Educational Institute of Epirus, 4Department of Nuclear Medicine, University of Ioannina Medical School, Ioannina, 5Department of Psychology, University of Thessalonica, Thessaloniki, 6Department of Radiology, University of Patras Medical School, Patras, Greece Background: Cognitive impairment (CI) is common in Multiple Sclerosis (MS) with prevalence rates ranging from 40 to 70%. Studies assessing regional cerebral blood flow (rCBF) and their relationship to neurocognitive findings in MS patients are lacking in the literature. Objective: To evaluate brain perfusion with 99mTc-HMPAO single photon emission computed tomography (SPECT) and Brodmann areas mapping in Relapsing Remitting Multiple Sclerosis (RRMS) patients using automated software (NeuroGamTM). Moreover, we evaluated brain perfusion in “cognitively impaired” versus “relatively cognitively intact” MS patients and relationships between neuropsychological functions and SPECT perfusion. Patients and methods: Thirty one RRMS patients with a mean EDSS = 3.65, SD = 0.95, who failed ⩾ 1 cognitive tests on a neuropsychological battery were evaluated with 99mTc-HMPAO SPECT. Their performance on brain perfusion was then compared with age and gender matched healthy subjects from the NeuroGam database. Patients were then divided into two groups (“cognitively impaired - CI”, (n =19) i.e failed ⩾ 2 cognitive tests or “relatively cognitively intact- RCI” (n=12) i.e failed 1 cognitive test, on the neuropsychological battery, and brain perfusion performance was compared and possible correlations investigated. Results: We found hypoperfusion for 52% of MS patients in the L frontal lobe, 46 % L parietal lobe, 36% L temporal lobe. In the Brodmann areas (BA) we found hypoperfusion in 77.4% in the L BA 9, 61. 3% L BA 10, 45.2% R BA 12. CI patients had significantly higher hypoperfusion values on the L and R frontal lobes, L temporal and R/L parietal lobes. Significant correlations were found between impaired measures of verbal fluency / executive function and hypoperfusion in the L frontal lobe. Conclusions: The present study underlines the potential utility of brain perfusion SPECT in assessing neurocognitive impairment in MS and the interrelationship between brain perfusion and neurocognitive function in these patients. Disclosure L. Messinis: There is no potential conflict of interest or anything relevant to this study to disclose D. Apostolopoulos D: There is no potential conflict of interest or anything relevant to this study to disclose G. Nasios: Registration to the congress and travel expenses will be covered from Genesis Pharma. This support is not relevant to this study. S. Tsiouris: There is no potential conflict of interest or anything relevant to this study to disclose

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T. Spiridonis: There is no potential conflict of interest or anything relevant to this study to disclose A. Fotopoulos: There is no potential conflict of interest or anything relevant to this study to disclose M.H. Kosmidis: There is no potential conflict of interest or anything relevant to this study to disclose P. Zampakis: There is no potential conflict of interest or anything relevant to this study to disclose P. Papathanasopoulos: There is no potential conflict of interest or anything relevant to this study to disclose

P573 Cognitive impairment and structural brain changes in patients with clinically isolated syndrome E. Hynčicová1, M. Vyhnálek1,2, A. Kalina1, L. Martinkovič1, T. Nikolai1,3, J. Lisý1, J. Hort1,2, E. Meluzínová1, J. Laczó1,2 1Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, 2International Clinical Research Center, St. Anne, Brno, 3Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, Prague, Czech Republic Background: Cognitive impairment is associated with cortical and subcortical atrophy and demyelinating lesions in patients with multiple sclerosis (MS). A profile of cognitive impairment and its structural correlates in patients with clinically isolated syndrome (CIS) are poorly understood. The aim was to characterize a profile of cognitive impairment in patients with CIS and its association with structural brain changes. Methods: Patients with CIS (n=51) and age-, gender- and education-matched healthy control participants (n=44) underwent testing with an extensive neuropsychological battery covering major cognitive domains and MRI brain scan with automated volumetric measurement of normalized brain parenchymal (nBP) volume, normalized white and grey matter (nWM and nGM) volume, regional cortical and subcortical grey matter volume and white matter lesion volume. Results: The CIS group had worse performance in verbal and nonverbal memory, information processing speed/attention/working memory, executive and visuo-spatial functions (p⩽.040), but not in language functions (p=.398) compared to controls. Cognitive impairment was present in 18 to 37% of participants in the CIS group. The CIS group had reduced nBP (p=.006), nWM (p=.029) and nGM (p=.027) volume and regional cortical and subcortical grey matter volume, predominantly in fronto-temporal regions and thalamus (p⩽.019) compared to controls. Worse performance in visuo-spatial functions was associated with lower nWM volume (r=0.31; p=.037). The higher EDSS score was related to lower nBP volume (r=-0.38, p=.011). Conclusion: Cognitive impairment was present in up to one third of patients with CIS and affected almost all cognitive domains with relative sparing of language functions. Brain atrophy was mostly pronounced in cortical grey matter of fronto-temporal regions and thalamus in patients with CIS. Lower nWM volume was associated with worse performance in visuo-spatial functions, while lower nBP volume was associated with greater clinical disability among patients with CIS.


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Disclosure Disclosure The authors report no conflict of interest. Grant support: Grant Agency of the Charles University in Prague Grants No. 546113 (Dr. Hynčicová); Internal Grant Agency of the Ministry of Health of the Czech Republic Grant NT/12385-5 (Dr. Meluzínová); European Regional Development Fund - Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123) and by project ICRC-ERAHumanBridge (no.316345) (Drs. Laczó, Vyhnálek, Nikolai, Hort); Ministry of Health, Czech Republic - conceptual development of research organization, University Hospital Motol, Prague, Czech Republic 00064203 (Drs. Laczó, Hynčicová, Martinkovič, Kalina, Vyhnálek, Nikolai, Hort, Meluzínová). P574 Ambulation and cognition following treatment with dalfampridine in multiple sclerosis A.S. Drake1, A. Smerbeck2, K. Kunker1, A. Khan1, M. Bucello1, D. Hojnacki1, C. Kolb1, K. Patrick1, B. Weinstock-Guttman1, R. Motl3, R.H.B. Benedict1 1Neurology, University at Buffalo, State University of New York, Buffalo, 2Rochester Institute of Technology, Rochester, NY, 3Kinesiology and Community Health, University of Illinois Urbana-Champaign, Urbana, IL, United States Background: Dalfampridine extended release is a potassium‐ channel blocker approved for improving walking in multiple sclerosis (MS). It has recently gained attention as a potential treatment for cognitive impairment, based on a few uncontrolled, observational studies. To date, data support that dalfampridine improves walking in MS, but there are no randomized controlled trials of its co-occurring effects on cognition. Methods: Using a double‐blind, placebo-controlled, randomized, study design, 61 patients meeting revised McDonald criteria for MS were enrolled. All participants further met inclusion criteria for cognitive impairment, defined as a z < −1.5 on the Symbol Digit Modalities Test (SDMT). The active arm received 10mg of dalfampridine extended release, bid, and was compared to a placebo group. Excluded were patients receiving steroids in last thirty (30) days or a relapse in the last ninety (90) days prior to enrollment. An extensive battery of tests was administered at baseline and 3 months follow-up, including SDMT, Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test-II (CVLT2), Brief Visuospatial Memory Test-Revised (BVMTR), Delis-Kaplan Executive Function System-Sorting (DKEFS Sorting), Timed 25 Foot Walk (T25FW), and 9 Hole Peg Test (9HPT). Patient reported outcomes included the Beck Depression Inventory Fast Screen (BDI-FS) and the Fatigue Severity Scale (FSS). The effects of treatment were evaluated via mixed factor ANOVA. Results: Treatment effects on the T25FW were replicated, with a Cohen’s d effect size of 0.27 for mean change in treatment vs. placebo. In contrast, there were no statistically significant interaction effects on cognitive function, fatigue or depression scores. Using a 20% change threshold, there were no significant interaction effects comparing responders vs. non-responders on any of the cognitive outcomes except PASAT, where responders had significant improvement relative to non-responders.

Conclusions: We confirm an effect of dalfampridine on timed ambulation in a placebo-controlled study. However, there were no effects on cognitive performance or self-report scales. Treated patients with a clinically meaningful improvement in ambulation had a benefit on auditory processing speed (PASAT), but no other change on cognitive or PRO outcomes. Thus, beneficial effects of dalfampridine on ambulation do not appear to be associated with gain in the other performance metrics examined. Disclosure This research was supported by an Acorda IIS. Allison S. Drake has nothing to disclose. Audrey Smerbeck has nothing to disclose. Anjum Khan has nothing to disclose. Margaret Bucello has received personal compensation for speaking and serving on advisory boards for Mallinckrodt, Biogen, Teva, Genzyme and Sanofi. David Hojnacki has received personal compensation for consulting, speaking, and serving on scientific advisory boards for Biogen, Teva Neuroscience, EMD Serono, Genentech, and Genzyme/ Sanofi Channa Kolb has received personal compensation for speaking and serving on a scientific advisory board for Biogen Idec, EMD Serono, Questcor, Novartis, Accorda and Teva. Kara Patrick has nothing to disclose. Bianca Weinstock-Guttman has received personal compensation for consulting, speaking and serving on scientific advisory boards for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Questcor and Genzyme& Sanofi. She has received financial support for research activities from NMSS, NIH, ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Genzyme. Robert Motl receives research support from Biogen, Acorda and Sun Health Technologies, provides consultation for Biogen and Acorda, and conducts CME for EMD Serono. Ralph HB Benedict receives research support from Biogen, Novartis, Genzyme, Acorda and Mallinckrodt, provides consultation for Biogen, Genentech, Teva, Novartis, and Sanofi, and conducts CME for EMD Serono. P575 Hippocampal atrophy as a neuroanatomical basis for memory deficits in MS: support for a degenerative model of MS memory decline J.F. Sumowski1, M.A. Rocca2, V.M. Leavitt3, G. Riccitelli2, A. Meani2, M. Filippi2 1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Neuroimaging Research Unit, Vita-Salute San Raffaele University, Milan, Italy, 3Department of Neurology, Columbia University Medical Center, New York, NY, United States Background: MS patients suffer memory decline, but the neuroanatomical basis of such deficits remains unclear. Only a handful of studies with small samples (Ns~50) have examined the link between memory and normalized volumes of the hippocampus: the brain’s chief memory structure. We investigated the relationship between memory and MRI-derived measures of global and regional brain atrophy in a large sample of MS patients, including deep grey matter and mesial temporal structures.


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Poster Session 1, 22(S3) Methods: Memory was evaluated in 218 patients (154 RR, 52 SP, 12 PP; 132 women; median EDSS=2.25) with the Selective Reminding Test and 10/36 Spatial Recall Test (combined into memory composite, adjusted for age and education, mean z=-0.75±1.03). 3.0T MRIs (analyzed with SIENAX and FAST) yielded normalized volumes of total brain, grey matter, white matter, thalamus, caudate, putamen, hippocampus, and amygdala. T2 lesion volume (T2LV) was also measured from dual echo scans using Jim 6.0. Correlations were performed between memory and MRI metrics. To identify MRI metrics independently contributing to memory, stepwise linear regression (entry p=.01, removal p=.05) predicted memory with all MRI metrics. Logistic regression (entry p=.01, removal p=.05, controlling for age and education) identified MRI metrics predicting memory status: intact (z>-1.5, N=164) vs impaired (z⩽-1.5, N=54). Results: All volumes (except white matter) significantly correlated with memory, but the largest correlation linked memory and hippocampal volume (r=.348, p< .001). Linear regression identified larger volumes of the hippocampus (p< .001) and amygdala (p=.007) as the only independent predictors of memory. Logistic regression identified smaller hippocampal volume as the only independent predictor of memory impairment (p< .001). [Note also that mediation analyses showed that hippocampal atrophy mediates (explains) aforementioned correlations between memory and other MRI metrics (e.g., T2LV).] Conclusion: This large MRI study identified hippocampal atrophy as the best predictor of memory in MS. Findings may help develop prognostic models to identify risk of memory decline in patients. Aligned with the reconceptualization of MS as both a white and grey matter disease, we may need to revise our thinking of memory deficits in MS to incorporate a hippocampally-mediated degenerative model rather than viewing memory deficits as the product of cognitive inefficiency (i.e., subcortical dementia model). Disclosure JF Sumowski: nothing to disclose. MA Rocca: received speakers honoraria from Biogen Idec, Excemed, and Novartis and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. VM Leavitt: nothing to disclose. G Riccitelli: nothing to disclose. A Meani: nothing to disclose. M Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. has received funding for travel from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Pepgen Corporation, and Teva Pharmaceutical Industries Ltd.; serves on speakers’ bureaus for Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen Idec, Novartis, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, CurePSP, and the Jacques and Gloria Gossweiler Foundation (Switzerland).

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P576 The cognitive profile of multiple sclerosis patients who respond to fampridine J.A. Matias-Guiu, A. Cortes-Martínez, R.-N. Villar-Quiles, P. Montero, I. González-Suárez, C. Oreja-Guevara, J. Matias-Guiu Neurology, Hospital Clinico San Carlos, Madrid, Spain Background: Fampridine is an oral treatment that has been shown to promote the conduction in demyelinated axons in Multiple Sclerosis (MS). It acts blocking the potassium channels, improving the gait. Some central nervous system secondary effects may appear, but it does not seem to affect cognitive functions. Several factors (lesion mechanism, conduction impairment, etc.) have been associated to cognitive impairment in MS, although the pathogenesis of deficits in specific functions is under discussion. The aim of this study was to compare the cognitive performance between responders and non-responders to this treatment. Methods: Retrospective study of a cohort of patients treated with fampridine. Walking speed was evaluated at baseline and 1 month after the onset of treatment. Exhaustive cognitive assessment was performed, using several tests of attention and executive function, processing speed, verbal and visual memory, visuospatial function, language, fatigue and mood. The Mann-Whitney U test was used to compare means between two groups. Binary logistic regression was also estimated. Lesion load in MRI was estimated using Statistical Parametric Mapping and the Lesion Segmentation Tool. Results: Thirty-two patients were treated with fampridine. Twenty-four (75%) were considered time-walked responders according to the assessment of walking speed at 1 month, and 8 (25%) non-responders. There were no differences in demographic factors between both groups. The responder group obtained lower scores in backward visuospatial span, and in the Tower of London test (total correct and total movements scores). Regression analysis classified correctly the 80% of cases. Conclusion: Higher-order executive function was associated to responsiveness to fampridine. This may suggest a possible role of conduction impairment in the pathogenesis of higher-order executive dysfunction in MS. Further studies are necessary to confirm this association. Disclosure Matias-Guiu JA: nothing to disclose Cortes-Martínez A: nothing to disclose Villar-Quiles RN: nothing to disclose Montero P: nothing to disclose González-Suárez I: nothing to disclose Oreja-Guevara C: nothing to disclose Matis-Guiu J: nothing to disclose P577 The impact of the disease and cognitive impairment in employment and socioeconomic status in multiple sclerosis patients in a Latin American country S. Vanotti1,2, A. Merino1, M.B. Eizaguirre1, R. Alonso1, B. Silva1, A.A. Iorio3, F. Caceres2, O. Garcea1 1Multiple Sclerosis Clinic, Ramos Mejia Hospital, 2INEBA Neurociencies Institute of Buenos Aires, 3Behavioral Biology Laboratory, IByME-CONICET, Buenos Aires, Argentina


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Background: In addition to clinical variables of Multiple Sclerosis (MS), there are social determinants such as employment and socioeconomic status that relate to the disease and the presence of cognitive impairment (CI) and impact on the quality of life of patients. Objective: To analyze the association between employment and socioeconomic status and the three contrasted groups (MS patients with CI, MS patients without CI and control group (CG)). Methods: 160 participants were studied: 33 MS patients with CI, 49 MS patients without CI and 78 participants from the CG. MS patients with CI: mean age: 45.39 ± 11.28 years; education: 12.73 ± 2.89 years and 69.7% females. Disease evolution: 14.32 ± 10.42 years; Expanded Disability Status Scale (EDSS): 4.33 ± 2.09. MS patients without CI: mean age: 38.12 ± 10.23 years; education: 15.37 ± 2.53 years and 67.3% females. Disease evolution: 8.98 ± 7.12; EDSS: 2.08 ± 1.88. CG: mean age: 41.50 ± 10.53 years; education: 14.77 ± 2.70 years and 73.1% females. Outcomes measures: EDSS, Brief Repeteable Neuropsychological Battery for MS, Ad hoc questionnaire to assess employment status and Socioeconomic status Index questionnaire. Results: Association between employment status (student / housewife, employed and unemployed / retired) and group membership in the three groups (p = .000 χ2 = 48.93) was found. MS patients with CI have 51.5% unemployment, MS patients without CI 20.4% and 3.8% GC. Total unemployed MS patients are 71.9%. Regarding the socioeconomic level, associations between socioeconomic groups, classified in lower class and upper middle class (P = .005 χ2 = 10.72) were found. 57.6% of MS patients with CI belong to the lower class, while MS patients without CI 36.7% and 25% in the control group. Conclusion: Higher unemployment rate is observed when compared with recently reported data from Slovakia (56.5%), Japan (59%), USA (47%) and Canada (44.7%). Considering Argentina’s socioeconomic difficulties, it is difficult to compare its socioeconomic level with that of other countries. Disclosure Vanotti S: nothing to disclose Merino A:nothing to disclose Eizaguirre MB: nothing to disclose Alonso R: nothing to disclose Silva B: nothing to disclose Iorio AA: nothing to disclose Caceres F: nothing to disclose Garcea O: nothing to disclose P578 fMRI correlates of cognitive impairment and cognitive reserve in multiple sclerosis F. Mattioli1, C. Pinardi2, C. Ambrosi2, F. Bellomi1, C. Scarpazza1, C. Stampatori1, R. Gasparotti2, R. Capra3 1Neuropsychology Unit Spedali Civili Brescia Italy, 2Radiology Unit University of Brescia, 3MS Center Spedali Civili, Brescia, Italy Cognitive reserve, defined as the lifetime cultural enrichment due to education and leisure activities, is known to mitigate cognitive decline of MS patients, supposedly by reducing the impact of

brain pathology. The functional MR correlates of cognitive reserve in MS are not completely investigated. Cognitive reserve of a sample of 20 MS patients and 13 age and education matched individuals was measured by means of the Cognitive Reserve Index and related to their cognitive impairment, measured with the BRB (Rao et al., 1991). An event related fMRI was performed in order to detect activations in brain areas during a n-back task and regression analyses were conducted on regions of interest. A positive correlation between cognitive impairment index and brain activation (i.e. the lower the cognitive impairment index, indicative of greater cognitive impairment, the smaller the brain activation) was found in the left (r=.84) and right (r=.89) inferior frontal gyrus, left (r=.89) and right (r=.78) medial orbital gyrus, right inferior parietal lobule (r=.93). On the contrary, a negative correlation (i.e. the greater the CR the lower the brain activation) was found between cognitive reserve and brain activation in the middle cingulum (r=.87), right (r=.85) and left (r=.83) inferior frontal gyrus, left (r=.89) medial orbital gyrus and right inferior parietal lobule (r=.93). These results might be explained by the greater brain functional efficiency in patients with higher cognitive reserve, as well as by a failure in compensatory hyper activation due to increased disease related cognitive impairment of MS. The clinical significance of brain activations might be differently interpreted in studies on MS and cognition. Disclosure Nothing to disclose P579 Benefits of a cognitive rehabilitation program in relapsingremitting multiple sclerosis patients J. Torres-Vela1, M. Jiménez-Morales1, V. Casado-Caballero1, M. Borges-Guerra2, A. Galvao-Carmona1,3, J.L. Ruíz-Peña2, G. Izquiero-Ayuso2, M. Vázquez-Marrufo1 1Department of Psychology, University of Seville, 2Multiple Sclerosis Unit, Virgen Macarena University Hospital, 3Department of Psychology, Universidad Loyola Andalucía, Seville, Spain Aim: Assessment of the benefits from a Cognitive Rehabilitation Program in Relapsing-Remitting Multiple Sclerosis (RRMS) patients. Equipment and methodology: The study was composed by three groups: 1.- Twenty-one RRMS patients who received the Rehabilitation Program; 2.- Nineteen RRMS patients who did not participate in any Rehabilitation Program; 3.- Twenty-six subjects free from the disease. The assessment of the possible benefits on patients from Group 1 was carried out by means of neuropsychological (BRB-N) and psychophysiological (a series of attentional and mnemonic tasks) evaluation in three different time points: A) Before applying the program; B) after the program; C) four months after the program ended. Groups 2 and 3 only undertook evaluations A and B. Results: Group 1 showed a wide range of improvements in several cognitive tasks: reaction time (RT) on Selective Attention


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Poster Session 1, 22(S3) tasks (r=0.01) and Working Memory Task (r=0.0008), and also in the percentage of correct answers in a Divided Attention task (r=0.02). There were not significant differences in the groups that did not receive rehabilitation, although some deterioration due to the progress of the disease was appreciated. The healthy control group did not show significant differences between measures, showing that these tasks are reliable and are suitable for longitudinal studies. Conclusions: The Cognitive Rehabilitation Program applied improved the cognitive impairment of RRMS patients, in comparison to the pathological group without treatment that showed a decline in their cognitive abilities. These improvements and no effects in other cognitive tasks show the difficulties in generalizing the benefits after cognitive rehabilitation in patients with RRMS, suggesting a complex process in the brain related with the cognitive rehabilitation program.

Disclosure Nothing to disclose

P581 An examination of cognitive fatigue and the interrelatedness of disease severity, fatigue, depression, and sleep quality J.A. Berard1, L.A.S. Walker2 1Psychology, University of Ottawa, 2Psychology, The Ottawa Hospital, Ottawa, ON, Canada

Disclosure Torres-Vela, J : nothing to disclose. Jiménez-Morales, M: nothing to disclose. Casado-Caballero, V: nothing to disclose. Borges-Guerra, M: nothing to disclose. A Galvao-Carmona: nothing to disclose. Ruíz-Peña, J.L: nothing to disclose. Izquierdo-Ayuso, G: nothing to disclose. Vázquez-Marrufo, M: nothing to disclose P580 Cognitive assessment with BICAMS battery during and after MS relapse N. Giedraitiene, R. Kizlaitiene, G. Kaubrys Clinic of Neurology and Neurosurgery, Vilnius University Faculty of Medicine, Vilnius, Lithuania Background: Cognitive impairment (CI) can present in multiple sclerosis (MS) patients at any time, regardless of the disease severity and activity. It seems that cognitive decline during MS relapses also can occur. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was recommended as brief, simple, and specific instrument for the evaluation of cognition in MS patients. However, it is unknown whether it is possible to detect the cognitive changes during MS relapse with BICAMS. Objectives: The purpose of the study was to assess the cognitive status with the Lithuanian version of BICAMS during MS relapse and 3-month follow-up period. Material and methods: 90 MS patients and 30 cognitively normal control subjects, matched on age, gender and level of education were enrolled. 60 MS patients were assessed during MS relapse, 1st and 3rd mth after relapse and 30 MS patients - during remission. Cognitive functions were assessed with the BICAMS tests. Results: MS patients performed significantly worse than controls on the three neuropsychological tests of BICAMS (p< 0.001). Relapsing MS patients performed SDMT test worse than remitting MS patients (p< 0.001). Significant increment of SDMT, BVMT-R and CVLT-II test scores was observed during the 1st mth after relapse in relapsing patients (p< 0.001) and of CVLT-II test - during the 3rd mth. The improvement of SDMT score after

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relapse was influenced by the EDSS score changes, age and education, the improvement of BVMT-R score - by the IFN-beta biological activity and duration of immunomodulatory therapy and the improvement of CVLT-II - by the duration of relapse (p< 0.001). Comparison of men’s and women’s memory changes after relapse revealed visual memory improvement in men and verbal learning in women (p< 0.05). Conclusions: Clinically meaningful impairment in cognitive status changes was observed in relapsing MS patients. The increment of SDMT, BVMT-R and CVLT-II scores after MS relapse was influenced by different factors.

Background: Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. While the study of CF is becoming more predominant, no research to date has yet examined the interrelatedness of CF and other associated characteristics of MS and their possible role in predicting CF. The current goal was to examine the interrelatedness of disease severity, fatigue, depression, sleep quality, and CF in multiple sclerosis (MS). Four theoretical models explaining the predictive roles of these variables were evaluated. Methods: Fifty-eight (58) individuals with a confirmed diagnosis of clinically definite MS were recruited through the MS Clinic at the Ottawa Hospital. CF was measured by examining last third versus first third performance on the Paced Auditory Serial Addition Test (PASAT). The PASAT and self-report measures of fatigue, depression, and sleep quality were administered as part of a larger neuropsychological battery. Path analysis was used to evaluate each of the proposed models. Results: CF was correlated only with depression (r = .362, p = .006) and sleep quality (r = .433, p = .001). Sleep quality was the greatest significant independent predictor of CF (β = .433, t(1,55) = 3.53, p < .001), accounting for 17.3 % of the total variance. The best fitting model showed sleep quality as the largest contributor to CF; however depression also played a smaller predictive role. Furthermore, depression emerged as the strongest predictor of sleep quality as well as fatigue. Disease severity only predicted depression in our sample. Conclusions: Findings indicate that sleep quality is the most significant predictor of CF (as measured by performance breakdown) in MS. Sleep quality itself, however, accounted for only 17.3% of the variance in CF suggesting that other variables which were not formally assessed in this sample (ex. anxiety, etc.) may also play a predictive role. Disclosure J.A. Berard: Nothing to disclose L.A.S. Walker: Nothing to disclose


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P582 Relationship between Vitamin D levels and cognitive impairment, depression and fatigue in relapsing remitting multiple sclerosis patients B.A. Silva, A. Merino, B. Eizaguirre, C. Yastremiz, C. Pita, R. Alonso, S. Vanotti, O. Garcea Multiple Sclerosis and Demyelinated Diseases Clinic, Ramos Mejia Hospital - University Center of Neurology ‘Dr JM Ramos Mejía’, School of Medicine, UBA, Buenos Aires, Argentina Introduction: There are few and controversial studies that approach the effects of vitamin D in cognitive status in Multiple Sclerosis (MS) patients. In some studies, a reduced level of serum vitamin D has been related with cognitive impairment, depression and fatigue. Objective: To evaluate relationship between serum vitamin D levels and cognitive impairment, depression and fatigue in Relapsing Remitting MS (RRMS) patients from Argentina. Methods: 61 RRMS patients were evaluated with Brief Repeteable Neuropsychological Battery for MS (BNS-EM), Symbol Digit Modalities Test (SDMT), Fatigue Severity Scale (FSS) and Beck Depression Inventory II (BDI II). Serum vitamin D levels were measured by chemiluminescence. Clinical data (Expanded Disability Status Scale -EDSS-, time of disease evolution) and demographic data (years of education, sex, age), were registered in all patients. Results: MS patients with ⩽ 20 ng/ml, n=21, 71.4% females, mean age: 42.8 ± 12.4 years; education: 13.6 ± 4.6 years, disease evolution (DE): 8.9± 8 years; EDSS: 3.2± 1.8. MS patients with ⩾20 ng/ml, n=40, 72% females, mean age: 36.4 ± 13.7 years; education: 13.1 ± 3.3 years, DE: 6.9± 7.7 years, EDSS: 2.4 ± 1.5. We have not found statistically significant differences between groups in age, sex, education, disease evolution and EDSS. Significant differences have been found regarding cognitive measures 7/24 test of the BNS-EM Battery (visual memory)- (p= < 0, 01 ) and SDMT (p= 0,041 ), FSS (p=< 0.01 ). In addition, was found association between depression severity and vitamin D levels (p=< 0.01, X2=30.7). Conclusion: According with previous studies in MS and other neurological diseases, correlation between less vitamin D levels and depression, fatigue and cognitive impairment have been found. Disclosure There is no conflict of interest of these authors for this work P583 Cognitive impairment in multiple sclerosis in a series of 228 patients: is SDMT useful as a screening tool? A. Cortés-Martínez, R.N. Villar-Quiles, J.A. Matias-Guiu, C. Oreja-Guevara, J. Matias-Guiu Neurology, Hospital Clinico San Carlos, Madrid, Spain Introduction: The frequency of cognitive impairment (CI) in multiple sclerosis (MS) is variable according to the studies published in the literature. One of the most consistent findings is the slowing of processing speed, which has been proposed as a screening parameter. The aim of this study was to analyse the prevalence of cognitive impairment in a large series of patients

with MS studied through a comprehensive battery of cognitive assessment. Methods: Prospective study of 228 patients diagnosed with MS (RR, SP and PP variants) (70.6 % women, mean age 47.60±10.01 years old, schooling 15.04 ± 3.80 years). The following neuropsychological tests were administered: Digit span, Corsi’s blocks, Trail making test, Symbol digit modalities test (SDMT), Stroop color-word interference test, Rey-Osterrieth complex figure, Free and cued selective reminding test, Verbal fluency, PASAT, Boston naming test, Tower of London and Judgement line orientation. Age- and education-adjusted scaled scores (average 10, standard deviation 3) with normative data from the Spanish project of conormalization NEURONORMA were used. Results: At least one cognitive test was impaired in the 72.8% of the sample. In 21.1% of the patients there was impairment in one test, in 11.8% of the patients in 2 tests and in 39.9% of the sample 3 or more tests were impaired. The most affected cognitive domains were attention (19.7%) and processing speed (19.2%) followed by memory (10.1%). The SDMT obtained an area under the curve of 0.779 (cut-off point scaled score 11/12) to detect alteration in at least one cognitive domain, and 0.857 to detect impairment in at least two domains (cut-off point scale score 10/11). Conclusions: CI is very common in MS. A normal-high performance on the SDMT allows excluding changes in other cognitive domains. However, due to the heterogeneity of cognitive profiles, it is necessary to perform a detailed neuropsychological assessment. Disclosure Ana Cortés-Martínez: nothing to disclose Rocío Nur Villar-Quiles: nothing to disclose Jordi A. Matías-Guiu: nothing to disclose Celia Oreja-Guevara: nothing to disclose Jorge Matías-Guiu: nothing to disclose P584 Depression, anxiety, and stress severities in multiple sclerosis patients using injectable vs. oral treatments F. Al-Hussain1, N. Al-Salloum2, N. Alazwary3, J. Saeedi4, S. Howaidi5, A. Daif1 1Department of Medicine, King Khalid University Hospital, King Saud University, 2Department of Family Medicine and Employee Health, King Fahad Medical City, 3Department of Medicine, Security Forces Hospital Program, 4Department of Neurology, King Fahad Medical City, National Neuroscience Institute, 5Department of Emergency Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia Background: Multiple sclerosis (MS) is a neurologic chronic inflammatory disease that has potential of causing disability and loss of function; these in turn have a stressful effect on the patient’s psychosocial wellbeing. Studies on MS in Saudi Arabia are scant particularly so on the psychological aspect of the disease. This study measures the severity of depression, anxiety and stress among Saudi patients, and compares the severity results to the type of Disease-Modifying Treatment (DMT) being used. Methods: A cross sectional study targeted 301 Saudis with Relapsing Remitting MS (RRMS), 18 years and older who have ever had a visit and an open file in any of these three large


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Poster Session 1, 22(S3) hospitals in Riyadh: King Khalid University Hospital, King Fahad Medical City, and Security Forces Hospital. Patients were contacted by a phone call, were informed about the study and their permission was taken before proceeding with the phone questionnaire. Demographic data and then questions of the DASS-21 were asked. Data analysis was done by using SPSS version 19. Results: 301 responses were included in this study. Mean age of RRMS patients was 34 years (SD±10), and 69% were female. Half the recruited (149) used an Interferon, 58 patients used Fingolimod and 28 used Natalizumab. Mean scores for all subjects was 8.25 (SD±6.89) for depression, 3.30 (SD±3.83) for anxiety and 3.85 (SD±5.73) for stress. Categories (in percentages %) for depression were: 59.6 normal, 17 mild, 17 moderate, 6 severe and 0.4 extremely severe. For anxiety: 80.4 normal, 10.2 mild, 7.2 moderate, 2.1 severe and none had extremely severe anxiety. And for stress: 93.6 normal, 3 mild, 2.6 moderate, 0.9 severe and none had extremely severe stress. Depression scores were similar among all demographic and drug groups, anxiety scores were significantly higher in Interferon users (ANOVA) compared to Natalizumab, and stress scores were within normal limits, but had a statistical difference (ANOVA) between Fingolimod and Natalizumab which was dismissed for being clinically insignificant. Conclusion: RRMS in Saudi patients was associated with mild to moderate depression secondary to the disease itself rather than a particular DMT. Mild anxiety was higher among Interferon users, which could be because of injection anxiety reasons. Comprehensive care, including psychiatric, for MS patients should be, therefore, encouraged regardless of patient’s demographic characteristics or the DMT that is being used. Disclosure Fawaz Al-Hussain: nothing to disclose Noura Al-Salloum: nothing to disclose Jameelah Saeedi: nothing to disclose Naael Al-Azwary: nothing to disclose Sara Howaidi: nothing to disclose Abdulkadir Daif: nothing to disclose

Disclosure

P585 Differences in cognitive impairment and corpus callosum index between relapsing remitting and progressive multiple sclerosis in Chile E. Ciampi1,2, M. Vasquez3, R. Uribe-San-Martin1,2, A. Marquez1, T. Labbe3, J.P. Cruz3, D. Reyes3, C. Pinto3, P. Feliu3, D. Weaver3, A. Reyes3, E. Vergara3, C. Carcamo1 1Neurology, Pontificia Universidad Catolica de Chile, 2Neurology, Hospital Sotero del Rio, 3Pontificia Universidad Catolica de Chile, Santiago, Chile Background: Cognitive impairment is common in MS, it is present throughout different disease courses and it is associated with brain atrophy. Corpus Callosum Index (CCI) is a simple and easy to perform measure of brain atrophy that correlates with selective cognitive impairment. Goals: To describe differences in cognitive performance between Relapsing Remitting (RR) and Progressive (Pr) MS patients and its relationship with CCI. Methods: A prospective cohort of MS patients was evaluated using a neurocognitive battery including episodic (visual/verbal)

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and working memory, processing speed, and cognitive-shifts tests.Total and regional (anterior, middle, posterior) CCI was obtained by a trained neurologist from sagittal T1 MRI and correlated with cognitive scores within 3 months of scanning. Cognitive Impairment diagnosis was considered when the Z scores of at least two tests were < -1.5. Disability (Expanded Disability Status Scale-EDSS), fatigue, depression and Quality of Life (QOL) scores were also obtained. Results: One-hundred and six (106) patients were recruited, 67 RR and 39 PrMs. As expected, patients with PrMS were significantly older (mean age 56.2 vs 34.1 years), had longer disease duration (mean 15.5 vs 5 years), higher disability scores (median EDSS 6 vs 1.5), and reported higher scores in depression, fatigue and QOL. No differences were found in gender distribution. RRMS had 25.9% of patients with Cognitive Impairment vs 86.8% in the PrMS group. Compared to RRMS, PrMS scored significantly lower in every test except for cognitive-shifts, and a significant reduction of anterior and middle CCI was observed, while no differences were found in total or posterior CCI. EDSS was correlated with CCI only in the RRMS group (rp=-0.495, p< 0.001). After adjusting for covariables (age, disease duration, EDSS, fatigue, depression and QOL), Verbal Memory was correlated with anterior CCI in RRMS; Visual Memory was correlated with total and posterior CCI in PrMS; Working Memory was correlated with anterior CCI in both groups and total CCI in PrMS; Processing Speed was correlated with total and regional CCI in both groups; and cognitive shifts was only correlated with posterior CCI in PrMS. Conclusions: Cognitive impairment is present in RR and PrMS patients with a more severe and widespread involvement in the latter group. Corpus Callosum Index correlates with selective cognitive performance and it is correlated with physical disability only in RRMS.

Ethel Ciampi declare no conflict of interest Macarena Vasquez declare no conflict of interest Reinaldo Uribe declare no conflict of interest Tomás Labbe declare no conflict of interest Juan Pablo Cruz declare no conflict of interest Arturo Marquez declare no conflict of interest Diego Reyes declare no conflict of interest Carmen Pinto declare no conflict of interest Ana Reyes declare no conflict of interest Elizabeth Vergara declare no conflict of interest Daniella Weaver declare no conflict of interest Patricia Feliu declare no conflict of interest Claudia Carcamo declare no conflict of interest P586 Cognition over the course of multiple sclerosis J. Gich1,2, M. Rivero2, J. Puig3, G. Blasco3, J. Salavedra2, C. Biarnés3, P. Danius i Estadella4, S. Pedraza3, L. Ramió-Torrentà2,5 1Neurology Department, Dr. Josep Trueta University Hospital, 2Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), 3Imaging Research Unit, Diagnostic Imaging Institiute (IDI), Dr. Josep Trueta University Hospital, 4Department of Computer Science,


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Applied Mathematics and Statistics, University of Girona, 5Neurodegeneration and Neuroinflammation Research Group, Dr. Josep Trueta University Hospital, Girona, Spain Background: Cognitive impairment has been studied in multiple sclerosis (MS), but presymptomatic and early stages of the disease have not been always analyzed. Objective: To compare cognitive impairment in different stages of MS. Methods: Cross sectional study of 116 subjects (84 patients with different forms of MS and 32 healthy subjects). Neuropsychological assessment: Selective Reminding Test (SRT), 10-36 Spatial Recall Test (10/36 SPART), Symbol Digit (SDMT), Paced Auditory Serial Addition Test (PASAT), Word List Generation (WLG), Boston Naming Test (BNT), Trail Making Test (TMT), LetterNumber Sequencing (L&N), Hospital Anxiety Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and Perceived Deficits Questionnaire (PDQ). Statistical analysis: multiple comparison testing with ANOVA. Results: 32 healthy subjects and patients with radiological isolated syndrome -RIS- (7), clinically isolated syndrome -CIS- (16) and relapsing-remitting MS -RR- (24), secondary progressive MS -SP- (20) and primary progressive MS -PP- (17) were studied. Among the control groups (32) and patients (84) differences were observed in all the tests evaluated. Comparison between controls and the initial phase (RIS-CIS) revealed differences in the SDMT, MFIS and PDQ. No test differences were observed between the inflammatory forms (RIS/CIS/RR) and between the two progressive forms (SP/PP). Differences were observed between the RISCIS-RR groups and the SP-PP groups in the following tests: SRT, 10/36 SPART, SDMT, WLG, BNT, TMT and L&N. No differences were observed between patient groups in the PASAT, total HADS, MFIS and PDQ. Conclusions: Cognitive deterioration (SDMT) and fatigue are present and perceived by patients in initial stages of MS. Deterioration is much greater in progressive types. Cognitive deterioration is similar within inflammatory subtypes (RIS/ CIS/RR) and within progressive subtypes (SP/PP). However, in RR, executive functions (working memory and cognitive flexibility) evolve at a rate similar to that observed in progressive types. Disclosure J. Gich has received consulting fees from Novartis and speaking honoraria from Bayer Schering Pharma, Biogen, EMD Merck Serono, Novartis, Teva Phramaceuticals, Almirall. M. Rivero: nothing to disclose J. Puig: nothing to disclose G. Blasco: nothing to disclose J. Salavedra: nothing to disclose C. Biarnés: nothing to disclose P. Danius i Estadella: nothing to disclose S. Pedraza: nothing to disclose Ll. Ramió-Torrentà has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. Funding: Novartis

Biomarkers P587 CSF markers of axonal damage, glial activation and immune response in acute myelitis M.A. Mañé-Martínez1,2, Á. Cobo-Calvo3, B. Olsson4, E. Matas2, L. Bau2, A. Ulf4, B. Kaj4, L. Romero-Pinel2, H. Zetterberg4,5, S. Martínez-Yélamos2 1Department of Neurology, Hospital Universtari Joan XXIIIUniversitat Rovira i Virgili, Tarragona, 2Department of Neurology, Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Spain, 3Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, Bron, France, 4Clinical Neurochemistry Lab. Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden, 5Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom Background: Acute myelitis could be the clinical presentation of an idiopathic acute transverse myelitis (IATM), a first clinical episode of relapsing-remitting multiple sclerosis (RRMS), considered as a clinically isolated syndrome (CIS) or a subsequent relapse of RRMS. Objective: To investigate axonal, glial and immune response biomarkers in cerebrospinal fluid (CSF) samples from patients with acute myelitis. Methods: Levels of NFL, GFAP, YKL-40, MCP-1 and cytokines (IL-6, IL-7, IL-12 and IL-16) were analysed in CSF samples collected during the acute phase of an acute myelitis. Fifteen MS patients (10 CIS and 5 RRMS) and 38 IATM (8 aquaporin-4 negative longitudinally extensive transverse myelitis (LETM) were included. Twentyfour patients suffering from neurological conditions (5 inflammatory and 19 non-inflammatory) were also evaluated. Results: Levels of NFL, YKL-40 and GFAP were significantly higher in LETM (NFL: 5693 ng/L (3792 - 17264); GFAP: 279 ng/L (108 - 4870); YKL-40: 229 ng/mL (146 - 309) vs CIS (NFL: 1325 ng/L (762 - 2224), p = 0.006; GFAP: 70 ng/L (70 - 82), p = 0.02; YKL-40: 61 ng/mL (39 - 113), p = 0.001). Levels of IL-7 and IL-16 were significantly higher in CIS (IL-7: 5.6 pg/mL (4.1 - 6.8); IL-16: 175 pg/mL (59 - 197) vs IATM (IL-7: 0.2 pg/mL (0.1 - 0.4), p < 0.0001; IL-16: 2.9 pg/mL (1.6 - 5.4), p < 0.0001) and LETM (IL-7: 0.2 pg/mL (0.2 - 0.5), p = 0.001; IL-16: 5.5 pg/mL (3.1 - 18.7), p = 0.001). However, the highest levels were found in RRMS (IL-7: 8.2 pg/mL (5 - 16), IL-16: 248 pg/mL (125 - 295). Conclusions: Patients with idiopathic LETM showed a higher astrocytic and axonal damage than MS patients. CSF levels of IL-7 and IL-16 were higher in acute myelitis related to MS. Disclosure M.Alba Mañé-Martinez: received research support from the Fundació Hospital Universitari de Tarragona Joan XXIII and Fundació Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Álvaro Cobo-Calvo: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma.


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Poster Session 1, 22(S3) Bob Olsson: nothing to disclose Laura Bau: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Ulf Andreasson: nothing to disclose Lucia Romero-Pinel: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Kaj Blennow: has served on Advisory Boards for Innogenetics, Belgium. Henrik Zetterberg: nothing to disclose. Sergio Martinez-Yelamos: received honoraria compensation to participate in Advisory Boards, collaborations as a consultant and scientific communications from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma, and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma.

P588 MRI biomarkers of opicinumab (Anti-LINGO-1) repair in relapsing MS: results from the Phase 2b SYNERGY trial M. Mellion1, R. Naismith2, D.L. Arnold3, A. Boyko4, N. Evangelou5, M. Valis6, K.C. Evans1, E. Fisher1, N. Richert1, J. Li1, L. Xu1, D. Cadavid1, on behalf of the SYNERGY investigators 1Biogen, Cambridge, MA, 2Center for Advanced Medicine, Neuroscience Center, Washington University, St. Louis, MO, United States, 3Montreal Neurological Institute, McGill University and NeuroRx Research, Montreal, QC, Canada, 4Pirogov’s Russian National Research Medical University and MS Centre at the Usupov’s Hospital, Moscow, Russian Federation, 5Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom, 6Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic Background: Opicinumab (anti-LINGO-1; BIIB033) is a potential CNS remyelinating agent. The recently completed placebocontrolled SYNERGY trial (NCT01864148) evaluated opicinumab vs placebo in active relapsing MS participants who received concurrent interferon (IFN) beta-1a. MRI biomarkers of myelin integrity and/or axonal repair are important to assess treatment with opicinumab. Goals: Determine the relationship between MRI biomarkers investigated in SYNERGY and clinical response associated with treatment. Methods: SYNERGY is a randomised, double-blind study of participants with RRMS or relapsing SPMS. Intravenous opicinumab 3, 10, 30 or 100 mg/kg or placebo was administered every 4 weeks (19 doses) in addition to intramuscular IFN beta-1a 30 mcg once weekly for 72-84 weeks. Brain MRI scans included conventional clinical sequences, magnetisation transfer ratio (MTR) imaging, and diffusion tensor imaging (DTI) parameters of fractional anisotropy and radial diffusivity. High resolution T1 weighted imaging for volumetric changes was also acquired. Images were

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collected before treatment, every 4 weeks for the first 24 weeks, and at weeks 48, 72, and 84. Standardized imaging acquisition was implemented across sites with centralised quality control; images were analysed by a single MRI reading centre blinded to treatment. Conventional MRI metrics included changes in whole and regional brain atrophy, and proportion of new gadoliniumenhancing (Gd+) lesions converting to chronic black holes. MTR measures included changes in whole brain and normal appearing white matter, and MTR recovery of new MTR lesions, new Gd+ lesions and non-enhancing T2 lesions. DTI measures included recovery of new Gd+ lesions, whole brain and non-enhancing T2 lesions. These MRI metrics were assessed for their ability to detect changes in line with opicinumab proposed mechanism of action and potential treatment effects. Associations with clinical endpoints and baseline predictors of treatment response were also explored. Results: 418 participants were randomised; 412 were included in these analyses. Analyses of opicinumab treatment response on candidate MRI biomarkers will be presented for the first time. Conclusions: SYNERGY is the first global MS study of a remyelinating candidate to include conventional MRI as well as DTI and MTR. The results will explore which MRI measure(s) may be useful as biomarkers of opicinumab treatment response. Disclosure This study was supported by Biogen (Cambridge, MA, USA). Michelle Mellion, Karleyton Evans, Elizabeth Fisher, Nancy Richert, Jie Li, Lei Xu and Diego Cadavid: employees of and stockholders in Biogen. Robert Naismith: consulting for Alkermes, Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, Pfizer. Douglas Arnold: personal fees for consulting from Acorda, Biogen, Hoffman La Roche, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis; grants from Biogen and Novartis; an equity interest in NeuroRx Research which was the image analysis centre for the trial. Alexey Boyko: consulting fees, speaker’s honoraria and compensation for advisory board activities from Bayer Schering, Merck Serono, Teva, Novartis, Biogen, Nycomed, Genzyme and Sanofi-Aventis. Nikos Evangelou: honoraria/consultant fees from Biogen, Merck, Novartis and Roche; research support from Biogen. Martin Valis: personal compensation from Biogen, Krka, and Merck. Biogen provided funding for medical writing support in the development of this abstract. Becky Gardner PhD (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P589 Soluble CD27 levels in CSF as a prognostic biomarker in clinically isolated syndrome R.M. van der Vuurst de Vries, J.Y. Mescheriakova, T.F. Runia, N. Jafari, D.A.M. Siepman, R.Q. Hintzen MS Centre ErasMS, Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands


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Background and objective: Several studies found the T-cell activation marker soluble CD27 (sCD27) increased in various autoimmune diseases including multiple sclerosis (MS). The objective of this study was to investigate whether CSF sCD27 levels, in patients with clinically isolated syndrome (CIS), predict a subsequent diagnosis of MS and are associated with a higher relapse rate. Methods: In this prospective study sCD27 levels were determined in CSF of 77 CIS patients using a commercially available ELISA. CIS patients underwent a lumbar puncture and MRI scan within 6 months after first onset of symptoms. Cox regression analysis was used to calculate univariate and multivariate hazard ratios (HR) for MS diagnosis. Association between sCD27 levels and annualized relapse rate (ARR) was assessed using a negative binomial regression model. Results: CIS patients had higher sCD27 levels in CSF than symptomatic controls (SCs). The geometric mean (95% CI) was 31.3 u/ mL (24.0-40.9) vs 4.67 u/mL (2.90-7.50) (p< 0.01). During a mean follow-up of 52.4 months, 39 out of 77 CIS patients were diagnosed with MS. In a model adjusted for MRI measurements, IgG index, and oligoclonal bands, sCD27 levels were associated with a diagnosis of MS (HR for MS diagnosis: 2.2 per 100 units/ mL increase in sCD27 levels (p=0.02)). Additionally MS patients with high sCD27 levels (>31.4 units/mL(median)) at time of CIS had a 5.7 times higher ARR than patients with low sCD27 levels (p=0.02). Conclusions: Soluble CD27, measured in CSF of CIS patients, predicts MS diagnosis and a high relapse rate. Therefore sCD27 is an activation marker directly related to the immunopathology of the disease and could be a valuable biomarker for selecting patients with higher disease activity. Disclosure RM van der Vuurst de Vries: nothing to disclose JY Mescheriakova: nothing to disclose TF Runia: nothing to disclose N Jafari: nothing to disclose DAM Siepman: nothing to disclose RQ Hintzen: nothing to disclose P590 Molecular signatures associated with cognitive dysfunctions in pediatric multiple sclerosis M. Liguori1, N. Nuzziello2, M. Simone2, V.F. Licciulli1, R.G. Viterbo2, N. Ancona3, A. Consiglio1, T. Creanza3, G. De Caro1, S. Liuni1, L. Margari2, M. Trojano2 1Biomedicine, National Research Council of Italy/Institute of Biomedical Technology, 2Basic Sciences, Neuroscience and Sense Organs, University of Bari, 3National Research Council of Italy/Institute of Intelligent System for Automation, Bari, Italy Background: Cognitive impairment is one of the most frequent symptoms in pediatric MS (PedMS) that may severely impact quality of life and school performances. Molecular markers predictive of its occurrence and progression have not been identified, so far. Objectives: To assess the expression levels of peripheral miRNAs and mRNAs by a Next-Generation Sequencing (NGS)

approach, and to uncover molecular pathway/s associated with PedMS. Methods: PedMS patients underwent clinical/neuropsychological evaluations; as neurological controls, age-matched Attention Deficit Hyperactive Disorder (ADHD) patients were included. Total RNA extraction from peripheral blood was followed by NGS, producing small-RNA and total-RNA reads. Small-RNA reads were analyzed by an in-house bioinformatics platform (ncaReNA) that implements a modular analysis pipeline able to identify/classify sequenced reads by a non-coding reference database; statistics based on p-value identify changes of expression profiles. To test the association between miRNAs expression, their mRNAs targets and changes of cognitive abilities, total-RNA reads were submitted to quantification for differential gene expression (DE). Results: 16 PedMS (mean age 14.8+/-2.8 years, mean age onset=12.3+/-3.7 years, median EDSS=2.5) and 11 age-matched ADHD patients were sequenced. The comparison of miRNAs expression levels between PedMS and ADHD revealed significant differences in 49 miRNAs (p< 0.05). MiR-15a-5p, miR-15b-3p, miR-16-5p miR-17-3p/5p, miR-22-3p, miR-23a-3p, miR-26a-5p, miR-27b-3p, miR-93-5p, miR-106b-5p, miR-128-3p, miR130a-3p, miR-144-5p, miR-148a-3p, miR-221-3p miR-223-3p, miR-486-5p, miR-532-5p and Let-7 family have been already reported associated with adult MS. Six PedMS (37.5%) resulted cognitively impaired (CI): the comparison of miRNAs expression levels between CI and cognitively preserved (CP) PedMS did not show significant differences. The comparison of RNA-Seq reads between CI and CP PedMS identified DE genes (p< 0.05); of note, EIF4G1 and NLRP2 have been reported associated with other neurodegenerative diseases, DBNDD1 was found influencing several cognitive functions. Conclusions: These results confirmed the involvement of miRNAs in PedMS and identified some interesting genes associated with CI-PedMS; a different signature seems to characterize CI-ADHD. A longitudinal evaluation on a larger sample size will allow to assess the predictive value of these markers on cognitive dysfunction progression. Disclosure This study is fully supported by FISM - Fondazione Italiana Sclerosi Multipla (Grant cod. 2014/R/10; Principal Investigator: Dr. Maria Liguori). Dr. Maria Liguori has nothing to disclosure Dr. Nicoletta Nuzziello has nothing to disclosure Dr. Marta Simone has nothing to disclosure Dr. Vito Flavio Licciulli has nothing to disclosure Dr. Rosa Gemma Viterbo has nothing to disclosure Dr. Nicola Ancona has nothing to disclosure Dr. Arianna Consiglio has nothing to disclosure Dr. Teresa Creanza has nothing to disclosure Dr. Giorgio Decaro has nothing to disclosure Dr. Sabino Liuni has nothing to disclosure Prof. Lucia Margari has nothing to disclosure Prof. Maria Trojano has served on scientific Advisory Boards for Biogen Idec, Novartis, Almirall, Roche and Genzyme; has received speaker honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva, Genzyme, Almirall and Novartis; has received research grants for her Institution from Biogen-Idec, Merck-Serono and Novartis.


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Poster Session 1, 22(S3) P591 sCD27, IgG and IgM index as potential CSF biomarkers for predicting MRI activity in newly diagnosed MS patients A.-K. Klein1, R. Selter1, C. Zimmer2, A. Berthele1, V. Biberacher1, M. Muehlau1,3, B. Hemmer1,3 1Neurology, 2Neuroradiology, Technical University Munich, 3Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Background: In patients presenting with a first clinical manifestation of multiple sclerosis (MS) or clinically isolated syndrome (CIS), individual disease course is still unpredictable. Cerebral spinal fluid (CSF) examination currently mainly serves diagnostic proposes. Therefore, the main aim of this study was to determine CSF parameters at the time of diagnosis, which are associated with early disease progression determined by cerebral MRI. Method: CSF and MRI data of 149 CIS and MS patients were analysed retrospectively. 52 patients did not receive immunomodulatory treatment (IMT) during the observation period. Lumbar puncture was performed less than 12 months after first manifestation of MS. Standardized 3T cerebral MRI was performed at baseline MRI (1-3 months after lumbar puncture) and after 12+/- 3 months. Progress on MRI was defined as the appearance of new T2 hyperintense and/or new gadolinium enhancing lesions on follow-up MRI. CSF parameters included intrathecal IgG, IgA and IgM determined according to Reiber’s formula and corresponding immunoglobulin indices. Furthermore, CSF levels of sCD27 were measured by ELISA in 84 of these patients. Results: Intrathecal production of IgG and IgM but not IgA is associated with earlier disease progression. Patients with intrathecal IgG and IgM production without IMT have a higher risk of developing a new lesion during the first 12 months (IgG OR=10.7 p=0.002; IgM OR=10.3 p=0.046). Furthermore, IgG and IgM indices in untreated patients are higher in those patients who show an MRI progress (IgG p=0.01; IgM p=0.04). Untreated MS patients with disease progression during the first 12 months also have elevated CSF levels of sCD27 compared to patients without MRI progress (p=0.03). We observed a high correlation between sCD27 levels and IgG index (Spearman r=0.82; p< 0.001). Conclusion: Elevated CSF levels of sCD27, intrathecal IgG and IgM synthesis seem to be predictors of inflammatory disease activity in newly diagnosed CIS and MS patients. The strong correlation between IgG index and sCD27 levels suggests a pathogenetic link between both biomarkers. Further studies in larger cohorts are warranted to confirm this finding and establish a hierarchy for the clinical relevance of the biomarker. Disclosure A. Klein, R. Selter, V. Biberacher, C. Zimmer: nothing to disclose; A. Berthele: reports grants from Bayer Healthcare, personal fees from Biogen, Merck Serono, Teva, Novartis, and Genzyme, compensations for clinical trials from Biogen, Novartis, Genzyme, Roche, and Alexion Pharmaceuticals; M. Mühlau: has received research support from Germany ministry for research and education, German Research Foundation, HertieFoundation, Merck-Serono, Novartis; B. Hemmer: has served on scientific advisory boards for Roche, Novartis, Bayer Schering, and Genentech; has received speaker honoraria from Biogen Idec and Roche; and has received research support from Chugai Pharmaceuticals. He holds part of a patent

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for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. P592 Long non coding RNA (LncRNAs) expression analysis in patients with multiple sclerosis: potential biomarkers of disease susceptibility and progression C. Fenoglio1, A. Calvi2, M. Serpente3, M. De Riz2, C. Comi4, E. Lecchi2, A.M. Pietroboni2, M. Arcaro2, S.M.G. Cioffi2, E. Oldoni2, R. Cantello4, D. Galimberti2, E. Scarpini2 1Department of Physiophatology and Transplantation, Neurology Section, 2University of Milan, 3Deptartment of Physiophatology and Transplantation, Milan, 4Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy Long non coding RNAs (lncRNAs) represent a novel class of transcripts, that are pervasively transcribed in the genome. Several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological and psychiatric disorders, but their expression has not been exhaustively investigated in MS so far. The main aim of this study was to identify a specific signature of cellular LncRNAs expression in Peripheral Blood Mononuclear Cells (PBMC) from a discovery cohort of MS patients compared with controls and to validate results in a larger independent validation population. LncRNA PCR arrays from SBI containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from 5 patients with Relapsing Remitting (RR)-MS, 5 with Primary Progressive (PP)-MS and 5 age matched controls. Best hits were validated by Real time PCR in a further independent Italian cohort consisting of 30 PBMC samples from MS patients and 30 controls. LncRNAs tested were found to be differentially expressed in MS patients compared with controls. Malat1, that is enriched in hippocampal neurons, was overexpressed in MS patients particularly in RR MS patients (10.2 fold change increase versus controls, P< 0.05). The same trend was observed for BC200, involved in the synaptic and neural network dysfunction and in Alzheimer’s disease, in particular PPMS patients showed the highest level (27.2 fold change increase, P< 0.05). Results were validated a further independent cohort of samples. We found robust dysregulations of several lncRNAs in MS patients compared with controls. Furthermore, considering the expression levels of lncRNAs known to be involved in brain function or neurological disorders, some important dysregulations emerged. The rationale of this study might then be used to set up a future study with the purpose of selecting potential biomarkers for disease aggressiveness and response to therapy. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression. Disclosure C. Fenoglio, A Calvi, M. Serpente, M. De Riz, C. Comi, E. Lecchi, AM. Pietroboni, M. Arcaro, SMG. Cioffi, E. Oldoni, R. Cantello, D. Galimberti, E. Scarpini have nothing to disclose


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P593 Neurofilament light chain and disease progression in MS A. Bhan1, C. Jacobsen1, K.-M. Myhr2, H. Nyland2, K. Lode1, E. Farbu3 1Stavanger University Hospital, Stavanger, 2University of Bergen, Haukeland University Hospital, Bergen, 3Stavanger University Hospital, University of Bergen, Stavanger, Norway Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with heterogenic disease course, but the role of biomarkers in use to predict clinical outcome is still debated. Objective: Our objective was to evaluate levels of NfL in CSF of patients with MS in relation to clinical progression of disease as measured by EDSS over a 10-year period. Material and methods: Newly diagnosed patients with MS between 1998 and 2000 in Rogaland and Hordaland, western Norway were asked to participate. Patients underwent a lumbar puncture and clinical assessment at baseline, and subsequent clinical assessments after five and 10 years. The CSF was analyzed using the commercially available Uman Diagnostics NF-light® ELISA kit. Results: Forty-four patients consented for lumbar puncture and were included with a mean age of 41.9 years at inclusion, and 68% were females. Thirty-five patients (80%) had a relapsing-remitting course of disease at time of inclusion. Male patients had higher mean concentrations of NfL (1661 ng/L) compared to 546 ng/L for female patients (p=0.004). Baseline level of NfL was significantly correlated with EDSS at five year follow up (r=0,298, p=0,026), but not with EDSS at baseline (r=0.247, p 0.053) or EDSS at ten year follow up (r=0.2, p=0.062). Patients who converted from RRMS to a secondary progressive form (SPMS) had a statistically significant higher mean concentration of NfL at baseline compared to those that remained as RRMS (1777.8 ng/L vs 693.2 ng/L , p=0.015). Conclusion: Level of NfL quantified in CSF at the time of diagnosis correlated with clinical progression of MS as measured by EDSS after five years, and may predict conversion from RRMS to SPMS. Disclosure Alok Bhan: Nothing to disclose. Cecilie Jacobsen: Nothing to disclose. Kjell-Morten Myhr:KM. Served on scientific advisory boards from Novartis Norway, Biogen Idec, Genzyme and Roche; received speaker honoraria, Genzyme, Sanofi-Aventis, Novartis, Biogen Idec and Teva; and received unrestricted research support from, Sanofi-Aventis, Novartis, Biogen Idec, and the Norwegian MS Society. Harald Nyland: Nothing to disclose. Kirsten Lode: Nothing to disclose. Elisabeth Farbu: Speaker honoraria from Genzyme, Novartis, Teva, Biogen, and advisory boards: Novartis, Genzyme, Biogen. P594 Prognostic role of cerebrospinal fluid neurofilament, chitinase-3-like and tau levels in patients with clinically isolated syndrome D. Ferraro, A.M. Simone, R. Bedin, F. Vitetta, A. Canovi, P.F. Nichelli, P. Sola University of Modena and Reggio Emilia, Modena, Italy

Introduction: In Multiple Sclerosis (MS), numerous findings suggest that axonal loss is ultimately responsible for the development of irreversible neurological deficits, which is likely to emerge as a consequence of nerve injury starting in early phases of the disease. Objective: The aim of our study was to investigate the prognostic role of cerebrospinal fluid (CSF) biomarkers related to axonal damage and glial activation such as neurofilaments (NFL), totaltau and chitinase-3-like 1 (CHI3L1) in patients with Clinically Isolated Syndrome (CIS). Methods and materials: CSF of patients with CIS was examined for the presence of NFL, total-tau and CHI3L1. The median biomarker level was used as a cut-off to define high or low levels. Outcomes for logistic regression and survival analysis were: diagnosis of Clinically Definite MS (CDMS), defined by a clinical relapse, and disability milestones defined as an EDSS of 3, 4 and 6. Correlations between biomarkers and clinical, MRI and CSF parameters, including IgMOB, were analyzed using Spearman’s rank test (with Bonferroni correction). Results: We included 101 patients in the study (64F, mean age: 35±10 years). Mean follow-up duration was 72 months (24-109). A relapse occurred in 52% of patients. Median CSF amounts of NFL, CHI3L1 and tau were: 995ng/ml, 118ng/ml and 156pg/ml, respectively. NFL levels correlated with number of baseline brain and spinal cord MRI lesions, with the number of brain gadolinium-enhancing lesion and with EDSS at two years and at final follow-up. CHI3L1 correlated with age at onset, IgG Index and with EDSS at two years. Tau correlated with number of baseline brain gadolinium-enhancing MRI lesions, with CSF/serum albumin and with EDSS at final follow-up. Only high NFL values were associated with an increased risk of a relapse (OR: 3.9 CI95: 1.7-8.9; p=0.001) and with a shorter time to a relapse during follow-up (Log-rank test: p=0.002) or to an EDSS of 3 or 4 (Logrank test: p=0.004 and: p=0.01, respectively). Conclusion: In patients with CIS, high CSF NFL levels, but not high CHI3L1 or tau levels, were shown to increase the risk of a CDMS diagnosis and were associated with a shorter time to a CDMS diagnosis and to disability milestones during follow-up. Disclosure Diana Ferraro has nothing to disclose in relation to the study. Anna Maria Simone has nothing to disclose in relation to the study. Roberta Bedin has nothing to disclose in relation to the study. Francesca Vitetta has nothing to disclose in relation to the study. Alessio Canovi has nothing to disclose in relation to the study. Paolo Frigio Nichelli has nothing to disclose in relation to the study. Patrizia Sola has nothing to disclose in relation to the study. P595 Endothelin-1 as a candidate cerebrovascular biomarker in multiple sclerosis C. Criscuolo1, R. Lanzillo1, A. Cianflone1, R. Liuzzi2, M. Moccia1, M.D. Di Taranto3, M. Incoronato3, R. Palladino4, O. Caporale4, M. Triassi4, M. Salvatore5, V. Brescia Morra1 1Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, 2Institute of Biostructure and Bioimaging, National Research Council,


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Poster Session 1, 22(S3) 3IRCSS

SDN Foundation, 4Department of Public Health, Biomedical Sciences, Federico II University, Naples,

5Advanced

Italy Background: Clinical and experimental evidence suggests that endothelin-1 (ET-1) plays a role in cardiac and vascular disease and inhibits remyelination. Patients with multiple sclerosis (MS) show global cerebral hypoperfusion. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems to be secondary to increased blood concentrations of ET-1. Objectives: To evaluate ET-1 in MS patients vs matched healthy subjects (HS) in the context of a larger study on the association among MS, amyotrophic lateral sclerosis (ALS), and vascular changes at molecular, genetic, anatomic and functional level. Methods: ET-1 serum levels were measured in MS patients, ALS patients and HS recruited over 3 years, with a commercially available ELISA kit, in blinded fashion by a laboratory assistant (detection range 0.39-25 pg/mL; R&D Systems). Clinical and demographic characteristics of patients and HS were recorded. Results: ET-1 serum levels were analysed in 274 MS patients (162 females, 112 males), 284 HS (168 females, 116 males) and in 35 ALS (16 females, 19 males). ET-1 median levels were significantly higher in MS compared to HS (1.73 vs 1.48 pg/mL) and were nonsignificant in ALS subjects compared to 37 matched HS. In MS patients ET-1 levels were positively related to age, disease duration (DD) and EDSS. In MS women ET-1 levels positively correlated with age (p= 0.014) and DD (p= 0.024), while in MS males they tended to be related to EDSS (p=0.058). No significant relationship was found between age and ET-1 in female HS. The mean values for age and DD in MS women vs men were nonsignificant. Conclusions: We confirm that serum ET-1 levels are significantly increased in MS patients. Furthermore, ET-1 levels are related to age, DD, and EDSS in MS patients in a different way between genders. These findings suggest a role for ET-1 in MS disease, and could also contribute to explain the different incidence and disease course of MS in men and women. Study Support: Research and University Ministery. Disclosure Criscuolo Chiara: nothing to disclose Lanzillo Roberta: nothing to disclose Cianflone Alessandra: nothing to disclose Liuzzi Raffaele: nothing to disclose Di Taranto Maria Donata: nothing to disclose Incoronato Mariarosaria: nothing to disclose Moccia Marcello: nothing to disclose Palladino Raffele: nothing to disclose Caporale Oreste: nothing to disclose Triassi Maria: nothing to disclose Salvatore Marco: nothing to disclose Brescia Morra Vincenzo: nothing to disclose P596 Kappa free-light chains in cerebrospinal fluid show prognostic significance for long-term disability progression in multiple sclerosis G. Makshakov1,2, V. Nazarov3, E. Surkova3, E. Kairbekova1, E. Shchegolkova1, M. Shumilina1, S. Lapin3, E. Evdoshenko1,4

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Outpatient Department, City Center of Multiple Sclerosis and other Autoimmune Diseases, 2Neurology and Neurosurgery, First Pavlov Saint-Petersburg State Medical University, 3Center for Molecular Medicine, Laboratory of Autoimmune Diagnostics, First Pavlov Saint Petersburg State Medical University, Saint Petersburg, 4SBI ‘Center of Clinical Trials Management and Performance of Moscow Department of Healthcare, Moscow, Russian Federation Background: Intrathecal synthesis of oligoclonal immunoglobulins (OCB) is the pathogenic hallmark of B-cell activation in multiple sclerosis. OCB positivity is a well-defined prognostic marker of higher rate of disability progression. Except for immunoglobulin production, B-cell activation is characterized by increased production of immunoglobulin free light chains kappa and lambda (k-FLC, λ-FLC). The influence of FLC on disease progression remains to be controversial. Objectives: To define correlations of intrathecal concentrations of FLC with clinical measures of MS progression and the risk of reaching disability milestones. Methods: We retrospectively analyzed 442 cases of multiple sclerosis, defined by the McDonald criteria 2005/2010, from our database. The mean duration of the disease was 10±7.4 years. The rate of clinical disability progression was measured by the Multiple Sclerosis Severity Score (MSSS), assessed at the date of the last follow-up. OCB were detected in cerebrospinal fluid (CSF) with isoelectric focusing electrophoresis. FLC concentrations in serum and CSF were measured using ELISA. Reference values were defined in our previous publications as >0.595 µg/ml for k-FLCCSF, >0.1 µg/ml for λ-FLCCSF and >0.0422 for Q-kappa. Correlations between MSSS and laboratory markers were counted using nonparametric Spearman’s r-value. Hazard ration for progression to EDSS 6.0 was defined for high and low k-FLCCSF, λ-FLCCSF, Q-kappa and positive and negative OCB with KaplanMeier survival analysis (log-rank). Results: Positive correlations were detected between MSSS and k-FLCSERUM (r=0.1576, p=0.0205), k-FLCCSF (r=0.1326, p=0.0347). No significant correlations were found between MSSS and λ-FLCCSF, λ-FLCSERUM and Q-kappa. Survival analysis revealed an increased risk for long-term progression of disability (EDSS=6.0) for high k-FLCCSF (HR=2.109, p=0.0316) and OCBpositivity (HR=2.722, p=0.0411). Concentrations of λ-FLCCSF and Q-kappa showed no significant impact on disability progression. Conclusions: k-FLC concentrations in serum and CSF showed significant correlations with MSSS. k-FLCCSF and OCB, but not λ-FLCCSF possess prognostic value for disability progression according to the survival analysis. Q-kappa wasn’t showed to be a prognostic biomarker, probably due to variations of FLC concentrations in the blood. Disclosure Gleb Makshakov reports no disclosures. Vladimir Nazarov reports no disclosures. Elena Surkova reports no disclosures. Elena Shchegolkova reports no disclosures. Ekaterina Kairbekova reports no disclosures. Maria Shumilina reports no disclosures. Sergey Lapin reports no disclosures. Evgeniy Evdoshenko has received and dedicated to research support fees for board membership, consultancy or speaking, or


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grants, in the last 2 years from Biogen Idec, Sanofi-Aventis, Genzyme, Pharmstandart, R-Pharm, Pharmsyntez, Genfa Medica, Takeda, Generium, Johnson & Johnson, CIA, GlaxoSmithKline, Bayer, Teva, Merck, Actellion, Roche, Biocad P597 No association of serum Netrin-1 with MRI based evidence of disease activity in early multiple sclerosis M. Voortman, D. Bachmayer, T. Seifert-Held, J.-J. Archelos, S. Ropele, A. Pichler, C. Enzinger, S. Fuchs, F. Fazekas, M. Khalil Medical University of Graz, Graz, Austria Introduction: Netrin-1 (NTN-1) belongs to laminin-related proteins that regulate glial cell migration, axon guidance, oligodendroglial maturation and angiogenesis. More recently, experimental studies on NTN-1 suggested that this protein may also play an important role in regulating blood-brain barrier (BBB) integrity and inflammation. Contrast enhanced MRI is an important tool to detect MS lesions with BBB breakdown and ongoing inflammation (active lesions). As serum NTN-1 values have recently been reported to be increased in MS we speculated that this might be a consequence of active lesions. Objective: To compare serum NTN-1 between MS patients with active vs. non-active lesions and patients with other non-inflammatory neurological diseases and to investigate the temporal dynamics of serum NTN-1 in MS patients in relation to MRI and clinical activity. Methods: 79 patients (clinically isolated syndrome, n=32; early RR MS, n=47), mean age 33.9 (SD 8.8) years, median Expanded Disability Status Scale (EDSS) score 1.0 (IQR 0.0-2.5) underwent gadolinium (Gd) enhanced 3 T MRI and simultaneous blood sampling at baseline and clinical and MRI follow-up (n=70, median follow-up time 1.4 years, IQR=1.0-2.3 years). 30 patients with other non-inflammatory neurological diseases, mean age 37.1 (SD 10.2) years, served as controls. Serum NTN-1 levels were assessed by ELISA (Cusabio Biotech, Wuhan, China). Results: At baseline serum NTN-1 levels were similar in the MRI active, i.e. Gd+ positive patients (n=47) and in MRI non-active (n=32) MS patients and we observed no difference to controls. In the subgroup of Gd+ patients serum NTN-1 was significantly decreased in those who were also clinically active (n=9) when compared to clinically non-active patients (n=38) (p=0.034). Longitudinally collected blood samples during MRI with nonactive lesions showed no temporal dynamics of serum NTN-1 in either initially MRI active or non-active subgroups. Serum NTN-1 was also unrelated to age, physical disability at remission and disease duration. Conclusion: Serum NTN-1 cannot serve as body fluid biomarker for subclinical disease activity as evidenced by contrast enhancing lesions on MRI. How NTN-1 levels change during a relapse may deserve further examination. Disclosure Ms. Voortman, MSc reports no disclosers. Ms. Bachmayer reports no disclosers. Dr. Seifert-Held received speaker honoraria and support from Teva, Novartis, Biogen, Eisai. Dr. Archelos reports no disclosers. Dr. Ropele reports no disclosers.

Dr. Pichler reports no disclosers. Dr. Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis Genzyme and Teva Pharmaceutical Industries Ltd./ sanofi-aventis; research support from Merck Serono, Biogen Idec., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd./sanofiaventis; academic editor for PLOSOne. Dr. Fuchs serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, Merck Serono, TEVA Pharmaceutical Industries and has received funding for travel and speaker honoraria from Bayer Schering, Merck Serono, Biogen Idec and Sanofi Aventis. Dr. Fazekas serves on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Multiple Sclerosis, the Polish Journal of Neurology and Neurosurgery, and the Swiss Archives of Neurology and Psychiatry; provides services for Actelion and Parexel and has received speaker honoraria and support from Almirall, Merck Serono, Novartis, Pfizer, Roche, Shire and Teva Pharmaceutical Industries Ltd. Dr. Khalil has received funding for travel and speaker honoraria from Bayer Schering Pharma, Novartis Genzyme, Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries.

P598 Serum exosomes as biomarkers of multiple sclerosis I. Selmaj, M. Namiecinska, M. Cichalewska, G. Galazka, K. Selmaj, M. Mycko Department of Neurology, Medical University of Lodz, Lodz, Poland Exosomes (Exs) represent a subfamily of membrane vesicles released from the endocytic compartment of live cells that play an important role in cell-to-cell communication. Exs contain material of cell of origin including proteins, lipids, DNA, mRNA, and miRNA and their specific composition reflects state of cell activation influenced by pathologic process. Serum is considered as a major compartment accumulating exs derived from different cells and tissues. In order to explore the potential changes in the composition of the serum exs as a biomarker for the multiple sclerosis (MS) we have analyzed exs samples from 80 remitting relapsing MS patients and 40 controls. Serum exs were isolated with the polymer formulation method and quantified by nanoparticle tracking analysis and specific immunostaining for marker proteins. RNA extracted from serum exs have been processed for the next generation sequencing analysis with the HiSeq platform. We have found that serum exs concentration ranged from 2 to 17 xE12 per ml and size varied from 45 to 105 nm in both controls and MS patients. RNA analysis have shown that serum exs are a reach source of the shortRNA (< 300 nt). The serum exs contained more than 59000 different RNA sequences. All the sequences have been grouped into 14 different RNA categories: CDBox, HAcaBox, RefSeq_antisense, lincRNA, lincRNA_antisense, miRNA, other_ncRNA, other_ncRNA_antisense, rRNA, piRNA, rfam, scaRNA, tRNA and tRNA_like. RefSeq_antisense, linc RNA and lincRNA_antisense represented the largest fraction of sequences derived from MS patients serum (27%, 22% and 21%,


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Poster Session 1, 22(S3) respectively). Interestingly, miRNA constituted about 2.5% of all exosomal RNA sequences. The average number of different exs miRNA ranged between 350 and 401 sequences. There was a tendency toward a decreased number of miRNA copies in serum exs in both remission and relapse MS patients when compared to control subjects. We have identified several sequences of short RNA, including miRNA, differentially expressed in MS patients. Our data demonstrate diverse RNA content in serum exs of MS patients and highlight potential role of short RNA sequences as a new biomarkers of MS. Disclosure All authors have nothing to nothing to disclose. P599 Extending the spectrum of anti-MOG antibody positive autoimmune inflammatory CNS disease: overlapping demyelinating syndromes in patients with systemic lupus erythematosus A.-K. Pröbstel1,2, M. Thanei2, B. Erni2, A.-C. Lecourt1,2, L. Branco3, R. André4, P. Lalive5, K. Koenig6, U. Huynh-Do7, C. Ribi8, C. Chizzolini4, L. Kappos1,2, M. Trendelenburg3,6, T. Derfuss1,2, Swiss Systemic Lupus Erythematosus Cohort Study Group 1Department of Neurology, University Hospital Basel, 2Department of Biomedicine, Clinical Neuroimmunology Lab, University Basel, 3Department of Biomedicine, Clinical Immunology, University Hospital Basel, Basel, 4Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, 5Department of Neurology/ Neuroimmunology, CHUV, Lausanne, 6Division of Internal Medicine, University Hospital Basel, Basel, 7Division of Nephrology, Hypertension and Clinical Pharmacology, University Hospital Bern, Bern, 8Department of Allergology and Immunology, CHUV, Lausanne, Switzerland Background: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting various organs. It is characterized by polyclonal B cell activation and autoantibody production. Although nervous system involvement most frequently results from vasculopathy, some patients present with demyelinating lesions or encephalitis. Previous studies have pointed towards autoimmune overlap syndromes between SLE and neuromyelitis optica or encephalitis. Aim: To assess the frequency of anti-MOG (myelin oligodendrocyte glycoprotein) and other established and novel anti-CNS/PNS antibodies, and to correlate antibody findings to clinical, laboratory, and MRI data in a large cohort of SLE patients. Methods: Using cell-based assays, we analyzed the presence of antibodies against MOG, aquaporin-4 (AQP4), neurofascin 186 (NF), NMDA-receptor, AMPA-receptor 1/2, GABAB-receptor, Glycin-receptor (GlyR), metabolic glutamate receptor 5 (mGluR5), Leucine-rich glioma inactivated 1 (LGI1), contactinassociated protein-like 2 (CASPR2), dipeptidyl-peptidase-like protein 6 (DPPX) as well as glutamic acid decarboxylase (GAD65) in 174 patients from the Swiss Lupus Cohort at baseline and follow-ups. Results: Anti-MOG antibodies were identified in 15 (8.6%), antiNF antibodies in 4 (2.3%), and low-titer anti-GAD65 antibodies in

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2 patients. One patient harbored anti-AQP4 and anti-GlyR-antibodies. Preliminary results reveal clinical and diagnostic evidence for CNS and/or PNS demyelination in a subgroup of patients incl. signs of demyelinating lesions of the CNS in anti-MOG and antiNF antibody-positive patients, demyelinating neuropathy in an anti-NF antibody-positive patient and diffuse nervous system involvement with demyelinating polyneuropathy, neuropsychiatric disorder, T2-lesions on cerebral MRI in an anti-GAD positive patient. Detailed data on the correlation of autoantibody findings with clinical manifestations and MRI results will be presented. Conclusion: Anti-CNS/PNS directed antibodies, most frequently anti-MOG, are present in a subgroup of SLE patients and are associated with CNS/PNS demyelination in at least some of these patients. Further clinical and diagnostic characterization of autoantibody positive patients will show whether anti-neuronal antibodies might serve as a biomarker to differentiate demyelination from vasculitic damage and allow for more targeted therapeutic approaches including B cell depletion. Disclosure AKP received research funding from the University of Basel, the Swiss National Science Foundation and Genzyme, travel support from Genzyme, support for educational activities from Baxalta and Merck and consulting fees from Bayer used for research support. MT, BE, ACL, LB, RA, PL, KK, UH, CR, CC have nothing to disclose. LK: institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. MT has nothing to disclose. TD serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, GeNeuro, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from the Swiss National Research Foundation, Biogen Idec, Novartis Pharma, the European Union, and the Swiss MS Society. P600 Comparison between recurrent and monophasic MOG antibody-associated demyelinating disease L. Salles, F.M.H. Jorge, S. Apóstolos-Pereira, R. Simm, D.K. Sato, D. Callegaro University of Sao Paulo, Sao Pablo, Brazil Background: Antibodies to myelin-oligodendrocyte glycoprotein (MOG) have been associated with central nervous system demyelinating disorders. The development of cell-based assays


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(CBA) allowed the detection of conformational-sensitive MOG autoantibodies, raising a possible role as a biomarker in clinical practice. Objective: To compare the clinical features of monophasic and relapsing MOG antibody-associated demyelinating disease. Methods: We included 30 positive patients for MOG antibody diagnosed with phenotype NMOSD/NMO followed at University of Sao Paulo. The sera were tested using cell-based assay with live transfected cells. Results: Among the total of 30 patients, 20 patients had relapses and 10 had a single attack. The median disease duration was 5.6 years (1-23.2). In relapsing cases, the median time for a second attack was 2.5 years (range 0.2-14). The median age of onset was 32 years (3-50) for the relapsing group and 29 years (21-45) for patients with a single attack. Age onset below 18 years old was present only in recurrent group and account for 25% (4/20) of the patients. None fulfilled MRI criteria for multiple sclerosis (MS). In patients with a single attack, infection, vaccine or delivery were not observed as a trigger for an attack. Among the recurrent patients, 10% (2/20) had longitudinally extensive transverse myelitis (LETM), 45% (9/20) had isolated optic neuritis (ON), 30% (6/20) had optic-spinal (short or extensive myelitis) and 15% (3/20) had brainstem plus myelitis. In patients with a single attack, 40% (4/10) had LETM and 60% (6/10) had isolated ON. There was no difference on MOG-antibody titers between groups. Discussion and conclusions: Isolated or recurrent ON is the most common phenotype for MOG-antibody positive cases. Recurrent patients may have myelitis or brainstem lesions during the disease course. Longitudinal antibody levels may identify the patients who are less likely to have relapses, requiring immunosuppression. Disclosure Nothing to disclose P601 Epigenetic profile of chromosome conformation signatures underlying multiple sclerosis and its severity J.P. Joseph1, C.R. Lim2, J. Patel2, K. Rajandran2, N.H. Nazri1, N. Mat Zain1, M.H. Rafia1, E. Hunter3, A. Ramadass3, H. Womersley3, A. Akoulitchev3 1Hospital Kuala Lumpur, Kuala Lumpur, 2Oxford Biodynamics (M) Sdn. Bhd., Penang, Malaysia, 3Oxford Biodynamics Limited, Oxford, United Kingdom Introduction: The variability in the clinical presentation and course of MS poses a challenge to physicians, and limited data are available to guide them in selecting effective therapy for their patients. Chromosome Conformation signatures (CCSs) define a genomewide framework of early regulatory controls in integrating environmental cues into the epigenetic and transcriptional machinery. As such, the changes in CCSs are the primary step in a cascade of gene deregulation due to pathology, constituting a highly informative systemic epigenetic biomarkers in a broad spectrum of disease indications. Objective: 1. To characterise Multiple Sclerosis (MS) patients from healthy individuals, and 2. To differentiate the severity of disease in patients with MS.

Methodology: We have collected 20 5-ml whole blood from healthy and 20 MS patients that have been clinically defined, as suffering from Mild and Severe forms of MS as determined by the Expanded Disability Status Scale, at Department of Neurology, Hospital Kuala Lumpur, Malaysia. Genomic DNAs were isolated based on EpiSwitch™, a proprietary epigenetic marker discovery platform by Oxford Biodynamics. Twenty-six loci chosen from a screening protocol using EpiSwitch™ microarray, have been tested for the formation of CCS for each sample. Result: We have segregated the samples into 2 groups, i.e. training (n=26) and testing (n=14). As a result, we have found 5 novel markers that can differentiate MS and healthy individuals at a positive predictive value of 100% and a negative predictive value of 71.43%. Furthermore, 6 novel markers can be employed to grade the severity of MS into mild, intermediate and severe, with the precision (T P/(TP+FP)) at 0.895 for the 3 group-classifier. (TP: True Positive; FP: False Positive). Conclusion: Although current study needs further validation, CCSs prove to be a powerful tool in assisting physicians with early detection of MS and diagnosis of MS severity by objective means of blood-based biomarkers. This pioneering application of CCS biomarkers to MS will be followed with further validation studies on independent patient cohorts. Disclosure JP Joseph: Nothing to disclose Chun Ren Lim: Employee of Oxford Biodynamics (M) Sdn. Bhd. Patel Janisha: Employee of Oxford Biodynamics (M) Sdn. Bhd. Rajandran Kushha: Employee of Oxford Biodynamics (M) Sdn. Bhd. Nazri NH: Nothing to disclose N Mat Zain: Nothing to disclose MH Rafia: Nothing to disclose Hunter Ewan: Employee of Oxford Biodynamics Limited, UK Ramadass Aroul: Employee of Oxford Biodynamics Limited, UK Womersley Howard: Employee of Oxford Biodynamics Limited, UK Akoulitchev Alexandre: Employee of Oxford Biodynamics Limited, UK P602 Molecular profiling of damage and repair in the CSF by translating transcriptome data to CSF proteome N.A. Martin1, A. Nawrocki1, M.R. Larsen1, V. Molnar2, P. Acs3, M. Palkovits2, F. Sellebjerg4, Z. Hegedus5, N. Alcaraz1, E.G.V. Barbosa1, J. Baumbach1, Z. Illes1,6 1University of Southern Denmark, Odense, Denmark, 2Semmelweis University, Budapest, 3University of Pecs, Pecs, Hungary, 4Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 5Biological Research Centre, Szeged, Hungary, 6Odense University Hospital, Department of Neurology, Odense, Denmark Hypothesis: Comparing the transcriptome of experimental deand remyelinating lesions to transcriptome of MS lesions may relate gene expression to damage and repair. Quantifying proteins of these homologous genes in the CSF proteome may identify novel biomarkers.


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Poster Session 1, 22(S3) Methods: Demyelination was induced in the corpus callosum by feeding mice with cuprizone; suspending cuprizone induced remyelination. Corpus callosum was microdissected and examined by 4x44K Agilent Whole Mouse Genome Microarray. Ingenuity pathway analysis (IPA) was used to explore pathways related to de- and remyelination. Proteomics of the CSF was examined by LC-MS/MS, and targeted quantitative proteomics of 91 individual CSF of MS patients was done by selective and parallel reaction monitoring (SRM/PRM). Results: 644 differentially expressed genes related to de- and remyelination were identified in the corpus callosum, and were compared to transcriptome data of MS brain lesions. We have found 137 overlapping homologous genes, and examined, whether corresponding proteins are present in CSF of patients with MS. CSF of 10 controls and 10 patients with primary progressive (PP), relapsing-remitting (RRMS) and secondary progressive (SP) MS, respectively were pooled and subjected to LC-MS/MS. We could detect 20 of the 137 proteins in this CSF pool, and also explored relevant databases in order to select peptides for the additional 117 proteins. Altogether, we have screened 132 peptides of 52 proteins of the 137 homologous genes by targeted quantitative proteomics in individual CSF obtained from 30 PPMS, 27 SPMS and 41 RRMS, respectively. Discussion: Differentially expressed genes in MS lesions can be related to pathological function by comparing transcriptome of experimental and MS lesions. Protein products of several of these genes could be detected in the proteome of CSF and quantified to identify potential biomarkers or biomarker combinations. Disclosure Lundbeckfonden, Scleroseforeningen, OTKA, Region of Southern Denmark, Odense University Hospital

P603 Longitudinal assessment of cervical cord atrophy across MS clinical phenotypes: a multicenter study P. Preziosa1, M.A. Rocca2, M. Aboul-Wafa2, P. Valsasina2, F. Barkhof3, H. Vrenken4, A. Rovira5, X. Montalban6, H. Kearney7, O. Ciccarelli7, L. Matthews8, J. Palace8, A. Gallo9, A. Bisecco9, A. Gass10, P. Eisele10, C. Lukas11, B. Bellenberg11, G. Comi12, M. Filippi2 1Ospedale San Raffaele - Vita-Salute San Raffaele University, 2Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience,, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, 3Department of Radiology and Nuclear Medicine, MS Centre Amsterdam, 4Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, 5Magnetic Resonance Unit, Department of Radiology (IDI), 6Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 7NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, London, 8Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom, 9I Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy, 10Department of Neurology, Universitätsmedizin Mannheim,

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Mannheim, 11Department of Radiology, St. Josef Hospital RuhrUniversity, Bochum, Germany, 12Department of Neurology, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Background: Multiple sclerosis (MS) is characterized by severe cervical cord atrophy. Aims. We evaluated whether cord atrophy development over time was different across phenotypes by analysing a large, multicentre dataset of MS patients acquired at 8 European sites. Methods: 3D T1-weighted cervical cord scans were acquired from 152 healthy controls (HC) and 350 MS patients (35 clinically isolated syndromes [CIS], 144 relapsing-remitting MS [RRMS], 89 secondary-progressive MS [SPMS], 45 benign MS [BMS] and 37 primary-progressive MS [PPMS]). Follow-up scans were obtained from 131 subjects (median follow-up time=1.05 years, range=0.5-2.1 years). Whole-cervical cord cross-sectional area (CSA) was assessed using the active surface method. CSA at baseline and its changes over time were compared between HC and MS patients and among clinical phenotypes using ANOVA models (adjusted for age, sex and site) and paired t tests. Results: Baseline CSA was lower in MS patients vs HC (p< 0.001), in PPMS vs HC and CIS (p< 0.001), in RRMS vs CIS (p< 0.001), and in SPMS vs PPMS and RRMS (p=0.04 and p< 0.001, respectively). Cord CSA change over time was +0.04% in HC (p=0.8) and -1.05% in MS (p=0.001), with a significant time x group effect (p=0.04). When the phenotypes were analyzed separately, significant cord tissue loss was found in RRMS (CSA change=-1.5%, p=0.003) and PPMS (CSA change=-1.96%, p=0.05), but not in the remaining phenotypes. Conclusions: Apart from CIS, significant cervical cord atrophy was found in all MS phenotypes. The cord tissue loss we observed over time was mainly driven from PPMS and RRMS patients. Study Supported by: Mohammad Aboul-Wafa has been supported by the ECTRIMS-MAGNIMS Fellowship in Magnetic Resonance Imaging. Disclosure Drs Preziosa, Aboul-Wafa, Valsasina, Kearney, Matthews, Gallo, Bisecco, and Bellenberg have nothing to disclose. Dr Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Dr Barkhof serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV, and Jansen Research. Dr Vrenken has received funding for collaborative research projects from Pfizer, Novartis, and Merck-Serono, and a speaker honorarium from Novartis; all funds paid directly to his institution. Dr Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer, Genzyme, SanofiAventis, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis, and Biogen Idec, and has research agreements with Siemens AG.


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Dr Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, Roche, Sanofi-Genzyme, Teva, and Trophos. Dr Ciccarelli received a grant from Novartis, Biogen-Idec, GE, and EPSRC; receives personal fees from Novartis and Genzyme. Dr Palace has received support for scientific meetings and honoraria for advisory work from Merck Serono, Biogen Idec, Novartis, Teva, Chugai Pharma and Bayer Schering, and unrestricted grants from Merck Serono, Novartis, Biogen Idec and Bayer Schering. Her hospital trust receives funds for her role as clinical lead for the RSS, and she has received grants from the MS society for unrelated research studies. Dr Gass has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from BayerSchering, Biogen, MerckSerono, Novartis. Dr Eisele has received travel expenses from Bayer Health Care. Dr Lukas has received consulting fees or speaking fees from Biogen Idec, Bayer Schering Germany, Teva, Genzyme, SanofiAventis and Novartis, as well as grant support from Bayer Schering Germany, Novartis and Merck Serono. Prof. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. Prof. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). P604 Gene expression and cytokine protein analysis of the cerebrospinal fluid in early multiple sclerosis: association with grey matter damage assessed by MR imaging D. Seppi1, A. Favaretto1, S. Pravato1, D. Poggiali1, S. Rossi2, F. Facchiano2, C. Veroni3, F. Rinaldi1, P. Perini1, S. Ruggero1, E. Toffanin1, P. Gallo1, F. Aloisi3, R. Magliozzi4 1Multiple Sclerosis Centre, Department of Neuroscience, Univerisity of Padova, Padova, 2Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 3Department of Cell Biology and Neuroscience - Unit of Inflammatory and demyelinating diseases of the nervous system, Istituto Superiore di Sanità, Rome, 4Department of Neurological and Movement Sciences, University of Verona, Verona, Italy Introduction: Grey matter (GM) damage in multiple sclerosis (MS) is evident since early disease stages and is the main determinant of clinical progression. Neuropathological studies have shown that meningeal inflammation associates positively with diffuse subpial cortical demyelination and disease progression, suggesting that chronic immune activation in the meninges plays

a key role in mediating damage in the adjacent cerebral cortex. It has been proposed that factors released by immune cells circulating in the cerebrospinal fluid (CSF) and/or settled in the subarachnoid space diffuse across the pial membrane and induce glial and neuronal pathological alterations, directly and/or indirectly through activated microglia. Aim: This study aims at identifying potential early biomarkers of GM pathology and associated disease progression by combining CSF gene expression and protein analysis with advanced magnetic resonance imaging (MRI) techniques, enabling assessment of cortical GM lesions and atrophy. Methods: CSF was collected, at the disease diagnosis, from 31 therapy-free MS patients and 13 patients with non-inflammatory neurological disease. All patients underwent a complete diagnostic work-up including MRI evaluation with non-conventional sequences (Double Inversion Recovery). By immunoassay protein analysis (Biorad-Bio-Plex, Pro Human Chemokine panel 40-plex), we performed a quantitative analysis of inflammatory chemokines and cytokines in cell-free CSF. We also carried out a gene expression analysis of the matched CSF cellular fraction using pre amplification real-time RT-PCR. Results: MS patients had higher CSF levels of CXCL13, CXCL10, CXCL11 and CCL22 proteins and of Tbet, FoxP3, IFNγ, LTα, CXCL13, CD20 and CD138 transcripts than controls. After stratification for extent of GM pathology, only CXCL13 protein and transcripts specific for the B-cell lineage (CD20, CD138) and GM-CSF, a cytokine promoting mature myeloid cell survival and activation, were significantly higher in patients with more extensive cortical damage. Conclusions: These preliminary data suggest a link between enhanced cortical pathology and intrathecal B cell recruitment and innate immunity stimulation at MS disease onset. Follow-up of the examined patients and a more detailed CSF molecular profiling may help understand whether combined CSF analysis and MRI assessment of grey matter pathology are potentially useful tools to predict/monitor MS evolution. Disclosure Dario Seppi has received funding for travel from Merck Serono, Teva, Biogen Idec, Sanofi-Aventis, Novartis and Bayer Schering Pharma, speaker honoraria from Biogen Idec and has received research grant from FISM (Fondazione Italiana Sclerosi Multipla) - FISM grant 2013/B/8. Alice Favaretto has received funding for travel from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and honoraria from Novartis, Teva and Almirall. Stefano Pravato, Davide Poggiali, Stefania Rossi, Francesco Facchiano, Caterina Veroni report no disclosures. Francesca Rinaldi serves as an advisory board member of Biogen-Idec and has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, Teva and Bayer Schering Pharma. Paola Perini has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and has been consultant for Merck Serono, Biogen Idec and Teva. Susanna Ruggero and Elisabetta Toffanin report no disclosures. Paolo Gallo has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received funding for travel and speaker honoraria from MerckSerono, Biogen Idec, Sanofi-Aventis, Novartis Pharma and BayerSchering Pharma; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has


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Poster Session 1, 22(S3) received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. Francesca Aloisi and Roberta Magliozzi report no disclosures. P605 Myeloid microvesicles and risk of multiple sclerosis in patients with clinically isolated syndromes G. Dalla Costa, T. Croese, A. Finardi, L. Moiola, B. Colombo, V. Martinelli, G. Comi, R. Furlan San Raffaele Hospital, Milan, Italy Introduction: Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of reactive microglia. We present the first exploratory study on the prognostic role of CSF MVs in patients with a clinically isolated syndrome (CIS). Methods: We investigated CSF MVs levels in 50 patients with CIS with a short conversion interval to McDonald 2010 multiple sclerosis (MS) (fast converters (FC), conversion time < 1 year); 51 patients with non-converting CIS (non-converters (NC), follow-up: 3.5 years (1.3-5.9)); and 50 controls. Results: MVs levels were higher in FC (855 per ml (415-2407)) than in NC (423 per ml (235-1010)) and in controls (320 per ml (215-542)) (OR=2.38; 95% CI 1.19 to 5.32; p=0.023 and OR= 6.41; 95% CI 1.38 to 41.5; p=0.03 respectively). The results did not change after adjustment for covariates of MS risk (MRI T2 lesions and gadolinium enhancing lesions, CSF oligoclonal bands, EDSS). When grouping FC and NC, increased CSF MVs concentration was significantly associated with increasing numbers of gadolinium-enhancing lesions (OR=2.07; 95% CI 1.02 to 4.63; p=0.05) at CIS diagnosis. The prognostic value of CSF MVs levels was particularly evident in patients with active lesions (OR=3.29; 95% CI 1.37 to 5.64). Conclusions: If replicated in future studies, CSF MVs may represent a reliable biomarker of microglial activation and prognostic factor in CIS and MS. Disclosure V.M. has received personal compensation for activities with Biogen, Merck Serono, Bayer Schering, TEVA and Sanofi as a speaker. G.C.has received compensation for consulting services and/or speaking activities from Bayer Schering, Serono, Merck Serono, Teva, Sanofi and Biogen. G.D.C, T.C., A.F., F.S., L.M., B.C., G.C., R.F. report no discosures.

Jefferson University, Philadelphia, PA, 4Vanderbilt University Medical Center, Nashville, TN, United States, 5London School of Medicine and Dentistry, London, United Kingdom, 6AbbVie Inc., North Chicago, IL, 7AbbVie Biotherapeutics Inc., Redwood City, CA, United States Background: There is growing acceptance that a neurophysical disability progression composite endpoint (NDPC) may provide a more objective, reliable and sensitive way to monitor disability progression (Mult Scler 2015; 21(11Sup):P638). DECIDE compared daclizumab high-yield process (DAC HYP, 150mg subcutaneous, every 4 weeks, N=919) and interferon beta-1a (IM IFN beta-1a, 30mcg intramuscular, once weekly, N=922). Here, individual domain contributions to the NDPC, and effects of DAC HYP on the NDPC were assessed. Method: Domain contributions to the NDPC were assessed in a pooled treatment group analysis of a 24-week confirmed disability progression (CDP) events with no relapse within the 74 days prior to onset. CDP on the NDPC was achieved by meeting one or more of: 20% increase from baseline (BL) in 9 Hole Peg Test (9HPT) or in Timed 25 Foot Walk (T25FW), or ⩾ 1.0 point increase in Expanded Disability Status Scale (EDSS). Efficacy of DAC HYP on the NDPC was compared post hoc to IM IFN beta1a using a cox regression model in a cohort of patients (pts) with BL EDSS score ⩾3.5, a population at-risk for CDP. Result: Of 264/1841 pts with the first instance of CDP on the NDPC, 90 (34.1%) were captured solely by EDSS, 29 (11.0%) by 9HPT, 128 (48.5%) by T25FW, and 17 (6.4%) by multiple domains. BL EDSS scores varied within groups of pts who had CDP captured by each individual domain, with no specific range captured by a specific domain (e.g. 8.9% of pts with BL EDSS score of 2.0 [n=348] had T25FW CDP, 5.8% of BL EDSS 2.5 [n=173], 6.9% of 3.0 [n=188], 6.6% of 3.5 [n=213], 10.2% of 4.0 [n=157], 6.7% of 4.5 [n=90], and 11.5% of 5.0 [n=87]). In pts with BL EDSS ⩾3.5, DAC HYP (n=260) was more effective than IM IFN beta-1a (n=291) in slowing the accumulation of disability exclusive of acute relapse, based on the NDPC, hazard ratio [95% CI]: 0.65 [0.44, 0.98], nominal p=0.04. Full safety data from DECIDE were previously described (N Engl J Med 2015; 373:1418-28). Conclusion: The individual domains of the NDPC appear to selectively capture pts´ first instance of CDP of upper extremity dexterity, lower extremity ambulatory or broader spectrum disability progression, with little overlap. The basis for this variable sensitivity did not appear to be related to BL disability (EDSS). Treatment with DAC HYP was more effective than IM IFN beta1a in slowing disability progression in relapsing-remitting MS pts with moderate/severe BL disability, independent of acute relapse. Disclosure

Immunomodulation/Immunosuppression P606 Accumulation of disability on the neurophysical disability progression composite: daclizumab high-yield process vs. interferon beta-1a in relapsing-remitting multiple sclerosis patients from the DECIDE study J.L. Bennett1, B.A.C. Cree2, T. Leist3, H. Moses4, G. Giovannoni5, J. Zhao6, M. Li6, L. Chiodo6, R.R. Robinson7, S.J. Greenberg6 1University of Colorado Denver School of Medicine, Aurora, CO, 2University of California, San Francisco, CA, 3Thomas

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Biogen and AbbVie Biotherapeutics Inc. participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. J.L. Bennett is on the editorial board for Journal of Neuro-ophthalmology, Multiple Sclerosis, and Neurology: Neuroimmunology & Neuroinflammation; holds patents for compositions and methods for the treatment of neuromyeltis optica, novel blocking monoclonal therapy for neuromyelitis optica; consulted for EMD-Serono, Questcor Pharmaceuticals, Alnaylam Pharmaceuticals, Medimmune, Abbvie, Novartis Pharmaceuticals, Chugai Pharmaceuticals, Genzyme, Genentech; received research


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support from Questcor Pharmaceuticals, Novartis Pharmaceuticals, NIH, Guthy-Jackson Foundation; holds stock in Apsara Therapeutics; and receives license fees and royalty payments from Aquaporumab. B.A.C. Cree has received compensation for consulting from Abbvie, Biogen, EMD Serono, MedImmune, Novartis, Sanofi Genzyme, Shire and Teva. T. Leist has received compensation for consulting from Abbvie, EMDSerono, Novartis, Genentech, Teva, Biogen, Bayer, Genzyme and for speaking from Novartis, Teva, Biogen,Genzyme. H. Moses has received compensation for consulting and speaking from Biogen, Bayer, Teva, EMDSerono, AbbVie, Genzyme and Novartis. G. Giovannoni received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, SanofiAventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. J. Zhao, M. Li, L. Chiodo, R.R. Robinson and S.J. Greenberg are full-time employees of AbbVie Biotherapeutics and may hold stock or options. P607 Placebo-controlled Phase 3 study of delayed-release dimethyl fumarate in patients with relapsing multiple sclerosis from Asia-Pacific and other countries T. Saida1, T. Yamamura2, T. Kondo3, J. Yun4, M. Yang4, J. Li4, L. Mahadavan4, B. Zhu4, S.I. Sheikh4 1Kansai Multiple Sclerosis Centre, Kyoto Min-iren Central Hospital, Kyoto, 2National Center Hospital, NCNP, Tokyo, 3Kyoto University Graduate School of Medicine, Kyoto, Japan, 4Biogen, Cambridge, MA, United States Background: The Phase 3 DEFINE and CONFIRM studies demonstrated a favourable benefit-risk profile of delayed-release dimethyl fumarate (DMF), mainly in Caucasian MS patients. Objectives: To study 24-week efficacy and safety outcomes of DMF in patients with relapsing MS from Asia-Pacific countries. Methods: This was a 24-week, randomized, double-blind and placebo-controlled Phase 3 study. A total of 225 patients from Japan (n=114), South Korea, Taiwan, the Czech Republic and Poland were randomized 1:1 to receive DMF 240 mg twice daily or matching placebo. The primary endpoint is the total number of new gadolinium-enhancing (Gd+) lesions over 4 brain magnetic resonance imaging (MRI) scans at Week 12, 16, 20 and 24; the secondary endpoints are the total number of new Gd+ lesions from Baseline to Week 24 and the number of new or newly enlarging T2 lesions at Week 24 compared with Baseline. An open-label safety extension is ongoing. Results: Two hundred thirteen patients completed this study. Compared with placebo, DMF reduced the mean number of new Gd+ lesions during Weeks 12-24 by 84% (P< 0.0001), mean number of new Gd+ lesions from Baseline to Week 24 by 75% (P< 0.0001), and mean number of new or newly enlarging T2-hypointense lesions at Week 24 by 63% (P< 0.0001). Commonly reported adverse events in DMF-treated patients included flushing and related symptoms (30% [DMF] vs 9% [placebo]) and gastrointestinal tolerability events (33% [DMF] vs 16% [placebo]). Mean absolute lymphocyte counts decreased

by approximately 16% from Baseline to Week 24 in DMF-treated patients, remaining within normal limits at all time points. The overall incidence of infection was similar with placebo (42%) and DMF (41%). Both efficacy and safety results in Japanese and Asian subgroups were consistent with the overall study population. Conclusions: These results indicate that the beneficial effects of DMF demonstrated in Caucasian patients extend to Asian (including Japanese) MS patients. Disclosure Supported by: Biogen Takahiko Saida: coordinating investigator; has received funding from, held board membership for, spoken at scientific meetings for, prepared manuscripts for, and had consulting agreements with Astellas, Biogen, Bayer-Schering, Daiichi-Sankyo, Eisai, Kaketsuken, Merck Serono, Mitsubishi-Tanabe, Nihon, Novartis, Ono , Sanofi, TDS Japan, and Teijin. Takashi Yamamura: Multiple Sclerosis Center, National Center of Neurology and Psychiatry; member of scientific advisory boards for Biogen and Chugai; received research support from Asahi Kasei Kuraray, Chugai, Mitsubishi Tanabe, Ono, and Teva; received speaker honoraria from Abbot Japan, Astellas, Bayer, Biogen, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe, Nihon, Novartis, and Santen; funded by the Japanese Ministry of Health, Labour and Welfare and the Japan Society for the Promotion of Science. Takayuki Kondo: research support from Bayer HealthCare, Biogen, Novartis, Mitsubishi Tanabe, Eisai, and Takeda; speaker honoraria from Bayer, Biogen, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, and Novartis. Jang Yun: employee of and holds stock/stock options in Biogen. Minhua Yang: employee of and holds stock/stock options in Biogen. Jie Li: employee of and holds stock/stock options in Biogen. Lalitha Mahadavan: employee of and holds stock/stock options in Biogen. Bing Zhu: employee of and holds stock/stock options in Biogen. Sarah I Sheikh: employee of and holds stock/stock options in Biogen. P608 Results of a non-randomised, parallel-group clinical trial to assess efficacy and safety of fingolimod in treatment-naïve and previously treated patients with relapsing-remitting multiple sclerosis. The EARLIMS Study X. Montalbán1, O. Fernández2, H. Butzkueven3, M. Barnett4, M. Nelson5, E. García6, EARLIMS Study Group 1Multiple Sclerosis Unit, Hospital Universitari Vall d’Hebron, Barcelona, 2Hospital Carlos Haya, Málaga, Spain, 3University of Melbourne, Parkville, VIC, 4University of Sydney, Camperdown, 5Novartis Pharmaceuticals Australia, Macquarie Park, NSW, Australia, 6Novartis Farmacéutica S.A., Barcelona, Spain Background and goals: Fingolimod is the first approved oral medication for relapsing-remitting multiple sclerosis (RRMS). The main objective of the study was to assess if fingolimod is superior in reducing the annualized relapse rate (ARR) in patients who have not previously been treated (naïve) with short duration RRMS (⩽5years) than in patients with the same features who


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Poster Session 1, 22(S3) have previously received glatiramer acetate or interferon beta-1 (post-BRACE). Methods: 12-month, multi-centre, open-label, non-randomised, parallel group clinical trial conducted in Spain and Australia. Patients of both sexes, ⩾18 and ⩽50 years, diagnosed with RRMS (McDonald criteria 2010), ⩾9 T2 brain lesions, disease duration 1-5years, ⩾2 relapses in the past 2 years (only Spain), Expanded Disability Status Scale (EDSS) score between 0 and 3.5, and that met Pharmaceutical Benefits Scheme (only Australia), were included. All patients included in the study were treated with 0.5mg oral fingolimod once a day for 12 months. The number of relapses and adverse events (AEs) were collected, T2 brain lesions and brain volume change was evaluated through Magnetic Resonance Imaging, disability status through EDSS scale and quality of life (QoL) with PRIMUS scale. Results: Spanish and Australian patients were enrolled from December 2011 to December 2015. All patients who meet selection criteria will be analysed. The results will be available on July 2016 and presented at the 2016 ECTRIMS congress. The primary efficacy endpoint of the study is the ARR (measured as number of confirmed relapses over a one-year period) and will be presented overall and by arm (naïve and post-BRACE). All secondary endpoints will also be presented overall and by arm. The previous treatments will be summarized for post-BRACE patients. Secondary efficacy endpoints to be described at the end of the 12-month follow-up with fingolimod include: ARR percentage reduction, percentage of patients that remained free of relapse, percentage of relapses that required IV steroids, percentage of relapses that required hospitalization, new or enlarged T2-weighted lesions, brain volume change, EDSS score changes, and QoL evolution. AEs will be also reported. Around 318 patients are expected to be analysed. Conclusions: We will report on the efficacy and safety of Fingolimod in a large (>300) group of patients with short duration RRMS. Results will be presented overall and by arm (naïve or post-BRACE) to explore potential differences between them.

Faculty of Medicine, Charles University in Prague, 3Institute of Haematology and Blood Transfusion in Prague, 4Dpt. of Radiodiagnostics, 1st Faculty od Medicine, Charles University in Prague, Prague, Czech Republic

Disclosure

Disclosure

Dr. Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, SanofiAventis, Teva Pharmaceuticals, GSK, Roche, Almirall, NMSS and MSIF. Editor for Clinical Cases for MSJ. Oscar Fernández has participated in clinical trials of Novartis Helmut Butzkueven has participated in clinical trials of Novartis Michael Barnett has participated in clinical trials of Novartis Morag Nelson has participated in clinical trials of Novartis E. Garcia is employee of Novartis Farmacéutica Spain

Supported from PRVOUK P26/LF1/4.

P609 Case-report: no evidence of disease activity in neuromyelitis optica patient 5 years after allogeneic hematopoietic stem cells transplantation E. Krasulova1, D. Pohlreich2, M. Trneny2, V. Valkova3, M. Markova3, P. Nytrova1, M. Vaneckova4, Z. Seidl4, E. Havrdova1 1Dpt. of Neurology, 1st Faculty od Medicine, Charles University in Prague, 21st Dpt. of Medicine - Dpt. of Haematology, 1st

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Background: Neuromyelitis optica (NMO) presents autoimmune disorder affecting predominantly optic nerves and spinal cord with high risk of severe disability. Current long-term NMO treatment include immunosuppressives, cytostatics and rituximab. In the case of inefficacy more intensive treatment could be considered based on the data from aggressive multiple sclerosis (MS) treatment. There is an option of high-dose immunoablation with autologous stem cells support (ASCT) or even allogeneic hematopoietic stem cells transplantation (alloSCT). Patient and method: 40-year-old woman with NMO (aquaporine-4-IgG seropositive), first symptoms in 1998 (optic neuritis), with non-responsivity to conventional treatment (azathioprine, cyclophosphamide, intravenous immunoglobulins, rituximab) and ASCT failure (September 2009) underwent alloSCT in April 2011. Patient experienced 9 acute relapses since ASCT and Expanded Disability Status Scale (EDSS) progressed from 6.0 to 6.5 at the time of alloSCT. Non-myeloablative regime (fludarabine, cyclophoshamide and antithymocyte globulin) was used. Results: 5 years after alloSCT there has been no NMO relapse, EDSS improved and remained stable (6.0), there is partial recovery and further stable finding on brain and spinal cord magnetic resonance imaging. Disease-specific aquaporine-4-IgG antibodies have been negative since alloSCT. So far no graft versus host disease has been clinically apparent (patient has no specific treatment, only hydrocortisone substitution) and autologous hematopoiesis is up to 0,1%. Conclusion: AlloSCT can be considered as an off-label therapeutic option for aggressive and unfavorable course of NMO in young patients. In our patient status of „no evidence of disease activity” (NEDA) has been achieved during 5-year follow-up thanks to alloSCT treatment.

P610 Alemtuzumab significantly improves disability in patients with active relapsing-remitting MS and an inadequate response to prior therapy as assessed using a novel, composite measure: confirmed disability improvement-plus: results from CARE-MS II B. Singer1, J. Dunn2, G. Izquierdo3, K. Thangavelu4, A. Mittal4, C. Pozzilli5, on behalf of the CARE-MS II Investigators 1MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, 2Stanford University Medical Center, Stanford, CA, United States, 3Virgen Macarena University Hospital, Seville, Spain, 4Sanofi Genzyme, Cambridge, MA, United States, 5Sapienza University, Rome, Italy Background: Disability is a primary contributor to the burden of multiple sclerosis (MS); one of the goals of therapy is thus to improve pre-existing disability. To date, few disease-modifying therapies have demonstrated confirmed disability improvement (CDI). In the CARE-MS II study (NCT00548405) in patients with


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active relapsing-remitting MS (RRMS) and inadequate response (⩾1 relapse) to prior therapy at baseline (BL), alemtuzumab significantly increased the proportion of patients with 6-month CDI (⩾1-point decrease in EDSS score) and reduced the risk of 6-month confirmed disability worsening (⩾1-point EDSS increase [⩾1.5-point if BL EDSS=0]), in addition to reducing the annualised relapse rate vs SC IFNB-1a over 2 years. While the EDSS is a widely used measure of disability in MS, it cannot effectively detect some contributors to disability, such as changes in short-range ambulation and upper extremity function. Goal: To evaluate reduction in pre-existing disability over 2 years with alemtuzumab vs SC IFNB-1a in CARE-MS II using a novel, composite endpoint, CDI-plus, which includes measures of upper extremity function and short-range ambulation. Methods: In the phase 3 CARE-MS II study, patients with RRMS received 2 courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) or SC IFNB-1a 44 µg 3×/week. CDI-plus was assessed in patients with BL EDSS ⩾2.0, and was defined as achieving ⩾1-point EDSS decrease from BL, 20% improvement from BL in the 9-Hole Peg Test (9HPT), or 20% improvement in the Timed 25-Foot Walk (T25FW), confirmed over a 6-month period. Results: A significantly higher proportion of alemtuzumabtreated patients (41%) achieved CDI-plus vs SC IFNB-1a (24%) (hazard ratio [HR] [95% CI]: 2.06 [1.41, 3.00], P=0.0002). Among the CDI components, significantly higher proportions of alemtuzumab patients achieved confirmed improvements vs SC IFNB-1a in EDSS (29% vs 13%; HR [95% CI]: 2.57 [1.57, 4.20], P=0.0002) and 9HPT (12% vs 5%; HR [95% CI]: 2.41 [1.06, 5.48], P=0.035) over 2 years. A numerically higher proportion achieved improvement in T25FW with alemtuzumab vs SC IFNB-1a (11% vs 9%; HR [95% CI]: 1.26 [0.65, 2.42], P=0.49). Conclusions: Compared with SC IFNB-1a, a significantly greater proportion of alemtuzumab patients achieved CDI-plus. CDI-plus is a novel composite measure of disability improvement encompassing measures in addition to traditional EDSS scores, and may have utility as an adjunctive treatment outcome metric in MS. Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. BS: Speaking and/or consulting (Acorda, Bayer, Biogen, EMD Serono, Genentech, Pfizer, Novartis, Sanofi Genzyme, and Teva); research support (Acorda, Biogen, MedImmune, Novartis, Roche, and Sanofi Genzyme). JD: Honoraria (Biogen and Sanofi Genzyme). GI: Speaking and/or advisory board honoraria (Almirall, Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva). KT and AM: Employees of Sanofi Genzyme. CP: Speaking and/or consulting (Almirall, Biogen, EMD Serono, Novartis, Sanofi Genzyme, and Teva); research support (Biogen, EMD Serono, Novartis, Sanofi Genzyme, and Teva).

P611 Effectiveness of mycophenolate mofetil as first line therapy in AQP4-IgG, MOG-IgG and seronegative neuromyelitis optica spectrum disorders A. Montcuquet1,2, N. Collongues3, C. Papeix4, H. Zephir5, B. Audoin6, D. Laplaud7, B. Bourre8, B. Brochet9,

J.-P. Camdessanche10, P. Labauge11, T. Moreau12, B. Stankoff13, J. De Sèze3, S. Vukusic2,14,15, R. Marignier2,14,15 1Department Neurology, CHU Dupuytren, Limoges, 2Service de Neurologie A and Eugène Devic EDMUS Foundation against Multiple Sclerosis, Observatoire Français de la Sclérose en Plaques (OFSEP), Hôpital Neurologique Pierre Wertheimer, Lyon, 3Department of Neurology, and INSERM CIC-1434, CHU de Strasbourg, Strasbourg, 4Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, 5Clinique Neurologique, University of Lille, Lille, 6Department of Neurology, Hôpital Timone, Marseille, 7Department of Neurology, University Hospital of Nantes, Nantes, 8Department of Neurology, University Hospital of Rouen, Rouen, 9Department of Neurology, and INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, 10Department of Neurology, University Hospital of Saint-Etienne, Saint-Etienne, 11Department of Neurology, University Hospital of Montpellier, Montpellier, 12Department of Neurology, University Hospital of Dijon, Dijon, 13Department of Neurology, Hôpital Tenon, Paris, 14Lyon’s Neuroscience Research Center, Team ONCOFLAM, Inserm U 1028 / CNRS 5292, 15Université de Lyon, Université Claude Bernard-Lyon1, Lyon, France Objective: To evaluate the effectiveness and tolerance of MMF as a first line treatment in a large Caucasian multicentre cohort of NMOSD patients, whatever the AQP4-IgG status. Methods: Retrospective review of 67 NMOSD patients treated by MMF as first line therapy from the nationwide NOMADMUS cohort. Fifty were female and mean age at disease onset was 37.9 years. 65 patients fulfilled 2015 NMOSD criteria, and 5 were MOG-IgG positive. Effectiveness was evaluated on percentage of patients continuing MMF, percentage of patients free of relapse, pre and post-treatment change of the annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS). Results: Among 67 patients, 40 (59.7%) continued treatment at last follow-up. Thirty-three (49.3%) were relapse free. The median ARR decreased from 1.0[0.1-3.2] pre-treatment to 0[0-3] posttreatment. Out of 53 patients with complete data about EDSS, the score was improved or stabilized in 44 patients (83%) (p< 0.05). Effectiveness was observed in AQP4-IgG, MOG-IgG, and seronegative NMOSD patients. In 16 patients with associated steroids, 13 (81.2%) continued MMF at the end of follow-up versus 15/28 (53.6%) in the non-steroid group (p=1). Conclusions and relevance: In this nationwide study, MMF showed effectiveness as a first line therapy in NMOSD, whatever is the AQP4-IgG status. Concomitant use of oral steroids at start could limit the risk of treatment failure. Disclosure Alexis Montcuquet- has received funding for travel from Merck Serono, Teva, Novartis, Sanofi-Genzyme and Biogen Nicolas Collongues serves on scientific advisory boards for and has received honoraria from Biogen Idec, Merck Serono, SanofiGenzyme, Novartis, Teva, Almirall, Bayer Schering Pharma and Alexion Pharmaceutical. Caroline Papeix serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Roche, Teva has received funding for travel from Novartis and Teva and receives research support from Novartis Hélène Zéphir received has served for scientific advisory board for Biogen Idec, Teva, Novartis, Bayer, Genzyme, has received


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Poster Session 1, 22(S3) research grant support from Teva and Genzyme, and fundings for congresses travels from Biogen Idec, Teva, Novartis, Merck, Bayer, Genzyme, Sanofi. Bertrand Audoin declares no conflict of interest David Laplaud declares no conflict of interest Bertrand Bourre serves on scientific advisory board for Merck Serono and has received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Teva Bruno Brochet serves on scientific advisory boards for and has received honoraria or research support from Biogen Idec, Merck Serono, Sanofi-Genzyme, Novartis, Bayer Schering Pharma, Teva and Roche. Jean-Philippe Camdessanché receive or have been received fees for lectures, consulting, writing of articles, or training courses from Biogen-Idec, CSL-Behring, Editions Scientifiques L&C, Expression Santé , Laboratoire Français des Biotechnologies, Natus, Merck-Serono, Novartis, Sanofi-Genzyme, Scien, SNFFloerger, and Teva. Pierre Labauge- serves on scientific advisory boards for Novartis, Sanofi-Genzyme, has received funding for travel from Novartis and Biogen Idec. Thibault Moreau serves on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, sanofi-aventis, Genzyme, Roche, Almirall and Teva; has received funding for travel from Merck Serono; and receives research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, Genzyme, Roche, Almirall and Teva. Bruno Stankoff declares no conflict of interest Jérôme De Sèze- has served on scientific advisory boards for Biogen Idec, LFB, Merck Serono, sanofiaventis, and Bayer Schering Pharma; and has received research support from Biogen Idec, LFB, Merck Serono, sanofi-aventis, and Bayer Schering Pharma. Sandra Vukusic- serves on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva; has received funding for travel from Merck Serono; and receives research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva. Romain Marignier - serves on scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Teva.

P612 Cutaneous events in daclizumab HYP-treated patients did not impact patient-reported outcomes in the DECIDE study Y. Liu1, R. Garland1, W.-S. Yeh1, P. Wang1, J. Ting1, X. Ye2, C. Wakeford1, G. Sabatella1 1Biogen, Cambridge, MA, 2AbbVie Inc., Mettawa, IL, United States Background: Cutaneous adverse events (CAEs) occurred in 37% of patients treated with daclizumab high-yield process (DAC HYP) vs. 19% of patients treated with intramuscular interferon beta-1a; most events were mild or moderate and did not result in treatment discontinuation (5% vs. < 1% discontinued due to CAEs, respectively). Patient-reported outcomes (PROs) may provide insight into the patient-perceived impact of CAEs on daily functioning and quality of life.

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Objectives: To examine the impact of CAEs on PROs in patients receiving subcutaneous DAC HYP 150 mg once monthly in DECIDE. Methods: This post hoc analysis included DAC HYP-treated patients from DECIDE. PROs included the EuroQol-5 Dimensions (EQ-5D) instrument, Multiple Sclerosis Impact Scale (MSIS-29) physical (PHYS) and psychological (PSYCH) subscales and 5 selected MSIS-29 items judged by investigators to be potentially affected by CAEs (being stuck at home more than you would like to be; cut down time spent on daily activities; feeling mentally fatigued; worries related to your MS; and feeling anxious or tense). Mean PRO scores of the visits most closely preceding, during and most closely following the development of moderate/severe CAEs were compared. The potential lasting effect of CAEs was examined by comparing mean changes in PRO scores from Baseline to Week 96 between patients who did/did not develop CAEs. Results: Among the 143 patients who experienced moderate/ severe CAEs, mean changes from pre to post CAE were very small and not statistically significant: EQ-5D utility index, −0.01 (P=.30); MSIS-29 PHYS, 0.1 (P=.93); MSIS-29 PSYCH, 0.7 (P=.59). Likewise, no significant changes were observed in these PROs from pre to during CAE and during to post CAE (additional data not reported). No significant change was observed for any of the 5 selected MSIS-29 items. At Week 96, patients who did (n=119) and did not (n=629) experience moderate/severe CAEs reported similar change from Baseline in EQ-5D (0.04 vs. 0.03; P=.21), MSIS-29 PHYS (-1.70 vs. -0.95; P=.47), MSIS-29 PSYCH (-4.74 vs. -4.41; P=.69) and the 5 selected MSIS-29 items. Conclusions: Occurrence of CAEs with DAC HYP did not result in observable impact on patient-reported physical and psychological health or general health status. Disclosure Ying Liu, Wei-Shi Yeh, Ping Wang, Craig Wakeford and Guido Sabatella: full-time employees of and hold stock/stock options in Biogen; Jie Ting: postdoctoral fellow at Biogen; Robert Garland: former full-time employee of and holds stock/ stock options in Biogen; Xiaolan Ye: full-time employee of and holds stock/stock options in AbbVie Inc., holds stock/stock options in Baxalta. Supported by: Biogen and AbbVie Biotherapeutics, Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Stephanie Douglas (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P613 Durable effect of alemtuzumab on MRI lesion outcomes over 5 years in patients with highly active relapsing-remitting multiple sclerosis who had an inadequate response to prior therapy (CARE-MS II) G. Comi1, R. Berkovich2, A. Rovira3, D. Pelletier2, S. Schippling4, A. Traboulsee5, P. Vermersch6, D.H. Margolin7, K. Thangavelu7, D.L. Arnold8,9, on behalf of the CARE-MS II Investigators


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San Raffaele University, Milan, Italy, 2University of Southern California, Los Angeles, CA, United States, 3University Hospital Vall d’Hebron, Barcelona, Spain, 4Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich and University of Zurich, Zurich, Switzerland, 5University of British Columbia, Vancouver, BC, Canada, 6University of Lille, Lille, France, 7Sanofi Genzyme, Cambridge, MA, United States, 8NeuroRx Research, 9Montréal Neurological Institute and Hospital, Montréal, QC, Canada Background: In the CARE-MS II study (NCT00548405), patients with relapsing-remitting multiple sclerosis (RRMS) with highly active disease (HAD; defined as ⩾2 relapses in the year before randomisation and ⩾1 gadolinium [Gd]-enhancing lesion) and an inadequate response (⩾1 relapse) to prior therapy at baseline (BL) showed significantly reduced clinical and MRI disease activity with alemtuzumab versus SC IFNB-1a over 2 years. An extension study (NCT00930553) has shown clinical efficacy to be durable through 5 years in the absence of continuous treatment in patients with HAD. Goal: To evaluate 5-year MRI outcomes in alemtuzumab-treated patients with HAD at BL. Methods: In CARE-MS II, patients received 2 courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days). Patients who completed CARE-MS II could enter the extension, with as-needed alemtuzumab retreatment for relapse or MRI activity. Another DMT could be initiated per investigator discretion. Assessments: MRI disease activity (defined as new Gd-enhancing T1 and new/ enlarging T2 hyperintense lesions), brain volume loss (BVL), and no evidence of disease activity (NEDA). Results: 92 of 103 (89%) alemtuzumab-treated patients with HAD completed the CARE-MS II core study and entered the extension; of those, 90 patients (98%) remained on study through 5 years. MRI activity remained low through the extension; in Year 5, most patients had no Gd-enhancing T1 lesions (92%) and no new/enlarging T2 hyperintense lesions (70%), and most achieved annual MRI NEDA (70%). In addition, most patients also had no new T1 hypointense lesions (89% in Year 5). Median yearly BVL decreased progressively over 3 years and remained low in Year 5 (-0.13%/ year). Over half of patients with HAD achieved NEDA (clinical and MRI) in each year of the extension (54% in Year 5). These results were achieved with 62% of patients with HAD receiving no additional treatment after their initial 2 courses of alemtuzumab. Conclusion: Alemtuzumab efficacy on MRI outcomes was durable through 5 years in patients with HAD and an inadequate response to prior therapy, reinforcing findings on clinical outcomes in these patients. MRI outcomes and NEDA observed with alemtuzumab in the HAD population were consistent with those observed in the overall study population. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for RRMS patients with HAD. Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. GC: Consulting fees (Actelion, Bayer, Merck Serono, Novartis, Sanofi Genzyme, and Teva); lecture fees (Bayer, Biogen Dompé, Merck Serono, Novartis, Sanofi Genzyme, Serono Symposia International Foundation, and Teva).

RB: Advisory boards and consulting (Acorda, Avanir, Bayer, Biogen, Novartis, Questcor, Sanofi Genzyme, and Teva). AR: Consulting and/or speaking fees (Bayer, Biogen, Bracco, Novartis, Sanofi Genzyme, and Stendhal). DP: Consulting and/or speaking fees and grant/research support (Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Vertex). SS: Research grants (Bayer, Biogen, and Sanofi Genzyme); consulting/speaking fees (Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva). AT: Consulting fees (Biogen, Chugai, MedImmune, Novartis, Roche, Sanofi Genzyme, Serono, and Teva Innovation); principal investigator on clinical trials (Roche and Sanofi Genzyme). PV: Consulting and/or speaking fees (Almirall, Bayer, Biogen, GlaxoSmithKline, Novartis, Merck Serono, Sanofi Genzyme, and Teva); research support (Bayer, Biogen, Merck Serono, and Novartis). DM and KT: Employees of Sanofi Genzyme. DLA: Honoraria (Acorda, Bayer, Biogen, Genentech, GlaxoSmithKline, Medimmune, Merck Serono, Novartis, Receptos, Roche, Sanofi Aventis, Sanofi Genzyme, and Teva); employee (NeuroRx). P614 Assessment of No Evidence of Disease Activity (NEDA-3) in alemtuzumab-treated patients with aggressive multiple sclerosis who failed multiple disease-modifying drugs L. Prosperini1, P. Annovazzi2, L. Boffa3, C. Buscarinu4, A. Gallo5, M. Matta6, L. Moiola7, L. Musu8, P. Perini9, C. Avolio10, M.R. Rottoli11, A. Bianco12, D. Farina13, E. Ferraro14, A. Francia1, F. Granella15, L. Grimaldi16, A. Laroni17, G. Lus5, F. Patti18, E. Pucci19, A.M. Repice20, P. Sarchielli21, Italian Alemtuzumab Study Group 1Neurology and Psychiatry, Sapienza University, Rome, 2S. Antonio Abate Hospital, Gallarate, 3Tor Vergata University, 4Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital, Rome, 5Dept. of Medical, Surgical, Neurological, Metabolic and Aging Sciences, 2nd University, Naples, 6Regional MS Centre, S. Luigi Gonzaga Hospital, Orbassano, 7S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, 8ASL-8 Cagliari University, Cagliari, 9Dept. of Neurosciences, MS Centre, University Hospital, Padova, 10Dept. of Medical and Surgical Sciences, University Hospital, Foggia, 11Papa Giovanni XXIII Hospital, Bergamo, 12Institute of Neurology, School of Medicine ‘A. Gemelli’, Rome, 13Dept. of Neuroscience and Imaging, University ‘G. d’Annunzio’, Chieti, 14S. Filippo Neri Hospital, Rome, 15Dept. of Neurosciences, University of Parma, Parma, 16Fondazione Istituto San Raffaele “G.Giglio’, Cefalù, 17Dept. of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, 18Dept. of Medical and Surgical Sciences and Advanced Technologies, Neuroscience Section, University of Catania, Catania, 19Neurology Unit, ASUR Marche AV3, Macerata, 20Neurology Unit, Careggi Hospital, Firenze, 21Neurology Unit, Perugia University, Perugia, Italy Background: The anti-CD52 humanized monoclonal antibody alemtuzumab was recently approved for the treatment of active relapsing-remitting multiple sclerosis (MS), based on phase-2


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Poster Session 1, 22(S3) (CAMMS223) and phase-3 clinical trials (CARE-MS I and CARE-MS II), where high-dose interferon beta-1a was used as active comparator. Both CAMMS223 and CARE-MS I recruited treatment-naïve patients with MS duration ⩽3 and 5 years (respectively) and Expanded Disability Status Scale (EDSS) ⩽3.0. By contrast, CARE-MS II recruited patients with MS duration ⩽10 years, EDSS ⩽5.0. and prior exposure to disease-modifying drugs (DMDs); however, about 3/4 of them did not respond to only one DMD. Therefore, the potential use of alemtuzumab in aggressive and treatment-refractory MS deserves further investigation. Objective: To assess the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) defined as no relapses, no disability worsening, and no magnetic resonance imaging (MRI) activity - after discontinuation of multiple DMDs because of lack of response or safety concerns. Methods: In this longitudinal, observational study we are prospectively collecting clinical and MRI data of a real-world cohort of patients treated with alemtuzumab between May 2014 and June 2015 in 21 tertiary Italian MS Centres according to a “free-ofcharge” protocol available before its approval by the Italian regulatory agency. Results: The study sample consists of 40 patients (33 F, 7 M) with a mean age of 34 years, mean MS duration of 12 years, median number of relapses in the prior year of 2, and median EDSS of 4.0 at first alemtuzumab course. At baseline brain scan, 72% of them had gadolinium-enhancing lesions. The median number of previous DMDs was 4 (interferons: n=36; natalizumab: n=32; fingolimod: n=29; glatiramer acetate: n=19; mitoxantrone: n=12; cyclophosphamide: n=7; dimethylfumarate :n=3; rituximab: n=1; autologous hematopoietic stem cells transplantation: n=1). After a mean follow-up of 1.5 years, 25 (62%) patients maintained NEDA-3, 32 (80%) were relapse-free, 37 (92%) were disability worsening-free, and 26 (65%) were MRI activity-free. Infusionrelated reactions were observed in 38 (95%) patients. At moment, 34 patients have received the second course. Discussion: Alemtuzumab promoted short-term remission of the disease in aggressive MS patients, independently from previous exposures to multiple DMDs. Further data collection and elaboration are in progress. Disclosure This study was supported by Sanofi-Genzyme. LP: speaker honoraria from Biogen, Genzyme, Novartis and Teva; consulting fees from Biogen and Novartis; research grant from Genzyme. PA: consulting and/or lecture fees from Biogen Idec, Genzyme, Novartis and Teva. LB: lecture fees from Merck Serono and Teva. MCB: consulting and/or lecture fees from Biogen, Teva, Genzyme, Novartis. AG: speaker and consulting fees from Biogen, Genzyme, Novartis and Teva. MM: honoraria from Biogen, Novartis, Almirall, Teva LM: speaking honoraria and/or consulting fees from Biogen, Bayer Schering Pharma, Merck Serono and Sanofi-Aventis. LM: speaking honoraria and/or consultant fees from Biogen and Genzyme. PP: speaking honoraria and/or consultant fees from Biogen, Merck Serono, Teva, Novartis and Genzyme.

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CA: speaking honoraria and/or consulting fees from Merck Serono, Novartis, Genzyme. MRR: honoraria from Biogen, Merck Serono, Teva, Genzyme, Novartis, Bayer Schering. AB: honoriaria from Almirall, Genzyme, Novartis. DF: nothing to disclose. EF: nothing to disclose. AF: research funding and lecture fees from Sanofi-Aventis, Biogen, Merck Serono and Novartis. FG: consulting fees for Biogen, Novartis and Sanofi Aventis and speaker honoraria from Biogen, Merck Serono, and Almirall. LG: scientific advisory board for Merck Serono, speaker honoraria from Merck Serono, Biogen, Sanofi-Aventis, Bayer Schering Pharma and Solvay Pharmaceuticals, Inc.; institutional research support form Teva Pharmaceuticals Industries Ltd, Biogen, Genzyme Corporation, Sanofi-Aventis, Merck Serono, Novartis and Eisai Inc.; research support from Merck Serono, Biogen and Ministero della Salute of Italy. AL: speaking honoraria from Biogen and Novartis GL: scientific advisory boards from Almirall, Novartis, Biogen, Sanofi-Aventis, Genzyme and Bayer Schering; speaking honoraria from Sanofi-Aventis, Biogen, Bayer Schering, Teva Neurosciences, Almirall, Genzyme and Novartis; research support from Novartis, ‘Fondazione C. Serono’, Biogen, Bayer Schering and Sanofi-Aventis. FP: consulting fees and speaking honoriaria from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme and TEVA. EP: personal fees and non-financial support from Biogen Idec, Merck Serono, Teva, Genzyme and Novartis. AMR: nothing to disclose. PS: nothing to disclose. P615 Rituximab treatment in italian NMOSD patients M. Radaelli1, U. Pensato1, F. Sangalli1, L. Moiola1, B. Colombo1, M. Comola1, M.A. Biancu2, G. Comi1, V. Martinelli1 1San Raffaele Hospital, Milan, 2Azienda Ospedaliera Universitaria Cliniche di San Pietro, Sassari, Italy Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system that generally involves the optic nerve and the spinal cord. Despite the severe prognosis there are no approved treatments for NMO even if Rituximab (RTX) has been proposed as the most promising therapeutic option. However there are still few studies with large cohort of patients and there are still some open questions as the best treatment scheme to adopt and the long term management of the drug. Objective: To assess the benefit-risk profile of repeated courses of rituximab in caucasian patients affected by NMOSD in every day clinical practice. Methods: Our study is a prospective observational study conducted in an Italian referral centre for Multiple Sclerosis and central nervous system inflammatory diseases. Starting from February 2006 we included patients affected by NMOSD who underwent at least one cycle of i.v. rituximab and at least six months of follow-up. Results: Forty patients (34 females) were included in the study. At a mean follow-up of 47 months we observed a significant reduction of ARR from 1,8 to 0,6 (p< 0,01) and of the median


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EDSS from 5,75 to 4,0 (p< 0,001). A complete control of the disease was obtained in 60% of patients. However if we consider only relapses occurred without an increase of CD19 the proportion of relapse free patients rise to 80%. Overall the EDSS after RTX was stable or improved in 90% of patients. Ten patients (25%) reported haematological adverse events consistent with a persistent grade II leucopoenia or hypogammaglobulinemia. Serious infective adverse events were reported by eight patients. They all had possible risk factors such as leucopoenia and hypogammaglobulinemia or high EDSS score at the beginning of rituximab. Conclusions: In a real world clinical practice a fixed treatment scheme of rituximab with re-treatment every six months is an efficacious treatment for NMO and related disorders with a relative good safety profile. However to assess the best risk-benefit ratio a close monitoring of CD19+ B cells should be performed before re-treatment in patients with high disability and concomitant leucopoenia and hypogammaglobulinemia. Disclosure Dr. Radaelli has nothing to disclose, Dr. Moiola reports speaking fees and/or travel expenses from Merck Serono and from Biogen, Dr. Pensato, Dr. Sangalli and Dr. Comola, has nothing to disclose, Dr. Colombo reports speaking fees and/or travel expenses from Merck Serono and from Teva Pharmaceuticals Dr. Martinelli reports consultancy, speaking fees and/or travel expenses from Biogen-Dompè SG, Merck Serono, Bayer Schering, Novartis, Sanofi-Aventis, Genzyme Europe,Teva Pharmaceuticals. Prof. Comi has received compensation for consulting services and/or speaking activities from Biogen, Novartis, Teva Pharmaceutical Ind, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Actelion and Serono Symposia Int. Found

P616 Real life efficacy and tolerability of Teriflunomide a multicentre study P. Annovazzi1, G. Mallucci2, M. Lo Re3, S. Miante4, R. Cavarretta5, L. Moiola6, V. Torri Clerici7, C. Zuliani8, C. Chiavazza9, B. Frigeni10, R. Bergamaschi2, A. Bertolotto3, P. Perini4, M. Rovaris5, S. Rossi7, P. Cavalla9, M.R. Rottoli10, M. Zaffaroni1, G. Comi1,6, A. Ghezzi1 1Multiple Sclerosis Study Center, ASST Valle Olona - PO Gallarate, Gallarate, 2Inter-Department Multiple Sclerosis Research Centre, Neurological Institute IRCCS Mondino, Pavia, 3Regional Multiple Sclerosis Centre, San Luigi Gonzaga Hospital, Orbassano, 4Department of Neurosciences, The Multiple Sclerosis Centre, University Hospital of Padova, Padova, 5Multiple Sclerosis Center, Scientific Institute Santa Maria Nascente, Don Carlo Gnocchi Foundation, 6Department of Neurology, Scientific Institute H. San Raffaele, University Vita-Salute, 7Neuroimmunology and Neuromuscular Diseases Unit, IRCCS Fondazione Isitituto Neurologico Carlo Besta, Milano, 8Department of Neurology, Mirano Hospital, Mirano, 9Department of Neurology, AOU City of Science and Health, Torino, 10Multiple Sclerosis Center, Department of Neurology, Papa Giovanni XXIII Hospital, Bergamo, Italy

Objectives: Aim of this study is to confirm post-marketing Teriflunomide (TFU) efficacy and safety profile, and to identify predictors of response to TFU. Materials and methods: We enrolled all patients receiving TFU in ten northern Italy MS centres. Patients were prospectively followed, collecting demographic and clinical data as well as laboratory assessment abnormalities. Results: We enrolled 550 patients (66% F) (mean age: 46,2 + 9,8 years; mean disease duration: 14 + 9,8 years). Mean Annualized Relapse Rate (ARR) in the two years before TFU was 0,38 + 0,4; median baseline EDSS was 2 (range 0-6,5). 112/550 patients were treatment naïve or quitted Disease Modifying Drugs (DMDs) more than 12 months before TFU start, 380/550 switched to TFU from injective DMDs (72% for loss of tolerability, 28% for inefficacy), 58/550 switched to TFU after a second line therapy for loss of tolerability or safety reasons. Mean follow up was 13 + 9 months. 82,7% of the patients are relapse-free at follow-up. Mean ARR at follow-up is 0,2 + 0,7. Predictors of relapse-free status are: lower baseline ARR (HR 2,6, 95% CI: 1,6-4,1; p < 0,001), use of TFU as first therapy or switch to TFU for lack of tolerability of previous DMD (HR 2,4; 95% CI: 1,3-4,6; p = 0,04) and lower number of previous therapies (HR 0,7; 95% CI: 0,9-0,4; p = 0.04). In 87,4 % of the patients switching to TFU for loss of tolerability on injective DMDs, ARR remained stable or improved compared to baseline. Most frequent adverse events (AEs) were diarrhoea or other gastrointestinal side effects (20,2%) and hair thinning (11,3%); Three severe AEs were reported (one Pancreatitis, one Acute Coronary Syndrome and one Glioblastoma). Most frequent laboratory testing abnormalities were lymphopenia (in 5,9% of the patients) and increase in liver function markers (in 5,1% of the patients). 105/555 patients stopped TFU after a mean of 7,6 + 6 months: causes of stop were AEs (65%) and disease activity (35%). Predictors of TFU interruption were higher baseline ARR (HR 2,1, 95% CI: 1,2-3,6; p < 0,003) and switch to TFU after a second line therapy (HR 1,7, 95% CI: 1,3-2,2; p < 0,03). Discussion and conclusion: Even with the limitations of an open label study, our data confirm the efficacy and tolerability profile of TFU, especially as a first-line agent or alternative to injectable therapies for a better tolerability. Disclosure PA received honoraria for advisory and speaking activities by Biogen, Merck Serono, Novartis, Sanofi Genzyme and TEVA GM received congress and travel expense compensations from Bayer Schering, Biogen-Idec, Genzyme, Merk Serono, Novartis, Sanofi- Aventis, Teva. MLR received travel expenses from Biogen, Novartis and Teva. SM has nothing to disclose RC has nothing to disclose LM received honoraria for speaking from Sanofi Aventis, Merck Serono and Biogen Idec in the last two years VTC acted as an Advisory Board member of Biogen Idec and Novartis, and received funding for traveling and honoraria for speaking or writing from Teva, Novartis, Genzyme, Almirall. She received support for research project by Almirall. CZ received honoraria for speaking and advisory board from: novartis, teva, sanofi, biogen, bayer, merck. CC has nothing to disclose


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Poster Session 1, 22(S3) BF has nothing to disclose RB has served on scientific advisory boards for Biogen Idec and Almirall; has received funding for travel and speaker honoraria from Sanofi-Aventis, Genzyme, Biogen Idec , Bayer Schering, Teva Neurosciences, Merck Serono, Almirall, and Novartis; received research support from Merck Serono, Biogen Idec, Teva Neurosciences, Bayer Schering, Novartis, Sanofi-Aventis. AB received honoraria for serving in the scientific advisory boards of Almirall, Bayer, Biogen, Genzyme with approval by the Director of AOU San Luigi University Hospital and received speaker honoraria from Biogen, Genzyme, Novartis, TEVA; his institution has received grant support from Bayer, Biogen, Merck, Novartis, TEVA from the Italian Multiple Sclerosis Society, Fondazione Ricerca Biomedica ONLUS and San Luigi ONLUS PP received honoraria from biogen serono novartis teva genzyme for lectures or advisory board MR received travel reimbursment and fees for lectures/presentations from Teva, Genzyme-Sanofi, Almirall, Biogen SR acted as an Advisory Board member of Biogen Idec, Bayer Schering, Merck Serono, Teva, Novartis and Genzyme, and received funding for traveling and honoraria for speaking or writing from Biogen Idec, Merck Serono, Teva, Novartis, Bayer Schering, Genzyme, Almirall. She received support for research project by Teva, Merck Serono and Bayer Schering and is involved as principal investigator in clinical trials for Teva and Roche. PC received travel support for scientific congresses and speaking honoraria from: Almirall, Biogen, Genzyme, Merck Serono, Novartis and Teva MRR reports speaking fees and/or travel expenses from Merck, Biogen, Teva Pharmaceutical and Novartis MZ serves on scientific advisory boards for Merck Serono, Teva, Sanofi Aventis, Almirall and Biogen; has received speaker honoraria from Teva, Sanofi Aventis, Biogen, Merck Serono, Novartis, and Sanofi Aventis. GC serves on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Teva, Sanofi Aventis, Novartis and Biogen-Idec; has received speaker honoraria from Teva, Sanofi Aventis, Serono Sumposia International Foundation, BiogenIdec, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis. AG serves on scientific advisory boards or as a consultant for Merck Serono, Novartis, Genzyme, Biogen Idec, Teva; received honoraria for speaking form Merck Serono, Serono Symposia International Foundation, Biogen Idec, Allmirall, Genzyme, Teva, and Novartis

Design, setting and participants: Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. Participants were patients with confirmed relapsing-remitting multiple sclerosis (McDonald 2005 criteria) 18 to 55 years old with at least 1 relapse or 1 gadolinium-enhancing MRI lesion in the prior year, with Expanded Disability Status Scale (EDSS) score 0-5,5 and relapse-free > 4 weeks. Interventions: Participants were randomized 2:2:1 to receive BCD-063 (20 mg), Copaxone® (20 mg), or placebo by daily subcutaneous injection for 48 weeks. MRI outcomes and measures: MRI outcomes included the number of combined unique active (CUA) lesions at week 48 as well as other magnetic resonance imaging parameters. Results: 121 participants were included in analysis of MRI outcomes in three groups: BCD-063 (n = 48), Copaxone® (n = 51), or placebo (n = 22). CUA lesions at week 48 were (M±sd) 0.89±1.43 in BCD-063 group, 1.06±1.69 in Copaxone® group, 2.71±3.3 in placebo group. No statistical difference was observed when CUA lesion numbers were compared in BCD-063 and Copaxone® groups (p=0,7189); paired difference test for both groups in comparison with placebo was statistically significant (p=0.0195 for BCD-063, p=0.0346 for Copaxone®). CUA lesions decrease (week 48 vs. week 24) was statistically significant in BCD-063 group, as well as in Copaxone® group (р = 0,000034 and р = 0,002547, respectively), unlike in placebo group, where change in CUA lesion number was non-significant. The number of Gd+ T1 lesions at week 48 decreased in BCD-063 (р = 0,00114) and in Copaxon® (р = 0,00036) groups, but statistically significant dynamics in placebo group was not observed (p=0.21157), which was expected. There were no statistically significant differences between glatiramer acetate groups. The number of new T2 lesions at week 48 did not have significant differences in BCD-063 and Copaxone® groups, with statistically significant differences between the groups of glatiramer acetate and placebo (p = 0.00002 for BCD-063 vs. placebo and p = 0.024 for Copaxone® vs. placebo). Conclusions and relevance: BCD-063 and Copaxone® have equivalent effects on MRI disease activity and similar safety profile in patients with RR-MS. Trial registration: Russia 346 06/10/13 Ukraine 151/KD 02/07/14

P617 Effects of generic glatiramer acetate (BCD-063) on magnetic resonance imaging outcomes in patients with relapsing multiple sclerosis. A randomized double-blind 48 weeks clinical trial A.N. Boyko1, M.N. Zakharova2, T.O. Simaniv2, E.V. Lysogorskaya2, F.A. Khabirov3, N.N. Babicheva3, E.V. Granatov3, T.I. Khaibullin3, M.S. Shustova4, R.A. Ivanov4 1Pirogov Russian National Research Medical University (RNRMU), 2Scientific Center of Neurology, Moscow, 3Tatarstan Republican Clinical Neurology Center, Kazan, 4Research and Development, BIOCAD, Saint Petersburg, Russian Federation

Disclosure

Objective: To evaluate whether generic glatiramer acetate (BCD063) is equivalent to the originator brand glatiramer acetate product (Copaxone®-Teva), as measured by imaging endpoints.

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This study was sponsored by JSC Biocad.

P618 Efficacy of daclizumab HYP versus intramuscular interferon beta-1a in patients without neutralising antibodies against interferon beta in the DECIDE study A. Bertolotto1, P. Soelberg Sørensen2, M. Ravnborg3, S. Cohan4, P. Wang5, S. Fam5 1AOU San Luigi Gonzaga, Regional Multiple Sclerosis Center, Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy, 2Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University, Rigshospitalet, Copenhagen, 3Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark, 4Providence


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Multiple Sclerosis Center, Providence Brain and Spine Institute, Providence Health & Services, Portland, OR, 5Biogen, Cambridge, MA, United States Background: Daclizumab high-yield process (DAC HYP) showed significantly greater efficacy over intramuscular (IM) interferon (IFN) beta-1a on key clinical and radiologic outcomes in relapsing-remitting multiple sclerosis in DECIDE. Patients previously treated with IFN beta could enrol in DECIDE if they did not have any contraindication, known intolerance, or history of noncompliance with IM IFN beta-1a at randomisation. Objectives: Evaluate the efficacy of DAC HYP versus IM IFN beta-1a in patients previously treated with IFN beta who did not have IFN beta neutralising antibodies (NAbs) at Baseline in DECIDE. Methods: At Baseline, 308 (34%) DAC HYP patients (n=919) and 311 (34%) IM IFN beta-1a patients (n=922) had previously been treated with IFN beta. The protocol did not require testing for IFN beta NAbs at Baseline, except where required by local IFN beta prescribing guidelines. Baseline serum samples from patients previously treated with IFN beta were collected prospectively and tested post hoc for IFN beta NAbs. Efficacy analyses were performed post hoc using statistical models prespecified in the overall population: annualized relapse rate (ARR) and T2 lesions (negative binomial regression), 12- and 24-wk confirmed disability progression (CDP; [Cox proportional hazards]; 24-wk CDP: multiple imputation used to impute CDP in patients with no assessment to confirm CDP), gadolinium-enhancing (Gd+) lesions (ordinal logistic regression), and each adjusted for relevant Baseline factors. Results: In the DAC HYP and IM IFN beta-1a groups, 12% (36/308) and 10% (32/311) of patients previously treated with IFN beta were determined to be IFN NAb positive at Baseline, respectively. After patients previously treated with IFN beta who were NAb positive at Baseline were excluded from the analysis population, efficacy analyses on the remaining patient data (DAC HYP, n=272; IM IFN beta-1a, n=279) were performed. For DAC HYP versus IM IFN beta-1a, ARR was reduced by 32% (95% CI: 13%-48%; P=.0027), risk of 12-week CDP by 31% (95% CI: −3%-53%; P=.0667), risk of 24-week CDP by 40% (95% CI: 3%-63%; P=.0371), the odds of having more Gd+ lesions by 72% (95% CI: 57%-82%; P< .0001), and the number of new/newly enlarging T2 hyperintense lesions by 45% (95% CI: 26%-58%; P< .0001). Conclusions: As was observed with the overall population in DECIDE, DAC HYP provided benefits over IM IFN beta-1a in patients previously treated with IFN beta who were not NAb positive at Baseline. Disclosure Antonio Bertolotto: received honoraria for serving on the scientific advisory boards of Admirall, Biogen, Merck, and received speaker honoraria from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva; his institution has received research support from Admirall, Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, and the Italian Multiple Sclerosis Society, Associazione Ricerca Biomedica and San Luigi Onlus; Per Soelberg Sørensen: received personal compensation for serving on scientific advisory boards, steering committees or independent data monitoring boards: Biogen, Forward Pharma, Genzyme, GlaxoSmithKline, medDay Pharmaceuticals, Merck

Serono, Novartis, and Teva Pharmaceutical Industries Ltd.; speaker honoraria: Biogen, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd. Danish Multiple Sclerosis Center, Department of Neurology has received research support from Bayer, Biogen, Merck Serono, Novartis, Roche, RoFAR, Sanofi-Aventis/Genzyme, Teva Pharmaceutical Industries Ltd, the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Programmes; Mads Ravnborg: received travel grants and advisory honoraria from Bayer Health, Biogen, Genzyme, Merck Serono, Novartis, and Sanofi Aventis; Stanley Cohan: paid consultant to serve on advisory boards for Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme; honoraria from speaker bureaus for Acorda, Biogen, Genentech, Novartis, and Sanofi-Genzyme; research support from Biogen, Genentech, Mallinckrodt, Novartis, Opexa, Roche, and Sanofi-Genzyme; funds for transportation, meals, and lodging from Acorda, Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme; Ping Wang and Sami Fam: employees of and hold stock/stock options in Biogen. Supported by: Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Alison Gagnon (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P619 Three-year real-world data in fingolimod treatment: the effects on cognitive function S. Ozakbas1, B. Piri Cinar2, P. Yigit1, T. Kahraman1, G. Kosehasanogullari3, Z. Mehdiyev1, Multiple Sclerosis Research Group 1Dokuz Eylul University, Izmir, 2Samsun Education and Training Hospital, Samsun, 3Usak State Hospital, Usak, Turkey Fingolimod is an oral treatment for patients with relapsing-remitting multiple sclerosis (MS). There has been no data regarding effects of fingolimod on cognition and a lack of evidence about its long term cognitive results in real-world populations. The aim of the study was to investigate the effects of fingolimod treatment on cognitive function in three years period. The patients included in this multi-centre, examiner-blinded, and prospective study were the adults with RRMS who initiated fingolimod treatment. They were followed up at three centres in Turkey. Patients with Expanded Disability Status Scale (EDSS) scores of 5.5 points or less enrolled in the study. To maintain treatment blinding, we used the two-physician principle: a treating neurologist and an evaluating neurologist. Neurological evaluations and cognitive tests were performed at baseline and every six months for 3 years. Age, sex and education-matched healthy control people were also evaluated cognitively at the same scheduled visits. For cognitive evaluation the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, which included the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) used. A total of 105 patients (79 female, mean age: 35.1±8) and 98 healthy control (74 female, mean age: 33.8±8.4) included in the study.


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Poster Session 1, 22(S3) SDMT score improved at month 6 vs baseline (41.3 vs. 42.7, p= 0.034. BVMTR score also improved at month 6 (25.7 vs. 26.9, p=0.02). CVLT2 improved from 49.1 to 51, p=0.03). 37 patients (35.2%) were found to be cognitively impaired at study entry on the basis of SDMT under -1 SD. At follow-up, 24 patients were cognitively impaired (p=0.009). Number of cognitively impaired patients decreased from 39 to 28 on the basis of CVLT, and 35 to 19 on the basis of BVMTR at month 6. Patients were stable at month 36. There were significantly less number of patients who had scores under -1 SD on SDMT after 3 years. All the cognitive function variables were significantly improved in the patients who had started fingolimod treatment due to the side effects of previous treatment (p< 0.05), whereas there was no such a significant difference in the patients who had changed the previous treatment due to its ineffectiveness (p>0.05). The results of this study have indicated that fingolimod treatment was effective on cognitive functions in patients with relapsing-remitting MS. Disclosure Serkan Ozakbas: nothing to disclose, Pinar Yigit: nothing to disclose Turhan Kahraman: nothing to disclose Bilge Piri Cinar: nothing to disclose Gorkem Kosehasanogullari: nothing to disclose Zaur Mehdiyev: nothing to disclose

preferences in different domains (e.g. health, financial, faith in other people, driving), and standardized questions about financial risk-taking developed with principles from behavioral economics . Specifically, participants were asked to choose the minimal amount of Euros they would prefer instead of the 50/50 option of winning 400 or 0 Euros. Risk seeking was defined as the preference for the financial option that was higher than the certainty equivalent (200 Euros). MS progression was defined as worsening of ⩾ 1 point on the EDSS scale. Management errors were defined according to a consensus of MS experts. Multivariable analysis was adjusted by age, sex, specialty status (general neurologist vs. MS specialist). Results: Overall, 96 of 160 invited participants completed the survey (response rate: 60%). Mean age: 40±8.5 years, 53% female. MS specialists represented 67% of participants; mean number of patients seen per week: 25±21 with a mean of 15±11 years in clinical practice. A higher number of MS patients seen per week was associated with higher willingness to take risks in different domains (p< 0.006). MS specialists were less likely to make errors in cases with evidence of disease progression (adjusted OR 0.23; 95%CI 0.07-0.74). Higher risk seeking was associated with management errors in cases with MS progression (adjusted OR 4.9; 95%CI 1.4-17.0). Conclusions: Willingness to take risk influenced therapeutic decision in MS care. Higher expertise in MS care was associated with lower management errors. Disclosure

P620 Does clinicians’ risk attitudes influence therapeutic decisions? Translating principles from behavioral economics to multiple sclerosis care G. Saposnik1, A.P. Sempere2, R. Raptis3, D. Prefasi4, D. Selchen5, C.C. Ruff6, P.N. Tobler6, J. Maurino4 1University of Toronto & University of Zurich, Toronto, ON, Canada, 2Department of Neurology, Hospital General Universitario de Alicante, Alicante, Spain, 3Applied Health Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada, 4Medical Department, Roche Farma, Madrid, Spain, 5Division of Neurology, St. Michael’s Hospital, Toronto, ON, Canada, 6Laboratory for Social and Neural Systems Research (SNS-Lab), Department of Economics, University of Zurich, Zurich, Switzerland Introduction: Clinicians have the challenge to tailor MS treatment based on activity level, individual patient characteristics/ preferences, and their personal expertise/preference, in order to identify the optimal balance between efficacy and safety. In this process, clinicians’ risk preferences may determine in part whether or not risky treatment options are selected. However, limited information is currently available on whether or not risk preference is associated with the MS management. Objectives: To determine the influence of clinicians’ risk preferences in therapeutic decisions of MS progression, using principles and methods from behavioral economics. Design: A web-based study comprising 96 neurologists with expertise in MS care from across Spain was conducted. Participants answered questions regarding the management of 20 case-scenarios commonly encountered in clinical practice, questions from the Socio-Economic Panel Study related to risk

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The study was sponsored by the Sociedad Española de Neurologia (SEN) and funded by an operating grant from Roche Farma Spain. D Prefasi and J Maurino are employees of Roche Farma Spain. G Saposnik, R Raptis, D Selchen, CC Ruff, PN Tobler: nothing to disclose. P621 Australian cladribine experience T. Kalincik1,2, N. Lizak1,3, V. Jokubaitis1,2, E. Butler4, J. Lechner-Scott5, M. Slee6, P. McCombe7, C. Shaw8, O. Skibina9, S. Vucic10, N. Shuey11, M. Barnett12, J. Parratt13, H. Butzkueven1,2,3, S. Hodgkinson14, Australian MSBase Study Group 1University of Melbourne, 2Royal Melbourne Hospital, 3Box Hill Hospital, 4Monash University, Melbourne, VIC, 5University Newcastle, Newcastle, NSW, 6Flinders Medical Centre, Adelaide, SA, 7Royal Brisbane and Women’s Hospital, Brisbane, QLD, 8Geelong Hospital, Geelong, 9The Alfred, Melbourne, VIC, 10Westmead Hospital, Sydney, NSW, 11St Vincent’s Hospital, Melbourne, 12Brain and Mind Centre, Sydney, VIC, 13Royal North Shore Hospital, 14Liverpool Hospital, Sydney, NSW, Australia Background: In 2011, 144 patients with multiple sclerosis (MS) were treated with cladribine through the Australian patient familiarisation program (PFP). Objective: To characterise the Australian MSBase cladribine cohort. Methods: Longitudinal data from 90 patients who received oral cladribine (1mg per kg, initial treatment consisting of 2 courses completed in 2 weeks) were captured in MSBase, including 66


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patients with disability information before and after cladribine. Descriptive evaluation of the demographic and clinical information was carried out. Results: Characteristics of the MSBase cladribine PFP cohort: 72% female, mean age 47 years (SD 12), mean MS duration 13 years (SD 9), 77% relapsing-remitting, 20% secondary progressive and 3% active primary progressive MS, median baseline EDSS 5 (quartiles 3-6), EDSS trajectory +0.3 step per year (quartiles 0.2-0.6) and annualised relapse rate 1 (quartiles 0.5-1.9). In 62 (69%) patients exposure to another disease modifying therapy (DMT) was recorded after cladribine, including 16 patients treated within a year of commencing cladribine. Most commonly, these included fingolimod (42%), dimethyl fumarate (23%) and natalizumab (15%). Seventeen patients experienced relapses prior to starting the subsequent DMT. Mean on-cladribine relapse rate reached 0.6-0.75 per year (quartiles 0-1). Median time to the first post-cladribine relapse was 3.3 years. The proportions of patients reaching 6-month confirmed EDSS progression were 12% and 20% at years 1 and 2, respectively. EDSS trajectory post-cladribine was increasing at +0.1 step per year (quartiles 0-0.2). In contrast to the pre-cladribine EDSS trajectory, the post-cladribine trajetory stabilised for approximately 18 months, after which the EDSS has resumed its ascending trajectory. Nineteen adverse events (of which 6 were reported as unrelated to cladribine) were recorded in 15 patients (17%). These included moderate cephalalgia that was likely retated to cladribine, and severe gastrointestinal symptoms and moderate arterial hypertension in which the relationship to cladribine was not suggested. During the treatment with the subsequent DMTs, 12 adverse events in 10 (11%) patients were recorded. It should be noted that the records of adverse events in MSBase are likely to be incomplete. Conclusion: The Australian cladrbine PFP suggested temporary amelioration of disability accrual in a cohort that was enriched for patients with progressive MS forms. Disclosure The study was supported by Merck. Tomas Kalincik served on scientific advisory boards for Roche, Genzyme, Novartis, Merck and Biogen, has received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi, Genzyme, Teva, BioCSL and Merck and has received research support from Biogen. Nathaniel Lizak did not disclose any conflict of interests. Vilija Jokubaitis received conference travel support from Novartis and Merck Serono. Ernest Butler did not disclose any conflict of interests. Jeannette Lechner-Scott accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen, CSL, Genzyme Sanofi, Merck Serono, Novartis and Teva. Mark Slee has participated in, but not received honoraria for, advisory board activity for Biogen, Merck Serono, Bayer Schering, Sanofi Aventis and Novartis. Pamela McCombe did not disclose any conflict of interests. Cameron Shaw received travel assistance from Biogen and Novartis. Olga Skibina did not disclose any conflict of interests. Steve Vucic did not disclose any conflict of interests.

Neil Shuey received travel compensation from Bayer Schering, Novartis, and Biogen Idec. Michael Barnett served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck-Serono and Novartis. John Parratt did not disclose any conflict of interests. Helmut Butzkueven served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. P622 Boswellic acids immunomodulate T cell populations in relapsing-remitting multiple sclerosis in the SABA phase IIa clinical trial K.H. Stürner1, J.-P. Stellmann1, J.-M. Dörr2, F. Paul2, O. Keminer3, L. Vaas3, O. Pless3, R. Martin4, C. Heesen1 1Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, 2NeuroCure Clinical Research Center (NCRC), Charité Universitätsmedizin Berlin, Berlin, 3Fraunhofer IME ScreeningPort, Hamburg, Germany, 4Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zürich, Zürich, Switzerland Background: Boswellic Acids (BAs), the main biologically active compound of frankincense (Boswellia ssp.), are orally available and have exhibited a safe and favourable side effect profile for the treatment of relapsing-remitting Multiple Sclerosis (RR-MS) in an open-label, two-center, baseline-to-treatment phase IIa trial. Effects on the primary MRI outcome and secondary clinical outcome parameters strongly suggest a positive influence on disease activity in RR-MS patients. BAs are known to exhibit anti-inflammatory activities, however, their immunological effect/s in RR-MS patients are not fully understood. Methods: In parallel to the phase IIa study with a standardized frankincense extract (produced by Alpinia Laudanum, Switzerland, and containing BAs as active ingredient) we performed an immunological substudy in n = 28 BA-treated RR-MS patients, who completed the study. Multicolour flow cytometric analysis was performed longitudinally ex vivo in n = 26 patients at three time points before, during early and during late treatment, respectively. Cytokine levels for interleukin(IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, tumor necrosis factor-alpha, interferon-gamma and transforming growth factor-beta in serum were measured at the same time points in n = 28 patients by highly sensitive single or multiplex analysis (MesoScale; Singulex) after all patients had completed the study. Results: We observed distinct alterations in CD3+ T cell subpopulations in our BA-treated patient cohort: While in the CD4+ T cell subset CTLA-4 expression and the percentage of CD4+ CD25high Foxp3+ T cells increased significantly during treatment (p < 0.01), we found a significant decrease in the percentage of IL17-producing CD8+ T cells coinciding with an increase in IL10-producing CD8+ T cells (p < 0.01). The analysis of other leucocyte and lymphocyte


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Poster Session 1, 22(S3) subpopulations, i.e. monocytes, B cells, natural killer cells and dendritic cells showed no alterations before and after BA-treatment. White blood cell counts and lymphocyte counts in general remained unaltered throughout the whole study. In regard to cytokine levels in serum, we observed significant decreases in IL-17A, GM-CSF and IL-2 during BA-treatment (p < 0.05). Conclusions: Treatment with boswellic acids in a phase IIa clinical trial leads to immunomodulatory effects on T cell subsets consistent with the inhibition of inflammatory disease activity as shown by MRI and clinical outcomes. Disclosure This study has been supported by Neu2 , Förderkennzeichen 0315610-0315620 by the German Federal Ministry of Education and Research. The Institute for neuroimmunology at the UKE has been supported by the Hertie-Stiftung. Klarissa Stürner: received payment for lectures as well as travel/ accommodation/meeting expenses from Merck-Serono, Novartis, Biogenidec and Teva. Jan-Patrick Stellmann: received payment for lectures as well as travel/accommodation/meeting expenses from Bayer Healthcare, Merck-Serono, Novartis, BiogenIdec and Teva as well as Sanofi-Aventis. Jan-Marcus Dörr: nothing to disclose. Friedemann Paul: received payment for lectures as well as travel/ accommodation/meeting expenses from Bayer Healthcare, Merck-Serono, Novartis, BiogenIdec and Teva as well as Sanofi-Aventis. Oliver Keminer: nothing to disclose. Lea Vaas: nothing to disclose. Ole Pless: nothing to disclose. Roland Martin: has served as advisor or member of speaker’s boards for Biogen Idec, Novartis, and Genzyme. The group of R. Martin has received unrestricted grants from Biogen Idec and Novartis. Christoph Heesen: received payment for lectures as well as travel/ accommodation/meeting expenses from Bayer Healthcare, Merck-Serono, Novartis, BiogenIdec and Teva as well as Sanofi-Aventis. P623 Preservation of CD25 protein expression on CD4+ Treg by vitamin D3 supplementation in relapsing remitting multiple sclerosis L. Rolf1,2, A.-H. Muris1,2, J. Damoiseaux3, R. Hupperts1,2, J. Smolders2,4 1School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, 2Academic MS Center Limburg, Zuyderland Medical Center, Sittard, 3Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, 4Neurology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands Background: Vitamin D upregulates IL-2 receptor alpha chain (CD25) expression on CD4+ T cells in vitro. Both activated T cells and regulatory T cells (Treg) express CD25. Furthermore, CD25targeted therapies are efficacious in relapsing remitting MS (RRMS). To differentiate between enhanced CD25 expression on

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activated T cells and Treg, we investigated the effect of high-dose vitamin D3 supplementation on CD25 protein expression on these T cell subsets directly ex-vivo. Methods: We conducted a sub-study of a randomized controlled clinical trial (RCT; NCT01285401) among interferon-beta treated RRMS patients, randomized to 48-weeks vitamin D3 (N=30) or placebo (N=23). With flowcytometry, CD25 mean fluorescence intensity (MFI) was quantified on the total CD4+ T cell-fraction, and in the CD4+ Treg-fraction (CD25+FoxP3+, CD25+CD127-, CD25+CD127-FoxP3+) at baseline and at 48 weeks. Results: In both treatment arms, there was no difference in total CD4+ T cell CD25 MFI during follow-up. In the placebo arm, there was a significant loss of CD25-MFI on all Treg definitions in 48 weeks of treatment (for CD25+CD127-FoxP3+ Treg MFI 5544 to 4871, P=0.002), which was not seen in the vitamin D3 group (MFI 5547 to 5124, P=0.100). Conclusions: A loss of CD25 protein expression on Treg may be an early detrimental event in RRMS, which is prevented by supplementation of vitamin D3. Promotion of CD25-expression appears to be restricted to beneficial Treg, and not potentially encephalitogenic activated T cells. Clinical outcomes of RCT’s on vitamin D3 supplementation should confirm the relevance of this mechanism for MS. Disclosure LR reports no conflicts of interest; AHM reports no conflicts of interest, RH received honoraria for advisory boards and research grants from BIOGEN,SANOFI AVENTIS, NOVARTIS and MERCK, JD reports no conflicts of interest, JS reports no conflicts of interest. P624 Teriflunomide (Aubagio®) reduces glutamate, and possible excitotoxicity, in cortico-basal ganglionic-thalamo-cortical connectivity in mouse model of multiple sclerosis C.M. Modica1,2, F. Schweser2,3, M. Sudyn1,2, N. Bertolino2, P. Polak2, D. Siebert2,4, J. Krawiecki2,5, M. Preda2, M. Sveinsson2, M.G. Dwyer2, R. Zivadinov2,3 1Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 2Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 3MRI Clinical and Translational Research Center, University at Buffalo, 4Exercise Science, School of Public Health and Health Professions, University at Buffalo, 5Department of Geology, University at Buffalo, Buffalo, NY, United States Background: Theiler’s Murine Encephalomyelitis Virus (TMEV) infection produces an immune-mediated demyelinating disease when induced via intracerebral inoculation. Similar to multiple sclerosis (MS), subjects exhibit atrophy and iron accumulation in the brain and motor impairment. Teriflunomide (Aubagio®) is an immunomodulatory treatment for MS which decreases immune cell proliferation and has been shown to decrease demyelination and axonal loss. This study investigated the effect of teriflunomide on neurochemistry in TMEV. Objective: We evaluated the effect of teriflunomide on the cortico-basal ganglionic-thalamo-cortical circuit (CxBGTh) by 9.4T


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MRI and behavior in TMEV model of MS. Glutamate excitotoxicity in this loop may play a role in pathology and phenotype of the disease. Methods: Forty-eight mice were tested at pre-disease baseline, injected with TMEV, then tested again at 8 and 26 weeks. Therapeutic intervention began 4 weeks after induction, with daily dosing of either 20mg/kg teriflunomide or vehicle placebo (24 mice each). MRI and spectroscopy was used to acquire volume and metabolite spectra, and cognitive and motor ability were tested. Results: Glutamate was decreased in teriflunomide subjects compared to placebo subjects at 8 weeks in the basal ganglia and thalamus, and at 26 weeks in the thalamus (p< 0.05, independent samples t-test). GABA change over time differed between the two conditions in the basal ganglia (p< 0.05, two-way repeated measures ANOVA). GABA decreased steadily with each time point in placebo subjects (p< 0.05 paired t-tests between 0-8 and 8-26 weeks), but the decrease in GABA was delayed until 8-26 weeks in teriflunomide subjects (p< 0.001 paired t-test between 8-26 weeks only). There was a significant relationship between lower motor ability at 26 weeks and decreased volume over 26 weeks in the basal ganglia and thalamus (p< 0.05, Pearson), and worse clinical signs at 26 weeks and decreased volume over 26 weeks in the thalamus (p< 0.05, Pearson) in placebo subjects, which was not evident in teriflunomide subjects. Conclusions: These findings suggest that teriflunomide reduces glutamate in the CxBGTh, delaying TMEV-associated decrease in GABA and preventing potential TMEV-associated excitotoxicity. Teriflunomide may also play a role in reducing the relationship of motor decline and clinical progression with tissue pathology. Disclosure Study supported by: Genzyme Claire M Modica, Ferdinand Schweser, Nicola Bertolino, Michelle L Sudyn, Danielle M Siebert, Jacqueline C Krawiecki, Marilena Preda, Michele Sveinsson have nothing to disclose. Michael G. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health.

P625 An open-label add-on trial of cetirizine for neuromyelitis optica: preliminary results I. Katz Sand1, R. Telford2, M. Fabian1, L. Cook2, M. Masilamani3, M. Chehade4, T. Kraus5, S. Ebel1, C. Farrell1, M.E. Riffle4, F. Lublin1 1Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 2University of Utah, Salt Lake City, UT, 3Pediatrics, allergy and immunology, 4Pediatrics, allergy and immunology; Gastroenterology, 5Microbiology; Obstetrics, Gynecology, and Reproductive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Background: NMO is a severe inflammatory disease affecting the CNS with the potential to cause serious neurological disability and in some cases, death. Granulocyte infiltration with subsequent neutrophil and eosinophil degranulation are critical to the ultimate destruction of astrocytes, demyelination, and neuronal/axonal loss. This trial was conducted to examine the efficacy and tolerability of cetirizine, an eosinophil-stabilizer approved for allergy treatment, as an add-on to currently-available therapies for NMO. Methods: Eligible patients met Wingerchuk 2006 NMO criteria or had optic neuritis or longitudinally-extensive transverse myelitis with positive NMO IgG, and were stable on current NMO therapy for 3 months. Subjects were followed clinically and with serum/CSF analysis for cytokines/chemokines associated with eosinophil priming, chemotaxis, degranulation, and expression of markers of activation and degranulation by flow cytometry for 1 year. Planned endpoints included relapse rates and relapse severity before and after cetirizine, tolerability with particular attention to drowsiness, and changes in immunological parameters. Results: 16 subjects were enrolled between April 2014 and February 2015, including 4 in the CSF sub-study. 15 were female, 7 were black, with median age 36.5. 13 were NMO IgG positive. 8 were on rituximab, 7 on mycophenolate, and 1 on azathioprine. 7 had previously experienced a total of 9 relapses while on the current treatment, 3 of which were in the year prior to study enrollment. There was 1 mild confirmed relapse during the study, characterized by eye pain with a small scotoma and red desaturation without decreased acuity. The pre and post study ARR differences were statistically significantly different from zero (p=0.047). Median EDSS was 3.0 at baseline and at study end. Mean Epworth Sleepiness Scale score was 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at study end (p=0.74). There were no significant drug-related adverse events. Analysis of immunological profiling is in process. Conclusions: Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. In our pilot study the drug was very well-tolerated with no significant increase in sleepiness. The very low pre-study relapse rates in our patient population preclude definitive conclusions related to cetirizine’s effect on relapse rates and severity, though results are promising and warrant further study. Disclosure This study was funded by a grant from the Guthy Jackson Charitable Foundation to Dr. Katz Sand, as well as by a philanthropic gift from the Muzio Family to Mount Sinai. IK: has received research support from the Guthy Jackson Charitable Foundation, the National MS Society, and the US Department of Defense FL: Sources of Funding for Research: Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi; Celgene; Transparency Life Sciences; NIH; NMSS Consulting Agreements/Advisory Boards/DSMB: Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Teva Neuroscience; Actelion; Sanofi/Genzyme; Acorda; Questcor/Malinckrodt; Roche/Genentech; MedImmune; Osmotica; Xenoport, Receptos; Forward Pharma; Akros; TG Therapeutics; Abbvie; Toyama; Amgen; Medday; Atara Biotherapeutics Speaker: Genentech (non-promotional); Genzyme (nonpromotional)


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Poster Session 1, 22(S3) Co-Chief Editor: Multiple Sclerosis and Related Disorders Current Financial Interests/Stock Ownership: Cognition Pharmaceuticals, Inc. CF: nothing to disclose SE: nothing to disclose MM: nothing to disclose TK: nothing to disclose RT: nothing to disclose LC: nothing to disclose MF: nothing to disclose MR: nothing to disclose MC: nothing to disclose

P626 Alemtuzumab long-lasting immunological effects: a 48 months follow-up observation L. Durelli1, S.F. De Mercanti1, A. Cucci1, D. Taverna1, S. Rolla1,2, V. Bardina2, E. Cocco3, A. Vladic4,5, S. SoldoButkovic5,6, M. Habek7, I. Adamec7, D. Horakova8, P. Annovazzi9, F. Novelli2, M. Clerico1 1Department of Clinical and Biological Sciences, University of Torino, San Luigi Gonzaga University Hospital, Orbassano, 2Department of Clinical and Biological Sciences, University of Torino, Center for Experimental Research and Medical Studies, Torino, 3Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy, 4Department of Neurology, Clinical Hospital Sveti Duh Zagreb, Zagreb, 5Josip Juraj Strossmayer University of Osijek, Osijek, 6Clinical Hospital Sveti Duh Zagreb, 7Department of Neurology, University Hospital Center, Referral Center for Demyelinating Diseases of the Central Nervous System, Zagreb, Croatia, 8Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospita, Prague, Czech Republic, 9AO S. Antonio Abate, Multiple Sclerosis Study Center, Gallarate, Italy Objective: To perform phenotypic and functional analysis of CD4+ T cell subsets and immunologically relevant molecules mRNA serum levels after alemtuzumab treatment in relapsing remitting multiple sclerosis (RRMS) patients for a 48 months period. Background: Alemtuzumab, a highly effective monoclonal antibody in RRMS, determines a long-standing lymphopenia, mainly of the T CD4+ cells subset. Design and methods: We enrolled 29 alemtuzumab-treated RRMS patients from 6 European sites involved in the CARE-MS I and CARE-MS II trials in a multicenter follow-up. Patients received two course of alemtuzumab at month 0 and 12. Clinical and immunological evaluation were performed at months 0, 6, 12, 18, 24, 36 and 48. The percentages of Treg, Th1 and Th17 cells in the peripheral blood mononuclear cells (PBMC) were evaluated by FACS analysis. mRNA levels of cytokines, chemokines, chemokine receptors and transcriptional factors with pro-inflammatory (IL-1β, IL-2, IL-6, IL-12, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-26, IFN-γ, Tbet, RORC, TNF-α, CCR3, CCR4, CCR5, CCR6, CXCR3, CXCL10, CCL20, VLA4) or anti-inflammatory function (IL-10, IL-27, TGF-β and FoxP3) were quantified by TaqMan® low density array(TLDA) real-time polymerase chain reaction in whole blood. Treg suppressor activity on Myelin basic

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protein(MBP)-specific Th17 and Th1 cells was assessed by IL-17 and IFN-γ ELISPOT on total PBMC and PBMC depleted of CD25highT cells. Results: In the PBMC, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Th1 and Th17 cells decreased after alemtuzumab and remained low till month 48. Treg cells percentage significantly increased at Month 24 and then slightly decreased, whereas Treg cells suppressive function significantly increased at Month 24 and persisted till month 48. No patient received further alemtuzumab courses after the first two years. Conclusions: Alemtuzumab long-lasting therapeutic effect in RRMS involves a shift in the cytokine balance towards inhibition of inflammation and it is associated with a reconstitution of the CD4 T-cell subsets, involving the expansion of Treg cells with increased suppressive function and a reduced response against myelin antigen. Disclosure S. De Mercanti, A. Cucci, D.Taverna, S. Rolla, V. Bardina, A. Vladic, S. Soldo-Butkovic, M. Habek, and I. Adamec report no disclosures. L. Durelli received personal compensation from Biogen Idec and Merck Serono for public speaking, editorial work and advisory boards. M.Clerico received personal compensation from Biogen Idec and Merck Serono for public speaking, editorial work and advisory boards. E.E. Cocco serves on scientific advisory boards for Bayer, Biogen, Merck,Novartis, Sanofi-Genzyme, and Teva; received travel support from Bio-gen, Merck, Bayer, Novartis, Genzyme, and Teva; received speaker feesfrom Biogen, Merck, Bayer, Novartis, Genzyme, Teva, and Almirall; and received research support from Fondazione Banco di Sardegnafunded by Italian Multiple Sclerosis Foundation. D. Horakova received travel funding, speaker honoraria, and/or consultant fees fromBiogen, Novartis, Merck, Bayer Schering, and Teva; is an associate editorforBMC Neurology; and received research support from Biogen and Czech Ministries of Education and Health. P. Annovazzi served on the scientific advisory board for Merck Serono, Novartis, Biogen, and Gen-zyme, and received speaker honoraria from Biogen, Genzyme, Novartis,and Teva. F. Novelli received research support from Fondazione ItalianaSclerosi Multipla. P627 Immune regulatory effects of high dose vitamin D3 supplementation in a randomized controlled trial in relapsing remitting multiple sclerosis patients receiving IFNβ: the SOLARIUM study A.-H. Muris1,2, J. Smolders2, L. Rolf1,2, M. Thewissen2, R. Hupperts1,2, J. Damoiseaux3, on behalf of the SOLARIUM Study Group 1School for Mental Health and Mental Neuroscience, Maastricht University Medical Center, Maastricht, 2Academic MS Center Limburg, Zuyderland Medical Center, Sittard, 3Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands


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Multiple sclerosis (MS) is characterized by a disturbed immune homeostasis and low serum vitamin D levels are associated with an increased disease activity. While vitamin D has been hypothesized to promote the maintenance of immune homeostasis, vitamin D3 supplementation could be of benefit to patients with MS. We investigated the immune regulatory effects of high dose vitamin D3 supplementation in the SOLARIUM study. Thirty Dutch relapsing remitting (RR)MS patients treated with IFNβ-1a received high dose vitamin D3 supplementation and 23 patients received placebo during a period of 48 weeks. Lymphocytes were characterized by flow cytometry and in vitro cytokine secretion was assessed in the presence or absence of 1,25(OH)2D3 using Luminex technology. The proportion of cells in the regulatory immune cell compartment (nTreg, iTreg and Breg) was not altered upon vitamin D3 supplementation. Proportions of T helper subsets were not affected by vitamin D3, except for the proportion of IL4+ Th cells, which decreased in the placebo but not in the vitamin D3 group. T cell cytokine secretion increased, most pronounced for IL5 and latency activated protein of TGFβ, in the placebo group but not in the vitamin D3 group. Lymphocytes remained equally reactive to in vitro 1,25(OH)2D3. In conclusion, high dose vitamin D3 supplementation did not result in a relative increase in lymphocytes with a regulatory phenotype. However, this study supports the hypothesis that vitamin D contributes to the maintenance of immune homeostasis by preventing further disturbance of the T cell compartment early in the disease course of MS. SOLARIUM study group: Prof. Dr. R. Hupperts, Zuyderland Medical Center, Sittard; Drs. J. Samijn, Maasstad Hospital, Rotterdam; Dr. F. Verheul, Groene Hart Hospital, Gouda; Dr. S. Frequin, St. Antonius Hospital, Nieuwegein, the Netherlands.

points following drug cessation. More detailed T-cell subset analysis was performed using flow cytometry of cryopreserved peripheral blood mononuclear cells; subsets included naïve (TN), central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA), regulatory (Treg) and recent thymic emigrant (RTE) cells. Results: At 2-3 months after fingolimod cessation, the CD4:CD8 ratio, which was reduced on treatment, was greater than 75% of baseline in four patients with pre-treatment comparators. The fingolimod-induced increase in TEM/TEMRA and reduction in TN frequencies had begun to reverse by this time point. However, a lower proportion of circulating cells were TN and a greater proportion were TEM compared to pre-treatment. At 8-9 months, TLC had returned to normal (1.22 - 2.13 × 109 cells/L) and were at least 90% of baseline. TLC reconstitution was predominantly due to an increase in CD4+ T cells (mean increase 621 ± 87 cells/ µL, p=0.0064), the subset most depleted by fingolimod. Despite normalized CD4:CD8 ratios at month 8-9, the altered TN/TEM proportions had still failed to fully revert to baseline. Low RTE counts also tended to persist at month 8-9 (130 ± 9 cells/µL, n=3) compared with untreated patients (309 ± 41 cells/µL, n=16; p=0.0815). Conclusions: Relative frequencies of circulating naïve and memory T cell subsets are altered during fingolimod treatment and may not return to pre-treatment levels for many months after cessation, even when clinical laboratory tests (TLC and CD4:CD8 ratios) return to normal. Whether this relates to prolonged sequestration in lymph nodes or altered turnover of the peripheral naïve T cells is unclear. Inhibition of thymic release of new T cells may underlie persistent low RTE counts. Prolonged alterations in the peripheral immune repertoire after fingolimod cessation may have implications for the timing and safety of commencing alternative MS therapies and warrant further study.

Disclosure AM, JS, LR, MT and JD report no disclosures. RH received honoraria for lectures and advisory boards and Research Grants from Merck, Biogen, Sanofi-Genzyme, Novartis and TEVA. This study was financially supported by Merck KGaA (Darmstadt, Germany) and the Nationaal MS Fonds (the Netherlands) P628 Long term changes in T cell subsets following cessation of fingolimod M. Ghadiri1,2, L. Fitz-Gerald3, A. Rezk1, R. Li1, M. Nyirenda1, D. Haegert3, P.S. Giacomini1, A. Bar-Or1, J. Antel1 1Montreal Neurological Institute, Montreal, QC, Canada, 2Brain and Mind Research Institute, Sydney, NSW, Australia, 3Department of Pathology, McGill University, Montreal, QC, Canada Background: Total lymphocyte counts (TLC) usually reach 80% of pre-treatment values three months after fingolimod cessation. Here we examine the profile of T cell subsets in patients whose TLC return to baseline months after fingolimod cessation. Methods: Five patients were followed for 2-3 months, and three of these patients were followed further up to 8-9 months post fingolimod cessation. TLC, CD4+ and CD8+ T cell counts were examined pre-treatment, on-treatment and at early and late time

Disclosure This study was supported in part by a grant from Novartis Pharmaceuticals Canada. Dr Mahtab Ghadiri is a recipient of the BMRI/McGill University Multiple Sclerosis scholarship, funded by Novartis. Leslie Fitz-Gerald: nothing to disclose. Ayman Rezk: nothing to disclose. Dr Rui Li: nothing to disclose. Mukanthu Nyrirenda was supported by postdoctoral fellowships from the Multiple Sclerosis Society of Canada (EGID: 1655 and EGID: 2470). Dr David Haegert: nothing to disclose. Dr Paul Giacomini has received personal compensation for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience, has received research support from Biogen Idec and Teva Neuroscience, has been a consultant for NeuroRx Research, an imaging Contract Research Organization, and has acted as a principal investigator or subinvestigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, Novartis, Ono, Roche-Genentech, Sanofi-Aventis and Teva Neuroscience. Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal.


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Poster Session 1, 22(S3) Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, GuthyJackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, SanofiGenzyme, Teva Neuroscience, Wyeth. P629 Efficacy of daclizumab HYP vs intramuscular interferon beta-1a on 24-week sustained disability progression using a modified multiple sclerosis functional composite S. Cohan1, L. Kappos2, G. Giovannoni3, H. Wiendl4, K. Selmaj5, E. Havrdova6, J. Rose7, S.J. Greenberg8, G. Phillips9, P. Wang9, G. Lima9, G. Sabatella9 1Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Providence Health & Services, Portland, OR, United States, 2Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 3Queen Mary University London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 4University of Münster, Münster, Germany, 5Medical University of Lodz, Lodz, Poland, 6First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 7Department of Neurology University of Utah and Neurovirology Research Laboratory VASLCHCS, Imaging and Neuroscience Center, Salt Lake City, UT, 8AbbVie Inc., North Chicago, IL, 9Biogen, Cambridge, MA, United States Background: In DECIDE, subcutaneous daclizumab high-yield process (DAC HYP) showed greater improvement vs intramuscular interferon (IFN) beta-1a on the Multiple Sclerosis Functional Composite (MSFC) z score (P=.0007) and the z scores of the 3 components (Timed 25-Foot Walk [T25FW], 9-Hole Peg Test [9HPT], Paced Auditory Serial Addition Test [PASAT], P< .05) at Week 96. As clinically interpreting z scores can be challenging, an alternative approach is to examine worsening of any MSFC component. Objective: Examine disability progression in DECIDE using a modified MSFC (MSFCS) comprising the T25FW, 9HPT, and Symbol Digit Modalities Test (SDMT), which may be more convenient and less impacted by practice effects than PASAT. Methods: Sustained MSFCS worsening was defined as 20% worsening in T25FW, 20% worsening in 9HPT, or ⩾4 point decrease in SDMT, at 2 consecutive visits separated by 24 weeks. Subgroup analyses based on Baseline characteristics were conducted; disability progression was analysed by Cox Proportional Hazards models adjusted for history of prior IFN beta use and baseline age (⩽35 vs >35), excluding covariates defining the subgroup. Results: A total of 28% (259/922) of IFN beta-1a and 24% (224/919) of DAC HYP patients met the criteria for 24-week sustained MSFCS progression. DAC HYP treatment resulted in a significant 20% reduction in risk of 24-week sustained MSFCS progression vs IFN beta-1a [hazard ratio (HR) (95%CI), 0.80 (0.67-0.95); P=.0132]. Across all key patient subgroups, risk of 24-week MSFCS progression was lower for DAC HYP vs IFN beta-1a (i.e. HR< 1) and nominal statistical significance (i.e. P< .05) was reached for the following subgroups [HR (95%CI)]: Age ⩽35 y, 0.76 (0.58-0.99), EDSS >3.5, 0.63 (0.47-0.86); Presence

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of gadolinium-enhancing (Gd+) lesions, 0.74 (0.56-0.97); T2 lesion volume ⩾median, 0.77 (0.60-0.98); No prior IFN beta use, 0.77 (0.62-0.96); Disease duration ⩾10 y, 0.56 (0.35-0.90); ⩾2 relapses in previous 12 months, 0.76 (0.58-0.98); No prior MS treatment (excluding steroids), 0.75 (0.60-0.95); and Low disease activity (defined as ⩽1 relapse in the year prior to enrolment or no Gd+ lesions at baseline MRI), 0.81 (0.66-0.99). Conclusion: DAC HYP resulted in significantly reduced risk of 24-week sustained MSFCS progression vs IFN beta-1a. Point estimates of the risk of 24-week sustained progression in MSFCS showed trends favouring DAC HYP over IFN beta-1a across several clinically important patient subgroups. Disclosure Stanley Cohan: paid consultant to serve on advisory boards for Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme; honoraria from speaker bureaus for Acorda, Biogen, Genentech, Novartis, and Sanofi-Genzyme; research support from Biogen, Genentech, Mallinckrodt, Novartis, Opexa, Roche, and Sanofi-Genzyme; funds for transportation, meals, and lodging from Acorda, Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme; Ludwig Kappos: institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees for Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB and Xenoport. Dr. Kappos has received speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva, royalties from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society and the Swiss National Research Foundation; Gavin Giovannoni: fees for participation in advisory boards for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, SanofiAventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis; Heinz Wiendl: honoraria and consultation fees from: Bayer HealthCare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries and has grants and contracts with Bayer HealthCare, Biogen, the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the Hertie Foundation, Merck Serono, Novartis, the NRW Ministry of Education and Research, the Interdisciplinary Center for Clinical Studies in Münster, Germany, the RE Children’s Foundation, sanofi-aventis/Genzyme, and Teva Pharmaceutical Industries; Krzysztof Selmaj: compensation for consulting services: Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking: Biogen; Eva Havrdova: honoraria/research support from Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva; and advisory boards for Actelion, Biogen, Genzyme, Novartis, Receptos and


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Teva; supported by the Czech Ministry of Education research project PRVOUK-P26/LF1/4; John Rose: research support from Arrien, Biogen, the Guthy Jackson Charitable Foundation, the National Multiple Sclerosis Society, Teva Neuroscience, and Veterans Affairs, member of the Medical Advisory Board for the DECIDE trial, which was funded by Biogen and AbbVie Biotherapeutics Inc.; Steven J Greenberg: employee of and holds stock/stock options in AbbVie Inc.; Glenn Phillips, Ping Wang, Gabriel Lima, and Guido Sabatella: employees of and hold stock/stock options in Biogen. Supported by: Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Rebecca Jarvis (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.

P630 Effect of dimethylfumarate treatment on lymphocytes and antigen presenting cells in multiple sclerosis patients M.A. Mazzola, R. Raheja, K. Regev, A. Paul, I. Pierre, P. Kivisakk, H.L. Weiner, R. Gandhi Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Background: Dimethylfumarate (DMF, Tecfidera) is one of the oral disease modifying treatments that have been approved for multiple sclerosis (MS). MS patients treated with DMF show lymphopenia with an altered CD4/CD8 ratio. The effect of DMF on other immune cells is still not fully understood. Objective: To characterize the phenotype of immune cells from MS patients at baseline, 6 months and 12 months after treatment with DMF. Methods: Peripheral blood mononuclear cells were collected from MS patients before treatment and 6 and 12 months post treatment with DMF. Immune staining and flow cytometry analysis was performed comparing longitudinal samples from the same patient. Results: Fifty percent of the patients presented a certain degree of lymphopenia after 12 months of treatment. Both CD4 and CD8 T cells were significantly reduced after 6 (22.5% reduction for CD4; 38.5% reduction for CD8) and 12 months (28.4% reduction for CD4; 51.8% reduction for CD8) of treatment compared to baseline. We observed a more pronounced reduction in CD8 T cells compare to CD4 T cells and an increased CD4/CD8 ratio (46.8% at 12 months). The analysis of different T cells subset showed a preferential reduction in memory T cells compared to naïve cells sub-population in both CD4 and CD8 T cell. We also observed a reduction in the expression of CD40 in myeloid dendritic cells and MHC class II in monocytes and plasmocytoid dendritic cells. Conclusion: Lymphocytes and specific T cell subsets are preferentially reduced by DMF treatment. The expression of CD40 and MHC class II is also reduced in antigen presenting cells. These findings suggest potential mechanisms of action wherein DMF affects lymphocyte and myeloid cells. In addition, this study highlights the need for a more stringent follow-up on patients under

DMF treatment to avoid adverse events such as progressive multifocal leukoencephalopathy (PML) due to this reduction in critical lymphocyte populations. Disclosure Maria Antonietta Mazzola: no disclocure. Radhika Raheja: no disclocure. Keren Regev: no disclocure. Anu Paul: no disclocure. Isabelle Pierre: no disclocure. Pia Kivisakk: grant support from Serono, Sanofi and Verily Howard Weiner: grant support from Serono, Biogen, Therapix, Novartis, Genzyme, Teva Roopali Gandhi: grant support from Serono, novartis and biogen. This project was supported by Biogen. P631 Seven-year follow-up of the efficacy of delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting multiple sclerosis: integrated analysis of DEFINE, CONFIRM, and ENDORSE R. Gold1, G. Giovannoni2, J.T. Phillips3, R.J. Fox4, J. Xiao5, C. Taylor5, J.L. Marantz5 1Dept. of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany, 2Queen Mary University of London, Blizard Institute, London, United Kingdom, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 4Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 5Biogen, Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favourable benefit-risk in patients (pts) with relapsing-remitting multiple sclerosis (RRMS) in clinical trials. ENDORSE (NCT00835770) is a 12-yr extension of the Phase 3 DEFINE/CONFIRM studies. Objectives: Report 7-yr clinical efficacy outcomes in RRMS pts treated with DMF. Methods: Pts randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or three times daily (TID) continued on the same dosage in ENDORSE. Pts randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized 1:1 to DMF BID or TID. Pts switched to DMF BID after regulatory approval. Here we report results for DMF BID. “Newly diagnosed” was defined as MS diagnosis ⩽1 yr prior to parent study entry and either treatment-naïve or previously treated with corticosteroids alone. As of 15 April 2015, the minimum follow-up was approximately 6 yrs: pts initially randomized to DMF BID in DEFINE/ CONFIRM who continued on DMF BID in ENDORSE (DMF/ DMF) received approximately ⩾6 yrs continuous DMF treatment; pts initially randomized to PBO who switched to DMF BID in ENDORSE (PBO/DMF) received 2 yrs PBO followed by approximately ⩾4 yrs DMF. Results: In the newly diagnosed population (n=144 DMF/DMF; n=85 PBO/DMF), at 6 yrs (ENDORSE Yr 4), annualized relapse rate (ARR) (95% CI) was 0.14 (0.10, 0.19) in DMF/DMF and 0.17 (0.11, 0.25) in PBO/DMF; rate ratio (95% CI) for DMF/DMF vs PBO/DMF was 0.81 (0.51, 1.31) (P=0.3988). In PBO/DMF, ARR (95% CI) was 0.26 (0.18, 0.37) from Yrs 0-2 (DEFINE/CONFIRM)


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Poster Session 1, 22(S3) and 0.10 (0.06, 0.16) from Yrs 3-6 (ENDORSE); rate ratio (95% CI) for Yrs 3-6 vs 0-2 was 0.39 (0.24, 0.63; P< 0.0001). KaplanMeier estimated proportion (95% CI) of pts with 24-wk confirmed disability progression (CDP) was 15.7% (10.3%, 23.7%) in DMF/ DMF and 24.3% (15.9%, 36.2%) in PBO/DMF; hazard ratio (95% CI) for DMF/DMF vs PBO/DMF was 0.51 (0.27, 0.97; P=0.0397). Over 6 yrs, 56.3% DMF/DMF and 50.6% PBO/DMF pts remained free from relapses and CDP. Updated results from the 7-yr interim analysis will be presented. Conclusions: The ARR and proportion of pts with 24-wk CDP remained low in pts treated with DMF over 6 yrs. In PBO/ DMF, ARR was significantly reduced after switching to DMF. Pts receiving continuous DMF treatment had substantially lower risk for 24-wk CDP over 6 yrs vs those who received delayed treatment. Over 50% of pts in the DMF/DMF and PBO/DMF groups remained free from relapses and 24-wk CDP over 6 yrs. Disclosure Supported by: Biogen. Ralf Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience. Gavin Giovannoni: honoraria from AbbVie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; compensation from Elsevier as co-chief editor of MS and Related Disorders; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis. J Theodore Phillips: served as a consultant for Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. Robert J Fox: served as a consultant for Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen and Novartis; research grant funding from Novartis. Annie Zhang: employee of and holds stock/stock options in Biogen. Catherine Taylor: employee of and holds stock/stock options in Biogen. Jing L Marantz: employee of and holds stock/stock options in Biogen. P632 Characterisation of the lymphadenopathy events observed in the daclizumab HYP clinical trials G. Lima1, P. McCroskery1, R. Dewar2, J.J. Castillo3, J. Holman4, K. Umans1, S. Fam1 1Biogen, Cambridge, MA, 2Department of Pathology, University of Michigan Health System, Ann Arbor, MI, 3Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 4AbbVie Inc., North Chicago, IL, United States Background: Daclizumab high-yield process (DAC HYP) is a humanised monoclonal antibody against the interleukin 2 (IL-2)

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receptor alpha subunit (CD25) that selectively modulates IL-2 receptor signalling and is in late-stage clinical development for the treatment of relapsing-remitting multiple sclerosis. Lymphadenopathy events, including lymphadenitis, were observed at an increased incidence with DAC HYP relative to intramuscular interferon (IFN) beta-1a in the DECIDE study. Objectives: To report the incidence and describe characteristics of the lymphadenopathy events observed in patients treated with DAC HYP across the clinical development program. Methods: Lymphadenopathy events were identified using a customised Medical Dictionary for Regulatory Activities (MedDRA) [V16.1] query to search the total DAC HYP experience (cut-off November 14, 2014; DAC HYP exposure: ~5,200 patient-years) clinical databases. Results: In the 2-3 year active-controlled DECIDE study, the incidence of lymphadenopathy events was higher for patients treated with DAC HYP (6% [59/919]) compared with those treated with the active comparator, IM IFN beta-1a (1% [10/922]). In a pooled safety analysis across all DAC HYP studies including 2236 DAC HYP-treated patients, a total of 159 lymphadenopathy events (an incidence of approximately 6% [124/2236]) was reported. Onset of events occurred throughout the treatment period (mean: 655.9 days; median [range]: 645.0 [1-2346] days). 52% (n=64) of patients with lymphadenopathy events experienced mild events only, 41% (n=51) experienced moderate events, and 7% (n=9) experienced an event classified as severe. Of all patients with lymphadenopathy events, 16% (20/124) experienced a serious event. The majority of serious events were otherwise asymptomatic. The majority (70%) of all cases resolved during study follow up, with a median event duration of 33.5 days (mean [range]: 89.0 [1-979] days). Study treatment was not interrupted nor discontinued in the majority of lymphadenopathy events (77% [123/159]). Conclusions: Lymphadenopathy events are an identified risk associated with DAC HYP therapy, occurring at an incidence of 6%. The majority of events were mild and asymptomatic and resolved without the need to discontinue treatment. Patients receiving DAC HYP who develop lymphadenopathy events should be referred for further clinical and diagnostic evaluation by a specialist at the discretion of their treating physician. Disclosure Gabriel Lima, Peter McCroskery, Kimberly Umans, and Sami Fam are employees of and hold stock/stock options in Biogen. Kimberly Umans’ family member holds stock in Sinovac Biotech. Rajan Dewar is a paid independent consultant to Biogen. Jorge J. Castillo has received consulting honoraria from Biogen. Joan Holman is an employee of and holds stock/stock options in AbbVie Inc. Supported by: Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Stephanie Douglas (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.


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P633 A randomized, open-label study to assess the immune response to vaccination in patients with relapsing forms of multiple sclerosis treated with delayed-release dimethyl fumarate compared to non-pegylated interferon C. von Hehn1, J. Howard2, S. Liu1, V. Meka1, J. Pultz1, S. Sheikh1 1Biogen, Cambridge, MA, 2NYU Langone Multiple Sclerosis Comprehensive Care Center, New York, NY, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is a twice daily, oral medication approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). DMF is thought to exert its effect through the activation of Nrf2. Given the immuno-modulatory properties of DMF, the effects on immune function, specifically the response to vaccinations in MS patients treated with DMF, was investigated. Objectives: To evaluate the immune response to tetanus diphtheria toxoids vaccine (Td) and 2 other antigens in DMF-treated compared to non-pegylated interferon (IFN)-treated patients with relapsing forms of MS. Methods: In this open-label, multicenter study (NCT02097849), patients received 3 vaccinations: (1) Td (Tenivac®) to test the integrity of the T cell-dependent anamnestic humoral response (2) Pneumovax® 23 (PPSV23) to assess the mostly T cell-independent humoral response, and (3) MCV4 (Menveo®) to test the integrity of the T cell-dependent neo-antigen response. Patients had to be treated with DMF (240 mg BID) for ⩾6 months or non-pegylated IFN (with a stable, approved dose) for ⩾3 months. In addition, patients had to have received a tetanus vaccination 2-15 years prior to Screening with an anti-tetanus immunoglobulin G (IgG) titer at Screening ⩽1/2 the upper limit of detection. Blood samples were taken at Screening, Day 1, and Week 4. The primary endpoint was the proportion of subjects with a ⩾2-fold rise in anti-tetanus serum IgG levels from pre-vaccination to 4 weeks after Td vaccination. Results: A total of 69 patients (38 in DMF group; 33 in IFN group) were enrolled in the study. Mean age was 45 years (range: 27-55); 85.5% were female. As measured by the primary endpoint, the responder rates to Td vaccination are comparable between the DMF and IFN-treated groups. Full results of the response to the 3 different vaccinations will be presented. Conclusions: Overall, the vaccine response to a recall antigen like Td in DMF-treated patients is comparable to that in IFNtreated patients. This study provides insights into the ability of DMF-treated patients to mount an immune response to a recall, neo-, and T-cell independent antigens. Disclosure Supported by: Biogen. Christian von Hehn: employee of and holds stock/stock options in Biogen Jonathan Howard: book contract with Demos-Springer publishing, stockholder in ReelDx.com Shifang Liu: employee of and holds stock/stock options in Biogen Ven Meka: employee of and holds stock/stock options in Biogen Joe Pultz: employee of Biogen

Sarah Sheikh: employee of and holds stock/stock options in Biogen P634 Effectiveness of delayed-release dimethyl fumarate on clinical disease activity and patient-reported outcomes in patients with relapsing-remitting multiple sclerosis in the real-world setting: a multicentre, open-label study (PROTEC) T. Berger1, B. Brochet2, P. Confalonieri3, P.S. Giacomini4, X. Montalbán5, A. Vasco Salgado6, M. Okwuokenye7, J.L. Marantz7, W. Mair7 1Universitätsklinik für Neurologie, Innsbruck, Austria, 2Groupe Hospitalier Pellegrin - Hôpital Pellegrin, Bordeaux, France, 3Fondazione IRCCS Istituto Neurologico Carlo Besta di Milano, Milano, Italy, 4MUHC - Montreal Neurological Institute & Hospital, Montreal, QC, Canada, 5Hospital Vall d’HebronBarcelona, Barcelona, Spain, 6Hospital Professor Doutor Fernando Fonseca, E.P.E., Amadora, Portugal, 7Biogen, Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong and sustained efficacy on clinical and neuroradiological measures, a beneficial effect on patient-reported outcomes (PROs), and a favourable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS) in DEFINE, CONFIRM, and ENDORSE. Objectives: To present results from PROTEC (NCT01930708), an open-label, single-arm study conducted to estimate annualised relapse rate (ARR) in RRMS patients treated with DMF over a 12-month period (primary objective) and assess the impact of DMF over a 12-month period on PROs (secondary objective). Methods: Eligible patients were ⩾18 years of age with a diagnosis of RRMS and no prior treatment with DMF, alemtuzumab, or MS therapies that are primarily prescribed second-line (eg, natalizumab, fingolimod). All patients received DMF 240 mg twice daily (approved dosing regimen). PROs were assessed at clinic visits scheduled at Baseline and 3, 6, and 12 months after initiation of DMF treatment. Relapses and adverse events were evaluated at scheduled and unscheduled visits . PROs included the Multiple Sclerosis Impact Scale (MSIS-29), Modified Fatigue Impact Scale-5 Item (MFIS-5), Treatment Satisfaction Questionnaire for Medication (TSQM), EuroQol-5D 5 level version (EQ-5D-5L), Patient-reported Indices for Multiple SclerosisActivity Limitations (PRIMUS-Activity Limitations), Work Productivity and Activity Impairment-Multiple Sclerosis Version (WPAI-MS), and Beck Depression Inventory-Fast Screen (BDIFast Screen). Six-month interim results are reported; final (12month) results will be presented. Results: A total of 1113 patients were enrolled with a mean age of 39 years; the majority were female (72%) and white (78%). Most (78%) had received prior MS treatment. Unadjusted ARR estimated for the 12 months prior to DMF initiation was 0.64 (95% confidence interval [CI]: 0.60, 0.68) and the ARR 6 months after DMF initiation was 0.17 (95% CI: 0.14, 0.21), representing a 73% lower ARR after DMF initiation (P< 0.0001). Mean scores on PROs generally improved or remained stable from Baseline to 6 months. ARR at 12 months relative to baseline and mean change in PROs from baseline to 12 months will be presented.


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Poster Session 1, 22(S3) Conclusions: The 6-month interim analysis of PROTEC suggests that DMF was associated with lower ARR and stable or improved PROs in patients with RRMS. Results of the final 12-month analysis, including safety outcomes, will be presented. Disclosure Supported by: Biogen. Thomas Berger: honoraria from Biogen for lectures and consultations, in addition his institution has received honoraria from Biogen for study participations. Bruno Brochet: participated on advisory boards for Biogen, Novartis, Roche, Genzyme, Merck-Serono, and his institution received support for clinical trials and research activities from Roche, Bayer, Biogen, Novartis, Genzyme, Medday, Teva, Actelion and Merck-Serono. Paolo Confalonieri: board member for Biogen and support for conference travel from Biogen and Merck Serono. Paul S. Giacomini: received honoraria for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen, EMD Serono, Genzyme, Merz, Novartis, Roche and Teva Neuroscience; received research support from Biogen and Teva Neuroscience; consultant for NeuroRx Research; principal investigator or sub-investigator for clinical trials for Actelion, Alexion, Bayer HealthCare, Biogen, Elan, EMD Serono, GlaxoSmithKline, Med-Immune, Novartis, Ono, Roche-Genetech, Sanofi-Aventis and Teva Neuroscience. Xavier Montalbán: speaker fees/travel expense reimbursement from and steering committees/advisory boards’ member for Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva Pharmaceutical. Antonio Vasco Salgado: consultant for Biogen, Novartis, Sanofi Genetech and Merck Serono; received fees from Roche and Boehringer Ingelheim. Macaulay Okwuokenye: employee of and holds stock/stock options in Biogen. Jing L. Marantz: employee of and holds stock/stock options in Biogen. Wolfgang Mair: employee of and holds stock/stock options in Biogen. P635 Cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis of infections in association with severe lymphopenia S. Cook1, T. Leist2, G. Comi3, X. Montalban4, E. Sylvester5, C. Hicking5, F. Dangond6 1Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, 2Division of Clinical Neuroimmunology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA, United States, 3Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 4Department of Neurology-Neuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5Merck KGaA, Darmstadt, Germany, 6EMD Serono, Inc., Billerica, MA, United States Background: The results from CLARITY, CLARITY Extension, ORACLE-MS and ONWARD show that cladribine tablets given

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annually for 2 years in short-duration courses are efficacious across a broad spectrum of patients. Lymphopenia, a dose-related expected event related to cladribine’s mechanism of action, has been well-characterised and consistently reported across studies with oral cladribine monotherapy. Objective: To assess the nature of infections observed in cladribine-treated patients, and to explore the association between severe lymphopenia and infections. Methods: Integrated safety data that comprised specific populations was used to assess infection in association with cladribine treatment. The cohorts were: monotherapy oral (MO; 1555 patients exposed to cladribine), placebo-controlled double-blind (PDB; 1458 patients exposed to cladribine) and all exposed (AllE; 1976 patients exposed to cladribine). Adjusted adverse events incidences per 100 patient years (Adj-AE per 100PY) were calculated for the integrated analyses. Results: Across the trials, when cladribine was given as monotherapy at a cumulative dose of 3.5 mg/kg, no evidence of an increase in the incidence of severe infections in patients with decreased lymphocyte counts was observed, except for herpes zoster. In All-E, herpes zoster was the most frequently reported herpetic infection, of note 90% (86/95) of these were non-severe. Severe herpes zoster occurred more frequently in the cladribine group than in the placebo group (PDB: 0.21 vs 0 Adj-AE per 100PY; All-E: 0.10 vs 0.04 Adj-AE per 100PY). All 9 severe events resolved. Overall, in patients exposed to cladribine in each cohort, the incidence of herpetic infections (reported as an adverse event of special interest) was higher in the period of treatment in which CTCAE Grade 3 or 4 lymphopenia occurred, compared to the time when the patients were not experiencing Grade 3 or 4 lymphopenia (MO 3.5 mg/kg dose had Adj-AE incidence per 100PY (95%CI) 2.16 (0.90-5.19) with lymphopenia, compared to 0.75 (0.50-1.12) without lymphopenia. Conclusions: Herpes zoster was the only severe infection reported more frequently with cladribine across the clinical program; herpetic infections were reported more frequently in patients experiencing Grade 3 or 4 lymphopenia. Herpes zoster infection is an important identified risk for cladribine tablets, for which risk mitigation strategies are proposed. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Stuart Cook has received honoraria for lectures/consultations from Merck, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, TEVA, and Actinobac Biomed Inc.; has served on advisory boards for Bayer HealthCare, Merck, Actinobac Biomed, TEVA Pharmaceuticals, and Biogen Idec; and received grant support from Bayer HealthCare.Thomas Leist is a consultant to EMD Serono, Teva Neuroscience, Biogen, Bayer, Pfizer; and is involved in clinical trials sponsored by EMD Serono, Teva Neuroscience, Bayer, ONO, Novartis, Daiichi, Acorda. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and


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trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering. Xavier Montalban has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Elke Sylvester and Christine Hicking are employees of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. P636 Benefits of cladribine tablets on the proportion of patients with multiple sclerosis free from clinical and radiological indicators of disease activity in the CLARITY EXTENSION study G. Giovannoni1, G. Comi2, S. Cook3, P. Rieckmann4, K. Rammohan5, P. Soelberg-Sorensen6, P. Vermersch7, A. Adeniji8, F. Dangond8 1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 3Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, United States, 4Neurologische Klinik, Akademisches Krankenhaus Sozialstiftung Bamberg, Bamberg, Germany, 5Ohio State University Hospital, Columbus, OH, United States, 6Danish MS Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark, 7Univ. Lille, CHU de Lille, LIRIC - INSERM U 995, Lille, France, 8EMD Serono, Inc., Billerica, MA, United States Background: Cladribine tablets (CT), given annually for 2 years in short-duration courses in CLARITY, significantly improved clinical (relapses and disability progression) and MRI outcomes, and freedom from disease activity in patients with relapsing multiple sclerosis (RMS) vs placebo (PBO). After a treatment gap (median duration ~41 weeks), the CLARITY Extension (EXT) study compared the safety and efficacy of 2 years’ additional CT treatment vs no additional treatment. Analysis of CLARITY EXT may provide insights into the proportions of patients remaining free from various markers of disease activity. Objective: Separate analyses of proportions of patients free from qualifying relapses, confirmed disability progression (CDP), new T1 Gd+ or combined unique (CU) lesions in CLARITY EXT. Methods: In CLARITY EXT, patients who received PBO in CLARITY were assigned to CT 3.5mg/kg body weight; those who received CT (3.5 or 5.25mg/kg) were re-randomised 2:1 to CT 3.5mg/kg or PBO, resulting in 5 groups: CP 3.5 (CT 3.5mg/kg in CLARITY/PBO in CLARITY EXT, n=98); CP 5.25 (CT 5.25mg/ kg in CLARITY/PBO in CLARITY EXT, n=92); CC 7.0 (CT 3.5mg/kg in CLARITY/ CT 3.5mg/kg in CLARITY EXT, n=186); CC 8.75 (CT 5.25mg/kg in CLARITY/ CT 3.5mg/kg CLARITY EXT, n=186); PC 3.5 (PBO in CLARITY/ CT 3.5mg/kg in CLARITY EXT, n=244). Results are presented for the proportions of patients qualifying relapse free, with no 3-month CDP, no new T1 Gd+ or CU lesions.

Results: The proportions of patients qualifying relapse free or 3-month CDP free were similar irrespective of CT dose or treatment order. Relapses (median follow-up 122.9 to 123.9 weeks): CP 3.5, 75.6% (68/98); CP 5.25, 75.3% (61/92); CC 7.0, 81.2% (134/186); CC 8.75, 76.7% (132/186) and PC 3.5, 79.6% (180/244); respective proportions without confirmed 3-month CDP (median time on study 121.5 to 124.4 weeks): 81.6% (80/98); 90.2% (83/92); 88.2% (164/186); 83.9% (156/186) and 83.2% (203/244). Proportions with no new T1 Gd+ lesions: CP 3.5, 73.0% (65/98); CP 5.25, 80.2% (65/92); CC 7.0, 88.9% (144/186); CC 8.75, 89.9% (152/186) and PC 3.5, 85.1% (188/244); respective proportions with no CU lesions: 34.4% (32/98); 27.6% (24/92); 37.1% (63/186); 43.7% (76/186) and 40.1% (91/244). Conclusions: Substantial proportions of patients remained free from disease activity measures in CLARITY EXT, including all subgroups, confirming the durable effect of 2 short annual courses of cladribine tablets, which extended for ⩾2 additional years. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Gavin Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering. Stuart Cook has received honoraria for lectures/consultations from Merck Serono, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, and Actinobac Biomed Inc.; has served on advisory boards for Bayer HealthCare, Merck, Actinobac Biomed, Teva Pharmaceuticals, and Biogen Idec; and received grant support from Bayer HealthCare. Peter Rieckmann has received honoraria for lectures/steering committee meetings from Merck, Biogen Idec, Bayer Schering Pharma, Boehringer-Ingelheim, Sanofi-Aventis, Genzyme, Novartis, Teva Pharmaceutical Industries, and Serono Symposia International Foundation. Kottil Rammohan has received honoraria for lectures and steering committee meetings from EMD Serono, Biogen Idec, SanofiAventis, Genzyme, Novartis, Teva Neurosciences, Acorda and Roche/Genentech. Per Soelberg-Sorensen has served on advisory boards for Biogen Idec, Merck, Novartis, Genmab, Teva, Elan, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Genmab, Teva, GSK, and Bayer Schering; has served as Editor-in-Chief of the European Journal of Neurology,


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Poster Session 1, 22(S3) is currently editorial board member for Multiple Sclerosis Journal, European Journal of Neurology, and Therapeutic Advances in Neurological Disorders; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, SanofiAventis, Genzyme, and Novartis; and has received payment for writing/reviewing manuscripts from IBI Consulting, a division of Informa plc; his department has received research support from Biogen Idec, Bayer Schering, Merck, Teva, Baxter, SanofiAventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, the Danish Multiple Sclerosis Society, the Danish Medical Research Council, the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. Patrick Vermersch has received honoraria and consulting fees from Biogen Idec, Sanofi, Bayer, Novartis, Merck, GSK, and Almirall; and research support from Biogen Idec, Sanofi, Bayer, and Merck. Abidemi Adeniji and Fernando Dangond are employees of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA.

P637 Metabolomics identifies novel effects of dimethyl fumarate on lipid metabolism in relapsing remitting MS P. Bhargava, K. Fitgerald, M. Kornberg, M. Smith, E.M. Mowry, P.A. Calabresi Johns Hopkins School of Medicine, Baltimore, MD, United States Background: The mechanism of action of dimethyl fumarate (DMF) has not been fully elucidated. Modulation of the Nrf2 pathway was initially proposed as the mechanism of action of DMF, but more recently, DMF has been noted to bind the hydroxycarboxylic acid-2 (HCA2) receptor that also binds niacin and beta-hydroxybutyrate. Goals: To utilize untargeted metabolomics to identify metabolic pathways affected by DMF in RRMS patients. Methods: RRMS patients initiating DMF and healthy controls (age-, sex- and race-matched) were enrolled. Demographic information and blood samples (including peripheral blood mononuclear cells) were obtained at baseline and 6-months post-initiation (or at equivalent time for controls). Plasma from each time point was subjected to untargeted metabolomics analysis at Metabolon Inc.(Durham, NC). The metabolite concentrations obtained were then pre-processed (imputation of missing values, log transformation and scaling of variables). Data were then analyzed using a weighted correlation network analysis (WGCNA) approach to identify modules of highly correlated metabolites. We then used a generalized estimating equations (GEE) model to identify modules that were altered with DMF treatment in RRMS patients. Results: 18 RRMS patients and 18 healthy controls were recruited. Metabolomics analyses identified 616 metabolites in the plasma of the participants. WGCNA identified 17 modules of highly-related metabolites. In subsequent GEE models, we identified three modules that were differentially altered in the RRMS group following DMF treatment. These modules consisted of phospholipids (phosphatidyl glycerols, phosphatidyl inositols and phosphatidyl cholines), which increased with DMF treatment (p=0.028), plasmalogens (anti-oxidant lipid species) and ascorbic acid metabolites (threonate, oxalate), which also increased

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(p=0.004), and fatty acids (saturated and poly-unsaturated fatty acids of variable chain lengths), which were reduced with DMF treatment (p=0.005). As expected, no change was observed in controls for these modules. Conclusions: DMF treatment produced alterations in lipid metabolism, including increases in multiple phospholipids and plasmalogens and reductions in multiple fatty acids. Alterations in lipid metabolism, perhaps through the HCA2 receptor, could play a role in the immunological effects of DMF. Experiments to correlate the described changes in the metabolome, to changes in the immunophenotype with DMF treatment are ongoing. Disclosure Dr. Bhargava is supported by an Insitutional Clinician Training Award from the NMSS. Dr. Firtzgerald: nothing to disclose. Dr. Kornberg is supported by a Clinician Scientist Training Award from the NMSS. Matthew Smith: nothing to disclose. Dr. Mowry is the PI of an investigator-intiated trial from Biogen, site PI of trials from Biogen and Sun Pharma and received free medication from Teva Neuroscience for a trial. Dr. Calabresi has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.His lab is supported by R01 NS082347 Imaging neurodegeneration in multiple sclerosis Supported by: An investigator initiated trial grant from Biogen. P638 A retrospective analysis of discontinuation rates and reasons for discontinuation in multiple sclerosis patients treated with delayed-release dimethyl fumarate (Biogen ONE Support Program) G. Vorobeychik1, J. Potts2, M. Smith3, M. Vlaicu3 1Fraser Health Multiple Sclerosis Clinic, Burnaby, BC, Canada, 2Biogen, Cambridge, MA, United States, 3Biogen, Mississauga, ON, Canada Background: The Biogen ONETM Support Program (The Program) provides reimbursement support and nursing clinical services for Biogen products to Canadian multiple sclerosis (MS) patients. A retrospective analysis of patient-reported and pharmacy data collected by The Program was performed to assess discontinuation rates and reasons in MS patients treated with delayed-release dimethyl fumarate (DMF). Objectives: The primary endpoint of this study was the proportion of patients discontinued at 12 weeks after their initial prescription fill date. The proportion of patients who discontinued DMF at 1 year and the reasons for discontinuation at 12 weeks and 1 year were also assessed. Methods: A random sample (n=409 patients) was drawn from The Program, which included prescription fill dates, strength and quantity, demographic data, and previous therapy use. As the exact discontinuation date was unavailable, this date was estimated as 4 weeks after a patient’s last prescription fill date plus fill supply, assuming a 240 mg BID dose. The proportion of patients discontinued at 12 weeks and estimated proportion of discontinuation using Kaplan-Meier (KM) curves at 1 year were used to evaluate discontinuation.


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Results: Of the 409 patient files reviewed, 340 patients were included in the primary analysis (the majority of excluded patients were due to missing data on discontinuation); 256 (75%) patients were female, median age was 40 (range: 18-74) years, median number of MS DMTs before initiating DMF was 1.0 (range: 0-5), 112 (33%) patients were naïve to prior DMTs, 217 (64%) received a prior DMT, and 11 (3%) had missing data. At Week 12 after DMF initiation, 22 (6.5%) patients had discontinued treatment: 9 (3%) due to gastrointestinal (GI) adverse effects; 3 (< 1%) due to flushing; 7 (2%) due to other adverse effects; and 3 (< 1%) due to reasons other than adverse effects such as reimbursement coverage reasons. At Year 1 after DMF initiation, the KM estimated discontinuation was 15.7%, including 13 patients due to GI adverse effects; 7 due to flushing; 3 due to lack of efficacy; 7 due to reasons other than AEs; 3 due to recommendation from their physician; and 2 due to missing data. Conclusions: In this study, 3% and 1% of patients discontinued treatment owing to GI or flushing events, respectively, at 12 weeks, and overall discontinuation was 6.5% at 12 weeks and 15.7% at 1 year. These observations are consistent with data from clinical trials. Supported by: Biogen Disclosure Galina Vorobeychik participated in advisory board, received ECTRIMS travel sponsorships, and research support (unrestricted educational grants, and participated in clinical trials) from Biogen Idec, EMD Serono, Genzyme, Novartis, Teva Neuroscience, UCB. James Potts, Maureen Smith, and Mihaela Vlaicu are employees of and hold stock/stock options in Biogen. P639 A novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice C. Higashi1, M. Hayashi2, N. Tsuda1, A. Kawaji1, F. Saitou1, M. Nakamura1, K. Nakao1, S. Furusako1, R. Saito2, T. Suzuki2, A. Uruno2, M. Yamamoto2 1Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, 2Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan Background: Nrf2 (NF-E2-related factor 2) is a key regulator for cellular protection against oxidative stress. A ubiquitin ligase adaptor Keap1 (Kelch-like ECH-associated protein 1) negatively regulates Nrf2 by proteasome-mediated protein degradation. Multiple sclerosis (MS) is an autoimmune disease provoked by inflammation-mediated oxidative stress. The loss of Nrf2 exacerbates the development of experimental autoimmune encephalomyelitis (EAE) in mice. An Nrf2 inducer dimethyl fumarate (DMF) has been approved for the treatment of MS, and the Keap1-Nrf2 system is a promising target for treatment of MS. We have identified as a novel Nrf2 inducer TFM-735 by high throughput screening campaign. In this study, we examined the pharmacological profile of TFM-735, and evaluated therapeutic effects of TFM-735 on EAE in mice. Methods: To examine the role of TFM-735 on Nrf2 stabilization, we performed immunoblot analysis by using thioglycollate-elicited mouse peritoneal macrophages from wild-type (WT) and

Keap1C151S/C151S knock-in mice. The T-cell-mediated autoimmunity was evaluated by using the BioMAP® T cell Autoimmune Panel system (BioSeek). C57BL/6J background WT mice and ICR background highly sensitive inflammation monitoring hIL-6BAC-Luc transgenic mice were immunized by myelin oligodendrocyte glycoprotein (MOG35-55) to induce EAE, and were orally administered with TFM-735 twice a day for 19 and 9 days, respectively. Results: Nrf2 protein expression levels were increased by TFM735 in the peritoneal macrophages from WT mice, but not in the macrophages from Keap1C151S/C151S knock-in mice. TFM-735 displayed an immune-modulative profile in BioMAP systems. TFM735 repressed IL-17 secretion from PBMCs stimulated by anti-CD3 and anti-CD28 antibodies in a dose dependent manner. Administration of TFM-735 to mice increased mRNA expression levels of a representative Nrf2-target gene Nqo1 in brain and spleen, and decreased the clinical scores for EAE compared to administration of vehicle. The plasma IL-17 levels were also lowered in TFM-735-treated EAE mice compared to vehicle-treated EAE mice. In hIL-6-BAC-Luc transgenic mice, TFM-735 treatment reduced EAE-induced bioluminescence for IL-6 in central nervous system as well as clinical scores. Conclusion: These results indicate that TFM-735 is a potent Nrf2 inducer that suppresses progression of EAE in mice. TFM-735 could be a promising therapeutic agent for MS. Disclosure All authors have nothing to disclose P640 Fingolimod in routine clinical practice: Canadian experience V. Bhan1, Y. Lapierre2, V. Devonshire3, F. Emond4, S.A. Morrow5, J.M. Burton6, J. Oh7, P. Haddad8, R. Schecter8 1Dalhousie University, Halifax, NS, 2McGill University Health Centre, Montreal, QC, 3University of British Columbia Hospital, Vancouver, BC, 4Hôpital de l’Enfant-Jésus, Quebec, QC, 5London Health Sciences Centre, London, ON, 6Foothills Medical Centre, University of Calgary, Calgary, AB, 7St. Michael’s Hospital, Toronto, ON, 8Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada Background: Gilenya® (fingolimod) was approved in Canada in March 2011 for RRMS. While well documented in the phase III trials, having information about the frequency of adverse events (AEs) or reasons for treatment discontinuation in routine clinical practice may be helpful for neurologists to better optimize patient care. Objective: To analyse retention to fingolimod therapy, reasons for treatment discontinuation and incidence of AEs during treatment. Methods: The Gilenya® Go ProgramTM was launched in March 2011 and offers education and support services, including coordination of first dose observation (FDO) and follow-up contact to reinforce monitoring recommendations and compliance. Data were collected and analysed for patients enrolled in the Canadian Gilenya® Go ProgramTM from launch to January 2016. Results: At data cut-off, 3956 patients had completed FDO, with 3201 patients being actively treated. Mean age at enrolment was 41.0 years; 74.9% were female. Overall fingolimod exposure was


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Poster Session 1, 22(S3) 7869 patient-years. Most recent previous therapies (n=3746) were glatiramer acetate (29.6%), subcutaneous IFN β-1a (21.7%), natalizumab (16.2%), intramuscular IFN β-1a (13.6%), subcutaneous IFN β-1b (8.0%), dimethyl fumarate (5.2%), teriflunomide (2.1%), none (1.9%), fingolimod (1.3%) and others (0.5%). Most common reasons for switching to fingolimod (n=3674) included lack of efficacy (31.8%), AEs (29.9%) and dissatisfaction/intolerance with injections (19.8%). Overall retention to therapy at data cut off (month 58) was 81.3%. There were 739 treatment discontinuations; the most common reasons were AEs (45.2%), physician request (11.4%), lack of efficacy (8.9%) and patient request (4.5%). AEs causing discontinuation and relative proportions included: (n=334) low lymphocyte count/abnormal haematology values (13.8%), gastrointestinal disturbance (6.9%), elevated liver enzymes (7.8%) and headache (5.4%). Seven cases of 2nd degree atrioventricular blocks (AVBs) and two cases of complete AVBs were reported. All AVBs occurred at first dose. Adherence to recommended 3-4 month ophthalmic examination was 92.4%. Conclusions: In real-world clinical practice in Canada, adherence to fingolimod treatment was high. Over the observation period (58 months), retention to therapy was >80%; adherence to monitoring was also high. The Gilenya® Go Program™ helps to meet the safety monitoring recommendations for RRMS patients treated with fingolimod. ®Gilenya is a registered trademark Disclosure FUNDING: This Program is funded by Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada. V. Bhan has received honoraria for speaking, consulting, and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience. He has acted as site principal investigator for clinical trials for Biogen Idec, EMD Serono, Novartis, Sanofi-Aventis and Teva Neuroscience. Y. Lapierre has participated in Ad-boards for Biogen-Idec, Novartis and Genzyme. He also has given presentations at conferences sponsored by Teva, EMD-Serono, Novartis and Genzyme in the past and taken part in clinical trials sponsored by Novartis, Biogen-Idec, EMD-Serono and Opexa. V. Devonshire has received honoraria for advisory meetings and speaker honorarium from EMD Serono, Biogen Idec, Teva Neurosciences, Novartis, Allergan and Genzyme. UBC has received payments for clinical trials in which Dr. Devonshire was the Principal Investigator from Novartis, Serono, and Genzyme. F. Emond has received honoraria for speaking, consulting, and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis, and Teva Neuroscience. He has acted or is currently acting as site principal investigator for clinical trials for EMD Serono and Roche. S. A. Morrow has received honoraria for speaking, consulting, and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis, and Teva Neuroscience. She has acted as site principal investigator for clinical trials for Biogen Idec. She has received investigator initiated study funds from Biogen Idec, Genzyme and Novartis and funding from the National MS Society and the Multiple Sclerosis Society of Canada. J.M. Burton: In past two years, participation on ad boards, CME speaking engagements and unrestricted educational support from Novartis, Biogen, Genzyme, EMD Serono.

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J. Oh: I have received personal compensation for consulting or speaking from EMD-Serono, Genzyme, Biogen-Idec, Novartis, Teva, and Roche. I recieve Research funding from the MS Society of Canada, Biogen-Idec and Genzyme. P. Haddad and R. Schecter are employees of Novartis Pharmaceuticals Canada Inc. P641 Benefits of cladribine tablets on the achievement of no evidence of disease activity (NEDA) status in patients with multiple sclerosis: analysis of pooled double-blind data from the CLARITY and ONWARD studies G. Giovannoni1, X. Montalban2, C. Hicking3, F. Dangond4 1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Department of Neurology-Neuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 3Merck KGaA, Darmstadt, Germany, 4EMD Serono, Inc., Billerica, MA, United States Background: Treatment with cladribine tablets in the CLARITY and ONWARD studies demonstrated efficacy vs placebo across a spectrum of patients with active multiple sclerosis. Combining efficacy data from the double-blind periods of these studies enables the effects of 2 years’ treatment with cladribine tablets (3.5mg/kg cumulative dose) on the proportion of patients with no evidence of disease activity (NEDA) to be assessed. Objective: To summarise proportions of patients with no evidence of disease activity in patients with relapsing MS (RMS) treated with cladribine tablets 3.5mg/kg, including various subgroups, in the CLARITY and ONWARD studies. Methods: Data from the 2-year, double-blind periods of CLARITY and ONWARD were used to summarise the efficacy of cladribine tablets 3.5mg/kg in patients with RMS (n=1067), and in subgroups defined by baseline characteristics. ONWARD subjects on cladribine or placebo were also taking IFN-beta. Data for patients achieving NEDA (defined as no qualifying relapses, no 3-month confirmed EDSS progression, no new or enhancing T1 Gd+ lesions and no new or active T2 lesions), were compared using odds ratios (OR) and 95% confidence intervals (95% CI) for patients treated with cladribine tablets 3.5mg/kg or placebo. Subgroups analysed included: patients with no T1 Gd+ lesions (n=759) or with ⩾1 T1 Gd+ lesions (n=308); EDSS score ⩽3.0 (n=653) or ⩾3.5 (n=414). Additional analyses included subgroups of patients with/without high disease activity; 0 or ⩾1 relapse in the prior 12 months; < 9 or ⩾9 T2 lesions; prior or no prior use of disease modifying drugs; males or females and age ⩽40 or >40 years (not described here). Results: Cladribine tablets 3.5mg/kg showed consistent benefits vs placebo in the proportion of patients achieving NEDA in the overall population (OR [95% CI]: 3.95 [2.90-5.37]) and in the subgroups: no T1 Gd+ lesions OR: 3.82 (2.71-5.38), ⩾1 T1 Gd+ lesions OR: 8.12 (3.31-19.90), EDSS ⩽3.0 OR 4.36 (2.90-6.56), EDSS ⩾3.5 OR 3.48 (2.17-5.57). Conclusions: Analysis of pooled data from CLARITY and ONWARD showed that cladribine tablets 3.5mg/kg significantly increased the proportion of patients with no evidence of disease activity compared with placebo in a population of patients with active RMS. Compared with placebo, cladribine tablets also


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showed significant increases in the proportion of patients with no evidence of disease activity across a range of patient subgroups. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Gavin Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Xavier Montalban has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Christine Hicking is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. P642 Benefits of cladribine tablets on magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis: analysis of pooled double-blind data from the CLARITY and ONWARD studies G. Giovannoni1, G. Comi2, X. Montalban3, C. Hicking4, F. Dangond5 1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 3Department of NeurologyNeuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 4Merck KGaA, Darmstadt, Germany, 5EMD Serono, Inc., Billerica, MA, United States Background: Treatment with cladribine tablets (CT) in the CLARITY and ONWARD studies demonstrated efficacy vs placebo across a spectrum of patients with active multiple sclerosis (MS). Combining efficacy data from the double-blind periods of these studies enables the assessment of the effects of 2 years’ treatment with CT 3.5mg/kg (cumulative dose) on magnetic resonance imaging (MRI) outcomes. Objective: To summarise MRI outcomes in patients with relapsing MS (RMS) treated with CT 3.5mg/kg vs placebo, including various subgroups, in pooled data from the CLARITY and ONWARD studies. Methods: Data from the 2-year, double-blind periods of CLARITY and ONWARD were used to analyse MRI outcomes for CT 3.5mg/kg in all patients with RMS (n=1067), and in subgroups defined by baseline characteristics. Patients from

ONWARD on CT or placebo were also taking IFN-beta. Risk of cumulative new T1 Gd+ or active T2 lesions was compared in terms of relative risk ratio (RRR) and 95% confidence intervals (95% CI; from a negative binomial regression model) for patients treated with CT 3.5mg/kg or placebo. Subgroups included patients with no T1 Gd+ lesions (n=759) or with ⩾1 T1 Gd+ lesions (n=308); EDSS score ⩽3.0 (n=653) or ⩾3.5 (n=414). Additional analyses included, among others, subgroups of patients with/without high disease activity; 0 or ⩾1 relapse in the prior 12 months; < 9 or ⩾9 T2 lesions; prior or no prior use of DMDs; males or females and age ⩽40 or >40 years. Results: Significant reductions in the risk of cumulative new T1 Gd+ lesions were seen in favour of CT 3.5mg/kg vs placebo in the overall population (RRR [95% CI]: 0.10 [0.076-0.140]) and the subgroups: no T1 Gd+ lesions RRR: 0.13 (0.080-0.194), ⩾1 T1 Gd+ lesions RRR: 0.09 (0.059-0.133), EDSS ⩽3.0 RRR 0.11 (0.073-0.152), EDSS ⩾3.5 RRR 0.09 (0.050-0.159). The risk of cumulative active T2 lesions was also significantly reduced overall (RRR: 0.29 [0.232-0.349]) and across patient subgroups: no T1 Gd+ lesions RRR: 0.30 (0.231-0.398), ⩾1 T1 Gd+ lesions RRR: 0.24 (0.183-0.322), EDSS ⩽3.0 RRR: 0.30 (0.231-0.377). EDSS ⩾3.5 RRR: 0.25 (0.176-0.360). Conclusions: Analysis of pooled CLARITY and ONWARD data showed that CT 3.5mg/kg significantly reduced the cumulative number of new T1 Gd+ and active T2 lesions compared with placebo in a population of patients with active RMS. Significant reductions in new T1 Gd+ and active T2 lesions were also seen with CT 3.5mg/kg vs placebo across a range of patient subgroups. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Gavin Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering. Xavier Montalban has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Christine Hicking is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA.


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Poster Session 1, 22(S3) P643 Benefits of cladribine tablets on relapse rates and disability progression in patients with multiple sclerosis: analysis of pooled double-blind data from the CLARITY and ONWARD studies G. Giovannoni1, X. Montalban2, C. Hicking3, F. Dangond4 1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Department of Neurology-Neuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 3Merck KGaA, Darmstadt, Germany, 4EMD Serono, Inc., Billerica, MA, United States Background: Treatment with cladribine tablets (CT) in the CLARITY and ONWARD studies demonstrated efficacy vs placebo across a range of patients with active multiple sclerosis. Combining efficacy data from the double-blind periods of these studies allows assessment of the efficacy of 2 years’ treatment with CT 3.5mg/kg (cumulative dose). Objective: To summarise the clinical efficacy of CT 3.5mg/kg vs placebo in patients with relapsing MS (RMS), including various subgroups, using pooled data from CLARITY and ONWARD. Methods: Data from the 2-year, double-blind periods of CLARITY and ONWARD were used to analyse the efficacy of CT 3.5mg/kg in patients with RMS (n=1067), and in subgroups defined by baseline characteristics. Patients from ONWARD on CT or placebo were also taking IFN-beta. Annualised relapse rates (ARR), 3-month (3-m) and 6-month (6-m) confirmed disability progression (CDP) were compared using relative risk ratios (RRR; from a Poisson regression model) and hazard ratios (HR; from a Cox proportional hazard model) and 95% confidence intervals (95% CI) for patients treated with CT 3.5mg/kg or placebo. The subgroups analysed included, among others, patients with no T1 Gd+ lesions (n=759) or ⩾1 T1 Gd+ lesions (n=308); EDSS score ⩽3.0 (n=653) or ⩾3.5 (n=414). Results: For ARR, consistent benefits were seen with CT 3.5mg/ kg vs placebo in the overall population RRR: 0.43 (0.35-0.52) and the subgroups: no T1 Gd+ lesions, 0.46 (0.36-0.59); ⩾1 T1 Gd+ lesions, 0.38 (0.27-0.53); EDSS ⩽3.0, 0.40 (0.31-0.53), EDSS ⩾3.5, 0.47 (0.34-0.64). Benefits favoured CT 3.5mg/kg vs placebo in the overall population for time to 3-mCDP (HR: 0.64 [0.48-0.86]) and 6-mCDP (HR: 0.61 [0.43-0.87]), and in each of these outcomes in a majority of subgroups. For 3-mCDP: no T1 Gd+ lesions HR: 0.59 (0.41-0.85), ⩾1 T1 Gd+ lesions HR: 0.75 (0.47-1.19), EDSS ⩽3.0 HR: 0.76 (0.51-1.14), EDSS ⩾3.5 HR: 0.55 (0.36-0.84). For 6-mCDP: no T1 Gd+ lesions HR: 0.59 (0.38-0.91), ⩾1 T1 Gd+ lesions HR: 0.66 (0.37-1.18), EDSS ⩽3.0 HR: 0.75 (0.46, 1.22), EDSS ⩾3.5 HR: 0.51 (0.31-0.85). Conclusions: Analysis of pooled data from CLARITY and ONWARD showed that CT 3.5mg/kg significantly decreased ARR (by 57%) and reduced the risk for 6-month confirmed disability progression (by 39%) vs placebo in a population of patients with active RMS; these effects were also shown in many subgroups. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW).

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Gavin Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Xavier Montalban has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Christine Hicking is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. P644 Cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis of safety from the multiple sclerosis clinical development program S. Cook1, T. Leist2, G. Comi3, X. Montalban4, E. Sylvester5, C. Hicking5, F. Dangond6 1Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, 2Division of Clinical Neuroimmunology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA, United States, 3Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 4Department of Neurology-Neuroimmunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5Merck KGaA, Darmstadt, Germany, 6EMD Serono, Inc., Billerica, MA, United States Background: Treatment with cladribine tablets in the CLARITY, CLARITY Extension and ORACLE-MS studies demonstrated efficacy vs placebo across a spectrum of patients with both early and relapsing multiple sclerosis (RMS). The adverse event (AE) profiles from these individual studies have been presented elsewhere. Pooling safety data for integrated analyses is an established route to a comprehensive characterisation of the safety profile of a therapy. Objective: To report the emergent overall adverse event (AE) profile from an integrated pool of safety data collected in trials which evaluated cladribine tablets as monotherapy, in patients with early or RMS. Methods: The monotherapy oral cohort (patients who received cladribine tablets only) was derived from CLARITY, CLARITY Extension, ORACLE-MS and the PREMIERE registry, and included 923 patients who received cladribine tablets 3.5 mg/kg: 3432.65 patient years exposure for this dose. 641 patients received placebo in this cohort (2025.97 patient years). Adjusted adverse events incidences per 100 patient years (Adj-AE per 100PY) were calculated for the integrated analyses. Results: The mean study period for patients was 194 weeks in the monotherapy oral 3.5 mg/kg cohort and 165 weeks in the placebo cohort; age (36.5 years), proportion of females (66.3%) and prior disease modifying drug experience were balanced among groups.


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Adj-AE per 100PY rates for cladribine 3.5 mg/kg and placebo were: treatment emergent AE (TEAE): 103.3 and 94.3; TEAEs leading to discontinuation: 2.1 and 1.1; serious AEs: 4.0 and 3.6; serious AEs leading to death: 0.26 and 0.25. With regard to the known, expected events with cladribine treatment, Adj-AE per 100PY for lymphopenia (preferred term) were 7.94 (3.5 mg/kg) and 1.06 (placebo), and for system organ class of infection and infestations, 24.93 (3.5 mg/kg) and 27.05 (placebo); herpes zoster (preferred term), 0.83 (3.5 mg/kg) and 0.20 (placebo). Adj-AE per 100PY for the system organ class of neoplasms, benign, malignant and unspecified were 1.14 and 1.01, for cladribine and placebo, respectively. Conclusions: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterised in a pooled population of patients with early and active MS. Lymphopenia was expected from the mode of action of cladribine tablets, but with no evidence for an overall increased risk of infections, or neoplasms. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Stuart Cook has received honoraria for lectures/consultations from Merck Serono, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, and Actinobac Biomed Inc.; has served on advisory boards for Bayer HealthCare, Merck, Actinobac Biomed, Teva Pharmaceuticals, and Biogen Idec; and received grant support from Bayer HealthCare. Thomas Leist is a consultant to EMD Serono, Teva Neuroscience, Biogen, Bayer, Pfizer; and is involved in clinical trials sponsored by EMD Serono, Teva Neuroscience, Bayer, ONO, Novartis, Daiichi, Acorda. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering. Xavier Montalban has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Elke Sylvester and Christine Hicking are employees of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. P645 Reduction of lymphopenia by cladribine tablets under retreatment guidelines: a long-term follow-up analysis of patients in the ORACLE-MS study T. Leist1, G. Comi2, M.S. Freedman3, B.A.C. Cree4, P.K. Coyle5, H.-P. Hartung6, P. Vermersch7, E. Sylvester8, D. Damian9, F. Dangond9

1Division

of Clinical Neuroimmunology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA, United States, 2Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 3Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4University of California, San Francisco, CA, 5Department of Neurology, Stony Brook University, Stony Brook, NY, United States, 6Department of Neurology, Heinrich Heine University, Düsseldorf, Germany, 7Univ. Lille, CHU de Lille, LIRIC - INSERM U 995, Lille, France, 8Merck KGaA, Darmstadt, Germany, 9EMD Serono, Inc., Billerica, MA, United States Background: In the ORACLE-MS study in patients with a first demyelinating event, treatment with two short courses at the beginning of two consecutive years of cladribine tablets (3.5 mg/ kg and 5.25 mg/kg) significantly reduced the risk of CDMS compared with placebo. Guidelines implemented in ORACLE-MS restricted cladribine retreatment to patients with Grade 0 or 1 lymphopenia at the beginning of the second year course. Objective: To assess severity and recovery from lymphopenia in the ORACLE-MS long-term follow-up (LTFU), among patients treated with cladribine tablets during the ORACLE-MS initial treatment period (ITP). Methods: ORACLE-MS patients were aged 18-55 years with a first clinical demyelinating event within 75 days before screening, ⩾2 clinically silent lesions of ⩾3 mm on a T2-weighted brain scan and an EDSS score of ⩽5. Patients were randomised (1:1:1) to placebo, cladribine tablets 3.5 mg/kg or cladribine tablets 5.25 mg/kg of bodyweight (cumulative over 2 years). Patients who did not convert to McDonald MS during the ITP did not receive any additional study medication during the LTFU, but were followed for safety and efficacy evaluations for 48 weeks after the end of ITP, or until McDonald MS or CDMS conversion. Results: CTCAE Grade 3/4 lymphopenia occurred in 46 (22.3%) and 74 (36.5%) patients receiving cladribine tablets 3.5 mg/kg and 5.25 mg/kg, respectively (ITP; up to 2 consecutive years). Grade 4 lymphopenia was limited to 3 patients (1 in 3.5 mg/kg and 2 in 5.25 mg/kg). In the 3.5 mg/kg group, 78 patients completed the 2 years of ITP, and 36 of these entered the LTFU and received no further treatment. At LTFU baseline, none of these 36 patients had Grade 3/4 lymphopenia, 4 patients had Grade 2 lymphopenia. All of these recovered to Grade 0 or 1 by LTFU week 13. Conclusions: In ORACLE-MS, the occurrence of CTCAE Grade ⩾3 lymphopenia was dose related. The retreatment guidelines introduced in ORACLE-MS appeared to limit the occurrence and duration of Grade 3/4 lymphopenia. All patients recovered to Grade 0 or 1 by week 13 in the long-term follow-up period. Disclosure This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). Thomas Leist is a consultant to EMD Serono, Teva Neuroscience, Biogen, Bayer, Pfizer; and is involved in clinical trials sponsored by EMD Serono, Teva Neuroscience, Bayer, ONO, Novartis, Daiichi and Acorda.


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Poster Session 1, 22(S3) Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering.. Mark S. Freedman has received compensation from Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva Canada Innovation. Bruce Cree has served as an advisor or consultant for: AbbVie Inc., Biogen, EMD Serono, Inc., Genzyme Corporation, MedImmune, Novartis Pharmaceuticals Corporation, Shire and Teva Neuroscience, Inc. Patricia K. Coyle has served as an advisor or consultant for: AbbVie Inc., Accordant, Acorda Therapeutics, Bayer HealthCare Pharmaceuticals, Biogen, EMD Serono, Inc., Genentech/Roche, Genzyme/Sanofi, Novartis Pharmaceuticals Corporation, Teva Pharmaceuticals USA, and received grants for clinical research from: Actelion Pharmaceuticals, Ltd., Biogen, Genentech/ Roche, Novartis Pharmaceuticals Corporation and Opexa Therapeutics, Inc. Hans-Peter Hartung has received honoraria for consulting, membership of steering committees and advisory boards, and speaking at symposia - with approval of the Rector of Heinrich-HeineUniversity - from Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis Pharma AG, Teva, SanofiAventis, Receptos and Roche. Patrick Vermersch has received honoraria and consulting fees from Biogen Idec, Sanofi, Bayer, Novartis, Merck, GSK, and Almirall; and research support from Biogen Idec, Sanofi, Bayer, and Merck. Elke Sylvester is an employee of Merck KGaA, Darmstadt, Germany. Doris Damian and Fernando Dangond are employees of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Massachusetts, USA. P646 Stable disability and patient-reported performance outcomes over 48 weeks of teriflunomide treatment: results from the Phase 4 Teri-PRO Study R. Gold1, B. Khatri2, K.R. Edwards3, S. Cavalier4, P. Rufi5, S. Brette6, P.K. Coyle7, for the Teri-PRO trial group 1St Josef Hospital, Ruhr University Bochum, Bochum, Germany, 2Regional MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, Milwaukee, WI, 3Multiple Sclerosis Center of Northeastern New York, Latham, NY, 4Sanofi Genzyme, Cambridge, MA, United States, 5Sanofi Genzyme, Chilly-Mazarin, 6Lincoln, Boulogne-Billancourt, France, 7Stony Brook University, Stony Brook, NY, United States Background: The phase 4 Teri-PRO study (NCT01895335) examined efficacy, safety, tolerability, and satisfaction with teriflunomide treatment using patient-reported outcomes, in patients with relapsing forms of MS (RMS). Objective: To describe disability and patient-reported performance outcomes up to Week 48 in the Teri-PRO study. Methods: Teri-PRO was a prospective, single-arm, open-label study in patients with RMS receiving once-daily teriflunomide 7 mg (US patients only) or 14 mg for 48 weeks, administered

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according to local labelling. Patients were enrolled in the US and in Europe, Canada, and Chile (ROW). Results from the following Teri-PRO secondary outcome measures are included: Expanded Disability Status Scale (EDSS), MS Performance Scale (MSPS), and Patient Determined Disease Steps (PDDS) scores at Week 48. Results: A total of 1000 patients were treated in the study (545 from the US and 455 from ROW); 594 patients switched from another disease modifying therapy (DMT) within the previous 6 months, while 285 had not received a DMT in the previous 2 years. EDSS scores at baseline were higher in the US vs ROW, and remained stable in both cohorts from baseline to Week 48: mean (standard deviation [SD]) scores at baseline/Week 48 were US, 3.7 (1.9), n=536/3.7 (2.0), n=453; ROW, 2.2 (1.6), n=445/2.4 (1.7), n=433; global, 3.1 (1.9), n=981/3.1 (2.0), n=886. MSPS total scores and PDDS scores at baseline were also higher for the US vs ROW. In the global cohort, MSPS total mean (SD) scores remained stable from baseline (12.2 [7.32], n=983) to Week 48 (11.9 [7.5], n=888), consistent with EDSS score results. The proportions of patients with normal/minimal disability increased or remained stable in 7 of the 8 MSPS subscales (Mobility; Hand function; Vision; Fatigue, Cognitive symptoms; Sensory symptoms, Spasticity symptoms) across 48 weeks, while a small decrease was seen for the Bladder/bowel subscale. PDDS mean (SD) scores were similar between baseline (2.3 [2.0], n=978) and Week 48 (2.2 [2.0], n=876). There was a strong correlation between PDDS and EDSS scores: rspearman=0.75 at baseline and rspearman=0.73 at Week 48 (P< 0.001 at both time points). Conclusions: Over 48 weeks, disability, as determined by EDSS, remained stable; this stability strongly correlated with patient performance, measured by MSPS and PDSS, and was observed regardless of baseline disease severity. Disclosure Study supported by Sanofi Genzyme. RG: Consulting fees (Bayer Schering, Biogen, Elan, Genzyme, Roche, Teva); grant/research support (Bayer Schering, Biogen, Genzyme, Teva). BK: Consulting fees (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva); speakers bureaus (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva). KRE: Consulting fees (Biogen, Genzyme); speakers bureaus (Biogen, Genzyme, Novartis); research support (Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/ Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis, Pfizer, Vaccinex). SC: Employee of Sanofi Genzyme, with ownership interest. PR: Employee of Sanofi Genzyme. SB: Employee of Lincoln, mandated by Sanofi. PKC: Consulting fees (AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, Teva); research support (Actelion, Genentech/ Roche, Novartis, NINDS, Opexa).

P647 Impact of teriflunomide treatment on real-world quality of life in the Phase 4 Teri-PRO Study R. Gold1, B. Khatri2, K.R. Edwards3, S. Cavalier4, P. Rufi5, S. Brette6, P.K. Coyle7, for the Teri-PRO Trial Group


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Josef Hospital, Ruhr University Bochum, Bochum, Germany, MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, Milwaukee, WI, 3Multiple Sclerosis Center of Northeastern New York, Latham, NY, 4Sanofi Genzyme, Cambridge, MA, United States, 5Sanofi Genzyme, Chilly-Mazarin, 6Lincoln, Boulogne-Billancourt, France, 7Stony Brook University, Stony Brook, NY, United States 2Regional

Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS. The efficacy, safety, tolerability, and satisfaction with teriflunomide were investigated in a real-world clinical setting in the global, phase 4 Teri-PRO study (NCT01895335). Objective: To evaluate patient-reported quality of life outcomes, measured by the Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire, up to Week 48 in the Teri-PRO study. Methods: In this prospective, single-arm, open-label, phase 4 study, patients with relapsing forms of MS received once-daily teriflunomide 7 mg (US patients only) or 14 mg for 48 weeks, administered according to local labelling in the US, Canada, Europe, and Chile; the primary outcome measure was Global Satisfaction at Week 48, measured by the Treatment Satisfaction Questionnaire for Medication. Here we describe results from the MusiQoL Questionnaire, one of the key secondary outcomes of Teri-PRO. Results: The efficacy population included 1000 patients, of which 594 switched from another disease-modifying therapy (DMT) within the previous 6 months, and 285 had not received a DMT in the previous 2 years. MusiQoL index total scores were comparable between baseline and Week 48: median (interquartile range [IQR]) scores at baseline (n=962) and Week 48 (n=850) were 68.1 (57.2, 78.9) and 70.3 (57.8, 81.3), respectively. Median (IQR) scores increased slightly from baseline to Week 48 in 3 of the 9 MusiQoL subscales (baseline/Week 48 scores: activities of daily living, 58.9 [37.5, 81.3]/62.5 [40.6, 84.4]; psychological wellbeing, 62.5 [43.8, 81.3]/68.8 [50.0, 87.5]; and relationships with friends, 58.3 [41.7, 75.0]/66.7 [41.7/75.0]); median (IQR) scores remained stable in the other 6 subscales (baseline/Week 48 scores: symptoms, 68.8 [50.0, 87.5]/68.8 [50.0, 87.5]; relationships with family, 75.0 [58.3/100.0]/75.0 [50.0, 100.0]; sentimental and sexual life, 62.5 [37.5, 75.0]/62.5 [37.5/75.0]; coping, 75.0 [50.0, 87.5]/75.0 [50.0, 100.0]; rejection, 100.0 [75.0, 100.0]/100.0 [75.0, 100.0]; and relationship with healthcare system, 83.3 [66.7/100.0]/83.3 [75.0, 100.0]). Conclusions: Over 48 weeks, patients in the Teri-PRO study demonstrated stable or improved quality of life. Disclosure Study supported by Sanofi Genzyme. RG: Consulting fees (Bayer Schering, Biogen, Elan, Genzyme, Roche, Teva); grant/research support (Bayer Schering, Biogen, Genzyme, Teva). BK: Consulting fees (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva); speakers bureaus (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva). KRE: Consulting fees (Biogen, Genzyme); speakers bureaus (Biogen, Genzyme, Novartis); research support (Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/ Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis, Pfizer, Vaccinex).

SC: Employee of Sanofi Genzyme, with ownership interest. PR: Employee of Sanofi Genzyme. SB: Employee of Lincoln, mandated by Sanofi. PKC: Consulting fees (AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, Teva); research support (Actelion, Genentech/ Roche, Novartis, NINDS, Opexa).

P648 Teriflunomide real-world safety profile: results of the Phase 4 Teri-PRO Study P.K. Coyle1, B. Khatri2, K.R. Edwards3, J. Meca Lallana4, S. Cavalier5, P. Rufi6, M. Benamor6, S. Brette7, R. Gold8 1Stony Brook University, Stony Brook, NY, 2Regional MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, Milwaukee, WI, 3Multiple Sclerosis Center of Northeastern New York, Latham, NY, United States, 4Hospital Virgen de la Arrixaca, Cátedra de Neuroinmunología Clínica y Esclerosis Múltiple, UCAM Universidad Católica San Antonio de Murcia, Murcia, Spain, 5Sanofi Genzyme, Cambridge, MA, United States, 6Sanofi Genzyme, Chilly-Mazarin, 7Lincoln, BoulogneBillancourt, France, 8St Josef Hospital, Ruhr University Bochum, Bochum, Germany Background: Teriflunomide, a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS, has demonstrated consistent efficacy on disability worsening and relapse outcomes in 2 large, phase 3 studies in patients with relapsing forms of MS (RMS), and has a well-characterized, longterm safety profile. The phase 4 Teri-PRO study (NCT01895335) investigated the efficacy, safety, tolerability, and satisfaction with teriflunomide treatment in routine clinical practice using patientreported outcomes. Objective: To report the safety outcomes with teriflunomide up to Week 48 in patients enrolled in the Teri-PRO study. Methods: In this prospective, single-arm, open-label study, 1000 patients with RMS received once-daily teriflunomide 7 mg (US patients only) or 14 mg for 48 weeks, administered according to local labelling in the United States, Canada, Europe, and Chile. The occurrence of adverse events (AEs) was reported at each study visit. Results: Treatment-emergent AEs were reported in 823 (82.3%) patients. The most commonly reported (⩾5% of patients) AEs were alopecia (23.0%, n=230), diarrhoea (17.3%, n=173), nausea (8.2%, n=82), headache (6.9%, n=69), urinary tract infection (6.7%, n=67), alanine aminotransferase (ALT) increase (6.3%, n=63), nasopharyngitis (5.4%, n=54), and fatigue (5.2%, n=52), and were mostly mild or moderate in severity. Serious AEs were reported in 127 (12.7%) patients; MS relapse (n=21), hypertension (n=6), ALT increase (n=6), urinary tract infection (n=5), pneumonia (n=4), syncope (n=4), chest pain (n=3), and non-cardiac chest pain (n=3) were reported in >2 patients. AEs resulted in treatment discontinuation in 109 (10.9%) patients, with diarrhoea (n=17), MS relapse (n=12), alopecia (n=9), ALT increase (n=6), fatigue (n=4), nausea (n=4), headache (n=3), influenza-like illness (n=3), pain (n=3), and vomiting (n=3), reported in >2 patients. Four deaths were reported during the study due to pneumonia, nonsmall cell lung cancer stage IV, MS relapse, and myocardial infarction; none of these were considered related to study treatment.


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Poster Session 1, 22(S3) Conclusions: In the Teri-PRO study, the real-world safety profile of teriflunomide was consistent with that previously observed in the clinical development programme, with no unexpected AEs reported, and a low rate of discontinuation due to AEs. Disclosure Study supported by Sanofi Genzyme. PKC: Consulting fees (AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, Teva); research support (Actelion, Genentech/ Roche, Novartis, NINDS, Opexa). BK: Consulting fees (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva); speakers bureaus (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva). KRE: Consulting fees (Biogen, Genzyme); speakers bureaus (Biogen, Genzyme, Novartis); research support (Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/ Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis, Pfizer, Vaccinex). JML: Consulting fees (Almirall, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva). SC: Employee of Sanofi Genzyme, with ownership interest. PR: Employee of Sanofi Genzyme. MB: Employee of Sanofi Genzyme SB: Employee of Lincoln, mandated by Sanofi. RG: Consulting fees (Bayer Schering, Biogen, Elan, Genzyme, Roche, Teva); grant/research support (Bayer Schering, Biogen, Genzyme, Teva). P649 Comparative analysis of adherence and persistence for delayed-release dimethyl fumarate versus interferons and glatiramer acetate - a population based study in Sweden A. Berglund1, N. Wu2, S. Berkö1, L. Lohm1, M. Ekelund1 1Biogen Sweden, Upplands Väsby, Sweden, 2Biogen, Inc., Cambridge, MA, United States Background: Disease modifying treatments (DMTs) for multiple sclerosis (MS) have been shown to reduce the risk for disease progression, and patients who have been persistent with and adherent to DMTs have a lower risk of relapse. Therefore, adherence and persistence are essential for optimizing treatment outcomes. Objectives: To evaluate adherence and persistence among MS patients in Sweden initiating delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) compared to those initiating interferons (IFN β-1a or β-1b) or glatiramer acetate (GA). Methods: Patients initiated on DMTs (DMF, IFN, or GA) in or after 2013 were identified in the nationwide Swedish Drug Prescribed Registry data between 1 January 2013 and 31 February 2016. Adherence and non-persistence rate of initiated DMT in 1 year after initiation were assessed based on pharmacy dispense records. Non-persistence was defined as having a treatment gap of ⩾90 days, or switching to another treatment. Adherence was calculated as the Medication Possession Ratio (MPR) and Proportion Days Covered (PDC). Results: A total of 2,149 patients were initiated on studied DMTs during the study period. Of these, 1,076 (50.1%) patients initiated

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DMF, 805 (37.5%) initiated IFN, and 268 (12.5%) initiated GA. The non-persistence rate within 1 year of initiation was significantly lower in DMF cohort (27.2%) than in IFN (47.3%) and GA (47.4%) cohorts (both p< 0.01). Compared with patients initiated on DMF, the hazard ratios adjusted for calendar period and treatment history for non-persistence were 3.17 (95% confidence interval [CI]: 2.52-3.98) for those on IFN, and 2.66 (95% CI: 2.10-3.38) for those on GA. The mean MPR for DMF cohort was significantly higher than that of the IFN cohort (0.94 vs. 0.70, p< 0.01), and similar to that in the GA cohort (0.94 vs 0.93, p=0.26). The mean PDC of DMF cohort was significantly higher than that of IFN (0.76 vs 0.52) and GA (0.76 vs. 0.66) cohorts (both p< 0.01). Conclusions: Preliminary findings of this analysis of real-world data in Swedish MS patients indicated that patients treated with DMF had higher rates of persistence and adherence compared with those treated with IFN. DMF had higher rates of persistence than GA, with similar adherence as assessed by MPR and higher rates of adherence as assessed by PDC. Disclosure Anders Berglund is an employee of, and holds stock/stock options in Biogen Ning Wu is an employee of, and holds stock/stock options in Biogen Sara Berkö is an employee of, and holds stock/stock options in Biogen Leif Lohm is an employee of, and holds stock/stock options in Biogen Mats Ekelund is an employee of, and holds stock/stock options in Biogen P650 Teriflunomide and dimethylfumarate: prescription and patients’ satisfaction in a real life setting X. Moisset1,2, M. Zuel1, S. Conde1, B. Pereira3, F. Taithe1, M. Lauxerois1, R. Colamarino4, P. Clavelou1,5, Reseau Neuro-SEP Auvergne 1Neurology, Clermont-Ferrand University Hospital, 2Clermont Université, Inserm U 107, NeuroDol, 3Biostatistics unit, Clermont-Ferrand University Hospital, Clermont-Ferrand, 4Neurology, Centre Hospitalier de Vichy, Vichy, 5Clermont Université, Inserm U 1107, NeuroDol, Clermont-Ferrand, France Background: Oral disease modifying treatments (DMT) take a growing place among MS treatments, but no clear data are available regarding indications in a real-life setting. Knowledges concerning patients’ satisfaction about these new DMTs are also scarce. Goals: To provide data concerning patients receiving teriflunomide or dimethylfumarate (DMF) in an unselected population of patients in France, with a special focus on patients’ satisfaction. Methods: Cross sectional study conducted from January to March 2015 for the DMF (available in France 05/2014) cohort and from January to March 2016 for the teriflunomide (available in France 11/2014) cohort. All the patients treated in Auvergne, an administrative area in the centre of France, have been included thanks to the collaboration of all the neurologists working both in liberal or


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hospital settings. The patients completed a self-administered postal survey corresponding to the Treatment Satisfaction Questionnaire for Medication (TSQM). Results: 146 patients receiving teriflunomide (46±11 years old; 86% women; EDSS = 2.1±1.7) and 161 receiving DMF (46±12 years old; 78% women; EDSS = 1.9±1.6) have been included. Patients receiveing DMF had a slightly higher annualised relapse rate at treatment initiation (0.6±0.7 vs 0.4±0.7; p=0.01). Concerning teriflunomide, one third of the patients had never received any DMT before and the median follow-up was 6 months. For those receiving DMF, 24% had received this treatment as a first DMT and the median follow-up was 5 months. At the time of the survey, 10% and 19% had discontinued teriflunomide and DMF, respectively (p=0.04). Detailed results from the TSQM will be presented. Conclusions: Teriflunomide and DMF were prescribed to the same type of patients in a real life setting. Both treatments were appreciated by the patients, but the discontinuation rate was slightly more important for patients receiving DMF. Disclosure Moisset: non-financial support from Merck-Serono, Biogen, Sanofi-Pasteur-MSD, Roche, GSK, Astrazeneca, Novartis, Pfizer, Teva and Genzyme, personal fees from Astellas and from Institut UPSA de la douleur Zuel: non-financial support from Genzyme and Novartis Conde: non-financial support from Lundbeck, Biogen, Genzyme, Bayer, Aguettant, Astrazeneca, Allergan, LFB, GSK and Novartis Pereira: Nothing to disclose Taithe: non-financial support from Biogen, Bayer, Merck Serono, Teva, Novartis, LFB and Genzyme. Lauxerois: non-financial support from Teva, UCB, and Eisai. Colamarino: non-financial support from Novartis, Genzyme, Teva, Bayer, Biogen, Merck Serono, Lundbeck, Astellas, Abbott, Mundipharma, Impeto medical, Almirall, Pfizer and Grünenthal. Clavelou: personal fees from Teva-Pharma, Merck-Serono, Novartis, Biogen, Genzyme, Bayer, Roche and Almirall P651 Real-life data from efficacy of fingolimod treatment in multiple sclerosis patients in Turkey M. Terzi1, M. Kürtüncü2, M. Eraksoy2, R. Karabudak3, A. Tuncer3, B. Altunrende4, A. Akcalı5, C. Boz6, S. Sevim7, Y. Nur8, Y. Tamam9, M. Bitnel10, O.F. Turan11, A. Soysal10, M. Ozerden10, Y. Terzi1 119 Mayis University, Samsun, 2Istanbul University, Faculty of Medicine, Istanbul, 3Hacettepe University Faculty of Medicine, Ankara, 4Bilim University, Istanbul, 5Gaziantep University, Gaziantep, 6Karadeniz Technical University, Trabzon, 7Mersin University, Mersin, 8Ege University, Izmir, 9Diyarbakir University, Diyarbakır, 10Bakirköy Education and Training Hospital of Neurology, Istanbul, 11Uludag University, Bursa, Turkey Introduction: Fingolimod is one of the oral immunomodulator agents with established efficacy on attacks, MRI and progression in relapsing remitting MS. In the present study, we aimed to share our fingolimod experience in MS treatment in Turkey. Method: Multiple sclerosis patients from 11 centers who have received fingolimod were evaluated based on the databases of the clinics.

Results: A total of 1361 multiple sclerosis patients who have used fingolimod were included in the study. Of the patients, 952 were females (69,9%). Mean age at disease onset was 26,61 ± 8,85 years. Drug treatment varied from 1 month to 104 months (mean 17,86 ± 13,22). The mean number of attacks prior to fingolimod treatment was 1 ± 0,94 and mean EDSS at the start of fingolimod treatment was EDSS 3,04 ± 1,8. During fingolimod treatment, the mean number of attacks was 0,19 ± 0,45 (n=1166) for the first year and 0,12 ± 0,37 (n=662) for the second year. There was a statistically significant reduction in the number of attacks both for the first and second years. Mean EDSS following treatment was significantly decreased at the end of the first year, while no statistically significant difference was observed after the second year. Of the patients, 1158 (85.1%) were still on fingolimod during the follow-up period with no medication changes needed for inefficacy or side effects. Fingolimod was the first immunomodulator choice in 94 (6,9%) of the patients. Brain MRI was performed one year after treatment in 545 patients and the results were compared with pretreatment brain MRIs. No new lesions were seen in 85,9% of these patients. No attacks, increased disability or new lesions with MRI was observed in 235 out of 662 patients with regular clinical and radiological monitoring over 2 years (35%) (NEDA 3). Mean EDSS during the first year and thereafter for the group of patients who started treatment with fingolimod with an EDSS of ⩽ 3 remained significantly lower than the other group (p< 0, 0001). Conclusion: The frequency of attacks and radiologic activation decreased during the first and second years of treatment with fingolimod compared to pre-treatment. Mean EDSS decreased significantly during the first year following treatment, but the significance was not maintained beyond one year. Efficacy in terms of disability was higher in patients who started fingolimod first line and had EDSS scores below 3. Disclosure Nothing to disclose P652 DMF induces differential apoptosis of T cell subsets and leads to a shift in the regulatory to effector T cell balance in MS patients M. Ghadiri1,2, A. Rezk1, R. Li1, F. Luessi3, F. Zipp3, J. Antel1, P.S. Giacomini1, A. Bar-Or1 1Montreal Neurological Institute, Montreal, QC, Canada, 2Brain and Mind Research Institute, Sydney, NSW, Australia, 3Department of Neurology, University Medical Center Mainz, Mainz, Germany Background: The mechanisms underlying both the therapeutic effect of dimethyl fumarate (DMF), as well as its ability to differentially decrease counts of particular lymphocyte subsets in treated patients, are not fully elucidated. Here, using a combination of in vitro and in vivo approaches, we considered whether these DMF effects are mediated by selective apoptosis of distinct T cell subsets. Methods: Total lymphocyte counts (TLC) as well as flow cytometry analysis of effector and regulatory T cell subsets within peripheral blood mononuclear cells (PBMC), were carried out on samples obtained from MS patients prior to


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Poster Session 1, 22(S3) and at 3-month intervals following DMF treatment initiation. In vitro, PBMC were cultured with addition of DMF, monomethyl fumarate (MMF) or appropriate vehicle controls, subsequently stained for markers of T cell subsets and apoptosis (Annexin V/ propidium iodide), then analyzed by flow cytometry. Results: As previously reported DMF therapy reduced TLC, particularly over the first 6 months (mean decrease 0.79 x 109 cells/L; n=13; p=0.0009), with a preferential reduction in CD8+ T cells resulting in increased CD4:CD8 ratios (mean fold increase 1.4; p=0.002). Greater decreases were noted for memory versus naïve T cell subsets, and for conventional versus regulatory T cell subsets. These differential effects resulted in increased ratios of regulatory to effector T cells, and of anti- to pro-inflammatory cytokine-expressing T cells. In vitro, DMF induced dose-dependent apoptosis of CD3+ T cells (increase in late apoptotic cells vs. vehicle: 11% for 10µM DMF, p=0.0181; 51% for 50µM DMF, p=0.0001). Greater DMF-induced apoptosis was seen for CD8+ versus CD4+ T cells (79% vs. 39%, p=0.0001); for memory versus naïve CD4+ and CD8+ T cell subsets (CD4+: 73% vs. 18%, p=0.0004; CD8+: 92% vs. 8%, p=0.0064), and for conventional versus regulatory T cell subsets (42% vs. 6%, p=0.0004). Conclusions: In vitro, DMF induces T cell apoptosis that disproportionately affects CD8+ T cells, memory T cells, and non-regulatory T cells. This differential in vitro susceptibility of distinct T cell subsets to DMF-induced apoptosis mirrors the observed differential in vivo effects of DMF on the same T cells subsets and may thus provide insights both into the therapeutic mode of action of DMF in MS, as well as the mechanism underlying DMFinduced lymphopenia. Disclosure Dr Mahtab Ghadiri is a recipient of the BMRI/McGill University Multiple Sclerosis scholarship, funded by Novartis. Ayman Rezk: nothing to disclose. Dr Rui Li reports: nothing to disclose. Dr Felix Luessi has received travel grants from Teva Pharma and Merck Serono. Dr Frauke Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. Her travel compensation has been provided for by the aforementioned companies. Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal. Dr Paul Giacomini has received personal compensation for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience, has received research support from Biogen Idec and Teva Neuroscience, has been a consultant for NeuroRx Research, an imaging Contract Research Organization, and has acted as a principal investigator or sub-investigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, Novartis, Ono, Roche-Genentech, Sanofi-Aventis and Teva Neuroscience.

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Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, GuthyJackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, SanofiGenzyme, Teva Neuroscience, Wyeth. P653 Interim report on the safety and efficacy of long-term daclizumab HYP treatment for up to 5 years in EXTEND L. Kappos1, S. Cohan2, D.L. Arnold3,4, O. Mokliatchouk5, S.J. Greenberg6, P. McCroskery5, G. Lima5 1Neurologic Clinic and Policlinic, the Departments of Medicine, Clinical Research, and Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 2Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR, United States, 3NeuroRx Research, 4McGill University, Montreal, QC, Canada, 5Biogen, Cambridge, MA, 6AbbVie Inc., North Chicago, IL, United States Background: EXTEND is an ongoing open-label extension study of DECIDE to assess the safety and efficacy of daclizumab highyield process (DAC HYP) treatment in relapsing-remitting multiple sclerosis (RRMS). Objective: To assess long-term safety and efficacy of DAC HYP in RRMS. Methods: Patients enrolled in EXTEND receive DAC HYP 150mg subcutaneous every 4 weeks for up to 5 years. An interim analysis of safety and efficacy endpoints was performed using data through Jan 11, 2016 (patients enrolled in pre-filled pen [PFP] substudy) or Sep 10, 2015 (non-PFP patients). Safety analyses included patients who completed DECIDE and enrolled in EXTEND. Analyses of 24-week confirmed disability progression (CDP) were performed for the combined DECIDE and EXTEND treatment periods and included all patients in the DECIDE intention-to-treat population. Results: Safety analyses included 1203 subjects, 597 of whom received intramuscular interferon (IFN) beta-1a in DECIDE and switched to DAC HYP in EXTEND (IFN/DAC) and 606 of whom received DAC HYP in DECIDE and continued in EXTEND (DAC/DAC). Among IFN/DAC patients, the incidence of treatment-emergent serious adverse events other than MS relapse was similar after a median of approximately 18 months of DAC HYP in EXTEND as compared to a median of 26 months of IFN beta1a exposure in IFN-treated patients in DECIDE (9% vs.10%). The annualized relapse rate (ARR) decreased from 0.317 to 0.152 after switching from IFN beta-1a to DAC HYP in EXTEND. Among DAC/DAC patients (n=606), ARR was similar in DECIDE and EXTEND (0.195 vs 0.156). In the combined DECIDE/EXTEND study period, patients treated with DAC HYP from DECIDE Baseline up to Week 168 had a 21% relative risk reduction for 24-week confirmed disability progression as compared with patients who were treated with IFN beta-1a (HR: 0.79; 95%CI: 0.62-1.00; P=.047). Conclusion: The safety profile of DAC HYP in EXTEND was consistent with that from DECIDE. Long-term treatment with DAC HYP was associated with a reduction in the relapse rate and


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confirmed disability progression when compared to earlier treatment with IFN beta-1a.

Lille, Lille, France, 8Sanofi Genzyme, Cambridge, MA, 9Hope Neurology, Knoxville, TN, United States

Disclosure

Background: Alemtuzumab is a humanised anti-CD52 monoclonal antibody that depletes circulating T and B lymphocytes. Following depletion, a distinctive pattern of T- and B-cell repopulation begins within weeks, potentially leading to a rebalancing of the immune system. Alemtuzumab demonstrated greater improvements in efficacy outcomes over SC IFNB-1a in patients with active relapsing-remitting MS (RRMS) who were treatment-naïve (CARE-MS I; NCT00530348) or had an inadequate response (⩾1 relapse) to prior therapy at baseline (CARE-MS II; NCT00548405) over 2 years. An extension study (NCT00930553) has shown durable efficacy through 5 years in the absence of continuous treatment. Goal: To evaluate the pattern of T- and B-cell depletion and repopulation in patients receiving only 2 courses of alemtuzumab and those receiving 1 or 2 retreatments. Methods: In CARE-MS I and II, patients received 2 courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). Patients completing the studies could enter the extension, with asneeded alemtuzumab retreatment for relapse or MRI activity. Blood counts were tested monthly; lymphocytes were phenotyped by flow cytometry. Results: In patients who received only the original 2 courses of alemtuzumab, mean CD4+, CD8+ and CD19+ counts at the start of Course 2 were 0.28, 0.24 and 0.34 x 109/L, respectively. Both T and B lymphocytes were depleted after the second course of alemtuzumab (N=369), reaching their lowest levels at 1 month after Course 2 (mean CD4+: 0.05; mean CD8+: 0.06; mean CD19+: 0.03 x 109/L). CD19+ counts repopulated quickly and reached the lower limit of normal (LLN; 0.1 x 109/L) by 3 months. T cells repopulated more slowly; CD8+ counts reached LLN (0.2 x 109/L) by about 6 months, and CD4+ counts reached LLN (0.5 x 109/L) at Month 24. Once reaching plateau (CD19+, 15 months; CD8+, 30 months; CD4+, 24 months), cell counts were stable through 48 months and remained above LLN. Depletion and repopulation of T and B cells were similar after 1 or 2 alemtuzumab retreatments (Course 3: n=79; Course 4: n=10). Conclusions: The distinct pattern of lymphocyte repopulation began within weeks after alemtuzumab treatment, with T- and B-cell counts remaining stable through 48 months after reaching plateau. This pattern remained unchanged with retreatment. These effects may explain the durable efficacy of alemtuzumab in the absence of continuous treatment.

Ludwig Kappos: Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee for and consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB and Xenoport; Dr. Kappos has also received speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva; royalties from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society and the Swiss National Research Foundation. Stanley Cohan: paid consultant to serve on advisory boards for Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme; honoraria from speaker bureaus for Acorda, Biogen, Genentech, Novartis, and Sanofi-Genzyme; research support from Biogen, Genentech, Mallinckrodt, Novartis, Opexa, Roche, and Sanofi-Genzyme; funds for transportation, meals, and lodging from Acorda, Biogen, Mallinckrodt, Novartis, and Sanofi-Genzyme. Douglas L Arnold: honoraria from Bayer HealthCare, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Roche, and Teva; employee of and stockholder in NeuroRx Research. Oksana Mokliatchouk, Peter McCroskery, and Gabriel Lima: employees of and hold stock/stock options in Biogen. Steven Greenberg: employee of and holds stock/stock options in AbbVie Inc. Supported by: Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Stephanie Douglas (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P654 Lymphocyte depletion and repopulation is consistent across alemtuzumab treatment courses in patients with relapsingremitting multiple sclerosis: 6-year analysis of patients from the CARE-MS studies A.N. Boyko1, E. Havrdova2, J. King3, V. Limmroth4, K.W. Selmaj5, B. Sharrack6, P. Vermersch7, D.H. Margolin8, E. Chou8, S. Wray9, on behalf of the CARE-MS I and II Investigators 1Pirogov’s Russian National Research University & Demyelinating Diseases Center at Usupov’s Hospital, Moscow, Russian Federation, 2First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 3Royal Melbourne Hospital, Melbourne, VIC, Australia, 4Klinik für Neurologie und Palliativmedizin, Cologne, Germany, 5Medical University of Łódź, Łódź, Poland, 6Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 7University of

Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. ANB: Consulting fees/participated in clinical trials (Bayer, Biogen, Merck Serono, Novartis, Sanofi Aventis, Sanofi Genzyme, and Teva). EH: Honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva) and support from Ministry of Education of Czech Republic, project PRVOUK-P26/LF1/4. JK: Consulting and/or speaker fees (Bayer, Bio CSL, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme) and principal investigator with funds to institution.


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Poster Session 1, 22(S3) VL: Honoraria for consulting and speaking at symposia (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva, with approval by the HR-Department, Cologne General Hospital, University of Cologne). KWS: Consulting and/or speaking fees (Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Synthon). BS: Nothing to disclose. PV: Consulting and/or speaking fees, and research support (Almirall, Bayer, Biogen, GlaxoSmithKline, Merck Serono, Novartis, Sanofi Genzyme, and Teva). DHM and EC: Employees of Sanofi Genzyme. SW: Consulting and/or speaking fees or principal investigator (Alkermes, Bayer, Biogen, EMD Serono, Sanofi Genzyme, and Teva).

P655 Rebound disease activity reduction in relapsing multiple sclerosis patients transitioned from natalizumab to teriflunomide S. Cohan1, K. Edwards2, C. Chen3, T. Gervasi3, J. O’Connor2, K. Smoot1, K. Kresa-Reahl1 1Providence Multiple Sclerosis Center, Providence Health & Services, Portland, OR, 2MS Center of Northeastern New York, Latham, NY, 3Providence Brain & Spine Institute, Providence Health & Services, Portland, OR, United States Background: Prolonged natalizumab (NTZ) treatment for relapsing multiple sclerosis (MS) is associated with increased risk of progressive multifocal leukoencephalopathy (PML) in JC virus (JCV) positive patients. Discontinuation of NTZ in JCV-positive patients has been associated with a high risk of relapse in the ensuing 6-12 months, the risk of relapse increasing with duration of post-NTZ “washout”. To date, no known prospective study has demonstrated a therapeutic strategy which reduces the risk of relapse following the discontinuation of NTZ. Objective: To determine if early introduction of teriflunomide (TFM) will be safe and effective in reducing the risk of disease activity after withdrawing NTZ treatment. Methods: Adult patients with relapsing MS, who had at least 12 consecutive relapse-free months of NTZ treatment, and the presence of serum anti-JCV antibodies, were switched to TFM within 28 ± 7 days after their last NTZ infusion. Full physical and neurological exam, 3T brain MRI, and labs were performed at baseline, monthly for 6 months, and at 12, 18, and 24 months after initiating TFM. A total of 60 subjects have been screened and 51 of them competed baseline; the results of the 39 subjects who started TFM 6 months or more ago will be reported in this abstract. Results: 39 subjects, 74.36% female, age 47.74 (± 9.45) years (range 19-63), with a mean baseline EDSS of 3.10 ± 1.28 (range 1.0-6.0) were included in the analysis. Mean duration of prior NTZ treatment was 45.05 ± 25.70 months (range 12-114) and mean duration of TFM therapy was 14.59 ± 5.33 months (range 4-24). 41% of subjects (n=16) had new T2, enlarging T2, or enhancing brain lesions and 10% (n=4) had clinical relapses. Seven subjects had mild hepatic enzyme elevation, and 18 had mild-to-moderate hair loss. No cases of PML have occurred. 4 of the 39 subjects were withdrawn from the study before month 12: 3 had breakthrough disease and 1 had dental infection. As of April 21, 2016, we have observed a non-significant change in EDSS,

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from 3.15 (±1.34) at baseline to 3.06 (±1.56) at month 12, for the 33 patients who received at least 12 months of TFM therapy. Conclusion: Our results demonstrate that early initiation of TFM was associated with a 10 % relapse rate following NTZ withdrawal, compared to previously reported rates of 30% or higher, which may be related, in part, to elimination of NTZ washout before initiating TFM therapy, and should inform decisions regarding washout strategies. Disclosure Stanley Cohan serves on steering committees and advisory boards for Biogen, Novartis, Sanofi-Genzyme, Genentech, and Mallinckrodt, receives research support from Biogen, Novartis, Sanofi-Genzyme, Roche, Opexa, and Mallinckrodt, receives speaking honoraria from Biogen, Novartis, Sanofi-Genzyme and Acorda; received support for air travel, lodging and meals from Biogen, Novartis, and Sanofi-Genzyme Keith Edwards received funding as consultant/advisor/speaker for Biogen & Genzyme and research support from Actelion, Biogen, Eli Lilly, Eisai, Forum Pharmaceuticals, Genentech, Genzyme/ Sanofi, Hoffman- La Roche, Novartis, Pfizer, Vaccinex Kyle Smoot serves on advisory board for Biogen and Teva, received speaking honoraria from Acorda, Biogen, Novartis, Serono, and Teva, and received research support from Biogen Kiren Kresa Reahl received research support from Biogen and Novartis; received speaking honoraria from Biogen, EMDSerono, Genzyme, Mallinchrodt, Novartis, Pfizer, and Teva. Tiffany Gervasi received travel support from Merck and TransTech. Chiayi Chen and Judy OĆonnor have nothing to disclose. P656 Efficacy of natalizumab and fingolimod in multiple sclerosis in real world clinical setting: a 2-year follow-up study R. Totaro1, M. Danni2, P. Bellantonio3, G. Costantino4, R. Cerqua2, C. Di Carmine1, R. Fantozzi3, S. Sciamanna1, A. Fuiani4, C. Carrocci1, D. Alunni Fegatelli5, A. Farcomeni5, D. Centonze3, C. Marini6, L. Provinciali2, A. Carolei6 1Department of Neurology, San Salvatore Hospital, L’Aquila, 2Department of Neurology, University of Ancona, Ancona, 3Department of Neurology, IRCCS NEUROMED, Pozzilli, 4Department of Neurology, Ospedali Riuniti di Foggia, Foggia, 5Department of Public Health and Infectious Diseases, University of Rome ‘Sapienza’, Rome, 6University of L’Aquila, L’Aquila, Italy Background and objectives: Although natalizumab and fingolimod are established second-line treatment for multiple sclerosis (MS) patients, to date only few observational studies compared efficacy between the treatments in real clinical setting, while there are still no head-to-head trial comparing their efficacy. The aim of this multicenter study was to compare the efficacy of natalizumab and fingolimod in relapsing-remitting MS (RR-MS) patients in real-world clinical setting. Methods: We enrolled 337 patients starting either natalizumab or fingolimod for RR-MS referred to four MS centers between March 2007 and July 2013. Out of 337 patients included, 226 were women and 111 men. Mean age was 36.7±9.4 years and mean duration of the disease was 9.3±6.9 years.


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The main end point was the proportion of patients showing disease activity at 2-year follow-up. Disease activity was defined by the occurrence of relapse and/or confirmed Expanded Disability Status Scale (EDSS) progression and/or new or newly enlarging T2 lesions and/or gadolinium enhancing lesions at MRI. Results: Out of 337 patients, 162 were treated with natalizumab and 175 with fingolimod. The incidence of disease activity was 25.3% in the natalizumab group and 45.1% in the fingolimod group. Multivariate logistic regression analysis showed that natalizumab (B=-0.787, P=0.001) and baseline EDSS values (B=-0.315, P=0.008) negatively influenced the probability to present new disease activity. Patients with baseline higher values of EDSS or patients treated with natalizumab had lower incidence of disease activity. Conclusions: Results from 2-year follow-up of treatment suggest higher efficacy of natalizumab compared to fingolimod in terms of proportion of patients with disease activity.

lesions (DMF 18.2%, FTY 13.1%; p>0.1), and GdE lesions (DMF 10.1%, FTY 6.9%; p>0.2). Among first line DMF and FTY patients, there were comparable proportions with relapses [OR= 1.07, 95% CI (0.18, 6.54)], new T2 lesions [OR= 2.0, 95% CI (0.20, 4.62)], and discontinuation [OR= 1.75, 95% CI (0.18, 3.13)]. Similar results were seen in patients treated with DMF and FTY as second line. 32% of patients discontinued first line DMF compared to 23% of FTY patients. 33% of patients discontinued second line DMF compared to 25% of FTY patients. The most frequent cause of discontinuation was adverse effects for both DMF (1st line, 100%; 2nd line, 77%) and FTY (1st line, 75%; 2nd line, 71%). Discussion: This analysis demonstrates no significant difference in disease activity between first line DMF and FTY at 12 months in clinical practice, similar to that observed in second line use. As expected, tolerability issues were the most common cause for discontinuation in DMF and FTY as both first and second line treatment.

Disclosure

Disclosure

RT received funding for travel or speaker honoraria from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA.

Dr. Carrie Hersh is supported by National Multiple Sclerosis Society Sylvia Lawry Physician Fellowship Award. Dr. Samuel Cohn - there is no conflict of interest. Ms. Claire Hara-Cleaver has received consulting or speaking fees from Biogen Idec, TEVA, EMD Serono, Acorda, Novartis, and Genzyme. Dr. Robert Bermel has received consulting or speaking fees from Biogen Idec, Novartis, TEVA, Genzyme, and Questcor. Dr. Robert Fox has received consulting fees from Biogen Idec, MedDay, Novartis, Questcor, TEVA, and Xeonport. Dr. Jeffrey Cohen has received consulting fees from Biogen Idec, EMD Serono, Genzyme, Novartis, Receptos, Synthon, TEVA, and Vaccinex. Dr. Daniel Ontaneda is supported by KL2 TR000440/TR/NCATS NIH Grant.

P657 Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod as first line and second line therapy in clinical practice C.M. Hersh1, S. Cohn2, C. Hara-Cleaver3, R.A. Bermel3, R.J. Fox3, J.A. Cohen3, D. Ontaneda3 1Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, 2Cleveland Clinic, 3Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, OH, United States Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are increasingly used as first line disease modifying therapies for relapsing forms of multiple sclerosis (MS) in the United States. Previous observational studies of large cohorts of DMF and FTY patients in clinical practice showed comparable efficacy but somewhat different discontinuation rates. Direct comparisons in treatment naïve subjects are limited. Objective: To assess efficacy and discontinuation of first line and second line DMF and FTY in clinical practice at 12 months. Design and methods: A total of 775 patients treated with DMF (1st line n= 38; 2nd line n= 420) and FTY (1st line n= 17; 2nd line n= 300) were identified from a single large academic MS center within the first year of respective DMT approval. Measures of disease activity and discontinuation were assessed using chisquare unadjusted comparisons and propensity score adjustment. Outcomes included proportions of patients with relapses, MRI activity, and discontinuation within 12 months of DMT initiation. Results: Patients treated with first line DMF and FTY overall showed excellent on-treatment disease control with low proportions with relapses (DMF 12.5%, FTY 11.8%; p>0.5), new T2-weighted lesions (DMF 12.5%, FTY 6.7%, p>0.5), and gadolinium-enhancing (GdE) lesions (DMF 6.3%, FTY 0%; p>0.5). Second line groups showed similar results with low proportions with relapses (DMF 14.1%, FTY 11.3%; p>0.3), new T2-weighted

P658 Differences in tolerability and discontinuation rates in teriflunomide-treated patients: a real-world clinic experience H. Alnajashi1, F. Alshamrani2, F. Bakdache3, M. Freedman4 1Neurology Division, King Abdulaziz University, Jeddah, 2King Fahad Hospital of the University - University of Dammam, Dammam, Saudi Arabia, 3Sanofi Genzyme, Mississauga, 4University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada Introduction: Tolerability of disease modifying treatments (DMT) can be challenging for treatment-naïve (TN) MultipleSclerosis (MS) patients. In comparison, previously-treated (PT) MS patients with prior experience on a DMT may have different tolerability thresholds upon switching to a new therapy. Objective: To assess the Real-World tolerability of Teriflunomide in the MS patients of a large Canadian MS Centre of Care in order to determine whether PT patients have different tolerability thresholds compared to TN patients thereby leading to differing discontinuation rates. Design and methods: This was a non-interventional, single-centre, retrospective chart review looking at all patients who had been prescribed commercial teriflunomide until May 2015.


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Poster Session 1, 22(S3) Results: 119 patient charts were reviewed. There were 29 TN patients (mean disease duration 6.3 years) and 90 PT patients (mean disease duration 12 years). Overall, 19 patients (15.9%) discontinued Teriflunomide after a mean treatment duration of 35 weeks. The most common reason for discontinuation was side effects in 8 patients (42%), followed by breakthrough disease activity needing escalation to second line DMT in 6 patients (31%, all PT) and, finally, patient choice in 5 patients (27%). Discontinuation due to tolerability alone occurred in 13 patients; 1 from the TN group and 12 from the PT group. The number of discontinuations was not sufficient to show a statistically significant difference between TN patients and PT patients (p=0.1). Conclusions: The retrospective chart review of this Canadian dataset provides some evidence about the Real-World tolerability of teriflunomide. Discontinuations were low overall and in line with what has been reported in clinical trial data. There was no significant difference in discontinuation rates between the patients in the TN and PT groups. Only 6 of 119 (5%) patients overall discontinued treatment due to breakthrough disease activity and all were from the PT group [almost 6% in the TEMSO] extension who had a disease duration nearly twice that of the NT group. In our opinion, Teriflunomide is the safest and best tolerated oral alternative to the injectable therapies.

scale (EDSS), multiple sclerosis functional composite (MSFC), modified fatigue impact scale (MFIS), and Beck depression inventory-II (BDI-II) were recorded at the beginning and end of the study. The relapse rate was recorded during the intervention. Patients underwent baseline and follow up brain MRIs. Results: The Mean ± SD of MSFC changes in the treated and placebo groups were -0.14 ± 0.20 and -0.31 ± 0.19 respectively. MSFC was improved significantly (P< 0.001) in the treated group. There was no significant differences between the Mean ± SD of EDSS changes in the treated (0.07 ± 0.23) and the placebo (0.08 ± 0.23) groups (p=0.73). There were also no significant differences between the Mean ± SD of annualized relapse rate in the treated (-0.36 ± 0.56) and placebo (0.53 ± 0.55) groups (p=0.20). The Mean ± SD of enhanced lesions in the treated group (0.4 ± 1.0) and in the placebo (0.2 ± 0.6) groups were not significantly different (p=0.26). The Mean ± SD of volume of T2 hyperintense lesions was not significantly different between treated (45 ± 137) and placebo (23 ± 112) groups (p=0.23). Conclusion: Vitamin A improved total MSFC score in RRMS patients, but it did not change EDSS, relapse rate and brain active lesions. Disclosure

Disclosure Hind Alnajashi: Receipt of educational grants from Genzyme. Foziah Alshemrani: has nothing to disclose. Mark Freedamn: Receipt of honoraria or consultation fees: Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, SanofiAventis, Teva Canada Innovation Member of a company advisory board, board of directors or other similar group: Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis Participation in a company sponsored speaker’s bureau: Genzyme P659 Impact of vitamin A supplementation on disease progression in patients with multiple sclerosis M.H. Harirchian1, S. Bitarafan1, A. Saboor-Yaraghi2, M.A. Sahraian2, M. Togha2, S. Nafissi2, N. Beladi Moghadam3, T. Roostaei2, F. Siassi2, H. Ghanaati2, S. Jafarirad2 1Tehran University of Medical Sciences, Iranian Center of Neurological Research, 2Tehran University of Medical Sciences, 3Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran Background: Many studies have shown that active vitamin A derivatives suppress the formation of pathogenic T cells in MS patients. The aim of the present study is to determine the impact of vitamin A on disease progression in MS patients. Methods: A total of 101 relapsing-remitting multiple sclerosis (RRMS) patients were enrolled in a 1-yr placebo-controlled randomized clinical trial. The treated group received 25000 IU/d retinyl palmitate for 6 mo followed by 10000 IU/d retinyl palmitate for another 6 mo. The results for the expanded disability status

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Sama Bitarafan, MD & PHD of nutrition: nothing to disclose Aliakbar Saboor-Yaraghi: nothing to disclose Mohammad Ali Sahraian: nothing to disclose Mansoureh Togha: nothing to disclose Shahriar Nafissi: nothing to disclose Nahid Beladi Moghadam: nothing to disclose Tina Roostaei: nothing to disclose Fereydoun Siassi: nothing to disclose Hossein Ghanaati: nothing to disclose Sima Jafarirad: nothing to disclose Mohammad- Hossein Harirchian: nothing to disclose P660 Recovery of demyelinating optic neuritis after treatment with bioequivalent high doses of oral vs. intravenous corticosteroids: a randomized single blinded clinical trial S.A. Morrow1,2, J.A. Fraser1,2, C. Day2, D. Bowman2, H. Rosehart2, M. Kremenchutzky1,2, M. Nicolle1,2 1Clinical Neurological Sciences, Western University, 2London Health Sciences Centre, London, ON, Canada Background: Acute Optic neuritis (AON) is a common presentation in Multiple Sclerosis. Based on the landmark optic neuritis treatment trial (ONTT), intravenous (IV) corticosteroids is thought to be superior to oral administration for the treatment of AON. However, the ONTT did not compare bioequivalent oral and IV doses, using a significantly lower corticosteroid dose in the oral group. Thus, it is not known if IV treatment is truly superior to oral treatment for AON. Objectives: To determine if treatment for AON with high dose corticosteroids administered IV is superior to a bioequivalent dose of oral corticosteroids. Methods: We recruited consecutive subjects, with or without known MS, presenting with AON requiring corticosteroids, without a history of AON in the same eye. Visual acuity (VA) had to be


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20/40 or worse, a relative afferent pupillary defect had to be present, symptoms were not improving and were present for less than 14 days. Subjects were randomized to 1000mg IV methylprednisolone daily or 1250mg oral prednisone daily for three days; subjects were not blinded but all assessors were blinded to treatment assignment. The primary outcome was recovery of the P100 visual evoked potential (VEP) latency signal at 6 months; secondary outcomes included P100 VEP signal at 1 month and VA at 1 and 6 months. Results: Fifty one subjects were initially recruited; 4 subjects (3 oral, 1 IV) were removed due to an alternative diagnosis to AON and 1 subject randomized to IV required re-treatment 4 weeks after recruitment, leaving 23 subjects in each of the oral and IV groups. 39 subjects completed all 3 assessments. The left eye was affected in 27/46 (58.7%); this was the 1st demyelinating event in 24 (52.2%). The median VA at time of presentation was 20/150 (range 20/40 to no light perception) and mean P100 was 192.3ms (SD 60.6). At baseline, VEP in the oral group was 202.7ms (SD 66.4) and 181.9ms (SD 53.6) in the IV group (p=0.251); median VA was 20/200 in the oral group and 20/100 in the IV group (p=0.916). At 6 months, VEP had improved significantly to 133.8ms (SD 31.5) in the oral and 119.0ms (SD 16.5) in the IV group, which was not significantly different (p=0.10). Similarly VEPs at 1 month were not significantly different between groups (p=0.75), nor was VA at 1 month (p=0.236) and 6 months (p=0.219). Conclusion: IV administration of high dose (> 1000mg) corticosteroids is not superior to bioequivalent oral treatment in AON. Disclosure This study was funded by a Physicians’ Services Incorporated Foundation Grant. Dr. Morrow has received honoraria for speaking, consulting, and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis, and Teva Neuroscience. She has acted as site principal investigator for clinical trials for Biogen Idec. She has received investigator initiated study funds from Biogen Idec, Genzyme and Novartis and funding from the National MS Society and the Multiple Sclerosis Society of Canada. Dr. Kremenchutzky has received research grants and research support from Biogen, the Canadian Institute of Health Research [CIHR], Genzyme, the MS Society of Canada, Novartis, Sanofi, Teva, and Wellesley Therapeutics. He has received personal compensation for consulting from Biogen, Genzyme and Novartis. Dr. Fraser, Dr. Nicolle, Ms. Bowman, Ms. Rosehart and Mr. Day have nothing to disclose. P661 Adherence and tolerability to dimethyl fumarate in 253 patients with MS T. Sejbaek1,2, Z. Illés1,2, T. Petersen3,4 1Odense University Hospital, Department of Neurology, 2Faculty of Health, Clinical Institute, University of Southern Denmark, Odense, 3Department of Neurology, Aarhus University Hospital, 4Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Background: Real-life experience with dimethyl fumarate (DMF) is limited. Data about tolerability and adherence are especially scarce.

Objective: We examined tolerability and adherence to DMF at two major MS centers in Denmark. Data were also compared between the two centers. Methods: Adverse events (AEs), treatment duration, reason for discontinuation and basic demographics were examined in patients started on DMF from March 2014 until November 2016. The two centers are 143 km apart from each other, national guidelines on MS treatment are the same, and the MS populations are similar. Results: A total of 253 patients were included: 103 patients from Center 1 (C1) and 150 from Center 2 (C2). Mean age at C1 was 40.9±10.9 years, and 76.7 % were female. Mean age at C2 was 40.2±10.7 years, and 64.7 % were female. No statistical difference was found with regards to age and gender. At C1, 18 patients were treatment naïve, 62 patients received injectable 1st line therapy and 23 patients received 2nd line therapy before switch to DMF. At C2, more patients were treatment naïve (n=56), 87 patients received injectable 1st line therapy and 7 patients were treated with 2nd line therapy before switch to DMF. Patients adherent to DMF were treated for mean 362±83 days at C1 and for mean 424±141 days at C2. Patients, who discontinued DMF were treated for mean 140±114 days at C1 and for mean 305±186 days at C2 (p< 0.0002). At C1, 44 patients stopped treatment because of AEs or disease breakthrough compared to 26 patients at C2, witch gives a converted odds ratio (OR) of 3.56 (p< 0.0001). Adverse event profile was comparable at the two centers. Conclusion: Adherence to DMF differs highly within a small geographic area of Denmark at two large MS centers. It was more likely that patients at C1 had received 2nd line therapy than patients at C2. We found a significant OR of 3.56 of stopping treatment in C1 compared to C2. Discontinuation also happened earlier at C1 than at C2 but with same distribution af AEs in both centers. These data indicate that management and interaction between healthcare professionals and patients maybe especially important in the early phase of DMF treatment. Disclosure All authors have recieved travel grants, speaking fees and participated in advisory boards from Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals and Novartis. P662 Significant increase of CD56+(bright) CD16- NK cells observed in multiple sclerosis patients treated with dimethylfumarate V. Camera1, R. Magliozzi1, M. Pitteri1, C. Romualdi2, M. Calabrese1 1Neurosciences, Biomedicine and Movements, University of Verona, Verona, 2Dept. of Biology, University of Padova, Padova, Italy Background: Dimethylfumarate (DMF) is an effective, new generation, disease modifying drug used to treat relapsing-remitting multiple sclerosis (RRMS) patients. DMF reduces preferentially CD4 and CD8 memory T cells, in particular TH1 cells, whereas increases TH2 cells and pTreg cells. Otherwise its effect on NK cells in multiple sclerosis is still unknown. The aim of this study is the long-term monitoring of lymphocyte subsets in peripheral blood of MS patients treated with DMF and


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Poster Session 1, 22(S3) the understanding of its possible mechanism that contribute to regulate immunosuppression. Materials and methods: The effect of DMF (administered 240 mg twice/day) on lymphocytes subsets has been studied in 51 RRMS patients (F:M=2:1, average age=38.6, average EDSS=2,5) who recently started DMF therapy, compared with 37 untreated RRMS patients. By using flow cytometry analysis, a detailed count of different lymphocytes subsets present in the peripheral blood of all the DMF treated patients has been performed at baseline of the treatment (T0) and at 1,3,6 and 12 months. Results: A reduction of lymphocytes count was observed in 27 treated patients: 25 showed lymphocytes count between 1000 and 500/µl and two showed lymphocytes count < 500/µl. After 12 months of treatment the mean lymphocytes count was significantly higher in the untreated group (2036,8/µl) compared to the treated group (1094/µl, p< 0.001). Total lymphocytes count diminished proportionally to the time of exposure to DMF with a total decrease of 24.1% between T0 and T12. Similar reductions were observed for CD4+ (-31.8%) and CD8+ cells (-55.4%). The most interesting data was represented by a significant increase (+65.2% compared to T0) of CD56+(bright) CD16+ NK cells at T12. The mean percentage of NK cells at T12 was also significantly higher in the treated group (36%) than in the untreated group (15,3%; p=0.032). Conclusions: Dimethylfumarate seems to regulate the increase of CD56+(bright) CD16- NK cells and such increase appears to compensate the reduction of other lymphocytes subsets in several patients. It may be suggested that NK cells may play a key regulatory role on immune system modulation, which may represent one of the mechanisms of action of DMF treatment in multiple sclerosis. Disclosure Prof. Calabrese´s disclosures: Advisory Board membership: Bayer-Shering, Genzyme, Biogen Idec Payment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer-Schering, Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA Valentina Camera, Roberta Magliozzi, Marco Pitteri and Chiara Romualdi have nothing to disclose. P663 Inflammatory biomarkers and serum nitric oxide concentrations in multiple sclerosis patients according to the different kinds of disease modifying therapy N. Niedziela1, M. Adamczyk-Sowa1, J.T. Niedziela2, B. Mazur3, E. Kluczewska4, P. Sowa5, M. Gasior2 1Department of Neurology in Zabrze, 23rd Department of Cardiology, SMDZ in Zabrze, 3Department of Microbiology and Immunology in Zabrze, 4Department of Radiology in Zabrze, 5Department of Laryngology in Zabrze, Medical University of Silesia, Zabrze, Poland Background: The role of nitric oxide and its reactive derivatives: nitrate and nitrite (NOx) is well-known in the pathogenesis of

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multiple sclerosis (MS). MS is an inflammatory disease while NOx seems to be important in coordinating inflammatory response. Goals: The purpose of the study was to assess serum nitrogen species and inflammatory parameters in relapsing-remitting MS (RRMS) patients and to compare effectiveness of the various types of disease modifying therapy (DMT) in reduction of nitric oxide and inflammatory biomarkers levels. Methods: 63 RRMS patients and 10 healthy subjects (HS) were included in the study. Serum NOx, C-Reactive Protein (CRP) and interleukin 1 beta (IL1β/IL-1F2) concentrations were evaluated. Annual Gadolinum (AGd+) -and T2 enhanced lesions (AT2) were obtained in magnetic resonance imaging (MRI). Patients were divided into 2 groups: LI: 44 patients whose received the first line of DMT (interferons beta 1a,-1b or glatiramer acetate) and LII: 19 patients treated with the second line of DMT (natalizumab or fingolimod). NOx, CRP, IL-1β/IL-1F2, Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) and MRI lesions were compared between the groups. Results: Higher NOx levels were noted in LI in comparison to the LII and HS (2.04±0.70, 1.57±0.31, 1.50±0.16 µM, p=0.03, respectively) without significant differences in CRP (2.13±2.47, 1.49±2.05, 1.19±0.55 mg/l, p=0.52, respectively) and IL-1β/ IL-1F2 (1.51±0.46, 1.76±0.92, 1.64±0.47 pg/mL, p=0.47, respectively). LI and LII did not differ in EDSS (2.48±0.48, 2.97±1.17, p=0.10, respectively), AGd+ (2.39±15.2, 0.53±1.43, p=0.60, respectively), AT2 (0.09±0.29, 0.21±0.54, p=0.42, respectively), ARR (0.36±0.57, 0.32±0.67, p=0.51, respectively). There was observed negative correlation between serum NOx level and time of MS in whole studied population (R= -0.3046, p< 0.05) which was not confirmed between NOx and EDSS (R= -0.19, p>0.05) or between NOx and AGd+ (R= -0.22, p>0.05), AT2 (R= -0.05, p>0.05) and ARR (R= 0.007, p>0.05). Conclusions: Only serum NOx concentration could reveal potentially efficacy of DMT with better reduction of NOx level by the second line agents of DMT. NOx serum concentration seems to be a biomarker of MS duration. Disclosure Natalia Niedziela: nothing to disclose Monika Adamczyk-Sowa: nothing to disclose Jacek Niedziela: nothing to disclose Bogdan Mazur: nothing to disclose Ewa Kluczewska: nothing to disclose Paweł Sowa: nothing to disclose Mariusz Gasior: nothing to disclose P664 Achievement of no evidence of disease activity by time interval with daclizumab HYP versus intramuscular interferon beta-1a treatment in DECIDE G. Giovannoni1, L. Kappos2, E. Havrdova3, B.O. Khatri4, S.A. Gauthier5, S.J. Greenberg6, P. Wang7, G. Giannattasio8 1Queen Mary University London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 2Neurologic Clinic and Policlinic, the Departments of Medicine, Clinical Research, and Biomedicine and Biomedical Engineering, University Hospital, Basel, Switzerland, 3First


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Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 4Center for Neurological Disorders and The Regional Multiple Sclerosis Center, Wheaton Franciscan Health Care, St. Francis Hospital, Milwaukee, WI, 5Judith Jaffe MS Center, Weill Cornell Medical College, New York, NY, 6AbbVie Inc., North Chicago, IL, 7Biogen, Cambridge, MA, United States, 8Biogen, Zug, Switzerland Background: In DECIDE, a significantly greater percentage of patients receiving daclizumab high-yield process (DAC HYP) 150 mg achieved no evidence of disease activity (NEDA) vs intramuscular (IM) interferon (IFN) beta-1a 30 mcg (24.6% vs 14.2%, odds ratio [OR; 95% CI], 2.059 [1.592-2.661]; P< .0001) from baseline to Week 96. Presence of residual disease activity from pre-treatment epoch emerging in the first months while a new therapy reaches full efficacy may impact evaluation of treatment effects on achievement of NEDA. Objective: To separately examine post hoc the percentage of patients achieving NEDA in DECIDE in the first 6 months (baseline to Week 24) and the following 18 months (Weeks 24-96) of treatment. Methods: NEDA was defined as the composite of no relapses, no 12-week confirmed disability progression (CDP), no new/enlarging T2 (NET2) lesions (vs start of time interval), and no gadolinium-enhancing (Gd+) lesions (at MRI scans performed after start of time interval). Analyses were based on logistic regression models adjusted for relevant baseline characteristics. Results: From baseline to Week 24, a significantly greater percentage of DAC HYP vs IFN beta-1a patients achieved overall NEDA (41.5% vs 32.6%; OR [95%CI], 1.507 [1.232-1.842], P< .0001), clinical NEDA (no relapses, no 12-week CDP) (86.5% [795/919] vs 82.2% [758/922]; OR, 1.393 [1.075, 1.806]; P=.0121) and MRI NEDA (no NET2, no Gd+ lesions) (47.1% [412/875] vs 39.0% [330/847]; OR, 1.442 [1.183, 1.758]; P=.0003). For Weeks 24-96, a significantly greater percentage of DAC HYP vs IFN beta-1a patients achieved overall NEDA (44.7% [347/776] vs 22.4% [173/773]; OR, 2.960 [2.364-3.708]; P< .0001); clinical NEDA (77.6% [685/883] vs 64.3% [547/851]; OR, 1.959 [1.581, 2.428]; P< .0001) and MRI NEDA (59.0% [441/748] vs 35.2% [255/725]; OR, 2.925 [2.349, 3.643]; P< .0001). ORs for the majority of measures were notably higher for Weeks 24-96. In patients who were not NEDA from baseline to Week 24 but achieved NEDA during Weeks 24-96, 80.0% of IFN beta-1a and 79.6% of DAC HYP had MRI activity only from baseline to Week 24. Conclusion: Superiority of DAC HYP vs IFN beta-1a on NEDA status was observed during the first 6 months of treatment in DECIDE and became even more evident during the following 18 months when treatments reached full efficacy and effects were less diluted by pre-treatment disease activity. Disclosure Gavin Giovannoni: fees for participation in advisory boards for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Merck, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Synthon, Teva and Vertex; has received speaker fees from AbbVie Biotherapeutics Inc., Bayer HealthCare, Biogen, Genzyme, Merck Serono, SanofiAventis and Teva; is co-editor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono and Novartis;

Ludwig Kappos: institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees for Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB and Xenoport. Dr. Kappos has received speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva, royalties from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society and the Swiss National Research Foundation; Eva Havrdova: honoraria/research support from Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva; and advisory boards for Actelion, Biogen, Genzyme, Novartis, Receptos and Teva; supported by the Czech Ministry of Education research project PRVOUK-P26/LF1/4; Bhupendra O. Khatri: consultant/speaker for Avanir, Biogen, EMD Serono, Genzyme, Mallinckrodt (formerly Questcor), Novartis, Pfizer and Teva; Susan A. Gauthier: honoraria from Genzyme and Genentech; and research support from Biogen, EMD Serono, Genzyme, Mallinckrodt, and Novartis; Steven J Greenberg: employee of and holds stock/stock options in AbbVie Inc.; Ping Wang and Giorgio Giannattasio: employees of and hold stock/stock options in Biogen. Supported by: Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Rebecca Jarvis (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P665 Acute respiratory distress syndrome following treatment with alemtuzumab for relapsing multiple sclerosis A. Pace, F. Jackson, W. Lusher, T. Mihalova, N. Sharaf, D. Rog, P. Talbot Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Salford, United Kingdom Background: Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS) that induces lysis of lymphocytes and other cells expressing CD52. Despite the resultant transient lymphopaenia, serious opportunistic infections (OI) are not frequently encountered. We describe a case of severe acute respiratory distress syndrome in a pwMS shortly following alemtuzumab therapy. Case report: A 54 year old woman received a 5-day course of alemtuzumab for RRMS, together with prophylactic acyclovir 400mg BD continued for 28 days after completion of treatment. She was diagnosed with RRMS in 2004 and had previously been on Betaferon, Copaxone and Avonex. Two months earlier she suffered a disabling relapse with left hemiparesis, spasticity and deteriorating mobility. Her last prior relapse had been 13 months earlier.


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Poster Session 1, 22(S3) Five weeks following treatment she presented to hospital with dyspnoea, cough and haemoptysis. On examination she was pyrexial, tachypnoeic, hypotensive and tachycardic. Oxygen saturation dropped to 72% on minimal exertion. Auscultation revealed inspiratory crepitations in both lower lobes, arterial blood gases indicated Type 1 respiratory failure, and chest X-ray showed bibasilar reticulonodular shadowing. CTPA excluded pulmonary embolism but showed patchy consolidation and ground glass opacities throughout both lungs, without lymphadenopathy or pleural effusion She was treated empirically with IV acyclovir, co-amoxiclav, clarithromycin and Primaquine, and was transferred to ICU for intubation and ventilation on the fourth day of admission. Broncho-alveolar washings confirmed the presence of Pneumocystis jirovecii (PJP) and blood PCR yielded a positive result for CMV (13008 IU/ml), both consistent with active infection. She gradually responded to treatment and was discharged after 25 days on viral and fungal prophylaxis. Despite her severe infection, she did not experience significant deterioration in neurological function. Conclusions: Serious OI infrequently complicate treatment with alemtuzumab for RRMS, but the potential for morbidity is high. Clinicians administering alemtuzumab should carefully weigh the risks and benefits of alemtuzumab use and be vigilant to possible early infections. It is uncertain if the recommended duration and dose of acyclovir prophylaxis post-treatment is truly protective against Herpetic infections. Standard prescription of PJP prophylaxis following treatment should also be considered. Disclosure Adrian Pace: nothing to disclose Fran Jackson: nothing to disclose William Lusher: nothing to disclose Tatiana Mihalova: nothing to disclose Nazar Sharaf: nothing to disclose David Rog: nothing to disclose Paul Talbot: nothing to disclose

Disclosure

P666 Glatiramer acetate immune modulates pathogenic B cell function and maintains clinical benefit after anti-CD20 induction therapy D. Häusler1, C.C.A. Bernard2, L. Feldmann1, W. Brück1, P.H. Lalive3, M.S. Weber1,4 1University Medical Center Goettingen, Institute of Neuropathology, Goettingen, Germany, 2Monash University / Monash Regenerative Medicine Institute, Melbourne, VIC, Australia, 3University Hospital of Geneva / Department of Pathology and Immunology, Geneva, Switzerland, 4University Medical Center Goettingen, Department of Neurology, Goettingen, Germany Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Glatiramer acetate (GA) is a widely used approved MS therapy. Anti-CD20-mediated B cell depletion is currently investigated in MS and has generated tremendously encouraging results. To date, no long-term treatment paradigm exists however and it remains unknown whether pathogenic B cell function returns upon cessation of treatment and

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B cell reappearance. Accordingly, we investigated in experimental autoimmune encephalomyelitis (EAE) whether GA could prevent (re)development of pathogenic B cell properties after cessation of anti-CD20 treatment. Methods: C57Bl/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) p35-55 or recombinant (r)MOG 1-117 protein. 150 µg GA/d was injected prior to immunization or after depletion of B cells, achieved by 3 weekly injections of 0.2 mg murine anti-CD20. In mice preventatively treated with GA, B cells were analyzed for expression of activation markers, co-stimulatory molecules and secretion of cytokines. For functional evaluation, B cells were co-cultured with naïve MOG-specific T cells; T cell proliferation and differentiation was evaluated by FACS. Results: GA-treatment ameliorated EAE induced by MOG p3555, which was associated with a reduced expression of CD69, an upregulation of MHCII and CD86 as well as a reduced secretion of IL-6 by B cells. When used as antigen presenting cells (APC), B cells from GA-treated mice revealed an increased capability to generate T regulatory cells whereas differentiation into Th1 and Th17 cells was unaltered. In experiments on the combined use of anti-CD20 and GA, B cell depletion exacerbated EAE induced by MOG p35-55, which referred to abrogation of regulatory B cell properties mediated by un-activated B cells. Added GA treatment reversed this exacerbation. Conversely, anti-CD20 ameliorated EAE induced by MOG protein, a model in which B cells get activated. Upon cessation of anti-CD20 treatment and reappearance of B cells, disease severity returned to the level of the control group, while initial clinical benefit mediated by anti-CD20 was prolonged by sequential GA treatment. Conclusion: The sequential combination of anti-CD20 and GA, maintaining and fostering B cell regulation upon reappearance of B cells could be a very powerful therapeutic approach in MS, which may circumvent continuous anti-CD20 treatment with an unknown long-term immunological risk profile.

Darius Häusler receives research support from the Startförderung Programm of the Universitätsmedizin Göttingen. Claude C.A. Bernard has nothing to disclose. Linda Feldmann has nothing to disclose. Wolfgang Brück has nothing to disclose. Patrice H. Lalive received honoraria for speaking from BiogenIdec, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees from Biogen-Idec, Geneuro, Genzyme, Merck Serono , Novartis, Sanofi-Aventis, Teva; research grants from Biogen-Idec, Merck Serono, Novartis. Martin S. Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme. He receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. P667 Return of clinical and radiological disease activity after cessation of natalizumab in patients with relapsing remitting and secondary progressive multiple sclerosis


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U. Proschmann, K. Thomas, T. Ziemssen Neuroimmunological Lab and Multiple Sclerosis Center, Center of Clinical Neuroscience, Dep. of Neurology, University Hospital Carl-Gustav Carus, Dresden University of Technology, Dresden, Germany Backround: Natalizumab (NAT) as highly efficacious therapy for relapsing remitting multiple sclerosis (RRMS) is associated with increased risk of developing progressive multifocal leukoencephalopathy (PML). On the other site, if NAT treatment is stopped because of PML concerns, a return or even increased rebound of disease activity is observed in relapsing remitting and even secondary progressive MS (SPMS) patients. Methods: 20 RRMS and SPMS (ASCEND trial) patients were monitored before and after cessation of NAT by clinical evaluation (relapse/EDSS) and MRI (new T2/gadolinium enhancing (GdE) lesions).In addition, blood samples were analyzed for free and cell bound NAT and VLA-4 expression before NAT cessation (baseline) and every 4 weeks after stopping NAT treatment. Free and cellbound NAT as well as VLA-4 expression were measured by FACS. Results: After cessation of NAT free plasma NAT concentration decreases to 67,2; 90,3; 98,6 and 99,9% after 4, 8, 12 and 16 weeks in both patient groups. Cell bound NAT could be demonstrated up to 16 weeks after last infusion. For VLA-4 expression a gradual increase was observed. Clinical confirmed relapses occurred in 80% of RRMS patients after 12-20 weeks whereas 20% of NAT-treated SPMS patients presented relapses after 12 weeks. New GdE lesions were detected 16 or/and 20 weeks after NAT cessation in nearly all RRMS patients whereas 30% of SPMS patients showed new GdE T2 lesions after 9 or 12 weeks. Conclusion: We could demonstrate that cessation of NAT treatment is associated with a return of clinical and radiological disease activity in RRMS and to some extent also in SPMS patients. Clinical relapses and new T2 lesions occur when free and cell bound NAT reaches values comparable to untreated MS patients. Measuring free and cell bound NAT as well as observing MR activity could be a potential tool to find an optimal and individualized timepoint to start another disease modifying therapy after NAT cessation. Disclosure U. Hainke received travel support from Biogen Idec and Novartis. K. Thomas received honorarium from Novartis, Bayer, and Biogen Idec. T. Ziemssen is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck-Serono, Teva, Genzyme, and Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, and Almirall; and has received research support from Bayer Healthcare, Biogen Idec, Genzyme, Novartis, Teva, and Sanofi.

Neuroprotection P668 Therapeutic effect of SINE compounds in a preclinical model of multiple sclerosis and an in vitro screening of related viruses

S. Tamir1, J.D. Haines2, O. Herbin3, K. Alexandropoulos3, Y. Landesman1, D. McCauley1, S. Shacham1, P. Casaccia4 1Karyopharm Therapeutics, Inc., Newton, MA, 2Department of Neuroscience, 3Division of Clinical Immunology, Department of Medicine, 4Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, United States Background: The nuclear export protein XPO1 (CRM1) has surfaced as an attractive target for the treatment of neurologic and inflammatory disorders like multiple sclerosis (MS), as well as various viral infections. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally-bioavailable, and well-tolerated XPO1 inhibitors. Here, we evaluate the neuroprotective and anti-inflammatory effects of SINE compounds in a preclinical model of MS and highlight their therapeutic potential for the treatment of MS and related viral infections. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female, C57BL/6J mice on day 0. At the onset of hind-limb paralysis (~ day 16), mice were dosed via oral gavage with either vehicle or SINE compound (75 mg/kg KPT-276 or 7.5 mg/kg KPT-350 QoD for 12 days). Clinical symptoms and hindlimb locomotor function were monitored. Mice were sacrificed on day 28 and spinal cords were removed, sectioned and treated with H&E for histopathological characterization or PBS for flow cytometry (FACS) analysis. Finally, an in vitro screen of SINE compound activity against a panel of 51 viruses was conducted. Results: SINE compounds slowed the progression of EAE symptoms with no overt signs of toxicity. Vehicle-treated mice progressed to full quadriplegia, while the motor activity of SINEtreated mice improved substantially (% change in disease score vs. vehicle: KPT-276: - 60%, KPT-350: -75%). Histopathological characterization demonstrated preserved axonal integrity in demyelinated axons and reduced inflammatory lesions in the lumbosacral spinal cord. FACS analysis of immune cells in the spinal cord after SINE compound treatment showed a reduction in CD45+ leukocytes, B220+ B cells, and CD4+ and CD8+ T cells vs. vehicle. Furthermore, SINE compounds inhibited the replication of >25 viruses, including 5 suspected causes of MS pathogenesis, relapse and comorbidity: JC virus, EBV, HSV, influenza A H1N1, and adenovirus. Conclusion: SINE compounds halt the symptoms of demyelination in a murine model of MS by modulating aberrant subcellular transport in neurons and immune cells, thereby reducing the inflammatory infiltrates and enhancing neuroprotection. These compounds also reduce viral replication with broad-spectrum effect. Collectively, these findings suggest the unique potential of SINE compounds to act as combined immunomodulatory, neuroprotective and antiviral treatments for MS and related viral infections. Disclosure Tamir: employee of Karyopharm Therapeutics, Inc.; Haines: nothing to disclose; Herbin: nothing to disclose; Alexandropoulos: nothing to disclose; Landesman: employee of Karyopharm Therapeutics, Inc.; McCauley: employee of Karyopharm Therapeutics, Inc; Shacham: executive of Karyopharm Therapeutics, Inc.; Casaccia: nothing to disclose.


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Poster Session 1, 22(S3) P669 Alterations in the secretome of MSCs isolated from patients with MS are in keeping with their reduced neuroprotective potential under conditions of oxidative stress J. Redondo1, P. Sarkar1, K. Kemp1, K.J. Heesom2, A. Wilkins1, N.J. Scolding1, C.M. Rice1 1MS and Stem Cell Laboratories, School of Clinical Sciences, 2Proteomics Facility, Biomedical Sciences, University of Bristol, Bristol, United Kingdom Cell-based therapy with mesenchymal stromal cells (MSCs) is being investigated as a treatment for multiple sclerosis (MS) in view of neuroprotective and anti-inflammatory properties of MSCs. However, we have recently shown that MSCs isolated from patients with MS (MS MSCs) have reduced expansion potential ex vivo and fail to protect neurons in a model of oxidative stress. Given that many MSC reparative properties are mediated via the MSC secretome - the collective term for factors secreted as soluble molecules and/or in extracellular vesicles - we compared the composition of media conditioned by MSCs isolated from patients with MS (MS MSCcm) and control subjects (MSCcm). MSCs were isolated from marrow donated by those undergoing total hip replacement or participating in the ‘ACTiMuS’ trial of unselected autologous marrow infusion in progressive MS (NCT01815632). Using tandem mass spectrometry, we noted relative reductions in the concentration of factors predisposing to increased oxidative stress in age-matched MS MSCcm including Cu-Zn superoxide dismutase1 (SOD1), mitochondrial fumarase, peroxiredoxin1 and glutathione transferase1. Reduced concentration of SOD1 was quantified using ELISA and reduced expression of SOD1, fumarase and glutathione transferase1 confirmed using western blot analysis. We also observed reductions in the expression of master regulators of ROS scavenging enzymes in MS MSCs including peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α) and nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, there was no significant change in expression of the peroxisomal enzyme catalase or in MSC secretion of a wide range of known neuroprotective growth factors. Our findings suggest that MS MSCs have altered secretion and expression of a number of proteins relevant to antioxidant defence and point towards altered mitochondrial function. We note that others have demonstrated that replicative senescence in MSCs is associated with reduced expression of antioxidant enzymes, raising the possibility of a link between oxidative stress and our finding of reduced MS MSC expansion potential. Further work will explore mitochondrial function and transfer in MS MSCs in greater detail and will determine whether the observed changes contribute to increased susceptibility of MS MSCs to oxidative stress as well as underlying the observed impairments in MSCmediated neuroprotection and expansion. Disclosure The authors have no relevant disclosures. P670 Teriflunomide impacts primary microglia and astrocyte functions in vitro A. Edling, L. Woodworth, R. Agrawal, A. Mahan, T. Garron, N. Hagan, B. Siders

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Sanofi Genzyme, Framingham, MA, United States Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS (RRMS). Teriflunomide selectively and reversibly blocks the mitochondrial enzyme dihydroorotate dehydrogenase, thereby limiting the expansion of peripherally activated T and B cells, and limiting the number of these cells available to enter the CNS and mediate inflammatory processes in MS. As teriflunomide crosses the blood brain barrier it may have a direct effect on activated CNSresident cells, such as microglia and astrocytes, which also contribute to both neuroinflammation and neurodegeneration in MS. Objective(s): To examine the direct in vitro effects of teriflunomide on microglia and astrocyte function and viability. Methods: Primary astrocytes and microglia were isolated from rat and mouse neonatal brains, respectively. Cells were pre-treated with teriflunomide at concentrations ranging from 0.8 µM to 25 µM for 16-24 hours prior to stimulation with lipopolysaccharide (LPS) or LPS and interferon (IFN)-γ. Cytokine production was measured by ELISA, cell viability by Cell Titer Glo® assay, phagocytosis by Zymosan particle assay, and nitrite production by Griess reaction assay. The protective effect of teriflunomide against hydrogen peroxide (H2O2)-induced cytotoxicity in astrocytes was measured by assessing cell viability. Results: Teriflunomide treatment followed by activation demonstrated no impact on primary rodent microglia or astrocyte viability. In activated microglia, teriflunomide pre-treatment decreased production of the pro-inflammatory mediators interleukin (IL)-6, IFNγ-induced protein-10, monocyte chemoattractant protein-1, IL-12p40 and nitrite, and increased production of the anti-inflammatory cytokine IL-10, while having no impact on phagocytic activity. Teriflunomide pre-treated and activated astrocytes showed a reduction in tumour necrosis factor-α, nitrite, and IL-1β production. In addition, teriflunomide pre-treatment also protected activated astrocytes from H2O2-induced cytotoxicity. Conclusions: Here, we demonstrate that in vitro teriflunomide can directly impact activated microglia and astrocyte functions, by altering cytokine production. These results suggest that teriflunomide may provide neuroprotective effects within the CNS, which could contribute to the clinical and radiological benefits observed in patients with RRMS treated with teriflunomide. Disclosure Study supported by Sanofi Genzyme. AE, LW, RA, AM, TG, NH, BS: Employees of Sanofi Genzyme. P671 MD1003 halts axonal degeneration and locomotor disability in a model of X-linked adrenoleukodystrophy C. Casasnovas1, S. Fourcade2,3, J. Parameswaran2,3, M. Ruiz2,3, L. Grau2,3, J. Riera2,3, F. Sedel4, A. Pujol2,3,5 1Hospital Universitari de Bellvitge, 2IDIBELL, 3CIBERER U 759, L’Hospitalet de Llobregat, Spain, 4MedDay Pharmaceuticals, Paris, France, 5ICREA, Barcelona, Spain Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases such as Multiple Sclerosis or adrenoleukodystrophy (X-ALD), in which oxidative stress, bioenergetic failure and/or inflammation are often identified


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as pathogenic factors. In this project we are using a mouse model of X-ALD to: i) investigate if MD1003 may be able to improve the clinical signs of the disease (axonal degeneration and locomotor deficits), and ii) elucidate by which molecular and biochemical mechanisms it operates. Results: X-ALD is a monogenic neurometabolic disorder caused by inactivation of the peroxisomal transporter of very long-chain fatty acids ABCD1. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress, bioenergetic failure and inflammation play major roles in the pathogenesis of X-ALD. Our results indicate that MD1003 normalizes ATP and mtDNA levels in Abcd1- mice spinal cords. This induction of mtDNA is correlated to an increase of mitochondrial biogenesis factors and to inhibition of the alternative NFkB pathway (NFkB2) and downstream cytokine production. Most importantly, the treatment halted the late-onset axonopathy and the associated locomotor disability as assessed by treadmill and bar-crossed tests in a mouse model of X-ALD (Abcd1-/abcd2 null mice). Conclusion: These results show preclinical safety and efficacy in a mouse model of X-ALD, and reveal novel molecular mechanisms of action of MD1003 in neurodegeneration. Future studies should address the effects of this drug on other axonopathies in which bioenergetic dysfunction and inflammation are contributing factors. Disclosure The study has been funded by MedDay Pharmaceuticals P672 Penetration of dimethyl fumarate into cerebrospinal fluid and brain: a pharmacokinetic and tissue distribution study in monkeys N. Penner, B. Zhu, C. Woodward, M. Rogge Biogen, Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been approved for the treatment of patients with relapsing multiple sclerosis (MS) or relapsing remitting MS. Studies of DMF in rats and mice suggested DMF and its metabolites penetrate into central nervous system (CNS), however, pharmacokinetics of CNS penetration in monkeys, the most relevant model for clinical translation, have not been studied. Objectives: To investigate the pharmacokinetics of monomethyl fumarate (MMF) in plasma and cerebrospinal fluid (CSF), and tissue distribution of DMF and its metabolites in brain and spinal cord of monkeys. Methods: Four cynomolgus monkeys were dosed intra-duodenally with 14C-DMF (25 mg/kg). Plasma and lumbar CSF samples were collected at pre-dose and then at 0.5, 1, 1.5, 2, 4, and 6 h post-dose. Tissue distribution in the CNS was examined at 2 and 4 h by quantitative whole-body autoradiography. Results: Consistent with previous findings, DMF was not detected in plasma or CSF samples at any time point. Monomethyl fumarate (MMF) was detected in all collected samples as a major metabolite of DMF. Glutathione conjugates of DMF and MMF

were minor in plasma and CSF. For MMF, plasma Tmax occurred at 0.5 hours post-dose, while CSF Tmax was delayed to 1.5 h post-dose. Total radioactivity profile was similar, with Tmax in plasma and CSF at 1 and 2 h, respectively. At CSF Cmax, CSF concentrations of MMF and total radioactivity were on average 15% and 30% of plasma concentration. In the terminal phase (3-6 h), the ratio increased to ~40% for both. The highest concentration of DMF-radioactivity in CNS tissues was observed in the frontal lobe cortex, the basal ganglia and thalamus; levels in white matter, optic nerve and spinal cord were 2-3-fold lower. It was shown that DMF-derived radioactivity in CNS is largely bound to tissues. Conclusions: DMF-derived radioactivity and MMF penetrate into CNS tissues and CSF of monkeys after an oral dose of DMF. Disclosure Supported by: Biogen Natalia Penner: employee of and holds stock/stock options in Biogen Bing Zhu: employee of and holds stock/stock options in Biogen Caroline Woodward: employee of and holds stock/stock options in Biogen Mark Rogge: employee of and holds stock/stock options in Biogen P673 Association of serum 25-hydroxyvitamin D levels with disability and relapses in relapsing-remitting multiple sclerosis H.A. Idrisoglu1, M. Idrisoglu2, D. Idrisoglu3, H. Memısoglu1, N. Polat3 1Neurology, Istanbul University Faculty of Medicine, 2Pharmaceutic Technology Department, World Medıcıne Drugs, 3Neurology, Merıd Health Company, Istanbul, Turkey Aim: The aim of this study was to evaluate the association of serum 25-hydroxyvitamin D(25(OH)D) with disability and frequency of relapses in relapsing-remitting multiple sclerosis(MS) patients. Methods: The study included 100 patients with relapsing-remitting MS who were receving immune-modulating drugs and no vitamin D supplementation.The concentration of 25 (OH)D was measured in January 2014-January 2016.The level of disability was assessed twice according to the Expanded Disability Status Scale(EDDS).The 25(OH)D levels were compared with the occurrence of relapses and the level of disability. Result: 100 patients were diagnosed with relapsing remitting multiple sclerosis between january 2014 january 2016. They are evaluated for 25 OH D levels. 30 healthy volunteer were taken to the study. There are 30 healhy control. There are 70 women, 30 men. Female/male ratio is 2.3/1. Average EDSS score was 2. Age interval of male patients was 22 - 65. Average (OH) D level in male patients was 8. Average age in 70 women was 40. The age interval varies 24 - 67. Average (25 OH) D was 11. The interval of (25 OH) D was 4 - 187. Conclusion: Male and female multiple sclerosis patients were compared with the control group. (25 OH) D level were lower in these patients. We observed that (25 OH) D supplementation along with the immunomodulators were effective on the relapse and symptoms.


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Poster Session 1, 22(S3) Discussion: Vitamin D3 played an important role in regulating the genes. Vitamin D3 deficiency increases the risk of cancer, osteoporosis, diabetes, multiple sclerosis, hypertension, immunological and inflamatory diseases. In this study we found low 25(OH)D) levels in MS patients.

Julie Falardeau: nothing to disclose Dennis Bourdette: nothing to disclose

Disclosure

P675 Safety and tolerability of opicinumab in relapsing multiple sclerosis: the Phase 2b SYNERGY trial S. Freeman1, K. Selmaj2, O. Fernandez3, L. Grimaldi4, E. Silber5, G. Pardo6, S.M. Freedman7, Y. Zhang1, L. Xu1, M. Mellion1, D. Cadavid1, on behalf of the SYNERGY Investigators 1Biogen, Cambridge, MA, United States, 2Medical University of Lodz, Lodz, Poland, 3Hospital Regional Universitario, Institute of Clinical Neurosciences, IBIMA, Málaga, Spain, 4Unità Operativa Neurologia, Fondazione Istituto San Raffaele ‘G. Giglio’ di Cefalù, Cefalù, Italy, 5King’s College Hospital, London, United Kingdom, 6OMRF Multiple Sclerosis Center for Excellence, Oklahoma City, OK, 7Raleigh Neurology Associates, Raleigh, NC, United States

The level of Vıtamın D3 was found in low concantratıon in the Relapsing-remitting Multiple Sclerosis. P674 Oral lipoic acid as a treatment for acute optic neuritis: a blinded, placebo-controlled randomized trial V. Yadav, M. Mass, G. Marracci, R. Wanchu, A. Fryman, B. Hills, J. Falardeau, D. Bourdette Oregon Health & Science University, Portland, OR, United States Background: Lipoic acid (LA) is an inexpensive, orally active antioxidant that can treat experimental acute optic neuritis (AON) and experimental autoimmune encephalomyelitis effectively. Recently, LA showed slower whole brain atrophy in secondary progressive multiple sclerosis, suggesting a neuroprotective effect. Thinning of the retinal nerve fiber layer (RNFL) as detected by optical coherence tomography (OCT) occurs 3-6 months following AON, indicating retinal nerve ganglion cells axonal degeneration. While corticosteroids speed AON recovery, neuroprotective therapies for AON are lacking. Goal: To determine whether LA is neuroprotective in AON. Methods: We conducted a double-masked, placebo-controlled 24-week long pilot trial to assess the effectiveness of LA in AON. Subjects were randomized within 14 days of AON diagnosis to receive LA (1200 mg orally once a day) or placebo for 6 weeks. The outcome measures included: Primary - difference in affected eye RNFL thickness from baseline to 24 weeks post-enrollment; Secondary - difference in affected eye RNFL thickness from baseline to 12 weeks post-enrollment, changes from baseline to 12 and 24 week in visual acuity, low-contrast sensitivity, and visual field. Results: We enrolled 30 subjects (average age - 38.6 years (SD: 10.3); 63% female) with 3 who were lost to follow-up. 13 (43%) of the subjects received steroid treatment. Mean baseline RNFL thickness in the affected eye and unaffected eye at: Baseline 106.3 µm (SD: 23.1) and 96.4 µm (SD: 10.5); 12 week - 88.5 µm (SD: 18.7) and 96 µm (SD: 13.3); 24 week - 79.4 µm (SD: 22.8) and 95.9 µm (SD: 15.2) respectively. Treatment was tolerated well. The last subject exits the study in June 2016. Conclusions: The results of the trials, including effects of LA on changes in RNLF and other outcome measures will be presented. Sponsor: National Multiple Sclerosis Society Foundation, Race to Erase MS Foundation Supported By: Pure Encapsulations® Disclosure Vijayshree Yadav: nothing to disclose Michele Mass: nothing to disclose Gail Marracci: nothing to disclose Rohan Wanchu: nothing to disclose Allison Fryman: nothing to disclose Bill Hills: nothing to disclose

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Neurorepair

Background: Current relapsing MS therapies reduce the risk of disease activity/progression related to inflammation while tissue reparative treatments remain an unmet need. Opicinumab (anti-LINGO-1; BIIB033) is a human monoclonal antibody candidate MS reparative agent that blocks LINGO-1, a CNS-specific negative regulator of myelination and neuroaxonal regeneration. A Phase 2a proof of biology study (RENEW) assessing participants with acute optic neuritis showed evidence of remyelination with opicinumab, and was welltolerated with a similar frequency of adverse events as placebo. Goals: Assess the safety/tolerability of opicinumab vs placebo in participants with relapsing MS when used chronically and concurrently with interferon (IFN) beta-1a. Methods: SYNERGY (NCT01864148) is a recently completed randomised, multicentre, double-blind, placebo-controlled study. Eligible participants were aged 18-58 y and had a diagnosis of RRMS (2005 McDonald criteria) or SPMS (Lublin and Reingold criteria) with disease activity in the previous year. Disease activity for RRMS was defined as ⩾2 distinct episodes of: clinical relapse, gadolinium-positive (Gd+) lesion or new T2 lesion on brain/spinal cord MRI; for SPMS it was ⩾1 occurrences of clinical relapse or Gd+ lesion on brain/spinal cord MRI. Enrolled participants were randomised to 3, 10, 30 or 100 mg/kg opicinumab intravenous or placebo (ratio 1:2:2:2:2) every 4 weeks (total=19 doses), also received IFN beta-1a 30 mcg intramuscular once weekly for 72-84 weeks, and were followed for 84 weeks. The parameters used to assess safety were: adverse events, serious adverse events, clinical laboratory test results (haematology, blood chemistry and urinalysis), physical examination findings, electrocardiogram, vital signs results, weight, serum antibodies to opicinumab, disease activity by brain MRI metrics, MS signs and symptoms, annualised relapse rate, concomitant medication use, and Columbia Suicide Severity Rating Scale score. Results: Individuals were screened at 72 sites in 12 countries and 330 participants with RRMS and 88 with SPMS (N=418) were randomised; 330 completed the study. Details of the safety/tolerability of opicinumab will be presented. Conclusions: Safety/tolerability information is important for the ongoing clinical development of opicinumab; SYNERGY will provide valuable data, including the most suitable dose to use in potential future trials, based on efficacy, safety and tolerability assessments.


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Disclosure This study was supported by Biogen (Cambridge, MA, USA). Stefanie Freeman, Yiwei Zhang, Lei Xu, Michelle Mellion and Diego Cadavid: employees of and stockholders in Biogen. Krzysztof Selmaj: consultant/speaker for Biogen, Genzyme, Novartis, Ono, Roche, Synthon, and Teva. Oscar Fernandez: consulting/advisor fees and research support from Actelion, Allergan, Almirall, Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva. Luigi Grimaldi: serves on a scientific advisory board for Merck Serono; has received funding for travel or speaker honoraria from Merck Serono, Biogen, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd. and Bayer HealthCare; and receives institutional research support from Biogen and the Serono Foundation. Eli Silber and/or his unit has received support and/or speaker/consulting fees from the following companies: Bayer HealthCare, Biogen, Merck Serono, Novartis, Roche and Teva. Gabriel Pardo: consultant/speaker for Biogen, EMD Serono, Genentech, Genzyme/Sanofi, Novartis and Teva. S. Mitchell Freedman: serves on advisory boards for Biogen, Genentech, Genzyme, Novartis and Teva, and is on the adjunct faculty (non-reimbursed position) of the University of North Carolina, Chapel Hill. Biogen provided funding for medical writing support in the development of this abstract. Becky Gardner PhD (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P676 Mesenchymal stem cell Labeling for In vivo cell tracking S.M. Planchon1, J. Reese-Koc2,3, B. Hooper2,3, D. Kaplan4, N. Kaye4, B.M. Helfer5, C.F. O’Hanlon5, J.A. Cohen1 1Mellen Center, Cleveland Clinic, 2Case Comprehensive Cancer Center and National Center for Regenerative Medicine, Case Western Reserve University, 3Seidman Cancer Center, University Hospitals Case Medical Center, 4CellPrint Biotechnology, LLC, Cleveland, OH, 5Celsense, Inc, Pittsburgh, PA, United States Background: Mesenchymal stem cell (MSC) transplantation is currently under investigation as a potential treatment for MS. The ability to track MSCs in vivo after administration is an important step in developing this therapy. Recent development of the paramagnetic cell label, Cell Sense (CS), provides a promising way for this analysis to be performed. CS is an aqueous colloidal nanosuspension of a perfluorocarbon polymer with high content of the nonradioactive 19F isotope, which permits detection of labelled cells by MRI. Objectives: To assess the feasibility of labeling MSCs with CS and evaluate the effect on viability, phenotype, and function. Methods: Optimization of CS labeling into the clinical protocol for ex-vivo expansion of healthy normal donor bone marrow derived MSCs was performed with both fresh and cryopreserved MSCs. CS dose and labeling time matrices were implemented to refine the procedure. CS uptake by MSCs was assessed by nuclear magnetic resonance (NMR). The impact of CS labeling on viability was assessed by trypan blue staining; phenotype by flow cytometric analysis of cell surface markers; and function by

assessing protein levels of thirteen key signaling molecules (with CellPrintTM), a sensitive and quantitative flow cytometric staining technique. Results: Labeling of fresh and frozen MSCs using an optimal dose of 5 mg/ml CS were incubated for 24 hours. CS uptake was three times more efficient with fresh cells (6.46 x 1011 atoms/cell) compared to recently thawed MSCs (2.19 x 1011 atoms/cell) as detected by NMR. Viability was not affected by labeling with CS at the optimized dose and time combination. CS labeling had no effect on the expression of MSC-specific cell surface of markers (CD105, CD90, CD73). Expression levels of p-AKT(308), Musashi-2, ATG7, FoxP1, VEGF, and TGF-b were moderately changed. No effect was observed for HGF, b-catenin, MyD88, iNOS, p-p38, p-ERK1/2 and MMP-1. Conclusions: These data indicate that labeling MSCs with CS does not significantly affect the viability or phenotype. Whether there are changes in cell function requires further investigation. These results suggest that cell tracking by MRI of MSCs following IV infusion in humans is feasible with the use of CS. Disclosure Sarah M Planchon: Nothing to disclose. Jane Reese-Koc: Nothing to disclose. Brittney Hooper: Nothing to disclose. David Kaplan is an owner of CellPrint Biotechnology, LLC. Nicholas Kaye is an employee of CellPrint Biotechnology, LLC. Brooke Helfer is an employee at Celsense, Inc, manufacturer of Cell Sense, the 19F imaging reagent used herein. Charles F O’Hanlon, III is an employee and shareholder of Celsense, Inc., the manufacturer of Cell Sense, the 19F imaging reagent used herein. Jeffrey A Cohen reports personal compensation for consulting for Genentech, Genzyme, Novartis, and Receptos; as a speaker for Teva; and as Co-Editor of Multiple Sclerosis Journal Experimental, Translational and Clinical. P677 Human embryonic stem cell -derived oligodendrocyte progenitor cells provide long term immune-regulation and protection in a chronic-relapsing model of multuple sclerosis Y. Nishri1, D. Hampton2, E. Ben-Shushan3, B.E. Reubinoff3, S. Chandran2, T. Ben-Hur1 1Neurology, Hadassah University Hospital Ein Kerem, Jerusalem, Israel, 2Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom, 3The Sidney and Judy Swartz Embryonic Stem Cell Research Center, Hadassah University Hospital Ein Kerem, Jerusalem, Israel Multiple studies have highlighted the immune-regulatory, neurotrophic and neuroprotective properties of stem cells, providing the current rationale for clinical translation of cell therapy in multiple sclerosis (MS). Neural precursor cells inhibited the immunemediated injury in experimental autoimmune encephalomyelitis (EAE), resulting in a milder long term sequel. However, to date, it has not been shown whether stem cells induce ongoing therapeutic effects in a chronic active, relapsing-progressive model of MS. Also, while Oligodendrocyte progenitor cells are the main remyelinating cell type in the adult CNS, it is not known whether these cells exhibit also therapeutic immune-regulatory effects.


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Poster Session 1, 22(S3) We therefore examined whether human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (hOPCs) inhibit chronic relapsing EAE in the Biozzi mouse model. EAE was induced in Biozzi mice by immunization with spinal cord homogenate. The mice developed an acute relapse, followed by a chronic relapsing course, with active neuroinflammation, manily in the spinal cord, and typical demyelinated plaques in the spinal tracts with variable degrees of axonal injury and loss. hESC cultures were neuralized, and then exposed to retionic acid and purmorphamine for caudalization and ventralization. hOPC enriched cultures were propagated for 7-8 weeks prior to transplantation. hOPCs were transplanted intracerebroventricularly into Biozzi mice at day 30 post-EAE induction, at remission from the first clinical relapse. Olig2+ hOPCs were detected along spinal cord meninges during the 65 days of follow-up. Following transplantation, the animals exhibited a significant milder disease, in terms of mean and cumulative clinical scores, and reduced risk of developing a second relapse, as compared to vehicle-injected EAE mice. The hOPC-transplanted mice exhibited significantly less neuroinflammation (as indicated by CD3+ T cell and IBA-1+ microglial/macrophage infiltration) and significantly less demyelination and axonal loss (as indicated by Gold-Black and Bielchowsky staining, as well as by Toluidine-blue semi-thin stained cervical spine sections). Thus, we show here for the first time that hOPCs possess immune-regulatory and neuroprotective properties. Moreover, their beneficial effects persist long-term in vivo, following transplantation into a clinical-relevant model of chronic active MS. Disclosure Tamir Ben-Hur: Scientific advisory board member of Kadimastem, Mapi Pharma, Regenera Pharma, Stem Cell Medicine. Benjamin Reubinoff: CSO of Cell Cure Neuroscience, Scientific advisory board member of Kadimastem Yossi Nishri, David Hampton, Etti Ben-Shushan, Siddharthan Chandran: nothing to disclose Supported by a grant from BIRAX - The British Council P678 Quantifying remyelination in vivo - metabolic labeling of myelin in an animal model of multiple sclerosis R. Aharoni, C. Rosen, E. Shezen, M. Sela, R. Arnon Immunology, The Weizmann Institute of Science, Rehovot, Israel Myelin repair is a major goal for multiple sclerosis (MS) therapy. However, the lack of in vivo biomarkers for the detection of myelin content changes is a major obstacle for testing potentially remyelinating therapies. In this study we aimed to develop quantitative strategy to assess remyelination in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), in particular in the proteolipid protein (PLP) 139-151 peptide-induced model, in which extensive demyelination and remyelination are characteristic. Towards this end, we used the metabolic incorporation of the choline analog - propargyl-choline (P-Cho) into the central nervous system (CNS) to in situ label and visualize newly synthesized myelin. To quantify the specific P-Cho incorporation into myelin we further developed an unbiased computerized colocalization analysis, in which in sections co-

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stained for P-Cho, myelin and cell bodies, a surface was created in the white matter, and the region of interest (ROI) was defined as the P-Cho incorporated area, subtracted by the infiltrating cell bodies stained area, colocalized with the myelin stained area. Injection of P-Cho to mice recovering from EAE, either spontaneously or following treatment with glatiramer acetate (GA), resulted in significant elevation of P-Cho incorporation into the myelin in the spinal cord white matter. Furthermore, colocalization analysis revealed more remyelination in GA-treated mice compared to untreated mice, as indicated by both the area and the intensity of the P-Cho incorporation specifically into the myelin. This can be linked to previous immunohistochemical analyses, transmission electron microscopy (TEM) and magnetic resonance imaging (MRI) studies, in which GA promoted myelination in EAE- as well as at postnatal development. These findings indicate that newly synthesized myelin in the CNS can be detected and quantified by in vivo metabolic labeling, thus offering a novel strategy to assess remyelination in animal models and the remyelination potential of candidate therapies. Disclosure This study was supported by a research grant form Teva

Long-term treatment monitoring P679 Efficacy and safety of alemtuzumab in patients with RRMS is durable over 10 years: follow-up from the CAMMS223 study K.W. Selmaj1, M. Habek2, A.D. Bass3, D. Brassat4, V. Brinar2, A.J. Coles5, A. Vladic2, S. Wray6, D.H. Margolin7, K. Thangavelu7, M. Chirieac7, L. Kasten8, E.J. Fox9, on behalf of the CAMMS223 Investigators 1Medical University of Łódź, Łódź, Poland, 2University Hospital Centre Zagreb, Zagreb, Croatia, 3Neurology Center of San Antonio, San Antonio, TX, 4UCSF Medical Center, San Francisco, CA, United States, 5University of Cambridge School of Medicine, Cambridge, United Kingdom, 6Hope Neurology MS Center, Knoxville, TN, 7Sanofi Genzyme, 8PROMETRIKA LLC, Cambridge, MA, 9Central Texas Neurology Consultants, Round Rock, TX, United States Background: In phase 2 (CAMMS223; NCT00050778) and 3 (CARE-MS I [NCT00530348]; CARE-MS II [NCT00548405]) trials, alemtuzumab improved clinical and MRI outcomes in relapsing-remitting MS (RRMS) patients versus subcutaneous interferon beta-1a. An extension study (NCT00930553) demonstrated durable efficacy of alemtuzumab in the absence of continuous treatment up to 10 years. Goal: To evaluate efficacy and safety of alemtuzumab over 10 years in patients from CAMMS223 enrolled in the extension. Methods: In CAMMS223, patients with ⩾2 relapses during the previous 2 years, Expanded Disability Status Scale (EDSS) score ⩽3, and ⩾1 Gd-enhancing (Gd+) lesion at baseline (BL) received 2 courses of alemtuzumab 12mg (Month 0: 5 days; Month 12: 3 days); a third course was possible based on T-cell counts. Patients could participate in an extended follow-up period, and then enroll in the extension with as-needed alemtuzumab retreatment for relapse or MRI activity. Another DMT could be provided per investigator discretion. Assessments: annualized relapse rate


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(ARR), EDSS, 6-month confirmed disability worsening [CDW: ⩾1-point EDSS increase; ⩾1.5-point if BL EDSS=0]), Gd+ lesions, lymphocyte counts, and AEs. Results: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the extension; 57 (95%) remained on study at Year 10. Over 10 years, 20 (33%) of patients received only 2 courses of alemtuzumab; 26 (43%), 7 (12%) and 6 (10%) received 3, 4 and 5 courses, respectively. Lymphocytes were depleted and then repopulated above the lower limit of normal after each treatment course. Through 10 years, ARR remained low (0.08), mean EDSS change from BL to Year 10 was +0.12, 78% had stable (⩽0.5-point change) or improved (⩾1-point improvement) EDSS, and 76% had no evidence of 6-month CDW. Over Years 1, 2, and 3 of the extension, most patients had no Gd+ lesions (Extension BL: 92%; Year 1: 94%; Year 2: 87%; Year 3: 95%). The most common AEs, infusion-associated reactions, decreased with additional courses. No patients withdrew due to AEs. Serious AE rate was low. The rate of thyroid AEs peaked at Year 3 and declined thereafter. Conclusion: Alemtuzumab demonstrated durable clinical efficacy through Year 10, with most patients receiving ⩽3 treatment courses. Safety findings were consistent with other alemtuzumab trials. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for patients with RRMS. Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. KWS: Consulting and/or speaking fees (Biogen, Roche, Merck, Synthon, Sanofi Genzyme, Novartis). MH: Nothing to disclose. AB: Consulting fees/fees for non CME services from commercial interest or their agents/ grant and Research Support (Biogen, Mallinckrodt, Novartis, Roche-Genentech, Sanofi Genzyme, Teva Neuroscience). DB: Advisory board participant, lecture and travel (Bayer, Biogen, Merck, Sanofi Genzyme, and Teva). VB: Nothing to disclose. AJC: Consulting fees, grant support, and lecture fees (Bayer Schering Pharma and Sanofi Genzyme) on behalf of the University of Cambridge; and personal remuneration for lecture fees from July 2014. AV: Nothing to disclose. SW: Consultant, principle investigator, and/or speaker (Alkermes, Bayer, Biogen, EMD Serono, Novartis, Roche-Genentech, Sanofi Genzyme, Teva). DHM, KT, and MC: are employees of Sanofi Genyme. LK: Compensation as a statistical consultant (Sanofi Genzyme). EF: Consultancy fees, honoraria, travel, and research support (Acorda, Bayer Healthcare, Biogen, Eli Lilly, EMD Serono, Novartis, Opexa Therapeutics, Roche-Genentech, Sanofi Genzyme, and Teva). P680 Alemtuzumab improves clinical outcomes over 4 years in patients with relapsing-remitting multiple sclerosis who switched from SC IFNB-1a: CARE-MS II extension study 4-year follow-up

A.N. Boyko1, M. Barnett2, D. Brassat3, D. Dive4, R.M.M. Hupperts5, J. Lycke6, X. Montalban7, B. Sharrack8, S. Wray9, D.H. Margolin10, K. Thangavelu10, M. Chirieac10, H. Wiendl11, on behalf of the CARE-MS II Investigators 1Pirogov’s Russian National Research University & Demyelinating Diseases Center at Usupov’s Hospital, Moscow, Russian Federation, 2University of Sydney, Sydney, NSW, Australia, 3Purpan Hospital and Mixed Unit of Research 1043, University of Toulouse, Toulouse, France, 4University Hospital Centre of Liège, Liège, Belgium, 5Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 6University of Gothenburg, Gothenburg, Sweden, 7Vall d’Hebron University Hospital, Barcelona, Spain, 8Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 9Hope Neurology, Knoxville, TN, 10Sanofi Genzyme, Cambridge, MA, United States, 11University of Münster, Münster, Germany Background: In CARE-MS II (NCT00548405), alemtuzumab significantly reduced the annualised relapse rate (ARR) versus SC IFNB-1a over 2 years in patients with active relapsing-remitting multiple sclerosis (RRMS) and an inadequate response (⩾1 relapse) to prior therapy at baseline (BL). Patients completing CARE-MS II could enter an extension study (NCT00930553), in which SC IFNB-1a-treated patients switched to alemtuzumab. Goals: To evaluate 4-year efficacy and safety of alemtuzumab in patients who switched from SC IFNB-1a in CARE-MS II. Methods: Following SC IFNB-1a discontinuation, patients received 2 courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days), followed by as-needed alemtuzumab for relapse or MRI activity or DMT per investigator discretion. Assessments: ARR, 6-month confirmed disability worsening (CDW; ⩾1-point EDSS increase [⩾1.5-point if BL EDSS=0]) and confirmed disability improvement (CDI; ⩾1-point EDSS decrease [BL score ⩾2.0]), EDSS stability (⩽0.5-point change) or improvement (⩾1.0-point decrease), no evidence of disease activity (NEDA), and adverse events (AEs). Results: 125/146 (86%) CARE-MS II SC IFNB-1a-treated patients who enrolled in the extension remained on study 4 years later. ARR decreased from 0.52 during SC IFNB-1a treatment to 0.15 over the first 2 years after switching to alemtuzumab. Proportions of patients with no evidence of relapse increased from 48% after SC IFNB-1a treatment to 80% over 2 years after switching to alemtuzumab; the proportion achieving NEDA increased from 14% to 41%. In Year 4, ARR remained low (0.17), and proportions with no evidence of relapse (85%) and achieving NEDA (60%) remained high. 70% of patients had improved/stable EDSS after switching. Over 4 years after switching, 80% had no evidence of 6-month CDW; 18% had 6-month CDI. These results were achieved with 71% of patients receiving no additional treatment after their initial 2 courses of alemtuzumab. The 4-year AE profile of alemtuzumab after switching was consistent with alemtuzumab-treated patients in the core study. Conclusion: Improvements in clinical outcomes were observed in the first 2 years after switching from SC IFNB-1a to alemtuzumab and were durable over the following 2 years, with most patients receiving no additional treatment. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for RRMS patients who switched from SC IFNB-1a.


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Poster Session 1, 22(S3) Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. ANB: Consulting fees/participated in clinical trials (Bayer, Biogen, Sanofi Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva). MB: Institutional support for research, speaking and/or participation in advisory boards (Biogen, Novartis, and Sanofi Genzyme), and research consultant (Medical Safety Systems). DB: Advisory board participant, lecture and travel (Bayer, Biogen, Merck, Sanofi Genzyme, and Teva). DD: Institutional honoraria for advisory board participation and travel grants (Bayer, Novartis, Merck-Serono, Sanofi Genzyme, and Teva). RMMH: Research grants, speaker´s fees, and honoraria for advisory boards (Biogen, Merck, Novartis, Sanofi Genzyme, and Teva). JL: Travel support and/or lecture honoraria (Biogen, Novartis, Sanofi Genzyme, and Teva); scientific advisory boards for (Almirall, Biogen, Novartis, Sanofi Genzyme, and Teva); editorial board of Acta Neurologica Scandinavica; and unconditional research grants (Biogen, Novartis, and Teva). XM: Consulting and/or speaking fees (Almirall, Bayer, Biogen, EMD Serono, Genentech, Geneuro, Merck, Neurotec, Novartis, Roche, Sanofi, Sanofi Genzyme, and Teva). BS: Nothing to disclose. SW: Consultant, principal investigator, and speaker (Bayer, Biogen, EMD Serono, Novartis,); consultant and principal investigator (Genentech and Roche); principal investigator (Alkermes); and principal investigator and speaker (Teva). DHM, KT, and MC: Employees of Sanofi Genzyme. HW: Consulting and/or speaking fees, and grant/research support (Bayer, Bayer Schering Pharma, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Novo Nordisk, Sanofi, and Teva Neuroscience).

P681 Durable suppression of disease activity by alemtuzumab in the absence of continuous treatment over 6 years in patients with active relapsing-remitting multiple sclerosis and an inadequate response to prior therapy (CARE-MS II) C. LaGanke1, J. De Sèze2, M.S. Freedman3, M. Habek4, R.M.M. Hupperts5, V. Limmroth6, R.A.L. Macdonell7, K.W. Selmaj8, D.H. Margolin9, K. Thangavelu9, E. Havrdova10, on behalf of the CARE-MS II Investigators 1North Central Neurology Associates, Cullman, AL, United States, 2Hôpital Hautepierre, Strasbourg, France, 3University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Department of Neurology, University of Zagreb, School of Medicine, Zagreb, Croatia, 5Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 6Klinik für Neurologie und Palliativmedizin, Köln, Germany, 7Brain Research Institute, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia, 8Medical University of Łódź, Łódź, Poland, 9Sanofi Genzyme, Cambridge, MA, United States, 10First Medical Faculty, Charles University in Prague, Prague, Czech Republic Background: In patients with active relapsing-remitting multiple sclerosis (RRMS) and an inadequate response (⩾1 relapse) to

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prior therapy at baseline, alemtuzumab treatment significantly reduced the annualised relapse rate and the rate of brain volume loss versus subcutaneous interferon beta-1a over 2 years (CARE-MS II; NCT00548405). Significantly higher proportions of alemtuzumab-treated patients also had no evidence of disease activity (NEDA) over 2 years. An extension study (NCT00930553) has shown durable efficacy through 5 years in the absence of continuous treatment. Goal: To evaluate disease activity over 6 years in alemtuzumab patients with an inadequate response to prior therapy. Methods: In CARE-MS II, patients received 2 treatment courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). Patients who completed CARE-MS II could enter the extension study, with as-needed alemtuzumab retreatment for relapse or MRI activity. An alternate disease-modifying therapy could be provided per investigator discretion. Assessments included the proportion of patients with NEDA and its individual components, including absence of relapse, clinical disease activity (CDA: ⩾1 relapse or 6-month confirmed disability worsening), and new MRI disease activity (gadolinium-enhancing T1 or new/enlarging T2 hyperintense lesions). Results: Of 423 alemtuzumab patients who completed CARE-MS II, 393 (93%) enrolled in the extension study; 344 (88%) remained on study through 6 years. The proportion of patients with no evidence of relapse remained high in each year of the extension (Year 3: 81%; Year 4: 80%; Year 5: 84%; Year 6: 88%). In Years 3, 4, 5, and 6, high proportions of patients had no evidence of CDA (76%, 75%, 80%, and 85%) and no evidence of new MRI disease activity (68%, 70%, 68%, and 69%). The majority of patients achieved NEDA annually (Year 3: 53%; Year 4: 54%; Year 5: 58%; Year 6: 60%). These results were achieved with 50% of patients receiving no additional treatment after their initial 2 courses of alemtuzumab. Conclusions: Alemtuzumab durably suppressed disease activity in patients who had an inadequate response to prior therapy. The majority of patients achieved NEDA in each year through Year 6, despite 50% receiving no additional treatment since the initial 2 courses of alemtuzumab. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for RRMS patients. Disclosure Study support: Sanofi Genzyme and Bayer Healthcare Pharmaceuticals. CL: Compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi Genzyme, Strativa, Teva, and UCB). JDS: Consulting and/or speaking fees, advisory board, and grant/ research support (Sanofi Genzyme). MSF: Honoraria or consulting fees (Actelion, Bayer Healthcare, Biogen, Canada Innovation, Chugai, EMD Canada, Hoffman-La Roche, Merck Serono, Novartis, Sanofi Aventis, Sanofi Genzyme, and Teva); serving on advisory boards, board of directors or other similar group (Actelion, Bayer Healthcare, Biogen, Hoffman-La Roche, Merck Serono, Novartis, Opexa, and Sanofi Aventis); and participation in speaker’s bureau (Sanofi Genzyme). MH: Nothing to disclose. RMMH: Research grants, speaker´s fees and honoraria for advisory boards (Biogen, Merck, Novartis, Sanofi Genzyme, and Teva).


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VL: Honoraria for consulting and speaking at symposia (Bayer Healthcare, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi, and Teva, with approval by the HR-Department, Cologne General Hospital, University of Cologne). RALM: Honoraria and travel support (Biogen Idec, Merck Serono, Genzyme, Bayer, and Novartis). Honoraria for speaking engagements and advisory boards are directed to N-CRESS at Austin Heath. N-CRESS also receives sponsorship from Biogen Idec, Merck Serono, Genzyme, CSL, Bayer, and Novartis. KS: Consulting and/or speaking fees (Biogen Idec, Merck, Novartis, Roche, Sanofi Genzyme, and Synthon). DHM and KT: Employees of Sanofi Genzyme. EH: Honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva), and support from Ministry of Education of Czech Republic, project PRVOUK -P26/LF1/4). P682 Alemtuzumab durably suppresses disease activity over 6 years in treatment-naive patients with active relapsingremitting multiple sclerosis in the absence of continuous treatment (CARE-MS I) H. Wiendl1, D. Dive2, M. Dreyer3, C. LaGanke4, O. Fernandez5, B. Sharrack6, B. Singer7, P. Vermersch8, D.H. Margolin9, K. Thangavelu9, E. Havrdova10, on behalf of the CARE-MS I Investigators 1University of Münster, Münster, Germany, 2University Hospital Centre of Liège, Liège, Belgium, 3Royal Hobart Hospital, Hobart, TAS, Australia, 4North Central Neurology Associates, Cullman, AL, United States, 5Fundacion IMABIS, Hospital Universitario Carlos Haya, Málaga, Spain, 6Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 7MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, United States, 8University of Lille, Lille, France, 9Sanofi Genzyme, Cambridge, MA, United States, 10First Medical Faculty, Charles University in Prague, Prague, Czech Republic Background: In the phase 3, CARE-MS I clinical trial (NCT00530348), alemtuzumab significantly reduced the annualised relapse rate and the rate of brain volume loss versus subcutaneous interferon beta-1a over 2 years in patients with active relapsing-remitting multiple sclerosis (RRMS) who were treatment-naive. Significantly higher proportions of alemtuzumabtreated patients also had no evidence of disease activity (NEDA) after 2 years. An extension study (NCT00930553) has shown that efficacy is durable through 5 years in the absence of continuous treatment. Goal: To evaluate disease activity over 6 years in alemtuzumab patients who were treatment-naive. Methods: In CARE-MS I, patients received 2 courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). At Month 24, patients who completed the core study could enter the extension study, with as-needed alemtuzumab for relapse or MRI activity. An alternative disease-modifying therapy could be provided per investigator discretion. Assessments included the proportion of patients with NEDA and its individual components, including absence of relapse, clinical disease activity (CDA: ⩾1 relapse or

6-month confirmed disability worsening), and new MRI disease activity (gadolinium-enhancing T1 or new/enlarging T2 hyperintense lesions). Results: Of the 367 alemtuzumab patients who completed CARE-MS I, 349 (95%) enrolled in the extension; of these, 325 (93%) remained in the study at 6 years. The proportion of patients with no evidence of relapse remained high in each year of the extension (Year 3: 84%; Year 4: 87%; Year 5: 88%; Year 6: 89%). In Years 3, 4, 5, and 6, high proportions of patients had no evidence of CDA (82%, 84%, 85%, and 86%) and no evidence of new MRI disease activity (72%, 70%, 70%, and 66%). The majority of patients achieved NEDA annually in the extension (Year 3: 62%; Year 4: 60%; Year 5: 62%; Year 6: 57%). These results were achieved with 63% of patients receiving no additional treatment after their initial 2 courses of alemtuzumab. Conclusions: Alemtuzumab durably suppressed disease activity in patients who were treatment-naive. The majority of patients achieved NEDA in each year through Year 6, despite most receiving no additional treatment since the initial 2 courses of alemtuzumab. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for RRMS patients. Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. HW: Consulting and/or speaking fees (Bayer, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi Genzyme, and Teva); grant/research support (Bayer, Biogen, Elan Corporation, Merck Serono, Novartis, Novo Nordisk, and Sanofi Genzyme). DD: Institutional honoraria for advisory boards and participations and travel grants (Bayer, Merck Serono, Novartis, Sanofi Genzyme, and Teva). MD: Consultant/ advisory board participant and research support (Sanofi Genzyme). CL: Compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi Genzyme, Strativa, Teva, and UCB). OF: Consulting and/or speaking fees (Allergan, Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva). Compensation for serving as a journal editor, associate editor, or member of an editorial advisory board (Revista Española de Esclerosis Múltiple). Grant/Research Support (Hospital Foundation FIMABIS). BSh: Nothing to disclose. BSi: Speaking and/or consulting (Acorda, Bayer, Biogen, EMD Serono, Novartis, Pfizer, Roche-Genentech, Sanofi Genzyme and Teva); research support (Acorda, Biogen, MedImmune, Novartis, Roche, and Sanofi Genyzme). PV: Consulting and/or speaking fees/Research support (Almirall, Bayer, Biogen, GlaxoSmithKline, Novartis, Merck Serono, Sanofi Genzyme, and Teva). DHM and KT: Employees of Sanofi Genzyme. EH: Honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva) and is supported by The Ministry of Education of Czech Republic (project PRVOUK -P26/LF1/4).


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Poster Session 1, 22(S3) P683 Durable reduction in MRI disease activity with alemtuzumab in treatment-naive patients with active relapsing-remitting multiple sclerosis: 6-year follow-up of the CARE-MS I study D.L. Arnold1,2, M. Barnett3, G. Comi4, G. Giovannoni5, D. Pelletier6, A. Rovira7, S. Schippling8, B. Van Wijmeersch9, D.H. Margolin10, K. Thangavelu10, A. Traboulsee11, on behalf of the CARE-MS I Investigators 1NeuroRx Research, 2Montréal Neurological Institute, McGill University, Montréal, QC, Canada, 3University of Sydney, Sydney, NSW, Australia, 4University Vita-Salute San Raffaele, Milan, Italy, 5Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 6University of Southern California, Los Angeles, CA, United States, 7Vall d’Hebron University Hospital, Barcelona, Spain, 8Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich and University of Zurich, Zurich, Switzerland, 9University of Hasselt, Hasselt, Belgium, 10Sanofi Genzyme, Cambridge, MA, United States, 11The University of British Columbia, Vancouver, BC, Canada Background: In the 2-year, phase 3 CARE-MS I clinical trial (NCT00530348), alemtuzumab significantly reduced the annualised relapse rate (ARR) and increased the proportion of patients with no evidence of MRI disease activity versus subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis (RRMS) who were treatment-naive at baseline (BL). Efficacy was durable through 5 years in the absence of continuous treatment in an extension study (NCT00930553). Goal: To evaluate the effect of alemtuzumab on MRI lesion outcomes over 6 years in patients who were treatment-naive at BL. Methods: In CARE-MS I, patients received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days). At the end of Year 2, patients who completed the study could enter the extension, with as-needed alemtuzumab treatment for relapse or MRI activity. Another disease-modifying therapy could be provided per investigator discretion. Baseline and annual MRI scans were assessed for gadolinium (Gd)-enhancing T1, new/ enlarging T2 hyperintense, and new T1 hypointense lesions. Assessments included the proportions of patients who had no evidence of MRI disease activity (defined as no new Gd-enhancing T1 and no new/enlarging T2 lesions) and no evidence of disease activity (NEDA). Results: Of the 367 alemtuzumab patients who completed CARE-MS I, 349 (95%) entered the extension; of these, 325 (93%) remained on study through 6 years. Throughout the extension, most patients remained free of new Gd-enhancing T1, new/ enlarging T2, and new T1 lesions (87%, 67%, and 82%, respectively, were lesion-free in Year 6). In each year through Year 6, most patients showed no evidence of MRI disease activity (66% had no evidence of MRI activity in Year 6) and the majority achieved NEDA (Year 3: 62%; Year 4: 60%; Year 5: 62%, and Year 6: 57%). These efficacy results were achieved with 63% of patients receiving no additional treatment after their initial two courses of alemtuzumab. Conclusion: The efficacy of alemtuzumab, as measured with MRI disease activity, was durable over 6 years in patients who were treatment-naive, despite most patients receiving no additional treatment since the initial two courses of alemtuzumab. Based on these findings, alemtuzumab may provide a unique

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treatment approach with durable efficacy in the absence of continuous treatment for RRMS patients. Disclosure Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. DLA: Compensation for serving as a speaker, consulting, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi, Sanofi Genzyme, and Teva). MB: Institutional support for research, speaking and/or participation in advisory boards (Biogen, Novartis, and Sanofi Genzyme); research consultant (Medical Safety Systems). GC: Consulting fees (Actelion, Bayer, Merck Serono, Novartis, Sanofi Genzyme, and Teva); lecture fees (Bayer, Biogen Dompé, Merck Serono, Novartis, Sanofi Genzyme, Serono Symposia International Foundation, and Teva). GG: Consulting and/or grant/research support (Abbvie, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GlaxoSmithKline, GW Pharma, Merck, Merck Serono, Novartis, Oxford Pharmagenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva Neuroscience, and UCB). DP: Consulting and/or speaking fees, and grant/research support (Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Vertex). AR: Consulting and/or speaking fees (Bayer, Biogen, Bracco, Novartis, Sanofi Genzyme, and Stendhal). SS: Consulting and/or speaking fees, and grant/research support (Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva). BVW: Research and travel grants, honoraria for MS expert advice and speaker’s fees (Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva). DHM and KT: Employees of Sanofi Genzyme. AT: Consulting and/or speaking fees, and grant/research support (Biogen, Chugai, Roche, Sanofi Genzyme, and Teva). P684 Natalizumab, first therapy to demonstrate a significant impact on multiple sclerosis disease severity F. Jacques, V. Sikati Foko, J. Fortin Clinique Neuro-Outaouais, Gatineau, QC, Canada Objective: To determine if natalizumab can impact the Multiple Sclerosis Disease Severity score over a period of nine years. Background: The Multiple Sclerosis severity score (MSSS) combines via an algorithm, disease duration with the expanded disease status score (EDSS). It is a measure of the rate of disability accumulation in multiple sclerosis (MS) patients i.e. disease severity. Studies have shown that several accepted MS therapies including interferon beta, glatiramer acetate and azathioprine do not impact the MSSS. Methods: This a single center, retrospective, chart review. Only patients with well documented, uninterrupted natalizumab therapy were considered. The MSSS was determined by using the table in the manuscript by Roxburgh et al.


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Results: We recorded data on 143 patients (111 female, 32 males) with mean age of 42 years, mean disease duration of 10.5 years (0-40 years). The mean EDSS was 3.1 and mean MSSS was 4.52. The follow-up ranged from 1-9 years with a mean of 4 years and a total of 586 patient-years. The overall, annual, mean MSSS decreased significantly (P=0.004) from baseline beginning in year 2 and was sustained for the rest of the 9 years period. Baseline EDSS appeared to influence the subsequent change in MSSS with patients starting with a moderate level of disability (EDSS 3.0-5.5) showing the greatest decrease in MSSS (5.5 to 2.0, p=0.01). Baseline MSSS showed a different pattern with patients with the greatest level of disease severity (MSS⩾7.0) achieving the greatest decrease (8.0 to 3.2 P=0.0005). Baseline disease duration showed an inverse relationship with the patients in the >10 years group showing no change in MSSS and those in the < 5 years group showed the greatest change in MSSS (p< 0.001). Conclusions: Our study corroborates with the Swedish Registry and demonstrates that natalizumab impacts significantly on MS disease severity. The benefit in our patient population became apparent in the second year of therapy and was sustained through years 3 to 9. The response was the greatest in patients with either a moderate baseline EDSS (3.0-5.5), a high MSSS (⩾ 7.0) or a short disease duration (< 5 years). Disclosure F. Jacques has received honorariums from several companies. Clinique Neuro-Outaouais operates an infusion clinic where Natalizumab (Tysabri) is administered. J. Fortin is an employee of Clinique Neuro-Outaouais. V. Sikati Foko is an employee of Clinique Neuro-Outaouais. P685 Predictors of long-term interferon discontinuation in newly diagnosed relapsing multiple sclerosis M. Moccia1, R. Palladino2, A. Carotenuto3, C. Russo1, M. Triassi4, R. Lanzillo1, V. Brescia Morra1 1Department of Neuroscience, Federico II University, Napoli, Italy, 2Imperial College London, London, United Kingdom, 3Federico II University, Napoli, 4Federico II University, Naples, Italy Interferon-β has long-term safety and efficacy profiles for Relapsing Remitting Multiple Sclerosis (RRMS). Therefore, the present study investigated predictors of Interferon-β discontinuation, in order to improve patient profiling for clinical decisions, and to prescribe the most appropriate and individualized treatment. The present retrospective observational cohort study included 499 newly diagnosed, drug naïve MS subjects receiving Interferon-β as first disease modifying treatment (DMT), during a 7.9±3.8 year period, up to treatment discontinuation. Possible markers of interest were recorded at the time of diagnosis (age, gender, disease duration, baseline EDSS) or during follow-up as variables of disease evolution (relapse occurrence, annualized relapse rate -ARR-, 1-point EDSS progression, reaching of EDSS 4.0) or of treatment (high-dose Interferon-β1a, low-dose Interferon-β1a, or Interferon-β1b). 217 patients (43.5%) discontinued the treatment during the follow-up period, with an incidence of 5% person-years

(95%CI=4.6-5.9%). A multivariate Cox regression model showed an increased rate of Interferon-β discontinuation for female gender (p=0.019; HR=1.428), higher baseline EDSS (p=0.026; HR=1.346), relapse occurrence (p=0.009; HR=1.618), higher ARR (p< 0.001; HR=5.269), and Interferon-β1b treatment (p=0.019; HR=1.506); and a reduced rate for occurrence of EDSS progression (p< 0.001; HR=0.299). Most of the factors associated with Interferon-β discontinuation are not modifiable, and are part of demographic features (i.e. gender), or of disease characteristics (i.e. disability at diagnosis), but should be taken into account when prescribing the first DMT for MS. However, the use of Interferon-β1b is associated with a 50% increased risk of discontinuation, as compared to high-dose Interferon-β1a, highlighting the importance of drug formulations in treatment persistence. Disclosure Authors have nothing to disclose. P686 Real world efficacy of fingolimod: experience from the Glasgow MS Centre (GMSC) in comparison with the FREEDOMS and TRANSFORMS studies K.J. Fitzpatrick1, S. Murdoch2, N. Fullerton3, J. Overell2, S. Webb2, L. Murray1 1Pharmacy and Prescribing Support Unit (PPSU), 2Institute of Neurological Sciences, 3Department of Neuroradiology, Queen Elizabeth University Hospital, Glasgow, United Kingdom Background: Fingolimod has been approved for use within Scotland since April 2013 for highly active relapsing remitting multiple sclerosis (RRMS). Its use is restricted to patients failing first line therapy, beta-interferon/glatiramer acetate (BIFN/GA) or switching from natalizumab due to concerns about risks or side effects. Data on its effectiveness in real world practice is needed. Objectives: To evaluate real world effects of fingolimod on annualised relapse rates (ARR), proportion relapse free and MRI disease progression in patients failing first line disease modifying therapies (DMTs) and switching from natalizumab. Design and methods: A retrospective review of electronic medical records and MRI was undertaken in all fingolimod patients within the GMSC (n=93). Patients were identified using prescription records. The cohort was split into 3 groups: (A) switchers from BIFN/GA (n=56), (B) switchers from natalizumab (n=24) and (C) other circumstances, for example, those starting fingolimod after treatment interruption. Results: 78.5% of patients remained relapse free (A:78.6%, B:79.2%) after a mean (95% CI) treatment duration of 407 days (354-459) (TRANSFORMS (360 days) 82.5% and FREEDOMS (720 days) 70.4%). The ARR for all fingolimod patients was 0.27 (0.12-0.42), which did not differ significantly between group A and B. Of the 93 patients studied, 86 had a pre-fingolimod MRI, on average 279 days (193-365) prior to fingolimod. The first follow up MRI was after an average of 329 days (268-390) (n=63) and showed: 58.7% without increased T2 lesion load and/or GAD+ lesions, 34.9% with new T2 lesions and 6.4% with GAD+ lesions. TRANSFORMS showed: 54.8% without increased T2 lesion load


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Poster Session 1, 22(S3) and/or GAD+ lesions, 35.3% with new T2 lesions and 9.9% with GAD+ lesions over a similar time period. Conclusion: The clinical and radiologic efficacy of fingolimod mirrored the findings from the pivotal trials in a real world cohort switching from both first line therapies and natalizumab.

Conclusion: Reduced neutrophil counts occur in the majority of patients treated with fingolimod. The reduction is of a greater magnitude (31-36%) than that stated in the UK-SPC, happens soon after initiation, and is maintained. It was not more common in patients who experienced infection in our cohort.

Disclosure

Disclosure

Kieran Fitzpatrick: Nothing to disclose Sheena Murdoch: Nothing to disclose Natasha Fullerton: Nothing to disclose James Overell: Nothing to disclose Stewart Webb: Nothing to disclose Lesley Murray: Nothing to disclose

Kieran Fitzpatrick: Nothing to disclose James Overell: Nothing to disclose Lesley Murray: Nothing to disclose

P687 Impact of fingolimod therapy on neutrophil counts: real world experience from the Glasgow MS Centre (GMSC) K.J. Fitzpatrick1, J. Overell2, L. Murray1 1Pharmacy and Prescribing Support Unit (PPSU), 2Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom

P688 Determinants of treatment persistence with glatiramer acetate in the French national Copaxone registry C. Lebrun-Frenay1, A. Moulignier2, C. Pierrot-Deseilligny3, T. Moreau4, B. Salin5, F. Monchecourt5 1Dept of Neurology, Centre Hospitalier Universitaire, Nice, 2Dept of Neurology, Fondation Adolphe de Rothschild, 3Dept of Neurology, Hôpital de la Salpêtrière, Paris, 4Dept of Neurology, Centre Hospitalier Universitaire, Dijon, 5Medical Affairs Dept, Teva France, La Défense, France

Background: Fingolimod was approved for use within Scotland in April 2013 for highly active relapsing remitting multiple sclerosis (RRMS). The occurrence and impact of reduced neutrophil counts in patients treated with fingolimod is not clearly defined in the real world setting. Reduced neutrophil counts are stated to be an uncommon effect of fingolimod in the UK Summary of Product Characteristics (UK-SPC), and chronic dosing is thought to lead to a decrease of approximately 20% from baseline. Objectives: To investigate the frequency of reduced neutrophil counts in RRMS patients treated with fingolimod in GMSC and determine the incidence in patients who experienced infection. Methods: A retrospective review of electronic medical records and blood results was undertaken in all fingolimod patients within GMSC (n=93), 76 had neutrophil counts available for analysis. Patients were identified using prescription records. Each patient’s blood results were split into 3 categories for analysis: first level taken after commencing fingolimod, lowest, and most recent. Results: Mean (95% CI) fingolimod treatment duration was 407 days (353-459). First bloods were measured on average 38 days (32-45) after commencing fingolimod. At this point, a fall in neutrophil count was observed in 74% of patients with a mean reduction of 1.26 x10^9/l (0.99-1.52), or 31% from mean baseline pre-fingolimod levels. Lowest neutrophil counts were observed after 162 days (123-201) of fingolimod treatment with a mean reduction of 36% from baseline (1.46 x10^9/l (1.19-1.73)). Most recent neutrophil counts were measured after 342 days (292-392) on treatment, and 68% of patients had reduced neutrophil counts at this time-point, with a mean reduction of 32% from baseline (1.29 x10^9/l (1.02-1.56)). All post-treatment mean neutrophil counts showed a statistically significant reduction from the baseline mean. In patients who had suffered infection during fingolimod therapy (n=21), 19 had neutrophil counts available for analysis. Of those, 74% had a reduced first neutrophil count and 68% had a reduced most recent count, exactly mirroring the frequency of reduced neutrophil counts in the whole cohort.

Background: The availability of a wider range of treatment options for multiple sclerosis (MS) offers the possibility of a dynamic treatment approach with switching between drug classes. In this context, it is important to document treatment persistence and understand the factors associated with treatment discontinuation. Objectives: To document treatment persistence in patients with a diagnosis of relapsing-remitting MS starting glatiramer acetate (GA) in everyday care in France and to identify factors associated with persistence. Methods: All neurologists in France were invited to participate in the study. All patients starting treatment with GA for the first time were eligible. Patients were enrolled between November 2005 and October 2008 and followed up according to French national guidelines with at least one study visit/year. Persistence was evaluated using Kaplan-Meier survival analysis and variables associated with persistence identified using a Cox proportional hazard model. Results: 852 patients (mean age 39.9 years, mean disease duration 8.1 years; mean EDSS score 2.4) were enrolled. At the end of the 5-year treatment period, 325 (38%) had discontinued GA but were still in the study. Median treatment duration was longer in patients discontinuing treatment for inadequate efficacy (527 days) or for personal convenience (504 days) than in those discontinuing for poor local (141 days) or general (198 days) tolerability. 13 patients discontinuing GA at some stage restarted, 226 (50%) received no further treatment, 96 (21%) were switched to interferon-β and 81 (18%) to natalizumab. Factors independently associated with a higher probability of discontinuing were having stopped work (HR: 1.45 [95%CI: 1.08; 1.93], younger age (0.98/ year [0.97; 0.99]), higher EDSS score at inclusion (1.11 [1.03; 1.20]) and ⩾5 previous relapses at inclusion (1.54 [1.25; 1.90]). Conclusions: Overall, 38% of patients had discontinued GA treatment at 5 years. Patients who discontinue for tolerability issues do so more rapidly than do those discontinuing for efficacy reasons. Half the patients stopping GA received no further treatment. The principal factor associated with discontinuation was more severe

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disease at inclusion. Personal convenience was also an important reason given for discontinuation. Disclosure CLF has received consultancy or speakers fees from Biogen Idec, Merck Serono, Genzyme, Almirall, Allergan, Teva, Sanofi, Bayer Schering AM has received consultancy fees from Sanofi and Teva CPD has received consultancy fees from Sanofi and Teva TM has received consultancy fees or speaking fees from Biogen Idec, Sanofi, Genzyme, Teva Pharma, Bayer Schering, Merck Serono, Roche, Almirall and Novartis BS and FM are employees of Teva Pharma Source of funding: Teva.Pharma P689 Effect of early versus delayed scIFN β-1a on radiological or clinical activity-free status in patients with CIS: a post-hoc analysis of REFLEXION M.S. Freedman1, G. Comi2, P.K. Coyle3, L. Chen4, K. Marhardt5, L. Kappos6 1Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 2Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy, 3Department of Neurology, Stony Brook University, Stony Brook, NY, 4EMD Serono, Inc., Billerica, MA, United States, 5Merck GmbH, Vienna, Austria, 6University Hospital Basel, Basel, Switzerland Background: Patients treated with subcutaneous interferon (scIFN) β-1a after clinically isolated syndrome (CIS) are more likely to achieve no evidence of disease activity up to 5 years than those treated after clinically definite multiple sclerosis. This study aimed to determine the effect of once weekly (qw) or three times weekly (tiw) scIFN β-1a vs delayed treatment (DT) after CIS on no evidence of radiological or clinical activity up to 2 and 5 years. Methods: In REFLEX, patients with CIS were randomized to double-blind scIFN β-1a 44 µg tiw, qw, or placebo for 24 months (upon clinically-definite multiple sclerosis, patients switched to openlabel scIFN β-1a tiw). In REFLEXION, placebo patients switched to tiw (DT); scIFN β-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n=171; qw, n=175; DT, n=171). All p values are nominal. Results: A numerically greater proportion of patients treated tiw than qw or with DT were radiological activity-free up to years 2 and 5 (2 years: tiw 29%, qw 18%, DT 9%; 5 years: tiw 12%, qw 4%, DT 1%). Up to years 2 and 5, the odds ratios of being radiological activity-free were higher for tiw than qw vs DT (2 years: tiw 4.11 [p< 0.0001], qw 2.14 [p=0.02]; 5 years: tiw 11.53 [p=0.0012], qw 3.55 [p=0.1]). Beyond 2 years, the proportions who were clinical activity-free in each treatment arm were similar (2 years: tiw 68%, qw 69%, DT 56%; 5 years tiw 37%, qw 42%, DT 36%). The odds ratios of being clinical activity-free were higher for tiw and qw up to 2 years vs DT but not up to 5 years (2 years: tiw 1.69 [p=0.02], qw 1.79 [p< 0.001]; 5 years: tiw 1.05, [p=0.8], qw 1.29 [p=0.2]). In patients with true CIS

(McDonald 2010 criteria), the respective proportions radiological activity-free up to 2 years and 5 years were numerically greater for tiw vs qw and DT (2 years: 32% vs 20% vs 10%; 5 years: 9% vs 3% vs 1%). In patients with McDonald 2010 relapsing remitting multiple sclerosis, the proportions radiological activity-free were also numerically greater for tiw vs qw and DT (2 years: 13% vs 9% vs 3%; 5 years: 5% vs 2% vs 0%). Conclusions: Early treatment with scIFN β-1a tiw led to greater likelihood of freedom from radiological disease activity vs DT up to 5 years post-randomization. The advantage of tiw or qw on freedom from clinical disease activity vs DT was seen up to 2 years. Disclosure Study supported by Merck KGaA, Darmstadt, Germany. MSF: honoraria or consultation fees from Actelion, Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Hoffman La Roche, Novartis, Sanofi, Teva. GC: honoraria and consultation fees from Serono Symposia International Foundation, EMD Serono, Novartis, Teva Pharmaceutical Industries, Sanofi-Aventis, Bayer Schering, and Biogen Dompè. PC: advisor or consultant for: AbbVie Inc.; Accordant; Acorda Therapeutics; Bayer HealthCare Pharmaceuticals; Biogen; EMD Serono, Inc.; Genentech/Roche; Genzyme/Sanofi; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA. Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Biogen; Genentech/Roche; Novartis Pharmaceuticals Corporation; Opexa Therapeutics, Inc. LK’s institution (University Hospital Basel): research support from Actelion, Addex, Bayer, Biogen, Biotica, CSL Behring, Genzyme, Lilly, Merck, Mitsubishi, Neurostatus Systems, Novartis, Ono Pharma, Pfizer, Receptos, Roche, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport, the European Union, the Roche Research Foundation, the Swiss MS Society, the Swiss National Research Foundation. KM: is an employee of Merck KGaA. LC: is an employee of EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany. P690 Outcomes of the TOPIC extension study of teriflunomide in patients with early multiple sclerosis: up to 7 years of clinical results A.E. Miller1, L. Kappos2, G. Comi3, M.S. Freedman4, J. Oh5, J. De Sèze6, P. Truffinet7, M. Benamor7, A. Purvis8, J.S. Wolinsky9, for the TOPIC Study Group 1Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2University Hospital Basel, Basel, Switzerland, 3University Vita-Salute San Raffaele, Milan, Italy, 4University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, 5St Michael’s Hospital, Toronto, ON, Canada, 6Strasbourg University, Hôpital Civil, Strasbourg, 7Sanofi Genzyme, ChillyMazarin, France, 8Sanofi Genzyme, Cambridge, MA, 9McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Background: TOPIC (NCT00622700) evaluated the efficacy and safety of teriflunomide, a once-daily oral immunomodulator,


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Poster Session 1, 22(S3) approved for relapsing forms of MS (RMS), in patients with a first clinical episode suggestive of MS (N=614). Patients completing TOPIC, still on-study at completion, or experiencing relapse determining conversion to clinically definite MS (CDMS; primary endpoint), were eligible to enrol in an extension, which continued until teriflunomide was locally reimbursed. Objective: To report clinical outcomes from patients in the TOPIC extension study throughout completion (up to 7 years of treatment). Methods: In TOPIC, patients received placebo or teriflunomide 7 mg or 14 mg for ⩽108 weeks. In the extension, teriflunomidetreated patients continued to receive their original dose; the placebo group was re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Safety data are reported for the extension period; clinical data are reported for core plus extension periods. Results: In the extension, 423 patients were randomized and treated. Cumulative teriflunomide exposures (from start of core study) were 242, 559, 248, and 606 patient-years for the placebo/7mg, 7-mg/7-mg, placebo/14-mg, and 14-mg/14-mg groups, respectively. Most patients (75%) completed the extension study; fewer patients receiving the 14-mg dose (20%) vs the 7-mg dose (27.5%) discontinued. Patient choice was the most common reason for discontinuation (43/107 discontinuations). Over the extension period, adverse events (AEs) occurred in 82% of patients. The nature and incidence of AEs were comparable to those in other teriflunomide clinical studies and their extensions. Across groups, annualized relapse rate was ⩽0.163, ⩾61% of patients remained free from relapse, and ⩾78% of patients remained free from disability worsening confirmed for ⩾12 weeks (no significant between-group differences). Most patients (⩾63% per group) did not experience relapse determining conversion to CDMS. The risk of relapse determining conversion to CDMS was lower in the 14-mg/14-mg (early treatment) group vs the placebo/14-mg (delayed treatment) group (hazard ratio [95% confidence interval] 0.529 [0.317, 0.883], P=0.0149). Conclusions: Together with data from studies in RMS, observations in patients with a first clinical episode suggestive of MS demonstrate the consistent safety and enduring efficacy during long-term treatment with teriflunomide across a range of RMS patient subtypes.

Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation). JdS: Consulting services, advisory boards (Genzyme). JO: Consulting or speaking fees (Biogen Idec, EMD Serono, Genzyme, Novartis, Roche); grant/research support (Biogen Idec, Genzyme, MS Society of Canada). PT: Employee of Sanofi Genzyme, with ownership interest. MB: Employee of Sanofi Genzyme. AP: Employee of Sanofi Genzyme. JSW: Within the last 3 years, consulting agreements (AbbVie, Actelion, Alkermes, Athersys, Inc., Bayer HeathCare, EMD Serono, Forward Pharma, Genzyme, Novartis, Roche, Taketa, Teva, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society); royalties (for monoclonal antibodies out-licensed to Chemicon International), through the University of Texas Health Science Center at Houston.

Disclosure

P691 Benefit of long-term treatment with teriflunomide on disability outcomes: results from TEMSO and TOWER F. Lublin1, M.S. Freedman2, G. Comi3, A.E. Miller4, K. Thangavelu5, P. Truffinet6, L. Kappos7 1Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3University Vita-Salute San Raffaele, Milan, Italy, 4Icahn School of Medicine at Mount Sinai, New York, NY, 5Sanofi Genzyme, Cambridge, MA, United States, 6Sanofi Genzyme, Chilly-Mazarin, France, 7University Hospital Basel, Basel, Switzerland

Study supported by Sanofi Genzyme, AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). LK: Author´s institution (University Hospital Basel) has received in last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck,

Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. In 2 pivotal phase 3 clinical trials in patients with relapsing forms of MS (RMS; TEMSO [NCT00134563], and TOWER [NCT00751881]), teriflunomide 14 mg consistently and significantly reduced risk of disability worsening confirmed for ⩾12 weeks. Advancement to Expanded Disability Status Scale (EDSS) score ⩾6 has been associated with poorer health-related quality of life and may also be associated with an increased burden on healthcare resources as patients become less independent. Objective(s): To evaluate impact of long-term treatment with teriflunomide 14 mg on risk of advancing to EDSS score ⩾6 and ⩾7 using pooled data from the TEMSO and TOWER core and extension studies. Methods: In TEMSO and TOWER, patients with RMS were randomized 1:1:1 to placebo, teriflunomide 7 mg, or 14 mg. Patients

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received treatment for 2 years in TEMSO. In TOWER, study duration was variable (385-765 days) ending 48 weeks after last patient randomized. Patients completing the core studies were eligible to enter the extensions. In the TEMSO extension (NCT00803049), patients originally randomized to teriflunomide 7 mg or 14 mg continued treatment; those previously receiving placebo were rerandomized 1:1 to teriflunomide 7 mg or 14 mg. All patients received teriflunomide 14 mg in the TOWER extension. Patients who received teriflunomide 14 mg at any point during TEMSO, TOWER, and their extensions are included in this analysis. 12-week confirmed disability worsening was analyzed in patients treated with teriflunomide 14 mg in TEMSO, TOWER, and their extensions. Probability of advancement to EDSS score ⩾6 or ⩾7 was derived from Kaplan-Meier estimates. Results: After 6 years’ follow-up of patients with baseline EDSS score < 6 and treatment with teriflunomide 14 mg, 93.7% (n=1316) had not advanced to EDSS score ⩾6. Over the same period, 99.5% (n=1336) of patients entering the studies with baseline EDSS score < 7 had not advanced to EDSS score ⩾7. No patients treated with teriflunomide 14 mg in the core studies reached EDSS score ⩾7 in the extension studies. Conclusions: A high proportion of patients receiving long-term treatment with teriflunomide 14 mg did not advance to EDSS score ⩾6 or ⩾7. These results are consistent with the efficacy of teriflunomide vs placebo in reducing risk of disability worsening in the core studies, and support the long-term efficacy in patients continuing teriflunomide. Disclosure Study supported by Sanofi Genzyme. FR: Research support (Acorda Therapeutics, Biogen Idec, Genzyme, National Institutes of Health, National MS Society, Novartis, Sanofi, Teva Neuroscience); consulting agreements, advisory board/DSMB membership (Abbott, Acorda, Actelion, Allozyne, Avanir, Bayer HealthCare, Biogen Idec, Celgene, EMD Serono, Genmab, Johnson & Johnson, Medicinova, MorphoSys, Novartis, Pfizer, Questcor, Roche, Sanofi, Teva Neuroscience); speaker bureaus/honoraria (EMD Serono, Teva Neuroscience); stock ownership (Cognition Pharmaceuticals). MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation). GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). KT: Employee of Sanofi Genzyme. PT: Employee of Sanofi Genzyme, with ownership interest. LK: Author´s institution (University Hospital Basel) has received in last 3 years and used exclusively for research support: steering

committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). P692 Outcomes of the TEMSO extension study of teriflunomide: 10.5 years of clinical results M.S. Freedman1, A.E. Miller2, G. Comi3, L. Kappos4, C. LeBrun-Frenay5, P. Truffinet6, A. Purvis7, M. Benamor6, J.S. Wolinsky8, for the TEMSO Study Group 1University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 2Icahn School of Medicine at Mount Sinai, New York, NY, United States, 3University VitaSalute San Raffaele, Milan, Italy, 4University Hospital Basel, Basel, Switzerland, 5Hôpital Pasteur, Nice, 6Sanofi Genzyme, Chilly-Mazarin, France, 7Sanofi Genzyme, Cambridge, MA, 8McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Background: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS. In the randomized, phase 3 TEMSO study (NCT00134563), patients with relapsing forms of MS (n=1086) received placebo or teriflunomide 7 mg or 14 mg for 108 weeks. Teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of disability worsening confirmed for ⩾12 weeks; 7 mg significantly reduced ARR. Patients completing TEMSO core study were eligible to enrol in an extension (NCT00803049), which continued until teriflunomide was locally reimbursed. Objective(s): To report safety and efficacy outcomes from patients in the TEMSO extension study through to completion at 10.5 years of treatment. Methods: Extension entry began in 2006 and ended in 2010. Upon entering the extension, teriflunomide-treated patients continued to receive their original blinded dose; the placebo group was rerandomized 1:1 to teriflunomide 7 mg or 14 mg (doseblinded). Safety results are presented for the extension; efficacy results are presented for the total treatment period (core plus extension). Study magnetic resonance imaging (MRI) scans were performed annually until 2012. Results: A total of 740 patients entered the extension. Cumulative teriflunomide exposures (from start of core study) were 811, 1639, 703, and 1687 patient-years for the placebo/7-mg, 7-mg/7mg, placebo/14-mg, and 14-mg/14-mg groups, respectively. Median treatment duration was 7 years. During the extension, 92% of patients experienced adverse events (AEs), the majority of which were mild in intensity; AEs led to discontinuation in < 13% of patients. The nature and incidence of AEs were consistent with other teriflunomide studies. ARR remained low in each year of the extension (288/740 patients remained free from relapse) and Expanded Disability Status Scale scores remained stable throughout. The majority of patients (413/740) remained free from disability worsening confirmed for 12 weeks. Between baseline and


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Poster Session 1, 22(S3) Year 5, the volume and number of gadolinium-enhancing T1 lesions per MRI scan remained low. Conclusions: Results from the completed TEMSO long-term extension study support previous observations that teriflunomide has a well-characterized and manageable long-term safety profile. ARR, rates of disability worsening, and MRI activity remained low throughout the extension, providing evidence that teriflunomide efficacy is maintained with long-term treatment. Disclosure Study supported by Sanofi Genzyme. MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation). AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). LK: Author´s institution (University Hospital Basel) has received in last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). CL-F: Consulting fees, honoraria, or scientific committee support (Allergan, Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva). PT: Employee of Sanofi Genzyme, with ownership interest. AP: Employee of Sanofi Genzyme. MB: Employee of Sanofi Genzyme. JSW: Within the last 3 years, consulting agreements (AbbVie, Actelion, Alkermes, Athersys, Inc., Bayer HeathCare, EMD Serono, Forward Pharma, Genzyme, Novartis, Roche, Taketa, Teva, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society); royalties (for monoclonal antibodies out-licensed to Chemicon International), through the University of Texas Health Science Center at Houston. P693 Alemtuzumab (Lemtrada®) in multiple sclerosis: lessons from social media in enhancing patient care L. Rath, N. Vijiaratnam, O. Skibina Neurosciences, Alfred Health, Melbourne, VIC, Australia

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Introduction: Alemtuzumab (Lemtrada®) is an anti CD52, monoclonal antibody that has recently been approved for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). Lemtrada® is associated with infusion reactions and potential autoimmune side effects and requires long-term safety follow up. Patient education and early detection of side effects is crucial to favourable outcomes. Objectives: Surveillance via automated blood-tracking algorithms, clinical review and patient education aim to help patients understand the risks associated with Lemtrada®. The primary objective of this study was to observe the communication on Facebook for type of post, accuracy of shared information and comparison to standard educational themes. Methods: We identified a Facebook group specific to Lemtrada® in RRMS. A 14-day consecutive window was observed. Posts were classified as “sharing” or “seeking information”. Information seeking posts were coded for themes and accuracy of replies. Results: 458 posts were reviewed. Our observation suggest patients contemplating or receiving Lemtrada® primarily used the social media platform Facebook for information gathering (54.6%), followed by seeking emotional support and sharing personal experiences (45.4%). The latter resulted in more “likes” (1 post to 34 “likes” in contrast to information seeking 1 post to 6.5 “likes”). The majority (83.6%) of shared experiences were positive. Themes for information were predominately consistent with standard protocols. Complications discussed included infection (15%), bone pain (12%), Immune thrombocytopenia (ITP) (8.1%) and fatigue (7.5%). Accuracy of replies were consistent with local protocol and product information with the exception of ITP. Up to a quarter of replies to this complication were inaccurate. Conclusion: Our findings illustrate that MS patients are increasingly looking for online groups for discussion and pear support but primarily information. Whilst administrators of these groups reinforce the discussions “do not replace medical advice” inaccurate information does occur and can lead to possible delays in seeking treatment. Health care providers transparent review and acknowledgement of these sites allows insight into the real world experiences and concerns of patients receiving Lemtrada®. Disclosure Louise Rath-Travel grants from Biogen & Novartis and Speakers Honorarium from Biogen, Novartis & Genzyme Nirosen Vijiaratnam- Unconditional educational grants from Ipsen & Biogen and travel grants from Ipsen & Abbvie Olga Skibina-Research grant from Biogen, Travel grants from Biogen, Novartis & Bayer and Speakers Honorarium from Bayer, Biogen, Genzyme & Novartis P694 Three years of clinical experience with dimethyl fumurate (DMF): data from the providence multiple sclerosis center’s DMF Registry K. Smoot, C. Chen, T. Stuchiner, E. Baraban, L. Lucas, L. Grote, S. Cohan Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Providence Health & Services, Portland, OR, United States


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Objective: To report our experience of DMF since the medication’s approval in March 2013. Background: Given the positive results of two pivotal Phase III trials and the greater convenience of an oral medication, we anticipated a strong interest in DMF use by patients. Because data concerning transition from prior disease modifying therapy to DMF is limited, a registry was established to monitor the utilization of DMF and the treatment outcomes. Methods: This was a retrospective chart review study of patients who were prescribed DMF 240 mg twice a day for relapsing MS between March 2013 and March 2016 at the Providence MS Center. Results: 412 adult patients with a diagnosis of relapsing MS and at least 6 months of DMF treatment, were included. The cohort had 76.9% female, a mean age of 49.44 ± 12.01 years, a mean disease duration of 11.08 ± 8.2, and a mean duration of DMF treatment of 16.7 ± 10.14 months. The largest number of patients were previously treated with interferon beta (n=140, 34.0%), or were not on therapy prior to starting DMF (n=122, 29.6%). 156 (37.9%) patients discontinued DMF, of whom 84 (53.9%) stopped within the first 6 months. The main reason for discontinuing was secondary to side effects (n= 115, 65.5%). Clinical relapses occurred in 59 (14.3%) patients - of those, 38/59 (64.4%) of the relapses occurred after 6 months of DMF treatment. The annualized relapse rate (ARR) was highest in patients switching off Tysabri (25%) or had been treatment naïve (23%). MRI results were available for 294 (71.4%) patients, 196 (66.7%) of which were stable. To date, 52 (29.6%) patients have stopped DMF secondary to clinical or radiographic progression. Grade III lymphopenia developed in 40 (11.3%) patients and 10 patients had persistent absolute lymphocyte counts below 0.5. Patients who developed lymphopenia were older (60.03 vs 48.37 years of age, p< .001) and had a longer disease duration (9.81 vs 7.68 years, p< .001). Discussion: The majority of our patients were previously on interferon beta or were treatment naïve prior to starting DMF. Almost 40% have discontinued DMF, mainly as a result of side effects. ARR was highest for patients who were previously treated with natalizumab or treatment naïve. A higher percentage of lymphopenia was seen compared to the controlled clinical trials, possibly reflecting the older age of our cohort. Disclosure KS - Consulting fees from Acorda, Biogen, EMDSerono, Genzyme, Novartis, and Teva. CC - Nothing to disclose TS - Nothing to disclose EB - Nothing to disclose LL - Nothing to disclose LG - Nothing to disclose SC - Received honoraria for lectures from Biogen, Sanofi Genzyme, Acorda, and Novartis, serves on steering committees or advisory boards for Biogen, Sabnofi Genzyme, Novaris, and Roche Genentech, and receives research support from Biogen, Sanofi Genzyme, Novartis, Roche Genentech, Opexa, and Mallinckrodt.

P695 A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of natalizumab (IMSE 1)

S. Johansson1, L. Forsberg1, J. Hillert1, P. Nilsson2, C. Dahle3, A. Svenningsson4, J. Lycke5, A.-M. Landtblom6, J. Burman6, F. Walentin7, C. Martin4, F. Piehl1, T. Olsson1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Department of Neurology, Lund University, Lund, 3Department of Clinical and Experimental Medicine, Linköping University, Linköping, 4Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Danderyd, 5Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 6Department of Neuroscience, Uppsala University, Uppsala, 7Örebro University Hospital, Örebro, Sweden Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (Aug 2006). Objective: To follow-up the long-term safety and effectiveness of NTZ in a real-world setting. Methods: In Sweden MS patients are registered in the nationwide Swedish Neuroregistry (Neuroreg). Adverse events (AEs), Extended Disability Status Scale (EDSS), MS Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), MS Impact Scale (MSIS-29) and JC-virus status (JCV) are registered. IMSE 1 includes patients starting NTZ treatment and data is collected from Neuroreg. The Wilcoxon Signed-Rank Test was used to assess changes in effectiveness. Results: 2822 patients (72% female; 89% RRMS) have been included in IMSE 1 from August 2006 until April 2016. Mean age at treatment start was 36 years. Mean treatment duration was 39 months. 1313/2822 were currently treated with NTZ at cut-off. 1667 patients (59%) discontinued NTZ treatment at some time point. Main discontinuation reasons were; anti-JCV antibodies (JCV+) (41%) and pregnancy/planning pregnancy (15%). Serious AEs reported to the Swedish MPA were rare (84 events, 3.0%) but included 8 cases (1 fatal) of progressive multifocal leukoencephalopathy (PML), reported between 2008 and the latest case in 2012. 20% of patients with current NTZ treatment were JCV+, compared to 58% when testing started. 587/846 patients were JCV- at baseline, 109 later converted to JCV+. 15 patients died during or within 6 months after NTZ discontinuation in Neuroreg. None were reported to be associated to NTZ. In patients with continuous NTZ treatment for ⩾5 years (n=592), long lasting stabilization of disease activity was observed. The 5 year follow-up showed significant retained improvements in all effectiveness measures: EDSS -15% (n=291), MSSS -40% (n=281), MSIS-29 physical/psychological -26%/28% (n=289), SDMT +27% (n=366). Conclusions: Neuroreg functions well as a post-marketing drug surveillance platform, providing long-term data on drug effects and AEs. NTZ is generally well tolerated with sustained effectiveness. The introduction of JCV testing has led to fewer treated JCV+ patients, which likely explains a reduced incidence of PML. Disclosure The IMSE 1 Study have received unrestricted grants from Biogen. Susanne Johansson and Linda Forsberg: Nothing to disclose.


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Poster Session 1, 22(S3) Jan Hillert, Fredrik Piehl, Charlotte Dahle and Tomas Olsson have received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi Genzyme. Claes Martin has received honoraria for lectures and advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi Genzyme. Jan Lycke has received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen, Novartis, Teva and Sanofi Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Sanofi Genzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Anders Svenningsson has served on advisory board for Sanofi Genzyme and has received travel funding from Biogen, Novartis and Baxter Medical. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Sanofi Genzyme, honoraria for lectures and advisory boards from Merck Serono and Sanofi Genzyme, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogen, Sanofi Genzyme, Hospira and Merck Serono; has received unconditional research grants from Biogen and Merck Serono. Anne-Marie Landtblom has received honoraria from Merck Serono, Teva, Biogen Sanofi Genzyme. Fredrik Walentin has received research grants from Biogen and Merck Serono. P696 Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod Y.D. Fragoso1, R. Alroughani2, M. Barnett3, J.B. Brooks1, H. Butzkueven4,5, C. Boz6, F. Granella7, J. Haartsen4, E. Havrdova8, A. Lugaresi9,10, J. Olascoaga11, J.L.S. Menoyo12, E. Pucci13, T. Spelman3, M. Terzi14, S. Vusic15, V. Ticha8,16, the Lymphopenia and Efficacy of Fingolimod MSBase Sub-Study Investigators 1Universidade Metropolitana de Santos, Santos, Brazil, 2Amiri Hospital, Kuwait, Kuwait, 3Brain and Mind Research Centre, Sydney, NSW, 4Royal Melbourne Hospital, 5Box Hill Hospital, Eastern Health, Melbourne, VIC, Australia, 6Karadeniz Technical University, Trabzon, Turkey, 7University of Parma, Parma, Italy, 8General University Hospital and Charles University in Prague, Prague, Czech Republic, 9Department of Biomedical and Neuromotor Sciences (DIBINEM), ‘Alma Mater Studiorum’, University of Bologna, 10IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy, 11Hospital Donostia, Donostia, 12Hospital de GaldakaoUsansolo, Usansolo, Spain, 13Neurology Unit, ASUR Marche AV3, Macerata, Italy, 14Mayis University, Samsun, Turkey, 15Westmead Hospital, Sydney, NSW, Australia, 16First Faculty of Medicine and General University Hospital, Prague, Czech Republic Background: Fingolimod is a relatively new, efficient and safe drug for treating relapsing-remitting multiple sclerosis (RRMS). In vivo, fingolimod is phosphorylated and resembles naturally occurring sphingosine 1-phosphate (S1P). S1P binds to receptors

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that are expressed in a wide range of cells involved in many biological processes relevant to RRMS. S1P plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Taking into consideration that lymphocyte sequestration into lymph nodes is the main mechanism of action of this drug, the present study analyzed, in a real-world setting, whether decreasing the lymphocyte count in peripheral blood could positively influence patients’ response to treatment. Method: Data were obtained from the MSBase Registry. Patients were divided into groups: those who reached less than 750 lymphocytes/mm3 in peripheral blood at any given time on fingolimod (< 750-ever group); and a propensity matched group who never had recorded less than 1000 lymphocytes/mm3 in peripheral blood (< 1000-never group) on fingolimod. Annualised Relapse Rate (ARR) was compared between groups using a paired signedranks test. Time to first relapse and time to six-month confirmed disability progression were compared using a marginal Cox model. Results: A total of 202 patients in the < 750-ever group were successfully propensity matched on a 2:1 basis to 101 patients in the < 1000-never group. Mean (SD) follow-up time for the < 750 and < 1000-never groups were 2.31 (1.28) and 1.91 (1.18) years respectively. There was no difference between groups in ARR (p=0.2967) with the < 750 ever group recording a mean (SD) ARR of 0.34 (0.84) compared with 0.52 (0.98) in the < 1000 never group. Similarly there was no difference between groups in either time to first relapse (HR 0.79; 95% CI 0.54, 1.15; reference = < 1000 never) or time to six-month confirmed disability progression (HR 0.96; 95% CI 0.47, 1.95; reference = < 1000 never). Conclusion: Decreasing the peripheral lymphocyte count below 750 cells/mm3 in RRMS patients on fingolimod was not associated with a difference in ARR, time to first relapse and disability progression rate relative to patients who maintained their lymphocyte count above 1000 cells/mm3 on fingolimod. Disclosure Yara Dadalti Fragoso has nothing to disclose in relation to this study and the participation in MSBase Raed Alroughani Received speaker´s honoraria from Biogen, Bayer, Merck-Sorono, Novartis, GSK, and Genzyme. Served on scientific advisory board of Bayer, Genzyme, Biogen, MerckSorono and Novartis Michael Barnett has served on scientific advisory boards for Biogen-Idec, Novartis and Genzyme and has received conference travel support from Biogen-Idec and Novartis. His institution has received research support from Biogen-Idec, Merck-Serono and Novartis. Joseph Bruno B. Books has nothing to disclose in relation to this study and the participation in MSBase Helmut Butzkueven has received consulting fees from Genzyme, Biogen, Novartis, Merck and Oxford PharmaGenesis; and grant/ research support from Biogen, Novartis, Merck and Genzyme Cavit Boz has nothing to disclose Franco Granella has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Aventis and has received funding for travel and speaker honoraria from Biogen Idec, Merck Serono, and Almirall Jodi Haartsen has received honoraria for talks and advisory boards, and support for scientific meetings, from Novartis, Biogen Idec, Merck-Serono and Genzyme.,


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Eva Havrdova eceived speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono Alessandra Lugaresi has served as a Bayer, Biogen, Merck Serono, Novartis and Genzyme Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi, Teva and Fondazione Italiana Sclerosi Multipla and research grants for her Institution from Bayer, Biogen, Merck Serono, Novartis, Sanofi, Teva and Fondazione Italiana Sclerosi Multipla. Javier Olascoaga has nothing to disclose José Luis Sánchez Menoyo has accepted travel compensation from Novartis, Merch Serono and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck Serono, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. Eugenio Pucci has nothing to disclose in relation to this study and the participation in MSBase Tim Spelman received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen Inc; speaker honoraria from Novartis. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Steve Vucic has nothing to disclose in relation to this study and the participation in MSBase Veronika Ticha has nothing to disclose in relation to this study and the participation in MSBase P697 A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of dimethyl fumarate (IMSE 5) L. Forsberg1, S. Johansson1, J. Hillert1, P. Nilsson2, C. Dahle3, A. Sveningsson4, J. Lycke5, A.-M. Landtblom6, J. Burman6, F. Walentin7, C. Martin4, F. Piehl1, T. Olsson1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Department of Clinical Sciences, Neurology, Lund University, Lund, 3Department of Clinical and Experimental Medicine, Linköping University, Linköping, 4Department of Clinical Science, Danderyd Hospital, Stockholm, 5Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 6Department of Neuroscience, Uppsala University, Uppsala, 7Örebro University Hospital, Örebro, Sweden Background: Dimethyl fumarate (DMF) is a novel oral therapy for relapsing-remitting multiple sclerosis (RRMS), the efficacy of which has been shown in phase II and III studies. However; postmarketing surveillance is important to determine the long-term safety and effectiveness in a real-world setting. DMF has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To follow-up the long-term safety and effectiveness of DMF in a real-world setting. Methods: MS patients in Sweden are registered into the nationwide web-based Swedish MS registry (SMSreg). The IMSE study includes descriptive data of adverse events (AEs), extended disability status scale (EDSS), MS severity scale (MSSS), symbol

digit modalities test (SDMT), MS impact scale (MSIS-29), European quality five dimensions (EQ-5D) and Visual Analog scale (VAS) obtained from SMSreg. Blood samples are collected at baseline and after 12 months of treatment. Drug survival was measured using the Kaplan-Meier curve and effectiveness measures were assessed using the Wilcoxon Signed Rank Test. Results: 1,565 DMF-treated patients have been included in the IMSE 5 study between March 25th, 2014 and March 31th, 2016 most of which have switched from interferons or glatiramer acetate (47%), 21% of the patients were treatment naïve (10% missing data on prior treatment). 89% of the patients have RRMS (6% missing data on MS phenotype). The mean treatment duration is 11.0±6.6 months, the mean age at treatment start is 41.0±11.0 years and 74% are female. The one year drug survival was 76% and discontinuation was significantly more common among female than male patients (p< 0.05). 355 patients terminated their treatment at some point. The most common reason for discontinuation was AEs (58%) and lack of effect (27%). In patients treated with DMF continuously for ⩾12 months (n=549), significant improvements in mean values at 12 months of treatment compared to mean baseline values have been noted for EDSS scores by 8%; MSSS by 16%; SDMT by 1%; MSIS-29 Psychological by 15% EQ-5D by 6%, and VAS by 3%. Conclusions: SMSreg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. DMF is generally well tolerated; however a longer follow-up period is needed to assess the real-world effectiveness and safety of DMF. Disclosure The IMSE 5 study has received unrestricted grants from Biogen. Susanne Johansson and Linda Forsberg: Nothing to disclose. Jan Hillert, Fredrik Piehl, Charlotte Dahle and Tomas Olsson have received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi Genzyme. Claes Martin has received honoraria for lectures and advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi Genzyme. Jan Lycke has received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen, Novartis, Teva and Sanofi Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Sanofi Genzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Anders Svenningsson has served on advisory board for Sanofi Genzyme and has received travel funding from Biogen, Novartis and Baxter Medical. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Sanofi Genzyme, honoraria for lectures and advisory boards from Merck Serono and Sanofi Genzyme, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogen, Sanofi Genzyme, Hospira and Merck Serono; has received unconditional research grants from Biogen and Merck Serono. Anne-Marie Landtblom has received honoraria from Merck Serono, Teva, Biogen Sanofi Genzyme.


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Poster Session 1, 22(S3) Fredrik Walentin has received research grants from Biogen and Merck Serono. P698 Adherence to fingolimod in multiple sclerosis patients taking part in a person-centred integrated care programme in Switzerland A. Bourdin1,2, M. Schneider1,2, I. Locatelli3, M. Schluep4, J. Berger1,2, O. Bugnon1,2 1Community Pharmacy, Department of Ambulatory Care & Community Medicine, University of Lausanne, Lausanne, 2Community Pharmacy, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Lausanne, 3Department of Ambulatory Care & Community Medicine, University of Lausanne, 4Division of Neurology, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Background: In Switzerland, fingolimod has been approved as a first-line treatment in patients with relapsing-remitting multiple sclerosis (MS). In 2013, the Community Pharmacy of the Department of Ambulatory Care & Community Medicine in Lausanne implemented a person-centred integrated care programme for optimising safety and effectiveness of fingolimod. This routine pharmacist-led programme is proposed to each consecutive patient starting fingolimod at the local University hospital (Centre Hospitalier Universitaire Vaudois, CHUV). It combines motivational interviews, adherence monitoring with an electronic monitor (EM), risk evaluation & mitigation strategies (REMS) and a collaborative practice with the neurologist and the MS-nurse. Objectives: To describe adherence (persistence and implementation) to fingolimod of patients taking part in the person-centred integrated care programme. Methods: EM data of each patient who took part in the programme since 2013 were analysed and reconciled with the pill count and interview notes. Adherence was characterized by two operational concepts: persistence and implementation. Persistence to fingolimod was defined as the length of time from initiation to “discontinuation” and estimated by a Kaplan-Meier curve. We compared two definitions of discontinuation: 1) as an interruption of fingolimod prompted by the patient alone, 2) as any interruption of fingolimod (decided alone or in collaboration with the physician). Implementation was computed at each day D as the proportion of patients taking fingolimod as prescribed, among patients still persistent at day D. A logistic Generalized Estimating Equation model was used to estimate implementation over time. Results: EM data of 40 patients (all were naive of fingolimod and 25 of any MS treatment), median age 33.5 years old [IQR: 27.0; 42.3], 23 women (58%), were analyzed. Median follow-up was 376 days [IQR: 207.5; 577.5]. The 1-year persistence of patients discontinuing fingolimod based on their own decision was 95%, and 88% when considering the physician’s decision as well. Implementation decreased over time during about 7 months (nadir at 85%). The tendency is reversed during the second part of the year (quadratic model). Conclusions: The 1-year fingolimod implementation and persistence in patients taking part in a person-centred integrated care programme were high. This on-going programme will provide data over longer periods of time with more patients for future analysis.

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Disclosure M. Schluep has served as a consultant for Merck-Serono, has received honoraria, payment for development of educational presentations and travel support from Biogen, Genzyme, MerckSerono, Novartis, Roche and Sanofi-Aventis. A. Bourdin, M. Schneider, I. Locatelli, J. Berger and O. Bugnon have nothing to disclose. The development of the patients’ programme was supported by an unrestricted grant from Novartis Pharma Schweiz AG.

P699 Defining non-adherence to the injectable disease-modifying therapies in multiple sclerosis K.A. McKay1, H. Tremlett1, S.B. Patten2, J.D. Fisk3, C. Evans4, K. Fiest5, T. Campbell6, R.A. Marrie7 1Department of Medicine, University of British Columbia, Vancouver, BC, 2Departments of Psychiatry & Community Health Sciences, University of Calgary, Calgary, AB, 3Departments of Psychiatry, Psychology, & Neuroscience, Dalhousie University, Halifax, NS, 4College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, 5Departments of Critical Care Medicine & Community Health Sciences, University of Calgary, Calgary, AB, 6Faculty of Health Professions, Dalhousie University, Halifax, NS, 7Departments of Internal Medicine & Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada Introduction: Estimates of adherence to the injectable diseasemodifying therapies (DMTs) for multiple sclerosis (MS) vary widely, possibly due to variation in the definition of adherence. We estimated adherence rates and examined characteristics potentially associated with non-adherence using two practical and clinically relevant definitions. Methods: Consecutive MS patients were recruited from four MS Clinics across Canada (2010-11) and followed to 2013. At three visits over two years, clinical, demographic, and self-reported information was collected. Questionnaires captured current DMT use, number of missed doses of DMT in the previous 30 days, health behaviours and comorbidities. Perceived cognitive difficulties were assessed using the single attribute scale of the HUI-III. Non-adherence was defined based on self-report in two ways: 1) < 80% of expected doses; 2) any missed doses. Logistic generalized estimating equation models were used to assess the odds of non-adherence relative to patient characteristics over the full study period, adjusted for confounders. Results: Of 949 participants, 485 reported use of an injectable DMT and were included in the analysis. Their mean (SD) age was 46(10) years and most (79%) were female. Using the first definition, 107 (22%) participants were non-adherent at least once during the follow-up. Using definition two, this increased to 255 (52%). All three interferon-β products were associated with higher odds of nonadherence (vs glatiramer acetate) using definition one, but this relationship was reversed when using definition two (all p< 0.05). For both definitions, participants with alcohol dependence or perceived cognitive difficulties had higher odds of non-adherence (ORs ranged between 2.1-2.6 for alcohol and 1.4-1.6 for cognition). Conclusions: Over 1 in 5 individuals reported taking < 80% of the expected DMT dose and over half missed at least one dose


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during the study. Both alcohol dependence and cognitive difficulties emerged as consistent factors associated with non-adherence; however, the relationship between the different DMT products and non-adherence varied considerably depending on the definition used. We highlight the impact that the definition of adherence can have on rates of adherence and associated characteristics. Ideally, a clinically meaningful and consistent definition of adherence should be established for future studies. Disclosure The study was sponsored by the Canadian Institutes of Health Research (CIHR CBG 101829), the Rx & D Health Research Foundation, by a Don Paty Career Development Award from the MS Society of Canada (to RAM). Kyla McKay, Charity Evans, and Kirsten Fiest report no disclosures. Helen Tremlett is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received: research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada (Don Paty Career Development Award and operating grants); the Multiple Sclerosis Scientific Research Foundation; the Michael Smith Foundation for Health Research (Scholar award) and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014, 2015, 2016), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). All speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by her research group. John Fisk receives research grant support from the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, the Multiple Sclerosis Society of Canada, and the Dalhousie Medical Research Foundation; and has received speaker honoraria from EMD Serono (2014). Scott Patten is a Senior Health Scholar with Alberta Innovates, Health Solutions. Trudy Campbell has received honoraria from EMD Serono, Teva Canada Innovation, Biogen, Novartis, Genzyme and Roche. Ruth Ann Marrie receives research funding from: CIHR, Public Health Agency of Canada, Manitoba Health Research Council, Health Sciences Centre Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, National Multiple Sclerosis Society, and has conducted clinical trials funded by sanofi-aventis. P700 Open-label prospective nonrandomized long-term study of interferon-beta biosimilars: efficacy of generic drugs in multiple sclerosis D. Kasatkin, N. Spirin, I. Stepanov, N. Spirina, N. Baranova Yaroslavl State Medical University, Yaroslavl, Russian Federation Introduction: Biosimilar is a medicinal product which is similar to the reference medicinal product and demonstrate comprehensive characteristic of the concerned product. Interferons-beta

(IFN) are immunobiological medicinal products produced by biotechnological processes. Nowadays all of them lost patent protection and we have an opportunity to evaluate new biosimilars: Infibeta (IFN-1b sc, Russia), Ronbetal (IFN-1b sc, Russia), Genfaxone (IFN-1a sc, Argentine), Cinnovex (IFN-1a im, Iran). Material and methods: 203 patients, RRMS, age - 35.5-40.2 (95%CI) years, with disease duration of 121-145 (95%CI) months at baseline; 30 months with every 6 month evaluation of EDSS score and relapse rate (RR); MRI evaluation at baseline and in 30month point. Results at baseline and month 30 visit were compared. Statistical analysis - nonparametric statistic: McNemar Chi-square, Kruskal-Wallis ANOVA, Median Test. Results: Total 203 patients included in study: Infibeta - 60, Ronbetal - 44, Genfaxone - 73, Cinnovex - 26. There was a significant decrease in the frequency of relapses in patients treated with biosimilars compared to baseline (Cinnovex by 0.30, Genfaxone by 0.29, Ronbetal by 0.13, Infibeta by 0.41). EDSS scores significantly increased for Cinnovex (+0.31), Genfaxone (+0.38), Ronbetal (+0.66), not significantly increase for Infibeta (+0.13). MRI results revealed an increase in the number of T2-lesions in Cinnovex (+17.6%), Genfaxon (+14.6%) and Ronbetal group (+10.6%) and a decrease of T2-lesions in Infibeta group (-14.5%). Conclusion: There are some differences between biosimilars and biosimilars and original drugs of IFN in efficacy in real clinical practice, not all biosimilar drugs provided effective treatment for RRMS. So, we need significant investment, technical capability, and clinical trial expertise to define their interchangeability. Disclosure Kasatkin D.S.: Nothing to disclose Spirin N.N.: Nothing to disclose Stepanov I.O.: Nothing to disclose Spirina N.N.: Nothing to disclose Baranova N.S.: Nothing to disclose P701 Long-term persistence with injectable therapy in relapsingremitting multiple sclerosis: evaluation of no evidence of disease activity in a 10-year longitudinal multiple sclerosis cohort S. Ozakbas1, Z. Mehdiyev1, G. Kosehasanogullari2, B. Piri Cinar3, H. Limoncu1 1Dokuz Eylul University, Izmir, 2Usak State Hospital, Usak, 3Samsun Education and Training Hospital, Samsun, Turkey Disease-modifying treatments (DMTs) comprise immunomodulating and immunosuppressant medications aimed at slowing the progression of multiple sclerosis (MS). The working hypothesis is that reducing or preventing new lesions and their sequelae slows the worsening of the disease. Long-term persistence with treatment is important to optimize treatment benefit. In this long-term, cohort study we aimed to examine persistence with the use of injectable DMTs, and to determine which factors impacted persistence. We also aimed to investigate no evidence of disease activity (NEDA) during 10 years. NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale (EDSS) score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual magnetic resonance


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Poster Session 1, 22(S3) imaging (MRI). All consenting adults with relapsing-remitting (RR) MS who started either glatiramer acetate (GA) or interferonbeta 1a/1b (IFNb) between September 1996 and December 2005 were included in the study. Follow-up continued to December 2015, which means all patients were followed up at least 10 years. A total of 1032 patients included in the study. 289 were initially prescribed GA and 743 were initially prescribed IFN-β. Median time-to-discontinuation of all injectable DMTs was 10.2 years. 613 participants remained on treatment after 10 years. Of 419 participants who discontinued injectable DMT, 201 (48%) started an oral or a second-line DMT. 211 (50.4%) patients started another injectable DMT. Only 7 (1.7%) patients remained untreated. Patients who had greater disability at treatment initiation and those who started treatment before age 35 were more likely to discontinue use of injectable. A total of 321 of 613 patients (52.4%) had NEDA 2 years. 112 of 613 (18.3%) maintained NEDA status after 10 years. No differences were found in NEDA status between patients with initially prescribed GA vs initially prescribed IFN-β. When comparing EDA and NEDA patients, EDA patients were found to use more second line drugs than NEDA patients (p=0.006). On the basis of disability, EDA patients progressed, while NEDA patients improved (p< 0.001). In conclusion, persistence in injectable DMTs was high in our cohort. Most patients who discontinued injectable DMT did not remain untreated. Our findings suggest that the combined NEDA measure allows for better early prediction of freedom from progression at as long as 10 years follow-up. Disclosure Serkan Ozakbas: nothing to disclose Zaur Mehdiyev: nothing to disclose Gorkem Kosehasanogullari:nothing to disclose Bilge Piri Cinar: nothing to disclose Hatice Limoncu: nothing to disclose P702 Comparison of fingolimod and dimethyl fumarate in the treatment of multiple sclerosis: two year experience B.L. Vollmer1, K.V. Nair2, S.H. Sillau1, J. Corboy1, T.L. Vollmer1, E. Alvarez1 1Rocky Mountain Multiple Sclerosis Clinic at University of Colorado, 2Skagg’s School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Objective: Compare discontinuation rates, efficacy, and adverse events(AEs) of fingolimod(FTY) and dimethyl fumarate(DMF) over two years. Backgrond: FTY and DMF are the most common MS oral therapies becoming available in 2010 and 2013, respectively. Limited comparative effectiveness data exists beyond one year of treatment. Methods: Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data including relapse history, adverse events(AEs), MRI outcomes, disease history and patient characteristics were retrospectively collected. Primary outcome was the probability of discontinuing drug by the end of year two. Reasons for discontinuation were also evaluated. Simple logistic

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regression and 1:2 nearest neighbor matching were used for data analysis controlling for age, disease duration, type of MS, previous natalizumab use, gender, and disease burden at baseline (missing, mild, moderate, severe) to estimate differences in the primary outcome. Results: A total of 271 and 342 patients initiated FTY and DMF and were followed for two years. Patients had a mean age of 46.2(FTY) and 48.1(DMF) years; were predominantly female(72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11 years for both groups. At ⩽24 months, 93(34.3%) and 161(47.1%) discontinued FTY and DMF respectively with an unadjusted odds ratio (OR) of 1.70(95%CI 1.23-2.37, p=0.002) and adjusted OR of 1.78(95%CI 1.16-2.73, p=0.009) with 2:1 matching with replacement. Primary reason for discontinuation was AEs, which was lower for FTY 46(17.0%) compared to DMF 82(24.0%) (OR 1.54, 95%CI 1.03-2.31, p=0.034). Of FTY patients who discontinued due to AEs, 11(23.9%), 8(17.4%), 7(15.2%), and 7(15.2%) experienced gastro-intestinal issues, headaches, increased infections, and lymphopenia, respectively. One FTY patient experienced a serious AE of alveolar hemorrhage. Of DMF patients who discontinued due to AEs, 66(80.5%), 25(35.5%), 6(7.3%) and experienced gastro-intestinal issues, flushing/rashes/hot flashes, and lymphopenia, respectively. Discontinuation due to disease activity (relapses and/or new MRI lesions) was similar FTY (10%) and DMF (11.1%) patients(OR 1.13, 95%CI 0.67-1.90, p=0.647). Conclusions: There were fewer discontinuations with FTY vs.DMF. Discontinuation rates in the first two years were driven by AEs. Natalizumab patient data (n=300) will also be presented to assess treatment effect/methods. Disclosure Brandi Vollmer: nothing to disclose Kavita V Nair: received grants from Novartis, Biogen, Gilead Sciences; consulting for Astellas and Genentech Stefan H Sillau: nothing to disclose John Corboy: research grants from NIH, Novartis, Sun Pharma, Celgene Therapeutics, National Multiple Sclerosis Society, has research grants from Juvenile Diabetes Research Foundation, National Multiple Sclerosis Society, Diogenix, Rocky Mountain MS Center; consulting for Novartis, Pharmagensis; medical legal work; editor for Neurology: Clinical Practice; board member of the National Multiple Sclerosis Society, ColoradoWyoming chapter Timothy Vollmer: research grants from Biogen, EMD Serono, Genzyme, NIH, Novartis, Ono Pharmaceuticals, Rocky Mountain MS Center, Teva, Roche; consulting for Acorda, Biogen, Consortium of MS Centers, DeltaQuest, Genentech, MedScape, Novartis, Novartis Canada, Novartis Japan, Pharmagenesis, Roche, Rocky Mountain MS Center, Teva, Teva Canada. Enrique Alvarez: research grants from Genzyme, Biogen Idec, Rocky Mountain MS Center, Novartis, Acorda and consulting for Genzyme, DeltaQuest, Teva, Acorda and Biogen P703 9% of multiple sclerosis patients taking dimethyl fumarate have a severe reduction in CD8+ T lymphocytes (CD8+ < 100 mm³) but have only grade 1 lymphopenia when measured as absolute lymphocyte count C. Spinelli1,2, B. Bagert1


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Sclerosis Center, Ochsner Health System, 2Tulane University, New Orleans, LA, United States Background: Recently published data suggests that CD8+ T lymphocytes are differentially affected in patients with multiple sclerosis (MS) taking dimethyl fumarate (DMF). The sample sizes of such research studies have been small (>35 patients). Reduction in CD8+ lymphocytes might be a better predictor of progressive multifocal leukoencephalopathy (PML) than the absolute lymphocyte count (ALC) in patients with MS taking DMF. We report CD8+ values as well as changes in ALC in patients taking DMF in a large MS Center. Methods: The study is a retrospective chart review of 174 patients at the Ochsner MS Center who took DMF between 2013 and 2016. The study was approved by the Ochsner Institutional Review Board (2016.090.C) on April 15th, 2016. POPULATION: 72% of patients taking DMF were women. The mean age of patients on DMF was 46.9 years. Results: The average duration of DMF use was 25 months at time of measurement for this study. Mean ALC in patients taking DMF decreased 27% (mean pretreatment ALC = 2052/µL; mean ALC during DMF treatment = 1283/µL). Pretreatment CD8+ lymphocyte values were not measured. CD8+ lymphocyte counts were collected on 155 patients on DMF in the fall of 2015: 46% of patients on DMF had CD8+ count < =200 mm³; 31% of patients on DMF had CD8+ < =150 mm³; 21% of patients on DMF had CD8+ count < =100 mm³; 12% of patients on DMF had CD8+ counts < =50 mm³. 9% of patients had CD8+ count < = 100 mm³ but also had ALC >= 800/µL (grade 1 lymphopenia). DMF was discontinued in 61 patients due to lymphopenia, and repeat CD8+ values were systematically collected after DMF discontinuation on 48 patients. 29% of patients continued to have CD8+ count < =100 mm³ after discontinuation of DMF (average of 2.5 months after discontinuation). Discussion: The CD8+ lymphocyte count may be a better predictor of PML risk than the ALC based on case reports of PML in patients taking fumarates for MS and psoriasis. Our data suggests that as many as 20% of patients with MS on DMF have severe lymphopenia as measured by CD8+ count < 100mm³, and that one third of this group has an ALC that shows only mild grade 1 lymphopenia. Measuring ALC alone would miss severe lymphopenia in 9% of our study population. A significant proportion (29%) of patients taking DMF had prolonged lymphopenia after DMF discontinuation. We suggest that all patients with MS treated with DMF be monitored with baseline and quarterly lymphocyte subset testing in addition to baseline and quarterly ALC testing. Disclosure Casey Spinelli: Nothing to disclose Bridget Bagert, MD, MPH: Nothing to disclose. P704 MSFIRST - utilising a longitudinal, prospective, comparative drug safety module for use in everyday MS clinical practice to evaluate and track incidence and characteristics of safety outcomes in MS patients on therapy over the long term

J. Haartsen1, T. Spelman2, J. Baker2, S. Agland3, J. LechnerScott3, T. Burke4, S. Vucic4, L. Rath5, O. Skibina5, M. Toubia6, M. Slee7, S. McGregor8, B. Taylor8, A. O’Connell9, M. Barnett9, S. Baker10, M. Sharma10, S. Hodgkinson10, S. Walters11, A. Kermode11, W. Hayes12, E. Butler12, N. Shuey13, C. Shaw14, R. Portley15, T. Hardy15, I.L. Tan16, H. Butzkueven1,2, on behalf of the MSFIRST Investigators. 1Box Hill Hospital, Eastern Health, 2Department of Medicine, Royal Melbourne Hospital, Melbourne, VIC, 3John Hunter Hospital, Newcastle, 4Westmead Hospital, Sydney, NSW, 5The Alfred, Melbourne, VIC, 6Flinders Medical Centre, 7Flinders University and Medical Centre, Adelaide, SA, 8Royal Hobart Hospital, Hobart, TAS, 9Brain and Mind Research Institute, Sydney, 10Liverpool Hospital, Liverpool, NSW, 11Western Australian Neuroscience Research Institute (WANRI), Nedlands, WA, 12Monash Medical Centre, Clayton, 13St Vincents Hospital, Fitzroy, 14Geelong Hospital, Geelong, VIC, 15Concord Repatriation General Hospital, Concord West, 16Macquarie University Hospital, Sydney, NSW, Australia Introduction: MSFIRST, a sub-study of the MSBase registry, is an Australian multi-centre study to implement a user-friendly safety module to track incidence and characteristics of safety outcomes in MS patients. The comparative long term safety profile of disease-modifying drugs (DMD) in MS treatment is unknown and incidence and trends over time in serious adverse events (SAEs) are less well reported in real world practice. Objective: MSFIRST is a prospective, longitudinal study, enrolling since 1 January 2012. The primary objective of this study is to track and compare the incidence of safety outcomes in MS patients who either receive DMD or no treatment. Methods: Rates of SAE’s by treatment group including fingolimod (FTY), natalizumab (NAT) and combined group of interferon and glatiramer acetate (IFN/GA) were calculated as no. of events per 100 person-years of follow-up. The relative risk of SAE by treatment group was estimated using a longitudinal Poisson regression model offset by DMD exposure time and adjusted for age, sex and disease duration. Results: At 6 April 2016 there were 3115 patients enrolled contributing 4590.8 person-years of follow-up at a mean (SD) of 17.4 months (14.2) per patient. 1303 adverse events have been observed. A total of 79 immunosuppression related or severe infection events, 75 herpes zoster, 56 non-melanoma skin cancer (NMSC) and 53 malignancy events observed at an incidence rate of 0.27, 0.33, 0.31 and 0.44 events per 100 person-years respectively. Natalizumab (NAT) was associated with 3.14 times the risk of infections (aRR 3.14; 95% CI 1.04, 9.46) relative to IFN/GA, whilst there was no difference between FTY and IFN/GA (aRR 2.06; 95% CI 0.72, 5.88). There was no difference in the risk of herpes zoster between FTY (aRR 1.00; 95% CI 0.44, 2.29) or NAT (aRR 1.37; 95% CI 0.54, 3.49) relative to IFN/GA group. Similarly, there was no difference in the risk of NMSC between IFN/GA and either FTY (aRR 0.79; 95% CI 0.28, 2.24) or NAT (aRR 0.79; 95% CI 0.21, 2.93). No difference in the risk of malignancy was observed between FTY (aRR 1.47; 95% CI 0.50, 4.30) or NAT (aRR 2.57; 95% CI 0.76, 8.70) compared with IFN/GA. Conclusions: The establishment of a large, prospective multidrug safety module for use in routine practice has been successful to date in Australia. Long term monitoring in clinical practice


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Poster Session 1, 22(S3) could provide important insights into both the incidence and timing of treatment-associated SAE’s. Disclosure Jodi Haartsen - JH has received honoraria for talks and advisory boards, and support for scientific meetings, from Novartis, Biogen Idec, Merck-Serono and Genzyme. Tim Spelman - TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen Inc; speaker honoraria from Novartis. Josephine Baker - JB has received travel assistance from Novartis/Bayer/Merck and advisory committees Novartis/ Biogen/Genzyme Susan Agland - SA has received honoraria for talks and advisory boards, and support for scientific meetings, from Bayer, Biogen Idec, Genzyme Merck, and Novartis. Jeannette Lechner-Scott - J L-S has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck, Novartis and TEVA. Therese Burke - Nothing to disclose Steve Vucic - Nothing to disclose Louise Rath - LR - travel grants from Biogen & Novatis and Speakers Honorarium from Biogen, Novartis & Genzyme Olga Skibina - OS - research grant from Biogen, Travel grants from Biogen, Novartis & Bayer and Speakers Honorarium from Bayer, Biogen, Genzyme & Novartis Marie Toubia - Nothing to disclose Mark Slee - Nothing to disclose Sue McGregor - Nothing to disclose Bruce Taylor - BVT has served on advisory boards for Novartis, Biogen, Genzyme and Bayer Schering. He has received travel assistance from Novartis and Teva. He is currently receiving research funding from the NHMRC Australia and MS research Australia. Annmaree O’Connell - Nothing to disclose Michael Barnett - Nothing to disclose Susanne Baker - SB has received honorarium educational, conference and travel support from Biogen Idec, Sanofi, Genzyme, Bayer, Novartis and Merck Serono. Meena Sharma - MS has received honorarium, professional development education and conference attendance support from Biogen Idec, Sanofi Aventis, Genzyme, Bayer Schering, Novartis and Merck Serono. Suzanne Hodgkinson - SH has received honorarium, travel, educational, and research grants from Genzyme, Biogen Idec, Bayer, Merck Serono, Novartis, Sanofi Aventis Susan Walters - Nothing to disclose Allan Kermode - Nothing to disclose Wendy Hayes - Nothing to disclose Ernest Butler - Nothing to disclose Neil Shuey - Nothing to disclose Cameron Shaw - CS received travel assistance from Biogen Idec and Novartis. Rosemarie Portley - Nothing to disclose Todd Hardy - TH has received honoraria for talks and advisory boards, and support for scientific meetings, from Novartis, Biogen Idec, Merck-Serono, Alexion and Genzyme. Ik Lin Tan - Nothing to disclose

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Helmut Butzkueven - HB has received consulting fees from Genzyme, Biogen, Novartis, Merck and Oxford PharmaGenesis; and grant/research support from Biogen, Novartis, Merck and Genzyme

Risk management for disease modifying treatments P705 Effect of fingolimod on an animal surgical wound healing model: a non-immunosuppressive profile R.C. Ginestal1, B. Perez-Köhler2, P. Perez-Lopez2, G. PascualGonzalez2, M. Rodriguez-Mancheno2, D. Cebrian3, F. GarciaMoreno2, J.M. Bellon2 1Neurology, Fundacion Jimenez Diaz, Madrid, 2Surgery Department, Alcala University, Alcala de Henares, 3Experimental Therapeutics Programme, Spanish National Cancer Research Centre, Madrid, Spain Objective: Fingolimod is the first oral compound approved in the US, Canada and the EU for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). Inducing a S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, it is considered an immunosuppressive agent. We used a well-defined experimental model to assess Fingolimod effects on cutaneous wound healing, a physiological process that involves neutrophils, lymphocytes and macrophages. Background: Immunosuppressants are known to interfere with surgical wound healing. This is the case of Azathioprine, another oral drug labeled in Spain to treat RRMS. The increasing use of immunosuppressive drugs in MS asks for a better understanding of their effects on wound healing. Design and methods: Sixty-three Sprague-Dawley rats received Fingolimod 0.3 mg/kg/day (n=21), Azathioprine 1.5mg/kg/day (n=21) or sham (n=21) for 6 weeks before a 2 cm linear dorsal surgical wound closed with surgical staples or a circular 2 cm diameter defect were performed. Animals were still receiving treatment for 7 (n=21, linear wound) and 21 (n=21 linear wound, N=21 circular defect) more days, until sacrifice, when surgical site tissue was collected and analyzed for optic microscopy (Masson´s tricromic), macrophage (total, M1 and M2 phenotypes) cell number (ED1) and collagen fiber content (Sirius red). Mass spectrometry was performed before surgery to confirm serum Fingolimod presence. The study followed the recommendations of the Guide for the Care and Use of Laboratory Animals of the National and European Institutes of Health. Results: No differences were obtained with the circular defect model. Linear wound model: On day 7, Azathioprine provoked macroscopical disruption of the scar in 5/7 rats, compared to only 2/7 in the Fingolimod treated animals. Moreover, Macrophage content was lower in Azathioprine compared to Fingolimod and sham treated groups. No difference between the three groups on collagen formation was observed on day 7, but on day 21, Azathioprine group showed less collagen content. Conclusions: Compared to Azathioprine, Fingolimod does not interfere with wound healing. Tissue repair was not delayed and is similar to the pattern observed in sham treated rats. Disclosure This study was funded by NOVARTIS PHARMA.


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Dr. Ricardo C. Ginestal received compensation from MerckSerono, Biogen-Idec, TEVA, Novartis and Bayer-Schering for consulting services, scientific advisory board and conference speaking. Dr. Perez-Köhler: nothing to disclose. Dr. Perez-Lopez: nothing to disclose. Dr. Pascual-Gonzalez: nothing to disclose. Dr. Rodríguez-Mancheno: nothing to disclose. Dr. Cebrian: nothing to disclose. Dr. Garcia-Moreno: nothing to disclose. Dr. Bellon-Caneiro: nothing to disclose. P706 Evaluation of switching to teriflunomide in high risk natalizumab patients K. Edwards, J. O’Connor, J. Siuta MS Center of Northeastern New York, Latham, NY, United States Background: Natalizumab (NTZ) may cause progressive multifocal leukoencephalopathy (PML) in patients with detected antiJCV-antibody after extended use. Prior use of immunosuppressive agents further increases risk of PML. There are no guidelines for switching from NTZ to another disease modifying therapy (DMT). Significant reactivation of the patient’s MS disease activity may occur after NTZ withdrawal. Objectives: To determine if teriflunomide is safe and effective in patients switching from NTZ to teriflunomide. Methods: Twenty-five consecutive RMS patients, ages 28 to 60, who had received 12 or more NTZ treatments and who were antiJCV antibody detected, were switched to teriflunomide and were analyzed using retrospective data collection. Teriflunomide treatment was started as soon as medication was available upon stopping NTZ. Prior use of an immunosuppressant was recorded. Clinical status was measured by tolerance and safety, clinical relapses and EDSS at 6 and 12 months. MRI findings were analyzed. Results: Mean age was 48 (SD 12); 80% were female. Mean number of NTZ treatments was 39 (SD 12). Mean months of teriflunomide treatment was 20 (SD 11). Nine patients had prior immunosuppression (36%) with a mean treatment duration with NTZ of 48 months (SD 11). Mean time between last NTZ dose and first teriflunomide dose was 6 weeks (SD 4). Mean EDSS at baseline was 3.5 (SD 1.5). After 6 months, the mean EDSS of remaining 23 patients was 3.3 (SD 1.5) and there were no clinical exacerbations. Two of the 25 patients discontinued due to gastrointestinal issues in the first few weeks of treatment. Five patients (20%) had temporary hair thinning with full recovery. There were no laboratory abnormalities. Between 6 and 12 months, four patients had mild exacerbations and switched to other therapies. There were no serious exacerbations (greater than 1 EDSS score). Of the 23 patients who had MRIs performed at 12 months, 21 patients had stable MRIs. One patient had new T2 lesions and one other patient had Gd+ lesions. No cases of PML occurred. Discussion: There is a need for a DMT for patients who are discontinuing NTZ due to risk of PML. Teriflunomide may be a safe and effective therapy for transition from NTZ. A shortened ‘washout’ interval appears to be effective with a low relapse rate. Disclosure Sponsored by an unrestricted educational grant from Genzyme, A Sanofi Company

Keith R. Edwards: Consulting and/or Speaking fees: Biogen, Genzyme; EMD Serono; Grant/Research support: Biogen, Eisai, Eli Lilly, Genentech, Genzyme/Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis JS: nothing to disclose JO: nothing to disclose P707 Acute motor axonal neuropathy following alemtuzumab treatment in relapsing-remitting multiple sclerosis patient - a case report P. Hradilek1, I. Woznicova1, J. Slonkova1, D. Zeman2, O. Zapletalova1, M. Cabal1 1Neurology, 2Clinical Biochemistry, University Hospital Ostrava, Ostrava, Czech Republic Background and objective: Alemtuzumab (ALM) is a humanized monoclonal antibody targeting the surface molecule CD52 on immune cells approved for the treatment of highly active relapsing-remitting multiple sclerosis (RRMS). The linkage between ALM and lymphocyte leads to cytolysis with subsequent development of new lymphocyte generation potentially without autoagressive signs of original population. Efficacy of this drug is very high and was confirmed by the results of large international trials however the treatment could be accompanied with some potentially serious side effects. We bring a case report of acute motor axonal neuropathy following ALM treatment. Case report: A female subject of Caucasian race born in 1980 without any special medical history was diagnosed with her RRMS in 2014 and the same year the treatment with beta-interferon was initiated. As she developed two severe relapses during one year on interferon therapy and was JCV positive with antibody index 3.6 we decided for ALM as next treatment option. The patient received first dosage of 5 infusions of ALM in early November 2015 with EDSS 4.0 at treatment initiation. ALM was generally well tolerated with only mild urticaria. A month later the worsening of gait and progression of paraparesis occurred with EDSS 6.5. The subject received high dose intravenous methylprednisolon (IVMP) for suspicious MS relapse. A normocytic anaemia also developed during December 2015 with haemoglobin level 91 grams per litre. After IVMP course there was no clinical improvement , on the contrary there was another progression of paraparesis of lower extremities after another month - the patient came wheelchaired with EDSS 8.0. In the clinical status we noticed rather peripheral paraparesis of lower extremities and performed electromyography showed acute motor axonal neuropathy. After 5 courses of plasma exchange we observed slight improvement in clinical status, patient was able to walk with bilateral assistance several meters and inpatient rehabilitation is now following. Discussion and conclusion: It is known that ALM could promote different autoimmune (AI) diseases (idiopathic thrombocytopenic purpura, thyroid or kidney autoimmunities) . Up to our knowledge, this is the first report of acute motor axonal neuropathy after ALM treatment. This adverse event is rather not caused directly by ALM, but such a treatment can install a special immunological milieu suitable for the development of AI diseases. Disclosure nothing to disclose


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Poster Session 1, 22(S3) P708 Neutropenia in two MS patients treated with alemtuzumab M.I. Gaitán, M.C. Ysrraelit, J. Correale FLENI, Buenos Aires, Argentina Introduction: Alemtuzumab, is a very effective treatment for multiple sclerosis (MS). Side effects include reactions during infusion, infections and autoimmune diseases. Objective: To report two MS cases of neutropenia occurring during Alemtuzumab administration. Methods: Description of the evolution of 2 patients. Results: A. 25 year-old women who had her first clinical attack in 2009. She was diagnosed with MS in 2012 and put on Interferon β1a. She had intolerance to treatment; she switched treatment to teriflunomide and developed refractory morbiliform rush. After accelerated teriflunomide elimination she was put in fingolimod, but she experience persistent disease activity. Since she was positive for JC virus, in September 2015 Alemtuzumab was indicated. Six weeks after drug infusion, she was hospitalized with febrile neutropenia (300 neutrophils). She received antibiotics intravenous (IV), and granulocyte stimulating factor (GSF) 300 mg for 3 days, she recovered from neutropenia. After one week, she had a new drop in neutrophils; GSF was indicated once again for 3 days. She recovered. To date there is no evidence of clinical or radiological MS activity. B. 23 years old men who was diagnosed with MS in 2011 and put on Interferonβ1a. In 2012, due to persistent radiological and clinical disease activity he switched treatment to Natalizumab. After 24 months, he was JC virus positive and switched treatment to fingolimod. Due to severe relapses and inflammatory radiological activity in May 2015 Alemtuzumab was indicated. Four weeks after drug infusion, neutropenia (470 neutrophils) was detected; he received GSF 300 mg for 3 days with rapid recovery. In the following days he developed severe acne with concomitant HVS I infection. He required prolonged hospitalization for IV antibiotics administration. He has severe keloid scars on his chest. To date there is no evidence of clinical or radiological MS activity. Conclusion: Neutropenia post-alemtuzumab infusion was detected in two patients within the first 6 weeks after infusion. Direct bone marrow toxicity or autoimmune cytopenia are two possible mechanisms involved. We recommend weekly blood test exams during the first two months after Alemtuzumab infusion for early diagnosis and treatment of this unreported side effect.

and TEVA-Tuteur Argentina as well as professional travel/accommodations stipends.

P709 VJC seroconversion is not related to disease modifying therapy in multiple sclerosis patients: searching for a seroconverter profile S. Eichau, M. Rus, S. Sánchez-Pérez, A. Dominguez-Mayoral, G. Navarro, G. Izquierdo Hospital Universitario Virgen Macarena, Seville, Spain Introduction: The risk of Progressive Multifocal Leucoencephatolopaty (PML) caused by JC virus (JCV) is increasing in Multiple Sclerosis (MS) patients treated with some disease modifying therapies (DMTs). JCV seroconversion has been related to Natalizumab use and its rate is about 3% in the general population. However, some studies have been reported higher rates in MS patients (more than 20%). Aim: To analyse the VJC seroconversion rate in MS patients with any DMT, included Natalizumab and to study their baseline characteristics in order to find a seroconverter profile for the VJC. Material and methods: Retrospective review of VJC MS patients from Virgen Macarena Hospital, Seville, Spain, whose first JCV serological status was negative, underwent a second serological VJC evaluation. The collected data included baseline and MS characteristics. The Stratify VJC test has been done in Denmarck using ELISA test. Index higher than 0.4 was considered positive. Results: 101 patients were studied, 64 of them were being treated with Natalizumab/Group 1 and 37 with others DMT/Group 2 (BRACE therapy (35) and Fingolimod (2)). 15% became positive in the second evaluation, 17% in Group 1 and 13,51% Group2 without significant statistical difference. No differences were found beetween seroconverters or not in any baseline or MS characteristics. Conclusion: Our results show that the seroconversion rate is not related with Natalizumab treatment. It is imperative to find an aceptable seroconverter profile in order to avoid PML cases. We didn´t find any characterisitic that could predict the PML risk. Disclosure Sara Eichau received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall.

Disclosure Dr. Gaitan has received reimbursement for developing educational presentations from Merck-Serono Argentina, Genzyme Argentina and Novartis Argentina and travel/ accomodations stipends from Biogen-Idec Argentina, Novartis Argentina, TevaTuteur Argentina and Merck-Serono Argentina Dr. Ysrraelit has received reimbursement for developing educational presentations and travel/accomodations stipends from MerckSerono Argentina, Biogen-Idec Argentina, Genzyme Argentina, Bayer Inc, Novartis Argentina and TEVA-Tuteur Argentina. Jorge Correale is a board member of Merck-Serono Argentina, Biogen-IdecLATAM, and Merck-Serono LATAM, and Genzyme global. Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, MerckSerono LATAM, Biogen-Idec Argentina, Genzyme Argentina,

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P710 BKPyV antibody level is associated with protection against development of PML F. Rossi1, L. Prosperini1, C. Pozzilli1, P. Cinque2, L. Passeri2, R. Capra3, N. De Rossi3, R. Viscidi4 1Sapienza University, Roma, 2San Raffaele Hospital, Milano, 3Azienda Ospedaliera Spedali Civili Brescia, Brescia, Italy, 4Johns Hopkins School of Medicine, Baltimore, MD, United States Background: Elevated seroreactivity against the JC Polyomavirus (JCPyV) is the main risk factor for natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). A negative correlation between antibody


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levels to JCPyV and BK Polyomavirus (BKPyV), another virus in the Polyoma family, is a common serological observation. There is also evidence that patients with HIV-associated PML have lower antibody levels to BKPyV capsids compared to matched controls up to 2 years prior to PML diagnosis, suggesting a protective role for BKPyV in this population. Objective: To investigate the association of BKPyV capsid antibody levels with natalizumab-associated PML in MS patients compared to control MS patients. Methods: We obtained serum samples at the time of PML diagnosis from 10 natalizumab-associated PML cases and 212 control MS patients, of whom 130 currently treated with natalizumab and 82 treated with other disease-modifying treatment and never exposed to natalizumab. The samples were tested in ELISA assays for antibodies to JCPyV and BKPyV serotype 1 and 4 capsids. Results: JCPyV antibody levels were higher in PML cases than controls (mean optical density [OD]: 1.461 vs. 0.415, p< 0.001). Among controls, natalizumab-exposed patients (n=130) had lower JCPyV, but higher BKPyV antibody levels, than patients (n=82) unexposed to natalizumab (p< 0.01). BKPyV serotype 1 antibody levels were significantly lower in PML cases than controls (mean OD: 0.628 vs. 0.932, p=0.033). This latter finding was confirmed in unadjusted (OR: 0.55, 95% CIs 0.32-0.98) and sex-, age-and natalizumab exposure-adjusted (OR: 0.45, 95% CIs 0.240.85) analyses. There was no significant difference in BKPyV serotype 4 reactivity between cases and controls. Conclusions: Our findings show that lower levels of antibody to BKPyV serotype 1 are associated with PML in natalizumabtreated MS patients. The lower antibody levels to JCPyV in natalizumab-treated patients compared to drug unexposed patients may reflect the STRATIFY-based decision not to take natalizumab. This decision could in part explain the difference in BKPyV seroreactivity given that antibody levels to the viruses are inversely correlated. We speculate that high BKPyV antibody levels may be a marker of protection against PML mediated by cross-reactive cellular immunity. Assessing antibody levels to BKPyV may be useful to mitigate the risk of natalizumab-associated PML. Disclosure Francesca Rossi: nothing to declare Luca Prosperini: nothing to declare Carlo Pozzilli: nothing to declare Paola Cinque: nothing to declare Laura Passeri: nothing to declare Ruggero Capra: nothing to declare Nicola De Rossi: nothing to declare Raphael Viscidi: nothing to declare P711 Effect of extended interval dose natalizumab therapy on CD19+ and CD34+ cell mobilization from bone marrow and JC Viremia L. Zhovtis Ryerson1, M.C. Monaco2, I. Kister1, G. ZunigaEstrada1, A. Jacob1, E. Major2 1NYU Langone Medical Center, New York, NY, 2NINDS, Bethesda, MD, United States Objective: Investigate when extending Natalizumab (NTZ) dosing interval may attenuate CD34+ cell mobilization from bone marrow.

Background: NTZ extended interval dosing (EID) (35 - 58 days) is an approach being explored to reduce the risk of PML without compromising effectiveness of drug. PML susceptibility has been associated, in part, to NTZ-induced mobilization of JC virus from the bone marrow into peripheral circulation via CD 19+ and CD34+ cells. Less frequent NTZ dosing may reduce mobilization of these cells, thereby decreasing risk of passage of JCV infected cells into the CNS. Methods: Blood from RRMS NTZ treated patients was separated using flow cytometry into CD34+, CD19+, and CD3+ subsets. DNA templates prepared using quantitative PCR for JCV DNA identification. Plasma was tested for anti-JCV antibodies by ELISA (NINDS) and compared to commercial assay (Focus). Patients on EID NTZ (35 - 58d) were compared to those on standard interval dose (SID) schedule (28 - 34d). Results: 20 EID and 7 SID patients: mean age (range) EID 45 (28-70); SID 43 (19-59) years ; EID 50% SID 57% female; mean of MS diagnosis (range) EID 14.1 (3-30) SID 9.8 (1-26) years; duration of NTZ treatment mean (range) EID 5.3 (2-9) SID 3.7 (1-7) years; mean (range) duration on EID 28 (14-64) months; JCV index mean (range) EID 0.58 (0.19 -2.82) and in SID 0.16 (0.09 - 0.26). Extent of CD34+ cell mobilization was similar in both groups. 1/20 EID patients and 1/7 SID patients are viremic with JCV. SID patient was seronegative (antibody titer, 640)(NINDS);JCV index of 0.12 (Focus). EID patient was seropositive (antibody titer 2560) (NINDS); JCV index 0.22 (Focus). Conclusion: This ongoing study is evaluating biological effects of EID NTZ dosing that may be pertinent to PML risk. Preliminary data does not show reduced CD34+ mobilization with EID NTZ schedule. Additional patient samples from time points further removed from previous NTZ dosing should be evaluated. Disclosure Lana Zhovtis Ryerson has received research support from Biogen Idec. She has received compensation for advisory board and speaker activities from Biogen Idec and Teva. Maria Monaco-Kushner has nothing to disclose. Ilya Kister has served on scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono, and Novartis. Guadalupe Estrada-Zuniga has nothing to disclose. April Jacob has nothing to disclose. Eugene Major reports personal fees from PML Consortium, Takeda/Millennium Pharma, Glaxo Smith Klein, Genentech Roche, and Sanofi Genzyme. P712 Infratentorial brain infections induced by JC virus after treatment with Natalizumab: clinical and radiological variability L. Kremer1, A.-M. Guennoc2, I. Sarafiant3, N. Collongues1, S. Kremer4, J. De Sèze1 1Service de Neurologie - CHU Hautepierre, Strasbourg, 2Service de Neurologie - CHU Tours, Tours, 3Service de Neurologie - CH Freyming Merlebach, Freming Merlebach, 4Service de Radiologie - CHU Hautepierre, Strasbourg, France


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Poster Session 1, 22(S3) Background: JC virus (JCV) brain infections after treatment with Natalizumab (NTZ) are well known. We describe 3 patients with atypical clinical and radiological presentation limited to the cerebellum. OBSERVATIONS: These 3 patients were treated with NTZ and developed a rapidly progressive cerebellar syndrome. Case 1: Male 36 years treated for 6 years by NTZ. 3 successive MRI showed rapidly progressive cerebellar atrophy, with cortical and vermis signal abnormalities without enhancement, evoking a cerebellar granular cell neuronopathy induced by JCV. Case 2: Female of 27 years treated with NTZ for 4 years. The initial MRI found minimal nonspecific cerebellar enhancement but subsequent checks made after clinical deterioration found the occurrence of significant signal abnormalities in the brainstem and the two cerebellar hemispheres associated with ehancement and mass effect in the infratentorial region suggestive of progressive multifocal leukoencephalopathy (PML). Case 3: Women treated for 8 years by NTZ. MRI performed found a nodular lesion of the cerebellar peduncle taking contrast and whose size is gradually evolving compatible with PML. In all cases, the diagnosis of JCV infection was confirmed by lumbar puncture. Discussion: These three cases illustrate the clinical and especially MRI variability of JCV infections limited to the cerebellum. Particular attention must be paid to the infratentorial MRI anomalies and the diagnosis of PML should be considered despite the atypical presentation, because of the high variability of MRI results. Conclusion: Any atypical cerebellar MRI picture in a patient NTZ should suggest researching PML, to start an early treatment for better prognosis. Disclosure Laurent Kremer: nothing to disclose Anne -Marie Guennoc: nothing to disclose Irina Sarafiant: nothing to disclose Nicolas Collongues: nothing to disclose Stéphane Kremer: nothing to disclose Jerome De Seze: nothing to disclose P713 Cytomegalovirus reactivation during alemtuzumab treatment in a patient with multiple sclerosis S.F. De Mercanti1, L. Durelli1, M. Iudicello2, C.A. Artusi1, P. Barbero1, A. Guerrasio1, M. Clerico1 1Department of Clinical and Biological Sciences, 2Division of Neurology, University of Torino, San Luigi Gonzaga University Hospital, Orbassano, Italy Objective: To better manage viral infections in multiple sclerosis (MS) patients treated with alemtuzumab. Background: Alemtuzumab, an hightly- effective immunosuppressive monoclonal antibody used in relapsing-remitting multiple sclerosis (RRMS) treatment, induces a long-standing lymphopenia, particularly of T CD4+ subset. Previous reports showed that Cytomegalovirus (CMV) reactivation occurs in 15-25% B-CLL patients receiving alemtuzumab. The reactivation usually occurs between 3 and 6 weeks after treatment, soon after the T cell count nadir. This reactivation should be recognized

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promptly to prevent CMV fatal complications. There are no guidelines regarding the monitoring of CMV-DNA in MS patients treated with alemtuzumab. Design and methods: A 29 year old woman with highly active MS form (three relapses in six months after ending natalizumab 24 courses) was treated with the first alemtuzumab course (12 mg/ day for 5 consecutive days). According to guidelines, oral prophylaxis for herpes infection was administered starting on the first day with acyclovir 200 mg twice a day. CMV DNA was tested with the PCR technology before treatment and weekly thereafter. Results: CMV DNA before treatment was negative. After a week the viral load (number of copies per ml) was 9800/ml and after two weeks 21900/ml. Patient referred abdominal pain and nausea. The patient was hospitalized, acyclovir was discontinued and patient was treated with ganciclovir 250 mg twice a day i.v. for 5 days. Patient became asymptomatic already after the first day of treatment and viral load went down to zero five days after. Conclusions: We recommend to perform a PCR CMV test weekly after alemtuzumab course even in asymptomatic patients, due to the possible rapid reactivation of CMV. To prevent serious adverse events, ganciclovir should be initiated in PCR CMV positive patients, and continued till the negativity of CMV viral load. Disclosure S. De Mercanti: nothing to disclose L. Durelli: received personal compensation from Biogen Idec and Merck Serono for public speaking, editorial work and advisory boards. M. Iudicello: nothing to disclose C. Artusi: nothing to disclose P. Barbero: nothing to disclose A. Guerrasio: nothing to disclose M. Clerico: received personal compensation from Biogen Idec and Merck Serono for public speaking, editorial work and advisory boards. P714 Pregnancy outcomes with delayed-release dimethyl fumarate: preliminary registry results N.J. Everage, S. Liu, T. Newhook, C. Prada Biogen, Cambridge, MA, United States Background: Women of childbearing age represent a considerable proportion of pts affected by multiple sclerosis (MS). Limited data from clinical trials show no evidence of increased risk of foetal abnormalities or adverse pregnancy outcomes with exposure to dimethyl fumarate (DMF) during pregnancy. Objectives: To assess the interim results of pregnancy outcomes in a cohort of women with MS exposed to DMF since the first day of their last menstrual period prior to conception or at any time during pregnancy in an international registry (NCT01911767). Methods: DMF-exposed women with MS participating in the registry were prospectively evaluated for live births and pregnancy loss, defined as elective or therapeutic pregnancy terminations, spontaneous abortions, and foetal death including stillbirth. Ectopic and molar pregnancies, birth defects, or congenital anomalies that occur ⩽52 wks of age, any infant death occurring


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⩽52 wks of age, and any maternal death occurring ⩽12 wks postdelivery were reported. Baseline data were collected at enrolment; follow-ups were conducted at 6-7 mos of gestation and 4 wks after the estimated delivery date or 4, 12, and 52 wks after birth. Gestational size (GS) was classified as small (< 10th percentile), appropriate (10th-90th), or large (>90th) based on WHO or country-specific growth charts. Results: As of 14 Dec 2015, 48 pts were enrolled in the registry with a mean (SD) age of 31 (5) yrs; 83% were white. Of the 38 pts with a known DMF exposure date, 92% occurred in the first trimester, 5% in the second, and 3% in the third. To date, 15 pregnancy outcomes have been reported for 16 foetuses (1 pt with multiple births), including 1 (6.7%) spontaneous abortion (< 22 wks). Of the 14 (93.3%) live births, 12 (85.7%) were full term (delivered ⩾37 wks) and 2 (14.3%) premature. There were no birth defects, or maternal, neonatal, perinatal, or infant deaths reported. One foetus had unknown live birth status. Of the 7 infants with GS data, 0 were classified as small, 6 (86%) appropriate, and 1 (14%) large. Conclusions: This currently enrolling pregnancy registry will provide essential information for women of childbearing age about the safety of DMF in pregnancy. The current data, while limited, do not suggest any adverse effects of DMF exposure on pregnancy outcomes. These findings are consistent with data on pregnancy outcomes from clinical trials and postmarketing reports. Additional data are required before drawing definite conclusions. Disclosure Supported by: Biogen. Nicholas J. Everage: employee of and holds stock/stock options in Biogen Shifang Liu: employee of and holds stock/stock options in Biogen Trevor Newhook: employee of and holds stock/stock options in Biogen Claudia Prada: employee of and holds stock/stock options in Biogen P715 Cumulative data on pregnancy outcomes after exposure to fingolimod and in comparison with the general population Y. Geissbühler1, J. Vile2, G. Koren3, H. Wang4, H. Butzkueven5,6, H. Tilson7, T.M. MacDonald8, K. Hellwig9 1Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 3The Hospital for Sick Children, Toronto, ON, Canada, 4Quintiles, Cambridge, MA, United States, 5Department of Neurology, Royal Melbourne Hospital, Parkvile, 6Department of Medicine, University of Melbourne, Parkville, VIC, Australia, 7University of North Carolina School of Public Health, Chapel Hill, NC, United States, 8Ninewells Hospital and Medical School, Dundee, United Kingdom, 9Department of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany Background: Relapsing MS is approximately 3-fold more common in women than in men, with an average age of onset of 30 years; hence at diagnosis many patients are women of childbearing age.

Objective: To present updated information on pregnancy outcomes in fingolimod-exposed women from internal data sources and put it in context with the general population. Methods: We report cumulative data on pregnancy outcomes (prospective and retrospective) from the Multinational Gilenya® Pregnancy Exposure Registry, prospective cases from the PRegnancy outcomes Intensive Monitoring program (PRIM, an enhanced data collection program for pregnancy cases reported to the Novartis safety database [NSD]), and the NSD. Prospective cases are: For the registry, those where the condition of the foetus was not assessed through prenatal testing and pregnancy outcome was not known at the time of enrolment; for the NSD and PRIM, those where the condition of the foetus was not known to be abnormal through prenatal testing and pregnancy outcome was not known at the time of reporting pregnancy, a broader definition (number of cases considered prospective may vary due to different definitions of prospective for the Registry and the NSD). Results: By end of February 2016, 926 prospective cases related to fingolimod exposure (maternal) were reported in the NSD, including 106 cases from the Registry (‘prospective’ as per NSD definition; 79 as per the Registry definition, see methods) and 449 cases from PRIM. Among cases with known outcomes in the NSD (n=512), Registry (n=59) and PRIM (n=190), cases of live birth were 324, 43 and 116, respectively. Prevalence (95% CI) of major congenital malformations in live births in the Registry and PRIM was 2.3% (0.1, 12.3) and 0%, respectively. Corresponding prevalence in the NSD (324 live births including 83 Registry and 116 PRIM cases) was 3.08% (1.49, 5.60) and all of the above were comparable with published reports from the general population (2.1% - 4.1%). Conclusions: Based on limited information at this point, the prevalence of major congenital malformations in live births following fingolimod exposure is similar to that observed in the general population. No unusual syndromes/unexpected multiples of the same defects were reported. The Registry and PRIM will continue to collect information to assess the risk of reproductive toxicity in fingolimod exposed patients. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Gideon Koren has nothing to disclose. Hong Wang is an employee of Quintiles, Cambridge, MA, United States. Helmut Butzkueven has received consulting fees from Genzyme, Biogen, Novartis, Merck and Oxford PharmaGenesis; and grant/ research support from Biogen, Novartis, Merck and Genzyme. Hugh Tilson is widely associated with the multinational pharmaceutical industry, including services rendered on several global pregnancy and disease registries. T.M. MacDonald has received compensation for serving as a consultant or speaker or he or the institution he works for has received research support from Novartis, Pfizer, Ipsen and Menarini, Kaiser Permanante, Takeda, Recordati, Servier, Menarini, NiCox and AstraZeneca. Kerstin Hellwig has received compensation for serving as a consultant or speaker or she or the institution she works for has received research support from Bayer, Schering Healthcare, Teva, Sanofi Aventis, Biogen Idec, Merck Serono and Novartis. Yvonne Geissbühler and Jere Vile are employees of Novartis.


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Poster Session 1, 22(S3) P716 Absolute lymphocyte count and lymphocyte subset profiles during long-term treatment with delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis R.J. Fox1, A. Chan2, R. Gold2, J.T. Phillips3, K. Selmaj4, R. Zhang5, I. Chang5, C. Prada5, S. Ray5, D. Mehta5, C. Taylor5, J.L. Marantz5 1Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States, 4Medical University of Lodz, Lodz, Poland, 5Biogen, Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF) has demonstrated a favourable benefit-risk profile in pts with relapsing-remitting multiple sclerosis (RRMS). The DMF label recommends considering treatment interruption in pts with absolute lymphocyte counts (ALCs) < 0.5 x 109/L persisting ⩾6 mos. Over 190,000 pts have been treated with DMF worldwide, representing 218,988 pt-years of exposure as of 31 December 2015. Objectives: Provide practical considerations for management of DMF-treated RRMS pts by reporting long-term ALC profiles in RRMS pts treated with DMF for up to 9 yrs, as well as lymphocyte subset profiles in a subset of pts. Methods: We conducted an integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies. The total safety population comprised 2513 pts and 8293 pt-years. ALCs were assessed at wks 4, 8, 12, and at least every 12 wks subsequently. Lymphocyte subsets were analyzed by flow cytometry in a subset of pts with available data. Results: A total of 2470 pts with any post-baseline ALC were included in the analysis. Mean ALCs decreased by approximately 30% during the first yr of treatment, then plateaued, remaining above lower limit of normal (LLN; 0.91 x 109/L). Among pts treated for ⩾6 mos (N=2098), 2.5% (n=53) experienced ALCs < 0.5 x 109/L persisting ⩾6 mos; 10.9% (229/2098) of pts experienced moderate lymphopenia (ALCs ⩾0.5 x 109/L to < 0.8 x 109/L) persisting ⩾6 mos. All ALCs remained consistently ⩾LLN in 84% of pts during the first 6 mos and 76% of patients during the first yr; of these patients, 0.3% and 0.1%, respectively, subsequently developed ALCs < 0.5 x 109/L persisting ⩾6 mos at any time. Of those 2050 with consistent ALC ⩾0.8 x 109/L for the first yr of treatment, 2 (0.098%) developed < 0.5 x 109/L persisting ⩾6 mos. The incidence of infections and malignancies in pts with prolonged lymphopenia will be presented. Preliminary lymphocyte subset analyses suggest that T-cells were preferentially reduced relative to B-cells and NK cells; CD8+ T-cell counts were preferentially reduced relative to CD4+ T-cell counts. Decreases in ALCs were associated with corresponding decreases in CD4+ and CD8+ counts. Conclusions: Based on up to 9 yrs of experience in patients treated with DMF, lymphocyte monitoring provides an effective means for early identification of pts at risk for subsequently developing prolonged lymphopenia. The overall benefit-risk of DMF remains favourable. Disclosure Supported by: Biogen.

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Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen and Novartis; research grant funding from Novartis. Andrew Chan: personal compensation for activities with Allmirall Hermal, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis. Ralf Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. J. Theodore Phillips: consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Sanofi, and Xenoport. Krzysztof Selmaj: compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking from Biogen. Ray Zhang: Employee of and holds stock/stock options in Biogen. Ih Chang: Employee of and holds stock/stock options in Biogen. Claudia Prada: Employee of and holds stock/stock options in Biogen. Soma Ray: Employee of and holds stock/stock options in Biogen. Devangi Mehta: Employee of and holds stock/stock options in Biogen. Catherine Taylor: Employee of and holds stock/stock options in Biogen. Jing Marantz: Employee of and holds stock/stock options in Biogen. P717 Lymphopenia with dimethyl fumarate and fingolimod in clinical practice C.M. Hersh1, S. Cohn2, C. Hara-Cleaver3, R.A. Bermel3, R.J. Fox3, J.A. Cohen3, D. Ontaneda3 1Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, 2Cleveland Clinic, 3Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, OH, United States Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for treatment of relapsing multiple sclerosis (MS). Both reduce circulating absolute lymphocyte counts (ALC), though the mechanism and significance differ. Current prescribing information recommends obtaining ALC before initiating treatment and during routine surveillance. Objective: To describe absolute lymphopenia in DMF and FTY in clinical practice. Design and methods: We identified 458 DMF and 317 FTY patients in a large academic MS center. ALC were evaluated at baseline and 12 months with data available for 360 DMF (78.6%) and 244 FTY (77.0%) patients. Unadjusted comparative data were analyzed via descriptive and chi-square statistical methods, and adjusted ALC comparisons were made via propensity score weighting. Results: Baseline mean ALC were DMF 1.94 and FTY 2.12. At 12 months 269 (74.7%) DMF patients had ALC within normal range defined as ALC ⩾1.0 x 109/L compared to 34 (13.9%) FTY patients. For DMF mean ALC decreased by 30% to 1.48 at 12 months, compared to a decrease of 82% to 0.63 with FTY. With


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DMF grade 1 lymphopenia (< 1.0-⩾0.8) was found in 5.8%; grade 2 (< 0.8-⩾0.5) in 13.8%; and grade 3 (< 0.5-⩾0.2) in 5.6%. No DMF patients developed grade 4 lymphopenia (< 0.2). Nineteen DMF patients discontinued treatment due to lymphopenia (grade 1 n = 9; grade 2-3 n = 10), though there were no associated infections. In FTY patients grade 1 lymphopenia developed in 1.6%; grade 2-3 in 81.1%; and grade 4 in 3.3%. Three patients discontinued FTY due to grade 4 lymphopenia, one of which was associated with moderately severe upper respiratory tract infection. Both unadjusted [difference= 0.85, 95% CI (0.72, 0.98)] and adjusted [difference= 0.80, 95% CI (0.65, 0.96)] comparisons showed higher mean ALC with DMF versus FTY at 12 months. There were no cases of fungal infection or PML with either DMT. Conclusion: Over one year, mean ALC decline in DMF and FTY patients in clinical practice was comparable to that reported in phase 3 clinical trials. As expected, absolute lymphopenia is less frequent with DMF compared to FTY, though the level of ALC reduction that is clinically concerning is different for the two DMTs. In our cohort clinical concern regarding lymphopenia led to more frequent discontinuation of DMF compared to FTY. Disclosure Dr. Carrie Hersh is supported by National Multiple Sclerosis Society Sylvia Lawry Physician Fellowship Award. Dr. Samuel Cohn - there is no conflict of interest. Ms. Claire Hara-Cleaver has received consulting or speaking fees from Biogen Idec, TEVA, EMD Serono, Acorda, Novartis, and Genzyme. Dr. Robert Bermel has received consulting or speaking fees from Biogen Idec, Novartis, TEVA, Genzyme, and Questcor. Dr. Robert Fox has received consulting fees from Biogen Idec, MedDay, Novartis, Questcor, TEVA, and Xeonport. Dr. Jeffrey Cohen has received consulting fees from Biogen Idec, EMD Serono, Genzyme, Novartis, Receptos, Synthon, TEVA, and Vaccinex. Dr. Daniel Ontaneda is supported by KL2 TR000440/TR/NCATS NIH Grant. P718 Alterations of serum lipid profile in multiple sclerosis patients treated with fingolimod S. Haars, R. Schmidt, J. Orthgieß, M. Stoppe, F. Then Bergh Department of Neurology, University of Leipzig, Leipzig, Germany Background: Fingolimod is a highly effective immunmodulatory treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Safety concerns state its potential association with cardiac events, mainly focusing on effects during treatment initiation. Since elevated blood cholesterol concentrations were described as adverse event in clinical trials, this study aims to quantify possible alterations of the lipid profile and to evaluate whether they contribute to potentially increased cardiovascular risk. Methods: Data from 43 MS patients treated with fingolimod for at least one year were analyzed cross-sectionally regarding blood concentrations of triglycerides, total cholesterol, LDL- (low density lipoprotein) and HDL- (high density lipoprotein) cholesterol. Longitudinal results including pre-treatment baseline concentrations

were available from 36 patients initiating fingolimod. The cardiovascular risk was calculated using the risk prediction tool PROCAM (Prospective Cardiovascular Münster). Results: 28 of the 43 patients (65,1%) presented alterations of the lipid profile: 24 patients (55,8%) showed increased total cholesterol and 7 (16,3%) increased LDL, while low HDL was present in 3 (6,9%) patients. Statin treatment was required in 3 patients after initiating fingolimod.Of the 36 longitudinally observed patients 11 (30,6%) developed an elevation of cholesterol concentrations compared to baseline, of which 7 patients (19,4%) had concentrations within the reference values at baseline. Estimations by the PROCAM score for those 11 patients revealed a slight to moderate increase of the 10-year acute coronary event risk depending on further cardiovascular risk factors. Conclusion: The typical population of MS patients without relevant comorbidities (pre-existing cardiac conditions, hypertension, diabetes mellitus) does not display a high cardiac risk in itself. Under treatment with fingolimod alterations of lipid profile were observed in MS patients and should be monitored. Clinically relevant increased cardiovascular risk however occurred in few patients and cannot be assessed by elevations of serun lipids alone. Disclosure No external funding, nothing to disclose. The authors have no conflict of interest related to this study. P719 Selection of first-line therapy in multiple sclerosis using riskbenefit decision analysis D. Bargiela1,2,3, M.T. Bianchi3,4, M.B. Westover3,4, L.B. Chibnik1,2,3, B.C. Healy1,5, P.L. de Jager1,2,3, Z. Xia1,2,6 1Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 2Broad Institute, 3Harvard Medical School, 4Department of Neurology, 5Department of Statistics, Massachusetts General Hospital, Boston, MA, 6Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States Background: Selection of first-line therapy for multiple sclerosis (MS) patients requires consideration of long-term treatment risks and benefits. We aimed to integrate measures of disease-modifying drugs (DMDs) efficacy and risk to guide selection of first-line treatment. Methods: We created a Markov decision model to evaluate disability progression and progressive multifocal leukoencephalopathy (PML) risk in patients receiving natalizumab (NTZ), fingolimod (FGL) or glatiramer acetate (GA) treatment across a 30-year course. Using published clinical trials, PML surveillance reports and the UK Multiple Sclerosis Risk Sharing Scheme (RSS), we integrated treatment utility, disability progression and risk of PML into quality adjusted life years (QALYs). Sensitivity analyses were performed to vary PML risk, PML-associated mortality and morbidity, and relative risk of disease progression across a clinically relevant range. Results: Over the entire reported range of NTZ-associated PML risk, NTZ as first-line therapy is predicted to provide a greater net benefit (15.06 QALYs) than FGL (13.99 QALYs) or GA (12.71 QALYs) treatment over 30 years, even after accounting for loss of


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Poster Session 1, 22(S3) QALYs due to PML or death (from all causes). NTZ treatment is associated with delayed progression to an Expanded Disability Status Scale score ⩾ 6.0 versus FGL or GA treatment (22.7 years, 17.0 years and 12.4 years, respectively). When compared to untreated patients, NTZ-treated patients have an increased relative risk of death in the early years of treatment that varies according to PML risk profile. Discussion: NTZ as a first-line treatment is associated with the highest net benefit across full ranges of PML risk, mortality and morbidity when compared to FGL or GA treatment. Integrated modelling of long-term treatment risks and benefits informs stratified clinical decision-making and can support individualized patient counselling on the benefits and risks of first-line treatment options. Disclosure Dr Bargiela: nothing to disclose Dr Bianchi: nothing to disclose Dr Westover: nothing to disclose Dr Chibnik: nothing to disclose Dr Healy: has received grant support from Merck Serono, Novartis, Genzyme, and Google Life Sciences and received consulting fees for serving on the Worldwide Medical Biostatistics MS Advisory Board for Biogen Idec. Dr de Jager: nothing to disclose Dr Xia: has received grant support from the National Institute of Health Funding: National Institute of Health P720 Infusion-related reactions with ocrelizumab in relapsing multiple sclerosis and primary progressive multiple sclerosis J. De Sèze1, D.L. Arnold2,3, A. Bar-Or2, G. Giovannoni4, H.-P. Hartung5, S.L. Hauser6, B. Hemmer7,8, L. Kappos9, F. Lublin10, X. Montalban11, K.W. Rammohan12, K. Selmaj13, A. Traboulsee14, J. Wolinsky15, P. Chin16, C. Li17, N. Mairon17, J. Napieralski17, G. Comi18, on behalf of the OPERA I, OPERA II and ORATORIO Clinical Investigators 1University Hospital of Strasbourg, Strasbourg, France, 2McGill University, 3NeuroRx Research, Montreal, QC, Canada, 4Queen Mary University of London, London, United Kingdom, 5Heinrich-Heine University, Düsseldorf, Germany, 6University of California, San Francisco, CA, United States, 7Technische Universität München, 8Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 9University Hospital Basel, Basel, Switzerland, 10Icahn School of Medicine at Mount Sinai, New York, NY, United States, 11Vall d’Hebron University Hospital, Barcelona, Spain, 12University of Miami, Miami, FL, United States, 13Medical University of Lodz, Lodz, Poland, 14University of British Columbia, Vancouver, BC, Canada, 15University of Texas Health Science Center at Houston, Houston, TX, 16Genentech, Inc., South San Francisco, CA, United States, 17F. Hoffmann-La Roche Ltd., Basel, Switzerland, 18University VitaSalute San Raffaele, Milan, Italy Background: Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+ B cells. Infusion-related reactions (IRRs) have been observed with the administration of OCR.

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Objective: To evaluate the pattern of IRRs in Phase III, randomised, double-blind studies in relapsing multiple sclerosis (RMS; OPERA I and II) and primary progressive MS (PPMS; ORATORIO). Methods: In the double-blind, double-dummy OPERA studies, patients were randomised (1:1) to OCR 600mg via intravenous (IV) infusion every 24 weeks or subcutaneous interferon beta-1a (IFNβ-1a) 44µg 3-times weekly over 96 weeks. In ORATORIO, patients were randomised (2:1) to OCR 600mg IV given as two 300mg infusions 14 days apart or matching placebo (PBO) every 24 weeks for ⩾120 weeks. Patients were pretreated with IV methylprednisolone 100mg or equivalent to maintain blinding; pretreatment with analgesics/antipyretics and antihistamines were recommended. Results: Safety analyses included 825 OCR- vs 826 IFNβ-1a– treated patients in OPERA I and II, and 486 OCR- vs 239 PBOtreated patients in ORATORIO. Proportions of patients with ⩾1 IRR were 34.3% with OCR (n=283) vs 9.7% with IFNβ-1a (n=80) in OPERA (over 96 weeks), and 39.9% with OCR (n=194) vs 25.5% with PBO (n=61) in ORATORIO (over ≈3 years); the majority of IRRs were mild to moderate in severity (OCR: 92.6% [n=262] vs IFNβ-1a: 98.8% [n=79] in OPERA; OCR: 96.9% [n=188] vs PBO: 93.4% [n=57] in ORATORIO). The most frequent (⩾10%) IRR symptoms with OCR were pruritus, rash, throat irritation and flushing in OPERA, and pruritus, flushing, rash, pyrexia, headache and throat irritation in ORATORIO. IRRs with OCR were highest with first infusion (27.5% [n=227] in OPERA; 27.4% [n=133] in ORATORIO) and decreased with subsequent doses (Dose 2: 13.7% [n=107] in OPERA; 11.6% [n=54] in ORATORIO). Grade 3 IRRs in OPERA were 2.4% with OCR (n=20) vs 0.1% with IFNβ-1a (n=1); n=6 vs 0 were reported post Dose 1. One patient, in the OCR group, had a Grade 4 IRR (bronchospasm). No Grade 4 IRRs were reported in ORATORIO; Grade 3: 1.2% with OCR (n=6) vs 1.7% with PBO (n=4); n=1 vs 4 were reported post Dose 1. Conclusions: In these Phase III studies in RMS and PPMS, OCR was generally well tolerated. The most common adverse event was IRRs, which were mostly mild to moderate in severity, most frequent with first infusion, manageable with premedication and symptomatic treatment, and decreased in incidence with further infusions. Sponsored by F. Hoffmann-La Roche Ltd. Disclosure Jérôme de Seze has received consultancy fees and served as an expert for advisory boards for Alexion, Allergan, Almiral, Bayer, Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd., Genzyme, LFB, Merck, Novartis, and Teva. Douglas Arnold reports equity interest in NeuroRx Research, which performed the MRI analysis for the trial, and consultation fees from Acorda Therapeutics, Biogen, Genzyme, F. Hoffmann-La Roche Ltd., Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi, and Teva. Amit Bar-Or has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Genentech, Biogen Idec, GlaxoSmithKline, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Ono Pharma, Receptos, Sanofi-Genzyme, and GuthyJackson/GGF; he has also received research support from Novartis and Sanofi-Genzyme. Gavin Giovannoni has received honoraria from AbbVie, Bayer HealthCare, Biogen, Canbex Therapeutics, Five Prime


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Therapeutics, Genzyme, GSK, GW Pharma, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, F. Hoffmann-La Roche Ltd., Synthon, Teva Neuroscience, UCB and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz and Novartis; and compensation from Elsevier. Hans-Peter Hartung has received honoraria for consulting, serving on steering committees and speaking at scientific symposia with approval by the Rector of Heinrich-Heine-University from Bayer, Biogen, GeNeuro, Genzyme, Merck Serono, MedImmune, Novartis, Octapharma, Opexa, F. Hoffmann-La Roche Ltd., Teva, and Sanofi. Stephen L. Hauser serves on the scientific advisory boards for Annexon, Symbiotix, Bionure; he has also received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd. for CD20-related meetings and presentations. Bernhard Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Novartis, Bayer Schering and Genentech; has received speaker honoraria from Biogen Idec and F. Hoffmann-La Roche Ltd.; has received research support from Chugai Pharmaceuticals; holds part of a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralising antibodies to interferon-beta. Ludwig Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer Health Care Pharmaceuticals, CLC Behring, Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharma, Pfizer, Receptos, F. Hoffmann-La Roche Ltd., Sanofi, Santhera, Siemens, Teva, UCB, and Xenport; royalties from Neurostatus AG; research grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis Research Foundation and Roche Research Foundation. Fred Lublin reports funding of research from Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc., Genzyme, Sanofi, Celgene, Transparency Life Sciences, NIH, NMSS; consulting agreements/advisory boards/DSMB for Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi, Acorda, Questcor/Malinckrodt, F. Hoffmann-La Roche Ltd., Genentech, Inc., Celgene, Genzyme, MedImmune, Osmotica, Xenoport, Receptos, Forward Pharma, BBB technologies, and Akros; is co-chief editor for Multiple Sclerosis and Related Diseases; and has current financial interests/stock ownership in Cognition Pharmaceuticals, Inc. Xavier Montalban has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, F. Hoffmann-La Roche Ltd., Sanofi, Teva and Trophos. Kottil Rammohan has received honoraria for participating in advisory boards and consulting for Acorda, Biogen, EMD Serono, Genentech, Inc./F. Hoffmann-La Roche Ltd., Genzyme and Teva; he has also received grants from Accera, Novartis and the United States Department of Defense.

Krzysztof Selmaj has received honoraria for advisory boards from Biogen, Novartis, Teva, F. Hoffmann-La Roche Ltd., Merck, Synthon, Receptos, and Genzyme. Anthony Traboulsee has received honoraria for advisory boards from Genzyme F. Hoffmann-La Roche Ltd. He is a steering committee member for F. Hoffmann-La Roche Ltd. Jerry Wolinsky has received compensation for service on steering committees or data monitoring boards for F. Hoffmann-La Roche Ltd., MedDay Pharmaceuticals, Novartis, Sanofi/Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, EMD Serono, F. Hoffmann-La Roche Ltd., Forward Pharma, Genentech, Inc., Novartis, Sanofi/Genzyme, Takeda, Teva, and XenoPort; research support from Sanofi/ Genzyme, the United States National Institutes of Health and the US National Multiple Sclerosis Society through The University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH. Peter Chin is an employee and/or shareholder of Genentech, Inc. Carrie Li is an employee of F. Hoffmann-La Roche Ltd. Nicole Mairon is an employee and/or shareholder of F. Hoffmann-La Roche Ltd. Julie Napieralski is an employee of F. Hoffmann-La Roche Ltd. Giancarlo Comi has received compensation for consulting services from F. Hoffmann-La Roche Ltd, Novartis, Teva, Sanofi, Genzyme, Merck, Excemed, Almirall, Chugai, Receptos, Forward Pharma, and received compensation for speaking activities from F. Hoffmann-La Roche Ltd, Novartis, Teva, Sanofi, Genzyme, Merck, Excemed, Almirall, Receptos. P721 The CSF JCV antibody index for diagnosis of early progressive multifocal leukoencephalopathy C. Warnke1, O. Adams2, M.T. Wijburg3, H.-P. Hartung1, J. Killestein3, M.P. Wattjes3 1Neurology, 2Virology, University of Duesseldorf, Duesseldorf, Germany, 3VU University Medical Center, Amsterdam, The Netherlands Background: Brain magnetic resonance imaging (MRI) screening for early detection of JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) is used in patients treated with natalizumab for MS. JCV DNA in the cerebrospinal fluid (CSF) in early cases of PML can be undetectable, hampering diagnosis of PML. Recently, we demonstrated that the detection of intrathecally produced anti-JCV IgG antibodies is highly specific for diagnosis of PML. Hence, the so-called CSF JCV antibody index (AIJCV) may be an added tool for earlier diagnosing PML in a proportion of cases. Aims: Our currently on-going studies aim at defining the diagnostic value of the AIJCV in early cases with MRI suspicion of PML. Cases with localized disease suspicious of PML that associate with low (< 100 copies/ml), or repetitively negative results for JCV DNA in CSF are of particular interest. Methods: Natalizumab-treated MS patients undergoing enhanced pharmacovigilance using brain MRI screening for new lesions suggestive of PML recruited at the VU medical center Amsterdam, Netherlands, and referrals, are included in the study. JCV DNA by qPCR, and the AIJCV in CSF are determined as published. For


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Poster Session 1, 22(S3) these assessments, serum and CSF are tested in an enzyme-linked immunosorbent assay using a JCV-VP1 protein fused to GST as antigen, and the AIJCV is calculated. The calculation of the AIJCV requires the additional determination of albumin and total IgG from serum and CSF (Warnke et al., Ann. Neurol. 2014). Results: In a case series of ten patients with MS with MRI suspicion of PML, five had a negative qPCR at time of first lumbar puncture, three patients JCV DNA copy numbers < 100 c/ml, and two JCV-DNA copy numbers > 100c/ml. Of the eight patients with low copy numbers, or undetectable JCV DNA, six had detectable anti-JCV antibodies in CSF. While we already confirmed a positive AIJCV in CSF (cut-off at AIJCV >1.5) in two of the patients, determination of albumin and IgG levels are ongoing in the other four cases. Conclusion: Brain MRI is a sensitive screening tool for PML in patients with MS treated with disease modifying therapy. In case of MRI suspicion of PML, the assessment of CSF for the detection of JCV DNA by qPCR alone might not be sufficient, and the absence of JCV DNA in CSF does not preclude the diagnosis of PML. The determination of the CSF AIJCV in parallel with the qPCR for JCV DNA may be an added tool in diagnosing probable cases of early PML. Disclosure C.W.: consultancy, speaking fees, grant support: Novartis, Bayer, Biogen, Teva, Charcot foundation, Hertie foundation O.A.: consultancy, speaking fees: Biogen M.T.W: nothing to disclose H.-P.H.: board membership, consultancy, speaking fees, grant support: Biogen, Geneuro, Genzyme, Medimmune, Merck Serono, Novartis, Opexa, Receptos, Roche, Teva, Sanofi-Aventis. J.K.: has accepted speaker and consultancy fees from MerckSerono, Teva, Biogen, Genzyme, Roche and Novartis. M.P.W.: speaking fees/grant support: Biogen, Novartis P722 NEDA after stratification of PML risk L. Romero-Pinel1, E. Matas1, L. Bau1, Á. Cobo-Calvo1, N. Iranzo1, I. León1, M.A. Mañé-Martínez2, M. Jato3, J.J. Hernández Regadera4, A. Martínez-Yélamos1, S. Martínez-Yélamos1 1Multiple Sclerosis Unit, Department of Neurology, Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, 2Department of Neurology, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili, Tarragona, 3Department of Neurology, Hospital de Viladecans, Viladecans, 4Department of Neurology, Hospital Sant Camil, Vilanova i la Geltrú, Spain Background: Nowadays the risk of progressive multifocal leukoencephalopathy (PML) is stratified in multiple sclerosis (MS) patients treated with natalizumab but disease activity risk after changing versus maintaining natalizumab has not been evaluated. Objective: To compare no evidence of disease activity (NEDA) when changing versus maintaining natalizumab after stratification of PML risk in MS patients treated with natalizumab. Patients and methods: All MS patients treated in our MS Unit with natalizumab at least during two years before stratifying their PML risk and followed-up at least one year after that moment were selected. A PML risk stratification moment (STRm) was

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established: the first time levels of JC virus antibodies were determined for patients with at least two years of treatment. Their treatment after the STRm (natalizumab versus fingolimod after two months of washout) was selected depending on their JC virus status. Clinical (MS relapses, Expanded Disability Status Scale (EDSS) worsening) and Magnetic Resonance Imaging (MRI) data (new T2 and Gadolinium enhancing lesions) were studied. NEDA (no relapses, no EDSS worsening and no brain MRI activity) after one year of follow-up was evaluated. Results: 84 patients were included, 44 patients (52.4% of the cohort) continued treatment with natalizumab and 40 patients (47.6%) switched to fingolimod. The proportion of NEDA after one year of follow-up was higher in the group maintaining natalizumab (81.8% versus 60%, p< 0.05). There were no significant differences in number of relapses or in proportion of patients having relapses (15.9% with natalizumab vs 25%, p=0.30). Only one patient in each group experienced a one-point EDSS worsening. Regarding MRI, a higher proportion of patients who withdrew natalizumab showed new T2 lesions in comparison with those who maintained treatment (22.5% vs 6.9%, p=0.044) as well as Gadolinium enhancing lesions (25.6% vs 0%, p< 0.001) one year after the STRm. In the multivariate analysis, natalizumab treatment, an older age at onset and a lower number of relapses during the two years before STRm were independent factors for NEDA after one year of STRm. Conclusion: Patients who withdraw natalizumab due to PML risk have a high risk of no NEDA after one year due to radiological disease activity. Disclosure L.Romero-Pinel received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. E.Matas received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. L.Bau received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. MA Mañé-Martínez received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. A.Cobo-Calvo received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. N.Iranzo received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. I.León received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono.


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M.Jato: nothing to disclose. JJ.Hernández-Regadera received funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. A. Martínez-Yélamos received received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. S. Martínez-Yélamos received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono.

P723 Diet composition and dimethylfumarate (DMF) side effects in relapsing-remitting multiple sclerosis (RRMS) patients: a pilot study M. Pugliatti1, C. Vettorazzi1, E. Della Coletta1, L.M. Caniatti2, E. Baldi2, S. Rossi3, P. Ragonese4, F. Ferracci5, R. De Gennaro6, P. Crociani7, P. Naldi8, A. Protti9 1Dept. of Biomedical and Surgical Sciences, University of Ferrara, 2University Hospital S. Anna, Ferrara, 3Neurological Institute ‘C. Besta’, Milano, 4University of Palermo, Palermo, 5Hospital San Martino, Belluno, 6Hospital ‘Dell’Angelo’, Mestre, 7Hospital ‘Casa Sollievo della Sofferenza’, S. Giovanni Rotondo, 8University Hospital ‘Maggiore’, Novara, 9Hospital ‘Niguarda Ca Granda’, Milan, Italy Introduction: DMF, a first line oral treatment for RRMS, reduces relapse rate and brain MRI active lesions load. However, its gastrointestinal (g-i) and flushing side can undermine adherence to treatment and can determine up to 5% drop-out rate in the first month of treatment. DMF intake with food has been empirically reported to increase tolerability, however no ad hoc studies are reported in literature. Objective: To assess the association between DMF-related g-i and flushing side effects, and food patterns in RRMS patients over their first month of treatment. Methods: A multicenter case-control study on RRMS patients was designed to involve MS referral health structures in Italy. The ‘case’ was defined by the presence of DMF-related side effects; a ‘control’ was a RRMS patient under DMF showing no side effects. Exposure to eating habits before starting DMF was assessed with a short version of a food frequency questionnaire. Risk was measured through crude and adjusted odds ratios (OR) and 95% confidence interval (95%CI), by means of logistic regression. Sex and body mass index (BMI) were collected as covariates. Results: Sixty-two RRMS patients (21 men, 41 women) were consecutively recruited from seven Italian centres; mean (SD) age was 37.6 (8.7) years in men and 40.3 (10.5) years in women, respectively (p=ns). Flushing (any degree) was reported by 70% of patients and over 60% reported g-i effects (any degree). The latter were reported more frequently in women (27%-36%) vs. men (5%-10%); flu-like syndrome was more prevalent among men (20%) than women (2.4%). A significant inverse association was found between DMF g-i side effects and intake of bread,

yoghurt or fruit at breakfast (ORadj=0.04 (95%CI: 0.01-0.36), 0.13 (95%CI: 0.02-0.74), and 0.21 (95%CI: 0.06-0.81, respectively)). Intake of aged cheese in the daily diet was found directly associated with flushing. To the study date 2 drop-outs (3.2%) were registered during the first month after DMF initiation. Conclusions: We have preliminarily shown that exposure to certain foods and/or dietary patterns may reduce the impact of DMFrelated g-i and flushing side effects. Our study highlights the potential of specific dietary regimens to increase RRMS patients’ adherence to DMF. Disclosure Pugliatti M was member in Advisory Board by Bayer Schering and Genzyme; has received travel or speaker honoraria by Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva Neurosciences. Vettorazzi C: nothing to disclose. Della Coletta E: nothing to disclose. Caniatti LM: nothing to disclose. Baldi E: nothing to disclose. Rossi S was member in Advisory Board by Biogen Idec, Bayer Schering, Merck Serono, Teva, Novartis and Genzyme, and received funding for traveling and honoraria for speaking or writing from Biogen Idec, Merck Serono, Teva, Novartis, Bayer Schering, Genzyme, Almirall. She received support for research project by Teva, Merck Serono and Bayer Schering and is involved as principal investigator in clinical trials for Teva and Roche. Ragonese P: nothing to disclose. Ferracci F: nothing to disclose. De Gennaro R: nothing to disclose. Crociani P has been P.I. in a clinical study by Roche. Naldi P: nothing to disclose. Protti A: traveling honoraria from Bayer, Biogen, Merck Serono, Novartis, Teva, Genzyme Aventis. P724 Prevalence and predictors of lymphopenia in multiple sclerosis (MS) patients treated with fingolimod (FG) or delayed -release dimethyl fumarate (DMF) M. Baharnoori, A. Chua, C. Diaz-Cruz, B.C. Healy, J. Stankiewicz, H.L. Weiner, T. Chitnis Partners MS Center, Brigham and Women’s Hospital (BWH), Harvard Medical School, Brookline, MA, United States Background: Oral multiple sclerosis (MS) medications, dimethyl fumarate (DMF) and fingolimod (FG) are associated with decreased absolute lymphocyte count (ALC). Lymphopenia is linked to increased risk of infections including few cases of progressive multifocal leukoencephalopathy (PML) in patients treated with these drugs. There is currently no guideline to identify patients at risk. Objective: To investigate the frequency of lymphopenia and its predictors in patients treated with DMF or FG. Methods: Eligible subjects from the Partners MS Center database were identified (DMF=405, FG=300). Univariate and multivariate analyses were performed via a logistic regression model to assess the association between patients’ demographics, baseline ALC, body mass index, vitamin D level and binary outcomes of lymphopenia grades. ALC grading defined as; grade 2 (500-800/


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Poster Session 1, 22(S3) mm3), grade 3 (200-500/mm3), grade 3b (< 350/mm3) and grade 4 (< 200/mm3). Leukopenia grading defined as; grade2 (WBC: 2000-3000/mm3) and grade 3 (WBC: 1000-2000/mm3). Results: In DMF group, the incidence of lymphopenia grade 2 and 2/3-3 within 3 years after treatment initiation was 17%; CI=(13%, 21%) and 11%; CI=(8%, 14%). Lower baseline ALC were associated with higher odds of lymphopenia grade 2 and grade 2/3-3 (p=0.0046, p=0.0021). In grade 2, older age was associated with higher odds of lymphopenia (p=0.0211). When age was stratified into the < 30 (OR=0.2, p=0.0298), 30-50 (OR=0.5, p=0.0085) and >50 years categories, younger patients were at a significantly lower risk of developing lymphopenia, as compared to >50 years. In FG group, lymphopenia grade 4 and grade 3b/4 were present in 17%; CI=(13%, 21%) and 59%; CI=(53%, 64%) within 5 years after treatment initiation. The odds of developing lymphopenia grade 4 and grade 3b/4 were significantly higher in female patients (p= 0.011 and p= 0.002). Prior treatment with natalizumab was associated with an increased odds of lymphopenia grade 4 (p= 0.012), while no previous treatment was associated with a lower odds of lymphopenia grade 3b/4 (p=0.03). Furthermore, patients without previous MS treatment and longer disease duration were at higher risk for leukopenia grade 2/3(p= 0.025 and p= 0.012). Conclusion: Older age, and lower baseline ALC were associated with lymphopenia with DMF use, while being a female and prior MS treatment are important determinant of lymphopenia with FG use. These factors can be used to develop risk stratification guidelines. Disclosure M.Baharnoori: nothing to disclose. A.Chua: has received support from Verily Life Sciences. C. Diaz-Cruz: has received research support from Merck Serono. B. Healy: received grant support from Novartis, Merck Serono, Genzyme and Verily Life Sciences. I am also on the Biogen Idec Worldwide Medical Biostatistics MS Advisory Board. James Stankiewicz: has received personal compensation for consulting with Hoffman-LaRoche, Biogen, Novartis, Bayer, EMD Serono, Genzyme, Teva neuroscience. Howard Weiner: has received personal compensation for consulting, speaking activities and has served on the scientific advisory board of companies including Biogen Idec, Novartis, EMD Serono, Teva. T. Chitnis: received personal compensation for advisory boards/ consulting for Hoffman-La Roche, Biogen and Novartis Pharmaceuticals and financial support for research activities from Biogen, Merck Serono and Novartis Pharmaceuticals

P725 Evaluating the safety of beta-interferons in multiple sclerosis: a series of nested case-control studies H.J.I. De Jong1,2, E. Kingwell1, A. Shirani1, J.W. Cohen Tervaert2, R. Hupperts2, Y. Zhao1, F. Zhu1, C. Evans3, M. Van der Kop4, A. Traboulsee1, P. Gustafson1, J. Petkau1, R.A. Marrie5, H. Tremlett1 1University of British Columbia, Vancouver, BC, Canada, 2Maastricht University Medical Centre, Maastricht, The Netherlands, 3University of Saskatchewan, Saskatoon, SK, Canada, 4Karolinska Institutet, Stockholm, Sweden, 5University of Manitoba, Winnipeg, MB, Canada

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Background: The beta-interferons (IFN-β) are widely prescribed therapies for relapsing-remitting multiple sclerosis (RRMS). Although reportedly safe in clinical trials, few studies have comprehensively and quantitatively assessed their safety in clinical practice. Objectives: We examined the association between IFN-β and potential adverse events using population-based health administrative data in British Columbia (BC), Canada. Methods: Patients with RRMS who were registered at a BC Multiple Sclerosis clinic between 1995 and 2004, and were eligible for IFN-β, were followed until death, emigration from BC, exposure to a non-IFN-β disease-modifying drug, or 31 December 2008, whichever came first. The cohort entry date was defined as the first clinic visit date at which the patient was eligible for IFN-β. Incidence rates were estimated for each potential adverse event. Adverse events were selected a priori based on a comprehensive literature search, and identified using International Classification of Diseases (ICD-9/10) diagnosis codes from physician and hospital claims. A nested case-control study was then conducted to assess the odds of previous IFN-β exposure for each potential adverse event for which there were >30 cases. Cases were matched by age (+/-5 years), sex and year of cohort entry, with up to 20 randomly selected controls via incidence density sampling from the study cohort. We estimated odds ratios (ORs) with 95% confidence intervals (CIs) using conditional logistic regression, adjusted for age (in years) at cohort entry. Results: Of the 2485 eligible patients, the mean (SD) age was 41.3 (10.0) years, 77.9% were women and 1031 were treated with IFN-β during follow-up. From the incidence analyses, 27 of the 47 potential adverse events had at least 30 cases. Patients with stroke (ORadj,1.83; 95%CI:1.16-2.89), migraine (ORadj,1.55; 95%CI:1.182.04), depression (ORadj,1.33; 95%CI:1.13-1.56) and haematological abnormalities (ORadj,1.32; 95%CI:1.01-1.72) were more likely to have had previous exposure to IFN-β than controls. Conclusions: Our study provides a comprehensive assessment of the potential risks for a broad range of adverse events related to IFN-β in a ‘real world’ clinical setting. Among RRMS patients, IFN-β exposure was associated with a 1.8 and 1.6-fold increase in the risk of stroke and migraine, and 1.3-fold increases in depression and haematological abnormalities. Disclosure Dr de Jong was funded by the Michael Smith Foundation for Health Research and the MS Society of Canada (Postdoctoral fellowships). Dr Kingwell: nothing to disclose. Dr Shirani: nothing to disclose. Prof Cohen Tervaert: nothing to disclose. Prof Hupperts received honoraria for lectures or advisory boards and research grants from Biogen, Merck, Sanofi-Aventis and Novartis. Dr Zhao: nothing to disclose. Mr Zhu: nothing to disclose. Dr Evans: nothing to disclose. Ms van der Kop: nothing to disclose. Dr Traboulsee has received grant funding from the MS Society of Canada, Canadian Institute for Health Research, Lotte and John Hecht Foundation, Vancouver Hospital Foundation, Roche, and Genzyme; served on clinical trial steering committee for Roche;


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received honoraria or travel grants from Teva Canada Innovation, Roche, Merck/EMD Serono, Genzyme, Chugai Pharmaceuticals. Prof Gustafson is supported by the Natural Sciences and Engineering Research Council of Canada. He has received consulting fees from Biogen. Prof Petkau holds research funding from the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the U.S. National Multiple Sclerosis Society, and over the past three years has received travel support, honoraria, consulting fees or fees for service on Data Safety Monitoring Boards or Steering Committees from the Canadian Study Group on CCSVI, EMD Serono, the Myelin Repair Foundation, and Novartis. Prof Marrie receives funding from: Canadian Institutes of Health Research (CIHR), Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Multiple Sclerosis Society, Rx&D Health Research Foundation, and has conducted clinical trials funded by Sanofi-Aventis. Prof Tremlett is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award); is a Michael Smith Foundation for Health Research Scholar and the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received: research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014, 2016), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014, 2015, 2016), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015, 2016). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group. P726 First dose effects of fingolimod: in depth electrocardiographic analysis of over 4.700 patients confirms first dose observation is usually uneventful V. Limmroth1, W. Haverkamp2, R. Dechend3, M. Lang4, J. Haas5, B. Wagner6, S. Richter6, H. Schieb7, G. Wendt7, T. Ziemssen8 1Department of Neurology, Cologne General Hospitals, University of Cologne, Cologne, 2Department of Cardiology, Division for Rhythmology and Electrophysiology, Charité Universitaetsmedizin Berlin, 3Experimental and Clinical Research Center, Charité-Campus Buch, Berlin, 4NTD Study Group, Neurologische Praxis, Ulm, 5Jewish Hospital Berlin, Berlin, 6NeuroMVZ Stuttgart, Stuttgart, 7Novartis Pharma GmbH, Nürnberg, 8Center of Clinical Neuroscience, University Clinic Carl Gustav Carus Dresden, Dresden, Germany Background: Fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, activates S1P1 receptors at the surface of cardiac myocytes after treatment initiation. This activation results in transient, reduction in heart rate and in rare cases atrioventricular conduction blocks (usually asymptomatic). Objective: The START study (cFTY720DDE17) evaluates in detail the first dose cardiac safety of fingolimod in a large real

world cohort over a 7 day period. Presented are results from an interim analysis. Design and methods: The START study (NCT01585298) is a prospective, 1-week, multicenter, open-label study enrolling up to 7,000 RRMS patients in more than 250 centers in Germany, according to the EU label of fingolimod. The study includes a screening period, a baseline visit at which the first fingolimod dose is taken, and a final visit after one week. The procedure at baseline is as follows: prior to the first intake of fingolimod, a 12-lead ECG is recorded. After the first dose, a continuous 6h Holter ECG is conducted, while pulse and blood pressure are measured in parallel every hour. Finally, a 12-lead ECG is performed post dose and after 7 days. All ECG recordings are centrally evaluated by cardiologists. Results: This interim analysis is based on 4.736/7.000 patient. In this cohort, 99 % of patients were discharged ⩽ 8 hours after the first dose of fingolimod. 0.8% of patients developed asymptomatic bradycardia (< 45 bpm) during the 6h monitoring. There was no QTcF-interval prolongation beyond 500msec. 1.5% of the patients experienced a 2nd degree AV-block of Mobitz type I or 2:1, but no patient experienced an AV block of higher degree. The concomitant intake of QT-interval-prolonging drugs (e.g. antidepressiva (SSRIs)) and fingolimod did not increase the occurrence of cardiac events. Data from the subpopulation of patients who previously were on fingolimod but interrupted treatment will also be presented. Conclusions: This analysis of the first 4.736 START patients confirms the overall benign cardiac safety profile of fingolimod in a real world setting with real-time ECG data-reading conditions which supports the cardiac data presented from the pivotal phase III studies. Disclosure V. Limmroth has received speaker’s honoraria, financial research support or consultancy fees from Antisence, Allergan, Allmiral, Bayer, Biogen, Bionorica, Genzyme, Novartis, Roche, Sanofi, Teva. W. Haverkamp is working as consultant to Novartis. R. Dechend has received speaker’s honoraria, financial research support or consultancy fees from Berlin Chemie, Novartis, Alnylam, Boehringer Ingelheim, Bayer, MSD. M. Lang has received travel grants, speaker’s honoraria, financial research support, consultancy fees from Teva, Merck Serono, Genzyme, Sanofi, Novartis, Bayer, Biogen Idec. J. Haas has received compensation from Almiral, Biogen, Bayer, Octapharma, Teva, Allergan and Novartis. Bert Wagner has received travel grants from Novartis, Biogen, Bayer, and Genzyme and speaker’s honoraria from Biogen and Novartis. S. Richter has received travel grants und compensation for scientific advisory boards from Novartis and travel grants from Biogen, Teva, Bayer, and Genzyme. H. Schieb is employed by Novartis Pharma GmbH, Germany. G. Wendt is employed by Novartis Pharma GmbH, Germany. T. Ziemssen has received compensation for consulting services from Almirall, Biogen Idec, Bayer, Genzyme, GSK, MSD, Merck Serono, Novartis, Sanofi, Teva and Synthon, and has received research support from Bayer, Biogen Idec, Hertie Foundation, Roland Ernst Foundation, German Diabetes Foundation, Merck Serono, Novartis, Teva and Sanofi Aventis.


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Tools for detecting therapeutic response P727 Sensitivity of magnetic resonance imaging to fingolimod dosage in a cuprizone mouse model L. Ziser1, N. Meyer-Schell1, R.K. Sullivan2, D.C. Reutens1, N.D. Kurniawan1, M. Chen1, V. Vegh1 1Centre for Advanced Imaging, 2Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

P728 Interferon-beta therapy in multiple sclerosis induces differential gene regulatory effects in distinct cell populations of the peripheral blood M. Hecker1,2, B. Fitzner2, D. Koczan3, I. Schröder1, H.-J. Thiesen2,3, U.K. Zettl1 1Department of Neurology, University of Rostock, 2Steinbeis Transfer Centre for Proteome Analysis, 3Institute of Immunology, University of Rostock, Rostock, Germany

Background: Fingolimod is an oral drug approved for the treatment of multiple sclerosis. This drug has been shown to positively affect myelination, and compounding evidence suggests that treatment efficacy depends on dosage. Researchers have used diffusionweighted imaging (DWI) in magnetic resonance imaging (MRI) to investigate dosage effects on diffusion metrics. Limitations of these findings involved the use of supra-clinical doses and a relapsing remitting animal model. Since DWI does not directly target myelination, MRI based measures of tissue magnetic susceptibility may provide additional sensitivity to dosage effects on myelination. Objective: Assess impact of dosage on myelination via MRI contrasts sensitive to changes in magnetic susceptibility in acute and chronic cuprizone mice treated with fingolimod. Methods: Eighty 6-week old C57BL/6 mice were separated into acute and chronic cohorts, each comprising of four groups. In each cohort, the four groups were normal diet, untreated cuprizone diet and cuprizone diet treated with either 0.1mg/kg fingolimod or the maximum equivalent clinical dose of 0.3mg/kg fingolimod. In vivo and ex vivo multiple echo time T2*-weighted gradient recalled echo data were obtained using a 9.4T Bruker animal scanner. The average voxel intensities of the white (corpus callosum) and grey (cortex) matter regions in each brain image were determined for T2*, frequency shift and susceptibility measures. Staining for myelin, oligodendrocytes, interneurons and microglia was performed. Results: Both fingolimod dosages displayed an increase in greywhite matter contrast (p < 0.001) compared to the cuprizone diet for acute and chronic in vivo MRI measures. For in vivo T2*, frequency shift and susceptibility respectively, the 0.3mg/kg dosage showed an increase in grey-white matter contrast that was 68%, 81% or 207% greater than the increase observed for 0.1mg/kg in the acute stage, and 11%, 63% or 78% greater in the chronic stage. Ex vivo MRI and myelin-basic protein antibody results also exhibited an increase in grey-white matter contrast with fingolimod treatment. Conclusions: Fingolimod treatment has a positive effect on myelination relative to the untreated cuprizone diet in both the acute and chronic demyelination stages, with a larger dosage amount showing a greater increase in grey-white matter contrast. Magnetic susceptibility was found to be the most sensitive to cuprizone and fingolimod induced changes.

Interferon-beta (IFN-beta) is an established first-line therapy in multiple sclerosis (MS). Previous studies have identified more than a hundred genes to be differentially expressed in response to this treatment. Most of these studies used mixed cell populations such as whole blood or peripheral blood mononuclear cells (PBMC), in which cell type-specific effects may be masked. We compared the gene expression profiles of 5 immune cell populations before and during treatment with subcutaneous IFN-beta to obtain deeper insights into the drug´s mechanisms of action and to confirm and refine potential biomarkers for therapy monitoring and disease prognosis. With written informed consent, blood samples were collected from 32 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) before as well as 2 days and 1 month after the start of IFN-beta therapy. T helper cells (CD4+), cytotoxic T-cells (CD8+), monocytes (CD14+), B-cells (CD19+) and PBMC were separated by Ficoll gradient and magnetic-activated cell sorting. The OpenArray real-time PCR platform was used for sensitive high-throughput quantification of 112 transcripts. Expression differences with t-test p-value < 0.05 and log2 fold-change >0.5 or < -0.5 were considered statistically significant. About 42300 real-time PCR reactions were evaluated. The data showed that the IFN-beta signature is induced in particular in monocytes. Approximately half of the IFN-beta-responsive genes seen after 1 month were significantly changed in expression already after the first injection. IFI44, MX1 and XAF1 were consistently expressed at higher mRNA levels in all 5 cell populations and at both time points during therapy. Differences in baseline expression of genes belonging to the JAK/STAT pathway distinguished patients with and without relapses in the clinical follow-up. The treatment with subcutaneous IFN-beta evoked different gene regulatory effects in different cell types of the blood. IFN-beta-responsive genes were typically increased in expression in monocytes after 1 month of therapy. Cell typespecific gene expression differences prior to therapy may be useful as biomarkers of the biological and clinical response to therapy.

Disclosure

Disclosure

The project was funded by Novartis Pharmaceuticals Pty. Ltd., Australia, as an investigator initiated trial. Laura Ziser: nothing to disclose Naja Meyer-Schell: nothing to disclose Robert Sullivan: nothing to disclose David Reutens: nothing to disclose Nyoman Kurniawan: nothing to disclose Min Chen: nothing to disclose Viktor Vegh: nothing to disclose

MH received speaking fees and travel support from Bayer, Biogen, Novartis and Teva. BF declares no conflicts of interest. DK declares no conflicts of interest. IS declares no conflicts of interest. HJT declares no conflicts of interest. UKZ received speaking fees and financial support for research activities from Bayer, Biogen, Merck Serono, Novartis, Sanofi, Almirall and Teva.

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P729 Individual response to disease modifying therapies: a global observational cohort study T. Kalincik1,2, L. Sobisek3, V. Jokubaitis1,2, T. Spelman1,2, D. Horakova4, E. Havrdova4, M. Trojano5, G. Izquierdo6, A. Lugaresi7,8, M. Girard9, A. Prat9, P. Duquette9, P. Grammond10, P. Sola11, R. Hupperts12, F. Grand’Maison13, E. Pucci14, C. Boz15, R. Alroughani16, V. Van Pesch17, J. Lechner-Scott18, M. Terzi19, R. Bergamaschi20, G. Iuliano21, F. Granella22, D. Spitaleri23, V. Shaygannejad24, C. Oreja-Guevara25, M. Slee26, R. Ampapa27, F. Verheul28, P. McCombe29, J. Olascoaga30, M.P. Amato31, S. Vucic32, S. Hodgkinson33, C. Ramo34, S. Flechter35, E. Cristiano36, C. Rozsa37, F. Moore38, J.L. Sanchez-Menoyo39, M.L. Saladino40, M. Barnett41, H. Butzkueven1,2,42, MSBase Study Group 1University of Melbourne, 2Royal Melbourne Hospital, Melbourne, VIC, Australia, 3University of Economics in Prague, 4Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 5University of Bari, Bari, Italy, 6Hospital Universitario Virgen Macarena, Seville, Spain, 7University of Bologna, Bologna, 8Istituto delle Scienze Neurologiche di Bologna, Bolog, Italy, 9CHUM and Universite de Montreal, Montreal, 10Centre de Réadaptation Déficience Physique Chaudière-Appalache, Lévis, QC, Canada, 11Nuovo Ospedale Civile Sant’Agostino/Estense, Modena, Italy, 12Zuyderland Ziekenhuis, Sittard, The Netherlands, 13Neuro Rive-Sud, Montreal, QC, Canada, 14Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy, 15KTU Medical Faculty Farabi Hospital, Trabzon, Turkey, 16Amiri Hospital, Kuwait, Kuwait, 17Cliniques Universitaires Saint-Luc, Brussels, Belgium, 18University Newcastle, Newcastle, NSW, Australia, 1919 Mayis University, Samsun, Turkey, 20C. Mondino National Neurological Institute, Pavia, 21Ospedali Riuniti di Salerno, Salerno, 22University of Parma, Parma, 23Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati, Avellino, Italy, 24Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran, 25Hospital Clinico San Carlos, Madrid, Spain, 26Flinders Medical Centre, Adelaide, SA, Australia, 27Nemocnice Jihlava, Jihlava, Czech Republic, 28Groene Hart Ziekenhuis, Gouda, The Netherlands, 29Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia, 30Hospital Universtario Donostia, San Sebastian, Spain, 31University of Florence, Florence, Italy, 32Westmead Hospital, 33Liverpool Hospital, Sydney, NSW, Australia, 34Hospital Germans Trias i Pujol, Badalona, Spain, 35Assaf Harofeh Medical Center, Beer-Yakov, Israel, 36Hospital Italiano, Buenos Aires, Argentina, 37Jahn Ferenc Teaching Hospital, Budapest, Hungary, 38Jewish General Hospital, Montreal, QC, Canada, 39Hospital de Galdakao-Usansolo, Galdakao, Spain, 40Institute of Neuroscience Buenos Aires, Buenos Aires, Argentina, 41Brain and Mind Centre, Sydney, NSW, 42Box Hill Hospital, Monash University, Melbourne, VIC, Australia Background: Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis (MS); however, treatment response varies greatly among patients. Comprehensive predictive models of treatment outcomes are lacking. Objective: To evaluate a large number of demographic, clinical and paraclinical predictors of individual response to 11 disease modifying therapies and to incorporate these into models informing clinical practice.

Methods: Longitudinal data from MSBase, a large global cohort study, were utilised to identify predictors of on-treatment relapses, disability progression and regression, using univariable survival models. The predictors comprised 51 variables. Multivariable survival models were used to design individual predictive algorithms. Dimensionality of the models was controlled with principal component analysis. Accuracy of the resulting models was tested in a training cohort. External validity was established using a validation cohort. Results: In the training cohort (n=8513), the most prominent predictors of treatment response comprised age, MS duration, MS course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous MS therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pre-treatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. In contrast, incidence of relapses was associated with pre-treatment relapse activity, age and relapsing MS course, with the strength of these associations varying among therapies. Accuracy and external validity (n=1196) of the resulting predictive models was high (>80%) for relapse incidence over the initial 2 years and disability outcomes, and moderate (>50%) for relapse incidence in years 3-4. Conclusion: Demographic, clinical and paraclinical information enables estimation of future individual response to disease modifying therapies. The resulting models constitute a framework that enables incorporation of multiple biomarkers and will be implemented in a web-based tool with the aim of supporting clinical practice. Disclosure Tomas Kalincik served on scientific advisory boards for Roche, Genzyme, Novartis, Merck and Biogen, has received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi, Genzyme, Teva, BioCSL and Merck and has received research support from Biogen. Lukas Sobisek received research fellowship from Novartis and long term institutional support for research activities from the Faculty of Informatics and Statistics, University of Economics, Prague. Tim Spelman received compensation for travel from Biogen. Vilija Jokubaitis received conference travel support from Novartis and Merck Serono. Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen and research grants from Charles University in Prague (PRVOUK-P26/LF1/4 and Czech Ministry of Health (NT13237-4/2012). Eva Havrdova received speaker honoraria and consultant fees from Biogen, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen, Merck Serono and research grants from Charles University in Prague (PRVOUK-P26/ LF1/4 and Czech Ministry of Health (NT13237-4/2012). Maria Trojano received speaker honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva , Novartis


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Poster Session 1, 22(S3) and Almirall; has received research grants for her Institution from Biogen-Idec, Merck-Serono, and Novartis. Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck Serono and Teva. Alessandra Lugaresi is a Bayer, Biogen, Genzyme, Merck Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Merck, Novartis, Sanofi, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institution received research grants from Bayer, Biogen, Merck, Novartis, Sanofi , Teva and Fondazione Italiana Sclerosi Multipla (FISM). Alexandre Prat did not declare any competing interests. Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD Serono. He has also received a research grant from Canadian Institutes of Health Research. Pierre Duquette served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigatorinitiated trials from Biogen, Novartis, and Genzyme. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen and Genzyme advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, TevaNeuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Patrizia Sola received travel grants and speaking honoraria from Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi/ Genzyme and Teva. Raymond Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen, Genzyme-Sanofi and Teva, research funding from Merck-Serono and Biogen, and speaker honoraria from Sanofi-Genzyme and Novartis. Francois Grand´Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. Helmut Butzkueven served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. Eugenio Pucci served on scientific advisory boards for Merck Serono, Genzyme and Biogen; he has received honoraria and travel grants from Sanofi Aventis, UCB, Lundbeck, Novartis, Bayer Schering, Biogen, Merck Serono, Genzyme and Teva; he has received travel grants and equipment from “Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche”. Cavit Boz received conference travel support from Biogen, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Raed Alroughani received honororia from Biologix, Biogen, Bayer, Genpharm, Genzyme, Merck-Serono, GSK and Novartis, and served on advisory board for Biologix, Biogen, Bayer, Genpharm, Genzyme, Novartis, Genzyme, Merck-Serono and Novartis. Vincent Van Pesch served on advisory boards for Biogen, Novartis Pharma and Sanofi-Genzyme; has received travel grants and consultancy fees from Biogen, Bayer Schering, Sanofi Aventis, Merck Serono, Sanofi-Genzyme and Novartis Pharma; has received research grants from Bayer Schering.

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Jeannette Lechner-Scott accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen, CSL, Genzyme Sanofi, Merck Serono, Novartis and Teva. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Roberto Bergamaschi received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, SanofiAventis, Teva; research grants from Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi-Aventis, Teva; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, SanofiAventis, Teva. Gerardo Iuliano had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi Aventis, and Teva. Franco Granella served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Aventis and received funding for travel and speaker honoraria from Biogen Idec, Merck Serono, and Almirall. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck-Serono. Vahid Shaygannejad did not declare any competing interests. Celia Oreja-Guevara received honoraria as consultant on scientific advisory boards from Biogen, Bayer-Schering, Merck-Serono, Teva and Novartis; has participated in clinical trials/other research projects by Biogen, GSK, Teva and Novartis. Mark Slee has participated in, but not received honoraria for, advisory board activity for Biogen, Merck Serono, Bayer Schering, Sanofi Aventis and Novartis. Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck Serono and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. Freek Verheul is an advisory board member for Teva Biogen Merck Serono and Novartis. Pamela McCombe did not declare any competing interests. Javier Olascoaga serves on scientific advisory boards for Biogen, Genzyme and Novartis; has received speaker honoraria from Biogen, Bayer-Schering, Genzyme, Merck-Serono, Novartis and Teva and research grants from Biogen, Merck Serono, Novartis and Teva. Maria Pia Amato received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck-Serono, Teva and Sanofi-Aventis; has received research grants by Biogen, Bayer-Schering, Merck-Serono, Teva and Novartis. Steve Vucic did not declare any competing interests. Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. Cristina Ramo received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. Shlomo Flechter received research funding, speaker honoraria and compensation for travel from and served as a consultant on advisory board for Bayer-Schering, Teva, Biogen, Merck Serono, Genzyme and Novartis.


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Edgardo Cristiano received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck-Serono, Genzyme and Novartis; has participated in clinical trials/other research projects by Merck-Serono, Roche and Novartis. Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck Serono and Bayer Schering. Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck Serono, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. Maria Laura Saladino did not declare any competing interests. Michael Barnett served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck-Serono and Novartis. Helmut Butzkueven served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck Serono, Novartis and Biogen. P730 Dose-response model for B cell count reduction under ofatumumab treatment M. Savelieva1, J. Kahn2, D. Leppert1, E. Wallstroem1 1Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Ofatumumab is an anti-CD20 human monoclonal antibody that depletes B cells and has demonstrated dose-dependent efficacy in MS patients during Phase 2 studies. Novartis is currently initiating Phase 3 clinical trials in relapsing MS. The efficacy of anti-CD20 therapy in MS is hypothesised to be directly related to how strongly it depletes circulating B cells. Thus, understanding the dose-response relationship between ofatumumab dose level administered and B cell dynamics is key for selecting a treatment regimen providing optimal efficacy with favourable safety. Objective: To develop a population dose-response model for B cell count under ofatumumab treatment as a function of time and patient-specific characteristics and to evaluate the predictive properties of this model. Data and methods: 231 patients from the Phase 2 MIRROR study in RRMS patients were dosed subcutaneously with either with placebo, 3 mg q12w, 30 mg q12w, 60 mg q12w, or 60 mg q4w. The treatment duration was 24 weeks, with treatment followup until Week 48. B cell counts were assessed at screening and every 4 weeks until the end of the study, and in a follow-up phase observing B cell recovery after treatment stop. Due to targetmediated drug disposition, pharmacokinetic (PK) samples were mostly below limit of quantification except at the highest dose. Therefore, we fitted a K-PD model where a dosing compartment drives a turnover response in B cells. We used nonlinear mixed effects methods to estimate the K-PD model parameter means and inter-patient variability.

Results: Predictive checks showed that the K-PD model adequately captured B cell depletion and repletion dynamics vs. dosing and demonstrated good predictive properties. Conclusion: The dose-response model well-described B cell dynamics, and could be used to compare performance of ofatumumab dosing regimens. Disclosure This abstract is supported by Novartis Pharma AG, Basel, Switzerland All authors are employees of Novartis. P731 Effect of teriflunomide on relapse and disability worsening: an analysis of the TOWER Study with 2 years of treatment K. Thangavelu1, J. Morawski1, M.S. Freedman2 1Sanofi Genzyme, Cambridge, MA, United States, 2University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada Background: TOWER (NCT00751881), a phase 3, randomized, placebo-controlled study of teriflunomide in patients with relapsing forms of MS (RMS), demonstrated that, compared with placebo, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12w-CDW), consistent with another pivotal teriflunomide trial (TEMSO, NCT00134563). Patients in TOWER had variable treatment duration (48-156 weeks), with the study ending 48 weeks after last patient randomization. This has seemingly led to challenges in conducting comparative analyses of other phase 3 trials of disease-modifying therapies (DMTs), which generally use a fixed 2-year treatment duration, thus leading to possible exclusion of TOWER results in meta-analyses, including health technology assessments. Objective: To evaluate relapse and disability worsening outcomes from patients in TOWER, over a fixed 2‑year study period. Methods: In TOWER, patients with RMS were randomized 1:1:1 to receive placebo or teriflunomide 7 mg or 14 mg, and were treated for ⩾48 weeks. In this post hoc analysis, ARR and 12wCDW outcomes were compared between the overall intent-totreat (ITT) population and a “fixed 2-year study” population (96-week treatment data, based on each patient’s respective randomization date, extracted from TOWER ITT population). Results: Of the overall ITT population (N=1165), 681 patients (58.5%) met the criteria for the fixed 2‑year study population; patient demographics and baseline disease characteristics were similar for both groups. In the overall ITT population, ARR was reduced in the teriflunomide 14-mg group (n=370) vs placebo (n=388), corresponding to 36.3% rate reduction (95% CI 20.7— 48.8; P=0.0001) whilst, in the 2‑year study population, reduction of ARR in the teriflunomide 14-mg group (n=223) vs placebo (n=228) was 40.2% (95% CI 20.6—54.9; P=0.0004). The probability of 12w-CDW was significantly reduced in the teriflunomide 14-mg group vs placebo in both the overall ITT and 2‑year study populations, corresponding to a risk reduction of 31.5% (95% CI -0.4—53.3; P=0.0442) and 38.7% (95% CI ‑0.1—62.4; P=0.0479), respectively. Conclusions: Reductions in both ARR and 12w-CDW following treatment with teriflunomide 14 mg (vs placebo) were comparable


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Poster Session 1, 22(S3) between the overall ITT population and the fixed 2-year study population in TOWER. Consistency in outcomes supports inclusion of TOWER study results when conducting comparative analyses vs other DMTs.

PBMC RNA profiles. Given the difference in inflammatory disease activity, this population structure could be leveraged to enhance the design of translational studies in MS and should be further investigated to assess whether it can inform clinical decision-making, when considered along with current parameters.

Disclosure Study supported by Sanofi Genzyme. KT: Employee of Sanofi Genzyme. JM: Employee of Sanofi Genzyme. MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation). P732 Confirmation of population structure among MS subjects: an MS subset has more disease activity E. Patrick1, L. Ottoboni2, D. Bargiela1, T. Harris3, J. Carrulli3, H. Weiner1, J. Goyal3, P. De Jager1 1Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States, 2San Raffaele Scientific Institute - INSPE, Institute of Experimental Neurology, Milan, Italy, 3Biogen, Inc., Boston, MA, United States Background: We have previously reported the existence of two subsets of MS subjects that were defined using transcriptomic profiles of peripheral blood mononuclear cells (PBMC) from untreated subjects, subjects treated with Glatiramer Acetate (GA) and interferon β. The smaller subset was reported to be more likely to have inflammatory disease activity Objective: To confirm (1) our report of structure in the MS patient population and (2) the association of the smaller subset of subjects with greater inflammatory disease activity. Methods: Relapsing remitting MS subjects (RRMS, n=163) from the Comprehensive Longitudinal Investigation of MS at the Brigham and Women’s Hospital (CLIMB) that are independent from the set of subjects used in the prior study (Ottoboni et al. Sci Trans Med 2012) and had been treated with GA for > 6 months were selected for this study. The outcome measure was the length of event-free time following profiling, (event= a clinical relapse, new T2 hyperintense and/or gadolinium-enhancing lesion, or a >6 months sustained increase of 1 EDSS point). . For each of the 163 PBMC samples, a cDNA library was constructed and sequenced to an average depth of 40 million paired end reads . As in the prior study, non-negative matrix factorization (NMF) was used to cluster subjects, and a Cox proportional hazards regression model was used to compare the time to an inflammatory event between the clusters of MS subjects. Results: In the new dataset of 163 GA-treated subjects, NMF analysis returns an optimal solution of k=2, as in the prior study: the data are best explained by the presence of two subsets of RRMS subjects, we also find that the smaller subgroup of subjects is more likely to have an inflammatory event after the date of sampling (Cox proportional hazard ratio = 0.33, p = 0.017), consistent with the original study. Conclusion: Among RRMS subjects treated with GA, we confirm the existence of two subsets that can be distinguished using

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Disclosure De Jager: This work was funded by a sponsored research agreement from Biogen. Drs. Carulli, Harris and Goyal are employees of Biogen. Patrick: nothing to disclose Bargiela:nothing to disclose Ottoboni: nothing to disclose Weiner: no pertinent disclosuresJG, JPC are full time employees of Biogen and hold stock/stock options in Biogen. TH currently at SV Lifesciences and was a Biogen employee at the time this study was executed and held stock/stock options in Biogen P733 Brain volume loss correlates with long-term disability worsening in patients with MS: SIENA analysis of TEMSO MRI data L. Kappos1, T. Sprenger1,2,3, E.-W. Radue3, J. Wuerfel3, K. Thangavelu4, M.A. Panzara4, S. Cavalier4, J.S. Wolinsky5 1University Hospital Basel, Basel, Switzerland, 2DKD Helios Klinik, Wiesbaden, Germany, 3Medical Image Analysis Center (MIAC AG), Basel, Switzerland, 4Sanofi Genzyme, Cambridge, MA, 5McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Background: Teriflunomide is a once-daily oral immunomodulator for relapsing-remitting MS. In 2 phase 3 studies, teriflunomide 14 mg significantly reduced risk of disability worsening vs placebo. This is consistent with significant effects of teriflunomide vs placebo on reducing brain volume loss (BVL) observed in a post hoc, blinded SIENA (structural image evaluation using normalization of atrophy) analysis of TEMSO magnetic resonance imaging scans. Further analysis of these data provided evidence of a strong correlation between BVL and disability worsening, and also showed that teriflunomide significantly slowed BVL vs placebo independent of disability worsening over the course of the 2‑year study. Objective(s): To explore the association of BVL and long-term disability worsening in an analysis of TEMSO (NCT00134563) and its long-term extension (NCT00803049). Methods: SIENA analysis was conducted on patient scans from TEMSO (n=969) to determine BVL in the first (n=808) and second (n=709) year of the study. Additional analyses were conducted on the total population (regardless of treatment allocation) by categorizing percentage brain volume changes (PBVC) from baseline to Year 2 into quartiles (Q1-Q4) and evaluating the probability of 12- and 24-week confirmed disability worsening over 5 years in the TEMSO extension. Probability of worsening was derived from Kaplan-Meier estimates and was compared between quartiles using a Cox proportional hazards model with PBVC categories, Expanded Disability Status Scale strata at baseline, and region as covariates. Results: The group with the most marked BVL from baseline to Year 2 (ie, Q1; n=177) had a significantly higher risk of both 12- and


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24-week confirmed disability worsening after 5 years than those in the quartile with the lowest BVL (Q4; n=178). Thus, in Q1, probability of 12-week confirmed disability worsening at 5 years was 0.487 (95% confidence interval [CI] 0.410, 0.569) vs 0.315 (95% CI 0.251, 0.391) in Q4 (hazard ratio [HR] for Q1 vs Q4: 0.611 [95% CI 0.432, 0.865]; P=0.0055). Similarly, probability of 24-week confirmed disability worsening at 5 years was significantly higher in Q1 vs Q4 (HR: 0.566 [95% CI 0.386, 0.830]; P=0.0036). Conclusions: These analyses provide further evidence of the association between BVL and later disability worsening. Greater rates of BVL over 2 years are predictive of longer term disability worsening at 5 years in the TEMSO extension. Disclosure Study supported by Sanofi Genzyme. LK: Author´s institution (University Hospital Basel) has received in last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation. TS: Author´s previous and current institution have received payments for research for consulting and speaking activities (Actelion, Biogen Idec, ElectroCore, Genzyme, Mitsubishi Pharma, Novartis); grants received (EFIC-Grünenthal, Novartis Pharmaceuticals Switzerland, Swiss MS Society, Swiss National Research Foundation). E-WR: Author’s institution, MIAC AG, has received payments used exclusively for research (Actelion, Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi). JW: CEO of MIAC AG Basel, Switzerland; speaker honoraria (Bayer, Biogen, Novartis, Teva); advisory boards and research grants (Biogen, Novartis); supported by the German Ministry of Science (BMBF/KKNMS) and German Ministry of Economy (BMWi). KT: Employee of Sanofi Genzyme. MAP: Employee of Sanofi Genzyme. SC: Employee of Sanofi Genzyme, with ownership interests. JSW: Within the last 3 years, consulting agreements (AbbVie, Actelion, Alkermes, Athersys, Inc., Bayer HeathCare, EMD Serono, Forward Pharma, Genzyme, Novartis, Roche, Taketa, Teva, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society); royalties (for monoclonal antibodies out-licensed to Chemicon International), through the University of Texas Health Science Center at Houston.

P734 Teriflunomide is effective in reducing brain volume loss in previously treated patients: a subgroup analysis of TEMSO SIENA data M.S. Freedman1, T. Sprenger2,3,4, E.-W. Radue3, J. Wuerfel3, A.E. Miller5, K. Thangavelu6, M.A. Panzara6, S. Cavalier6, L. Kappos4

1University

of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 2DKD Helios Klinik, Wiesbaden, Germany, 3Medical Image Analysis Center (MIAC AG), 4University Hospital Basel, Basel, Switzerland, 5Icahn School of Medicine at Mount Sinai, New York, NY, 6Sanofi Genzyme, Cambridge, MA, United States Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. In both TEMSO (NCT00134563) and TOWER (NCT00751881), teriflunomide 14 mg significantly slowed disability worsening vs placebo, and was highly correlated with the significant effects of teriflunomide in reducing brain volume loss (BVL) observed in a SIENA (structural image evaluation using normalization of atrophy) analysis of TEMSO (no MRI analysis was performed in TOWER). In subgroup post hoc analyses of TEMSO and TOWER, teriflunomide 14 mg had positive effects on annualized relapse rate and disability worsening in both treatment-naïve patients and those previously exposed to disease-modifying therapy (DMT). Objectives: To report effects of teriflunomide on BVL according to prior DMT exposure in a subgroup analysis of TEMSO. Methods: Blinded SIENA analysis was conducted on patient scans from TEMSO (n=969) to determine BVL in Year 1 (n=808) and Year 2 (n=709). Post hoc analyses were performed according to prior DMT status in the 2 years before study entry. Betweengroup comparisons were made using rank ANCOVA. Results: At baseline, normalized brain volume was lower in the prior-treated vs treatment-naïve group. Teriflunomide 14 mg significantly reduced BVL vs placebo in both groups, with a greater effect in prior-treated patients. In treatment-naïve patients, median percentage BVL from baseline to Year 1 was -0.40 for teriflunomide 14 mg (n=189) and -0.57 for placebo (n=209); relative change, 30% (P=0.0025); this effect was also observed from baseline to Year 2: teriflunomide 14 mg, -0.93 (n=177); placebo, -1.12 (n=182); relative change, 17% (P=0.0109). In prior-treated patients, median percentage BVL from baseline to Year 1 was -0.31 (n=74) and -0.67 (n=67) for 14 mg and placebo, respectively (relative change, 53%; P=0.0119); corresponding changes at Year 2 were -0.73 (n=58) and -1.51 (n=52); relative change, 51% (P=0.0019). Effect sizes were maintained when the prior-treated group was further stratified by number of DMTs received. Conclusions: These data support the beneficial effects of teriflunomide on slowing BVL in both prior-treated and treatment-naïve patients, vs placebo. Although prior-treated patients already had significant BVL compared with treatment-naïve patients at baseline, teriflunomide 14 mg was associated with a more profound effect on slowing BVL in prior-treated patients, consistent with previously reported positive clinical and MRI outcomes. Disclosure Study supported by Sanofi Genzyme. MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation). TS: Author´s previous and current institution have received payments for research for consulting and speaking activities (Actelion, Biogen Idec, ElectroCore, Genzyme, Mitsubishi


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Poster Session 1, 22(S3) Pharma, Novartis); grants received (EFIC-Grünenthal, Novartis Pharmaceuticals Switzerland, Swiss MS Society, Swiss National Research Foundation). E-WR: Author’s institution, MIAC AG, has received payments used exclusively for research (Actelion, Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi). JW: CEO of MIAC AG Basel, Switzerland; speaker honoraria (Bayer, Biogen, Novartis, Teva); advisory boards and research grants (Biogen, Novartis); supported by the German Ministry of Science (BMBF/KKNMS) and German Ministry of Economy (BMWi). AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). KT: Employee of Sanofi Genzyme. MAP: Employee of Sanofi Genzyme. SC: Employee of Sanofi Genzyme, with ownership interests. LK: Author´s institution (University Hospital Basel) has received in last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation. P735 Clinical predictors of fingolimod response over 2-year follow-up in an Italian cohort of multiple sclerosis relapsing remitting patients F. Esposito1,2, F. Clarelli2, L. Ferrè1,2, G. Sferruzza1,2, M. Radaelli1, F. Sangalli1, M. Rodegher1, M. Romeo1, L. Moiola1, B. Colombo1, M.A. Rocca1,3, M. Filippi1,3, F. Martinelli Boneschi1,2, G. Comi1,2, V. Martinelli1 1Department of Neurology, San Raffaele Scientific Institute, 2Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit & INSPE, San Raffaele Scientific Institute, 3Neuroimaging Research Unit, INSPE, San Raffaele Scientific Institute, Milan, Italy Introduction: Multiple sclerosis (MS) treatment options have dramatically changed in the recent years. The early identification of patients with a better response to fingolimod (FTY) would be highly beneficial towards a more personalized management. Aims: To assess FTY effectiveness and to identify baseline clinical predictors of response in an Italian monocentric cohort of relapsing-remitting (RR) MS patients. Methods: RRMS patients treated with FTY and prospectively followed at San Raffaele (Milan) for 2 years were evaluated. Baseline characteristics were tested as predictors of response. Treatment response was assessed as follows: proportion of patients with no evidence of disease activity (NEDA-3) and time to first relapse. Time to confirmed disability progression was also evaluated. NEDA analysis was conducted under a logistic regression model;

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the survival analyses were performed with a Cox proportional hazard model. Univariable and multi-variable analyses were conducted, with manual backward variable selection. Results: We enrolled 367 RRMS. Female:male ratio was 2.3, mean age at FTY start was 37.8±9.4 and mean disease duration was 9.9±6.9. Eighty-six patients (23%) were treated with natalizumab (NAT) in the 12 months before FTY. The 48% of patients were NEDA at 2-year follow-up and the mean time to first relapse was 19.1±7.0 months.Alater disease onset (p-value=0.002,OR=0.96) and being male (p-value=0.009,OR=0.53) were predictive of NEDA status, whereas a higher annualized relapse rate (ARR) in the 2 years before treatment (p-value=0.03,OR=1.5) and previous NAT treatment (p-value=0.009,OR=2.08) were associated with an increased probability of disease activity. A longer disease duration was associated to an earlier relapse under FTY treatment (p-value=0.009,HR=1.04), as well as a higher ARR in the 2 years before (p-value=6.4x10-8,HR=2.55) and recent NAT treatment (p-value=0.002,HR=2.17). As regards disease progression, being older (p=0.02,HR=1.05) and with a longer disease duration (p=2.9x10-3,HR=1.07) appeared to be associated to an earlier disease progression under FTY treatment. Conclusions: Our study confirmed FTY effectiveness, with almost 50% of patients being NEDA at 2-year follow-up. Patients with a higher baseline relapse rate and previously treated with NAT had a poorer response to FTY according to both NEDA and time to first relapse outcome. Additional analyses are ongoing, stratifying patients according to the previous NAT treatment. Disclosure F. Esposito received honoraria from TEVA and Merck. L. Moiola received honoraria for speaking at meetings or for attending to advisory board from Sanofi-Genzyme, Biogen-Idec, Novartis and TEVA. B. Colombo received travel grant from Biogen-Idec, Merck, Bayer, Genzyme. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis and Excemed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. M. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). F. Martinelli Boneschi has received compensation for activities with Teva Neuroscienze as speaker and/or advisor. G. Comi has received compensation for consulting services with the following companies: Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma and compensation for speaking activities from Novartis, Teva, Sanofi, Genzyme, Merk, Biogen, Excemed, Roche. V. Martinelli has received honoraria for consulting and speaking activities from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme.


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M. Romeo has received personal compensation for speaking activities from Genzyme and support for participation in International Congress from Merck. F. Clarelli: nothing to disclose. L. Ferre’: nothing to disclose. G. Sferruzza: nothing to disclose. M. Radaelli: nothing to disclose. F. Sangalli: nothing to disclose. M. Rodegher: nothing to disclose. This study is supported by the “Fondazione Italiana Sclerosi Multipla”, project 2013/R/13

P736 Utilizing brain volume loss as an additional predictor of longterm treatment outcomes: analysis of TEMSO MRI SIENA data M.P. Sormani1, J. Wuerfel2, K. Thangavelu3, N. De Stefano4 1University of Genoa, Genoa, Italy, 2Medical Image Analysis Center (MIAC AG), Basel, Switzerland, 3Sanofi Genzyme, Cambridge, MA, United States, 4University of Siena, Siena, Italy Background: Identifying predictors of treatment response is an important step in optimizing patient management in MS. Scoring systems have been used to predict long-term response to diseasemodifying therapies according to relapses and MRI lesions during early treatment. Brain volume loss (BVL) is correlated with disability worsening, and the predictive value of scoring systems may be enhanced by the addition of BVL measures. Teriflunomide has shown consistent slowing of both disability and BVL vs placebo. Objective(s): To predict probability of 12-week confirmed disability worsening in patients treated with teriflunomide in the TEMSO core (NCT00134563) and extension (NCT00803049) studies, using a scoring system based on relapses, new and enlarging T2 lesions, and a threshold for BVL. Methods: After 1 year of teriflunomide treatment, patients (n=501) were classified for risk of disease worsening according to relapse status (0 to ⩾2 relapses) and occurrence of new and enlarging T2 lesions (⩽ or >3). Patients with scores of 0, 1, or 2-3, were categorized as having a low, intermediate, or high risk of poor treatment response, respectively. Patients with a score of 1 were re-categorized according to percentage BVL obtained from SIENA (structural image evaluation using normalization of atrophy) in a blinded post hoc analysis of TEMSO: category 1a, ⩽−0.8; category 1b, >−0.8. Between-group comparisons were made using the log-rank test; risk reductions were based on a Cox proportional hazards model. Results: The majority of patients (>90%) were categorized as having low (n=329) or intermediate (n=125) risk of disability worsening after 1 year of treatment. Patients in the intermediate group were re-categorized as follows: low risk, 1a (BVL ⩽−0.8), n=90; high risk, 1b (BVL >−0.8), n=35. The probability of being free of disability worsening over 7 years in the TEMSO extension for patients in the low-risk groups (scores 0+1a) was significantly increased vs the high-risk groups (scores 1b+2-3); 68.5% (95% CI: 17%, 242%), P=0.0022. Over 7 years, >84% of patients receiving teriflunomide were at a low risk of disability worsening. Conclusions: Classification of patients based on relapses and lesion activity after 1 year of teriflunomide treatment predicted

the differential rate of long-term disability worsening. Additional predictive value was provided using BVL. Over 7 years, most patients receiving teriflunomide were at a low risk of disability worsening. Disclosure Study supported by Sanofi Genzyme. MPS: Consulting fees (Biogen, Genzyme, Merck Serono, Novartis, Roche, Synthon, Teva). JW: CEO of MIAC AG Basel, Switzerland; speaker honoraria (Bayer, Biogen, Novartis, Teva); advisory boards and research grants (Biogen, Novartis); supported by the German Ministry of Science (BMBF/KKNMS) and German Ministry of Economy (BMWi). KT: Employee of Sanofi Genzyme. ND: Consulting fees, speaking, travel support (Biogen Idec, Genzyme, Merck Serono, Novartis, Schering, Teva); advisory boards (Merck Serono, Novartis); research grant support (Italian MS Society). P737 Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis P. Kosa1, D. Ghazali1, M. Tanigawa1, C. Barbour2, I. Cortese3, W. Kelly1, B. Snyder1, J. Ohayon3, K. Fenton3, T. Lehky4, T. Wu5, M. Greenwood2, G. Nair3, B. Bielekova1 1Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 2Department of Mathematical Sciences, Montana State University, Bozeman, MT, 3Neuroimmunology Clinic, National Institute of Neurological Disorders and Stroke, 4EMG Section, National Institute of Neurological Disorders and Stroke, 5Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States Background: There are no effective treatments for progressive multiple sclerosis (MS). Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for therapeutic advancement in progressive MS. The purpose of this study was to compare 58 prospectively-acquired candidate outcomes in the real-world situation of progressive MS trials, to select and validate the best-performing outcome. Methods and findings: The one year pre-treatment period of adaptively-designed IPPoMS (NCT00950248) and RIVITaLISe (NCT01212094) Phase II trials serves to determine the primary outcome for the subsequent blinded treatment phase by comparing eight clinical, one electrophysiological, one optical coherence tomography, seven MRI volumetric, nine quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over one year (Δ) in the predetermined analysis of the IPPoMS trial and seven out of them have been validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratio (SNR) and recorded overlapping values between healthy volunteers (HV) and MS patients with moderate-severe disability.


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Poster Session 1, 22(S3) Therefore, using statistical modeling, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and nine hole peg test. CombiWISE outperformed all clinical scales (Δ=9.10%; p=0.0003) and detected yearly changes in all three longitudinal progressive MS cohorts with comparable sensitivity to the bestperforming MRI biomarkers. In contrast to MRI biomarkers, CombiWISE recorded no overlapping values between HV and disabled MS patients, had high SNR and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects with MS, other neurological disorders, and HV. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with standard error of 0.10. Conclusions: A novel validated clinical outcome CombiWISE has more than doubled sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale currently utilized for regulatory approval, EDSS. Disclosure Funding: Intramural Research Program of National Institute of Neurological Disorders and Stroke. Peter Kosa: nothing to disclose Danish Ghazali: nothing to disclose Makoto Tanigawa: nothing to disclose Irene Cortese: nothing to disclose William Kelley: nothing to disclose Blake Snyder: nothing to disclose Joan Ohayon: nothing to disclose Kaylan Fenton: nothing to disclose Tanya Lehky: nothing to disclose Tianxia Wu: nothing to disclose Chris Barbour: nothing to disclose Mark Greenwood: nothing to disclose Govind Nair: nothing to disclose Bibiana Bielekova: nothing to disclose P738 CD56 positivity of T cells as a candidate of a predictive biomarker for relapse of multiple sclerosis under fingolimod therapy C. Fujii1, T. Kondo2, H. Ochi3, Y. Okada2, Y. Hashi2, S. Matsumoto4, R. Takahashi2, M. Nakagawa1, T. Mizuno1 1Kyoto Prefectural University of Medicine, 2Kyoto University, Kyoto, 3Ehime University, Toon, 4Azuke Kofukai Foundation, Medical Research Institute, Osaka, Japan Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervoussystem (CNS). Fingolimod, one of the disease-modifying drugs for MS, prevents the egress of central memory T cells (TCM) expressing CCR7 from secondary lymphoidorgans into the circulation, resulting in the reduction of autoaggressive T cell infiltration into the CNS. Although the superior therapeutic efficacy of fingolimod supports the hypothesis that autoaggressive T cells are primarily CCR7+ TCM, relapses can occur even while on fingolimod, and relapsed lesions tend to be unusually tumefactive or severe. It remains unclear whether relapse is merely due to the remaining TCM in circulation or if

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other potential immunomechanisms are associated with relapse on fingolimod. Here, we analysed the T cell phenotypes of fingolimod-treated (n=16), fingolimod-untreated patients (n=20), and healthy subjects (n=10). The frequency of CCR7+ T cells was not associated with relapse on fingolimod in our study (14.0% in remission vs 11.6% at relapse under fingolimod therapy). We found that CD56+ T cells were significantly increased at the mean frequency of 10.8% in relapse-free fingolimod-treated patients compared with those in fingolimod-free patients and healthy subjects (approximately 2%) (p< 0.001, for each comparison). Moreover, there was a remarkable increase in CD56+ T cells to a mean value of 54.4% during relapse on fingolimod. The frequency of CD56 expression increased both in CCR7+ T cells (26.2%), as well as CCR7- T cells (9.18%) in these fingolimod-treated patients. T cells under fingolimod therapy showed increased frequencies of granzyme B- (59.2%), perforin- (17.3%), and Fas ligand- (3.3%) positive cells and exhibited a biased production of interferon (IFN)-γ (27.4%) upon stimulation. Moreover, the frequency of IFN-γ-producing T cells reactive to myelin basic protein was significantly higher in CD56+ T cells compared with CD56- T cells (5.71% vs 3.39%, p=0.0082). Collectively, fingolimod-treated MS patients have altered immunological features, which are more enhanced during relapse. Of clinical importance, it needs to be tested whether T cell CD56 positivity is a biomarker for relapses while on fingolimod. Disclosure The authors have no competing financial interests. P739 Validation of an algorithm to detect severe MS relapses in administrative health databases J.J. Marriott1, R.A. Marrie1,2, H. Chen3, R. Fransoo2,3 1Department of Medicine, Section of Neurology, 2Department of Community Health Sciences, University of Manitoba, 3Manitoba Centre for Health Policy, Winnipeg, MB, Canada Background: Severe relapses (those requiring treatment) were important outcomes in the sentinel trials of disease-modifying therapy (DMTs). Identifying such relapses in administrative data would allow comparative-effectiveness studies of DMTs in realworld clinical settings. Methods: All relapsing-remitting multiple sclerosis (RRMS) patients living in Manitoba between 1999-2014 were identified using a validated case definition and crosslinking to the Manitoba MS clinic database. All health-care interactions potentially due to relapse were extracted from province-wide hospital, physicianclaims and drug dispensation databases. These “relapse markers” included varying thresholds of outpatient prednisone scripts, dayhospital or emergency room (ER) codes for intravenous (IV) methylprednisolone therapy, family physician, neurologist or ER physician billing codes and hospital admissions due to MS. Algorithms using combinations of these markers were compared with a gold standard list of MS neurologist-defined relapses. The analyses were repeated limiting the timeframe to 2009-2014; representing a period when relapse treatment shifted to predominant use of outpatient high-dose oral prednisone. Results: 1224 RRMS patients (72% female) were found from 1999-2014 and 312 (73% female) from 2009-2014. Analysis of


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the 1999-2014 cohort was limited by inconsistent coding of sameday admissions for IV methylprednisolone. 208 relapses, of which 101 had documented treatment, were found in an unselected sample of MS Clinic patients from 2009-2014. After eliminating relapse markers with low sensitivity/specificity, 40 algorithms were tested. Of these, the best match to MS clinic-documented severe relapses consisted of outpatient oral prednisone prescriptions >50mg/day for between 3-30 days and same-day hospital or ER assessment codes with MS as the most responsible diagnosis (sensitivity 53%, specificity 94%, positive predictive value 93%, negative predictive value 55%, kappa 0.41). Conclusions: Severe relapses can be abstracted from administrative datasets with a reasonable accuracy. The trend since 2009 towards outpatient relapse treatment will improve the sensitivity of relapse detection with longitudinal follow-up of this cohort and will allow comparison of severe relapse rates between different DMTs. In conjunction with planned analyses of health resource utilization, this will enable comparison of the effectiveness and health resource costs of standard and emerging DMTs. Disclosure J.J. Marriott: Study was supported by a grant from the Multiple Sclerosis Society of Canada, has also received research support from Research Manitoba, Multiple Sclerosis Scientific Foundation, Consortium of MS Centers and Manitoba Medical Service Foundation and for MS trials from Biogen Idec, Roche, SanofiAventis and honoraria from Biogen Idec, Roche, and EMD Serono. R.A. Marrie: receives research funding from Canadian Institutes of Health Research, Public Health Agency of Canada, Research Manitoba, Health Sciences Centre Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, and National Multiple Sclerosis Society, and has conducted clinical trials funded by sanofi-aventis. Hui Chen: nothing to disclose. Randall Fransoo: nothing to disclose. P740 Optical coherence tomography detects significant retinal atrophy in progressive MS which is modulated by disease modifying therapies S. Saidha1, J. Button1, E. Martinez-Lapiscina2, R. Nolan3, A. Brandt4, D. Conger5, A. Conger5, E. Frohman5, T. Frohman5, L. Balcer3, F. Paul4, P. Villoslada2,6, P.A. Calabresi1, IMSVISUAL Consortium 1Neurology, Johns Hopkins University, Baltimore, MD, United States, 2Neurology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Bareclona, Spain, 3Neurology, New York University Langone Medical Center, New York, NY, United States, 4Neurology, Charite - Universitätsmedizin Berlin, Berlin, Germany, 5Neurology, UT Southwestern Medical Center, Dallas, TX, 6Neurology, UCSF, San Francisco, CA, United States Background: Optical coherence tomography (OCT) derived estimates of retinal nerve fibre layer (RNFL) and composite ganglion cell+inner plexiform layer (GCIP) thicknesses have been proposed as reliable, objective outcomes for assessing neurodegeneration in MS. These measures correlate with and predict MS disability scores. GCIP thinning also mirrors brain atrophy over time in MS. However, there has been a paucity of OCT study in

progressive MS (PMS), in which accurate outcome assessments are lacking. It is unknown whether disease modifying therapies (DMTs) similarly impact rates of retinal atrophy in PMS, as in relapsing MS, or whether secondary (SPMS) and primary PMS (PPMS) patients have similar rates of retinal layer atrophy. Goals:To retrospectively determine whether there are differences in rates of retinal layer atrophy between (1) PMS and healthy controls (HCs) (2) PMS patients treated vs. untreated with DMTs and (3) SPMS and PPMS patients, in an international, multicenter study. Methods: 151 PMS patients (PPMS:47, SPMS:104) and 47 HCs who underwent longitudinal spectral-domain OCT at four sites were included. Automated macular segmentation was utilised to compute GCIP thicknesses from Cirrus HD-OCT scans. Conventional segmentation software on Cirrus HD-OCT and Spectralis OCT were used to generate RNFL thicknesses. Retinal layer thickness changes were analysed using mixed-effects linear regression. Results: At baseline there were no differences in age, sex, or mean OCT follow-up duration (3.2 years) between the SPMS or PPMS cohorts. Excluding eyes with optic neuritis history (38% of SPMS vs. 0% of PPMS patients, p< 0.001), baseline RNFL and GCIP thicknesses were not different between SPMS and PPMS. Adjusting for age, sex, disease duration, and baseline retinal layer thickness, SPMS and PPMS patients did not differ in their rates of RNFL and GCIP thinning during follow-up (p=0.430 & p=0.467 respectively). RNFL thinning in PMS was 0.37um/year faster than in HCs (-0.58 vs. -0.21um/year respectively, p=0.03). GCIP thinning in PMS patients treated (-0.12um/year) vs. untreated (-0.52um/year) with DMTs was 0.40µm/year slower (p=0.02). Conclusions: Rates of retinal layer atrophy do not differ between SPMS and PPMS, suggesting their grouping into a single PMS cohort is feasible in OCT studies. Our findings suggest rates of retinal atrophy in PMS are faster than in HCs and may be reduced by DMTs, indicating a utility for OCT outcome measures in PMS trials. Disclosure Shiv Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, Educational Grant Support from Novartis & Teva Neurosciences, speaking honoraria from the National Association of Managed Care Physicians, Advanced Studies in Medicine and the Family Medicine Foundation of West Virginia, and served on scientific advisory boards for BiogenIdec, Genzyme & Novartis. He is a researcher in the OCTIMS study. He receives research funding from the Race to Erase MS and Genentech Corporation. Julia Button has no disclosures Elena H Martinez-Lapiscina is a researcher in the OCTIMS study, an observational study for validating OCT as a biomarker for MS sponsored by Novartis (this study does not involve any specific therapies). Rachel Nolan has no disclosures Alexander U. Brandt is a founder and holds stock options in Motognosis; and is named as co-inventor on several patent applications unrelated to this study. He has received research grants, speaker honoraria or consulting fees from Biogen, Teva, Novartis and Bayer. He is a researcher in the OCTIMS study.


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Poster Session 1, 22(S3) Darrel Conger has no disclosures Amy Conger has no disclosures Elliot Frohman has received speaker and consulting fees from Novartis, Genzyme, Acorda and TEVA. Teresa Frohman has received speaker and consulting fees from Novartis, Genzyme and Acorda. Laura Balcer has received consulting fees from Biogen and Genzyme and has received research funding from Biogen. Friedemann Paul has received research grants and personal compensation for activities with Alexion, Bayer, Chugai, Novartis, Merck, Teva, Sanofi, Genzyme, Biogen, MedImmune. He is a researcher in the OCTIMS study sponsored by Novartis and serves on the steering committee and his research group serves as reading center for the PASSOS study sponsored by Novartis. FP serves as a principal investigator for a German OCT study sponsored by Biogen. Pablo Villoslada has received consultancy fees from Heidelberg Engineering regarding the clinical applications of OCT. He serves as academic editor of Current Treatment Options in Neurology, Neurology & Therapy, Multiple Sclerosis & Demyelinating Disorders, PloSONE and MS in focus. He is founder and hold stocks in Bionure Inc and Spire Bioventures Inc. He has received consultancy fees from Roche, Novartis, Health Engineering and stock options from Mint-Labs. He has received unrestricted grants from Genzyme, Roche and Novartis. He is a researcher in the OCTIMS study. Peter A Calabresi has received consulting fees from Vertex, Abbvie, and Merck and has received research funding from Biogen, Novartis and MedImmune. He is co-chairman of the scientific advisory board of the OCTIMS study. P741 Apheresis therapy in multiple sclerosis patients with histopathologically classified immunopathological patterns L. Stork1, D. Ellenberger2, T. Beißbarth2, T. Friede2, C. Lucchinetti3, W. Brück1, I. Metz1 1Institute of Neuropathology, 2Institute of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany, 3Department of Neurology, Mayo Clinic, Rochester, MN, United States Apheresis therapies include plasma exchange (PLEX) and immunoadsorption (IA), second line therapies to treat steroid unresponsive multiple sclerosis (MS) relapses that show a comparable response rate of 40 - 90%. Early active MS lesions can be classified into three main, intraindividually stable immunopathological patterns of demyelination (IP I-III), which suggests pathogenic heterogeneity and may also predict therapy response to PLEX/IA. A prior study of 19 patients showed that patients with an IP II, characterized by immunoglobulin and complement deposition, responded to PLEX treatment in contrast to patients with IPs I and III who had no treatment effects. We aimed to evaluate the PLEX/IA response for MS relapses in relation to histopathologically defined IPs in a larger cohort of 69 patients. For this we retrospectively analyzed the efficacy of PLEX/IA in patients with early active demyelinating MS lesions classified into IPs I-III, diagnosed in brain biopsies taken for differential diagnostic purposes. Primary outcome was a functional improvement of the neurological deficit occurring with the relapse. MRI and

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expanded disability status scale (EDSS) changes were used as secondary outcome parameters. Clinical records of 69 patients (IP I - 16, IP II - 40, IP III - 13) were assessed. The highest response rate to PLEX/IA was 55% (22/40 patients) observed among IP II patients compared to no improvement found in patients with IP III (0/13; p< 0.001). However, one third of IP I patients also benefited from therapy (5/16 patients, IP I vs IP III p=0.03). Radiological assessment showed a decreasing lesion size or less contrast enhancement in 56% of patients with an IP II, 25% with an IP I and 11% with an IP III. Responders showed a reduction in the mean EDSS one month after PLEX/IA of 1.0 in IP II and of 0.7 in IP I patients. Brain stem involvement was found to be a negative predictive factor for therapy response. The highest predicted probability of clinical improvement after PLEX/IA was thus found in patients with an IP II who had no brainstem involvement (78%). In conclusion, we confirmed that the therapy response to apheresis treatment is related to histopathologically defined IPs. Importantly, patients with both patterns I and II improved clinically after apheresis treatment; however, those patients with signs of a humoral immune response profited most from therapy. No clinical improvement was observed in patients with an IP III. Disclosure L. Stork: nothing to disclose D. Ellenberger: nothing to disclose T. Beißbarth: nothing to disclose T. Friede reports personal fees for consultance (including DMCs) from Novartis, Biogen, AstraZeneca, Bayer, Janssen, SGS, and Pharmalog outside the submitted work. C. Lucchinetti reports grants from Biogen, Sanofi, Novartis, NMSS outside the submitted work. W. Brück has received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. Dr Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders. I. Metz reports grants from German Ministry for Education and Research (BMBF “German Competence Network Multiple Sclerosis (KKNMS), Pattern MS/NMO), grants from BiogenIdec as well as personal fees from BiogenIdec, Bayer Healthcare, TEVA, Serono and Novartis outside the submitted work.

Treatment of progressive MS P742 Anti-inflammatory disease modifying treatment does not attenuate disability progression in secondary progressive multiple sclerosis J. Lorscheider1,2, V. Jokubaitis1,2, T. Spelman1, G. Izquierdo3, A. Lugaresi4, E. Havrdova5, D. Horakova5, M. Trojano6, P. Duquette7, M. Girard7, A. Prat7, F. Grand’Maison8, R. Hupperts9, P. Grammond10, E. Pucci11, C. Boz12, P. Sola13, D. Spitaleri14, J. Lechner-Scott15,16, M. Terzi17, V. Van Pesch18, G. Iuliano19, R. Bergamaschi20, R. Fernández Bolaños21,


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C. Ramo-Tello22, F. Granella23, M.E. Rio24, C. Oreja-Guevara25, H. Butzkueven1,2,26, T. Kalincik1,2, MSBase Study Group 1Department of Medicine, University of Melbourne, 2Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia, 3Hospital Universitario Virgen Macarena, Seville, Spain, 4Department of Biochemistry and Neuromotor Sciences, University of Bologna, Bologna, Italy, 5Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 6Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari, Bari, Italy, 7Hôpital Notre Dame, Montreal, 8Neuro RiveSud, Hôpital Charles LeMoyne, Greenfield Park, QC, Canada, 9Orbis Medical Center, Sittard, The Netherlands, 10Hôtel-Dieu de Lévis, Lévis, QC, Canada, 11Neurology Unit, ASUR Marche, AV3, Macerata, Italy, 12Karadeniz Technical University, Trabzon, Turkey, 13Nuovo Ospedale Civile Sant’Agostino/ Estense, Modena, 14AORN San Giuseppe Moscati, Avellino, Italy, 15Department of Neurology, John Hunter Hospital, 16School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia, 17Medical Faculty, Mayis University, Samsun, Turkey, 18Cliniques Universitaires Saint-Luc, Brussels, Belgium, 19Ospedali Riuniti di Salerno, Salerno, 20Mondino National Neurological Institute of Pavia, Pavia, Italy, 21Hospital Universitario Virgen de Valme, Seville, 22Hospital Germans Trias i Pujol, Badalona, Spain, 23University of Parma, Parma, Italy, 24Hospital São João, Porto, Portugal, 25University Hospital San Carlos, Madrid, Spain, 26Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia Background: To date, there is little evidence from randomized controlled trials to suggest that immunomodulatory or immunosuppressive agents ameliorate disability progression in patients with secondary progressive multiple sclerosis (SPMS). Nevertheless, such drugs are used to treat this condition in clinical practice. Objective: Our aim was to investigate a potential effect of antiinflammatory disease modifying treatment on disability outcomes in SPMS. Methods: Using MSBase, a large, international, observational, prospectively acquired cohort study, we identified patients that were either untreated or treated with one of the following drugs at the time of diagnosis of SPMS: Interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, mitoxantrone, or rituximab. Quasi-randomization with propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses, adjusted for time on treatment, visit density and observed annualized relapse rates. Results: Of the 2381 included patients, 1378 patients were matched (treated, n=689; untreated n=689). Median on-study pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8). No difference in the risk of experiencing 6-month sustained disability progression events was observed between the groups (HR [hazard ratio] 0.9, 95%CI [confidence interval] 0.7-1.1, p=0.27). We also did not find significant differences in any of the secondary endpoints: Risk of reaching a confirmed Expanded Disability Status Scale (EDSS) ⩾7 (HR 0.6, 95%CI 0.4-1.1, p=0.10), sustained disability regression (HR 1.0, 95%CI 0.8-1.3, p=0.79), or change in cumulative disability burden (quantified as area under the disability-time curve, β=-0.05 EDSS-years, p=0.09). Secondary and sensitivity analyses confirmed the results of the primary analysis.

Conclusion: Our study suggests that anti-inflammatory disease modifying treatment has no substantial effect on relapse-independent disability progression in SPMS without a distinct inflammatory phenotype. Disclosure Johannes Lorscheider has accepted conference travel support from Novartis and has received research support from Biogen. Vilija Jokubaitis has received conference travel support from Merck, Novartis and honoraria from Novartis and Biogen. Tim Spelman received compensation for travel from Biogen Idec. Guillermo Izquierdo received speaking honoraria from BiogenIdec, Novartis, Sanofi, Merck Serono and Teva. Alessandra Lugaresi is a Bayer Schering, Biogen Idec, Genzyme, Merck Serono Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva, and Associazione Italiana Sclerosi Multipla and her institution received research grants from Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi, Teva, and Fondazione Italiana Sclerosi Multipla. Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck, Novartis, Genzyme and Teva, as well as support for research activities from the Czech Ministries of Education and Health (NT13237-4/2012, PRVOUK-P26/LF1/4) and Biogen Idec and Merck Serono. Dana Horakova received speaker honoraria and consulting fees from Biogen Idec, Merck Teva, Genzyme, and Novartis, as well as support for research activities from the Czech Ministries of Education and Health (NT13237-4/2012, PRVOUK-P26/LF1/4) and Biogen Idec. Maria Troiano received speaking honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva and Novartis; has received research grants from Biogen-Idec, MerckSerono, and Novartis. Pierre Duquette has served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen-Idec, Novartis, Genzyme, and TEVA Neuroscience. Dr Duquette holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen-Idec, Novartis, and Genzyme. Marc Girard: nothing to disclose. Alexandre Prat: nothing to disclose. François Grand´Maison received honoraria or research funding from Biogen Idec, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. Raymond Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen-Idec, GenzymeSanofi and Teva, research funding from Merck-Serono and Biogen-Idec, and speaker honoraria from Sanofi-Genzyme and Novartis. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen Idec and Genzyme advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Eugenio Pucci served on scientific advisory boards for Genzyme, Merck-Serono and Biogen-Idec; he received honoraria and/or congress and travel/accommodation expense compensations from


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Poster Session 1, 22(S3) Sanofi Aventis, Novartis, Biogen-Idec, Merck-Serono, Genzyme, Teva and Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Cavit Boz received conference travel support from Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Patrizia Sola: nothing to disclose did not declare any competing interests. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono. Jeanette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Vincent van Pesch has served on advisory boards for Biogen Idec, Novartis Pharma and Sanofi-Genzyme; has received travel grants and consultancy fees from Biogen Idec, Bayer Schering, Sanofi Aventis, Merck Serono, Sanofi-Genzyme and Novartis Pharma; has received research grants from Bayer Schering. Gerardo Iuliano. had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva. Robert Bergamaschi has served on scientific advisory boards for Biogen Idec and Almirall; has received funding for travel and speaker honoraria from Sanofi-Aventis, Genzyme, Biogen Idec , Bayer Schering, Teva Neurosciences, Merck Serono, Almirall, and Novartis; received research support from Merck Serono, Biogen Idec, Teva Neurosciences, Bayer Schering, Novartis, Sanofi-Aventis. Ricardo Fernandez Bolanos received speaking honoraria from Biogen-Idec, Novartis, Merck Serono and Teva. Cristina Ramo-Tello received research funding, consulting/ advisory fees or compensation for travel from Biogen-Idec, Novartis, Genzyme and Almirall. Franco Granella: nothing to disclose. Maria Edite Rio: nothing to disclose. Celia Oreja-Guevara received honoraria as consultant on scientific advisory boards from Biogen-Idec, Bayer-Schering, Merck-Serono, Teva and Novartis; has participated in clinical trials/other research projects by Biogen-Idec, GSK, Teva and Novartis. Helmut Butzkueven has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen Idec and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen Idec and Novartis, and has received research support from Merck Serono, Novartis and Biogen Idec. Tomas Kalincik has served on an advisory scientific board for Novartis, Merck-Serono and Biogen, has received conference travel support and speaker honoraria from Novartis, Biogen, Sanofi Aventis, Genzyme, Teva, BioCSL and Merck Serono and has received research support from Biogen.

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P743 Access and use of clinical services and disease modifying therapies by people with progressive multiple sclerosis in the UK E. Campbell1, E. Coulter1, P.G. Mattison2, L. Miller2,3, A. McFadyen4, L. Paul1 1School of Medicine, The University of Glasgow, Glasgow, 2Multiple Sclerosis Service, NHS Ayrshire & Arran, Irvine, 3School of Health and Life Sciences, Glasgow Caledonian University, 4AKM-Stats, Glasgow, United Kingdom Introduction: Current National Institute for Health and Care Excellence guidelines state that people with Multiple Sclerosis (MS) should have access to an MS specialist service. In addition, the Progressive MS Alliance has highlighted rehabilitation of people with progressive MS as a priority research area. To date, however, there has been no investigation into the level of access and use of clinical services by people with progressive MS. Objective: To investigate access and use of clinical services and Disease Modifying Therapies (DMTs) by people with progressive MS in the United Kingdom and to make comparisons between Primary Progressive MS (PPMS) and Secondary Progressive MS (SPMS). Methods: People with PPMS and SPMS were recruited via the UK MS register and answered an online survey between August and September 2015. Participants were asked about access and use of MS specialist and clinical services, historic and current DMT use. Demographics, Multiple Sclerosis Impact Scale (MSIS29), and EQ-5D health questionnaire were supplied from routinely collected data on the UK MS register. Results: 1298 people with progressive MS responded [mean age 59±8 years, mean Time Since Diagnosis (TSD) 16±9 years]. 37% had PPMS (n=486) and 63% SPMS (n=812). Mean EQ-5D index was 0.49±0.2 and MSIS-29 physical and psychological sub-scores were 56±12 and 20±6 respectively. 82% reported having access to an MS specialist service. Most commonly accessed services were MS specialist Doctor/Nurse (50%), General Practitioner (45%) and Physiotherapist (32%). 5% were currently taking DMTs (PPMS=20%, SPMS=80%) and 24% had previously taken DMTs (PPMS=12%, SPMS=88%). There were statistically significant associations (p< 0.01) between access to MS specialist services and current use of DMTs (X2=6.97) and to historic DMT use (X2=9.32). Those with PPMS had a statistically significant higher EQ-5D index than those with SPMS (0.57 and 0.50 respectively) and lower MSIS-29 physical (55 and 58) and psychological sub-scores (19 and 20) but also had a shorter TSD (9 and 18 years) (all p< 0.01). Conclusion: This was one of the largest studies to date investigating service access by people with progressive MS. This study has found that access and use of clinical services is high in the United Kingdom and access is associated with DMT use. In the sample those with PPMS had a shorter TSD, better quality of life and lower MSIS-29 scores than those with SPMS. Disclosure Evan Campbell: nothing to disclose. Lorna Paul: nothing to disclose. Elaine Coulter: nothing to disclose.


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Angus K McFadyen: nothing to disclose. Linda Renfrew: nothing to disclose. Paul Mattison: nothing to disclose. P744 Progressive multiple sclerosis: effectiveness of a medical education activity in improving the knowledge of novel approaches to treatment T. Finnegan1, G. Giovannoni2 1Medscape Education, New York, NY, United States, 2Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom Introduction: Although the relapse refractory form of multiple sclerosis (MS) is the most common form of the disease, those with progressive forms represent the bigger management challenge due to lack of effective therapies. It is therefore important that clinicians are aware of all investigational therapies or strategies with evidence of efficacy in progressive disease. A study was undertaken to evaluate the effectiveness of an online educational intervention developed with the goal of improving neurologists’ knowledge of new and emerging approaches to the management of progressive forms of MS. Methods: The online continuing medical education (CME) activity format consisted of a 30-minute video panel discussion with three expert faculty on the management of progressive forms of MS. Educational effect was assessed by comparing a matched sample of neurologists’ responses to four identical questions presented before and directly after exposure to the intervention. A chi-square test was used to identify significant differences between pre- and post-assessment responses. P values were calculated and those < 0.05 were considered statistically significant. Cramer’s V was used to calculate the effect size of the online education. Data from the participants in the educational intervention who answered all pre- and post-assessment questions were collected between June 24, 2015 and September 2, 2015. Results: Participation in the CME intervention improved knowledge as indicated by the large educational effect size (n = 116; V=0.424; P < 0.05). As a result of their participation in this educational intervention, significant overall improvements were observed pre- vs post-participation in several specific areas, including knowledge of clinical trial outcomes for biotin in progressive MS (82% relative improvement; P < 0.05), the molecular target of ocrelizumab (102% relative improvement; P < 0.05), the therapeutic agent that preserved retinal nerve fibers in optic neuritis (168% relative improvement; P < 0.05), and the efficacy of fingolimod in primary progressive MS (107% relative improvement; P < 0.05). Conclusions: The results indicated that the intervention was effective at improving knowledge of emerging therapies for the treatment of progressive MS. Due to the high level of relative improvement following participation in the intervention, future education should continue to focus on emerging therapeutic approaches to the management of progressive forms of MS. Disclosure The intervention and outcomes analysis was supported by the unrestricted educational grant from Biogen. Thomas Finnegan: Nothing to disclose

Gavin Giovannoni has received funding from AbbVie Inc., Biogen Idec Inc., Canbrex Corporation, EMD Serono, Inc., FivePrime Therapeutics, Genzyme Corporation, Novartis Pharmaceuticals Corporation; Roche; Sanofi, Synthon BV and Teva Pharmaceuticals Industries Ltd. P745 Fear of falling and participation following the use of functional electrical stimulation for the lower limb in people with multiple sclerosis T. Street1, I. Swain2,3, P. Taylor3,4 1Clinical Science and Engineering, Salisbury NHS Foundation Trust, Salisbury, 2Bournemouth University, Bournemouth, 3Odstock Medical Ltd, 4Salisbury NHS Foundation Trust, Salisbury, United Kingdom Background: A fear of falling may be detrimental to people participating in activities due to a reduced confidence, however, fear of falling may also act as a protective factor. Previous research has found a correlation between history of falling, static postural control and fear of falling using the Falls Efficacy Scale International (FES-I)1. A fear of falling increases the risk of falling due to anxiety on attentional processes and “stiffening strategies”.2 FES has been found to reduce the frequency of falls.3 So if individuals have a reduced falls risk this may reduce fear of falling and increase participation. FES may also enable greater participation through faster walking speeds and being able to walk further. The aim of the study was to examine whether FES leads to a reduction in fear of falling and increase in participation. Methodology: 48 people with multiple sclerosis (41 female, 7 male, mean age 54 years, age range: 40-70 years) and drop foot. The FES-I was completed at baseline and after 20 weeks. A further questionnaire which was adapted to examine participation in the areas identified in the FES-I was also included. Results: The results revealed a significant difference (Z = 5.09, p< 0.001) between fear of falling prior to using FES and after using FES for 20 weeks (md=8, IQR=2.75-14). The item with the largest change was “walking around the neighbourhood” followed by “visiting a friend”. A significant difference (Z = 3.98, p< 0.001) was also found between participation prior to using FES and after using FES (md=5, 1-9.25). The item which acquired the largest difference in participation was “cleaning the house”, followed by “answering the telephone before it stops ringing”. Conclusions: The results suggest that FES for the lower limb enables people to reduce their fear of falling and increase their levels of participation. Disclosure Tamsyn Street: has received a grant from the Salisbury Charitable Trust to complete this work. Paul Taylor: holds shares in OML, the manufacture of the device used in this study. Ian Swain: Ian Swain is Professor of Clinical Engineering at Bournemouth University and is also Clinical Director and a shareholder in Odstock Medical Limited who manufacture the equipment and provide the clinical treatment that is the subject of this research.


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Poster Session 1, 22(S3) P746 An exploratory analysis of 12- and 24-week composite confirmed disability progression in patients with primary progressive multiple sclerosis in the ORATORIO trial G. Giovannoni1, D.L. Arnold2,3, A. Bar-Or2, J. De Sèze4, B. Hemmer5,6, X. Montalban7, K.W. Rammohan8, S. Belachew9, C. Bernasconi9, P. Chin10, H. Garren9, D. Masterman10, A. Sauter9, W. Wei9, J. Wolinsky11, on behalf of the ORATORIO Clinical Investigators 1Queen Mary University of London, London, United Kingdom, 2McGill University, 3NeuroRx Research, Montreal, QC, Canada, 4University Hospital of Strasbourg, Strasbourg, France, 5Technische Universität München, 6Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 7Hospital Vall d’Hebron University, Barcelona, Spain, 8University of Miami, Miami, FL, United States, 9F. Hoffmann-La Roche Ltd., Basel, Switzerland, 10Genentech, Inc., South San Francisco, CA, 11University of Texas Health Science Center at Houston, Houston, TX, United States Background: Data from Phase III trials suggest that selective B-cell targeting may be a potential therapeutic approach in relapsing and primary progressive multiple sclerosis (PPMS). Ocrelizumab (OCR), a humanised monoclonal antibody that selectively targets CD20+ B cells, has shown superior efficacy compared with placebo (PBO) in the Phase III ORATORIO study in patients with PPMS, in which the primary endpoint was 12-week confirmed disability progression (CDP). To address limitations in using the Expanded Disability Status Scale to define clinical disability progression, a composite measure of CDP (cCDP), which also includes measures of upper extremity function and ambulation speed, was used to assess the effect of OCR in patients with PPMS. Objective: To assess the effect of OCR on 12- and 24-week cCDP in patients with PPMS. Methods: Patients were randomised (2:1) to receive OCR 600mg as two 300mg intravenous infusions 14 days apart or matching PBO every 24 weeks for ⩾120 weeks until an overall prespecified number of CDP events occurred. cCDP was defined as time to first onset of either CDP, ⩾20% worsening on the timed 25-foot walk (T25FW) test or ⩾20% worsening on the 9-hole peg test (9HPT) sustained for ⩾12 or ⩾24 weeks. In this exploratory analysis of 12- and 24-week cCDP among the ORATORIO intentionto-treat population, 244 PBO- and 488 OCR-treated patients were evaluable. Results: Compared with PBO, OCR significantly reduced the risk of 12- and 24-week CDP by 24% (hazard ratio [HR] [95% confidence interval (CI)]: 0.76 [0.59-0.98]; p=0.0321) and 25% (HR [95% CI]: 0.75 [0.58-0.98]; p=0.0365), respectively. OCR vs PBO reduced the risk of 12- and 24-week cCDP by 26% (HR [95% CI]: 0.74 [0.61-0.89]; p=0.0014) and 29% (HR [95% CI]: 0.71 [0.58-0.87]; p=0.0008), respectively. Compared with PBO, OCR also consistently and significantly reduced the risk of 12and 24-week confirmed ⩾20% worsening on T25FW by 25% (HR [95% CI]: 0.75 [0.61-0.92]; p=0.0053) and 27% (HR [95% CI]: 0.73 [0.59-0.91]; p=0.0055), respectively, and the risk of 12and 24-week confirmed ⩾20% worsening on 9HPT by 44% (HR [95% CI]: 0.56 [0.41-0.78]; p=0.0004) and 45% (HR [95% CI]: 0.55 [0.38-0.77]; p=0.0006), respectively. Conclusions: In ORATORIO, OCR treatment showed consistent benefit on disability progression, ambulation and upper limb

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function, as demonstrated by significant reduction in the risk of cCDP in patients with PPMS. Sponsored by F. Hoffmann-La Roche Ltd. Disclosure Gavin Giovannoni has received honoraria from AbbVie, Bayer HealthCare, Biogen, Canbex Therapeutics, Five Prime Therapeutics, Genzyme, GSK, GW Pharma, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, F. Hoffmann-La Roche Ltd., Synthon, Teva Neuroscience, UCB and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz and Novartis; and compensation from Elsevier. Douglas L. Arnold reports equity interest in NeuroRx Research, which performed the MRI analysis for the trial, and consultation fees from Acorda Therapeutics, Biogen, Genzyme, F. Hoffmann-La Roche Ltd., Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi, and Teva. Amit Bar-Or has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Genentech, Biogen Idec, GlaxoSmithKline, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Ono Pharma, Receptos, Sanofi-Genzyme, and GuthyJackson/GGF; he has also received research support from Novartis and Sanofi-Genzyme. Jérôme de Seze has received consultancy fees and served as an expert for advisory boards for Alexion, Allergan, Almiral, Bayer, Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd., Genzyme, LFB, Merck, Novartis, and Teva. Bernhard Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Novartis, Bayer Schering and Genentech; has received speaker honoraria from Biogen Idec and F. Hoffmann-La Roche Ltd.; has received research support from Chugai Pharmaceuticals; holds part of a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralising antibodies to interferon-beta. Xavier Montalban has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, F. Hoffmann-La Roche Ltd., Sanofi, Teva and Trophos. Kottil W. Rammohan has received honoraria for participating in advisory boards and consulting for Acorda, Biogen, EMD Serono, Genentech, Inc./F. Hoffmann-La Roche Ltd., Genzyme and Teva; he has also received grants from Accera, Novartis and the United States Department of Defense. Shibeshih Belachew is an employee and shareholder of F. Hoffmann-La Roche Ltd. Corrado Bernasconi is contractor of F. Hoffmann-La Roche Ltd. Peter Chin is an employee and/or shareholder of Genentech, Inc. Hideki Garren is an employee and shareholder of F. Hoffmann-La Roche Ltd. Donna Masterman is an employee and/or shareholder of Genentech, Inc. Annette Sauter is an employee and shareholder of F. Hoffmann-La Roche Ltd. Wei Wei is an employee and shareholder of F. Hoffmann-La Roche Ltd. Jerry Wolinsky has received compensation for service on steering committees or data monitoring boards for F. Hoffmann-La


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Roche Ltd., MedDay Pharmaceuticals, Novartis, Sanofi/Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, EMD Serono, F. Hoffmann-La Roche Ltd., Forward Pharma, Genentech, Inc., Novartis, Sanofi/Genzyme, Takeda, Teva, and XenoPort; research support from Sanofi/ Genzyme, the United States National Institutes of Health and the US National Multiple Sclerosis Society through The University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH. P747 Biotin in multiple sclerosis in real world: a cohort of 50 patients A. Fromont1, G. Romain2, A.L. Vialatte1, L. Maugest1, D. Audry1, T. Moreau1 1Neurology, 2Epidemiology, University Hospital of Dijon, Dijon, France Background: Biotin is vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis and could promote remyelination. One double blind placebo controlled trial showed improvement in a significant proportion of patients with progressive multiple sclerosis (MS). Biotin is available in France in temporary use since July 2015. Objective: To study baseline characteristics and follow up of patients treated with Biotin in Dijon (Burgundy). Method: We studied all progressive MS treated with biotin included in EDMUS database. EDMUS is used in Dijon since 2000 and includes patients from burgundy MS center. We calculated number of primary progressive (PP) or secondary progressive (SP) form of MS, mean age and EDSS at biotin initiation, proportion of patients for which biotin was used as add on therapy, number of adverse events mean, Clinical Global Impression (CGI) Scale assessed by patient.. Results: 50 patients were treated with biotin, 38 (63% women) had SPMS and 12 (42% women) PPMS. The mean age at MS onset was 30.18 and 42.83 years respectively. Mean age at biotin initiation was 54.79 years with mean EDSS at 7.0 for SPMS; 59.5 years and 6.5 for PPMS. The mean duration of treatment was 57 days. 13 patients had biotin as add on therapy among SPMS (11 immunosupressor 2 immunomodulator) and 1 for PPMS (1 immunosuppressor). Four patients with SPMS reported adverse events (skin rash, hyperpilosity, diarrhea, false hyperthyroidism) and 1 patient with PPMS (constipation). No neurological worsening was noticed for all patients with mean CGI at 4. Conclusions: Biotin is well tolerated. The false hyperthyroidism corresponds to biological abnormality due to biotin-streptavidin based hormonal dosage. Disclosure The authors have nothing to disclose P748 Safety and tolerability of ALKS 8700 in relapsing-remitting multiple sclerosis: Phase 3 open-label study design (EVOLVE-MS-1) R.T. Naismith1, A.E. Claxton2, R.A. Leigh-Pemberton2, Y. Du2, M.L. Hard2, L. von Moltke2, J.S. Wolinsky3

1Washington

University School of Medicine, St. Louis, MO, Inc., Waltham, MA, 3University of Texas Health Science Center at Houston Medical School, Houston, TX, United States 2Alkermes,

Background: ALKS 8700 is being developed as an oral diseasemodifying treatment for relapsing forms of multiple sclerosis (MS). ALKS 8700 is an aminoethyl ester of monomethyl fumarate (MMF), which is rapidly converted presystemically to MMF. MMF is the active metabolite of dimethyl fumarate (DMF), approved as an oral treatment for relapsing forms of MS. Oral DMF was approved based on compelling Phase 3 efficacy data including robust reductions in annualized relapse rates compared with placebo. However, gastrointestinal adverse events (AEs) were frequently reported and were the leading cause of study discontinuation due to AEs, negatively impacting the tolerability profile of DMF. ALKS 8700 was designed to effectively treat relapsing forms of MS in a manner similar to DMF but with improved gastrointestinal tolerability. This study evaluates the long-term safety and tolerability of ALKS 8700 in patients with relapsing-remitting MS (RRMS). Methods: This global, prospective, interventional, open-label, Phase 3 study (EVOLVE-MS-1) assesses the long-term safety, tolerability, and treatment effect over time of ALKS 8700 (462 mg twice daily) in approximately 600 patients with RRMS (ClinicalTrials.gov: NCT02634307). Main inclusion criteria include the following: patients aged 18-65 years with confirmed diagnosis of RRMS according to the 2010 revised McDonald criteria, Expanded Disability Status Scale score ⩽6.0, and no evidence of relapse within 30 days before study start. Main exclusion criteria include the following: diagnosis of primary progressive, secondary progressive, or progressive relapsing MS; pregnancy; or history of other clinically significant disease. De novo patients as well as patients continuing from other eligible ALKS 8700 clinical trials (eg, EVOLVE-MS-2) will be enrolled for up to 96 weeks of treatment with ALKS 8700. Safety will be assessed via AE reporting and standard clinical, laboratory, and imaging measures. Additional exploratory assessments for treatment effect over time will be undertaken. Results: This study began enrollment in December 2015 and is expected to be completed by the end of 2019. A total of approximately 600 patients is planned for enrollment at sites in the United States, Eastern Europe, and Western Europe. Conclusions: Results from this long-term study over a period of 96 weeks will provide valuable information regarding safety and tolerability of ALKS 8700 (462 mg twice daily) in patients with RRMS. Disclosure This study is sponsored by Alkermes, Inc, Waltham, MA, USA. RN has consulted for Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, and Pfizer and was on the speaker bureau for Acorda, Biogen, and Genzyme. AC, RP, YD, MH, and LVM are employees and stockholders in Alkermes, Inc. JW has received compensation for serving as consultant or speaker from AbbVie, Actelion, Alkermes, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Sanofi, Takeda, Teva, and XenoPort and has received royalties for monoclonal antibodies out-licensed to Chemicon International via The University of Texas Health Science Center at Houston.


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Others P749 Therapeutic inertia in multiple sclerosis care: lessons learned from behavioral economics G. Saposnik1, A.P. Sempere2, R. Raptis3, D. Prefasi4, D. Selchen5, C.C. Ruff6, P.N. Tobler6, J. Maurino4 1University of Toronto & University of Zurich, Toronto, ON, Canada, 2Department of Neurology, Hospital General Universitario de Alicante, Alicante, Spain, 3Applied Health Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada, 4Medical Department, Roche Farma, Madrid, Spain, 5Division of Neurology, St. Michael’s Hospital, Toronto, ON, Canada, 6Laboratory for Social and Neural Systems Research (SNS-Lab), Department of Economics, University of Zurich, Zurich, Switzerland

P750 Cholecalciferol supplementation in relapsing multiple sclerosis patients treated with subcutaneous interferon beta-1a: a randomized controlled trial W. Camu1, C. Pierrot-Deseilligny2, P. Hautecoeur3, A. Besserve4, A.-S. Jean Deleglise4, P. Lehert5, J.-C. Souberbielle6 1CHU de Montpellier, Montpellier, 2Hopital Pitié Salpetriere, Paris, 3GHICL St Vincent de Paul, Lille, 4Merck, Lyon, France, 5Faculty of Economics, UCL Mons, Louvain, Belgium, 6Hospital Necker, Paris, France

Introduction: Clinical and radiological progression is the standard criterion used for decisions to increase therapy in patients with multiple sclerosis (MS). Therapeutic inertia (TI) is defined as lack of treatment escalation when there is clinical-radiological evidence of disease progression. Limited information is currently available on physicians’ factors influencing TI in MS. Objectives: To evaluate physicians’ factors associated with TI in the management of MS by applying principles from behavioral economics. Design: A web-based study comprising 96 neurologists with expertise in MS care throughout Spain was conducted. Participants answered questions regarding the management of 20 case-scenarios commonly encountered in clinical practice and completed 3 surveys and 4 experimental paradigms from behavioral economics. Surveys and experiments included standardized tests to measure aversion to risk and ambiguity, physicians’ reactions to uncertainty, and questions related to risk preferences in different domains. Ambiguity aversion is a preference for known risks over unknown risks. We used different MS score criteria (e.g. clinical+radiological, EMA, Prosperini’s scheme) to take into account physicians’ differences in escalating therapy. Multivariable analysis was adjusted for age, sex and specialty status reported as OR; 95%CI. Results: 96 participants completed the survey. TI was present in at least one case-scenario in 68.8% of participants. Similar results were observed for definitions of TI only based on radiological progression. TI was observed in 29.2% of participants when applying the EMA criteria. TI was less common among MS experts (OR 0.29; 0.11-0.73). Low tolerance to uncertainty was associated with higher prevalence of TI (85.4% vs. 56.4%; adjusted OR 4.48, 1.52-13.1). Aversion to ambiguity was associated with TI (82% vs 52%; adjusted OR 4.2; 1.1-16.1). Conclusions: TI is a common phenomenon affecting 6 out of 10 physicians caring for MS patients. Physicians’ factors including aversion to ambiguity, tolerance to uncertainty, and MS expertise were associated with lower prevalence of TI.

Background: Although hypovitaminosis D is a known risk factor for developing multiple sclerosis (MS), there is no evidence base supporting Vitamin D3 (VD) as a treatment in MS. Objectives: To evaluate the benefit of add-on therapy with VD 100 kIU twice monthly over 2 years in relapsing MS (RMS) patients treated with subcutaneous interferon beta-1a 44µg 3 times weekly. Methods: Double blind randomized placebo controlled 2 year multicenter trial on RMS with serum VD levels⩽75nmol/L. The primary endpoint was the annualized relapse rate (ARR). Expanded Disability Status Scale (EDSS), magnetic resonance imaging parameters, laboratory monitoring, quality of life and cognitive abilities were secondary endpoints. Intention to treat (ITT) and completers selection were considered as primary and secondary, respectively. The primary analysis was a general linear model featuring Poison regression and negative binomial model for overdispersion adjusting for baseline values and exposure duration as on offset. The sample size was calculated to provide a power of 80% of detecting a ratio rate (RR) as large as 0.75, in assuming an ARR=1.5 for the placebo group and a correlation ratio=0.7, between baseline and final ARR. Results: 129 patients were randomized: 63 in VD group and 66 in placebo group. A non-significant benefit was found in the VD group (ARR=0.34) compared with placebo (ARR=0.45) with a RR=0.80 ([0.48, 1.32], p=0.379). On the completers sample (n=45 in both VD and placebo groups), we identified a higher and significant VD benefit (RR=0.40, [0.20, 0.81], p=0.011) on ARR and a lower count of new or enlarged weighted lesions (RR=0.22, [0.10, 0.49] p< 0.001 and 0.23, [0.09, 0.57], p=0.001 for T1 and T2 lesions, respectively). No significant difference was found on change in quality of life (p=0.78). The two groups were characterized by a similar safety profile: 11 and 10 patients reported serious treatment emergent adverse events in the VD and placebo group respectively. Conclusion: Although a strong effect was observed in reducing relapses of 60% on completers (RR=0.40), we failed to find a significant effect of VD on an ITT basis. In spite of an observed clinically relevant effect size of RR=0.80 (20% reduction in relapse rate), the unexpected low relapse rate in the control group (ARR=0.45) underpowered the study. A more thorough statistical analysis of this trial is on the way.

Disclosure

Disclosure

The study was sponsored by the Sociedad Española de Neurologia (SEN) and funded by an operating grant from Roche Farma Spain. D Prefasi and J Maurino are employees of Roche Farma Spain. G Saposnik, R Raptis, D Selchen, CC Ruff, PN Tobler: nothing to disclose.

Pr W. Camu: received lecture fees, honoraria and/or travel expenses refund from Actelion, Biogen, Effik, Merck and Sanofi. Pr C. Pierrot Deseilligny: received lecture fees and /or hotel/ travel expenses from Merck Serono, Novartis and Schering.

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Pr P. Hautecoeur: received consulting fees from Merck Serono, Bayer, Biogen, Genzyme, Novartis. A. Besserve: is an employee of Merck, France Dr AS. Jean Deleglise: is an employee of Merck, France Dr P. Lehert: has served as a statistical consultant for several pharmaceutical companies including Merck. Dr JC. Souberbielle: received lecture fees and/or travel/hotel expenses from DiaSorin, Roche Diagnostics, Abbott, Amgen, Shire, MSD, Lilly and Rottapharm. P751 Autologous haematopoietic stem cell transplantation in multiple sclerosis: a meta-analysis M.P. Sormani1, I. Schiavetti1, A. Signori1, P.A. Muraro2, R. Saccardi3, G. Mancardi4 1Department of Healt Sciences - Section of Biostatistics, University of Genova, Genova, Italy, 2Division of Brain Sciences, Imperial College London, London, United Kingdom, 3Haematology Department, Careggi University Hospital, Firenze, 4Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova and IRCCS AOU San Martino-IST, Genova, Italy Background: Immunoablative therapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatmentrefractory MS. Objective: To quantitatively summarize all the published evidence about the efficacy of aHSCT on MS progression after transplant, to estimate transplant related mortality (TRM) and overall mortality (OM), and to evaluate the effect of patients’ characteristics and transplant procedures on these outcomes. Methods: We prospectively collected all the published studies of aHSCT in MS from 1995 to 2016; we included studies assessing aHSCT on any form of MS, collecting >=5 patients, reporting data on mortality and on clinical follow-up. We carefully excluded studies that were updates of previous records. Endpoints were TRM, OM over the first and the second year after transplant, rate of progression, defined as 1 EDSS point increase (0.5 if baseline EDSS>=5.5), and No Evidence of Disease Activity (NEDA) status at 2 years. A weighted metaregression based on a Poisson model was run, assessing whether there were study specific characteristics with a relevant effect on TRM and progression. Results: 17 studies including 887 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 1.9% (95%CI=1.2%,3.1%), the 1-year OM was 2.3% (95%CI=0.54%,3.2%), and OM during the second year after transplant was 0.9% (95%CI=0.4%,1.8%). No TRM was observed among the 325 patients transplanted after 2008 (6 studies), vs a TRM of 3.0% (95%CI=1.9%,4.9%, p< 0.001) among the 562 patients in the 11 older studies. Studies with a proportion of RRMS patients>=40% (median value) had a TRM=0.5% (95%CI=0.1%,2.1%), while those with a proportion of RRMS< 40% had a TRM=3.0% (95%CI=1.8%,4.9%, p< 0.001). An older age and a higher baseline EDSS were also significantly associated to a higher TRM. Pooled rate of progression was 19.2% at 2 years (95%CI=11.9%,26.5%) and 30.5% (95%CI=18%,42.9%) at 5 years. Lower 2 year progression rate was significantly associated

with higher proportions of RRMS patients (p=0.008) and with more recent year of transplant (p=0.008). The pooled proportion of NEDA patients at 2 years was 77% (95%CI=70%,84%). Conclusion: The emerging evidence of the efficacy of this therapeutic approach in aggressive MS calls for a concerted action to plan a clinical trial defining its role with evidence level acceptable by the neurological community and regulators. Disclosure Maria Pia Sormani has received personal compensation for consulting services and for speaking activities from Genzyme, Merck Serono, Teva, VertexRoche, Novartis and Biogen. Irene Schiavetti reports no disclosures Alessio Signori has received research grant from MSBase Foundation and fee from Novartis for teaching activities Paolo Muraro has received travel support and speaker honoraria from Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis. Riccardo Saccardi has received travel support and speaker honoraria from Sanofi Aventis. Gianluigi Mancardi has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, Sanofi - Aventis, Merck Serono Pharmaceuticals, Novartis, Genzyme and Teva. P752 Effects of high- and low-fat meals on the pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator J.Q. Tran, J.P. Hartung, C.-A. Tompkins, P.A. Frohna Celgene, Summit, NJ, United States Background: Ozanimod (RPC1063) is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. Since food has the potential to significantly influence the rate and extent of drug absorption, we designed and conducted a food-effect study with ozanimod. Objective: To characterize the effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod in healthy adult subjects. Methods: This was a randomized, open-label, 3-period, 6-sequence, crossover study. Twentyfour healthy adult subjects were enrolled to receive a single 1-mg oral dose of ozanimod under 3 different conditions separated by washout periods of 7 days: fasted (treatment A), with a standard FDA high-fat meal (treatment B), and with a low-fat meal (treatment C). PK parameters for ozanimod and its two active metabolites (RP101988 [major] and RP101075 [minor]) were calculated. Point estimates and 90% confidence intervals (CIs) about the geometric mean ratio between treatments for maximum concentration (Cmax) and overall exposure (AUC0-inf or AUC0-last) were determined using linear mixed-effects models. Results: Twenty subjects completed both treatments A and B and 23 subjects completed both treatments A and C and provided PK data for the pair-wise comparison of fed vs fasted. The 90% CIs between fed (high-fat or low-fat) and fasted treatments for the Cmax and AUC0-inf of ozanimod and RP101988 were all within the no-effect boundary of 0.80 to 1.25. For the minor metabolite


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Poster Session 1, 22(S3) RP101075, the 90% CIs between high-fat and fasted for AUC0-last and the 90% CIs between low-fat and fasted for Cmax and AUC0-last were within the no-effect boundary. While the 90% CI between high-fat and fasted treatments for RP101075 Cmax (0.76 to 0.88) fell outside the lower bound of the no-effect boundary, this decrease was not considered to be clinically meaningful. Median time to reach Cmax (Tmax) for ozanimod was delayed following a high-fat meal (12 hours) compared to fasted and low-fat meal conditions (8 hours), but the range (6 to 12 hours) was the same. Mean elimination half-life (t1/2) values for ozanimod and its active metabolites ranged from 17-21 hours and were similar across all 3 treatments. Overall, single oral doses of 1 mg ozanimod were considered generally well tolerated. Conclusion: Ozanimod may be taken with or without food. Disclosure Funding for this study was provided by Celgene. Jonathan Q. Tran is an employee of Celgene. Jeffrey P. Hartung is a former employee of Celgene. Cindy-ann Tompkins is an employee of Celgene. Paul A. Frohna is an employee of Celgene. P753 Favourable changing course of multiple sclerosis in the last 15 years: the role of neurologists G. Comi1, M. Romeo2, B. Colombo2, G. Dalla Costa2, D. De Feo2, F. Esposito2, L. Ferrè2, C. Guaschino2, S. Guerrieri2, G. Liberatore2, F. Martinelli Boneschi2, L. Moiola2, M.J. Messina2, P. Preziosa2, M. Rodegher2, F. Sangalli2, V. Martinelli2 1Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, University Vita-Salute San Raffaele, San Raffaele Hospital, 2Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital, Milan, Italy Introduction: The aim of our study was to evaluate, in a realworld clinical setting, the beneficial changes of multiple sclerosis (MS) course in the last 15 years and to investigate the influence of Neurologists’ behaviour on these changes. Methods: This is an observational, single-centre study, carried out in 3 large cohorts of relapsing-remitting MS patients who started treatment with interferon beta (IFN-beta) or glatiramer acetate (GA) in 3 consecutive periods: first cohort (2000-2003), middle (2004-2007) and last cohort (2008-2011). We compared these 3 cohorts at baseline and for clinical and MRI variables during the 4-year follow-up. Results: A total of 1068 patients had complete MRI data during the follow-up. The patients of the last cohort began treatment earlier after MS diagnosis [p< 0.0001], MRI scan at baseline had a lower number of T2 lesions [p< 0.0001] and a lower number of Gadolinium T1 lesions than patients of previous cohorts. Moreover, during follow-up, the patients of this cohort presented a lower number of relapses [p< 0.0001], a lower disability worsening [p:0.001] and reached more frequently the NEDA3 [p< 0.0001] than other cohorts. Finally, these patients started high dose of IFN-beta or GA as first treatment [p< 0.0001] and switched to second-line therapy [p< 0.0001] more frequently than patients of other cohorts. Conclusions: Our study confirms the changing of MS course over time. Both early treatment and early switching to a second-line

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therapy in suboptimal responders are important therapeutic strategies to definitely improve the course of the disease in the real world clinical practice. Disclosure Comi received compensation for consulting services from the following companies: Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma and compensation for speaking activities from: Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed and Roche. Romeo received personal compensation for speaking activity from Genzyme and travel grant from Merck Serono. Colombo received travel grants from Biogen-Idec, Merck, Bayer and Genzyme. Esposito received honoraria from TEVA and Merck Martinelli Boneschi received honoraria for activities with Teva Neuroscienze, Sanofi-Genzyme and Biogen. Moiola received honoraria for speaking at meetings or for attending to advisory board from Sanofi-Genzyme, Biogen-Idec, Novartis and TEVA. Dalla Costa, De Feo, Ferrè, Guaschino, Guerrieri, Liberatore, Messina, Preziosa and Sangalli report no disclosures. Rodegher is on the scientific advisory board for Novartis and received travel support from Merck Serono, Bayer Schering, Teva, and Sanofi Aventis. Martinelli V. received personal compensations for consulting or speaking activities from Biogen-Idec, Merck-Serono, Bayer, TEVA, Novartis and Genzyme. P754 Multiple sclerosis triggered during tocilizumab therapy. Report of a new case G. Cruz-Velásquez1, J. Artal1, B. Sebastián1, M. Seral1, J.-V. Pérez-Moreiras2, J. Martín1, J.-R. Ara1 1Neurología, Hospital Universitario Miguel Servet, Servicio Aragonés de Salud, IIS Aragón, Zaragoza, 2Centro Oftlamológico Moreiras, Instituto Internacional de Órbita y Oculoplástica, Santiago de Compostela, Spain Introduction: Tocilizumab is a recombinant human monoclonal antibody against the interleukin-6 receptor. Recently a case of a patient who developed multiple sclerosis (MS) while under treatment with Tocilizumab and methotrexate has been reported. So we describe a new case of Tocilizumab-related MS. Case report: 41-year old woman was diagnosed with breast cancer 9 years ago and underwent successfully treatment with surgery, chemotherapy and radiotherapy. In 2014, she was diagnosed with Graves´ disease with orbitopathy and Tocilizumab treatment was begun. One year later acute weakness and numbness in her left hand appeared. Magnetic Resonance Imaging (MRI) showed more than 9 demyelinating lesions, some ovoid, located at subcortical, periventricular and infratentorial level. One of subcortical lesions was enhanced with gadolinium. Cerebrospinal fluid analysis presented positive IgG oligoclonal bands. Thyroid function, antithyroid peroxidase and antithyroglobulin antibodies were normal. Autoantibodies (ANA, anti-DNA, anti-ENA, ANCA) were negative. Tocilizumab was stopped and the patient was treated with high-dose intravenous methylprednisolone (1000 mg for 5 days). Six months later the patient was asymptomatic and there


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was no change in the number and size of lesions in her brain MRI, none of them indicating gadolinium enhancing. Conclusions: It has been considered that IL6 has anti-inflammatory properties, therefore the effect of such anti-IL-6 agents as Tocilizumab may lead to demyelinating diseases. In fact, some central and peripheral inflammatory demyelinating diseases have been reported. Although its real implication is still unknown, practitioners should be cautious in respect to their usage, especially in patients with demyelinating diseases.

single subsequent relapse or new MRI lesion was noted. Some patients showed progression but the majority were stable or showed improvements (76%). There were no unusual post-transplant complications noted (autoimmune thyroiditis n=3, deep vein thrombosis n=1 and shingles n=1). Conclusions: These results continue to support the treatment option of immunoablation and haematopoietic stem cell transplantation for a particularly aggressive subgroup of relapsing MS patients.

Disclosure

Disclosure

Cruz-Velásquez G: nothing to disclose. Artal J: nothing to disclose. Sebastián B: has received honoraria for lecturing or travel expenses for attending meetings from Bayer, Biogen Idec, Genzyme and Novartis. Seral M: has received honoraria for lecturing or travel expenses for attending meetings from Biogen Idec, Genzyme and Novartis. Pérez-Moreira JV: nothing to disclose Martín J: has received consulting honoraria from Genzyme, and honoraria for lecturing, travel expenses for attending meetings, or financial support for research from Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva. Ara JR: has received consulting honoraria from Genzyme, and honoraria for lecturing, travel expenses for attending meetings, or financial support for research from Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva.

Mark Freedman: Receipt of research or educational grants: None Receipt of honoraria or consultation fees: Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva Canada Innovation Member of a company advisory board, board of directors or other similar group: Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis Participation in a company sponsored speaker’s bureau: Genzyme Harold Atkins: nothing to disclose Marjorie Bowman: nothing to disclose Heather MacLean: nothing to disclose Carolina Rush: nothing to disclose

P755 Immunoablation and haematopoietic stem cell transplantation completely aborts inflammation in aggressive relapsing forms of MS M.S. Freedman, H. Atkins, M.J. Bowman, H. MacLean, C. Rush The Ottawa Hospital, Ottawa, ON, Canada Background: We have been using a standard regimen of immunoablation and haematopoietic stem cell transplantation for the treatment of aggressive forms of relapsing MS that typically are poor responders to first or second line treatments. Objective: To report on the experience obtained at our centre since the completion of a previously reported phase II trial. Methods: Patients (n= 41) with aggressive forms of relapsing MS were identified from the MS clinic of The Ottawa Hospital and haematopoietic stem cells were mobilized with cyclophosphamide and filgrastim, collected by leukophoresis and CD34+ stem cells isolated by immunomagnetic separation. Immunoablation was accomplished using high dose cyclophosphamide and busulphan followed by rabbit anti-thymocyte globulin. Routine posttransplant antibiotics, antiviral and antifungal agents along with IVIG were administered for up to a year. Results: We have now treated a total of 41 patients; 24 were previously reported as part of a longstanding study, and 17 were treated since the completion of enrollment into the study. Baseline characteristics of these post-study patients were similar in age (mean 31, range 20-51), duration of MS (mean 4.2 years, range 5 months-10.3 years), baseline EDSS (mean 4.0, range 1.5-7.5), as the study patients and a median follow-up of 2.8 years (range 2 months-13 years), though patients were not followed as part of a pre-planned prospective study. Similar to the study patients, not a

P756 Intermediate intensity regimen in autologous HSCT for severe multiple sclerosis: a large, single center experience R. Saccardi1, A.M. Repice2, C. Innocenti1, A. Mariottini2, M.P. Amato2, S. Guidi1, A. Fani1, R. Nistri2, M. Giannini2, E. Portaccio2, A. Barilaro2, C. Nozzoli1, A. Gozzini1, L. Massacesi2 1Hematology Department, University of Florence, Florence, 2Neurological Department, University of Florence, Firenze, Italy High dose chemotherapy with autologous hematopoietic stem cell transplantation (aHSCT) is a promising approach for treatment of aggressive multiple sclerosis (MS). Data reported in the literature are derived from either small, single center or larger registry analysis, with a wide variability in the transplant techniques and clinical conditions at baseline. We report a large retrospective, single-center analysis of 62 consecutive MS patients treated with an uniform transplant protocol. Material and methods: we included 62 MS patients transplanted between 1999 and 2015. Female/male ratio was 0.76, median age was 36 ( 20-54). 37 patients (59.7%) were diagnosed with Relapsing-Remitting (RR) MS, 23 (37.1%) with Secondary Progressive (SP) MS, 2(3.2%) had Primary Progressive (PP) MS. Median EDSS score at transplant was 6.0 (range 1-7.5). PBSC were mobilized with cyclophosphamide 4 gr/sqm + G-CSF and conditioned with BEAM/ATG, except for 2 patients who could not accomplish the conditioning with BEAM due to either BCNU reaction or detection of Meropenem- resistant Klebsiella respectively. Results: All patients mobilized adequately. Median duration of follow up is 4.2 years (range 0.1-14.9). Three out of 62 patients relapsed at 3.9, 4.9 and 5 years from transplant, respectively, without disability progression thereafter. Overall progression rate was


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Poster Session 1, 22(S3) 27.4% at a median time of 2.2 (0.47-4.39) years from HSCT: among progressed patients, 11 out of 23 had SPMS, 4 out of 37 RRMS and 2 out of 2 PPMS (RR vs SP, p=0.012). We had no transplant-associated mortality. Two severe adverse event occurred during the procedure: an anaphylactic shock to carmustine and a E. Coli-related sepsis. FUO (62.9%) and diarrhea (40.3%) were the most frequently recorded adverse events in the first 100 days. CMV and EBV reactivations occurred in 29% and 51% of patients. Adverse events occurred beyond 100 days were documented pneumonia (3), HVZ reactivation (4), transient monoclonal gammopathy (9) and autoimmune thyroiditis (3). Disclosure Saccardi: nothing to disclose Innocenti: nothing to disclose Fani: nothing to disclose Repice: nothing to disclose Massacesi nothing to disclose Barilaro nothing to disclose Mariottini nothing to disclose Guidi:nothing to disclose Nozzoli: nothing to disclose Nistri: nothing to disclose Gozzini: nothing to disclose Amato :nothing to disclose Giannini: nothing to disclose Portaccio: nothing to discolse

Disclosure Study funded by Almirall S.A. (Barcelona, Spain)

Treatment of specific symptoms P757 Tetrahydrocannabinol + cannabidiol oromucosal spray for multiple sclerosis resistant spasticity on daily practice, new data P. Vermersch1, M. Trojano2 1Neurology, Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille), Lille, France, 2Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari, Bari, Italy Background: THC:CBD oromucosal spray (Sativex) is a cannabinoid based add-on drug available in Italy since 2013 for multiple sclerosis (MS) resistant spasticity. Earlier availability in Germany allowed daily practice data collection there (Flachenecker 2014). Differences between countries such as the compulsory health authorities registry in Italy for all patients might influence the results. Moreover, observational studies complement the clinical trials experimental setting data. Aim: Collect effectiveness and tolerability data in everyday life conditions from a large sample of patients starting Sativex. Methods: Observational, prospective, 3 months follow-up study under approved conditions in Italy (34 centres), Norway and Denmark (3 centres). 1 month trial period (only patients improving at least 20% their spasticity NRS score could continue). Spasticity (0-10 NRS scale as main endpoint), associated symptoms, quality of life (QoL) and tolerability evolution collected. Results: 433 patients recruited, 98% in Italy. 50.9 y mean age, 55% female, 12.9 y with MS (51.5% Secondary Progressive MS) and 7.4 y with MS spasticity. EDSS mean score of 5.94. Baclofen

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was used by 78.1% of participants. 349 of participants were prescribed beyond the trial period 1st month visit (80.6%) and 281 (64.9%) beyond the third month visit.Mean used dose was 6 sprays/d. Spasticity improved with stat. significance in the 3 months remaining patients in all the different scales used: 0-10 NRS (mean 6.9 to 5.4), Ashworth scale (mean 2.6 to 2.3) and categorical scale (37.2% to 12.9% severe). Associated symptoms improved also with stat. significance: spasms, fatigue, pain, sleep quality and bladder dysfunction. Patients restricted in daily abilities were reduced from 30.2 to 22.8% (stat. significant), and the QoL EQ-5D VAS improved from 49.5 to 54.2 (p< 0.0001)A subgroup of patients (19.9%) improved ⩾30% their NRS score (mean 48%) and also showed higher improvements in the secondary parameters.10.4% of patients reported adverse events, none severe or serious. Dizziness was the commonest (3.7%). Conclusions: THC:CBD oromucosal spray is a valid option for managing MS resistant spasticity and associated symptoms, providing clinically noticeable improvement in about 2/3 of the treated subjects with lower than clinical trials reported doses (6 vs 8 sprays/d) and good tolerability. Associated symptoms tracking is important. No relevant differences versus previous published results has been seen.

P758 Diffusion tensor imaging correlates of gait impairment in multiple sclerosis S. Klineova1, R. Farber1, C. Saiote2, C. Farrell1, B.N. Delman3, J. Friedman2, M. Inglese2,3,4, F.D. Lublin1, S. Krieger1 1The CGD Center for MS, 2Department of Neurology, 3Department of Radiology, 4Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States Objective and background: The majority of multiple sclerosis (MS) patients experience impaired walking ability which impacts quality of life. Timed 25-foot walk (T25FW) is commonly used to gauge gait impairment but varies widely and may be insensitive. Objective biological markers that correlate closely with disability are needed. Diffusion tensor imaging (DTI), quantifying fiber tract integrity, might provide such information. In this project we analyzed relationships between T25FW, conventional and DTI MRI markers. Design and methods: A subset of our previously established cohort of gait-impaired patients we intended to treat with dalfampridine underwent brain and cervical spinal cord MRI. DTI mean diffusivity (MD), axial and radial diffusivity and fractional anisotropy (FA) were measured at brain cortico-spinal tracts (CST) and spinal rFOV at C2/3. We analyzed relationships between baseline T25FW, conventional and DTI MRI markers. We also identified the CST causing greater lateralized pyramidal dysfunction on neurological exam on a per-patient basis, and then used the brain DTI metrics from the causative tract in the regression analysis. Results: Thirteen patients were imaged for this study. Mean T25FW was 8.26 sec, 61% of patients had progressive disease and 46% used a gait assistive device. Mean brain CST FA was 0.53 (SD=0.038), mean CST MD was 0.8x10-3 µm2/ms (SD=0.06). Mean brain CST axial diffusivity was 1.32 mm2/s ×10-3 (SD 0.06) and mean brain CST radial diffusivity was 0.54 mm2/s ×10-3 (SD 0.06).


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Multivariate linear regression showed statistically significant associations between several MRI and DTI metrics and T25FW: brain MD CST (p= 0.004), brain CST axial and radial diffusivity (p= 0.004 and 0.02), GMV (p= 0.05), WMV (p= 0.03) and NBV (p= 0.01). The regression model containing MD CST and controlled for gait assistance was the best fit model (p= 0.004). Analysis of the brain CST causative of the pyramidal dysfunction showed significant association between T25FW and brain CST MD (p=0.023) as well as brain CST axial diffusivity (p=0.008). Conclusions: Our results suggest an association between DTI metrics and gait impairment, evidenced by brain MD CST and T25FW. This could be explained by the higher sensitivity of DTI metrics for axonal damage and consequent disability. We plan to further utilize these results focusing on brain CST MD as a main candidate biomarker to predict dalfampridine response. Disclosure B. N. Delman received compensation for consulting/ advisory board work for Bayer HealthCare. M. Inglese received research grant from NIH, NMSS, Novartis Pharmaceuticals and Teva. F.D. Lublin received compensation for consulting /advisory board work with Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Teva; Actelion; Sanofi/Genzyme; Acorda; Questcor/Malinckrodt; Roche/Genentech; Celgene, MedImmune; Osmotica; Xenoport, Receptos; Forward Pharma; BBB technologies; Akros; TG Therapeutics; Abbvie, research grants from Biogen Idec; Novartis Pharmaceuticals Corp; Teva, Inc.; Genzyme; Sanofi; Celgene; Transparency Life Sciences; NIH; NMSS. S. Krieger received compensation for consulting /advisory board work with Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genentech, Genzyme, Questcor, and Teva, and gave non-promotional lectures with Biogen Idec and Genzyme. S.Klineova, R.Farber, C. Farrell, C. Saiote and J.Friedman have nothing to disclose. P759 A multicenter randomized controlled trial of two group programs in multiple sclerosis: effects on fatigue and selfefficacy C. Hugos1, Z. Chen2, Y. Chen2, M. Cameron1, K. Wick1, A. Turner3, J. Haselkorn3, A. Sloan3, T. Chiara4, S. Mc Coy4, C. Bever5, A. Kunce5, D. Bourdette1,2 1VA Portland Health Care System, 2Oregon Health & Science University, Portland, OR, 3VA Puget Sound Health Care System, Seattle, WA, 4North Florida/South Georgia Veterans Health System, Gainesville, FL, 5VA Maryland Health Care System, Baltimore, MD, United States Background: Fatigue is a common symptom among people with multiple sclerosis (MS). A structured group program Fatigue Take Control (FTC) was developed based on the Fatigue and MS clinical practice guideline. Despite being widely used by chapters of the National MS Society (NMSS), the effectiveness of FTC in decreasing fatigue or improving self-efficacy has not been demonstrated. Objectives: To determine whether MS participants in the FTC program experienced decreased fatigue and increased self-efficacy compared to those in a general MS education program referred to as MS Take Control (MSTC).

Methods: MS subjects with Modified Fatigue Impact Scale scores (MFIS) >24 were randomized to participate in FTC or MSTC. Subjects took the MFIS and the MS Self-Efficacy Scale (MSSE) at baseline (Visit 1), completion of their assigned program (Visit 8) and 6-months later (Visits 10). Both programs entailed participating in small groups led by a trained facilitator and consisted of 6 weekly sessions each lasting 2 hours. FTC differed from MSTC in two ways: FTC focused on fatigue management with education and behavioral change and included goal setting with emphasis on participant engagement in finding ways to improve their fatigue. MSTC consisted of participants reading a different NMSS pamphlet on some aspect of MS before each session and discussing the content of the pamphlet during the session. Results: 218 subjects were randomized at 4 sites. Baseline MFIS and MSSE scores did not differ between the two groups. MFIS scores improved in both groups between Visit 1 and Visit 8 (FTC mean change -4.4, p< 0.001; MSTC mean change -3.8, p< 0.001) but the degree of improvement did not differ between the groups at any time. The FTC group improved significantly on the MSSE compared with the MSTC group (mean increase of 37.7 vs -16.4, p=0.04) at Visit 8 but was not sustained. Conclusions: Small group programs improved fatigue in MS participants with the effect increasing slightly 6 months after the program. Participants taking FTC demonstrated significant improvement in self-efficacy initially compared to MSTC that was sustained for 6 months but no longer significantly different from MSTC. The results of this study suggest the need to develop a program for fatigue management that includes support for participants to accomplish goals they set for themselves. Disclosure Sources of funding: VA RR&D F7777-R and OCTRI NCATS-funded CTSA grant (UL1TR000128 Hugos: Nothing to disclose. Z Chen: Nothing to disclose. Y Chen: Nothing to disclose. Cameron: Nothing relevant to disclose. Wick: Nothing to disclose. Turner: Nothing to disclose. Haselkorn: Nothing to disclose. Sloan: Nothing to disclose. Chiara: Nothing to disclose. McCoy: Nothing to disclose. Bever: Nothing to disclose. Kunce: Nothing to disclose. Bourdette: Nothing relevant to disclose. P760 Evaluating the effect of patients expectations on clinical response to fampridine treatment F.F. Ladeira1, A.S. Correia1,2, M. Viana-Baptista1,2 1Neurology Department, Hospital de Egas Moniz, 2CEDOC, Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal Background: It is known that expectations may affect response to numerous treatments. In multiple sclerosis, it has been shown to


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Poster Session 1, 22(S3) influence the adherence and ultimately the response to treatments. Our aim was to evaluate if patients’ expectations regarding fampridine, assessed before initiating treatment influenced their clinical response. Methods: We designed a prospective study from June 2015 to April 2016. We invited all consecutive patients considered for fampridine treatment in our centre to participate. Clinical data was collected and patients completed a questionnaire which included a question about fampridine information sources, a portuguese version of the Stanford Expectations of Treatment Scale (SETS) and the HADS scale to assess depression and anxiety. We analysed the effect of positive expectancy, as well as sex, age, EDSS score, and disease duration in the response at 4 weeks through a logistic regression. Chi square or Fisher analysis were used as apropriate. Results: Out of 36 patients proposed to fampridine treatment, 32 agreed to participate in our study. 69.7% (23) were female; mean age was 52.5 years, median EDSS was 6. A benefit higher than 20% in T25FW at week 4 was observed in 72.7% (24) of patients. A high positive expectancy on SETS was the only factor associated with benefit at 4 weeks, being associated with a five-fold increase in odds of benefit at 4 weeks (OR= 5.0, 95% CI 1.0125.57, p=0,049). Fampridine information sources, anxiety and depression scores weren’t related to SETS results. Conclusions: In our sample, the expectations of patients seemed more relevant than sex, age, EDSS score and duration of disease in patients’ response to fampridine after 4 weeks of treatment. It would be interesting to assess with bigger samples if indeed patients’ expectations regarding treatment are an important factor in fampridine response.

depressive symptoms in MS, and that the immunomodulatory properties of vitamin D explain the effects. Methods: This study was part of the SOLARIUM trial (NCT01285401), a randomized controlled trial (RCT) in which relapsing remitting (RR) MS patients (n=53) received either high dose vitamin D3 supplementation (14 000 IU/day) or placebo during 48 weeks. Pre- and post-supplementation depression scores were measured in 20 patients in each group, using the subscale Depression of the Hospital Anxiety and Depression Scale (HADS). Furthermore, tumor necrosis factor alpha (TNFα) and interleukin (IL)-10 cytokine secretion by lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) was measured using Luminex technology, and the proportions of TNFα, interferon-gamma (IFNγ) and IL-10 producing CD8+ T cells were measured using flow cytometry. Results: After 48 weeks, a significant decrease in HADS depression (HADS-D) scores was observed within the vitamin D3 treated patients (median HADS-D 4.0 to 3.0, p=0.023) and a trend towards a decrease within the placebo group (median HADS-D 3.0 to 2.0, p=0.059), which did not significantly differ between groups (p=0.763). Also, no changes in cytokine secretion, neither by PBMC nor by CD8+ T cells, were found in the vitamin D3 supplemented arm compared to the placebo arm. Conclusions: In this RCT we found no evidence for amelioration of depressive symptoms in RRMS by vitamin D3 supplementation. Whether vitamin D3 supplementation in actual depression in MS is of benefit, however, needs to be assessed by additional studies. Disclosure

Disclosure Filipa Ladeira has received travel fees from Biogen,Teva, Genzyme Ana Sofia Correia received an educational sponsorship from Merck Serono, honorarium for advisory role from Novartis, research support and honorarium for lecturing from Biogen Idec and support for scientific meetings from Novartis, Biogen Idec, Teva and Bayer. Miguel Viana-Baptista has no conflicts of interest P761 High dose vitamin D3 supplementation does not ameliorate depressive symptoms in relapsing remitting multiple sclerosis: results of a randomized placebo-controlled trial L. Rolf1,2, A.-H. Muris1,2, Y. Bol2,3, J. Damoiseaux4, J. Smolders5, R. Hupperts1,2 1School for Mental Health and Neuroscience, Maastricht University Mecical Center, Maastricht, 2Academic MS Center Limburg, 3Department of Medical and Clinical Psychology, Zuyderland Medical Center, Sittard, 4Central Diagnostic Laboratory, Maastricht University Mecical Center, Maastricht, 5Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands Background: Depressive symptoms are very common in multiple sclerosis (MS). Both depression and MS have been associated with a poor vitamin D status, and cytokine-mediated inflammatory processes play a role in the pathogenesis of both disorders. We hypothesized that vitamin D3 supplementation ameliorates

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LR reports no conflicts of interest; AM reports no conflicts of interest, YB reports nog conflicts of interest, JD reports no conflicts of interest, JS reports no conflicts of interest, RH received honoraria for advisory boards and research grants from BIOGEN, SANOFI AVENTIS, NOVARTIS and MERCK. P762 Enhanced cognitive performance independent of depression scores in patients with multiple sclerosis treated with fampridine M. Fernández-Fournier1, I. Puertas1, B. Chamorro1, A. Tallón Barranco1, P. López Ruiz2, G. Lubrini2 1Neurology, Neuroinmunology and Multiple Sclerosis Unit, 2La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain Background and aims: Fampridine is an oral treatment that has been shown to improve walking speed in patients with multiple sclerosis (MS) and a walking disability (EDSS 4-7). The mechanism of action described is an improvement of nerve impulse transmission, blocking potassium channels. We aimed to study the effect of treatment with Fampridine on patients’ cognitive performance. Methods: A prospective study of MS patients aged 18-59, responders to Fampridine. “Responders” were defined by >20% improvement in walking speed after 14 days of treatment.


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Extensive neuropsychological testing including the Brief Neuropsychological Battery(BNB), forward and reverse digits, the Stroop test and the Trail Making Test(TMT) A and B, as well as the Beck Depression Inventory(BDI), were performed at treatment initiation and 5 months later. Results: Twelve patients (58% women, mean age 48.8years SD8,6, mean BDI score 10,9) were studied. Overall patients showed an improvement of 38% (SD12,0) in walking speed at 14 days that persisted after 5 months. On cognitive testing, patients showed a trend towards improvement in most cognitive tests performed at 5 months, which was statistically significant for the words Stroop-tests (p = 0.04), indirect digits (p = 0.029) free delayed recall test and categorical evocation (p = 0.03). No significant differences were found on the BDI scores. Conclusion: Fampridine-responder MS patients might benefit from treatment with Fampridine beyond the improvement in motor function. Disclosure Dr. Fernández-Fournier: reports no disclosures Dr. Puertas: reports no disclosures MS, Chamorro: reports no disclosures Dr. Tallón Barranco: reports no disclosures Dr. López Ruiz reports no disclosures Dr. Lubrini: reports no disclosures. P763 Medical and surgical treatment of trigeminal neuralgia in patients with multiple sclerosis: a literature review D. Johannsen1, J.L. Frederiksen2,3 1Copenhagen University Hospital, 2Dept. of Neurology, Rigshospitalet Glostrup, 3University of Copenhagen, Copenhagen, Denmark Objective: The aim of this literature review is to evaluate advantages and limitations of medical and surgical treatment of trigeminal neuralgia (TN) in patients with multiple sclerosis (MS), and which treatment, or combination of treatments, has the best outcome. Materials and methods: A systematic literature search in PubMed was performed using the MeSH key words multiple sclerosis, trigeminal neuralgia and treatment. Results: Eight articles described pain relief after medical treatment with Lamotrigin in 22/23 patients, with Gabapentin in 11/13 patients, with Gabapentin and either Lamotrigin or Carbamazepin in all 11 patients, with Misoprostol in 4/25 and a 50%-reduction in attack frequency in 14/25 patients, and with Topiramat in 5/6 patients. Six articles described surgical therapy with microvascular decompression (MVD); three found advantages and three advised against MVD. Ten articles found a good outcome when treated with glycerol and radiofrequency rhizotomy, balloon compression (BC), gamma knife surgery (GKS), low level laser (LLLR) and trans-cranial electromagnetic stimulation (TMS). In general, monotherapy with Carbamazepin or Oxcarbazepin, or in combination with Misoprostol or Gabapentin respectively had a good outcome, however with side effects. MVD had a good outcome when neurovascular contact was present, when no plaques along trigeminal pathways were found and when the constant pain in patients had evolved from an episodic pain

component. It was recommended that BC is performed with a pearshaped balloon and that time of compression does not exceed 5 minutes. No statistical significant difference was found between radiofrequency and glycerol rhizotomy. GKS, LLLR and TMS had the best outcome as they modulate the neural activity in the stimulated areas. LLLR has antiinflammatoric properties and can reduce pain. Conclusion: Both medical and surgical treatment are at least partly effective, but more and bigger studies are needed to establish the optimal treatment for patients with MS and TN, especially concerning medical treatment. Disclosure Dagmar Johannsen: nothing to disclose Jette Lautrup Frederiksen: nothing to disclose P764 Big conductance calcium-activated potassium channel activation is a novel way to control spasticity without sedation D. Baker1, G. Pryce1, C. Visintin2, A.I. Bondarenko3, W.S.V. Ho4, T.E. Williams1, I. Sevastou2, W.F. Graier3, M.D. Baker1, G. Giovannoni1, D.L. Selwood2 1Queen Mary University of London, 2University College London, London, United Kingdom, 3Medical University of Graz, Graz, Austria, 4St George’s University of London, London, United Kingdom Background: Spasticity in multiple sclerosis develops as a consequence of nerve damage and results in an increase in muscle tone due to hyper-excitable stretch reflexes, spasms and hypersensitivity to normally innocuous sensory stimuli. This can be controlled by a number of different agents, but their use is hampered by doselimiting, sedative, side-effects. These limit compliance and early adoption following diagnosis of spasticity. (R, Z)-3-(6(dimethylamino)-6-oxohex-1-enyl)-N-(1-hydroxypropan-2-yl) benzamide (VSN16R) was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drug-like agents to target spasticity. Objective: To develop a treatment for spasticity, lacking the sedative potential of current treatments, including plant-based cannabinoids. Results: VSN16R induced no significant adverse-effects in rodents at 1g/kg p.o. in contrast with other anti-spastic agents, which caused sedation. Using a mouse experimental autoimmune encephalomyelitis model of multiple sclerosis, VSN16R entered the central nervous system and dose-dependently reduced spasticity, without affecting normal muscle tone. A therapeutic effect was achieved with ⩾1mg/kg oral VSN16R, at plasma levels that were easily achievable and safe, when tested in pre-clinical toxicity and human phase I studies. Interestingly, VSN16R did not bind to cannabinoid-related (CB1, CB2, GPR55) receptors and many other receptors. The VSN16R-target was pharmacologically and electrophysiologically identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa) channels. Importantly, other structurally-unrelated BKCa openers were also found to inhibit spasticity and this effect could be blocked with the BKCa inhibitor paxilline. VSN16R can induce state-dependent, neural membrane hyperpolarization by increasing neuronal BKCa


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Poster Session 1, 22(S3) channel activity, which can limit excessive excitability within the spinal reflex to control spasticity. Conclusions: This identifies a novel therapeutic use of BKCa channels and a new route to control spasticity using a new, safe, non-sedating and selective type of ligand with potential application to treat spasticity and other neurological conditions. Phase II studies in spasticity in MS (NCT02542787) are ongoing. Disclosure David Baker and David Selwood are: founders; shareholders and consultants to Canbex Therapeutics Limited a university spin-out company developing VSN16R and have recieved research funding from Canbex therapeutics. Cristina Visintin is a founder and shareholder in Canbex therapeutics. Gavin Giovannoni is a shareholder and consultant to Canbex therapeutics. His other company associated activities are not relevant to the current presentation. Gareth Pryce is a shareholder in Canbex therapeutics. Alexander Bondarenko/Wolfgang Graier and Vanessa Ho have received research funding from Canbex Therapeutics. Thomas E. Williams, Ioanna Sevastou, and Mark Baker have nothing of relevance to declare. Source of funding: This work was supported by funding to Canbex Therapeutics Limited by: Fastforward, Innovate UK, MS ventures, The Wellcome Trust and University College London business. P765 Network analysis for understanding the effect of fampridine in gait of primary progressive multiple sclerosis I. Pulido-Valdeolivas1, D. Gómez-Andrés1,2, I. GonzálezSuárez3, A. Montero1, J.A. Martín-Gonzalo4, I. Rodriguez4, C. Oreja-Guevara3, E. Rausell1 1Anatomía, Histología y Neurociencia, Universidad Autónoma de Madrid, Madrid, 2Child Neurology Unit, Hospital Universitario Infanta Sofia, San Sebastian de los Reyes, 3Neurology, Hospital Universitario Clínico de San Carlos, 4Laboratorio de Marcha, Escuela de Fisioterapia ONCE-UAM, Madrid, Spain Introduction: Gait impairment is the first and the most common symptom in the majority of primary progressive multiple sclerosis (PPMS) patients. The gait as a system has to be adapted in these patients to maintain its function of translation with an adequate control support during displacement. In previous studies we have demonstrated (by network analysis) that gait in PPMS is rearranged to maintain the maximum control of pelvic-femoral joints’ movement (Gómez-Andrés et al. ECTRIMS 2015). Fampridine has been recently approved for symptomatic management of gait impairment in MS. Its efficacy has been demonstrated by clinical scales that measure changes in walking speed. However, gait impairment in PPMS is far more complex. Therefore, techniques that cope with that complexity are needed. Objective: To compare the structure of gait system before and after 15 days of fampridine treatment in patients with PPMS by means of network analysis. Methods: 43 left and 43 right spatiotemporal and kinematic gait parameters were collected from 12 healthy subjects and 10 PPMS

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patients (before and after treatment with fampridine) by means of instrumented gait analysis. Three networks (healthy subjects, prefampridine and post-fampridine) were built using gait parameters as nodes and bivariate Spearman’s rho correlation coefficient as edges. Integration, segregation, modularity, assortativity and centrality were assessed in each network. Result: After the treatment with fampridine the network structure changes. Central parameters differ from pre-treatment to posttreatment network. In pre-fampridine network, the parameters that are more correlated with the rest of the network are spatiotemporal ones and those related with the range of knee flexion. However, in post-fampridine network these parameters are less correlated. The assortativity of the patients network decreases after treatment to become similar to the healthy subjects network (before 0.204; after 0.124; healthy 0.096). Integration, segregation and modularity are similar to normalcy and do not change with the treatment. Conclusion: Fampridine modifies the interaction between gait parameters in PPMS patients. The flexibility of the gait structure improves after treatment with fampridine. Particularly, kinematic parameters seem to be less influent on gait spatiotemporal properties pointing out a not previously proposed mechanism for gait improvement after fampridine. Disclosure Irene Pulido-Valdeolivas: Nothing to disclose David Gómez-Andrés: Nothing to disclose Estrella Rausell: Nothing to disclose Juan Andres Martin Gonzalo: Nothing to disclose Andrea Montero: Nothing to disclose Irene Rodriguez: Nothing to disclose Inés González-Suarez has received honoraria for speaking from Biogen and Merck Celia Oreja-Guevara has received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Sereno, Roche, Teva and Novartis. P766 Effects of dual-task balance training on postural performance in patients with multiple sclerosis: a doubleblind, randomized controlled trial S. Monjezi1, H. Negahban2, S. Tajali1 1Musculoskeletal Rehabilitation Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 2Department of Physical Therapy, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran Objective: To investigate the effects of dual-task balance training on postural performance in patients with multiple sclerosis as compared with single-task balance training. Design: Double-blind, pretest-posttest, randomized controlled pilot trial. Setting: Local Multiple Sclerosis Society. Subjects: A total of 47 patients were randomly assigned to two equal groups labeled as single-task training and dual-task training groups. Interventions: All patients received supervised balance training sessions, 3 times per week for 4 weeks.The patients in the single-task group performed balance activities, alone. However,


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patients in dual-task group practiced balance activities while simultaneously performing cognitive tasks. Main measures: The 10-Meter Walk Test and Timed Up-and-Go under single-task and dual-task conditions, in addition to Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment were assessed pre-, and post intervention and also 6-weeks after the end of intervention. Results: Only 38 patients completed the treatment plan. There was no difference in the amount of improvement seen between the two study groups. In both groups there was a significant effect of time for dual-10 Meter Walk Test (F1, 36=11.33, p=0.002) and dualTimed Up-and-Go (F1, 36=14.27, p=0.001) but not for their single-tasks. Moreover, there was a significant effect of time for Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment (P< 0.01). The results of pairwise comparisons for those who completed the follow-up testing showed that the benefits of improvement were maintained at follow-up testing; i.e. 6-weeks after completion of the intervention (P< 0.01). Conclusions: This pilot study did not show more benefits from undertaking dual-task training than single-task training. A power analysis showed 71 patients per group would be needed to determine whether there was a clinically relevant difference for dualtask gait speed between the groups. Keywords: Dual-task, balance, training, multiple sclerosis, outcome Disclosure The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Master thesis grant (no: PHT-9229) in Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Therapy - Symptomatic - Quality of life P767 Pain in neuromyelitis optica: characterization and its impact on quality of life: a cross-sectional study in Venezuela G.A. Chique-Alfonzo1,2, A. Soto2,3, E. Armas1,2 1Department of Neurology, Hospital Universitario de Caracas, Universidad Central de Venezuela, 2Department of Neurology, Centro Médico Docente La Trinidad, 3Neurology Unit, Hospital Dr. Domingo Luciani IVSS, Caracas, Bolivarian Republic of Venezuela Background: Neuromyelitis Optica (NMO) comprises 11.8% of all Idiopathic Inflammatory Demyelinating Diseases (IIDDs) cases in South America (SA). Venezuela exhibits the highest frequency of NMO cases (43.3%) in SA. NMO has unique characteristics that could distinguish it from Multiple Sclerosis (MS). Recently, Pain in NMO, has been described as a disabling symptom that can affect health related quality of life (HRQOL). Objective: To characterize and compare pain differences between NMO and MS in Venezuelan population, and determine its impact on HRQOL. Methods: In a cross-sectional study, 23 patients with NMO compared to 16 patients with MS were studied at the Department of

Neurology, Hospital Universitario de Caracas, Venezuela. We used Brief Pain Inventory (BPI) to characterize pain, determine Pain Severity Index (PSI) and localize painful body areas. Douleur Neuropathique 4 (DN4) for determining neuropathic pain, Short Form 36 (SF-36) to measure HRQOL. Extended Disability Status Scale (EDSS) and Timed 25-Foot Walk (T25-FW) to assess disability and mobility. We determined the presence of Painful tonic spasms and the pain medication more commonly used, and ⩾2 or more pain medication. We compared the NMO and MS patients´ profiles by Fisher exact probability test. We carried out all statistical analyses using SPSS version 22.0 (SPSS Inc.) Results: Pain in NMO seems to be more common, more severe and it shows particular characteristics compared to Pain in MS. EDSS NMO 6.11 vs. MS 4.97 (p=0.032). PSI in NMO 5.41±2.66 vs. MS 4.08 ±2.88 (p=0.220).Neuropathic Pain and Painful Tonic Spasms found (NMO) in 81% and 65% respectively. Severe painful areas in NMO were trunk and upper limbs bilateral (banding) while in MS were lower limbs unilaterally. NMO group had lower quality of life in physical and mental component of SF-36, compared to MS; and required ⩾2 or more pain medication in 56.52%, especially NSAIDS and OPIOIDS. Comparing our data to international NMO studies, it seems that our results are consistent and show a more similar pattern to western North American studies than Asians do. Conclusion: Pain in NMO showed different characteristics compared to MS; and it had a severe impact on quality of life in our patients. It requires a specialized diagnostic and therapeutic approach. Keywords: Neuromyelitis Optica, pain, neuropathic pain, brief pain inventory, SF36, quality of life Disclosure nothing to disclose P768 Improvements in quality of life over 5 years with alemtuzumab are associated with confirmed disability improvement in patients with active relapsing-remitting multiple sclerosis who had an inadequate response to prior therapy (CARE-MS II) R. Arroyo González1, D. Dive2, M. Dreyer3, R.M.M. Hupperts4, C. LaGanke5, J. Lycke6, T. Moreau7, B. Singer8, D.H. Margolin9, K. Thangavelu9, G. Giovannoni10, on behalf of the CARE-MS II Investigators 1Hospital Clinico San Carlos, Madrid, Spain, 2University Hospital of Liège, Liège, Belgium, 3Royal Hobart Hospital, Hobart, TAS, Australia, 4Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 5North Central Neurology Associates, Cullman, AL, United States, 6University of Gothenburg, Gothenburg, Sweden, 7University of Burgundy, Dijon, France, 8MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, 9Sanofi Genzyme, Cambridge, MA, United States, 10Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom Background: Disability significantly contributes to the impact of MS on patients’ quality of life (QoL). Patients with active RRMS and an inadequate response (⩾1 relapse) to prior therapy at baseline (BL) had improved clinical outcomes with alemtuzumab


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Poster Session 1, 22(S3) versus SC IFNB-1a over 2 years in CARE-MS II (NCT00548405). A significantly higher proportion of alemtuzumab patients achieved confirmed disability improvement (CDI). An extension study (NCT00930553) demonstrated durable efficacy of alemtuzumab through 5 years in the absence of continuous treatment. Goal: To evaluate the relationship between CDI and QoL in alemtuzumab-treated patients over 5 years. Methods: In CARE-MS II, patients received 2 courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). Patients who completed CARE-MS II could enter the extension, with asneeded alemtuzumab for relapse or MRI activity. Another DMT could be provided per investigator discretion. CDI was defined as ⩾1.0-point EDSS score decrease sustained over 6 months. QoL assessments included FAMS, EQ-5D VAS, SF-36 PCS and MCS. Results: 393 of 423 (93%) alemtuzumab patients who completed CARE MS II entered the extension; 357/393 (91%) remained on study at Year 5. Patients with CDI (n=61 [18%]) or without (n=269 [82%]) had stable/improved QoL. In Years 1-5, mean improvements from BL in FAMS, EQ-5D VAS, and SF-36 PCS scores were significantly greater in patients who achieved CDI versus those who did not (FAMS: 14.3, 12.7, 11.7, 10.0, and 9.7 versus 6.2, 3.5, 0.9, -0.4, and -0.9, respectively; EQ-5D VAS: 11.1, 11.2, 7.9, 8.3, 7.7 versus 4.4, 3.4, 1.2, 0.8, and 0.2; SF-36 PCS: 5.5, 5.1, 4.1, 3.8, and 3.6 versus 2.2, 1.9, 0.6, -0.2, and -0.1; all P< 0.05). SF-36 MCS improvements were also greater for patients with CDI (4.2, 3.2, 3.2, 3.1, and 3.5) than without (3.0, 1.6, 1.1, 1.1, and 0.1, respectively; Year 5 P< 0.05). Proportions with improved (⩾5-point increase) or stable (< 5.0-point change) scores were higher for patients with CDI than without on the SF-36 PCS (Years 1-5: 90.2%, 83.3%, 84.6%, 86.4%, and 88.5% vs 85.8%, 81.3%, 79.9%, 72.4%, and 78.5%; all P< 0.05) and MCS (83.6%, 76.0%, 74.0%, 77.1%, and 78.8% vs 76.6%, 73.5%, 69.8%, 67.3%, and 68.7%; Years 4 and 5: P< 0.05). Conclusion: In alemtuzumab-treated patients with or without CDI, QoL measurements are improved or stable over 5 years. Improvements are greater in patients achieving CDI, demonstrating that this outcome measure is clinically meaningful. Disclosure Study support: Sanofi Genzyme and Bayer Healthcare Pharmaceuticals. RAG: Advisory board participant and speaker (Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, Teva). DD: Honoraria for advisory boards and participations and travel grants from Bayer, Merck-Serono, Novartis, Sanofi Genzyme, and Teva. MD: Consultant, advisory board participant, and research support from Sanofi Genzyme. RH: Research grants, speaking fees and honoraria for advisory boards from Biogen, Merck, Novartis, Sanofi Genzyme, and Teva. CL: Compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi Genzyme, Strativa, Teva, and UCB). JL: Travel support and/or lecture honoraria (Biogen, Novartis, Sanofi Genzyme, and Teva); serving on scientific advisory boards (Almirall, Biogen, Novartis, Sanofi Genzyme, and Teva); serves on the editorial board of the Acta Neurologica Scandinavica; unconditional research grants (Biogen, Novartis, and Teva). TM: Consulting fees and speaking fees (Almirall, Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva).

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BS: Speaking and/or consulting (Acorda, Bayer, Biogen, EMD Serono, Genentech, Novartis, Pfizer, Sanofi Genzyme, and Teva); research support (Acorda, Biogen, MedImmune, Novartis, Roche, and Sanofi Genzyme). DM and KT: Employees of Sanofi Genzyme. GG: Personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees (Bayer Healthcare Pharmaceuticals, Biogen, Canbex, Eisai, Elan, Five Prime Therapeutics, Genentech, GlaxoSmithKline, Ironwood, Merck Serono, Novartis, Pfizer, Roche, Sanofi Genzyme, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals). P769 A non-randomized, open label, exploratory study of dalfampridine- extended release and sexual dysfunction in women with multiple sclerosis R. Berkovich1, J. Aparicio2, L. Tarlow2, A. Palomeque2, L. Amezcua2 1University of Southern California, 2Neurology, University of Southern California, Los Angeles, CA, United States Multiple sclerosis (MS) is associated with sexual dysfunction and affects mostly women. Approved for walking impairment in MS, dalfampridine-extended-release (D-ER) is thought to act by restoring conduction in focally demyelinated axons and enhancing neurotransmission, thereby leading to improved neurological function. It is plausible that D-ER could improve sexual function and other physical aspects of MS such as bladder function and fatigue. Objective: To explore whether D-ER has an effect in sexual function domains in women with MS. Methods: Women with MS with stable disease who were newly prescribed D-ER (10 mg twice daily) for approved indication were invited to participate in this observational, exploratory study. 33 were screened for sexual dysfunction, 28 met inclusion criteria. The female Sexual Function Questionnaire was completed using semi-structured interviews before (n=28) and 8±2 weeks after start of D-ER(n=11). Demographic and clinical data were also obtained from interview and medical chart review. Paired t-test was used to assess the change before and after in sexual function domains: desire, arousal (i.e. sensation, lubrication, cognitive), orgasm, pain, enjoyment, and partner. Bladder and fatigue components from the MS quality of life inventory were also completed. Spearman rank correlations were performed between sexual function domains and EDSS, timed 25-foot walk (T25FW), fatigue, and bladder function. Results: Most were on MS therapy (n=23,86%) and T25FW ranged from 8 to 26 seconds (Mean10.9,SD±4.1). Sexual function scores fell in the dysfunctional level for all. Among those that completed the second questionnaire and were on D-ER for >8 weeks, there was significant improvement in desire (p=0.01), sensation (p=0.003), lubrication (p=0.03), cognitive (p=0.005), orgasm (p=0.04), pain (p=0.02), enjoyment (p=0.002) and partner scores (p=0.02). Each domain transitioned from high probability to borderline sexual dysfunctional scores with the exception of orgasm and lubrication. While bladder did not significantly improve, T25FW (Mean7.8,SD±1.4, p=0.03) and fatigue scores did (Mean35.3,SD±16.5, p=0.009). An inverse correlation was seen between fatigue score and partner domain (r=0.6, p=0.002).


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Conclusion: Preliminary data support further investigation on the effects of D-ER in treating sexual dysfunction in women with MS. We speculate that pelvic rich voltage-sensitive-potassium channels involved in sexual response are responsive to D-ER. Disclosure Dr. Berkovich has consulted and is a speaker for ACORDA, Biogen, Genzyme, Bayer, Mallinckrodt, Novartis, Serono, and TEVA. L. Tarlow has consulted and is a speaker for ACORDA, Biogen, Genzyme, Bayer, Mallinckrodt, Serono, Novartis and TEVA. J. Aparicio and A. Palomeque have nothing to disclose. Dr. Amezcua has consulted for Genzyme, Biogen, and has funding from Novartis. Funding source: The following research was supported by ACORDA through an investigator-initiated study (PI: L. Amezcua) P770 Illness- and medication-perceptions are key aspects affecting health-related quality of life in patients with MS S. Ratzabi1, E. Neter2, I. Lejbkowicz1,3, L. Glass-Marmor1,3, I. Lavi4, A. Miller1,3 1Multiple Sclerosis Center & Neuroimmunology Unit, Carmel Medical Center, Haifa, 2Ruppin Academic Center, Emek Hefer, 3Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 4Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel Background: Health-Related Quality of Life (HRQoL) is an important patient reported outcome (PRO) in MS disease management. Physical disability and emotional factors were identified as affecting HRQoL of persons with MS (PwMS), while the effects of perceptions were considered only scarcely. Aims: To assess the effects of physical disability, illness and medication perceptions and emotional factors on the HRQoL of PwMS. Methods: Pilot study of 66 Relapsing Remitting PwMS treated at our MS Center. Questionnaires assessing HRQoL, demographic data, illness and medicine perceptions, and emotional factors were filled by the participants. Physical disability (EDSS) was evaluated by the treating neurologist. Univariable analysis and Hierarchical Forced Step Regression were performed to assess association of the variables with HRQoL. Results: Univariable analysis indicated that socio-economic status (SES), EDSS, illness perception, medication perception and emotional factors were significant associated with HRQoL. Hierarchical Forced Step Regression was performed in five steps. The analysis revealed a weak association of SES (β=0.36, p< 0.01, R²model=9.9%) in the demographic step and no significant effect of EDSS in the physical disability step (R²model=12.4%). A strong significant association of illness and medicine perceptions (β=0.36, p< 0.01and β =0.23, p=0.05, respectively, and R²model=29.2%) were found in the perceptions step, in addition to the strong association of the emotional factors anxiety (β =-0.41, p< 0.01and R² model = 37.1%) and depression (β =-0.486, p=0.02 and R² model =43.0%) shown in the fourth and fifth steps. The addition of emotional factors to the final steps of the model masked the effect of factors significant in the previous steps.

Conclusions: Our study suggests that illness- and medicationperceptions, malleable constructs, are key aspects associated with HRQoL in PwMS, in addition to the already-known impacts of depression and anxiety. Recognizing the contribution of perceptions can have practical implications on application of personalized and tailored psychological interventions that may contribute to a better HRQoL of PwMS. Disclosure Sharonne Ratzabi: nothing to disclose Efrat Neter: nothing to disclose Izabella Lejbkowicz: nothing to disclose Lea Glass-Marmor: nothing to disclose Idit Lavi: nothing to disclose Ariel Miller: nothing to disclose P771 Prospective validation of a short version of MSQOL-54 (MSQOL-29): preliminary findings R. Rosato1, S. Testa1, A. Bertolotto2, F. Scavelli2, P. Confalonieri3, A.M. Giovannetti3, F. Patti4, C.G. Chisari4, A. Lugaresi5,6, E. Pietrolongo5, M.G. Grasso7, I. Rossi7, A. Toscano1, B. Loera1, A. Giordano3, A. Solari3 1University of Turin, Turin, 2Regional Referral Multiple Sclerosis Centre (CReSM), University Hospital San Luigi Gonzaga, Orbassano, 3Foundation IRCCS Neurological Institute C. Besta, Milan, 4University Hospital Policlinico Vittorio Emanuele, Catania, 5G. d’Annunzio University of Chieti-Pescara, Chieti, 6University of Bologna, Bologna, 7IRCCS S. Lucia Foundation, Rome, Italy Background: We recently developed a short version of Multiple Sclerosis Quality Of Life-54 (MSQOL-54) using factor analysis and item response theory [Rosato et al., Plos ONE 2016]. The short version, named MSQOL-29 (25 items grouped in 7 subscales, plus 4 single items) is also available in electronic, selfadministered form, with automatic scoring (eMSQOL-29). Objectives: To prospectively assess the clinical and metric properties of the eMSQOL-29. Methods: Patients from 5 Italian MS centers completed (in citation order) eMSQOL-29, Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Multiple Sclerosis (FAMS), and European Quality of life Dimensions-3L (EQ-5D-3L). The neurologist administered the Extended Disability Status Scale (EDSS), the symbol digit modality test (SDMT) and recorded patient general and clinical information. Correlations were assessed using Pearson’s r. Cronbach’s alpha and confirmative factor analysis (CFA) of MSQOL-29 subscales were also performed. Results: Between September 2015 and April 2016, 588 MS patients were assessed (mean age 44.1 years; 68% women). Median EDSS score was 2.0 (range 0-9.0), mean SDMT was 47.5 (SD 14.9, 46.9% had score < 49). Mean FAMS score was 125.3 (SD 26.8); mean HADS-Anxiety score was 6.0 (SD 4.0, 27.6% had score >8), mean HADS-Depression score was 4.2 (SD 3.7, 15.1% had score >8); and mean EQ-5D-3L score was 0.85 (SD 0.17). Three of the 4 Sexual Function items were preceded by a filter question, and were filtered out in 276 patients (47%). Of the remaining items, missing replies ranged from 2.4% (item 1) to 8%


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Poster Session 1, 22(S3) (item 29). Subscales with maximum score >10% were Physical Function, Sexual Function, Cognitive Function, Pain and Health Distress. No subscales had minimum score >10%. Cronbach’s alpha ranged from 0.78 (Sexual Function) to 0.96 (Physical Function). CFA of eMSQOL-29 subscales showed good overall fit (RMSEA 0.032; CFI 0.99; SRMR 0.042). Correlations between the four eMSQOL-29 and FAMS subscales addressing similar domains ranged from 0.62 (p< 0.001) to 0.85 (p< 0.001); correlation of eMSQOL-29 Emotional Wellbeing with HADS-Anxiety was -0.57 (p< 0.001), with HADS-Depression was -0.54 (p< 0.001); correlation of eMSQOL-29 Cognitive Function with SDMT was 0.29 (p< 0.001). Conclusions: eMSQOL-29 showed good internal consistency, factor structure, and no floor effect, while most subscales had some ceiling effect. Concurrent validity was good except for low correlation for cognitive domain. Disclosure Funding: This study was supported by the Fondazione Italiana Sclerosi Multipla (FISM, www.aism.it, grant No. 2013/R/20 to RR). Conflict of interest: The authors have nothing to disclose. P772 Social support and depression in individuals with multiple sclerosis M.P. Jensen, A.R. Smith, I.R. Molton Rehabilitation Medicine, University of Washington, Seattle, WA, United States Introduction: Social support is known to be associated with depression in individuals with multiple sclerosis (MS). However, the majority of studies have examined these relationships using cross-sectional designs. Relatively few studies have examined how social support might change over time, and how changes in social support are associated with changes in depression in people with MS. Methods: Individuals with MS (N=210; mean age: 53.79 years; 82% women) completed surveys assessing demographic variables (age, sex), depression (PROMIS Depression item bank scales) and social support (MPSS) on two occasions, separated by about 3.5 years (Timepoints 1 and 2). ANOVAs tested for changes in perceived social support over time, and a regression analysis examined the effects of changes three social support domains (support from a significant other, friends, and family) on change in depression. Results: Analyses indicated no systematic changes from Timepoint 1 to Timepoint 2 in perceived support from significant others, family, or friends. However, there was individual variability in perceived social support over time, with SDs in social support scores ranging from 1.51 to 1.67 on a scale that can only range from 1 to 7. After controlling for the depression score at Timepoint 1, the demographic variables did not contribute significantly to the prediction of depression at Timepoint 2. Change in the three social support domains made a significant contribution to the prediction of depression at Timepoint 2 (R-square change = .06, F-change (3,203) = 5.84, p = .001). However, change in support from the significant other (Beta = .20, t = 2.65, p =.009) made a statistically significant independent contribution to the second depression score.

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Conclusions: The findings indicate that individuals with MS do not perceive systematic changes over time in the amount of social support they receive from their significant others, friends, and family. However, there was variability social support changes, and these changes were significantly associated with changes in depression, with increases in support being associated with decreases in depression. Most of this effect is due to changes in perceptions of support from the participant’s significant other. This suggests the possibility that support from one’s significant other may be particularly important in this population - at least as a predictor of changes depression. Disclosure The contents of this presentation were developed under a grant from National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR grant number 90RT5023-0100). NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). The contents of this presentation do not necessarily represent the policy of NIDILRR, ACL, HHS, and readers should not assume endorsement by the Federal Government. P773 Adaptation and preliminary testing of Six Neuro-QoL Item banks for use in the Swedish neuro-registries/multiple sclerosis registry (NEUROreg/MSreg) J.E. Chaplin1, K. Lycke2, L. Egertz3, E. Helmersson4, L. Stawiarz2, J. Hillert2 1Institute of Clinical Sciences, Pediatrics, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 2Karolinska Institute, 3Stockholm County Council, 4Swedish MS Registry, Stockholm, Sweden Aim: Neuro-QoL provides a clinically relevant and psychometrically robust tool for assessment of quality of life (QoL) in both adults and children with common neurological disorders. We report here the protocol for the translation and cultural adaption of a subset of Neuro-QoL item banks into Swedish and the integration strategy for the Swedish Neuro-registries/Multiple Sclerosis registry (NEUROreg/MSreg). Method: A multidisciplinary team including patient representation was established. Six Neuro-QoL item banks were selected representing the needs for patient reported data collection in MS. These included two full item banks (cognition and fatigue) and four short-form item banks (upper and lower extremity function, positive affect, satisfaction, and ability to participate in social roles and activities). A protocol for the translation and cultural adaptation of the item banks was agreed, which followed the standardised approach outlined by the Neuro-QoL assessment centre. This included two forward translations, one back translation, three reviewers, cognitive debriefing and a finalisation review. Results: Initial analysis indicates a close agreement with the original items, however some cultural adaption, clarification and updating is required. Terms which might be clear in the English context may not be in the Swedish context for example “work at home” might mean distance work or housework. Questions using topical terms or referring to technology eg “touch tone key-pad” need to be updated regularly or avoided. More fundamental


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cultural issues also arose such as the extent to which someone would use absolute terminology eg. “my life had purpose” as opposed to “my life felt like it had purpose”. Conclusion: Subtle differences in meaning between the English and Swedish translations will be explored via expert review and a thorough cognitive debriefing process with MS patients from two regions in Sweden. Item banking will contribute to the integration of the patient’s perspective into the quality data registry and lead to a better understanding of quality of life in MS. In the future, comparisons of PRO registry data will be possible both nationally and internationally. Results and reflections from the cultural adaption process will be reported. Disclosure John Chaplin - Nothing to disclose. Karin Lycke - Nothing to disclose. Lillemor Egertz - Nothing to disclose. Eva Helmersson - Nothing to disclose. Leszek Stawiarz - Nothing to disclose. Jan Hillert - has received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme and Novartis. P774 A comparison of the association between multiple sclerosis symptoms and quality of life among people with relapsing and progressive multiple sclerosis C. Chen1, E. Baraban1, T. Stuchiner1, L. Lucas1, S. Cohan2 1Providence Brain & Spine Institute, 2Providence Multiple Sclerosis Center, Providence Health & Services, Portland, OR, United States Background: Multiple Sclerosis (MS) disease course and severity varies widely among individuals and can result in debilitating symptoms that negatively impact quality of life (QOL). The aim of this study was to investigate the impact of MS symptoms on QOL in people with progressive forms of multiple sclerosis (PMS) as compared to people with relapsing MS (RMS). Methods: Cross-sectional patient reported data from the Pacific Northwest MS Registry were used. Patient demographics, disease history, symptoms, and the Multiple Sclerosis Impact Scale (MSIS) physical and psychological scores were examined among RMS and PMS participants who returned surveys from 2013 to 2016. Maximum Likelihood Exploratory Factor Analysis for binary variables was used to group twenty symptoms into composite factors. Multiple linear regression was applied to determine which factors were most highly correlated with quality of life indicators among the RMS and PMS cohorts. Results: For the RMS cohort (n=1,298), symptoms clustered into 4 factors: pain and sensory problems, dysphasia/speech problems and immobility, sexual and bladder/bowel dysfunction, and cognitive/ psychological impairment. Among this group, pain and sensory problems had the most influence on the physical score (Relative Risk (RR) =9.88, p< .001) and cognitive/psychological impairment had most influence on the psychological score (RR=11.02, p< .001). For those with PMS (n=794), the symptom factors were pain and sensory problems, dysphasia/speech problems and visual loss,

and bladder/bowel dysfunction and spasticity. Among the PMS cohort, bladder/bowel dysfunction and spasticity had the most influence on the physical score (RR=10.07, p< .001) and pain and sensory problems had most influence on the psychological score (RR=9.88, p< .001). Conclusion: The results demonstrated that certain symptom factors affect the psychological and physical dimensions of QOL differently among RMS and PMS. While the psychological score was most highly correlated with the sensory and pain factor for PMS, the strongest influence on the psychological score for RMS was cognitive/psychological impairment. The physical score for the PMS group was most correlated with bladder/bowel dysfunction and spasticity, while pain and sensory problems were most influential for the RMS cohort. Future studies will attempt to elucidate underlying physiological or pathophysiological features that contribute to the symptom clusters derived from factor analysis. Disclosure Chiayi Chen, Elizabeth Baraban, Tamela Stuchiner, and Lindsay Lucas have nothing to disclose. Stanley Cohan serves on steering committees and advisory boards for Biogen, Novartis, Sanofi-Genzyme, Genentech, and Mallinckrodt, receives research support from Biogen, Novartis, Sanofi-Genzyme, Roche, Opexa, and Mallinckrodt, receives speaking honoraria from Biogen, Novartis, Sanofi-Genzyme and Acorda; received support for air travel, lodging and meals from Biogen, Novartis, and Sanofi-Genzyme. P775 Perception of disease severity in patients with multiple sclerosis I. León1, L. Bau1, E. Matas1, L. Romero-Pinel1, M.A. Mañé-Martínez2, S. Macho1, A. Martínez-Yélamos1, S. Martínez-Yélamos1 1Department of Neurology, Hospital Universitari de BellvitgeIDIBELL, Hospitalet de Llobregat, 2Department of Neurology, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain Background: Differences between patient and health professional perception of chronic disease have been studied, although little is known about perception of disease severity in people with multiple sclerosis (PwMS). Decision-making should be a shared process between patients and health professionals in order to achieve an agreement on medical decisions. We have to be aware that discrepancies between health professionals and PwMS in disease severity perception may arise. Taking into account these discrepancies may help to avoid possible conflict in the decision making process. Objective: To assess the concordance between disease severity perception and objective clinical severity. To analyze the influence of personality traits, depression, cognitive impairment and clinical characteristics in patients’ disease perception. Methods: An observational pilot study was performed in a Multiple Sclerosis unit. Patients were asked to evaluate their disease severity with Visual Analogue Scale (VAS), depression with Patient Health Questionnaire (PHQ-9), personality with Ten Item Personality Measure (TIPI) and cognition with Verbal Fluency


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Poster Session 1, 22(S3) Test (FAS). Age, sex, Multiple Sclerosis Severity Score (MSSS), Expanded Disability Status Scale (EDSS), time from the last relapse and disease duration were also collected. A Pearson correlation test was performed between MSSS (objective clinical severity) and VAS (patient perception). A linear regression model was performed to explain the difference between VAS scale and MSSS. Results: 30 patients were selected, 25 women and 5 men. Patients characteristics were: Mean age 46 (±10.5) years, EDSS 3.4 (±2.2), disease duration 17 (±10) years, MSSS 3.68 (±2.79). Only MSSS independently correlated with the difference between perception and objective clinical severity (VAS-MSSS): patients with higher MSSS showed more negative values in the difference between VAS-MSSS. For each one MSSS point increase, this difference increased -0.464 (95% CI -0.449 to -0.058). MSSS scores explained 21.5% of this difference variability. Conclusion: Patients with higher MSSS scores show a more optimistic perception of their disease. This perception it is not influenced by personality traits, depression, cognitive impairment or clinical characteristics. Disclosure I.León received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. L.Bau received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. E.Matas received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. L.Romero-Pinel received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. MA Mañé-Martínez received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. S.Macho received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono A. Martínez-Yélamos received received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono. S. Martínez-Yélamos received research support, funding for travel and congress expenses and honoraria from speaking engagements and scientific advisory board from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer HealthCare Pharmaceuticals and Merck Serono.

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P776 Long-term quality of life outcome in subjects with multiple sclerosis responding to treatment with fampridine F.A. Rodriguez-Leal, J. Eisele, U. Hainke, U. Konofalska, K. Thomas, T. Schultheiss, T. Ziemssen Center for Clinical Neuroscience. University Hospital Carl Gustav Carus, Dresden, Germany Introduction: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative neurological disease, causing walking disability in up to 70% of subjects affected with the disease. Quality of life (QoL) is an important aspect of MS closely related to walking capability. Fampridine is the first medication approved for improving walking disability in MS, but its impact on QoL has not been explored in a long term follow-up. Objective: To analyze QoL in subjects with MS responding to fampridine in a period over two years. Methods: QoL was monitored with the EQ-5D questionnaire, the Würzburger fatigue inventory for MS (WEIMuS) and the Common Depression scale (ADS-L), which were applied before starting treatment with fampridine, two weeks after beginning of treatment, and once annually. Gait assessment was performed by Timed-25 Foot Walk Test (T25FW). Results: 134 subjects with diagnosis of MS and responding to Fampridine were included, of which 87 were female (65.4%) and 46 (34.6%) were male, their mean age was 54.3 (SD± 11.4), mean EDSS was 5.2 (SD ± 1.3); 55 (42%) had a diagnosis of Relapsing-remitting MS, 40 (30.5%) had secondary progressive MS, and 36 (27.5%) had primary progressive MS. Their mean disease evolution time in years since diagnosis was 13.5 (SD ±8.4). All subjects had a mean significant improvement in the EQ-5D, ADS-L and WEIMuS from baseline to two weeks (p< .05) afterwards [EQ-5D= 5.4 (SD±1.9) and 6.31 (SD+1.7); ADS-L= 14.8 (SD±8.3) and 12.6 (SD±7.3); WEIMuS= 16.5 (SD±7.1) and 12.9 (SD± 7.2), at baseline and two weeks later, respectively], and a non-significant improvement one year and two years after the beginning of treatment, as compared to baseline. Compared to the two week time point, a non-significant decrease [EQ-5D= 5.6 (SD± 2.04) and 5.5 (SD± 2.0); ADS-L= 15.1 (SD±9.5) and= 14.6 (SD± 7.4); WEIMuS= 15.3 (SD ± 7.2) and 15.3 (SD ± 6.8) ] was observed one year and two years after baseline, respectively. In gait analysis, there was a significant speed improvement in the T25FW from a mean baseline time of 16.4 (SD 27.2) to 12.3 (SD 17.2) after two weeks (p= .05), but not a sustained speed improvement after one and two years. Conclusion: QoL in subjects with MS responding to Fampridine is affected in a similar fashion as walking speed in the long term follow up which is probably part of the ongoing clinical process. Further functional outcomes and their relationship to the effects of fampridine must be explored in the future. Disclosure Francisco Rodriguez-Leal: Nothing to disclose Judith Eisele: nothing to disclose Undine Heinke: Nothing to disclose Urszula Konofalska: Nothing to disclose


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Katja Thomas: received speaker honoraria from Novartis, Bayer, Biogen Idec; J. Schultheiss T: Nothing to disclose Tjalf Ziemssen: is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Genzyme, MSD, GDSK, Novartis, Teva, Sanofi, Almirall, is section editor for BMC Neurology, received research support from Bayer Healthcare, Biogen Idec, Genzyme, Novartis, Teva, Sanofi.

P777 Factors associated with acceptance to intramuscular interferon β-1a in patients with multiple sclerosis: results from the ADOPTE study C. Mekies1, M. Coustans2, S. Bourée3, Y. Bourhis3, S. Nouet4, M. Debouverie5 1Clinique du Parc, Toulouse, 2Centre Hospitalier, Quimper, 3Mapi, Lyon, 4Biogen France SAS, Nanterre, 5Hôpital Central, Nancy, France Background: ACCEPT® is a 32-items self-administered questionnaire validated to measure patient acceptance to treatment. Acceptance is defined as the balance between advantages and disadvantages of treatment as rated by the patient and is likely to predetermine patient behavior towards their treatment. Objective: To assess patient acceptance to intramuscular interferon β-1a (IM INFβ-1a) in patients with multiple sclerosis (MS) and to investigate the factors associated with acceptance to IM INFβ-1a. Methods: ADOPTE was an observational, prospective, longitudinal, multicenter study conducted in France by 105 neurologists. A total of 397 adult patients with MS initiating a treatment with IM INFβ-1a were enrolled. Baseline demographic, clinical and therapeutic data were collected at patient inclusion. ACCEPT® was completed by patients and caregivers 3, 6, 12 and 24 months after IM INFβ-1a initiation. Medication-taking Adherence Scale (MMAS), Multiple Sclerosis Knowledge Questionnaire (MSKQ) and therapeutic alliance questionnaires were completed during follow-up. Data from 335 patients who fulfilled all selection criteria and attended at least one follow-up visit were analysed. Analyses of covariance (ANCOVA) were conducted to identify factors associated with patient acceptance. Results: Mean age of patients was 38.4 (±10.3) years and 77.9% were female. Median time since MS diagnosis was 3.4 (±6.1) years. Mean Expanded Disability Status Scale score was 1.6 (±1.3). Mean general acceptance scores (0: poor acceptance; 100: good acceptance) at month 3, 6, 12 and 24 were respectively 44.9 (±29.2), 45.7 (±29.7), 48.6 (±30.7) and 50.0 (±31.9). No significant association between early acceptance and late adherence was observed. Mean general acceptance score at month 12 increased significantly with IM INFβ-1a persistence at month 24 (60.1 (±28.0) in persistent patients vs. 40.5 (±29.9) in patients who discontinued their treatment, p< 0.001). ANCOVA analyses showed that higher general acceptance scores were significantly associated with higher caregiver acceptance score and higher level of therapeutic alliance at month 3. In addition, higher general acceptance scores at month 6, 12 and 24 were significantly associated with higher general acceptance score at month 3. Conclusion: These results highlight a strong association between acceptance and IM INFβ-1a persistence and the major role of

caregivers and physicians in improving patient acceptance to IM INFβ-1a. Disclosure Mékies C: consulting research and/or workshops for Novartis, Biogen, Bayer, Merck, Teva, Genzyme/Sanofi, Allergan, Almirall, EISAI, Coloplast, Lundbeck, and Pfizer Coustans M: consulting research and/or workshops for Novartis, Biogen, Teva, and Genzyme Bourée S: full-time employees of MAPI Bourhis Y: full-time employees of MAPI Nouet S: full-time employee of Biogen France SAS Debouverie M: consulting research and/or workshops for BayerSchering, Biogen, Genzyme, Merck-Serono, Novartis, SanofiAventis, and Teva P778 Loneliness and pessimism are independent predictors of timed 25-feet walk worsening at 5 years among ageing MS patients enrolled in the New York State Multiple Sclerosis Consortium B. Weinstock-Guttman1, K.S. Kavak1, A. Bushra1, K. Noyes2, P. Coyle3, L. Krupp3, A. Goodman4, B. Jubelt5, K. Edwards6, M. Gottesman7, R.H. Benedict8, C.B. Vaughn1, New York State Multiple Sclerosis Consortium 1Dept. of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Buffalo, 2School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, 3Dept. of Neurology, SUNY Stony Brook School of Medicine, MS Comprehensive Care Center, Stony Brook, 4Dept. of Neurology, University of Rochester Medical Center, Rochester, 5Dept. of Neurology MS Clinic, SUNY Upstate Medical University, Syracuse, 6MS Center of Northeastern New York, Latham, 7Winthrop Comprehensive MS Care Center, Mineola, 8Department of Neurology, School of Medicine and Biomedical Sciences, Buffalo, NY, United States Background: The Timed 25-Foot Walk (T25FW) is a simple and quick walking test that is frequently used as a quantitative mobility performance test for multiple sclerosis (MS) patients. Studies have reported that a 20% increase in T25FW is indicative of significant gait and disease worsening. Objective: To identify predictors of T25FW worsening in an ageing MS sample. Methods: This is a retrospective study of subjects enrolled in the New York State MS Consortium (NYSMSC), a 20-year longitudinal, population-based registry of MS patients. In this study, patients 60 years or over at their most recent follow-up and with a disease duration of ⩾15 years were analysed. Time to complete the T25FW test was compared between baseline and a follow-up visit 5 years later. Worsening was defined as a 20% increase in time to complete the test. Independent samples t-tests and chi-square tests were used to investigate group differences. Logistic regression analyses were carried out to adjust for covariates. Results: Of the 272 patients in our database with complete data, 119 (43.8%) had a 20% increase in time it took to complete the T25FW. At year 5, those who worsened had a mean score of


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Poster Session 1, 22(S3) 20.7±20.8 seconds, while subjects who did not worsen had a mean score of 8.3±6.3 seconds, and baseline scores were similar between the groups (9.1±7.0 seconds vs 9.2±7.9 seconds, respectively). There were no differences in age, sex, disease duration, DMT use, or self-reported physical difficulties between subjects with a worsening in T25FW compared to those who did not. Patients who worsened had higher Kurtzke Expanded Disability Status Scale (EDSS) scores at baseline (3.9±1.6 vs 3.4±1.7, p=.023) and were more likely to report feeling lonely (12.6% vs 4.7%, p=.017) and pessimistic (25.2% vs 14.6%, p=.028). Furthermore, patients who had worsened T25FW scores also had higher EDSS scores at year 5 (5.3±15 vs 3.8±1.7, p< .001). Results remained significant after adjusting for age, disease duration, and marital status. Conclusion: Loneliness and pessimism, a hallmark of neuroticism, in addition to higher EDSS scores at study enrolment were predictive of T25FW worsening over 5 years in a sample of MS patients with a disease duration of 15 years or longer supporting the need for neurobehavioural evaluation and counselling. Disclosure Bianca Weinstock-Guttman: received personal compensation for consulting, speaking and serving on a scientific advisory board for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Questcor and Genzyme& Sanofi and has received financial support for research activities from NMSS, NIH (not for the present study), ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Genzyme. Katelyn Kavak: nothing to disclose. Aisha Bushra: nothing to disclose. Katia Noyes: nothing to disclose. Patricia Coyle: receives consulting fees from AbbVie, Accordant, Acorda, Bayer, Biogen, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, and Teva. She also receives research support from Actelion, Genentech/Roche, NINDS, Novartis, and Opexa. Lauren Krupp: received either consulting fees, honoraria, or royalty payments from the following: Biogen, Pfizer, Teva Neurosciences, EMD Serono, Janseen, Biogen, Novartis, Abbvie. Andrew Goodman: received personal compensation for consulting from the following commercial entities: Abbvie, Acorda Therapeutics, Atara, Bayer, Biogen Idec, Genentech, Sanofi Genzyme, Novartis, Purdue, Teva. Dr. Goodman´s employer, the University of Rochester, received research support for conducting clinical trials from the following commercial entities: Acorda Therapeutics, Avanir, Biogen-Idec, EMD-Serono, Novartis, Ono, Roche, Sanofi Genzyme, Sun Pharma, Teva. Burk Jubelt: received Clinical Trial Grants from: Sanofi-Aventis (Relapsing MS/Teriflunomide), Genzyme (MS/Alemtuzumab), Novartis (Secondary Progressive MS/Fingolimod/Siponimod), Grifols (Post Polio Syndrome/Flebogamma), Receptos (MS/ RPC1063), NY Stem Cell Program (Secondary Progressive MS), NIH/NINDS (SUNY Next Clinical Site), Clinical Studies: BiogenIdec, Continuing Medical Education Speaker:CMEducation Resources LLC,Prime Education, Inc., Patient Education Speaker: National Multiple Sclerosis Society, Multiple Sclerosis Resources of Central New York. Keith Edwards: Consulting services: Biogen, Genzyme. Speaker bureaus: Biogen, Genzyme. Research support: Actelion, Biogen, Eisai, Eli Lilly, Forum Pharmaceuticals, Genentech, Genzyme/

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Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis, Pfizer, Vaccinex.Malcolm Gottesman: has served as a consultant for Biogen, Teva, and Genzyme. Ralph Benedict: receives research support from Biogen, Novartis, Genzyme, Acorda and Mallinckrodt, provides consultation for Biogen, Genentech, Teva, Novartis, and Sanofi, and conducts CME for EMD Serono. Caila Vaughn: nothing to disclose.

Multi-disciplinary rehabilitation P779 Effects of high frequency repetitive transcranial magnetic stimulation on gait and balance in patients with chronic multiple sclerosis H.S. Shehata, N.M. Shalaby, A. Elmazny Neurology Department, Cairo University, Cairo, Egypt Gait disturbance is among the most common mobility limitation in chronic multiple sclerosis (MS). It is often of multifactorial origin and is characterized by decreased walking endurance, speed, cadence and step length. Emerging evidence suggests a role of prefrontal attention networks in gait modulation. High-frequency repetitive transcranial magnetic stimulation (rTMS) is known to enhance cortical excitability in the stimulated cortex and its connections. Objective: Investigated the safety and efficacy of high-frequency (10 Hz) prefrontal rTMS on gait parameters and balance in patients with chronic relapsing/remitting (RR) or secondary progressive (SP) MS with residual gait disability. Subjects and methods: This was a randomized, placebo controlled single blinded pilot study that included 31 MS patients (13 RR, 18 SP) with Expanded Disability Status Scale (EDSS) (4.5 6.0) and with residual disability in gait symptoms (aged 38.4 ± 8.9 years). During the 4-weeks study duration, patients were randomized to receive 20 sessions of either real (n=16) or sham (n=15) rTMS sessions, both groups received the same rehabilitation program that included gait training, enhancing motor learning and balance exercises. In real rTMS sessions, a total 2000 pulses of 10-Hz rTMS were delivered through 20 trains at 90% of motor threshold over the left prefrontal area. All patients were assessed at baseline and after the intervention using Timed Up and Go Test (TUG), 10-Meter Walking Test (TMWT), Berg Balance Scale, Four Square Step Test (FSST) and functional gait assessment (FGA). Results: Both groups showed significant improvement after completion of the study protocol in all efficacy variables. On comparing between real and sham groups, there were significant decrease in the performance time for TMWT (p< 0.02) and TUG (p < 0.05) with improvement of FGA (p< 0.01) and balance parameters (p< 0.02) for those who received real rTMS. There were no reported adverse events apart from mild and transient headaches. Conclusions: High-frequency rTMS on the left prefrontal cortex is a possible effective and safe treatment option for patients with MS to improve walking function and balance capabilities in addition to the standardized physical therapy. Disclosure Hatem S. Shehata: nothing to disclose Nevin M. Shalaby: nothing to disclose Alaa Elmazny: nothing to disclose


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P780 Telerehabilitation in multiple sclerosis: results of a randomized, 3-arm, rater blinded, feasibility and efficacy pilot study; patient-reported outcomes report C. Fjeldstad, A. Thiessen, G. Pardo Multiple Sclerosis Center of Excellence, OMRF, Oklahoma City, OK, United States Background: MS commonly results in physical and cognitive disability. Functional improvement of established physical deficits can be achieved through rehabilitation methods to include physical therapy (PT). Access to specialized rehabilitation services is limited due to a variety of factors including availability, geographical distance, mobility limitations, transportation difficulties, and financial constraints. Telecommunication technology offers the capacity to supervise and direct a PT program remotely through audio and visual real-time communication. Objectives: Demonstrate the feasibility of a tele-health rehabilitation program in individuals with ambulatory deficits secondary to MS and to evaluate its efficacy when compared to conventional physical therapy. Methods: This was a single-center, prospective, randomized, three-arm, evaluator blinded, 8-week study. Thirty individuals were included (female 69%, mean age 54.7 years, RMS 60%. SPMS 23%, PPMS 17%, mean EDSS 4.3). A home-based exercise program (HEP) was performed unsupervised 5 days a week for 8 weeks. Interventions were as follows: Group 1- HEP alone; Group 2- HEP plus remote PT supervised via audio and visual real-time telecommunication 2-3 times per week; Group 3- HEP plus in-person PT at the medical facility 2-3 times per week. Patient-reported outcomes and gait and balance assessments (reported separately) were performed. Results: Patient-reported outcomes showed improvement from baseline in the Modified fatigue impact scale (MFIS) for groups 2 (p=0.05) and 3 (p=0.01) and SF36-mental (SF36m) for groups 2 (p=0.04) and 3 (p=0.01). Groups 2 and 3 were comparatively equivalent in SF36m p=0.06, balance confidence p=0.47, MFIS p=0.37, and self-efficacy p=0.79. Group 3 was better than groups 1 and 2 only in the SF36-physical. One participant dropped out due to an MS relapse. Conclusions: Telerehabilitation is a convenient and practical method to perform PT in MS individuals and is overall equivalent to conventional in-person PT as measured by patient reported outcomes of fatigue, confidence and self-efficacy. Gait and balance outcomes were also favorable and are presented separately. Telerehabilitation should be researched further and used more extensively as a mean to improve function and quality of life in MS.

K. Riemann-Lorenz1, M. Eilers1, K.-H. Schulz2, G. von Geldern3, A. Rahn1, S. Köpke4, C. Heesen1 1Institute of Neuroimmunology and MS, 2Clinic for Medical Psychology, UMC, Hamburg, Germany, 3UW MS Center, University of Washington, Seattle, WA, United States, 4Social Science in Medicine, UKSH, Lübeck, Germany Background: Dietary factors have been discussed to influence risk or disease course of multiple sclerosis (MS) and specific diets and dietary supplements are widely used among people with MS (PwMS). Therefore, we aimed to assess PwMS’ dietary habits and information needs in order to develop and pilot-test an evidence based patient education programme on nutrition in MS. Methods: We performed a systematic literature search in 9/2010 with an update in 6/2015 on the effectiveness of dietary interventions in PwMS. In a next step, a web-based survey among n=337 PwMS and n=136 healthy controls assessed knowledge, dietary habits and information needs using a self-developed questionnaire. Based on the results an interactive group education programme was developed and piloted. Results: Fifteen randomised-controlled trials (RCTs) were included in the systematic review of which nine studies assessed fatty acid intake and six vitamin D supplementation. Overall, quality of evidence was low and no clear benefit could be seen for either treatment. Of the 337 PwMS who completed the survey, 143 (42%) had tried special diets for PwMS. Main reasons were: improving overall wellbeing (78%) and slowing down disease progression (73%). 30% of PwMS reported to adhere to a `Mediterranean Diet` compared to 14% of healthy controls (p< 0.001), but less often to a `Mixed Diet´ (PwMS: 42%, controls: 60%, p< 0.001). PwMS’ most important information needs addressed effectiveness of MS diets (44%) and relation between nutrition and MS (43%). The newly developed evidence-based patient education programme comprised basic knowledge on research methodology, relevant outcome measures of MS studies, information on widespread MS-diets and results of RCTs on diet and MS. A pilot test with 13 participants showed very good comprehensibility. Participants rated the amount of information as adequate and the MS-specific content as very important. However, the poor evidence base for MS diets was perceived as disappointing. Conclusions: There is no conclusive evidence on dietary interventions for PwMS. Nevertheless many PwMS use special diets which are widely advertised. The weak evidence base is disappointing for PwMS, but is acknowledged as important information. Based on the results of the pilot study, a, easy-accessible possibly web-based intervention should be developed and evaluated. Disclosure

Disclosure Cecilie Fjeldstad, PhD: nothing to disclose Amy Thiessen, PT: nothing to disclose Gabriel Pardo, MD: nothing to disclose This project was funded in part by the National Multiple Sclerosis Society P781 Multiple sclerosis and diet: systematic review, internetbased survey and pilot-testing of an evidence based patient education programme

K. Riemann-Lorenz has nothing to disclose. M. Eilers has nothing to disclose. S. Köpke has nothing to disclose. G. van Geldern has nothing to discölose. A. Rahn has nothing to disclose. K.H. Schulz has nothing to disclose. C. Heesen has received grants from, Biogen, Genzyme, Novartis. P782 Instrumented version of the modified dynamic gait index: a pilot study


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Poster Session 1, 22(S3) E. Gervasoni, G. Bovi, D. Anastasi, C. Grosso, M. Rovaris, M. Ferrarin, D. Cattaneo Don C. Gnocchi Foundation, Milan, Italy Background: Postural and gait instability are common impairments in Multiple Sclerosis (MS) leading to an increased risk of falls. The Dynamic Gait Index (DGI) is a widely used clinical assessment tool measuring dynamic balance. The modified DGI (mDGI [1]) is a recently introduced scoring system which allows a more precise evaluation of the patients´ performances. Inertial Measurement Units (IMUs) are wearable, low-cost devices which are widely used in balance disorders assessment. The aim of this study was to develop and validate an instrumented version of the mDGI to quantitatively measure dynamic balance. Design: Cross sectional study. Method: Ten people with MS (PwMS) with Expanded Disability Status Scale (EDSS) lower than 6.5 and mean age (Standard Deviation) of 49.5 (17.7) years and 10 Healthy Controls (HC) aged 55.1 (13.7) years were recruited. The subjects underwent clinical evaluation with the Timed Up and Go test, TUG, and mDGI. During the assessment of the mDGI tri-axial accelerometry and gyroscopic data were collected by means of a single IMU (X-sens, The Netherlands) positioned on the sternum through an elastic chest strap. For each of the eight mDGI items, a set of quantitative features related to dynamic balance was derived from the acceleration and angular signals. Factor Analysis (Principal Components with Normalized Varimax rotation) was performed on each set, and the main Factor Score (mFS) was extracted and used as a synthetic item performance score. The Instrumented mDGI score (ImDGI) was calculated as the mean of the mFSs of the eight items. Spearman correlation coefficients were calculated between clinical (mDGI and TUG) and ImDGI scores. Mann Whitney test was used to assess differences between PwMS and HC. Results: Median (Interquartile Range, IQR) mDGI score of PwMS and HC were respectively 37(13.75) and 64 (1) (P< 0.05). Median (IQR) ImDGI score of PwMS and HC were respectively -0.32 (0.24) and 0.36 (0.16) (P< 0.05). High correlation was found between mDGI and ImDGI (r=0.93), while moderate correlation was found between TUG and mDGI (r=-0.83) and TUG and ImDGI (r=-0.79). Conclusions: These preliminary results suggest that the proposed method can provide a valid, quantitative and objective measure to finely detect dynamic balance disorders in PwMS. A larger sample of subjects will be enrolled to further validate our results. Disclosure Elisa Gervasoni: Nothing to disclose. Gabriele Bovi: Nothing to disclose. Denise Anastasi: Nothing to disclose. Cristina Grosso: Nothing to disclose. Marco Rovaris: Nothing to disclose. Maurizio Ferrarin: Nothing to disclose. Davide Cattaneo: Nothing to disclose.

C. Gnocchi Foundation, Milan, 2DINOGMI, University of Genova, Genova, Italy Background: Upper limb dysfunctions display a main role of the disability in the activities of daily living. A high percentage of People with Multiple Sclerosis (PwMS) report upper limb dysfunctions, even in the early stage of the disease. The assessment of the dysfunctions of the upper limb may give additional information about the disability level and contribute to a better planning of rehabilitation programs. The aim of this study was to assess the fine hand motor function in PwMS measured by quantitative assessment of fingers motor performance and its relationship with the disability level. Design: Cross-sectional study. Methods: So far 25 PwMS (Mean age (Standard Deviation)) 55.04 (8.91) years; Expanded Disability Status Scale (EDSS) 6.08 (1.07) and 19 healthy controls (HC) (Mean age 48.26 (11.38) years) performed a repetitive finger-to-thumb opposition movement sequence with their dominant hand at spontaneous and maximal velocity, and unimanual metronome-paced. A sensor-engineered glove Peregrine (Iron Will Innovations Canada Inc) was used to measure in terms of Touch Duration (TD), Inter Tapping Interval (ITI), Global Rate (GR), and Number of corrected sequences (CS). Mann-Whitney U test was used to compare motor performances between PwMS and HC. A Spearman correlation was calculated between fingers motor performance and EDSS. Results: Fingers motor tests in terms of TD, ITI, GR and CS demonstrated significantly worse performances in PwMS than in HC at spontaneous and maximal velocity (p< 0.05). Further, in the MS group only TD at spontaneous velocity significantly correlated with the EDSS (r =0.59; p=0.007). During unimanual metronome-paced performances only TD showed statistically significant difference (p=0.03). Conclusions: A simple, quantitative and objective method measuring finger motor performances could be useful to discriminate PwMS and HC with moderate disability. Further investigations are needed to better profile upper limb dysfunctions. Disclosure Elisa Gervasoni: Nothing to disclose Davide Cattaneo: Nothing to disclose. Giulia Caprioglio:Nothing to disclose. Marco Rovaris: Nothing to disclose. Ambra Bisio: Nothing to disclose. Marco Bove: Nothing to disclose. P784 An android application to assess attention deficits in people with Multiple Sclerosis A. Tacchino1, F. Florio2, M. Venturini2, V. Sanguineti2, G. Brichetto1 1Italian Multiple Sclerosis Foundation (FISM), 2University of Genoa, Genoa, Italy

P783 A sensor-engineered glove to quantitatively assess fine hand motor function in MS E. Gervasoni1,2, D. Cattaneo1, G. Caprioglio1, M. Rovaris1, A. Bisio2, M. Bove2

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1Don

Background: Attention is mediated by three networks: alerting, responsible for increasing and maintaining vigilance and readiness to an upcoming stimulus; orienting, responsible for selecting an information in the context of numerous inputs; executive, responsible for selection and resolution of conflicts. In particular,


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people with Multiple Sclerosis (PwMS) exhibit a degradation in alerting and executive networks. Several studies have addressed attention deficits in PwMS using the Attention Network TestInteraction (ANT-I). However, the correlation between attentional performance and clinical conditions were no deeply evaluated up to now. Aim: To evaluate the correlation between attentional performance and clinical conditions in PwMS, using the Android version of ANT-I. Methods: 26 healthy subjects (HS) (mean age: 38 y, range: 21-69) and 30 PwMS were recruited (mean age: 51 y, range 26-70; course: RR, SP; EDSS: 1-7). After practice ANT-I consists of four experimental blocks, each one of 72 trials. In each trial warning tones or/and visual cues precede a central target (a fish, either looking toward left or right). It can be flanked by other distractors (other fishes, looking in congruent or incongruent directions). Subjects have to indicate the direction of the target fish as quickly and accurately as possible. ANT-I allows to examine the three networks. Clinical evaluations were Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), Symbol Digit Modalities Test (SDMT), Nine Hole Peg Test (9HPT). A mixed effects model for multivariate regression evaluated the clinical scores/attention coefficients (alerting, orienting, executive) relationship. The model is: β0 + b0i + β1 * FSSi + β2 * BDIi + β3 * 9HPTi + β4 * SDMTi + β5 * AGEi + εi , whit βi (i= 0-5), fixed and common to all subjects; b0i, random for each subject; εi, noise. Results: Reaction time and alerting, orienting, executive coefficients are significantly (p< 0.001) correlated to clinical variables through the mixed effects model. For PwMS a higher FSS and 9HPT score and a lower SDMT score corresponded to a longer reaction time; SDMT is specifically correlated with a better executive control. Conclusions: The main determinants of attention are fatigue (FSS), symbolic processing speed (SDMT) and incoordination (9HPT). Symbolic processing speed also correlates with an improved executive function. These results suggest a clear relation between attentional performance and clinical state. Disclosure Tacchino A.: nothing to disclose Florio F.: nothing to disclose Venturini M.: nothing to disclose Sanguineti V.: nothing to disclose Brichetto G.: nothing to disclose

Symptoms management P785 Content and extent of upper limb rehabilitation in multiple sclerosis across Europe I.G. Løyning1, P. Feys2, J. Jansa3, E. Santarmarta4, K. Rasova5, L. Kallmayer6, A. Tacchino7, A. Golewska8, T. Smedal9, S. Nødtvedt10, N. Filló11, J. Raats12, L. Kerhofs13, I. Baert2 1Occupational Therapy Dept., MS-Senteret Hakadal, Hakadal, Norway, 2REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium, 3University Medical Center Ljubljana (UMCL), Ljubljana, Slovenia, 4Eugenia Epalza Rehabiltation Center Bilbao, Bilbao, Spain,

5Charles

University and General Faculty Hospital, Prague, Czech Republic, 6MS Hospitals, Haslev and Ry, Haslev and Ry, Denmark, 7FISM Scientific Research (AISM), Milan, Italy, 8John Paul II Rehabilitation Center for People with MS, Borne Sulinowo, Poland, 9Haukeland University Hospital (Norwegian Multiple Sclerosis Competence Centre and Dept. of Physiotherapy), 10Haukeland University Hospital, Bergen, Norway, 11MS Center of Catalonia (Cemcat), Vall Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, 12AZ Klina, Campus de MICK, Brasschaat, 13Revalidatie en MS Centrum, Overpelt, Belgium Background: Very little is known on current clinical practice of upper limb rehabilitation (ULR) in multiple sclerosis (MS). Rehabilitation treatment taxonomy has been developed to classify the ‘active ingredients’ of rehabilitation treatment. Aim: To describe activities and interventions used in ULR for persons with MS (pwMS) across Europe. Methods: Data were collected from 11 European centers (RIMS network). General therapy characteristics (total therapy time, average duration and frequency of sessions, setting, goal) were recorded at the end of the rehabilitation program by the main attending occupational or physical therapist. To describe and record the trained activities and interventions in ULR, we used the standardized classification form developed by De Jong and colleagues. Results: One-hundred-and-twenty-eight pwMS were included, of which almost half were inpatients. Main goals were manual dexterity (29%), strength in UL (21%) and mobility in UL (20%). They received mean 17 (SD10) therapy sessions, mean duration of 45 min (SD14), mean 3 session/week (SD1.7) for mean 6.5 weeks (SD 3.9). The majority of therapy was individual (66.6%), besides group therapy (22.9%). Most frequently trained activities were “upper extremity control” (40.1% of time spent on all activities), “functional mobility” (16.5%) and “home management” (10.5%). Interventions most frequently used were “strengthening” (19.8%), “motor learning” (17.4%) and “mobilization/manual therapy” (12.4%). Interventions provided most frequently during “upper extremity control” were: “strengthening” (20.6%), “motor learning” (12.9%) and “Bobath” (12.4%); during “functional mobility”: “Bobath” (22.4%), “strengthening” (18.9%) and “motor learning” (16.7%); and during “home management”: “energy conservation” (21.6%), “adaptive equipment” (18.6%) and “environmental adaptation” (10%). Conclusion: Upper extremity control, Functional mobility and Home management cover 67% of all activities used in ULR. The high percentage of Upper extremity control can be due to the fact that this activity includes a broad range of concepts, while e.g. Feeding/eating is a very specific activity. In Bathing, Dressing and Home management the majority of interventions are Adaptive/ compensatory interventions, while for Upper extremity control and Functional mobility, neuromuscular and musculoskeletal interventions are more often used. Disclosure Inger Grethe Løyning: nothing to disclose Peter Feys: nothing to disclose Jelka Jansa: nothing to disclose Elisabeth Santarmarta: nothing to disclose Kamila Rasova: nothing to disclose Lene Kallmayer: nothing to disclose


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Poster Session 1, 22(S3) Andrea Tacchino: nothing to disclose Aleksandra Golewska: nothing to disclose Silje Nødtvedt: nothing to disclose Tori Smedal: nothing to disclose Núria Filló: nothing to disclose Joke Raats: nothing to disclose Lore Kerkhofs: nothing to disclose Ilse Baert: nothing to disclose Funding: a unrestricted educational grant from Novartis Pharma AG to RIMS-network P786 Determinants of discontinuation of Botulinum Toxin Type A treatment for spasticity in multiple sclerosis L. Castelli1, P. Latino2, G. Taborri2, L. Prosperini1, C. Pozzilli1,2, M. Giovannelli2 1Neurology and Psychiatry, Sapienza University, 2S. Andrea Hospital, Rome, Italy Background: Botulinum Toxin Type-A (BoNT-A) is a wellestablished treatment for spasticity due to multiple sclerosis (MS). The advantage of BoNT-A lies in its focal use, long-lasting action (over many weeks), complete reversibility of effect, and additive use in patients with systemic treatment. However, no studies have been performed so far to investigate the long-term treatment persistence (defined as “the duration of time from initiation to discontinuation of therapy”) with BoNT-A treatment. Objective: To investigate the effect of long-term treatment persistence with BONT-A and determinants of its discontinuation in daily clinical setting. Methods: We retrospectively collected data of patients with definite MS who started BoNT-A injections and underwent regular routine follow-up visits. Determinants of BoNT-A discontinuation were explored in a time-to-event Cox regression analysis which included as independent variables the following baseline (i.e. at the beginning of BoNT-A treatment) characteristics: age, MS duration, Expanded Disability Status Scale score, MS phenotype (relapsingremitting, secondary progressive, primary progressive), Modified Ashworth Scale, neurological picture (monoparesis, hemiparesis, paraparesis, tetraparesis), ongoing disease-modifying treatment, ongoing oral anti-spastic drugs, absence or presence of a stable caregiver, regular rehabilitation (yes or not) and frequency (sessions per week). Results: From 2002 to 2014 a total of 185 patients started BoNT-A treatment. Of them, data on 121 were considered in our analysis. At follow-up (September 2015), 53 (44%) patients were still on treatment and 68 (56%) patients discontinued the treatment after a median time of 1.2 years (interval: 6 months to 7.4 years). Reasons for discontinuation were loss of efficacy (n=45); logistic problems or barriers to reach the structure (n=16); adverse events (n=7). According to the multivariable time-to-event analysis, the absence of caregiver (HR=0.59, p=0.03) and lack of rehabilitation (HR=0.59, p=0.02) were two independent predictors of discontinuing BoNT-A treatment. Discussion: Our study confirms the beneficial effect of combining BoNT-A injections with regular rehabilitation on overall response to BoNT-A treatment in people with MS. The absence of caregiver may have a deleterious effect on persistence with treatment, highlighting the crucial role of caregivers for achieving better long-term outcomes in chronic conditions, such as MS.

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Disclosure LC: consulting fees from Almirall. PL: nothing to disclose. GT: nothing to disclose. LP: consulting fees from Biogen and Novartis; speaker honoriaria from Biogen, Genzyme, Novartis, Teva; research grants from Genzyme. CP: consulting fees and/or speaker honoraria from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Roche, Teva; research grants from Merck Serono and Novartis. MG: consulting fees from Allergan and Ipsen. P787 Oculomotor re-training in people with progressive Multiple Sclerosis and cerebellar signs: A proof of concept study L. Vanbuel1, L. Bunn2, M. Hollands3, A. Lavrysen4, P. Feys1, J. Marsden2 1University of Hasselt, Hasselt, Belgium, 2School of Health Professions, Plymouth University, Plymouth, 3John Moore University, Liverpool, United Kingdom, 4University of Leuven, Leuven, Belgium Background: Cerebellar Ataxia is seen in up to 80% of people with Multiple Sclerosis (MS) with symptoms being more frequent in people with progressive MS. Many activities that people with cerebellar signs find difficult such as manipulation balancing and walking require accurate oculomotor control. Aim: This study investigated: (a) differences in oculomotor control, upper limb function and balance between people with progressive MS and healthy participants (b) the effects of a 4 week oculomotor training program on clinical signs and visuo-motor ability in people with MS. Methods: Baseline outcome measures as symptom severity, SARA and functional capacity tests in people with MS were compared to matched healthy participants. People with Progressive MS were randomised to the intervention (n=15) or control group (n=13). Intervention consisted of 15 minutes of individualised home-based oculomotor training every day for 4 weeks. The control group continued with usual care. Before and after intervention period measures were taken of clinical outcome (Functional Reach FRT; 25 foot walking test; box and blocks test; 9 hole peg test; Scale for Assessment and Rating of Ataxia) and visuomotor performance (postural sway and step- or ramp eye-hand tracking). Differences in baseline scores between groups were compared using unpaired t -tests. Changes with intervention in people with MS were assessed using a between groups repeated measures ANOVA Results: Twenty eight people with progressive MS (Age 54.4± 8.7 yrs; EDSS 6, range 2.5-8) and 22 healthy participants (age 54.9±9.1) were recruited. People with MS were significantly impaired on all clinical outcome measures. Antero-posterior postural sway was greater (P< 0.05) and error during step and ramp eye-hand tracking was worse in people with MS. Baseline measures between the MS intervention and usual care groups were not significantly different. Two people in the experimental group were lost to follow up. Functional balance (FRT) decreased in the experimental group by 5 cm (P< 0.05) but manual dexterity was not affected. There were no differences in postural sway between groups or over time. Movement error during step tracking significantly improved with oculomotor training (Group x time interaction P< 0.05).


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Conclusions: People with progressive MS and cerebellar signs show impairments in visuomotor skills. Oculomotor training can improve eye hand co-ordination but not clinical functional measures. Disclosure This study was funded by the International MS Alliance, challenges in Progressive MS scheme (PA 0053)

Neuropsychology and fatigue management P788 Effectiveness of energy conservation management on fatigue and participation in multiple sclerosis: a randomized clinical trial L.J.M. Blikman1, J. van Meeteren2, J. Twisk3, F. de Laat4, V. de Groot5, H. Beckerman5, H.J. Stam1, H. Bussmann1, TREFAMS ACE group 1Erasmus MC, 2Rijndam, Location Erasmus MC, Rotterdam, 3Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, 4Libra Rehabilitation Medicine & Audiology, Tilburg, 5VU University Medical Centre, Amsterdam, The Netherlands Objectives: To evaluate the effectiveness of an energy conservation management (ECM) intervention versus an MS-nurse control intervention for treating fatigue in persons with multiple sclerosis (MS). Design: Single-blind, two-parallel-arms randomized clinical trial (RCT). Setting: Two outpatient rehabilitation departments. Subjects: Adult persons with definite MS, severe fatigued, and being ambulatory. Interventions: The individual-based ECM intervention (12 sessions in 4 months) is based on the Packer group program and was given by occupational therapists. The control intervention (3 sessions in 4 months) consisted of MS-nurse consultations. Method: Primary outcome measures were Fatigue (Checklist Individual Strength-CIS20r domain subjective experience of fatigue) and participation (Impact on Participation and AutonomyIPA). Additional secondary outcome measures on fatigue, activity and participation were done. Measurements, evaluated by blinded assessors, were at baseline and 8, 16, 26 and 52 weeks after randomization. Linear Mixed Models analyses with a three level structure (repeated measures, patients and therapists) were performed. Results: Intention to treat analysis was based on 76 patients (ECM n=36; MS-nurse n=40). No significant intervention effects were found for fatigue (overall difference CIS20r between the groups = -0.81; 95% CI -3.71 to 2.11; p=0.58), and for four out of five IPA domains. For the IPA domain social relations, an overall unfavorable effect for the ECM group was found (difference between the groups = 0.19, 95% CI 0.03 to 0.35, p=0.02). Conclusion: Energy conservation management does not lead to significant and clinically relevant changes in fatigue and participation compared to MS nurse consultations. Although both treatments achieved a statistically significant decline of fatigue during the treatment period, and for the ECM group also at long-term followup, these effects must be considered as clinically non-relevant.

Disclosure Study is funded by Fonds NutsOhra and ZonMw. Lyan Blikman: nothing to disclose Jetty van Meeteren: nothing to disclose Jos Twisk: nothing to disclose Fred de Laat: nothing to disclose Vincent de Groot: nothing to disclose Heleen Beckerman: nothing to disclose Henk Stam: nothing to disclose Hans Bussmann: nothing to disclose P789 Physical behavior is associated with physical fatigue in persons with multiple sclerosis related fatigue J. van Meeteren1, L.J.M. Blikman2, D. Rizopoulos2, V. de Groot3, H. Beckerman3, H.J. Stam2, H.B.J. Bussmann2, TREFAMS ACE Group 1Rijndam, Location Erasmus MC, 2Erasmus MC, Rotterdam, 3VU University Medical Centre, Amsterdam, The Netherlands Objective: To study associations between dimensions of physical behavior and dimensions of fatigue in persons with multiple sclerosis (MS) related fatigue. Design: cross-sectional analysis. Setting: Outpatient rehabilitation departments. Physical behavior monitoring was conducted in participants´ daily environment. Method: Participants: 212 persons with MS from a multicenter RCT study. Persons with MS were severely fatigued, Fatigue Severity Scale median: 5.4 (4.8-5.9), and minimally to moderately neurological impaired, Expanded Disability Status Scale: 2.5 (2.0-3.5), 73.1% had Relapsing Remitting MS. Interventions: not applicable. Main Outcome Measures: Physical behavior was measured using an accelerometer and fatigue was measured by questionnaires (i.e., Checklist Individual Strength, Modified Fatigue Impact Scale). Fatigue questionnaires subscales and physical behavior outcomes were standardized and categorized in dimensions. For fatigue: subjective, physical, cognitive and psychological fatigue; for physical behavior: activity amount, activity intensity, day pattern and distribution of activities. Results: Physical behavior dimensions were significantly associated with only the physical fatigue dimension (omnibus F-test: 3.96, df1 = 4, df2 = 207, p = .004). Additional analysis showed that activity amount (B= -0.16, 95% CI = -0.27 to -0.04, p = .007), activity intensity (B= -0.18, 95% CI= -0.31 to -0.06, p= .004) and day pattern (B= -0.17, 95% CI = -0.28 to -0.06, p = .002) were the physical behavior dimensions that were significantly associated with physical fatigue. Age and gender did not confound these associations. Conclusions: Physical behavior is weakly associated with physical fatigue and not with other fatigue dimensions, such as cognitive and psychological. This supports the notion that fatigue is multidimensional, and may imply that different treatment modalities should be considered in the treatment of fatigue. Disclosure Study is funded by Fonds NutsOhra and ZonMw L.J.M Blikman: nothing to disclose


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J. van Meeteren: nothing to disclose D. Rizopoulos: nothing to disclose, V. de Groot: nothing to disclose, H. Beckerman: nothing to disclose, H.J. Stam: nothing to disclose, J.B.J. Bussmann: nothing to disclose

P790 Voxel-based lesion symptom mapping to explain the cognitive-posture interference phenomenon in multiple sclerosis S. Ruggieri1,2, F. Fanelli1, L. Castelli1, N. Petsas1,3, L. De Giglio1, L. Prosperini1 1Neurology and Psychiatry, Sapienza University, 2Neurosciences, S Camillo-Forlanini Hospital, 3IRCCS S. Lucia Foundation, Rome, Italy Background: Cognitive-posture interference (CPI) refers to deterioration of balance while performing a concurrent cognitive task. This phenomenon can be estimated as dual-task cost (DTC), i.e. the change in postural sway from single-task (ST) to dual-task (DT) performance. There is emerging evidence that people with multiple sclerosis (MS) may present pathological CPI level compared to general population, with detrimental consequences on their quality of life and increased risk of falls. Objective: To investigate the disease-altered structure-function relationship underpinning the CPI phenomenon in people with MS. Methods: We measured the postural sway in quiet standing (ST condition) and while performing the Stroop color-word test (DT condition) of 64 patients and 64 sex- and age-matched healthy controls by a force platform. The patient group also underwent a magnetic resonance imaging scan of the brain with a 1.5T magnet. Brain lesions on T2 and T1-weighted images were outlined by a semi-automated edge contour technique (Jim 7.0 software) to obtain binary T2 and T1-lesion masks and the corresponding lesion volumes (LV). Correlations between behavioural data from the dual-task experiment and lesion location was determined by means of a non-parametric permutation-based approach generating voxelbased lesion symptom maps (VLSM) (MRIcron software). Results: Patients had larger postural sway in both ST and DT conditions (p-values< 0.001), and a greater DTC (42% vs 28%, p=0.005) than controls. The overall T2-LV correlated neither with patients’ postural sway in both ST and DT conditions nor with the DTC of balance (p-values>0.10). There were moderate correlations between T1-LV and postural sway in both ST and DT conditions (rho=0.334 and rho=0.442, respectively; p-values< 0.01) and a weak correlation between T1-LV and DTC of balance (rho=0.254; p=0.045). We found clusters of T2 lesions in distinct anatomical regions (anterior corona radiata, sagittal stratum, posterior thalamic radiations, bilaterally) to be correlated with DTC of balance (p< 0.01 false discovery rate-corrected). The VLSM did not reveal any significant association with behavioural data using T1-lesion masks. Discussion: Our findings suggest that the CPI phenomenon in MS has multifactorial causes, including neurodegenerative processes driven by chronic axonal loss and disconnection along specific areas implicated in visuo-spatial attention and task-switching abilities.

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Funded by AISM/FISM (grant 2014/R/17) and Sapienza University (grant C26A15PS9H) SR: nothing to disclose. FF: nothing to disclose. LC: consulting fees from Almirall. NP: speaker honoraria from Biogen. LDG: nothing to disclose. LP: consulting fees from Biogen and Novartis; speaker honoriaria from Biogen, Genzyme, Novartis, Teva; research grants from Genzyme. P791 The positive effect of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: results of a randomized controlled trial L. van den Akker1, H. Beckerman1, E.H. Collette1, J. Twisk1, G. Blijenberg2, H. Knoop2, J. Dekker1, V. de Groot1, TREFAMSACE Study Group 1VU University Medical Center, Amsterdam, 2Radboud University Medical Centre, Nijmegen, The Netherlands Background: MS-related fatigue is a common symptom in Multiple Sclerosis (MS) that restricts societal participation. Literature suggests that Cognitive Behavioral Therapy (CBT) alleviates MS-related fatigue, but evidence is inconclusive. The study objective was to evaluate the effectiveness of CBT to improve MS-related fatigue and participation in patients with MS. Methods: In a multicenter, assessor-masked, randomized-controlled trial in 3 Dutch healthcare institutions, participants with severe MS-related fatigue were assigned to the CBT or control study group. The CBT study group received twelve individual face-to-face sessions with a certified psychologist; the control study group received 3 individual sessions with an MS-nurse, both for a duration of 16 weeks. Assessments took place at baseline, 8, 16 (i.e. post-intervention), 26 and 52 weeks follow-up. Primary outcomes were the Checklist Individual Strength-fatigue subscale (CIS20r-fatigue) and the Impact on Participation and Autonomy questionnaire (IPA). Data were analyzed with the intention-to-treat principle using Mixed Model Analysis. The Controlled Trials registration number is ISRCTN58583714. Findings: Between December 2011 and August 2014, 91 patients were randomly assigned to the CBT (n=44) or to the MS-nurse study group (n=47). The between-group analysis showed a positive post-intervention effect for CBT on the CIS20r-fatigue (T16: -6•7 [95%CI -10•7; -2•7] points) that diminished during follow up (T26: -3•5 [95%CI -7•4; 0•5]; T52: 0•5 [95%CI -3•6; 4•4]). No clinically relevant effects were found on societal participation. Post-intervention (T16), 22 out of 39 in the CBT, and 9 out of 37 patients in the control study group showed a clinically-relevant improvement of 8-points or more on the CIS20r-fatigue, leading to a number needed to treat of 3•3 (95%CI 1•9;10•6). Interpretation: Severe MS-related fatigue can be reduced effectively with CBT. However, effects wear off after cessation of treatment, societal participation does not improve. Disclosure Lizanne E van den Akker: nothing to disclose Heleen Beckerman: nothing to disclose


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Emma H Collette: nothing to disclose Jos Twisk: nothing to disclose Gijs Bleijenberg: nothing to disclose Hans Knoop: nothing to disclose Joost Dekker: nothing to disclose Vincent de Groot: nothing to disclose

Exercise P792 Changes in gait and balance in people with multiple sclerosis attending a 12-week Pilates exercise program A. Kalron1, L. Frid2, S. Berkowitz2, A. Achiron2,3 1Department of Physical Therapy, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 2Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Objective: Evaluate the effects of a Pilates exercise programme on walking and balance in people with multiple sclerosis and compare this exercise approach to conventional physical therapy sessions. Design: Randomized controlled trial. Settings: Multiple Sclerosis Center, Sheba Medical Center, TelHashomer, Israel. Subjects: Forty-five people with multiple sclerosis, 29 females, mean age (SD) was 43.2 (11.6) years; mean Expanded Disability Status Scale (S.D) was 4.3 (1.3). Interventions: Participants received 12 weekly training sessions of either Pilates (n=22) or standardized physical therapy (n=23) in an outpatient basis. Main measures: Spatio-temporal parameters of walking and posturography parameters during static stance. Functional tests included the Time Up and Go Test, 2 and 6-minute walk test, Functional Reach Test, Berg Balance Scale and the Four Square Step Test. In addition, the following self-report forms included the Multiple Sclerosis Walking Scale and Modified Fatigue Impact Scale. Results: At the termination, both groups had significantly increased their walking speed (P=0.021) and mean step length (P=0.023). According to the 2-minute and 6-minute walking tests, both groups at the end of the intervention program had increased their walking speed. Mean (SD) increase in the Pilates and physical therapy groups were 39.1 (78.3) and 25.3 (67.2) meters, respectively. There was no effect of group X time in all instrumented and clinical balance and gait measures. Conclusions: Pilates is a possible treatment option for people with multiple sclerosis in order to improve their walking and balance capabilities. However, this approach does not have any significant advantage over standardized physical therapy. Disclosure This work was supported by a grant (EMR200136_642) from the Merk KGaA, Damstadt, Germany. P793 Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? The TREFAMS-A multicentre randomised trial M. Heine1,2, O. Verschuren2, E. Hoogervorst3, E. van Munster4, H. Hacking3, A. Visser-Meily2, J. Twisk5,6, H. Beckerman1,6,

V. de Groot1,6, G. Kwakkel1,7,8, TREFAMS-ACE Study Group 1Rehabilitation Medicine, VUmc MS Center, VU University Medical Center, Amsterdam, 2Brain Center Rudolf Magnus and Center of Excellence for Rehabilitation Medicine, University Medical Center Utrecht and Rehabilitation Center de Hoogstraat, Utrecht, 3Multiple Sclerosis Center, St. Antonius Hospital, Nieuwegein, 4Neurology, Jeroen Bosch Hospital, Den Bosch, 5Epidemiology and Biostatistics, 6EMGO+ Institute for Health and Care Research, VU University Medical Center, 7Neurorehabilitation, Reade Centre of Rehabilitation and Rheumatology, Amsterdam, The Netherlands, 8Physical Therapy and Human Movement Sciences, Northwestern University, Evanston, IL, United States Background: Aerobic training may prove a viable treatment to alleviate the commonly reported fatigue in patients with multiple sclerosis (MS). However, limited evidence is available for its effectiveness in fatigued patients with MS. Methods: Treating fatigue in multiple sclerosis - Aerobic training (TREFAMS-A) is a multicentre, observer-blinded, randomised controlled trial in 90 ambulant patients with MS suffering from severe fatigue. Patients were allocated 1:1 to 16 weeks individual, partly supervised, aerobic training or a control intervention consisting of three consultations with an MS-specialized nurse. Primary outcomes were perceived fatigue (Checklist Individual Strength [CIS] fatigue subscale) with, and societal participation (Impact on Participation and Autonomy [IPA] scale). An improvement of ⩾ 8 points on the CIS fatigue subscale was considered clinically relevant. Secondary outcomes included measures of physical fitness, and complementary fatigue measures. Assessments were performed at baseline, 8, 16, 26, and 52 weeks. Random coefficient analysis was used to assess the group-by-time interaction effects. This study is registered with Controlled-trials. com number ISRCTN69520623. Findings: Between 1 October 2011 and 1 October 2014, over 925 patients were approached, 207 patients with MS were assessed for eligibility, and 90 were included. The mean difference (MD) between-groups, post-intervention on the CIS fatigue subscale was 4.708 (Standard Error [SE] = 1.890; P = .014) in favour of aerobic training. This was preceded by a significant increase in peak power output following 8 weeks of training (MD = 11.701; SE = 5.868; P = .048). At 8 weeks, also a significant reduction on the Modified Fatigue Impact Scale psychosocial subscale (MD = -0.771; SE = 0.325, P = .019) was shown. No significant effect was found on societal participation. Interpretation: Aerobic training in MS patients with severe fatigue does not lead to clinically meaningful reductions in fatigue and does not improve societal participation when compared to three consultations offered by an MS-specialized nurse. Disclosure Funding: This study was funded by the Fonds NutsOhra (ZonMw 89000005). M. Heine: nothing to disclose O. Verschuren: nothing to disclose E.L. Hoogervorst: nothing to disclose E.Th.L. van Munster: nothing to disclose H.G.A. Hacking: nothing to disclose J.M.A. Visser-Meily: nothing to disclose J.W. Twisk: nothing to disclose


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Poster Session 1, 22(S3) H. Beckerman: nothing to disclose V. de Groot: nothing to disclose G. Kwakkel: nothing to disclose P794 Effects of normobaric hypoxic training on physical fitness and immunoregulatory functions in patients with multiple sclerosis: a pilot study A. Mähler1, L. Klug1, A. Balogh2, J. Steininger1, D.N. Müller2, M. Boschmann1, F. Paul1 1Charite - Universitätsmedizin Berlin, 2Max Delbrueck Center for Molecular Medicine, Berlin, Germany Objective: Increased endogenous erythropoietin (EPO) levels might be able to prevent the progression or even ameliorate a number of neurodegenerative diseases, including multiple sclerosis (MS). Endogenous EPO production can be induced by hypoxic conditions and by increasing cardiorespiratory fitness through physical activity. We studied the effects of intermittent hypoxic training on EPO production, walking ability, cardiorespiratory fitness, and on immunoregulatory functions relevant to the disease course of MS. Methods: So far, 14 patients with relapsing-remitting MS (six men, EDSS 0.0 - 4.0) were assigned within a randomized, singleblind, parallel-group study (NCT02509897) to either hypoxic (HO) or normoxic (NO) treadmill training, both 3 times/week for 1h over 4 weeks. Before (V1) and after (V2) training, serum EPO concentrations, 10 m Walk Test, 6 min Walk Test, maximal oxygen consumption (VO2max) and performance in an incremental treadmill test, and immunoregulatory functions of peripheral mononuclear blood cells were assessed. Results: Both HO and NO training slightly increased EPO concentrations (HO: 7.5 ± 2.5 vs. 9.4 ± 2.8 mU/mL, NO: 10.2 ± 2.6 vs. 12.0 ± 2.8 mU/mL; V1 vs. V2, both NS). Time needed to walk 10 m decreased by 0.4 s in the HO and by 1.0 s in the NO group (HO: 6.0 ± 1.0 vs. 5.6 ± 1.0 s, NO: 7.5 ± 1.0 vs. 6.5 ± 0.9 s; V1 vs. V2, both NS). The distance patients walked in 6 min increased by 36 m in the HO group (550 ± 116 vs. 586 ± 106 m, P = 0.06) and by 27 m in the NO group (469 ± 52 vs. 496 ± 49 m, NS). Maximal performance in the incremental treadmill test increased markedly in the HO group (128 ± 79 vs. 167 ± 77 W; V1 vs. V2, P = 0.01) and moderately in the NO group (137 ± 73 vs. 179 ± 80 W; V1 vs. V2, P = 0.06), both at only slightly increased VO2max (NS). Conclusion: Four weeks of moderate treadmill training induced favourable effects on walking speed, endurance capacity and performance under both HO and NO conditions. However, HO training had a slightly greater effect on endurance and performance. At the meeting, we will present data from 24 patients and first results of immunoregulatory functions. Disclosure AM has nothing to disclose. LK has nothing to disclose. AB has nothing to disclose. JS has nothing to disclose. DNM has nothing to disclose. MB has nothing to disclose. FP received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi Aventis/Genzyme, and

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Merck Serono; is an Associate Editor for Neurology® Neuroimmunology & Neuroinflammation; is an Academic Editor for PLoS ONE; has consulted for SanofiGenzyme, BiogenIdec, and MedImmune; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Deutsche Forschungsgemeinschaft, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, Guthy Jackson Foundation, and National Multiple Sclerosis Society. P795 Customizable exergames Nintendo Wii balance board-based for rehabilitation in multiple sclerosis S. Caggiari1, B. Leban1, F. Corona1, G. Coghe2, M.G. Marrosu3, E. Cocco2, M. Pau1 1Department of Mechanical, Chemical and Materials Engineering, 2Multiple Sclerosis Center, Department of Health, Clinical and Molecular Medicine, 3Sport Physiology Lab, Department of Medical Sciences, University of Cagliari, Cagliari, Italy Background: Commercial consoles like Nintendo Wii, originally developed for recreational purposes, are used as balance rehabilitation tool for people with Multiple Sclerosis (pwMS). However, the commercially available games are scarcely adaptable to each patient’s conditions and needs and they mainly stimulate the postural control system in Medio-Lateral (ML) direction with respect to Anterior-Posterior (AP). Aim: We developed new customizable routines that, using the Balance Board (BB) as input device, allow visualizing the user’s center of pressure (COP) and require to follow a specific trajectory (elliptical, eight shaped etc.) or to hit a target. The study aims to demonstrate that such games has a score system able to reflects the balance impairment and that the score is correlated with the balance abilites assessed by means of a static stabilometry. Methods: Sixty-five pwMS (EDSS range 1-6.5) followed at Regional Center for Multiple Sclerosis were enrolled for the study. They underwent a static posturography and then were asked to perform 3 repetitions of the new exercises for 60 seconds. Their performance was assessed on the basis of their ability to follow, with their own COP, the displayed trajectory at a predetermined velocity or hit a target as quickly as possible. One-way ANOVA was used to assess score differences between pwMS and a control group of healthy people. Pearson correlation coefficient was calculated to analyze correlation between stabilometric data and scores. Results: Scores were found significantly lower in pwMS for all games (p< 0.01) thus indicating that the games are sensitive to balance impairments. Score was also found significantly correlated with ML displacement (for all games r=-0.319 p=0.009, r=-0.361 p=0.003, r=-403 p< 0.001), AP displacement (for eight and target game r=-0.259 p=0.04, r=-0.362 p=0.003), COP path length (for two trajectory games r=-0.438 p< 0.001, r=-0.475 p< 0.001) sway area (for all games r=-0.296 p=0.015, r=-0.345 p=0.005, r=-0.405 p< 0.001), ML velocity (for two trajectory games r=-0.288 p=0.019, r=-0.384 p=0.002), AP velocity (for two trajectory games r=-0.482 p< 0.001, r=-0.479 p< 0.001). Conclusions: The proposed approach allows full personalization of the balance training and avoids problems associated with the


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scarce flexibility of the commercial software. The score system reflects impairments and improvements of the patients. Supported by FISM - Fondazione Italiana Sclerosi Multipla - Cod. 2014/R/13. Disclosure Silvia Caggiari: nothing to disclose Bruno Leban: nothing to disclose Federica Corona: nothing to disclose Giancarlo Coghe: nothing to disclose Maria Giovanna Marrosu: nothing to disclose Eleonora Cocco: nothing to disclose Massimiliano Pau: nothing to disclose

Conclusions: This small pilot RCT provides exciting proof-ofconcept data supporting progressive TMWX training for potentially improving processing speed, cardiorespiratory fitness, and thalamocortical RSFC over time in fully-ambulatory persons with MS. This pattern of preliminary results seemingly supports an adaptive compensatory mechanism whereby TMWX training improves cardiorespiratory fitness, which might result in improved processing speed, which may be explained by increased thalamocortical RSFC. Disclosure

P796 Treadmill walking exercise training effects on processing speed and thalamic resting-state functional connectivity in multiple sclerosis: a pilot study B.M. Sandroff1, G.R. Wylie1, C.L. Johnson2, B.P. Sutton2, J. Deluca1, R.W. Motl3 1Kessler Foundation, West Orange, NJ, 2Beckman Institute of Advanced Sciences, 3Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United States Background: Cognitive impairment is common and debilitating among persons with multiple sclerosis (MS), and might be managed with exercise training. This is based on a rigorous and systematic line of research that identified progressive (both intensity and duration) treadmill walking exercise (TMWX) as an optimal exercise stimulus for improving cognition in fully-ambulatory persons with MS. Objective: The present pilot study adopted a single-blind randomized controlled trial (RCT) design and is the first to examine the effect of a TMWX training intervention on cognition and functional MRI (fMRI) outcomes among fully-ambulatory persons with MS. Methods: Eight fully-ambulatory females with relapsing-remitting MS were randomly assigned into exercise training intervention or waitlist control conditions. The intervention condition involved 12-weeks of supervised, progressive chronic TMWX training that was designed based on pilot work. Participants underwent measures of processing speed (i.e., Symbol Digit Modalities Test; SDMT) and cardiorespiratory fitness (i.e., peak aerobic capacity; VO2peak) before and after the 12-week period. Participants further underwent fMRI scans for measurement of resting-state functional connectivity (RSFC) between the thalamus and frontal cortical regions before and after the 12-week period. Results: Overall, there were large intervention effects on SDMT performance (d=0.72) and VO2peak (d=0.88). There further were large intervention effects on RSFC between the thalamus and right middle frontal gyrus (MFG; d=1.92) and anterior cingulate cortex (ACC; d=1.70), respectively. The change in VO2peak was moderately associated with change in SDMT performance (r=.60), and change in RSFC between the thalamus and right MFG (r=.48) and ACC (r=.54), respectively. Further, change in SDMT was moderately associated with change in RSFC between the thalamus and right MFG (r=.42) and ACC (r=.53), respectively.

Brian M. Sandroff: Nothing to disclose Glenn R. Wylie: Nothing to disclose Curtis L. Johnson: Nothing to disclose Brad P. Sutton: Nothing to disclose John DeLuca: Nothing to disclose Robert W. Motl: Nothing to disclose This abstract presentation was supported in part by grant MB 0024 from the National Multiple Sclerosis Society. P797 Rhythmic cued motor imagery in people with multiple sclerosis: effects and mechanisms B. Seebacher1, R. Kuisma1, A. Glynn1, T. Berger2 1School of Health Sciences, University of Brighton, Eastbourne, United Kingdom, 2Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria Background: Our previous study showed that music and metronome cued motor imagery with verbal cueing improved walking, fatigue and quality of life (QoL) in people with multiple sclerosis (MS). However, the mechanisms of rhythmic cued motor imagery interventions have not yet been investigated in this population. Objectives: Aims of this study were to explore the motor imagery ability in people with MS and to compare the effects of differently cued motor imagery. Methods: A pilot study in 15 adults with MS and Expanded Disability Status Scale scores of 1.5-4.5 was conducted at the MS Clinic Innsbruck, Austria. Participants were randomised to one of three groups, 1. music and verbal cueing or 2. music only cueing and 3. no cueing. Participants were asked to practice 17 minutes of motor imagery 6 times per week, for 4 weeks. Participants were called weekly for support. Primary outcomes were motor imagery ability (Kinaesthetic and Visual Imagery Questionnaire, KVIQ-G-10, Time-Dependent Motor Imagery screening test, TDMI) and gait synchronisation with music beat (video-assisted gait analysis). Further, walking speed (Timed 25-Foot Walk), walking distance (6-Minute Walk Test, fatigue (Modified Fatigue Impact Scale), and QoL (Multiple Sclerosis Impact Scale-29) were assessed. Results: All participants were able to perform motor imagery as shown by median KVIQ-10 scores of 40 (26-50). On the TDMI, a very strong positive correlation between the number of imagined stepping movements within three different time periods (15, 25 and 45 seconds) was observed (Pearson´s r= 0.85-0.88). Gait synchronisation with fast (110 beats per minute, BPM), but not slow (75 BPM) music beat was increased after music and verbally cued motor imagery as indicated by reduced step length and step time


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Poster Session 1, 22(S3) variability. However, the ratio of the music tempo expressed in BPM over the gait cadence improved similarly in all groups. Walking speed, walking distance, fatigue and QoL results were comparable to our previous study. Participants reported that they appreciated the support and well accepted the interventions. All participants completed the study. Conclusions: Findings from this pilot study showed that people with mild to moderate MS were able to motor image. Cueing might influence the synchronisation between cues and imagined steps, which could be transferred to actual walking. A larger study seems feasible, requiring a sample size of 20 per group, based on group differences in walking distance. Disclosure Barbara Seebacher: nothing to disclose Raija Kuisma: nothing to disclose Angela Glynn: nothing to disclose Thomas Berger: nothing to disclose The material costs of the study were funded by the Austrian MS Research Society. P798 Objective physical activity measurement in people with multiple sclerosis: a review of the literature B. Casey1, S. Coote1, A. Donnelly2 1Clinical Therpaies, 2Physical Education and Sports Science, University of Limerick, Limerick, Ireland Background: Current descriptive epidemiology rates of physical activity (PA) levels in people with Multiple Sclerosis (MS) rely heavily on recall-based measurements of PA. Healthy population literature suggests these may lack resolution and places a strong emphasis on the use of objective PA measures in large scale cohort and intervention studies. At present, there is no gold standard objective PA measurement tool for use in MS literature. It is also unclear which aspect of PA MS researchers should be reporting.

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Objective: 1) To identify the objective PA measurement tools and outputs that are most commonly used within Multiple Sclerosis literature and 2) To determine which PA measurement tools and outputs should be used in future MS and PA research. Methods: A systematic search strategy was conducted on 8 databases (2000-2016) using keywords associated with MS and PA. This review forms part of a more detailed systematic review and meta-analysis that aims to establish current physical activity levels in pwMS. Once the search was complete, information on objective PA devices used and PA outputs reported were extracted and narratively described. Results: This review includes 32 papers of which there are 3 intervention studies, 3 reliability/validity studies and 26 cohort/ case control studies. Uni-axial accelerometers were the most popular objective PA measurement tool in this review (68%). Pedometers (14%) and multi-sensor systems (3%) were the second and third most common devices used. PA outputs included activity counts per day, steps per day, energy expenditure (kilocalories) per day, minutes of moderate-vigorous PA (MVPA), minutes of light PA, minutes of sedentary behaviour and daily dynamic activity. Both activity counts per day (n=21 studies) and steps per day (n=11 studies) were most commonly used representing 78% of the PA output in current literature. Conclusion: Uni-axial accelerometers and pedometers are the most popular PA measurement tools used in MS literature. However, these tools may not be the most accurate measure of PA and other options including multi-sensor systems should be investigated. Additionally, PA is widely being expressed as activity counts and step counts per day. Single metric description of PA may not be accurate. Attention to capturing the duration, frequency, intensity and energy expended during daily PA is warranted. Disclosure Bláthín Casey: Nothing to disclose Prof Susan Coote: Nothing to disclose Prof Alan Donnelly: Nothing to disclose
