Recent Gains in Clinical Multiple Sclerosis Research

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Recent Gains in Clinical Multiple Sclerosis Research T.F. Runia§, E.D. van Pelt-Gravesteijn§ and R.Q. Hintzen* Department of Neurology, Erasmus MC, Rotterdam, The Netherlands Abstract: Multiple sclerosis (MS) is a common neurological disease mainly affecting young people. Around the world, over 2.5 million people suffer from this central nervous system (CNS) disorder. Although the exact disease mechanism is not completely clear, it is known that both environmental and genetic factors influence the development of MS. Here we aim to summarize a few major highlights of recent progress that have been made in clinical MS research. A genetic predisposition in combination with Epstein-Barr virus infection seems to be essential to get MS. Recently more than 50 susceptibility genetic loci for MS have been described. MS prevalence has a latitudinal gradient indicating that sunlight exposure and therefore vitamin D are important contributors to MS risk. Several studies found an inverse association between MS prevalence and serum vitamin D levels. In most cases, MS starts with an acute episode involving one or more sites of the CNS. The role of the recently revised McDonald Diagnostic Criteria for the diagnosis of MS, which sometimes allow the diagnosis after a first attack, is discussed. Most patients with MS suffer from exacerbations and remissions of neurological deficits: relapsing-and remitting MS. With time, the majority of these patients enter a disease phase characterized by continuous, irreversible neurological decline; this is called secondary progressive MS. In 10-20% of patients, the disease is progressive from onset. Life expectancy of patients after diagnosis with MS is around 35 years, and MS patients die 5-10 years earlier than the general population. A substantial percentage of MS patients have their first attack during childhood. Clinics of childhood-onset MS versus adult-onset are explained, as are diagnostics, differential diagnoses and therapeutic options for children with MS. Also another demyelinating disease of the CNS, neuromyelitis optica (NMO) is highlighted. Since NMO has been considered as a variant of MS and also has been misdiagnosed as MS, recent insights in the pathology of NMO are explained.

Keywords: Multiple sclerosis, review, pediatric multiple sclerosis, epidemiology, disease course. INTRODUCTION Multiple sclerosis (MS) is a common disease of the central nervous system (CNS), mainly affecting young adults [1]. It is thought to be a CNS-specific autoimmune disease, arising in people with a genetic susceptibility after exposure to certain environmental factors [2]. In the past decades, an enormous amount of research on MS has been performed worldwide, resulting in a better understanding of MS etiology, the possibility for earlier diagnosis and new types of treatment. Here we aim to summarize a few major highlights of recent progress that has been made in clinical MS research. ADULT-ONSET MS Epidemiology Around the world, over 2.5 million people suffer from MS [1]. The disease incidence and prevalence are distributed unevenly over the world: a high prevalence is found in Western Europe and North America, and the lowest prevalence in Asia, the Middle East and Africa [3]. MS prevalence has repeatedly been reported to have a latitudinal gradient being more prevalent in temperate areas further away from the equator [4-6]. This latitudinal gradient is one of the reasons for sunlight or vitamin D to be seen as an *Address correspondence to this author at the Erasmus MC, Kamer Ee2230, Postbus 2040, 3000 CA Rotterdam, The Netherlands; Tel: +31-10-7043980; Fax: +31-10-7044727; E-mail: [email protected] §

These authors contributed equally to the manuscript. 1871-5273/12 $58.00+.00

environmental factor for MS risk: one of the strongest epidemiological arguments being the fact that migrants from the United Kingdom to the south of Australia have a significantly higher MS risk than those who migrated to the north of Australia [7]. However, recent evidence suggests that the latitudinal gradient might be decreasing [8] or might not have existed at all in some areas [3]. Nevertheless, the effect of vitamin D on MS has a biological plausibility. Different cells of the immune system, including macrophages and activated T lymphocytes [9] and B lymphocytes [10], contain vitamin D receptors. 1,25Dihydroxyvitamin D3 ((the active form of vitamin D) inhibits the production of inflammatory cytokines in vitro [11] and promotes the development of regulatory T lymphocytes [12, 13]. Furthermore, a correlation between serum 1,25-dihydroxyvitamin D3 concentrations and a more anti-inflammatory Th1/Th2 ratio has been found [14]. Also, many studies found an inverse association between MS prevalence and solar radiation [15, 16] and MS prevalence and serum vitamin D levels [17]. Evidence is now growing that vitamin D could influence the disease course of MS [18] (Runia, in press1). UV light could also act as an immune modulator separately from vitamin D [19, 20]. Taken together this suggests that there is indeed an association between latitude and MS risk, possibly attributable to UV light and vitamin D. However, the latitudinal gradient has been leveled out in the northern hemisphere, possibly due to differences in sun-bathing 1

Runia, T.F.; Hop, W.C.; De Rijke, Y.B.; Buljevac, D.; Hintzen, R.Q. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology, 2012, 79. © 2012 Bentham Science Publishers

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behavior between northern and southern Europeans, to higher dietary intake of vitamin D in northern countries, or to migration of many people from around the equator to more prosperous northern countries. Perhaps genetic factors also play a role here [3, 21]. A recent meta-analysis confirmed the association between latitude and MS prevalence [21]. Another important environmental factor associated with MS risk is Epstein-Barr virus (EBV). Nearly all MS patients are seropositive for anti-EBV antibodies. People who are EBV seronegative have practically no risk of developing MS, which makes it plausible that EBV infection is a prerequisite for the development of MS [22]. Especially after EBV-induced infectious mononucleosis, the risk of MS is increased, and even more so if infectious mononucleosis occurs after the age of 15 [23]. It should be noted however, that in matched controls of MS patients, EBV seropositivity is also very common (90-95%), so most EBV infected people do not develop MS [22]. MS is more common in women than in men, and this sex ratio (female: male exceeding 3.2:1) [24] seems to be increasing. Worldwide, the incidence of MS has been increasing over the last decades, particularly in women [3]. Although this increasing incidence could be due to a higher awareness or earlier diagnosis because of new diagnostic criteria, this seems unlikely because of 2 reasons. First, the use of the McDonald criteria [25, 26] and the 2005 revisions of the McDonald criteria [27] did not lead to an increased number of MS diagnoses [28]. Second, in some studies, such as a Danish study on MS epidemiology [29], incidence figures were based on year of symptom onset rather than year of diagnosis, so even persons who remained undiagnosed for years would eventually be registered according to their year of onset [29]. Also, the increasing female: male ratio makes it more likely that there is in fact a true increase in incidence, explained by a changing environmental exposure, particularly in women. Although there are some obvious candidates, for example smoking, certain jobs and use of contraceptives, the real culprits have not been identified yet. There are differences in MS prevalence among different ethnic groups: MS is very rare in Samis, Turkmen, Uzbeks, Kazakhs, Kirgizis, native Siberians, North and South Amerindians, Canadian Hutterites, Chinese, Japanese, African blacks and New Zealand Maoris, and there is a high risk for MS among Sardinians, Parsis and Palestinians [30]. In Asian people, a different form of MS is more prevalent, called opticospinal MS. This form is characterized by selective involvement of the optic nerve and the spinal cord and a relapsing-remitting disease course, and in comparison to ‘western-type MS’, there are more often gadoliniumenhancing lesions on spinal cord magnetic resonance imaging (MRI) and fewer lesions on brain MRI [31]. The regional differences in MS prevalence and the difference between ethnic groups argue for influence of genetic factors on the development of the disease, as does the increased risk for MS in family members of patients. Recently, more than 50 susceptibility loci for MS have been described [32]. These loci, all associated with relatively small risks, lie mostly in genes with functions in cellmediated immunity, most importantly the major

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histocompatibility complex (MHC), especially the HLADRB1*15:01 allele. In summary, the epidemiology of MS is determined by multiple factors, both genetic and environmental. A genetic predisposition in combination with EBV infection seems to be essential to get the disease. Furthermore, vitamin D and sunlight are important contributors to MS risk. The increasing incidence of MS particularly in women argues for other, thus far unknown, environmental factors to be important. Clinical Course of Multiple Sclerosis In most cases (around 80%), MS starts with an acute episode involving one or more sites of the CNS, called ‘clinically isolated syndrome’(CIS) [2]. The chance that a person with CIS will eventually experience a second attack (and thus fulfill the diagnostic criteria for relapsing-remitting MS) varies from 20% if the baseline MRI scan is normal to around 80% at 20 years if the baseline MRI scan shows white matter abnormalities [33]. Type of CIS (optic neuritis, brainstem, spinal cord, other) is of limited prognostic value, although a relatively large part of optic neuritis patients have a normal brain MRI scan, which makes this subgroup fall in the lower-risk category for developing clinically definite MS [34, 35]. With time, the majority of relapsing-remitting MS patients (around 65%) enter a disease phase characterized by continuous, irreversible neurological decline instead of exacerbations and remissions; this is called secondary progressive MS (SPMS). In 10-20% of patients, the disease is progressive from onset (primary progressive MS, or PPMS) [2]. Where inflammatory demyelinating focal white matter lesions dominate the pathology in relapsing remitting MS, the progressive stage of both PPMS and SPMS is thought to be due to accumulating axonal loss, implicating that MS might not only be an inflammatory but also neurodegenerative disease. In both SPMS and PPMS, onset of progression occurs at around 40 years of age [36, 37], after which the rate at which the disease progresses is similar for the different types of progressive MS, independent of prior disease duration or attack frequency [37]. Being older at disease onset is associated with a shorter time to disability [38]. All this suggests that an age-related neurodegenerative process might underly progressive MS. Indeed, a recent paper by Scalfari et al. [39] confirms that PPMS and SPMS start at a similar age, from there on progressing at similar pace, reaching disability milestones at similar age, implying that age is a main factor in disease progression in MS. Life expectancy of patients after diagnosis with MS is around 35 years, and MS patients die 5-10 years earlier than the general population. In studies investigating the cause of death in MS patients, in around 50% MS death was directly attributable to MS according to the death certificates [40]. However, as few patients actually die from an MS attack, it might be suspected that in most of these cases infection is the major cause of death and MS the underlying cause [41, 42]. One of the causes of death that is far more frequent among MS patients than the general population is suicide: MS patients have been reported to be up to 7 times more likely to commit suicide [43]. Depression and anxiety are

Recent Gains in Clinical Multiple Sclerosis Research

also very common in MS, with a lifetime prevalence of major depression in MS of almost 50% [44]. This is in part due to the fact that the disease strikes young people that now face a very insecure future with a high chance of becoming disabled, but also to changes in the brain by the disease process itself, given that depression in MS patients is associated with lesion load and atrophy on brain MRI [45]. Besides suffering from depression, MS patients also often experience symptoms that can relate to both depression and MS, such as fatigue, insomnia, and impaired memory and concentration [46]. Furthermore, depression can worsen cognitive dysfunction in MS patients [44]. Because MS is a disease most common in young adults, women who get the disease are mostly in their childbearing years. During pregnancy, the disease is known to be less active: relapse rates decrease to around 30% in the third trimester compared to the year before pregnancy. However, after giving birth, around one-third of patients experience an exacerbation within 3 months. The risk for a postpartum relapse is higher in patients with a higher number of relapses before or during pregnancy and longer disease duration [47, 48]. An association between breastfeeding and the occurrence of less postpartum relapses has been reported [49] but insufficient evidence for this association exists [50, 51]. Recent Developments in the Diagnostics of MS Since the publication of the Poser criteria in 1983 [52], the diagnosis of MS has been based on the demonstration of dissemination in space and time: evidence that the disease has affected more than one part of the CNS on more than one occasion. Since then, attempts have been made to adjust the criteria in such a way that the diagnosis of MS could be made earlier and easier. Several revisions to the criteria have been published by the International Panel on Diagnosis of MS, the first in 2001 adding the MRI scan as an important diagnostic tool, that could be used for the criterion for dissemination in space [25]. Recently, the McDonald Criteria for the diagnosis of MS have been revised again [53]. Aims were to simplify the use of brain MRI for the diagnosis and to allow earlier diagnosis in different populations. In Table 1, the 2010 revisions to the McDonald criteria are shown. As can be seen, with the 2010 criteria the diagnosis of MS can sometimes already be made in patients with only a single attack (CIS), after a single baseline brain MRI scan. Another important difference is that the cerebrospinal fluid has no longer a role in the diagnosis of MS. When applied to a cohort of CIS patients, the 2010 criteria were shown to be simpler and more sensitive then previous criteria, without loss of specificity [54]. The implication of the new diagnostic criteria is that the diagnosis of MS can be made easier and earlier. Of course, this is particularly important for the counseling of patients, who are often in the prime of their lives and face a very uncertain future. It may also be important for treatment reasons, although thus far there is no evidence that immediate immunomodulatory treatment changes long-term outcome. The risk that more patients who later turn out to have a different disease than MS are wrongly treated because of the use of the new diagnostic criteria is small, because the

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specificity of the 2010 criteria is comparable to the previous criteria. It has been suggested that the increase in MS incidence is due to a greater awareness and new diagnostic criteria. However, there are several arguments against such a simple explanation, as stated earlier. In the diagnosis of MS, MRI nowadays plays an important role. In the past decade, many new developments have arisen in the MRI field. A different paper in this issue will address this topic in more detail. A relatively new assessment tool in MS research is Optical Coherence Tomography (OCT). This is an ophthalmologic instrument that measures the retinal nerve fiber layer (RNFL) thickness with a method analogous to ultrasound, but using near-infrared light instead of sound. Because it is increasingly recognized that MS is not only an inflammatory but also a neurodegenerative disease [55], and neurodegeneration is likely to be the key determinant of long-term prognosis [39], it is important to have a tool that can accurately measure axonal loss in MS patients. With MRI, global brain atrophy can be measured reproducibly, but this technique does not correlate well with clinical disability scores [56], and lacks specificity for location and tissuespecific processes such as demyelination, axonal loss or gliosis [57]. With OCT, the RNFL can be measured accurately and reproducibly. The RNFL contains ganglion cell axons that are continuous with the optic nerve and are unmyelinated, which makes them suitable for measuring neurodegeneration. After optic neuritis, the RNFL thickness decreases rapidly: loss of retinal nerve fibers occurs within 1 month after optic neuritis and continues for 3-6 months [58]. In eyes of MS patients that did not suffer from optic neuritis, RNFL thickness has also been shown to decrease over time [59, 60]. OCT findings correlate well with high contrast and low contrast visual acuity, visual field measurements, MRI measures of brain atrophy and with Kurtzke Expanded Disability Status Scale (EDSS) [59, 60]. Because OCT also has a good intra-patient and inter-centre reliability [61], it can become a useful tool for the demonstration of neurodegeneration in clinical trials. PEDIATRIC MS Pediatric-onset MS is considered to be rare, although approximately ten percent of MS patients have their first attack during childhood prior to their 18th birthday [62]. In the past years the disease is worldwide more recognized in children, also thanks to MRI. The incidence of acquired demyelination syndromes (ADS) was estimated 0.9 per 100 000 children in a Canadian study [63]. In a recent study by Langer-Gould et al. [64] the incidence rate of ADS in children was estimated 1.66 per 100 000 person-years and the incidence of pediatric MS was 0.51 per 100.000 personyears. A first acute demyelinating event in children, as in adults, can present with symptoms caused by a single lesion (monofocal) or by multiple lesions (polyfocal) [62]. Any type of ADS can be the first presentation of MS in children [65]. In the Canadian pediatric cohort the most common presentations of ADS were optic neuritis (23%), acute disseminated encephalomyelitis (ADEM) (22%) and

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Table 1.

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2010 Revisions to the McDonald Criteria [53] McDonald 2010

DIS

a) Objective clinical evidence of 2 lesions, or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack involving a different CNS site b)  1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS: - Periventricular - Juxtacortical - Infratentorial - Spinal cord (symptomatic lesions in patients with brainstem or spinal cord syndrome are excluded)

DIT

a) 2 attacks separated by a period of at least a month b) Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time c) A new T2 and/or gadolimium-enhancing lesion on follow-up MRI, irrespective of its timing with reference to a baseline scan

PPMS

1 year of disease progression (prospectively or retrospectively determined) and 2 of 3 of the following criteria: - Evidence for DIS based on 1 T2 lesions in the MS-typical regions (see above) - Evidence for DIS in the spinal cord based on 2 T2 lesions in the cord - Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

DIS = dissemination in space, DIT = dissemination in time, CNS = central nervous system, PPMS = primary progressive MS, CSF = cerebrospinal fluid.

transverse myelitis (22%) [63]. Compared to adult-onset MS, pediatric-onset MS patients present more often with isolated optic neuritis and isolated brainstem dysfunction and less often with isolated dysfunction of long tract [66]. As in adults MS can be diagnosed in children who suffered two or more demyelinating events separated in time and space [67]. Other causes of acute CNS demyelination in pediatrics must be excluded [62]. Important disorders in the differential diagnosis are ADEM, CNS infection, intracerebral malignancy and primary small-vessel vasculitis [62, 68]. Distinction between these disorders is of therapeutic importance. ADEM is an acute CNS demyelinating event often preceded by viral infections and characterized by polyfocal neurological deficits and encephalopathy [67]. Encephalopathy, described as behavioral change and/or alteration in consciousness, is not a typical feature of MS. In children with an initial diagnosis of ADEM a third demyelinating event is necessary for the diagnosis of MS, because a second non-ADEM event might still reflect a transient demyelinating disease [67]. Age over 10 years old, optic neuritis and absence of encephalopathy are risk factors for a second demyelinating event and thus for the diagnosis of MS [69]. Also environmental factors as reduced serum 1,25dihydroxyvitamin D3 or previous EBV infection and genetic factors as presence of HLA-DRB1*15 alleles can increase the risk to develop MS [70]. In childhood-onset MS both males and females are equally affected, but after puberty females are more often affected [62, 66]. This indicates that gender also plays a role in the risk of MS development. Relapsing-remitting MS is the most frequent initial disease course in childhood-onset MS, approximately 97% compared to 85-90% in adults. Relapses are, like in adults, defined as new neurological deficits which persist for 24 hours or longer [65]. The relapse rate in pediatric-onset MS patients is reported to be higher compared to adult-onset MS [71]. Both laboratory investigation and MRI have a pivotal role in the diagnostic work-up of acute CNS demyelination

in children [62, 65]. CSF analysis can be a helpful tool for early diagnosis of pediatric MS [72]. CSF oligoclonal IgG is detected in 92% of pediatric MS patients and therefore is a sensitive diagnostic tool. Cerebrospinal fluid (CSF) analysis can be helpful to exclude other diagnoses. For example CSF oligoclonal IgG is not a characteristic feature of ADEM and therefore its absence or presence differentiates between ADEM and MS [62, 65, 72]. Brain MRI is crucial to demonstrate inflammatory demyelination and also to exclude other diagnoses [62]. MRI in MS patients typically shows T2 lesions in locations characteristic for MS: periventricular, juxtacortical, infratentorial and spinal cord [53]. Compared to adults, pediatric MS patients had a higher number of total T2-lesions at disease onset in an American retrospective analysis [73]. The 2010 revised diagnostic McDonald criteria for MS are thought to serve well for most childhood-onset MS patients [53]. Sedani and colleagues validated the criteria in a retrospective cohort of pediatric MS patients and found that the 2010 McDonald criteria are more sensitive than the 2007 proposed pediatric MS criteria and allow diagnosis at first presentation of ADS in fifty percent of the cases [67, 74]. Early diagnosis of pediatric MS is of therapeutic importance. The aim of studies at ADS in pediatric patients is to describe prognostic factors which predict disease progression to MS. Recently specific MRI parameters were developed to predict early MS diagnosis in children [75]. This Canadian prospective cohort study demonstrates that the presence of periventricular lesions and T1-weighted hypo-intense lesions highly increase the risk of MS diagnosis in pediatrics. The care of patients with pediatric-onset MS should be managed in multidisciplinary teams [62]. Acute demyelination in pediatric and adult patients is managed with corticosteroid therapy [62, 72]. No specific studies of dose or effectiveness of corticosteroids have been reported. Common regimen for acute severe demyelination is 10-30 mg/kg/dose of methylprednisolone intravenous for 3 – 5 days. Disease-modifying therapies in children with MS have not been officially approved because they were not formally

Recent Gains in Clinical Multiple Sclerosis Research

assessed in large clinical trials [62, 72, 76, 77]. Since early treatment improves long-term prognosis in adults, immunomodulatory therapies are increasingly offered to pediatric patients. The safety and tolerability of treatment with interferon-beta and glatiramer acetate have been reported in some small studies [62, 73, 77, 78]. These firstline treatments for MS also reduce relapses and disease progression in pediatric patients. Difficulties of the off label treatment with disease-modifying therapies in childhoodonset MS is that it is not clear how the dosage should be adapted [77]. Natalizumab for the second-line treatment of relapsing and remitting MS was studied in an Italian cohort of 19 children with MS [79]. During treatment no serious events occurred and patient EDSS scores improved. Longterm effects on growth, puberty and adverse effects of immunomodulatory therapies for MS in children have yet to be established [77]. Although pediatric-onset MS patients seem to have a higher relapse rate than adult-onset MS patients they have a slower rate of disease progression [66, 80]. It takes longer for pediatric-onset patients to reach states of irreversible disability, but they do so at younger age than patients with adult-onset MS [66]. As a possible explanation for this, it has been suggested that the developing CNS of childhood-onset MS patients has more plasticity to recover [80]. NEUROMYELITIS OPTICA Neuromyelitis optica (NMO or Devic syndrome) is a rare CNS demyelinating syndrome characterized by (bilateral) optic neuritis and acute myelitis [81]. Neuromyelitis optica used to be frequently misdiagnosed as MS. In 2004 a specific auto-antibody (anti-NMO-IgG) was discovered and confirmed NMO as an antibody-mediated pathogenesis [82]. Anti-NMO contributes to the distinction of NMO from MS. This IgG marker binds to aquaporin-4 water channels in the CNS [83]. NMO can be diagnosed if the 2 absolute criteria (optic neuritis and myelitis) are fulfilled and at least 2 of 3 supportive criteria: a. presence of contiguous spinal cord MRI lesion extending over three or more vertebral segments, b. MRI criteria not satisfying the revised McDonald diagnostic criteria for MS, and c. NMO-IgG in serum [81]. For NMO diagnosis it is important that there is no evidence for other diseases, like sarcoidosis or vasculitis [84]. In most NMO patients (>80%) the disease has a relapsing course [81, 85, 86]. The mean age at onset is 39 years, compared to 29 years in MS patients [86]. NMO is nine times more prevalent in women. Clinical, laboratory and MRI features can help distinguish NMO from MS [85]. NMO patients usually have optic neuritis and myelitis sequentially [86]. The interval between attacks can be years to decades. Common NMO features are: ocular pain with vision loss and transverse myelitis with sensory loss, paraplegia and bladder dysfunction. The anti-aquaporin-4 antibodies are highly specific for NMO and can distinguish NMO from MS [87]. Indirect immunofluorescence is the current gold standard for NMOIgG detection and has a sensitivity of approximately 5876%. Recently a new and more sensitive cell-based assay was developed [88]. Although this assay cannot detect other

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auto-antibodies simultaneously it is able to monitor antiaquaporin-4 antibodies serum concentration, which may be of future importance to measure treatment. Monophasic NMO patients may have a different pathogenesis, which is supported by a Dutch cohort study [89]. In this study anti-aquaporin-4 antibodies were not detected in any of the included NMO patients. Instead NMOIgG is also highly specific in recurrent NMO spectrum disorders like recurrent optic neuritis and longitudinally extensive transverse myelitis [90]. CSF analysis typically reveals oligoclonal bands in 85% of the MS patients and only in 15-30% of NMO patients [85, 86]. Brain MRI in NMO patients is usually normal. NMO spinal cord lesions are usually longitudinally extensive and localized central in the spinal cord, unlike MS where spinal cord lesions are usually short and localized more peripheral in the spinal cord [86]. NMO patients have a significantly worse disease course than MS patients [85, 91]. Also they have more residual disability from initial relapses compared to MS patients. A recent French cohort study demonstrates after a first optic neuritis 22% of the NMO patients show severe residual visual loss [92]. The first episode of myelitis was followed by an EDSS score of  4 in 37.7% of NMO cases. Since the disease course is severe and has high morbidity early diagnosis and treatment of NMO are very important [82]. Acute exacerbations are first treated with high dose intravenous corticosteroid therapy [86, 91]. Patients who do not respond to corticosteroid therapy can benefit from plasmapheresis. Immunosuppressive drugs like azathioprine and rituximab are regarded to be the best maintenance therapy for NMO patients [82, 86, 91]. Future treatment development focuses on anti-aquaporin-4 as a target for therapy [93]. Recently monoclonal anti-aquaporin-4 antibodies (aquaporumab) were engineered to selectively block NMO-IgG binding [94]. These antibodies have already been used to successfully prevent the development of NMO lesions in a mouse model. FUTURE MS is a complex disease, a result of a deleterious interplay of genetic traits and environmental factors within an individual. The exact pathways involved have largely remained an enigma, though recent progress in research is beginning to shed some light. This CNS disease affects young people in the prime of their lives, in whom it not only causes physical disability but also cognitive and psychosocial problems. The substantial number of patients that have their onset below 18 years of age, is now starting to receive the attention it deserves. Unfortunately, the incidence of MS seems to be increasing, especially in women, presumably because of changing environmental factors. For future research, it appears important to focus on (female) lifestyle changes. Furthermore, the neurodegenerative aspects and the progressive phases of the disease should get more attention, these being the main determinants of disability in MS. In trials for disease-modifying drugs targeting the neurodegenerative processes in MS, OCT might be a useful new tool.

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ACKNOWLEDGEMENT

[12]

EDVP-G and TFR performed the literature search and drafted the manuscript. RQH critically revised the manuscript.

[13] [14]

CONFLICT OF INTEREST The authors report no conflict of interest.

[15]

ABBREVIATIONS ADEM

= Acute disseminated encephalomyelitis

ADS

= Acquired demyelination syndrome

CIS

= Clinically isolated syndrome

CNS

= Central nervous system

CSF

= Cerebrospinal fluid

EDSS

= Kurtzke Expanded Disability Status Scale

MRI

= Magnetic resonance imaging

MS

= Multiple sclerosis

NMO

= Neuromyelitis optica

OCT

= Optical Coherence Tomography

PPMS

= Primary progressive multiple sclerosis

RNFL

= Retinal nerve fiber layer

SPMS

= Secondary progressive multiple sclerosis

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Verkman, A.S.; Ratelade, J.; Rossi, A.; Zhang, H.; Tradtrantip, L. Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica. Acta Pharmacol. Sin., 2011, 32(6), 702710. Tradtrantip, L.; Zhang, H.; Saadoun, S.; Phuan, P.W.; Lam, C.; Papadopoulos, M.C.; Bennett, J.L.; Verkman, A.S. Aquaporumab:

Received: January 12, 2012

Revised: April 5, 2012

9

a non-pathogenic anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. 2011.;5th Joint triennial congress of the European and Americas Committees for treatment and research in multiple sclerosis. Amsterdam, The Netherlands. 2011.

Accepted: April 6, 2012

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 22583434