J Neurol (200■) 25■:000–000 DOI 10.1007/s00415-008-0778-x
Bernhard Kis Bastian Rumberg Peter Berlit
Received: 29 April 2007 Received in revised form: 1 October 2007 Accepted: 16 October 2007 Published online: 19 February 2008
B. Kis, MD · B. Rumberg, MD · P. Berlit, MD Dept. of Neurology Alfried Krupp Hospital Essen, Germany B. Kis, MD (쾷) Dept. of Psychiatry University of Duisburg-Essen Rheinische Kliniken Essen Research Unit Virchow Str. 174 45147 Essen, Germany Tel.: +49-201/7227-190 Fax: +49-201/7227-310 E-Mail:
[email protected] B. Rumberg, MD Dept. of Diagnostic and Interventional Radiology and Neuroradiology University of Duisburg-Essen Essen, Germany Drs. Kis and Rumberg contributed equally to this work.
ORIGINAL COMMUNICATION
Clinical characteristics of patients with late-onset multiple sclerosis
■ Abstract We evaluated clinical presentation, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) in patients with late-onset multiple sclerosis (LOMS). Fifty-two patients with definitive multiple sclerosis (MS) diagnosed after the age of 50 years were identified between 1991 and 2002. Data pertaining to clinical characteristics, CSF analysis, and cerebral and spinal MRI were compared with those of 52 young-onset MS (YOMS) patients matched for sex and disease duration. Mean age at the time of diagnosis was 57 years in the LOMS group – the oldest patient was 82 – and 29 years in the YOMS group. Motor symptoms were significantly more often present in the LOMS than in patients with YOMS (90 % vs. 67 %, p = 0.014). Visual symptoms, residual signs of optic neuritis, and dysarthria were less frequent for LOMS. Sensory symptoms, ataxia, oculomotor symptoms, cognitive disorder, or fatigue did not differ between both groups. The majority of LOMS patients (83 %) had a primary progressive disease course, whereas 94 % of the YOMS group had a relapsing-remitting course. MRI showed typical multifocal
supratentorial (LOMS vs. YOMS: 96 % vs. 98 %) and infratentorial (44 % vs. 62 %) lesions without significant group differences. Of particular interest, spinal lesions were more common (81 %) in LOMS compared to YOMS (48 %, p = 0.024), and cerebellar lesions were less frequent in the LOMS group (11 % vs. 44 %, p = 0.001). Gadolinium-enhanced lesions were initially present in less LOMS patients (15 %) than in YOMS (63 %, p < 0.001). CSF analysis revealed pleocytosis less frequently in LOMS (34 %) compared to YOMS (67 %, p = 0.006) but oligoclonal banding occurred without in both groups without differences. YOMS patients responded to corticosteroids (93 %) to a significantly greater degree than LOMS patients (73 %; p = 0.004). For individuals who develop LOMS, a primary progressive course is frequent, with motor symptoms as the prominent feature. Vigilance is necessary to recognise MS in this population because of its unusual presentation. ■ Key words multiple sclerosis · age of onset · cerebrospinal fluid · magnetic resonance imaging
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Introduction Reports on clinical characteristics of patients with multiple sclerosis (MS) and an age at onset above 50 years are infrequent in the literature [1, 11, 22, 24, 32, 37]. The clinical course of late-onset MS (LOMS) is likely progressive and manifests more rapidly than in patients with a young age at onset [1, 3, 11, 12, 16, 23, 25]. Regarding the initial symptoms and outcome, the literature is equivocal. Some reports describe motor symptoms as initial signs [1, 22], while others find no differences between LOMS and young-onset MS (YOMS) groups [12, 16]. Several studies report that LOMS has a poorer prognosis than YOMS [15, 27, 33, 34, 36]. However, other studies do not support those reports [19]. In the present retrospective study, we compared demographic and clinical data of patients with LOMS to those of patients with YOMS from a single-center cohort. The purpose of the systematic study was to describe clinical aspects of LOMS with regard to published criteria [17].
Methods ■ LOMS Patients diagnosed with MS with an age at diagnosis of > 50 years between January 1991 and December 2002 (i.e., primary search criteria) were evaluated for study. Case collection was clinic-based. All files of the Department of Neurology at the Alfried Krupp Hospital, Essen, Germany were searched for in- and outpatients fulfilling the primary search criteria who were treated between 1991 and 1998. Data subsequent to 1998 were obtained from the institutional medical information system, according to the International Classification of Diseases (ICD-10). MS diagnoses were based on published criteria [17].
as being typical of MS by neurological examination. In addition, fatigue and active or residual signs of optic neuritis were documented accessorily. The mean Expanded Disability Status Scale (EDSS) scores were assessed at the time of the first documented neurological examination and at the time of the last examination. The progression index (EDSS score/disease duration) for each group was also determined. The course of the disease was defined according to published criteria as relapsing-remitting, secondary progressive, primary progressive, and “benign” forms. “Benign” courses were defined in those patients with a score on the Expanded Disability Status Scale (EDSS) of ≤ 3 at least 10 years after disease onset [10, 26]. Initial misdiagnoses were documented when available. Gadolinium-enhanced and T2-weighted cerebral and spinal magnetic resonance imaging (MRI) scans were examined for the occurrence of lesions, and the number of patients with MRI lesions were assessed. Magnetic- and sensory- (visual, somatosensory, acoustic) evoked potentials were analysed. Oligoclonal banding, cell count, and cerebrospinal fluid (CSF) protein concentration were documented. Therapeutic regimes during the course of MS were classified as (a) high-dose corticosteroid infusion (1 g each for 3 days) in cases of acute relapse; (b) interval therapy with different types of interferonbeta, glatiramer acetate, azathioprine, or immunoglobulins; and (c) mitoxantrone in severe cases of active forms. Response to corticosteroids was defined as an improvement of the EDSS score of at least 0.5. Responders and non-responders to corticosteroids after relapse were assessed. ■ Statistical assessment Analyses were performed with the statistical package for social sciences (SPSS), version 12 (SAS Institute Inc., Cary, IN). Differences in first-reported neurological symptoms, new symptoms reported during course of the disease, additional symptoms identified by neurological examination, evoked potentials, cerebral and spinal MRI, and oligoclonal banding were evaluated in the LOMS and YOMS groups using the Fisher’s exact test. Differences in the course of the disease were assessed using the chi-square test. The independent samples t-test was used to evaluate differences in cell count and CSF protein concentration. Values of p < 0.05 were considered significant.
Results ■ YOMS The YOMS comparison group was comprised of in- and out-patients with a diagnosis of definitive MS based on published criteria [17]. Age at diagnosis was < 40 years. Data were obtained from the institutional medical information system, according to the ICD-10. YOMS patients treated between January 2000 and December 2002 comprised the complete YOMS cohort. The comparison group of YOMS cases was randomly selected from the complete cohort. Patients in the LOMS group and the YOMS comparison group were matched for sex and for disease duration. ■ Measures Information on the age at diagnosis, disease duration, age at firstreported symptoms that were (a) accompanied by an abnormal neurological examination and (b) confirmed as being typical of MS, was collected. The neurological symptoms were classified as motor or sensory disturbances, ataxia, oculomotor symptoms, visual disturbances, and dysarthria. Cognitive abilities of all MS patients were routinely assessed at our center by a neuropsychologist using a neuropsychological test battery. Neurological symptoms were classified as first-reported symptoms, new symptoms reported during the course of the disease, and additional symptoms that were confirmed
■ Clinical data Between January 1991 and December 2002, 52 MS patients (30 females and 22 males; female to male ratio 1.4:1) were identified according to the primary search criteria. The complete cohort of YOMS patients consisted of 593 patients. From that group, 30 females and 22 males were randomly selected for the YOMS comparison group. Mean age at diagnosis (± SD, range) was 57 (± 7, 50–82) years in the LOMS group and 29 (± 7, 17–42) years in the YOMS comparison group. The mean disease duration (± SD, range) at the time of evaluation was 10 (± 6, 2–21) years in the LOMS group and 10 (± 6, 1–24) years in the YOMS group. The age at first-reported symptoms (± SD, range) was 54 (± 8, 33–81) years in the LOMS group and, identical to the mean age at diagnosis, 29 (± 7, 17–42) years in the YOMS group. Table 1 shows the distribution of neurological symptoms in LOMS and YOMS groups. LOMS and YOMS groups differed significantly on
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Table 1 Neurological symptoms in LOMS and YOMS patients were classified as a) first-reported symptoms, b) new symptoms reported during the course of the disease, and c) symptoms confirmed as being typical MS signs by neurological examination Modality
Motor symptoms Sensory symptoms Ataxia Oculomotor symptoms Visual disturbance Dysarthria Cognitive dysfunction Fatigue Optic Neuritis
a) First reported
b) New during course
c) Examined
LOMS N (%)
YOMS N (%)
p
LOMS N (%)
YOMS N (%)
p
LOMS N (%)
YOMS N (%)
p
35/44 (80) 20/44 (45) 11/44 (25) 2/44 (5) 2/44 (5) 0/44 (0) 0/44 (0)
12/41 (29) 29/41 (71) 5/41 (12) 6/41 (15) 15/41 (37) 2/41 (5) 0/41 (0)
< 0.001 0.028 > 0.05 > 0.05 0.001 > 0.05 > 0.05
5/26 (19) 8/26 (31) 4/26 (15) 3/26 (12) 1/26 (4) 0/26 (0) 6/26 (23)
25/38 (66) 14/38 (36) 7/38 (19) 6/38 (16) 7/38 (18) 3/38 (8) 2/38 (5)
0.001 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 0.016
47/52 (90) 40/52 (77) 30/52 (58) 21/52 (40) 7/52 (13) 4/52 (8) 8/52 (15) 4/52 (8) 5/52 (10)
35/52 (67) 44/52 (85) 33/52 (63) 26/52 (50) 22/52 (42) 17/52 (33) 4/52 (8) 3/52 (6) 23/52 (44)
0.014 > 0.05 > 0.05 > 0.05 0.010 0.014 > 0.05 > 0.05 0.001
LOMS late-onset multiple sclerosis; YOMS young-onset multiple sclerosis; N (%) values represent number of patients/total group size and (%)
the incidence of motor symptoms with paraparesis or quadriparesis, first-reported sensory symptoms, firstreported and examined visual symptoms, examined dysarthria, cognitive dysfunction during the course of disease, and optic neuritis. The mean EDSS score at the time of the first documented neurological assessment was 3.5 ± 1.0 for the LOMS group and 2.8 ± 1.5 for the YOMS patients (p = 0.034). At the time of the last examination, the mean EDSS score was 6.5 ± 2.0 for LOMS and 3.9 ± 1.7 for YOMS (p = 0.001). The progression index was 0.60 for the LOMS and 0.35 for the YOMS. A relapsing-remitting course was more frequent in the YOMS comparison group (49/52, 94 %) than the LOMS group (4/52, 8 %; p < 0.001). Conversion to a secondary progressive course was evident in 14/52 (27 %) YOMS cases but none of the LOMS cases (p < 0.001). A primary progressive course was more frequent in the LOMS group (43/52, 83 %) than the YOMS group (3/52, 5 %; p < 0.001). The “benign” form of MS was encountered in 5/52 (10 %) LOMS cases and 1/52 (2 %) YOMS cases (p > 0.05).
unspecified inflammatory process of the CNS in 4 cases, vasculitis in 2 cases, and myelopathy in 2 cases.
■ MRI data Results of cerebral and spinal MRI scans are listed in Table 2. There were significant between-group differences in cerebellar and spinal lesions and infratentorial and spinal contrast enhancement.
■ Evoked potentials Delayed latencies of magnetic-evoked potentials were more frequent in LOMS (38/44, 86 %) than YOMS (32/46, 70 %) patients (p = 0.049). Reduced amplitudes of sensory-evoked potentials were more frequent in Table 2 Number of patients with lesions in a) cerebral and b) spinal location according to MRI scans in LOMS and YOMS patients Lesion location
LOMS N (%)
YOMS N (%)
p
a) Supratentorial Infratentorial Pontine Cerebellar Other infratentorial location Contrast agent enhancement
50/52 (96) 21/52 (44) 11/52 (21) 6/52 (11) 8/52 (15) 8/52 (15)
51/52 (98) 31/52 (62) 20/52 (38) 23/52 (44) 6/52 (12) 33/52 (63)
> 0.05 0.047 > 0.05 0.001 > 0.05 < 0.001
b) Spinal Contrast agent enhancement
25/31 (81) 2/31 (7)
16/33 (48) 12/33 (36)
0.024 0.001
■ Misdiagnoses The correct diagnosis of LOMS was delayed in 21 (40 %) patients for an average of 3 years. Misdiagnoses included unspecified inflammatory process of the CNS in 9 (33 %) cases, cervical myelopathy in 4 (15 %) cases, polyneuropathy in 2 (7 %) cases, stroke in 2 (7 %) cases, and 1 (4 %) case each of paroxysmal vertigo of unknown origin, Morbus Meniere, myelitis, tumour, gait disorder of unknown origin, Guillain-Barré syndrome, ataxia of unknown origin, trigeminal neuralgia, spastic spinal paralysis, and collagenosis. With regard to the YOMS, misdiagnoses were evident in 8 patients (15 %):
LOMS late-onset multiple sclerosis; YOMS young-onset multiple sclerosis; N (%) values represent number of patients/total group size and (%)
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YOMS (36/51, 71 %) than LOMS (18/ 49, 37 %) patients (p = 0.001). There were no significant between-group differences in the number of reduced magnetic-evoked amplitudes, delayed latencies of somatosensory-evoked potentials, or delayed latencies and reduced amplitudes of visual- and acoustic-evoked potentials.
■ CSF findings The incidence of positive oligoclonal banding (LOMS: 51/52, 98 %; YOMS: 48/52, 92 %), the frequency of elevated CSF protein concentration (LOMS: 25/41, 61 %; YOMS: 20/40, 50 %), and the absolute value of CSF protein concentration (LOMS: 48.9 mg/dl, range 30.4–74.4 mg/dl; YOMS: 48.0 mg/dl, range 22.1–79.6 mg/dl) was not different between the groups (data on CSF protein concentration were not available in all cases). The incidence of elevated CSF cell count was more frequent in the YOMS group (28/42, 67 %) than in the LOMS group (15/44, 34 %; p = 0.006). The mean value of CSF cell count was 5 cells/μl (range 0–41 cells/μl) in the LOMS cases and 14 cells/μl (1–132 cells/μl) in the YOMS cases (p = 0.002).
■ Therapeutic regimen High dose corticosteroid infusions were administered in cases of acute relapse in 43/52 (83 %) LOMS patients and 51/52 (98 %) YOMS patients. Interval therapy with different types of interferone-beta were used in 5/52 (10 %) LOMS cases and 28/52 (54 %) YOMS cases. Azathioprine was given to 4/52 (8 %) LOMS patients and 7/52 (13 %) YOMS patients. Immunoglobulins were given to 2/52 (4 %) LOMS patients and 3/52 (6 %) YOMS patients. Mitoxantrone was given to patients with severe reactive forms of LOMS (2/52, 4 %) and YOMS (3/52, 6 %). The groups differed significantly in response to corticosteroid relapse therapy. YOMS patients responded to corticosteroid therapy (39/42, 93 %) to a significantly greater degree than LOMS patients (29/40, 73 %; p = 0.004). Nine YOMS cases and three LOMS cases were not documented.
Discussion The ratio of females to males in the LOMS group was 1.4 : 1. The female:male ratio for the entire international MS population is 2:1 [31], and there is a smaller proportion of females with a primary progressive course [22]. Weinschenker and Sibley [36] reported more males than females in the progressive course subgroup. In the present report, a progressive course was found more often in the LOMS group than the YOMS group. It remains
unclear if this ratio is related to age at onset or other factors. The mean age at onset of first symptoms was 54 years in the LOMS group, which suggests a 3-year delay in diagnosis. Delays in diagnosis up to 4.7 years have been reported [6, 10]. The frequent initial misdiagnoses in the LOMS group (52 %) included myelopathy in 15 %, polyneuropathy in 7 %, and stroke in 7 %. Less frequent misdiagnoses were paroxysmal vertigo, Morbus Meniere, myelitis, tumour, gait disorder of unknown origin, acute polyneuroradiculitis, ataxia of unknown origin, trigeminal neuralgia, spastic spinal paralysis, and collagenosis in 4 % of those cases. The mean interval before correct diagnosis was 3 years. In YOMS patients, a diagnosis of definitive MS was made at inital presentation or within 1 year of symptom onset. These findings emphasise that misdiagnosis of MS in older patients might be a common phenomenon [7]. Motor symptoms were more prominent in the LOMS group than the YOMS group. This finding supports the reports of Noseworthy et al. [22], Hooge and Redekop [11], Polliack et al. [24], and Hawkins and McDonelle [10] that motor symptoms are characteristic of LOMS. The results are also consistent with our magnetic-evoked potentials and MRI data. MRI indicated spinal lesions more frequently in the LOMS group. Tartaglino et al. [29] reported 47–90 % spinal lesions in this age group. Compared to YOMS patients, LOMS patients did report fewer incidents of new motor symptoms during the disease course. This may be explained by an initial high rate of motor symptoms in LOMS patients. In addition, a primary progressive course manifests more likely in a worsening of pre-existing deficits rather than in the onset of new symptoms. LOMS patients had fewer sensory symptoms than YOMS patients. Moreira et al. [20] reported that sensory symptoms were the most frequent intial symptom in patients with with mean age at onset of 29.6 years. Gomez-Garcia et al. [9] emphasised that sensory symptoms were more frequent in YOMS than LOMS. In addition, sensory symptoms did not develop during the course of the disease in LOMS patients. Demyelinating lesions in LOMS may be more often subclinical, whereas YOMS patients suffer from a manifest demyelination. None of our patients had cognitive deficits at the time of diagnosis. Dujmovic et al. [8] reported cognitive deficits in 3.2 % of patients. On the other hand, Leye et al. [14] emphasised that mild cognitive deficits may be present in up to 60 % of patients when systematically evaluated with neuropsychological tests. However, in a subgroup of older patients, cognitive deficits might be associated with other degenerative diseases [28]. The difficulty regarding the definition of different disease courses is that they were defined only by clinical presentation. Biological markers and MRI data were not taken into account.
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The relapsing remitting course was significantly more frequent in the YOMS group compared to LOMS. Similarly, Moreira et al. [20] diagnosed a relapsing remitting course in 72 % of a group of patients with a mean age of 30 years. Myhr et al. [21] reported a better prognosis for patients with a relapsing remitting course. In addition, they reported optic neuritis and sensory symptoms as initial symptoms and a younger age at onset in that group. In patients with first presentation after 40 years of age, there were more primary and secondary progredient courses [9]. Conversion to a secondary progressive course is crucial for further prognosis [13]. A conversion within the first 5 years is associated with a worse course. A primary progressive course was more frequent in the LOMS group than in the YOMS group. Similar findings have been reported elsewhere [7, 24]. In the entire international MS patients population, 10–20 % [5, 30] were reported to have a primary progressive course. An accurate description is difficult because it is often the case that initial symptoms are not reported or remembered by patients [18, 35]. MRI is reported to be the most specific and sensitive examination tool for diagnosing MS [17]. In older MS patients, MRI specificity declines due to the co-occurrence of microangiopathic lesions. Thompson et al. [31] reported that MRI detected less frequently minor lesions in patients with a primary progressive course than in those with a relapsing remitting or secondary progredient course. On the other hand, Dujmovic et al. [8] found no patients with primary progressive course
that did not have lesions based on MRI. We observed MRI changes in 96 % of the LOMS patients and 98 % of the YOMS patients in the present study. In the present study, infratentorial lesions were significantly more frequent in the YOMS patients. A similar finding was reported by Thompson et al. [31]. The present study is limited by its retrospective design. We compared two groups of patients that were defined by their age at onset of disease and matched for sex. However, our ability to compare the present results with the total international MS population is limited. We included only those patients that fulfilled the McDonald criteria [17] for diagnosing MS, in oder to make reliable comparisons. This allowed us to screen a relatively large population, using standardised diagnostic criteria. Further prospective studies are necessary to validate our data.
Conclusion We found that in individuals who developed LOMS, a primary progressive course was more frequent than in patients with YOMS. Motor symptoms were the prominent feature. Vigilance is necessary to recognise MS in this population because of its unusual presentation. ■ Acknowledgements We thank Markus Neuhäuser of the Institute for Medical Informatics, Biometry, and Epidemiology of the University of Duisburg-Essen for statistical assistance. The authors Kis, Rumberg, and Berlit have nothing to disclose.
References 1. Cazzullo CL, Ghezzi A, Marforio S, Caputo D (1978) Clinical picture of multiple sclerosis with late onset. Acta Neurol Scand 58:190–196 2. Confavreux C (2002) Infections and the risk of relapse in multiple sclerosis. Brain 125:933–934 3. Confavreux C, Aimard G, Devic M (1980) Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 103:281–300 4. Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–782 5. Cottrell DA, Kremenchutzky M, Rice GP, Koopman WJ, Hader W, Baskerville J, Ebers GC (1999) The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 122(Pt 4):625–639
6. de Seze J, Stojkovic T, Ferriby D, Gauvrit JY, Montagne C, MounierVehier F, Verier A, Pruvo JP, Hache JC, Vermersch P (2002) Devic’s neuromyelitis optica: clinical, laboratory, MRI and outcome profile. J Neurol Sci 197:57–61 7. Delalande S, De Seze J, Ferriby D, Stojkovic T, Vermersch P (2002) Late onset multiple sclerosis. Rev Neurol (Paris) 158:1082–1087 8. Dujmovic I, Mesaros S, Pekmezovic T, Levic Z, Drulovic J (2004) Primary progressive multiple sclerosis: clinical and paraclinical characteristics with application of the new diagnostic criteria. Eur J Neurol 11:439–444 9. Gomez-Garcia AO, Fernandez-Concepcion O, Milan-Ginjauma E (1997) Clinical-epidemiological characteristics of late onset multiple sclerosis. Rev Neurol 25:1863–1866
10. Hawkins SA, McDonnell GV (1999) Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 67: 148–152 11. Hooge JP, Redekop WK (1992) Multiple sclerosis with very late onset. Neurology 42:1907–1910 12. Leibowitz U, Alter M, Halpern L (1964) Clinical studies of multiple sclerosis in Israel. 3. Clinical course and prognosis related to age at onset. Neurology 14: 926–932 13. Levic ZM, Dujmovic I, Pekmezovic T, Jarebinski M, Marinkovic J, Stojsavljevic N, Drulovic J (1999) Prognostic factors for survival in multiple sclerosis. Mult Scler (Houndmills, Basingstoke, England) 5:171–178
6
14. Leyhe T, Laske C, Buchkremer G, Wormstall H, Wiendl H (2005) Dementia as a primary symptom in late onset multiple sclerosis. Case series and review of the literature. Nervenarzt 76:748–755 15. Liguori M, Marrosu MG, Pugliatti M, Giuliani F, De Robertis F, Cocco E, Zimatore GB, Livrea P, Trojano M (2000) Age at onset in multiple sclerosis. Neurol Sci 21:S825–S829 16. Lyon-Caen O, Izquierdo G, Marteau R, Lhermitte F, Castaigne P, Hauw JJ (1985) Late onset multiple sclerosis. A clinical study of 16 pathologically proven cases. Acta Neurol Scand 72: 56–60 17. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50: 121–127 18. McDonnell GV, Hawkins SA (1998) An epidemiologic study of multiple sclerosis in Northern Ireland. Neurology 50:423–428 19. Moreau T, Confavreux C (2000) Can the prognosis of multiple sclerosis be predicted? Pathologie-biologie 48:132–138 20. Moreira MA, Felipe E, Mendes MF, Tilbery CP (2000) Multiple sclerosis: descriptive study of its clinical forms in 302 cases. Arq Neuropsiquiatr 58: 460–466 21. Myhr KM, Riise T, Vedeler C, Nortvedt MW, Gronning R, Midgard R, Nyland HI (2001) Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Sclers (Houndmills, Basingstoke, England) 7:59–65
22. Noseworthy J, Paty D, Wonnacott T, Feasby T, Ebers G (1983) Multiple sclerosis after age 50. Neurology 33: 1537–1544 23. Noseworthy JH (1993) Clinical trials in multiple sclerosis. Curr Opin Neurol Neurosurg 6:209–215 24. Polliack ML, Barak Y, Achiron A (2001) Late-onset multiple sclerosis. J Am Geriatr Soc 49:168–171 25. Poser S, Raun NE, Poser W (1982) Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurol Scand 66:355–362 26. Ramsaransing G, Maurits N, Zwanikken C, De Keyser J (2001) Early prediction of a benign course of multiple sclerosis on clinical grounds: a systematic review. Mult Scler (Houndmills, Basingstoke, England) 7:345–347 27. Runmarker B, Andersson C, Oden A, Andersen O (1994) Prediction of outcome in multiple sclerosis based on multivariate models. J Neurol 241:597–604 28. Savettieri G, Messina D, Andreoli V, Bonavita S, Caltagirone C, Cittadella R, Farina D, Fazio MC, Girlanda P, Le Pira F, Liguori M, Lugaresi A, Nocentini U, Reggio A, Salemi G, Tedeschi G, Trojano M, Valentino P, Quattrone A (2004) Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol 251:1208–1214 29. Tartaglino LM, Friedman DP, Flanders AE, Lublin FD, Knobler RL, Liem M (1995) Multiple sclerosis in the spinal cord: MR appearance and correlation with clinical parameters. Radiology 195:725–732
30. Thompson AJ, Montalban X, Barkhof F, Brochet B, Filippi M, Miller DH, Polman CH, Stevenson VL, McDonald WI (2000) Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 47:831–835 31. Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi MMX, De Sa J (1997) Primary progressive multiple sclerosis. Brain 120(Pt 6): 1085–1096 32. Tremlett H, Devonshire V (2006) Is late-onset multiple sclerosis associated with a worse outcome? Neurology 67:954–959 33. Trojano M, Avolio C, Manzari C, Calo A, De Robertis F, Serio G, Livrea P (1995) Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 58:300–306 34. Visscher BR, Liu KS, Clark VA, Detels R, Malmgren RM, Dudley JP (1984) Onset symptoms as predictors of mortality and disability in multiple sclerosis. Acta Neurol Scand 70:321–328 35. Weinshenker BG (2000) Progressive forms of MS: classification streamlined or consensus overturned? Lancet 355: 162–163 36. Weinshenker BG, Sibley WA (1992) Natural history and treatment of multiple sclerosis. Curr Opin Neurol Neurosurg 5:203–211 37. White AD, Swingler RJ, Compston DA (1990) Features of multiple sclerosis in older patients in South Wales. Gerontology 36:159–164
