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OBJECTIVE To study ten-year change in MS prevalence in the Province of Western Finland in Tampere University Hospital District located in 62.7°N, 23.7°E. METHODS Age-standardized prevalence/105 by using direct standardization in European Standard Population (ESP2013) and crude prevalence/105 with 95% confidence interval (95% CI) were assessed among resident MS cases fulfilling Poser criteria by sex and disease course in 31.12.2000 and 31.12.2010. MS-related disability and disease-modifying treatment (DMT) use were estimated in 31.12.2010. RESULTS Crude prevalence increased 49% from 129/105 (95% CI 121-137) in 2000 (N 1080) to 196/105 (187-203) in 2010 (N 1666). Age-standardized prevalence increased 45% from 133/105 (127-140) to 192/105 (184-200) and peaked in 40- to 49-year age-group. Age-standardized prevalence increased 58% among women from 176/105 (171-176) to 277/105 (270-284) and 31% among men from 91/105 (87-95) to 119/105 (115-124). Increase in RRMS was 61% from 111/105 (105-117) to 179/105 (171-186), and decrease in PPMS was 14% from 21/105 (19-24) to 18/105 (15-21). In 2010 among the 52% RRMS cases on DMT, MS-related disability was mild in 50%. In total, cohort disability was mild in 46%, moderate to severe in 47%, and information was not available in 14%. CONCLUSION A significant increase in prevalence was observed in Western Finland. Increase was higher among women and in relapsing-remitting onset MS. Disability showed age- and disease course-specific variation.

In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics.This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS.In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P0.0001) and MS (2005 McDonald criteria; HR=0.485; P0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P0.0001), and number of T2 lesions (HR=0.417, nominal P0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS.In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.

The aim of this study was to investigate the demographic and clinical characteristics of patients with multiple sclerosis (MS) diagnosed between 1986 and 2015. 333 patients with definite MS were divided into four subgroups according to the following diagnostic criteria: Group A) Poser (n = 145), Group B) McDonald 2000 (n = 66), Group C) McDonald 2005 (n = 62), and Group D) McDonald 2010 (n = 60). We investigated: 1) patient sex and age at diagnosis, 2) symptoms and number of relapses that prompted MS diagnosis, 3) time between first symptoms suggestive of MS and confirmed diagnosis, and 5) Expanded Disability Status Scale (EDSS) score at disease onset. The overall female-to-male ratio was 2.3:1, but in the subgroups it differed significantly (A - 1.9; B - 1.6; C - 4.7; D - 3.6). The mean age at diagnosis (in years) decreased from 39.6 ± 13.3 in Group A to 29.9 ± 9.3 in Group D, p < 0.001. Pyramidal signs remained the most common manifestation regardless of the diagnostic criteria, although an increased trend of visual dysfunction was observed (A - 16%, B - 14%, C - 19%, D - 23,3%; A vs D, p < 0.001). The number of relapses before diagnosis decreased from median 4.0 to 2.5 in Group A and Group D, p < 0.001. Time from the first symptom to diagnosis shortened from 88.9 ± 80.2 months (Group A) to 33.6 ± 68.2 months (Group D), p < 0.0001. Mean EDSS score at diagnosis also decreased: A - 4.4 ± 2.3; B - 3.1 ± 1.7; C - 2.7 ± 1.3; D - 2.8 ± 1.4, p < 0.001. Our study indicates significant differences in demographic and clinical characteristics of MS diagnosed according to the changing criteria.

Magnetic resonance imaging has improved the diagnosis and evaluation of disease activity in multiple sclerosis (MS), and its widespread use has contributed to creating the concept of radiologically isolated syndrome (RIS) to describe patients without symptoms of MS whose magnetic resonance imaging findings suggest they might be at risk of future demyelinating events. Indeed, using the revised McDonald criteria now allows some patients who would have been diagnosed with clinically isolated syndrome (CIS) in the era of Poser criteria to be diagnosed as having MS before a second episode. The present review discusses the current concepts of RIS and CIS, and the risk factors for conversion from these conditions to MS. Clinical trials involving participants with CIS at high risk of developing clinically definite MS have shown that disease-modifying drugs significantly suppressed the conversion from CIS to MS, and that early treatment with these drugs could improve future disease prognosis in patients who subsequently developed MS. When a patient presents with RIS or CIS, the primary concern for the physician and patient should be the probability of conversion to MS, and the patient should be followed up taking into consideration the risk factors for conversion from RIS or CIS to MS.

Background: In this study, we examined multiple sclerosis (MS) point prevalence in the well-defined island population of Iceland. Methods: This study included all registered residents of Iceland with MS on the prevalence day, December 31, 2007. All included patients met at least one of the following criteria: McDonald criteria; Poser criteria for clinically definite MS, laboratory-supported definite MS, clinically probable MS; or criteria for primary progressive MS. The patients’ medical records were reviewed, including all available MRI data acquired prior to the prevalence day. Results: We identified 526 patients, of whom 73% (382) were women. The crude point prevalence of MS was 167.1 per 100,000 population on the prevalence day. With age adjustment made to the 2000 U.S. population, the prevalence was 166.5 per 100,000 population. The mean patient age on the prevalence day was 47 years(range 13–89) for both men and women. The mean age at diagnosis was 36 years (range 13–77): 35 years for women and 36 years for men. Conclusion: MS prevalence was high in Iceland compared to the prevalence mentioned in reports from most of the world, and was similar to prevalence rates in other Nordic countries.

Purpose To characterise uveitis in association with multiple sclerosis (MS). Methods We conducted a retrospective chart review of patients with uveitis and MS at two uveitis centres (Portland, Oregon, USA and Heidelberg, Germany). Baseline characteristics and ophthalmic data were collected at the patient9s first and last visits. Additionally, neurological records were obtained when possible. Results We identified 113 patients (196 eyes) with uveitis and MS. Of these, 53 had a diagnosis of MS confirmed by review of neurological records, 50 additional patients fulfilled the Poser criteria for MS and 10 with MS were referred by an outside neurologist. Among them, 83 (73%) were women and the mean age of presentation was 40.6 years (range 13–64 years). The average visual acuity in affected eyes at presentation was 20/39. There were 90 patients (80%) who presented with intermediate uveitis and 24 patients (15%) with anterior uveitis. Posterior and pan-uveitis were found in four patients (3%) and two patients (2%), respectively. During a median follow-up of 3.2 years (range 0.04–21 years), visual acuity improved –0.09 logMar/year. Compared with our location-matched controls with idiopathic intermediate uveitis (n=16), patients with MS and intermediate uveitis were significantly older when diagnosed with uveitis (p=0.027) and more likely to be female (p=0.01). There was no statistical difference in visual acuity or rate of vision change between our cases and controls (p=0.58 and p=0.36, respectively). Conclusions Uveitis with MS generally presents as intermediate uveitis with a minority presenting with anterior uveitis. Patients are significantly older and more likely to be women than patients with idiopathic intermediate uveitis. The visual prognosis is generally favourable.

With no specific histologic, laboratory or imaging features the diagnosis/classification of Behçet's Disease (BD) remains clinical. As such, disease criteria are needed. The International Study Group Criteria set is the most widely used. It has some limitations, especially in telling BD from Crohn's disease. On the other hand the main issue, as it also applies to many of the other criteria sets in rheumatology, is our lack of appreciation of a list of misconceptions--some examples of which are unluckily also found in the 2010 ACR/EULAR RA Criteria set--about diagnostic/classification criteria making and their implementation. 1. The view that classification and diagnostic criteria should be different is ill advised in that the cerebral/arithmetic basis of both are the same. 2. The default promise of diagnostic criteria to come once we formulate a classification criteria set is an extension of the previous misconception. 3.Taking pains to avoid circularity in criteria making is unwarranted since the essence of criteria making is circular. In addition we fail to exploit the utility of the disease criteria in ruling out, rather than ruling in, the diseases we seek. Finally we also fail to appreciate the paramount importance of the Bayesian prior (the pretest) probability in formulating and implementing these disease criteria. To formulate criteria tailored to subspecialties, as well as giving the often forgotten family history more importance in our criteria sets are some ways to improve the prior probability on which our diagnostic/classification decisions will be based. We first have to reconcile with ourselves that probabilities are very important in our practice and research. Moreover that reconciliation must also be shared with the public, which includes our patients.

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

Multiple sclerosis may have a non-progressive symptomatology for decades; however, it is not clear whether the disease activity may abate completely. We identified a cohort of patients, resident in Gothenburg at the time of disease onset, between the years 1950–64 ( n = 307). These geographical and temporal restrictions, along with favourable conditions for a ‘spider’ epidemiological study, were optimal for an unbiased selection; this 15-year incidence cohort was essentially followed prospectively for 37–59 years after onset. The shortest follow-up time for patients without primary or secondary progression was 45 years. For patients with an initial relapsing–remitting course and multiple sclerosis diagnosis according to the Poser criteria ( n = 202), the probability of non-progressive disease after 40 years was 22% (standard error 3.0%), and after 50 years it was 14% (standard error 3.2%). For attack onset including patients with possible multiple sclerosis, the corresponding probabilities after 40 and 50 years were 35% (standard error 3.3%) and 28% (standard error 3.5%), respectively. At the last follow-up in 2009–10, when patients reached the average age of the Swedish population life expectancy, only 13 patients from the multiple sclerosis diagnosis cohort, according to the Poser criteria, remained alive and non-progressive. Their annualized attack frequency diminished with time from 0.29 to 0.015. These patients had been functioning well socially. Nine patients had an Expanded Disability Status Scale score of 0–2.5, and four patients had a score of 3 or 3.5, with deficits dating back to attacks decades ago. Eight patients participated in a complete neuropsychological examination, which showed a slight difference ( P < 0.01) concerning verbal memory and executive function compared to an age and socially matched reference group, whereas results for five other cognitive domains were within the normal range. Magnetic resonance images fulfilled the Barkhof–Tintore criteria for multiple sclerosis in 10 of 11 patients, with conspicuously few subcortical lesions relative to extensive periventricular lesions and lesions extending from the inferior midline aspect of the corpus callosum. Prediction of the non-progressive stage was possible with moderate hazard ratios and low sensitivity. Early features that predicted a non-progressive course were complete remission of the onset attack, low or moderate initial relapse frequency and—when the patients with possible multiple sclerosis were included—dominating afferent symptoms. The clinical disease activity had abated in these 13 patients, with the caveat that transition to secondary progression continued to occur after four decades, albeit with decreasing risk. * Abbreviations : EDSS : expanded disability status scale

In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event.We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352.517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a.Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study.Merck Serono SA, Geneva, Switzerland.

Vatne A., Mygland A., Ljostad U. Multiple sclerosis in Vest-Agder county, Norway. Acta Neurol Scand: 2011: 123: 396–399. © 2010 John Wiley & Sons A/S. Objective – To examine multiple sclerosis (MS) prevalence, rate of immunomodulatory treatment and frequency of Borrelia Burgordorferi (Bb) antibodies in Vest-Agder, Norway. Materials and methods – Patients in the period 1996–2006 who met the Poser criteria for definitive or probable MS were included. Clinical and demographical data, and presence of Bb antibodies were registered. Results – A total of 295 patients were identified. The crude prevalence was 180 per 100,000 population (95% CI = 160.9–218.0), age-adjusted prevalence was 186 per 100,000 population (95% CI = 166.3–225.3). The age-adjusted incidence rates were 7.5 and 8.0 for 1996–2000 and 2001–2006, respectively. Thirty-eight per cent were treated with immunomodulatory agents when compared to 28% in the rest of the country. Bb serum antibodies were detected in 7% of patients with MS. Conclusions – Vest-Agder county has the highest prevalence of MS reported in Norway, and a high treatment rate. Bb antibodies were not more prevalent than in healthy individuals.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011

International audience; Few studies report a protective role of childhood solar exposure to multiple sclerosis. Our objective was to confirm the protective role of childhood solar exposure in multiple sclerosis in Cuba, Martinique and Sicily. This was a matched case- control study, and cases met Poser criteria for clinically, laboratory (definite, probable) multiple sclerosis. Controls were resident population, without neurological disorder, living close to cases (within 100 km), matched for sex, age (+/-5 years), residence before age 15. We recruited 551 subjects during a 1-year period (193 cases, Cuba n = 95, Sicily n = 50, Martinique n = 48; 358 controls). Some (89%) met definite clinical multiple sclerosis criteria (relapsing remitting form (with and without sequel) (74%), secondary progressive (21%), primary progressive (5%)). Odds ratios in a uni-variate analysis were: family history of multiple sclerosis (5.1) and autoimmune disorder (4.0); wearing shirt (3.5), hat (2.7), pants (2.4); sun exposure causing sunburn (1.8); sun exposure duration (1 h more/day; weekends 0.91, weekdays 0.86); bare-chested (0.6); water sports (0.2). Independent factors in the multivariate analysis were family history of multiple sclerosis (4.8 (1.50-15.10)), wearing pants under sunlight (1.9 (1.10-3.20)), sun exposure duration (1 h more/ day, weekdays 0.90 (0.85-0.98), weekends 0.93 (0.87-0.99)), water sports (0.23 (0.13-0.40)). We conclude that outdoor leisure activities in addition to sun exposure reports are associated with a reduced multiple sclerosis risk, with evidence of dose response.

Objective – To evaluate the discharge diagnosis of demyelinating diseases in the central nervous system (CNS) and analyze the predictive value of the new diagnostic criteria in Suzhou, China. Materials and methods – We collected clinical information and data of laboratory examinations for all cases with a diagnosis of various demyelinating diseases in the CNS. All data were reviewed individually by four senior neurologists, and a diagnosis was finally given to each patient according to the McDonald criteria and the Poser criteria for multiple sclerosis (MS). Results – In the analysis, 176 patients with a diagnosis of demyelinating diseases in the CNS at discharge were included. In 82 patients with a diagnosis of MS at discharge, the MS diagnosis was confirmed for 74 patients according to the McDonald criteria for MS, and the positive predictive value for the discharge diagnosis of MS was 90.2% (74/82). According to the Poser criteria, 61 patients were diagnosed as MS. The consistency of the two diagnostic criteria for MS was 78.4%, based on the results of the evaluation. Conclusions – Under-diagnosis of MS could be one of the explanations for the low prevalence of MS in China. Compared to the Poser criteria, the McDonald criteria had a higher sensitivity for the diagnosis of MS.

Background: Current MRI criteria can help predict a second attack after a clinically isolated syndrome (CIS). Given the known association between corpus callosum lesions (CC) and multiple sclerosis (MS), such lesions on MRI could provide additional predictive information. This study assessed whether the presence of CC lesion on MRI could, next to the modified Barkhof criteria, further enhance prediction of conversion from CIS to MS. Methods: Follow-up study of 158 patients with CIS who underwent MRI after CIS was performed. MRI were scored for the Barkhof criteria and CC lesion. Patients were classified as having MS according to Poser criteria. Cox regression models were used for the time to conversion from CIS to MS. Results: The Barkhof criteria and CC lesion were strongly associated with conversion to MS with hazard ratios (HR), respectively, of 2.6 (95% confidence interval [CI] 1.5-4.3) and 2.7 (95% CI 1.6-4.5). The HRs of CC lesion adjusted for the Barkhof criteria and the Barkhof criteria adjusted for CC lesion were similar (HRs 1.8, not significant). The combined prediction of the Barkhof criteria and CC lesion was 3.3 (95% CI 1.9-5.7). Patients not fulfilling the Barkhof criteria had a fourfold increased risk of MS (HR 3.8, 95% CI 1.5-9.3) when they had a lesion in the CC. Conclusions: Corpus callosum (CC) lesion and the Barkhof criteria both predicted conversion to multiple sclerosis (MS). When both variables were combined, the association was stronger. The assessment of CC lesion may be a useful additional tool for predicting conversion to MS in patients with clinically isolated syndrome. Neurology (R) 2009; 73: 1837-1841

Objective To examine whether self-rated physical health, as measured by the Physical Functioning Scale (PF) and the Role-physical Scale (RF) of the SF-36 Health Survey, could predict change in disability measured by the Expanded Disability Status Scale (EDSS) in patients with multiple sclerosis (MS) over a follow-up period of 3 years. Methods A group of 156 clinically definite MS patients (Poser criteria), who had never been treated with disease-modifying therapies, were recruited consecutively from an outpatient clinic setting at the Institute of Neurology, Belgrade. The self-rated physical health was measured by using PF and RF of the SF-36. Results At follow-up, 33 out of 156 patients (21%) had dropped out. The mean EDSS score had increased from 3.7 to 4.5. Multiple regression analyses using change in EDSS as the dependent variable and baseline scores of EDSS and RF as independent variables showed a significant effect for RF (standardized beta = –0.21). A similar but non-significant effect was found for PF. Dichotomizing change in disability according to clinically meaningful deterioration and using logistic regression, an odds ratio of 1.27 (95% confidence interval 1.01–1.62) was found for the smallest unit of change in the self-rated scale. This means that patients who rated their own physical health as poor had a higher increase in disability compared with patients with the same level of disability at baseline who rated their physical health better. Conclusions MS patients’ perception of their health comprises information predictive for disease development not included in the more objective measure of disability status.

There are two distinct subtypes of multiple sclerosis (MS) in Asians: optic-spinal (OSMS) and conventional (CMS). Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are characteristic of patients with OSMS, yet in Asians, one-fourth of CMS patients also have LESCLs. To clarify the distinction between LESCLs in OSMS and CMS, and to characterize the relationship between the presence of LESCLs and brain magnetic resonance imaging (MRI) findings, we studied 142 patients with clinically definite MS of relapsing-remitting onset and 12 patients with primary progressive MS (PPMS) by MRI of the whole spinal cord and brain. The former was diagnosed by Poser criteria, including 57 with OSMS, 67 with CMS and 18 with brainstem-spinal form of MS, while the latter by McDonald criteria. The presence of LESCLs throughout the entire clinical course was significantly more common in OSMS patients than in CMS patients, while brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) were significantly more common in CMS patients than OSMS patients. LESCLs in OSMS patients most frequently affected the upper to middle thoracic cord, with either holocord or central gray matter involvement. By contrast, 70% of LESCLs in CMS patients predominantly affected the peripheral white matter of the mid-cervical cord. LESCLs in patients with PPMS also showed preferential involvement of the peripheral white matter of the mid-cervical cord. One-third of OSMS patients had neither LESCLs nor Barkhof brain lesions more than 10 years after disease onset, and showed significantly milder disability than OSMS patients with LESCLs. These findings suggest that LESCLs are heterogeneous between OSMS and CMS patients, and that there are distinct subtypes of MS in Japanese, according to clinical and MRI findings.

Background The McDonald criteria were introduced in 2001 as guidelines to facilitate early and accurate diagnosis of multiple sclerosis (MS). They were revised in 2005. Although validated in a number of research-focused clinical centres, their adequacy and utility in the general neurology setting is less certain. Objective In this study, we assessed new diagnoses of MS in our practice for compliance with both the original and the revised criteria. Methods We retrospectively identified new diagnoses of MS from 2001. Clinical notes and imaging were evaluated for compliance with McDonald criteria. Results Sixty-two patients were included: 53 with `practice-definite' and nine with `practice-possible' diagnoses of MS. At the time of diagnosis, 47% of the `practice-definite' group fulfilled the 2001 criteria and 49% the revised criteria. Among patients not satisfying the criteria at time of diagnosis, 21% went on to fulfil the McDonald criteria over the 23-month follow-up. Conclusions There is a considerable gap between the clinical diagnosis of MS in a general neurology setting and compliance with the McDonald criteria. Failure to perform follow-up MRI on patients with clinically isolated syndromes is a sizeable factor in this diagnostic-gap and needs to be improved. In this setting, practical differences between the original and revised criteria appear to be small.

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.

International audience; Objectives – To report on multiple sclerosis (MS) incidence in Brittany, north-western France. Materials & Methods – From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated. Results – Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/ probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32–5.51], 6.68 [4.75–8.60], and 2.21 [1.12–3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25–29 years and progressive onset MS at 40–44 years in women (20–24 years and 45–49 years in men, respectively). Conclusions – Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25-to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10−11). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10−5 using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10−6 for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10−8). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10−9 using Poser criteria; P = 5.6 × 10−11 for McDonald criteria) and more rapid development of disability (P = 1.8 × 10−10). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis., E.C. is supported by a contract from the “Fondo de Investigación Sanitaria” – FIS [contract number FI 09/00705], Ministry of Science and Innovation, Spain. R.N. is supported by the “Programa Juan de la Cierva” from the Ministry of Science and Innovation, Spain. Local CSF biobanking of the multiple sclerosis group in Prague was supported by Research Project Charles University in Prague (PRVOUK P34/LF3).

Multiple sclerosis is a chronic demyelinating disease of the central nervous system that occurs primarily in young adults. There is no single diagnostic test to recognize the disease. The diagnostic criteria, based on clinical examination and laboratory tests, have changed considerably over time. The first guidelines involved only the results of the patient's neurological examination. The diagnostic criteria developed by Poser in 1983 were based largely on the results of additional tests, including visual evoked potentials and analysis of cerebrospinal fluid. The McDonald criteria, developed in 2001 and updated in 2005 and 2010, reflected the diagnostic breakthrough caused by widespread use of magnetic resonance imaging (MRI). Currently, the diagnosis depends largely on the results of the MRI examination. An early diagnosis is particularly important for starting disease-modifying treatments.

Multiple sclerosis is one of the main causes of disability among young Cuban women. The objective of these studies was to evaluate the clinical and social economic status of Cuban women with MS. First, an epidemiological case-control study was conducted among 50 women with clinically definite MS (by Poser criteria). The controls were women ranging from 15 to 65 years who were matched for age. Data collection forms were modified from Boiko's guidelines. Risk factors for MS included having two or more children (OR = 2.84; 95% CI = 1.22–6.59), acute stress (OR = 3.76; 95% CI = 1.64–8.62), and insomnia (OR = 2.95; 95% CI = 1.14–7.14). A disability and socioeconomic analysis was conducted based on data from the Cuban Computed Register of MS (CUBARMS) of 271 women with clinically definite MS as defined by Poser or McDonald criteria. Most were between 31 and 50 years of age (61.2%) and Caucasian (73.06%). There were antecedents of familial psychiatric diseases (34.69%), neurological disorders (26.57%), general autoimmune diseases (21.7%), and MS (7.85%). Triggered factors at onset of MS were present in 56%, the most frequent being acute stress (52%). 169 patients (62.36%) drank coffee. Main initial symptoms of MS were weakness in limbs (51.66%); numbness of limbs (28.04%); poor balance (20.3%); blurred vision (18.81%); and paresthesias (18.81%). The most frequent symptoms of MS in women at the time of their medical consultation included weakness of limbs (71.59%); numbness (29.15%); paresthesias (28.41%); fatigue (24.73%); poor balance (23.62%); loss of vision (22.51%); rigidity (22.14%); blurred vision (17.71%); incontinence (16.97%); lack of coordination (16.24%); memory disorders (14.39%); and depression (12.92%). Expanded Disability Status Scale (EDSS) scores ranged between 1 and 6.5 in 78.6% of patients, while Scripps Neurological Rating Scale (SNRS) scores ranged between 61 and 80 in 69.9%. In terms of social status, 58.3% were married; 33.9% were single or divorced; 32% had a high school education; 29.1% had university-level education, and 21% had secondary education. Over half (53.1%) were unemployed; 18% of female MS patients lived alone, and 48.6% received a monthly income between 100 and 401 pesos. The data gathered in these studies highlight the importance of improving knowledge of MS in Cuba, mainly in the primary care setting, in order to increase early diagnosis. With these data, we expect to achieve a better quality of life for female MS patients, thus improving their socioeconomic and work status. A program is in progress to improve the primary medical attention, disability, handicap, quality of life, and socioeconomic status of Cuban women with MS.

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

A new approach for the classification of patients with Sjogren's syndrome (SS) has been recently proposed. Although these new criteria substantially differ from the American European Consensus Group criteria, which have represented the gold standard for the last decade, when compared with each other the two sets show a high statistical degree of agreement. However, the fact that two different criteria to classify patient with SS could be available may introduce some additional difficulties in the scientific communication, making cohorts of patients selected by using different methods less than completely equivalent, and the results of epidemiological studies and therapeutic trials not entirely comparable. Consequently, to reach a consensus agreement on universally accepted classification criteria for SS seems to be a very desirable objective.

Objectives – A confident and accurate diagnosis of multiple sclerosis (MS) is important, but a specific diagnostic test for the disease does not exist. The traditional diagnostic criteria of Poser et al. were published in 1983, and recently, McDonald et al. recommended new criteria for the diagnosis of MS. Patients and methods – In this study these two diagnostic schemes were compared by prospectively applying both of them to 76 patients with clinical features suggesting a new diagnosis of MS. Results – Using the Poser criteria, 29 patients (38%) were classified as clinically definite and 35 patients (46%) as laboratory definite MS. According to the new McDonald criteria, MS was diagnosed in 39 (52%) patients, 37 patients (48%) had ‘possible MS’. All patients with a clinically definite MS with the Poser criteria were also given the diagnosis of MS as recommended by McDonald et al. Of those 35 patients with laboratory definite MS according to Poser et al., four patients could be classified as having MS with the McDonald criteria, 89% of them had ‘possible MS’. Conversely, 75% of the 39 patients, who fulfilled the new McDonald criteria for MS were assigned to the category of clinically definite MS according to the Poser criteria, and 83% of the patients with a ‘possible MS’ using the McDonald criteria, had a laboratory definite MS with the Poser criteria. Conclusion – MS according to the McDonald criteria was diagnosed more often than ‘clinically definite MS’ according to Poser et al., but combining the categories of clinically and laboratory definite MS, the diagnosis of MS could clearly be established more frequently using the Poser criteria.

Several in vivo and in vitro studies showed that mitoxantrone (MTX), a novel anthracendione antineoplastic agent, had an immunomodulatory effect that suppressed humoral immunity, reduced T-cell numbers, lessened helper activity, enhanced suppressor function and had some positive effect on acute and chronic experimental allergic encephalomyelitis in rats. Up to now, several trials of therapy with MTX have been performed in patients with multiple sclerosis (MS). MTX has been recently shown to reduce disease activity, as expressed by reducing relapse rate and decreasing new, active MRI lesions, in a selected group of patients with active relapsing-remitting (RR) MS. Furthermore, more recently, it has been demonstrated that MTX reduce neurological disability in secondary progressive MS. We designed the open-label clinical trial involving 35 MS patients with active disease in order to evaluate the long-term clinical effects of 6-months MTX treatment during a follow-up period of 20-46 months (mean, 30 months). The study comprised 35 patients, who met the Poser criteria for clinically definite MS. All patients were clinically treated at the Institute of Neurology, Clinical Centre of Serbia, Belgrade, during the period from March 1996 to August 2000. The neurological disability state was evaluated at the entry, every month until completion of the therapy and every six months until August 2000, by means of Kurtzke Expanded Disability Status Scale (EDSS) score. All patients had active MS. The criteria for disease activity were: 1) at least 2 relapses within the previous 2 years, or 2) progression of at least 1.0 point on EDSS scale during the same period. The included patients did not receive immunosuppressive therapy six months prior to the entry. The patients were assigned to receive MTX 20 mg intravenously (iv) per month and methylprednisolone 1g iv per month, over six months. The clinical characteristics and demographic data of patients included in the study were shown in table 1. The parameters monitored during the trial were shown in table 2. Clinical assessment showed a significant improvement of the final mean EDSS score after 6 months of the therapy as compared to the value at entry in the total MS group (p=0.00001). Although EDSS value showed an increasing tendency during the follow-up period (20-46 months), the mean EDSS value was still significantly lower at the end of the follow-up comparing to the value at entry (p=0.013) (Figure 1). Overall, MTX was well tolerated and only minor side effects occurred. Cardiotoxicity was not registered. Our findings further support the notion that mitoxantrone reduces neurological disability in active relapsing and secondary progressive multiple sclerosis patients. However, follow-up suggests that this effect slowly subsides after discontinuation of therapy, implying the need for prolongation of such treatment (up to 120 mg/m2) for a period as long as possible.

During more than 5 decades, a variety of criteria to enable the diagnosis of multiple sclerosis (MS) have been proposed and often widely utilized in clinical practice. Early criteria, such as those of Schumacher,1 were purely clinical. The Poser criteria,2 which were often used and cited in the 1980s and 1990s, began to incorporate “paraclinical” testing, including imaging, evoked potentials, and CSF into a complex scheme of varying diagnostic certainty. Then, beginning with the first iteration of the McDonald criteria in 2001,3 MRI came to occupy a central role in the diagnostic process.

Somatosensory evoked potentials (SEPs) play a less important role in the diagnosis of multiple sclerosis (MS) than visually evoked potentials. Since standard SEPs only reflect the dorsal column function, we now investigated spinothalamic tract function in patients with MS using laser-evoked potentials (LEPs).LEPs to thulium laser stimuli (3ms, 540 mJ, 5mm diameter) were recorded from 3 midline positions (Fz, Cz, Pz) in 20 patients with MS, and 6 patients with possible but unconfirmed MS. Peak latencies and peak-to-peak amplitude of the vertex potential negativity (N2) and positivity (P2) were evaluated and compared with normative values from 22 healthy control subjects. Median and tibial nerve SEPs were recorded with standard methods. Depending on the results of sensory testing, two skin areas (both hands, both feet, or one hand and foot of the same body side) were assessed in each patient.In group comparisons, LEPs in patients with MS were significantly delayed and reduced in amplitude compared with healthy subjects (P0.001) or patients with suspected but unconfirmed MS (P0.05). In intraindividual comparisons within the patients with MS, LEP amplitude was significantly lower (P0.01) and latencies were significantly longer (N2: P0.01; P2: P0.05) for a clinically hypoalgesic skin area than an unaffected control area. On a single case basis, LEPs were abnormal in 12 (60%) and SEPs in 8 (40%) of the patients with MS; combined analysis of LEPs and SEPs raised sensitivity to 75% (15 patients). LEPs were also abnormal for 7 skin areas with clinically normal nociception and thermal sensitivity, indicating subclinical lesions. Standard SEPs detected subclinical lesions in 5 areas with normal tactile sensitivity.In patients with multiple sclerosis, spinothalamic tract function and LEPs were impaired more often than dorsal column function and SEPs. LEPs also detected subclinical lesions. Combined assessment of LEPs and SEPs can help to document dissemination of demyelinating CNS lesions and thus contribute to the diagnosis of multiple sclerosis.

Objective: To determine the prevalence of multiple sclerosis (MS) on the Island of La Palma, Canary Islands, Spain. Methods: A population-based transverse study was carried out on the Island of La Palma (population: 81,507), from 1995 to 1998. The 15 December 1998 was established as prevalence day. Sources of information were periodically obtained from case records from public primary care centres, private hospitals, private centres, magnetic resonance units and others. In accordance with the Poser criteria all cases of definite or probable MS were included. Results: 34 cases of MS were found on prevalence day (9 male and 25 female): 32 cases were clinically definite and 2 were clinically probable MS. Crude prevalence was 42/100,000. Incidence during time of study was 2.25/100,000. Conclusions: The island of La Palma could be considered as an area of medium-high risk, the risk being higher than that expected because of the geographical latitude of the island. This study confirms the hypothesis of the high prevalence of MS in Spain. We have not found significant clinical differences in MS patients from those in other studies.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow-up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

Background: Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Tumor necrosis factor-α (TNF-α) microsatellite as a proinflammatory cytokine is believed to play an important role in the etiology of this disease. Objectives: The aim of this study was to investigate the association of TNF-α microsatellite sequence variation in patients with MS and its risk factor in the southern Iranian population. Patients and Methods: This polymorphism was investigated in an Iranian population of 163 native southern people [81 patients with MS according to the poser criteria and 82 healthy controls (HC) with the same age, sex, social, ethnical and geographical features (Hormozgan and Fars provinces)]. All the controls were nonimmunological, neurological patients. All the cases and controls were chosen randomly and genotyped for polymorphism of TNF-α microsatellite. Results: The frequencies of TNF-α*11 (0.25, P < 0.005) and TNF-α*10 (P < 0.005) alleles increased in patients with MS compared with controls, showing a significant difference among the studied population. Conclusions: The current study adds evidence to the association of TNF-α gene polymorphism and MS in this southern south Iranian population which is consistent with the genetic analysis of MS in Europeans (GAMES) project reports and these two alleles reported in this study may be one of the genetic risk factor for MS. Furthermore, this data can be used to build the Iranian gene bank for future studies.

Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany.

Background and objective: A population-based study is reported of MS in French Afro-Caribbeans (FAC) in Martinique. FAC are descendants of interracial mating that occurred between French Caucasians and black Africans in the 17th and the 18th centuries. Methods: The authors surveyed the entire island of Martinique (area 1,128 km 2 , population 357,000) between November 1997 and October 1999. Results: Sixty-two patients (46 females, 16 males, ratio 2.9:1) were identified with definite or probable disease by the Poser criteria. Prevalence for all patients on December 31, 1998, was 17.4/10 5 (95% CI 13.1 to 21.7) and 14.3/10 5 (95% CI 10.4 to 18.2) for clinically definite cases (n = 51). Age range of patients on prevalence day was 17 to 73 years (mean ± SD 39 ± 11.3 years). Mean age at onset was 31.2 ± 11 years. Overall, 9.7% had primary progressive disease and 19.4% had benign MS. A low proportion of definite and probable MS cases had oligoclonal bands in CSF (50.9%). Seventeen patients, 13 of whom were alive on prevalence day, had a relapsing form of neuromyelitis optica. Conclusion: The island of Martinique appears to have a low to medium prevalence of MS. MS was almost unknown in FAC in Martinique until the late 1970s. The apparent recent increase may be explained by improved recognition of patients, increased availability of MRI for diagnosis, increased disease awareness among physicians, increased survival of MS patients, or an actual increase in disease frequency.

Objective: An epidemiologic survey was conducted to determine the prevalence and incidence of MS in the city of Catania, Sicily, Italy. Prevalence rate was calculated as point prevalence at January 1,1995, and incidence during 1974 to 1995. Methods: The authors studied the frequency of MS in the community of Catania in a population of 333,075 inhabitants according to the 1991 census. The primary sources for the case ascertainment were the neurologic and motor rehabilitation departments, the MS Center, the Italian MS Association, private neurologists, and family doctors. All patients who satisfied the Poser criteria for clinically definite MS, laboratory-supported definite MS, clinically probable MS, and laboratory-supported probable MS were considered prevalent and incident cases. Results: One hundred ninety-five patients with MS who had had the onset of disease on prevalence day in a population of 333,075 inhabitants were detected. The prevalence rate was 58.5 per 100,000 (95% CI 50.7 to 67.5). Prevalence was higher in women (62.0/100,000) than in men (54.8/100,000). The age-specific prevalence showed a peak in the group aged 35 to 44 (145.1/100,000). From 1975 to 1994, 170 subjects with MS had the clinical onset of the disease. The mean annual incidence was 2.3 per 100,000 (95% CI 2.0 to 2.6). Age-specific incidence showed a peak in the group aged 25 to 34 (6.32/100,000). Incidence for 5-year intervals increased from 1.3 during 1975 to 1979 to 3.9 during 1990 to 1994. Conclusions: These prevalence and incidence rates are close to those reported in other similar surveys carried out in Italy and southern Europe.

Objectives To update prevalence and incidence rates of MS among Sardinians. Materials and methods The present work is a "spider" kind of population based survey, conducted over the interval 1968-97, on patients with MS (Poser criteria) living in the province of Sassari, Northern Sardinia (454,904 population). Results A crude total prevalence rate of 144.4 per 100,000, an onset-adjusted prevalence rate of 149.7 per 100,000 and an average annual incidence rate of 8.2 for the period 1993-7 were found. Conclusion Repeated epidemiological assessments of MS in Sardinia over decades have shown that the island is at high risk for MS. The present work highlights that MS incidence in Sardinia has been increasing over time. Although a substantial and widely spread improvement in MS case ascertainment can be postulated as the reason for such observations, a comparison between our data and those recently reported from a more industrialized province in Northern Italy seems to prove an at least partially real increase in MS risk among Sardinians and favours the hypothesis of a MS "Sardinian focus" as related to its latitude.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) of presumed autoimmune etiology, characterized by localized areas of inflammation, demyelination, axonal loss and gliosis in the brain and spinal cord. Although the clinical presentation and course of the disease are highly variable, several disease types can be recognized, including relapsing-remitting-(RR), primary-progressive-(PP), secondary-progressive-(SP), progressive-relapsing-(PR) MS and clinically-isolated syndrome (CIS). There is no single clinical feature or diagnostic test that is sufficient to diagnose MS, and the diagnosis is mainly a clinical one. Over the years, several sets of criteria have been proposed for the diagnosis of MS, based on the principles of dissemination in space (DIS) and dissemination in time (DIT) of CNS lesions, and the exclusion of other diseases with similar characteristics. With each revision, new diagnostic criteria modified disease definitions and diagnostic thresholds, while aiming at maintaining sensitivity and improving specificity. According to the older Schumacher and Poser criteria, MS can be diagnosed clinically by demonstrating 2 separate attacks (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). The 2001 McDonald criteria and their 2005 revision incorporated defined magnetic resonance imaging (MRI) criteria for DIS and DIT that provided guidance on how to diagnose MS after CIS. The most recent 2010 McDonald criteria simplify requirements for DIS and DIT and may allow for an earlier diagnosis of MS from a single baseline brain MRI if there are both silent gadolinium-enhancing and nonenhancing lesions. Despite these important advances in the diagnosis of MS, some questions still remain regarding the application and the implications of the new criteria in the daily clinical practice and in clinical trials. Most importantly, thorough clinical evaluation and judgment along with careful differential diagnosis still remain the basics in the diagnosis of MS.

Objective—To estimate the prevalence of multiple sclerosis in the L’Aquila district, central Italy. Methods—All available case sources were screened. Definite and probable cases of multiple sclerosis, classified according to the Poser criteria, were considered as prevalent cases. Results—On the prevalence day, 31 December 1996, 158 patients (105 women and 53 men; ratio 2:1) aVected by definite (n=131) or probable (n=27) multiple sclerosis were alive and resident in the L’Aquila district. Mean (SD) age was 38.4 (11.9) years (38.9 (11.7) years for women and 38.5 (12.3) years for men, p=0.9). The overall crude prevalence was 53.0/100 000 (95% confidence interval (95% CI)=45.4‐ 62.0); 68.4/100 000 (95% CI=56.5‐82.8) in women, and 36.7/100 000 (95% CI=28.1‐ 48.0) in men. The prevalence was similar (55.9/100 000) when standardised to the 1996 European population. Mean (SD) age at onset of multiple sclerosis was 29.4 (9.6) years and mean (SD) duration of the disease was 9.4 (7.4) years, without any significant diVerence between sexes. Mean age at onset was significantly higher in patients with the primary progressive than in those with the relapsing-remitting course (p=0.0002, ScheVe’s test). Conclusions—The prevalence found in the L’Aquila district gives support to the consideration of Italy as an area in which multiple sclerosis has been shown to have high prevalence at least in the populations that were surveyed recently. (J Neurol Neurosurg Psychiatry 2000;68:349‐352)

Multiple sclerosis (MS) and its treatment have broad-ranging effects on quality of life. This article reviews recent efforts to assess the impact of MS on activities of daily living (ADLs) and health-related quality of life (HRQL), and describes the development of the Multiple Sclerosis Quality of Life Inventory (MSQLI). The MSQLI is a modular MS-specific HRQL instrument consisting of a widely-used generic measure, the Health Status Questionnaire (SF-36), supplemented by nine symptom-specific measures (covering fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships). Content validation consisted of evaluating its adherence to a conceptual model of the impact of MS, and review by MS specialists (neurologists and allied health professionals), HRQL experts, patients, and caregivers. The reliability and construct validity of the MSQLI were rigorously evaluated in a field test with 300 North American patients (198 female, 102 male) with definite MS (Poser criteria) and a broad range of physical impairment (EDSS=0.0-8.5). This article concludes by comparing the MSQLI with two other MS-specific HRQL measures (MS Quality of Life-54 (QOL-54) and Functional Assessment of Multiple Sclerosis (FAMS)) and discussing key issues to consider in selecting an HRQL instrument for a collaborative database.

Patients with primary progressive multiple sclerosis have atypical clinical and magnetic resonance imaging (MRI) characteristics which present unique problems in designing and recruiting to therapeutic trials. The first randomised controlled therapeutic trial specifically for primary progressive multiple sclerosis is now underway. Although only an exploratory phase II study, it has provided further insight into difficulties in diagnosis, classification and choice of clinical and MRI outcome measures. Patients with primary progressive multiple sclerosis have a wide differential diagnosis and do not readily conform to the Poser criteria. They may therefore present diagnostic uncertainty, particularly as their classification often relies on a retrospective history. This was highlighted during the recruitment to this study of interferon-beta1a. Of the 138 patients referred with a definite diagnosis of primary progressive multiple sclerosis only 50 were enrolled in the study. Of the 88 patients not included, 50% either did not have primary progressive multiple sclerosis, or the diagnosis was not secure. Outcome measures pose particular problems. Clinically the focus must be on progression, and the measure should be both responsive and reliable. In relation to MRI, the currently recommended measures for therapeutic trials in relapsing/remitting and secondary progressive multiple sclerosis show little change in primary progressive multiple sclerosis, and therefore more pathologically specific MRI measures are required. Strict clinical guidelines and further developments in clinical and MRI measures are required to facilitate future therapeutic trials in primary progressive multiple sclerosis.

Producción Científica, The aim of this study was to ascertain the prevalence of multiple sclerosis (MS) in a northern Spanish region and to compare it with that from the most recent epidemiological studies in the country. MS prevalence was studied for a period of 2 years using multiple sources of information in the province of Valladolid, with a sample comprising a total population of 92,632. Patients were classified according to the Poser criteria. The crude prevalence of definite and probable MS was 58.3 per 100,000 (95% confidence interval: 43.7–75.7). The same methods have been used in ascertaining similar prevalence rates in Vélez-Málaga, Osona, and Gijón and a slightly lower rate in Teruel. Our survey confirms Spain as a high-risk area for MS, with prevalence rates over 50 per 100,000

A high prevalence of major mood disorders in multiple sclerosis (MS) patients has been reported. In this study, we investigated the frequency of previous or present major mood disorders in 65 patients with clinically definite multiple sclerosis (Poser criteria) and in 31 polyneuropathy (PNP) patients. All patients underwent a questionnaire designed after DSM-IV definitions for major mood disorders. A higher lifetime risk for development of a major mood disorder was evident in MS patients (log rank test.,p

Objective—To investigate the clinical and demographic characteristics of primary progressive multiple sclerosis (PPMS) in Northern Ireland and to establish a database of such patients for genetic and immunological studies and future therapeutic trials. Methods—Diagnosis and categorisation were performed by two neurologists, potential cases being identified from the following sources: neurology outpatient clinics; neurology inpatients; a review of hospital discharges; and an ongoing epidemiological study of multiple sclerosis in Northern Ireland. Only those with a progressive course from onset and a clear history of no prior relapses were accepted. Potential cases were invited for interview and assessment, the minimal record of disability (MRD) being established. Results—One hundred and eleven cases of PPMS have been identified,63 women and 48 men (ratio 1.3:1), with a mean age at onset of 39.5 (SD 11.0) (range 17‐66)years, and mean disease duration of 13.6 (SD 9.3)years. The mean interval between onset and diagnosis was 4.7 (SD 4.2) years. Nineteen patients (17.1%) did not satisfy the requirements for any category in the Poser criteria. Motor disturbance was the commonest mode of onset (67.6%) with visual loss occurring only rarely at onset (3.6%). Kurtzke EDSS scores were concentrated at the upper end of the scale with a median of 6.0 and levels of unemployment and financial dependence were high. Conclusions—PPMS in Northern Ireland has a generally later age at onset, lower female preponderance, and predominantly motor onset compared with other subgroups of multiple sclerosis. The delay to diagnosis reflects the often insidious onset and the nature of the clinical course makes application of the Poser criteria diYcult. Levels of neurological impairment, disability, and handicap as measured by the MRD are high. (J Neurol Neurosurg Psychiatry 1998;64:451‐454)

We wanted to establish the point prevalence of MS in Northern Ireland. Northern Ireland has been a known high-risk area for MS since the original work of Allison and Millar in 1951. Studies demonstrated a rising prevalence in 1951 of 41 (95% CI, 37 to 44), in 1961 of 57 (95% CI, 53 to 61), and in 1986 of 104 (95% CI, 85 to 128)/10(5) population for probable/early probable and latent disease. We surveyed four districts (area 2,030 km2, population 151,000). Case sources included Regional Neurology Service records, postal survey of general medical practitioners, hospital databases, MS charities, and MS respite facilities. We used the Poser and Allison and Millar criteria in diagnosis. From a provisional list of 402 patients, 254 (177 female, 77 male, ratio 2.3:1) were identified with definite or probable disease by the Poser criteria, prevalence 168.2/10(5) (95% CI, 147.5 to 188.9/10(5)) with 34 suspected patients and an overall prevalence 190.7/10(5) (95% CI, 168.7 to 212.7/10(5)). We interviewed and examined over 87% of these 288 patients. There were 246 patients classified as probable/early probable and latent by Allison and Millar, prevalence 162.9/10(5) (95% CI, 142.6 to 183.3/10(5)). Seventy-six probable or definite patients had onset between 1985 and 1992 (estimated incidence, 6.5/10(5)/yr). Age range of prevalent patients was 18 to 79 years (mean +/- SD, 49.2 +/- 13.3 years). Mean age at onset was 31.6 +/- 10.1 years. Overall, 12.5% had primary progressive disease and 20% had benign MS. Northern Ireland has an extremely high and rising MS prevalence. This may reflect a true increase in disease incidence or may be explained by increasing survival, improved case ascertainment, increased disease awareness, or improved laboratory and radiologic diagnosis.

This study investigates whether the presence of serum and plasma anti-myelin oligodendrocyte glycoprotein (MOG) and anti-myelin basic protein (MBP) in patients presenting with a clinically isolated syndrome compatible with demyelination (CIS) predicts early conversion to multiple sclerosis (MS). Forty-seven patients with CIS (46 with optic neuritis) had anti-MOG and anti-MBP antibodies analysed at baseline, and clinical and magnetic resonance imaging assessments. There was no evidence that the MS status based on either the McDonald or Poser criteria relates to the antibody status.