Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

BACKGROUND AND PURPOSE: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. METHODS: In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. RESULTS: The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). CONCLUSIONS: Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

BACKGROUND: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. OBJECTIVE: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. METHODS: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores. RESULTS: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p < 0.001) and EDSS (ß = 0.16, p < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p = 0.01) and EDSS (ß = -0.06, p < 0.001). Neither presentation was associated with changes in relapse risk. CONCLUSION: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

Early clinical markers of aggressive multiple sclerosis.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.

Risk of secondary progressive multiple sclerosis: A longitudinal study.

BACKGROUND: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. OBJECTIVE: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. METHODS: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. RESULTS: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. CONCLUSION: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.

Genetic Analysis of TREM2 Variants in Tunisian Patients with Alzheimer's Disease.

OBJECTIVE: Rare variants in the TREM2 gene have been reported to significantly increase the risk of Alzheimer's disease in Caucasian populations. Hitherto, this association was not studied in North African populations. In this work, we aimed to study the association between TREM2 exon 2 variants and the risk of late-onset Alzheimer's disease (LOAD) in a Tunisian population. SUBJECTS AND METHODS: We sequenced exon 2 of TREM2 in a Tunisian cohort of 172 LOAD patients and 158 control subjects. We used the Fisher exact test to compare the distribution of allelic frequencies between the two groups. RESULTS: We identified 4 previously reported nonsynonymous variants (p.Asp39Glu, p.Arg62His, p.Thr96Lys, and p.Val126Gly) and 1 novel synonymous variant (p.Gln109Gln), none of which was significantly associated with the risk of Alzheimer's disease. Moreover, the rare TREM2 variant (p.Arg47His), which was considered to be a risk factor for Alzheimer's disease in European descent populations, was not detected in our cohort. CONCLUSION: These findings do not support a major role for TREM2 in the pathogenesis of LOAD in the Tunisian population.

Isolated spinal cord compression syndrome revealing delayed extensive superficial siderosis of the central nervous system secondary to cervical root avulsion.

CONTEXT: Cervical root avulsion secondary to traumatic plexus injury is a rare etiology of superficial siderosis (SS) of the central nervous system (CNS). We describe the case of an isolated progressive compressive myelopathy revealing this complication and discuss the pathogenesis of such a presentation, its clinical and imaging peculiarities with a literature review. FINDINGS: We report on the case of a 48-year-old man with history of left brachial plexus injury at the age of 2 years. Since the age of 38 years, he had presented with a progressive paraplegia, bladder and erectile dysfunction, neuropathic pain and sensory level. The diagnosis was made by spinal cord and brain magnetic resonance follow-up imaging revealing hypointensity T2-weighted gradient echo linear dark rim around the entire neuraxis and cervical dural pseudomeningoceles. These MRI findings were suggestive of extensive hemosiderin deposition consolidating the diagnosis of SS of CNS. CONCLUSION/CLINICAL RELEVANCE: Our case report illustrates diagnosis difficulties in unusual or paucisymptomatic presentations of SS. A history of brachial plexus trauma with nerve root avulsion should prompt gradient-echo T2-weighted imaging to bring out such a complication. Superficial siderosis of the CNS should be included in the panel of differential diagnosis of the parethospastic syndromes and compressive myelopathy.

Fast multiple sclerosis progression in North Africans: Both genetics and environment matter.

OBJECTIVE: To compare multiple sclerosis (MS) disability progression among North Africans (NAs) living in France (NAF) and in Tunisia (NAT) and Caucasian patients born and living in France (CF). METHODS: Patients with MS admitted to the day hospital in the Neurology Department at Pitié-Salpêtrière Hospital (France) and Razi Hospital (Tunisia) were questioned on their place of birth and the place of birth of their parents. To compare delay to outcomes, log-rank tests were used. Univariate and multivariate Cox models were used to determine factors influencing time to Expanded Disability Status Scale (EDSS) 6. RESULTS: We consecutively included 462 patients: 171 CF, 151 NAT, and 140 NAF. Sex ratio, disease forms, and delay from disease onset to diagnosis were similar between the groups. NAF differed from other groups, with a shorter median time to reach EDSS 3, 4, and 6, and a more frequent incomplete recovery after first relapse (p < 0.0001). Furthermore, the NA second-generation group showed the youngest median age at onset (26.5 ± 8.8 years, p = 0.001), the shortest median time to EDSS 6 in relapsing-remitting patients, and an increased mean number of relapses during the first 5 years of the disease (6.1 ± 3.7, p = 0.01) compared to CF. The Cox proportional hazard models demonstrate that (1) NA ethnicity is a significant predictor of fast progression even when adjusting for major covariates and (2) treatment did not influence the models. CONCLUSION: Our study further supports severity of MS in NAs and unravels the particular severity in NAs living in France, mainly for the second generation.

Long-term evolution of EEG in Unverricht-Lundborg disease.

OBJECTIVES: To describe the EEG characteristics of patients with Unverricht-Lundborg disease (ULD) and their changes during the long-term evolution of the disease. METHODS: A retrospective study including all patients with ULD confirmed by molecular biology and more than 15 years' duration of disease progression at the time of inclusion. EEGs were recorded at inclusion, 2 years and 5 years of follow-up. Patients who discontinued treatment during follow-up had an EEG monitoring 1 year after reintroduction of therapy. RESULTS: Forty-seven EEGs were performed in 17 patients. The mean age at onset was 12.0±5.5 years. The mean duration of follow-up was 26.5±6.9 years. The average background rhythm was 8.2 c/s, and was normal in 30 EEGs (64%), slow in 17 (36%) and disorganized in 11 (23%). Epileptic abnormalities were found in 22 EEGs (47%). Myoclonic jerks were found in 13 EEGs (28%). After re-adaptation of antiepileptic medication in patients who had previously stopped treatment, control EEG showed a normal background rhythm with no epileptic abnormalities throughout the monitoring period. CONCLUSION: This study shows that the progressive disappearance of EEG abnormalities is rather due to antiepileptic treatment than a gradual spontaneous tendency to decrease over time.

Evaluation of an Arabic version of the non-motor symptoms scale in Parkinson's disease.

Non-motor symptoms (NMS) of Parkinson Disease (PD) are common and can cause severe disability. They are often under-recognized and remain untreated. Tools to evaluate these symptoms in Arabic-speaking patients are still lacking. The objective of this study was to evaluate an Arabic version of the non-motor symptoms scale (NMSS) of PD as an instrument for measuring NMS in Arabic-speaking patients. Sixty-two PD patients clustered around Hoehn & Yahr Stages 2-3 were evaluated by the Arabic version of NMSS. They also underwent a battery of standard psychometric assessment measures that included the scales for outcomes of Parkinson's disease-autonomic (SCOPA-AUT), the Pittsburgh sleep quality index (PSQI), the Beck depression inventory, the geriatric depression scale (GDS), the mini-mental state examination (MMSE), the visual analogical scale for pain(VAS) and the neuro-psychiatric inventory (NPI). The metric properties of the NMSS were studied as well as its correlation with other standard tests evaluating NMS. The mean NMSS score was 82 ± 56 (skewness 0.88). There were highly significant correlations between the NMSS and the SCOPA-AUT as well as the NMSS and PSQI scores. Significant positive correlations between NMSS and GDS, BECK and VAS were also observed. The sleep/fatigue domain significantly correlated with the PSQI, the cardiovascular/urinary/sexual function/gastrointestinal domains significantly correlated with the SCOPA-AUT, the mood/cognition domain significantly correlated with the GDS and BECK findings. The mean Cronbach's alpha coefficient was 0.87, showing a satisfactory internal consistency. The Arabic version of NMSS can be considered a comprehensive and reliable measure for non-motor symptoms in Arabic-speaking PD patients.

Season of birth and multiple sclerosis in Tunisia.

BACKGROUND: Recent studies on date of birth of multiple sclerosis (MS) patients showed an association between month of birth and the risk of developing MS. This association has not been investigated in an African country. OBJECTIVE: We aimed to determine if the risk of MS is associated with month of birth in Tunisia. METHODS: Data concerning date of birth for MS patients in Tunisia (n = 1912) was obtained. Birth rates of MS patients were compared with all births in Tunisia matched by year of birth (n = 11,615,912). We used a chi-squared analysis and the Hewitt's non-parametric test for seasonality. RESULTS: The distribution of births among MS patients compared with the control population was not different when tested by the chi-squared test. The Hewitt's test for seasonality showed an excess of births between May and October among MS patients (p = 0.03). The peak of Births of MS patients in Tunisia was in July and the nadir in December. CONCLUSION: Our data does support the seasonality hypothesis of month of birth as risk factor for MS in Tunisia. Low vitamin D levels during pregnancy could be a possible explanation that needs further investigation.

Clinical features and disability progression in multiple sclerosis in Tunisia: do we really have a more aggressive disease course?

BACKGROUND: Few epidemiological data are available on multiple sclerosis (MS) patients in North Africa (NA). Studies of immigrants from NA showed a more aggressive course compared to European patients. OBJECTIVE: The aim of this study is to describe clinical and long term course characteristics of MS in Tunisia and to compare it to European cohorts. METHOD: A total of 437 MS patients from three hospital based cohorts in Tunisia and having prospective follow up between 2010 and 2012 were analyzed. We considered as endpoints the time to reach EDSS scores of 3, 4 and 6 in the different clinical forms of MS and the beginning of a secondary progressive (SP) phase. RESULTS: Sex ratio was 2.34. Mean age of onset was 30.3 years. The course was relapsing-remitting (RR) in 91% of patients and primary progressive (PP) in 9%. The most frequent isolated onset symptoms were respectively motor (28%), optic neuritis (20%) and sensory (16%) dysfunction. Median time to SP onset was 19.1 years. Median times from onset of multiple sclerosis to assignment of a score of 3, 4 and 6 were 8, 10.7 and 15 years respectively. Benign form of MS represented 31.5%. Median interval from the onset of the disease to EDSS score of 3, 4 and 6 was shorter in PP-MS than in RR-MS. However, there was no difference between these two groups for the median time from the assignment of EDSS 4 to the assignment EDSS 6. CONCLUSIONS: Our study shows that Tunisian MS patients have a quite similar clinical feature to European patients. Still, larger MS multicenter cohort studies in NA with longer follow-up duration could clearly respond to the issue.

Bipolar disorder and multiple sclerosis: a case series.

BACKGROUND: The prevalence of psychiatric disturbance for patients with multiple sclerosis (MS) is higher than that observed in other chronic health conditions. We report three cases of MS and bipolar disorder and we discuss the possible etiological hypothesis and treatment options. OBSERVATIONS: All patients fulfilled the McDonald criteria for MS. Two patients were followed up in psychiatry for manic or depressive symptoms before developing MS. A third patient was diagnosed with MS and developed deferred psychotic symptoms. Some clinical and radiological features are highlighted in our patients: one manic episode induced by high dose corticosteroids and one case of a new orbitofrontal MRI lesion concomitant with the emergence of psychiatric symptoms. All patients needed antipsychotic treatment with almost good tolerance for high dose corticosteroids and interferon beta treatment. CONCLUSIONS: MRI lesions suggest the possible implication of local MS-related brain damage in development of pure "psychiatric fits" in MS. Genetic susceptibility is another hypothesis for this association. We have noticed that interferon beta treatments were well tolerated while high dose corticosteroids may induce manic fits.

[The arteriovenous fistula is an additional risk factor for developing carpal tunnel syndrome in hemodialysis patients]. / La fistule artérioveineuse est un facteur supplémentaire de risque de développer un syndrome du canal carpien chez le patient hémodialysé

INTRODUCTION: Carpal tunnel syndrome (CTS) is the most frequent entrapment neuropathy reported in patients with renal failure undergoing periodic haemodialysis. The role of arteriovenous fistula was discussed. The aim of this study was to investigate this relationship. METHODS: Subjects for this study were hemodialysis patients who underwent systematic electroneuromyography between January 2003 and December 2010. Only patients with unilateral fistulae were included for the study. RESULTS: One hundred and thirty-four out of 155 patients were examined. CTS was noted in 106 patients and was detectable only in ENMG in 42% of cases. It was more frequent (P<0.001) and more severe in the side of fistulae (P=0.08). Besides, development of CTS was only correlated with the longer duration of dialysis (P=0.005). This duration was significantly shorter in patients with CTS and diabetes. CONCLUSION: The positive correlation between CTS and aretriovenous fistulae confirms the pathogenic role of this latter. The risk rises in these patients with the duration of hemodialysis and the presence of diabetes.