Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Do modern therapies change natural history of Neuromyelitis optica?

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon antibody-mediated disease of the central nervous system. Approximately 75% of patients have antibodies against aquaporin-4, a water channel expressed on astrocytes. Untreated, approximately 50% of NMOSD patients will be wheelchair users and blind, and a third will have died within 5 years of their first attack. Unlike multiple sclerosis, a progressive clinical course is very unusual and the accrual of disability is related to relapses. Aggressive treatment of attacks and highly efficient maintenance therapies to prevent attacks are therefore crucial to prevent residual disability. In this article, we review how high dose steroids and most importantly apheresis and modern therapies implicating B cell depletion, inhibition of complement and IL-6 reception are effective to change its natural history. We will emphasize the results of three recent double blind randomized controlled studies using monoclonal antibodies allowing strong hope to modify natural history of NMOSD.

Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. OBJECTIVE: To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). METHODS: We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. RESULTS: Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). CONCLUSIONS: This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

Different HLA class II (DRB1 and DQB1) alleles determine either susceptibility or resistance to NMO and multiple sclerosis among the French Afro-Caribbean population.

BACKGROUND: Despite similarities, neuromyelitis optica (NMO) can be distinguished from multiple sclerosis (MS) by clinical, radiological and serological findings. OBJECTIVE: This case-control study aimed to determine whether patients with NMO or with MS in an Afro-Caribbean population originating from French West Indies shared the same or different HLA class I and II pattern distribution. METHODS: The association with HLA class II (DRB1 and DQB1) alleles was tested in 42 NMO patients, 163 MS patients and 150 healthy controls. HLA-DRB1 and DQB1 typing was undertaken on genomic DNA extracted from peripheral blood leucocytes. RESULTS: By comparison with healthy controls, significantly increased frequency of HLA-DRB1 03 (26.2% vs. 13%, odds ratio 2.4, 95% confidence interval 1.31-4.28, p after correction, cp 0.045) was observed in patients with NMO. By contrast, in MS patients, HLA-DRB1 15 (24.8% vs. 13%, odds ratio 2.21, 95% CI 1.45-3.36, cp < 0.0015), but not DRB1 03 allele, was positively associated with the disease. Moreover, a modest protective effect of HLA-DRB1 11 in the MS group, independently of DRB1 15 association, was found (13.7% vs. 7% in controls, odds ratio 0.48, p 0.006), but did not survive Bonferroni correction. CONCLUSION: In conclusion, comparison of the HLA-DRB1 and DQB1 distribution in NMO and MS in this Afro-Caribbean population shows important differences in the HLA associations among NMO and MS.

[Control of the transfusion risk in HE: Reflection on the a priori risk approach]. / Maîtrise du risque transfusionnel en ES : réflexion sur la démarche a priori des risques.

Haemovigilance and blood safety became closely linked initially to the quality system, then very quickly to risk management in health-care institutions. The complexity of the transfusion process and the uniqueness of the transfusion act have been the source of a wide range of in-depth analyzes, via methods most often derived from the industry, that aimed at preventing the occurrence of unwanted situations with potential adverse effects on transfused patients. Though these methods have widely been successful, the experience gained over more than two decades indicates that many reported incidents are still avoidable. The time devoted to training, file analyzes (even in the absence of any reported incident), and simulating patient care remains essential. It is fundamental to bear in mind that there is no such thing as risk zero, no one is immune, and this does not happen to others. In this context, developing a different perspective, a new reflection, a vision integrating the complexity of fieldwork and the idea of risk may be an approach worthy of investigation. Indeed, an analysis centered on both of the ways a team copes with difficult situations and the variety of the interactions between professionals would allow medical practitioner to better position themselves through a better assessment and understanding of their role. Such a deeper reflection, through the mobilization of all the stakeholders of the many successful steps of the transfusion process, would increase blood safety and the overall resilience of the system.

Multiple sclerosis and solar exposure before the age of 15 years: case-control study in Cuba, Martinique and Sicily.

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.

Treatment of MOG antibody associated disorders: results of an international survey.

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD. METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

Relapsing neuromyelitis optica: long term history and clinical predictors of death.

BACKGROUND: Relapsing neuromyelitis optica (RNMO) is an uncommon but devastating inflammatory disorder of the central nervous system. Long term history in a wide series of RNMO is required for better knowledge of the course of the disease and identification of patients at high risk of death. METHODS: Clinical features of patients with RNMO (88 women/eight men) obtained from the geographic Caribbean database (Cuba and French West Indies) were used to determine the progression of disability and to identify clinical predictors of death. RESULTS: Median age at onset of RNMO was 29.5 years (range 11-74). Median duration of disease was 9.5 years (1-40). Median relapse rate was 0.7 attack/patient/year (0.1-3). 66 patients experienced severe visual loss in at least one eye and 46 in both eyes. Median time from onset to unilateral and bilateral severe visual loss was 3 and 15 years, respectively. Median times to reach Kurtzke Disability Status Scale 3, 6 and 8 from onset of RNMO were 1, 8 and 22 years. There were 24 deaths (25%); within 5 years in 63% of cases. A higher attack frequency during the first year of disease (p = 0.009), blindness (p = 0.04) and sphincter signs at onset (p = 0.02) and lack of recovery of first attack (p = 0.003) were independently associated with a shorter time to death. CONCLUSION: RNMO is a very rapidly disabling disease affecting primarily young women. This study has identified clinical features that predict a poor outcome. These findings suggest that early and aggressive immunotherapy might be warranted in RNMO.

Evaluation of the 2005 McDonald MRI criteria for dissemination in space in Afro-Caribbean patients with clinically isolated syndromes.

BACKGROUND: In 2005, the McDonald MRI criteria for dissemination in space were revised to improve diagnosis of multiple sclerosis (MS) in non-Caucasians. METHODS: We included patients with a first clinically isolated syndrome (CIS) to assess their performance in the Afro-Caribbean population. Baseline brain and spine MRI examinations were available within 3 months after onset of CIS. The development of a second clinical event was used as the main outcome indicating clinically definite MS. RESULTS: A total of 66 patients (52F/14M) were included between January 1998 and January 2008 (mean age: 34.7; median follow-up: 34 months). CIS was classified as spinal cord (30.3%), optic neuritis (28.8%), brainstem (24.2%), multiregional (10.6%), hemispheric (4.5%), or undetermined (1.5%). Overall conversion rate was 42.4% (median: 11 months). The McDonald criteria revised for dissemination in space were fulfilled in 33.3% (sensitivity: 0.39 (+/-0.18); specificity: 0.66 (+/-0.15), positive predictive value: 0.46 (+/-0.20), negative predictive value: 0.60 (+/-0.15). CONCLUSION: The Afro-Caribbean population is characterized by a strong proportion of CIS in the spinal cord and a lower burden of disease on the baseline brain MRI. This may explain the low sensitivity of the 2005 McDonald criteria for dissemination in space. Further prospective studies emphasizing MRI spinal cord features are needed to improve diagnostic criteria in a population of African descent.

[Star fruit (Averrhoa carambola) toxic encephalopathy]. / Encéphalopathie toxique par ingestion de carambole (Averrhoa carambola).

Ingestion of star fruit (Averrhoa carambola) can induce severe intoxication in subjects with chronic renal failure. Oxalate plays a key role in the neurotoxicity of star fruit. We report the cases of two patients with unknown chronic renal insufficiency who developed severe encephalopathy after ingestion of star fruit. The two patients developed intractable hiccups, vomiting, impaired consciousness and status epilepticus. Diffusion-weighted MR imaging showed cortical and thalamic hyperintense lesions related to epileptic status. They improved after being submitted to continuous hemofiltration which constitutes the most effective treatment during the acute phase.

[Descriptive epidemiology of neuromyelitis optica in the Caribbean basin]. / Epidémiologie descriptive de la neuromyélite optique dans le bassin caraïbéen.

INTRODUCTION: Data on epidemiology of neuromyelitis optica (NMO) remained scarce in the last century, but the recent development of diagnostic criteria now enables inclusion of both monophasic and relapsing NMO in epidemiologic studies. Given the rarity of NMO, multicentric studies are needed to confirm a presumed higher frequency in women and in populations of black/Asian ancestry. The Caribbean basin is a suitable area for collecting a large NMO cohort and to assess the prevalence, incidence, and mortality of this disorder. PATIENTS AND METHODS: This population-based survey of the NMO spectrum in the French West Indies (FWI) and Cuba included 151 cases. RESULTS: Ninety-eight patients (female/male ratio: 9.8) had NMO. Age of onset in NMO patients was 30.9 years. Mean annual incidence of NMO in the French West Indies for the period July 2002 to June 2007 was 0.20/100,000 inhabitants (IC 95% 0.05-0.35). Incidence rates were steady in the FWI during the 1992 to 2007 period. Decreasing mortality in the FWI during the 1992 to 2007 period explained the increasing prevalence which was 4.20/100,000 inhabitants (IC 95% 3.7-5.7) in June 2007. The prevalence of NMO in Cuba on November302004 was 0.52/100,000 inhabitants. (IC 95% 0.39-0.67). Prevalence rates did not differ significantly by ethnic group in Cuba, however, black Cubans exhibited the highest prevalence. DISCUSSION: Epidemiologic studies on NMO in each population are needed to determine whether aggressive therapies can reduce the mortality of this devastating disorder. CONCLUSION: In the Caribbean basin, NMO involves almost exclusively young women; the epidemiologic data confirm its predilection for populations of African ancestry. In the FWI, recent and aggressive therapy has lowered mortality but with an increase in the prevalence of NMO.

MRI of the spinal cord in neuromyelitis optica and recurrent longitudinal extensive myelitis.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) is a severe inflammatory and necrotizing disease that clinically affects the optic nerves and spinal cord in a relapsing course. We assessed the baseline and follow-up MRI characteristics of cord attacks in NMO and recurrent longitudinal extensive myelitis (RLEM). METHODS: We retrospectively reviewed MRI data of 20 Afro-Caribbean patients diagnosed with either NMO or RLEM. MRI data from 51 cord or mixed attacks were evaluated, and 65 follow-up MRI studies were available for 30 baseline acute examinations. RESULTS: The cervical cord was involved in 63% of cases. Four attacks were limited to the brainstem. MRI of the spinal cord revealed longitudinal extensive signal abnormalities extending over three vertebral segments, associated with cord swelling in 67% of the 51 relapses. Gadolinium enhancement was observed, preferentially surrounding edema, in 69% of attacks. In the axial plane, signal abnormalities typically involved central areas of the cord. Cavitation was observed in 16% of attacks. Cord attacks recurred in the same or contiguous areas in 67% of cases. Follow-up MRI revealed a gradual decrease in cord swelling and T2 signal hyperintensity, with fragmentation of signal abnormalities in some cases. Cord atrophy was evident in 57% of the follow-up MRI. CONCLUSION: Given the poor prognosis of NMO and RLEM, radiologists need to be aware of the MRI pattern to prevent further attacks with the use of aggressive treatment.

[Steroid treatment in four cases of anti-GAD cerebellar ataxia]. / Traitement des ataxies cérébelleuses à anticorps anti-GAD par cures séquentielles de corticoïdes.

INTRODUCTION: Few neurological diseases are linked with anti-glutamic acid decarboxylase antibodies (GAD-ab); stiff man syndrome is an example. Cerebellar ataxia is a new feature of this expanding spectrum. No therapeutic trial is yet available in these diseases. We here report on four patients suffering from cerebellar ataxia linked with GAD-ab and review the data in the literature on this recently described syndrome. METHOD: We conducted an open trial with monthly pulsed steroids. Steroid pulses were given six months followed with placebo for another six months. Main clinical and biological parameters were monitored monthly (International Cooperative Cerebellar Ataxia Rating Scale [ICARS] and GAD-ab). RESULT: The clinical response was found limited and inconstant. Transient decline in GAD-ab level was noted in two patients. Moreover, GAD-ab level was found highly variable and did not correlate with clinical parameters. DISCUSSION: Cerebellar ataxia with GAD-ab is an increasingly described syndrome. Outcome can be severe, leading to definitive cerebellar atrophy. Diagnosis is supported by high level of serum GAD-ab with intrathecal secretion. Experimental data have suggested a direct excitotoxic effect of GAD-ab on Purkinje cells. Response to various treatments is often disappointing. Improvement has been obtained with veinoglobulins in individual patients. A weak clinical and biological response was associated with monthly steroid pulses.

[Failure of rituximab in relapsing neuromyelitis optica: case report with two-year prospective follow-up]. / Echec thérapeutique du rituximab dans un cas de neuromyélite optique rémittente: suivi prospectif longitudinal sur deux ans.

Neuromyelitis optica (Devic's disease, NMO) is an inflammatory disease of the central nervous system preferentially involving the spinal cord and optic nerves in either a monophasic or relapsing-remitting course. B-cell induced pathogenesis was recently described for NMO. Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen, which causes depletion of B-cells. Rituximab might be effective in treatment of NMO. We report the two-year clinicoradiological and biological follow-up data from a patient included in July 2005 in a prospective trial of rituximab for severe NMO refractory to immunosuppressant therapy. Blood B-cell depletion after rituximab induction was maintained for 10 months. Seven attacks occurred during a two-year follow-up. EDSS increased from 7.0 to 8.0. Left visual acuity decreased from 20/20 degrees to 20/60 degrees. Spinal cord atrophy worsened.