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.

Pregnancy with multiple sclerosis.

Multiple sclerosis (MS) is usually diagnosed between twenty and forty years of age, when people often plan to have children. A lot has been said about the effect of pregnancy on the course of MS. The individual factors responsible for the disease modifying effect of pregnancy are not well determined. Having MS neither affects the fertility or the course of pregnancy itself. During pregnancy, many women find that their symptoms stay the same or even improve. Epidural and spinal analgesia appear to be safe and in general are not contraindicated for patients with MS. The management of disease-modifying treatments (DMTs) in pregnancy is a new issue for consideration in the clinical practice. There is limited information available into the safety of DMT use during pregnancy, especially for the most recent ones. In general, discontinuation of DMTs is recommended before conception to minimize risk of fetal harm. Women with very active MS before pregnancy who stop second-line treatments may show an increase in disease activity during pregnancy. Therefore, it might be discussed to maintain patients on DMTs until pregnancy is confirmed, and sometimes throughout pregnancy, to avoid a rebound of disease activity and severe relapses during pregnancy in very active patients.

Clinical failure of natalizumab in multiple sclerosis: Specific causes and strategy.

BACKGROUND: Natalizumab is a very effective treatment of multiple sclerosis (MS). Failure is rare and should lead to consider some specific etiologies. The purpose of our study was to describe causes of subacute neurological events under natalizumab. METHODS: Observational single-center retrospective study in the MS expert center of Lyon, France. INCLUSION CRITERIA: any patient with definite MS who received at least three infusions of natalizumab between April 2007 and February 2017. Clinical data were extracted from the Lyon EDMUS/OFSEP database. Events of interest: occurrence of a subacute neurological deficit, characterized by new clinical symptoms. We excluded pseudo-relapses and progression. FINDINGS: A subacute neurological deficit occurred in 35 cases, for 607 patients treated with natalizumab. Ten patients presented natalizumab antibodies, nine had progressive multifocal leukoencephalopathy (PML), five presented an isolated subacute neurological deficit and two had AQP4 antibodies. No myelin oligodendrocyte glycoprotein (MOG) antibodies were found. INTERPRETATION: The occurrence of an acute or subacute neurological deficit with natalizumab is rarely a MS relapse and should lead systematically to explore some important alternate etiologies, eliminating PML first.

MRI characteristics of MOG-Ab associated disease in adults: An update.

Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

A comparative evaluation of different neuromyelitis optica spectrum disorder sets of criteria.

BACKGROUND AND PURPOSE: Three different sets of criteria have been proposed for the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The objective was to compare the specificity, sensitivity and diagnostic accuracy of the three different sets of NMOSD criteria in patients presenting with inflammatory disorders of the central nervous system suggestive of NMOSD. METHODS: For 236 suspected NMOSD patients referred for serum aquaporin-4 immunoglobulin G antibody (AQP4-IgG) testing between 2012 and 2014, the three sets of NMOSD criteria [1999, 2006 NMO criteria and 2015 International Panel for NMO Diagnosis (IPND) criteria] were applied and compared to the final diagnosis. RESULTS: Seventy-six patients fulfilled at least one set of criteria and 28 patients fulfilled all NMOSD sets of criteria. The final diagnosis was NMOSD in 66 cases, multiple sclerosis according to the MacDonald 2010 criteria in 85 cases and another diagnosis in 85 cases. The 2006 NMO criteria have the highest specificity (99%) and the 2015 IPND NMOSD criteria the highest sensitivity (97%). For the 1999, 2006 and 2015 IPND NMOSD criteria, the accuracy was respectively 82%, 87% and 97%. CONCLUSIONS: Our study highlights the limitations of the first set of criteria that include the optico-spinal form of multiple sclerosis. The accuracy of NMOSD diagnostic criteria improved from 1999 to 2015. It confirms the increased performance of the last set of criteria which covers a larger spectrum of clinical presentation. This study raises some concerns for classifying patients with seronegative transverse myelitis or optic neuritis, and myelin oligodendrocyte glycoprotein (MOG) antibody- associated disease.

MSCopilot, a new multiple sclerosis self-assessment digital solution: results of a comparative study versus standard tests.

BACKGROUND AND PURPOSE: Assessing patients' disability in multiple sclerosis (MS) requires time-consuming batteries of hospital tests. MSCopilot is a software medical device for the self-assessment of patients with MS (PwMS), combining four tests: walking, dexterity, cognition and low contrast vision. The objective was to validate MSCopilot versus the Multiple Sclerosis Functional Composite (MSFC). METHODS: This multicentre, open-label, randomized, controlled, crossover study enrolled 141 PwMS and 76 healthy controls (HCs). All participants performed MSCopilot and MSFC tests at day 0. To assess reproducibility, 46 PwMS performed the same tests at day 30 ± 3. The primary end-point was the validation of MSCopilot versus MSFC for the identification of PwMS against HCs, quantified using the area under the curve (AUC). The main secondary end-point was the correlation of MSCopilot z-scores with MSFC z-scores. RESULTS: In all, 116 PwMS and 69 HCs were analysed. The primary end-point was achieved: MSCopilot performance was non-inferior to that of MSFC (AUC 0.92 and 0.89 respectively; P = 0.3). MSCopilot and MSFC discriminated PwMS and HCs with 81% and 76% sensitivity and 82% and 88% specificity respectively. Digital and standard test scores were highly correlated (r = 0.81; P < 0.001). The test-retest study demonstrated the good reproducibility of MSCopilot. CONCLUSION: This study confirms the reliability of MSCopilot and its usability in clinical practice for the monitoring of MS-related disability.

Immunization and multiple sclerosis: Recommendations from the French Multiple Sclerosis Society.

OBJECTIVES: To establish recommendations on immunization for patients with multiple sclerosis (MS). BACKGROUND: Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients. METHODS: The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975-June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain. RESULTS: Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs. CONCLUSION: Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS.

Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders

There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.

Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid.

BACKGROUND: Devic's neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial. METHODS: To explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgG(AQP4+), NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats. RESULTS: We showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively). In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-IgG-depleted condition. We did not find a major immune cell infiltration and microglial activation nor complement deposition in the central nervous system, in our model. CONCLUSIONS: We establish a link between motor-deficit, NMO-like lesions and astrocytopathy mediated by intrathecal AQP4-IgG. Our study validates the concept of the intrinsic effect of autoantibody against surface antigens and offers a model for testing antibody and astrocyte-targeted therapies in NMO.

Efficacy of rituximab in refractory neuromyelitis optica.

BACKGROUND: Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy. OBJECTIVE: The purpose of this study was to assess RTX as a maintenance therapy in RNMO. METHODS: Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months. RESULTS: After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening. CONCLUSIONS: RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.

A rare case of SPG11 mutation with multiple sclerosis.

We describe a patient with SPG11 hereditary spastic paraplegia (HSP), who developed walking disorder in childhood. He presented three episodes of subacute gait disorders worsening between the age of 20 and 22 years. Brain and spinal MRI revealed multiple T2 hypersignal lesions, consistent with inflammatory lesions. Surprisingly, CSF analysis showed neither oligoclonal bands nor increased IgG index. He was dramatically improved by intravenous methylprednisolone. A relapsing-remitting multiple sclerosis (MS) was suspected. This is the first description of SPG11 HSP associated with MS.

Neuromyelitis optica: a positive appraisal of seronegative cases.

Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system. The hallmark of NMO is the presence of specific autoantibodies directed against aquaporin 4 (AQP4-IgG). AQP4-IgG, included in diagnostic criteria, has enlarged the clinical spectrum of NMO and serves to predict relapses. Moreover AQP4-IgG has provided unprecedented insight in the immunopathology of NMO, representing a rationale for therapeutic intervention with relevant novel treatment strategies specific for NMO. However, some patients remain seronegative for AQP4-IgG despite a definite diagnosis of NMO and the use of the finest methods for antibody detection. Interestingly, seronegative NMO (NMO(neg)) patients exhibit different demographic and disease-related characteristics in comparison to seropositive patients. The recent association with autoantibodies specific for myelin oligodendrocyte glycoprotein (MOG) is the main indication that disease mechanisms might differ in NMO(pos) and NMO(neg), challenging the position of NMO(neg) patients in the spectrum of demyelinating diseases and therapeutic strategies to be adopted. Thus, a reappraisal of the NMO(neg) population is needed to improve NMO care. Here the current knowledge regarding NMO(neg) is reviewed and hypotheses on its pathogenesis are made including a comprehensive description of detection methods and the prevalence of AQP4-IgG and a review of the epidemiological, clinical and paraclinical characteristics of NMO(neg); finally an integrated view of the general pathophysiological mechanisms underlying NMO(neg) is provided.

OFSEP, a nationwide cohort of people with multiple sclerosis: Consensus minimal MRI protocol.

Multiple sclerosis (MS) is most generally considered as a severe disease with high physical and mental risks of disability. Since the end of the 1990s, several high cost long-term disease-modifying treatments provided some clinical efficiency. However, patient's follow-up was needed for the detection and the assessment of their side-effects. The "Observatoire français de la sclérose en plaques" (OFSEP) project aims to improve the clinical, biological and imaging systematic longitudinal follow-up of patients. It should increase the quality, efficiency and safety of patients' care, with a unique opportunity of large scale, about 41,000 patients followed in 62 French centers using the European Database for Multiple Sclerosis (EDMUS) software. OFSEP is divided into three working groups (clinical, biological and imaging). The imaging working group defines standards for routine MRI follow-up in the whole cohort and contains three subgroups: acquisition, workflow, and data processing. A common and feasible brain and spinal cord acquisition protocol has been defined by the acquisition group, and accepted by the OFSEP steering and scientific committees. This protocol can be implemented in all French MRI centers. The major MRI manufacturers have agreed to provide the dedicated collection of sequences as an "OFSEP box" with every software upgrade or new MRI machine. The new OFSEP protocol will provide a unique opportunity to study a population-based collection of data from people with MS.

Mycophenolate mofetil in multiple sclerosis: a multicentre retrospective study on 344 patients.

OBJECTIVES: Mycophenolate mofetil (MMF) is an immunosuppressive agent, sometimes used as a disease-modifying therapy for multiple sclerosis (MS). Several studies have reported the relative safety of this treatment but, to date, its efficacy has rarely been described. We performed a retrospective study to assess the safety and efficacy of MMF in patients with MS. METHODOLOGY: Three French MS centres included all of their patients treated by MMF. The main outcome criterion was annualised relapse rate (ARR) in the 1 year period after onset of MMF compared with the 1 year control period. Treatment with another immunosuppressive drug, such as mitoxantrone or cyclophosphamide, in the 2 years preceding initiation of MMF was included in a subgroup analysis. MMF safety and progression of the Expanded Disability Status Scale (EDSS) score were also assessed. RESULTS: 344 patients were included; 149 patients were previously treated with another immunosuppressant (IS group). Mean MMF treatment duration was 25.3±1.1 months. During the 1 year control period, ARR was 1.11±0.08, and for the 1 year treatment period, ARR was reduced significantly to 0.35±0.05 (p<0.0001, Wilcoxon paired test). Adverse events (occurring in 11% of patients) were mainly digestive disorders, benign infections, asthenia and transitory lymphopenia. Concerning the progression of disability, in the subgroup of patients without previous immunosuppressant treatment, EDSS remained stable between initiation and 1 year after the beginning of MMF. INTERPRETATION: Our results suggest that MMF can improve or stabilise MS patients and can be used as an alternative therapy.

[Sequential MRI imaging of progressive bilateral rostro-caudal medullary infarction]. / Infarctus bulbaire paramédian bilatéral d'évolution progressive: à propos de deux cas documentés en imagerie par résonance magnétique séquentielle.

Bilateral medial medullary infarction is exceptional. Initial symptoms can be misleading, even for a trained neurologist. We report two patients who presented progressive quadriplegia, anarthia and dysphagia. Sequential MRI showed progressive constitution of the characteristic "heart appearance" sign.