NUTRISEP: Assessment of the nutritional status of patients with multiple sclerosis and link to fatigue.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (PwMS) and reduces quality of life. Several hypotheses for the pathogenesis of fatigue in MS are proposed ranging from neurological lesions to malnutrition, but none has been conclusively validated through clinical research. OBJECTIVES: The goal of this study was to examine the correlation between fatigue and nutritional status and dietary habits in PwMS. METHODS: This was a cross-sectional, multicenter study conducted at 10 French MS centers and enrolling PwMS with an Expanded Disability Status Scale (EDSS) score between 0 and 7. Plasma level of albumin, magnesium, calcium, iron, vitamin D and B12 evaluated nutritional status. A semi-structured eating behavior questionnaire has been developed to evaluate dietary habits. Evaluation of fatigue used specific questionnaire (EMIF-SEP). Quality of sleep was evaluated by visual analogue scale (VAS), depression with Beck Depression Inventory (BDI-II); dysphagia by DYsphagia in MUltiple Sclerosis questionnaire (DYMUS) and taste disorders by gustometry. Association between nutritional deficiencies and different data such as socio-demographic data, disease characteristics, swallowing and taste disorders, food intake, depression and sleep quality was investigated. RESULTS: A total of 352 patients mean age: 48.1±10.1 years, mean duration of MS: 15.3±9.1 years and median EDSS: 4 were analyzed. Bivariate and multivariate analyses showed a statistically significant correlation between fatigue and depression and use of sleeping pills, while none of the variables related to dietary habits or nutritional status correlated significantly with fatigue. CONCLUSIONS: Dietary habits and nutritional status have little impact on fatigue and general population nutrition recommendations remain the rule for PwMS. In cases of fatigue, specific attention should be paid to depression and use of sleeping pills.

Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria.

BACKGROUND: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. METHODS: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. RESULTS: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. CONCLUSIONS: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

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.

Drug safety in multiple sclerosis: From reporting to signal detection and benefit-risk management.

BACKGROUND: Pharmacovigilance (PV) rules emerged in the late 60s-early 70s. Since that time, the World Health Organization Center for International Drug Monitoring carries out the corresponding tasks. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that generally starts in young adults between 20 and 40 years of age. Over the last 25 years, MS patients have benefited from the development of a plethora of disease modifying drugs (DMD). These changes in the therapeutic armamentarium have been associated with some serious adverse reactions challenging health authorities and neurologists involved in treatment and care for MS patients. METHODS: The present review aims to describe, for MS DMDs, how adverse drug reactions are reported during clinical trials and the post-marketing period and how important signal detection and benefit-risk management have been in this disease until now. Several examples are reported to illustrate the different steps of PV processes. CONCLUSION: Improvement of the PV system procedures has led to significant progress in the detection of signals, allowing better assessment of the benefit-risk balance and the implementation of risk management plans for MS treatments. The involvement of neurologists is essential to improve knowledge on the benefit-risk balance of these drugs. In addition, adverse drug reactions reporting by persons with MS should be encouraged.

Retrospective evaluation of regional telemedicine team meetings for multiple sclerosis (MS) patients: Experience from the Caen MS expert center in Normandy, France.

INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease requiring multidisciplinary care coordination. Recent development of diagnosis criteria and disease modifying treatments have encouraged the setup of regional team meetings by MS expert centers, known as CRC Sep, to improve the quality of care provided to patients with complex cases. The CRC Sep in Caen initiated regional telemedicine meetings named Télé-SEP, operating since 2016. The objective of this study was to evaluate the Télé-SEP used by neurologists, on MS patient care management in Normandy. METHODS: An internal ex-itinere evaluation was conducted with a retrospective descriptive observational study from July 2016 to June 2018. The Télé-SEP meetings were organized with 41 neurologists using a regional telemedicine platform (Therap-e). Data were collected from online records and a declarative voluntary survey. Twenty indicators were classified in the categories: volume of activity, clinical profile, quality and impact. RESULTS: Fifteen meetings were organized with a median of 13 senior neurologists. One hundred forty MS cases were discussed and there was a 33% increase in the second year of Télé-SEP. Median patient age was 44 years with a 72-month median length of disease. Most patient cases required second-line treatment. Relapsing remitting MS was diagnosed in 51.4% of cases. Télé-SEP satisfaction rate was 4.5/5 and 96% of neurologists applied the medical decisions and recommendations given in the meetings. CONCLUSION: Without Télé-SEP, 54.5% of patients would have been referred to a physical expert consultation in the CRC Sep. This study showed the feasibility and relevance of regional telemedicine team meetings for MS cases in the Normandy region.

Outcomes and treatment management of a French cohort suffering from multiple sclerosis: A retrospective epidemiological study.

BACKGROUND: Despite a recent interest in Real World Data, such studies are scarce in multiple sclerosis (MS) disease. The objective was to describe the patients, disease progression and use of DMDs in France and compare clinical effectiveness of first-line injectable DMDs. METHODS: We conducted a retrospective multicenter study in France, using data collected by 11 expert centers with the EDMUS software. RESULTS: Overall, 15,039 French MS patients were followed for a mean of 11.5 years. Mean age at start of disease was 32 years and 74% were women. After the disease onset, median time to reach EDSS 3 was 11 years and 51.8% of patients were relapse-free 2 years after the disease's onset. The mean delay between onset of disease and initiation of treatment was 5.7 ±â€¯6.9 years. Over time, it decreased from 8.8 ±â€¯7.8 to 0.7 ±â€¯0.7 years for initiation of treatment before 2000 vs. after 2010, respectively. Two years after the initiation of treatment, the persistence rate of injectable disease modifying drugs (DMDs) was 60.7%. The effectiveness of these drugs were quite similar. CONCLUSION: This study brings new insight on the natural history of MS and the use and effectiveness of injectable DMDs in this condition.

Evidence of attentional impairments using virtual driving simulation in multiple sclerosis.

BACKGROUND: Detection of attentional disorders in complex situation related to daily life activities in multiple sclerosis patients needs better adapted tools than traditional cognitive assessment. OBJECTIVE: To investigate the usefulness of virtual reality assessment of attention in multiple sclerosis, especially to evaluate alertness and divided attention using driving simulation. METHODS: In this preliminary study, 11 relapsing-remitting patients (median EDSS: 2; mean disease duration of 10.3 years) and 11 healthy matched controls performed a driving simulation under three conditions (monotonous driving, divided attention driving and urban driving) where Standard Deviation of Lateral position (SDLP) was the main evaluated criteria. In comparison, traditional cognitive assessment of attentional functions was administered (SDMT, alertness and divided attention of TAP battery). Statistical non-parametric Mann-Whitney U tests were used to compare performances between groups in the two types of assessments. Exploratory correlational analyses were further conducted. RESULTS: No significant difference was observed between groups for traditional attentional assessment except for information processing speed (SDMT; p < 0.01). Considering virtual reality, patients were less efficient than controls on the primary parameter of safe driving (SDLP; p < 0.05). They also committed more errors and omissions (p < 0.01) and speed fluctuations (p < 0.01) during the divided-attention driving condition. Urban driving did not reveal difference between groups. Lack of significant correlations between traditional and virtual reality attentional assessment suggested that they do not evaluate the same cognitive processes. CONCLUSION: Patients experienced difficulties in maintaining the trajectory and the speed of the simulated vehicle which may be indicative of attentional difficulties, especially alertness and divided attention. These impairments were not revealed by the traditional cognitive assessment. Results of this preliminary study shed new light about the usefulness of virtual reality techniques and their future interest as a part of cognitive rehabilitation programs. They also highlights the need to develop driving preventive measures in MS.

High-dose transdermal nicotine in Parkinson's disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study.

BACKGROUND AND PURPOSE: Studies of the effects of nicotine on motor symptoms in Parkinson's disease (PD) brought out discordant results. The aim of the present study was to evaluate the efficacy and safety of high doses of transdermal nicotine on motor symptoms in PD. METHODS: Forty PD patients were randomly assigned to a treated and untreated arm in an open-label study. Treated patients received increasing doses of nicotine to reach 90 mg/day by 11 weeks. This dosage was maintained for 28 weeks (W39) and then reduced over 6 weeks. Final evaluation was performed 6 weeks after washout. The main outcome measure was the OFF-DOPA Unified Parkinson's Disease Rating Scale (UPDRS) motor score measured on video recordings by raters blinded to the medication status of the patients. RESULTS: There was no significant difference in OFF-DOPA UPDRS motor scores between the nicotine-treated and non-treated groups, neither at W39 (19.4 ± 9.3 vs. 21.5 ± 14.2) nor considering W39 differences from baseline (-1.5 ± 12.1 vs. +0.9 ± 12.1). The 39-item Parkinson's disease questionnaire scores decreased in nicotine-treated patients and increased in non-treated patients, but the difference was not significant. Overall tolerability was acceptable, and 12/20 treated patients reached the maximal dosage. CONCLUSIONS: High doses of transdermal nicotine were tolerated, but our study failed to demonstrate significant improvement in UPDRS motor scores. Improvement in unblinded secondary outcomes (UPDRS-II, UPDRS-IV, doses of l-DOPA equivalents) suggest a possible benefit for patients treated with nicotine, which should be confirmed in larger double blind, placebo-controlled studies.

Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study.

Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event.

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.

High-risk syndrome for neuromyelitis optica: a descriptive and comparative study.

BACKGROUND: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies. OBJECTIVE: To describe HRS patients and compare them with NMO patients. METHODS: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database. RESULTS: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup. CONCLUSION: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.

[Cognitive rehabilitation in multiple sclerosis: a review of the literature]. / Remédiation cognitive dans la sclérose en plaques: revue de la litérature.

INTRODUCTION: Cognitive impairment is now well-known in multiple sclerosis (MS). However, few rehabilitation interventions are proposed or really efficient. OBJECTIVES: To present a review of cognitive rehabilitation intervention research conducted in people with multiple sclerosis (MS), regarding different findings about episodic memory, working memory, attention and executive function disorders in MS. DATA SOURCES: A search of Medline (yield 20 papers) and of PsychInfo (yield 1 article), using combinations of the following terms: cognitive rehabilitation, multiple sclerosis, cognitive therapy, neuropsychological rehabilitation, in the title or in the abstract, from 1960 to March 2010, excluding animal studies. RESULTS: Episodic memory rehabilitation studies appear to be promising. Programs on working memory, attention and executive functions are in the very early phases. CONCLUSIONS: Results are encouraging and allow specific recommendations for future research about: (1) inclusion criteria, often not defined, (2) a specific baseline adapted to the program of rehabilitation, (3) a control measure regarding program efficiency and (4) a role for the psychologist (presence and advice during the program).

[The default mode network: cognitive role and pathological disturbances]. / Le réseau cérébral par défaut : rôle cognitif et perturbations dans la pathologie.

INTRODUCTION: A "resting state" or "default mode network" has been highlighted in functional neuroimaging studies as a set of brain regions showing synchronized activity at rest or in task-independent cognitive state. STATE OF THE ART: A considerable and increasing number of studies have been conducted over the last few years so as to unravel the cognitive function(s) of this brain network. PERSPECTIVES: This review gives an overview of anatomical, physiological and phenomenological data regarding the default mode network. Different hypotheses have been proposed regarding the role of this network. Several studies have highlighted its involvement in autobiographical memory, prospection, self, attention, and theory of mind. The influence of the attention level and consciousness onto resting state brain network activity has also been discussed. Specific changes have been described in normal aging, Alzheimer's disease (AD) and multiple sclerosis (MS). CONCLUSIONS: These studies altogether contribute to a better definition of the default mode network, in terms of implicated brain structures, subtending mechanisms, and potential cognitive roles. For instance, similarities and relationships were found between self-related brain activity and resting-state activity in regions belonging to this network, namely posterior cingulate and prefrontal areas that may reflect introspective activity experienced, more or less consciously, when the brain is not specifically engaged in a cognitive task. As a whole, the default mode network appears as a non human-specific intrinsic functional network, active all over the life from birth until aging where it is progressively modified, and sensitive to different pathologies including AD and MS. On the other hand, many points remain to be clarified concerning this network, such as the exact part of its activity dedicated to self-related cognitive processes (introspection, imaginary mental scenario based on past autobiographical experiences) and that involved in a sentinel-like attentional process designated to react to possible environmental events. Indeed, it seems that this network is functional even in case of low level of consciousness, i.e., during light sleep. Conversely, a loss of self and environment perception as in coma, deep sleep or anesthesia might modulate its connectivity along the anteroposterior axis, i.e., frontal activity disappearance associated with a parietal reinforcement of connectivity. Since studies aiming at highlighting these points are still uncommon to date, exhaustive and objective explorations are needed to better understand all these resting state processes.

Neuromyelitis optica in France: a multicenter study of 125 patients.

BACKGROUND: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. METHODS: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. RESULTS: Mean age at onset was 34.5 years (range 4-66) with a mean disease duration of 10 +/- 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score > or = 4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity < or = 1/10. CONCLUSIONS: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

Home administration of intravenous methylprednisolone for multiple sclerosis relapses: the experience of French multiple sclerosis networks.

BACKGROUND: One single center study has provided support for a home-based approach to the therapeutic management of multiple sclerosis (MS) relapse. OBJECTIVE: To report a multicenter series of patients with MS who were treated at home for a relapse with a 3-day course of intravenous methylprednisolone. METHODS: The home administration of intravenous methylprednisolone was coordinated by four MS networks in France; patients with MS with a relapse were referred by their neurologists, and treatment was administered by a local nurse. We analyzed the safety and efficiency of this approach and estimated the related cost savings. Patients completed a patient satisfaction questionnaire. RESULTS: Eight hundred and seven patients received intravenous methylprednisolone at home. The mean disease duration was 10.3 +/- 7.9 years. Treatment was often prescribed by community-based neurologists. The delay between prescription and treatment was 2.8 +/- 0.5 days if treatment was initiated at home and 1.9 +/- 3.0 days if treatment was initiated in hospital (the subsequent two injections were always administered at home). Home treatment was well tolerated; three serious side effects requiring hospital transfer were observed (anxiety, thoracic oppression, and arrhythmia), which were fully reversible. Overall, 93.8% of patients were satisfied with the treatment approach, and 98% wished to receive future treatment courses at home. The overall cost savings of home-based treatment versus hospital-based treatment were evaluated at EUR1,091,482. CONCLUSION: Safety data, patient satisfaction, and economic considerations support home-based treatment of MS relapses with intravenous methylprednisolone, provided strict patient selection criteria are observed and the process is coordinated and closely monitored by an MS network.