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.

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.

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.

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.

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.

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.

[Place of local thrombolytic therapy in the treatment for cerebral venous thrombosis]. / Thrombolyse in situ dans la thrombose veineuse cérébrale.

INTRODUCTION: Cerebral venous thrombosis (CVT) is uncommon with a variable clinical presentation and an unpredictable outcome. Heparin is used for first-line treatment in association with symptomatic and etiologic management. Despite adequate anticoagulation, the condition may deteriorate in some patients warranting the use of local thrombolysis (LT) known for good efficacy and safety. But there are few cases and trials upon which to base guidelines for the use of LT. METHODS: A retrospective review of the medical and radiological records of patients with CVT was managed in the Caen hospital over a six-year period. We compared clinical factors of poor prognosis and radiological findings according to treatment delivered. RESULTS: Thirty-six patients are treated for CVT. LT was performed in eight of them; dose-adjusted intravenous heparin was the only treatment in the 28 others. Good outcome was achieved in two thirds of the patients with functional sinus patency in all cases. Based on an analysis of the radiological data of the 36 patients, we propose a summary of radiological risk factors associated with a worsening condition despite adequate anticoagulation. DISCUSSION/CONCLUSION: Based on our experience and a review of the literature which includes 98 previous cases, LT appears to be a relative effective end safe procedure even in the presence of a hemorrhagic infarct. The treatment by LT should be considered in patients who present clinical criteria of gravity and radiological risk factors associated with failure of heparin treatment. The usefulness of LT remains to be determined in a randomized trial comparing heparin alone and heparin associated with LT.

[Current management of brain metastases]. / Traitement actuel des métastases cérébrales.

INTRODUCTION: Cerebral metastases occur in 15 to 20% of cancers and their incidence is increasing. The majority occur at an advanced stage of the disease, but metastasis may be the inaugural sign of cancer. The aim of treatments, which are often palliative, is to preserve the neurological status of the patient with the best quality of life. STATE OF ART: Corticosteroids are widely used for symptomatic palliation, requiring close monitoring and regular dose adaptation. Antiepileptic drugs should be given only for patients who have had a seizure. In case of multiple cerebral metastases occurring at an advanced stage of the disease, whole brain radiation is the most effective therapy for rapid symptom control. However, radiotherapy moderately improves overall survival, which often depends on the progression of disseminated systemic disease. On the contrary, surgery is indicated in case of a solitary metastasis, particularly when the patient is young (less than 65 years), with good general status (Karnofsky greater than 70), and when the systemic disease is under control. Radiosurgery offers an attractive alternative for these patients with good prognostic factors and a small number of cerebral metastases (< or = 4). PERSPECTIVES: Chemotherapy, considered in the past as not effective, is taking on a more important place in patients with multiple nonthreatening metastases from chemosensitive cancers (breast, testes...). Radiosurgery and whole brain radiotherapy are complementary techniques. Their respective role in the management of multiple metastases (< 4) remains to be further investigated. CONCLUSIONS: Therapeutic options are increasingly effective to improve the functional prognosis of patients with cerebral metastases. Ideally, a multidisciplinary assessment offers the best choice of therapeutic modalities.

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.

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.

[Therapeutic management of cognitive disorders in multiple sclerosis]. / Prise en charge thérapeutique des troubles cognitifs dans la sclérose en plaques: données et perspectives.

Taking in charge cognitive disorders is a new concept in the global care of MS patients. Cognitive disorders are observed in the all forms of the disease, sometimes early on in the evolution. These disorders can be evaluated in details even detected despite any complain in the patient. Because of the lack of clear demonstration that disease-modifying treatments could act on cognition, new specific therapeutic issues have emerged during last years. This article first discusses relationships between disease-modifying treatments and cognition for the different forms of the disease, then analyse the effects of symptomatic drug therapy especially the use of anticholinesterasics. In the last part of the article new issues about antagonists of excitatory amino-acids and individual or group cognitive training are discussed. Recent functional imaging data concerning cerebral adaptation and their modifications by drug or non-drug procedures in MS patients suggest interesting therapeutic development in a next future.

[CARIMS (Cancer Risk In Multiple Sclerosis) project: impact of long-term treatment]. / Cancer et sclérose en plaques. Impact des traitements de fonds et présentation du projet CARIMS (Cancer Risk In Multiple Sclerosis).

Controversial results have been published on potential link between cancer and multiple sclerosis. Multiple sclerosis has been linked to reduced rates of cancer prior to the era of immunomodulating or immunosuppressive treatments and until today, only 9 studies can be found in the literature. New strategies and early use of IM or IS drugs in MS justify to study and follow patients to detect a potential increase of cancer's incidence in treated patients. It is important to follow and collect prospectively in MS centers, patients with history of cancer, to document histologies, and potential relations with repeated IM or IS treatments. A prospective study is in progress in French MS centers on behalf the Club Francophone de la SEP (CARIMS Project).