ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

Peripheral late reactivation of a previously typical monofocal Baló's concentric sclerosis lesion.

We report a 41-year-old woman with rapidly progressive left hemiparesis, revealing an inflammatory reactivation of a previously known parietal Baló's concentric sclerosis lesion. The first attack occurred five years before. After a slow recovery following high-dose steroid infusions the patient stabilized. Because of recurrent ataxia and left hemiparesis a new magnetic resonance imaging was performed showing an extension of the initial lesion with a peripheral gadolinium enhancement on T1-weighted images. Such a reactivation pattern of an isolated Baló's concentric sclerosis lesion, occurring some years later, is described for the first time.

[Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects]. / Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques.

INTRODUCTION: Cerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid. METHOD: We report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients. RESULTS: The average age at diagnosis was 39years (range 27-65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28-65years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n=5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died. CONCLUSION: Patients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.

[Implementation of a massive transfusion protocol in an emergency department]. / Mise en place d'un protocole de transfusion massive dans un service d'urgences.

We present here the massive transfusion protocol implemented in our institution in 2013. It will improve our management of critical massive bleeding, a situation which is rare in in our hospital, but carries a high mortality risk.

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.

Impact of intermittent catheterization on the quality of life of multiple sclerosis patients.

PURPOSE: Lower urinary tract dysfunction is common in multiple sclerosis (MS). The purpose of this study was to prospectively evaluate the impact of intermittent catheterization (IC) on the quality of life of patients affected by MS. METHODS: Between 2007 and 2009, we admitted 23 patients to teach them the technique of IC. Their quality of life was evaluated before and more than 6 months after the beginning of learning the technique, when the urinary situation was stable. Two questionnaires were used: one specific for urinary disorders (QUALIVEEN(®)) and one general (SF-36(®)). RESULTS: Twenty-two patients followed this different way of bladder emptying. More than 6 months (9.3 ± 3 months on average) after first learning to use IC, the impact of urinary disorders explored by Qualiveen(®) had significantly decreased (the overall quality of life; bother with limitation; fears; feelings; Wilcoxon's test, respectively p = 0.004; 0.007; 0.02; 0.02) while the quality of life was not diminished. CONCLUSION: Intermittent catheterization (IC) in association with overall urinary management, among patients affected by MS, is well accepted and reduces the impact of urinary dysfunction on their quality of life.

Unexpected entropy response to saline spraying at the end of posterior fossa surgery: a few cases report.

The Spectral Entropy proposed to monitor the depth of anesthesia includes the State Entropy (SE) computed from the EEG (0.8-32 Hz frequency band), and the Response Entropy (RE) computed from EEG and facial muscles activity (0.5-47 Hz frequency band). We report an unexpected Entropy response to saline spraying at the end of posterior fossa surgery. Six patients undergoing scheduled functional surgery of the posterior fossa were included in this report. They were anesthetized with propofol and remifentanil using TCI and received an intubation dose of rocuronium. At the end of surgery, saline spraying, performed for hemostatic purpose and wreckage elimination, resulted in a sustained increase in RE and SE without hemodynamic modification in four patients, while no change was observed in the two other ones. In one of the responding patients, 0.1 mg kg(-1) rocuronium attenuated the Entropy response. In the two non responders, repetition of spraying or rocuronium administration did not change Entropy value. Recovery from anesthesia was comparable in all patients and none of them complained from awareness. We conclude that Entropy can increase during posterior fossa surgery in non-paralyzed patients. This response probably reflects an increase in facial muscle activity rather than a change in depth of anesthesia, as far as it can be attenuated by a small dose of rocuronium. While this hypothesis requires further investigation, these observations suggest that saline spraying may confound interpretation of Entropy during posterior fossa surgery.

[Pseudoxanthoma elasticum and obstetric epidural analgesia: report of a case]. / Analgésie épidurale obstétricale et pseudoxanthome élastique : à propos d'un cas.

Pseudoxanthoma elasticum is a rare inherited disorder of the elastic tissue characterised by multisystem manifestations. Skin, eyes, gastro-intestinal system and cardiovascular system are the major affected systems. We describe the anaesthetic management of a parturient affected by this disease.

Gender effects on intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: analysis of 1406 patients.

BACKGROUND: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNß)-1a in patients with relapsing-remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. METHODS: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNß-1a were analyzed. One analysis examined data for all patients treated with IM IFNß-1a from all studies. Separate analyses were conducted of pooled IM IFNß-1a-treated groups from all studies and pooled IFNß-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. RESULTS: All efficacy assessments indicated similar treatment effects of IM IFNß-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNß-1a between men and women. CONCLUSIONS: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNß-1a in patients with RRMS or CIS.

EFNS guidelines on diagnosis and management of neuromyelitis optica.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.

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.

[Multiple sclerosis in Haute-Garonne: an important underestimation of case numbers]. / La SEP en Haute-Garonne : une sous-estimation importante du nombre de cas.

INTRODUCTION: In France, the prevalence of multiple sclerosis is estimated between 65 and 125 patients per 100,000 inhabitants with a South-West towards North-East gradient. Nevertheless, the epidemiology of multiple sclerosis remains still imperfectly known, the recent studies being realized, either in a region of France, or from a single data source and thus suscepted not to be exhaustive. OBJECTIVE: Assessing the prevalence of the multiple sclerosis in 2005 in Haute-Garonne by matching several data sources completed by a capture-recapture method; estimating the exhaustivity of each of the sources. METHODS: The data sources were hospital data (DRG for the hospitalization, data of consultation), data of public health insurance system (main health insurance, agricultural health insurance, social welfare for self employed), and data from the MIPSEP network. The linkage was based on name, maiden name, first name, date of birth and sex and allowed a first estimation of the number of cases. Models of loglinear regression allowed estimating the total number of case and the sensitivity of each source. RESULTS: The total number of cases obtained by matching several sources of information amounted to 1549. The use of several data sources increased by 25.6 % the maximum number of patients identified with a single source of information (national health insurance, any insurance). According to the model used, the method of capture-recapture estimated the number of cases up to 1722. Therefore, this study estimated a prevalence of multiple sclerosis between 110 and 149 cases per 100,000 inhabitants in Haute-Garonne. CONCLUSION: The prevalence of the multiple sclerosis is largely underestimated in Haute-Garonne and questions the magnitude over the so-called gradient. Matching several sources of information is indispensable to improve collection of the total number of cases.

The World Congress on Treatment and Research in Multiple Sclerosis (joint meeting of ECTRIMS, ACTRIMS, LACTRIMS).

This congress was the first joint meeting for European, North and South American neurologists and neuroscientists to discuss 1 year of progress in treatment and research on multiple sclerosis (MS). More than 4500 delegates attended and with 83 oral presentations and 909 posters, it is difficult to select the highlights from this large amount of information. Probably the most interesting topic for neurologists and patients was new treatments.

Jean-Martin Charcot. 1825 to 1893.

During the 31 years of his working life, Jean-Martin Charcot built up an exceptional career in Salpétrière hospital, and was a pioneer in different fields. He developed an organized teaching and research centre, contributed to increase the medical knowledge with a systematic use of physiology and pathology besides a rigorous clinical analysis, he founded geriatry and neurology and finally tried to create a scientific psychological approach for hysteria.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.