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.

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.

[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.

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.

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.

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.

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.

[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.

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France?

Early onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000.

Levorotatory form of 5-hydroxytryptophan in Friedreich's ataxia. Results of a double-blind drug-placebo cooperative study.

OBJECTIVE: To study the effect of the levorotatory form of 5-hydroxytryptophan on the cerebellar symptoms of Friedreich's ataxia. DESIGN: Cooperative double-blind study of the levorotatory form of 5-hydroxytryptophan vs placebo. SETTING: Twelve centers in research hospitals. PATIENTS: Twenty-six patients were included; 19 completed the study (mean +/- SD age of patients, 25.9 +/- 8.1 years). Of these 19 patients, eight were treated with placebo and 11 were treated with the drug. MAIN OUTCOME MEASURES: A semiquantitative scale for kinetic and static ("postural") cerebellar functions and quantitative measurements of time in standard tests that evaluated stance, speech, writing, and drawing. RESULTS: In the active treatment group, a significant decrease of the kinetic score was observed (P = .03), indicating an improvement in coordination. CONCLUSIONS: These results demonstrated that the levorotatory form of 5-hydroxytryptophan is able to modify significantly the cerebellar symptoms in patients with Friedreich's ataxia. However, the effect is only partial and not clinically major.

A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.

BACKGROUND: Interferon beta-1a (IFNbeta-1a; Avonex) is effective for the treatment of relapsing MS; however, the optimal dose of IFNbeta-1a is not known. OBJECTIVE: To determine whether IFNbeta-1a 60 micro g IM once weekly is more effective than IFNbeta-1a 30 micro g IM once weekly in reducing disability progression in relapsing MS. METHODS: In a double-blind, parallel-group, dose-comparison study, 802 patients with relapsing MS from 38 centers in Europe were randomized to IFNbeta-1a 30 micro g (n = 402) or 60 micro g (n = 400) IM once weekly for >/=36 months. The primary endpoint was disability progression, defined as time to a sustained increase of >/=1.0 point on the Expanded Disability Status Scale (EDSS) persisting for 6 months. Additional endpoints included relapses, MRI, safety, immunogenicity, and subgroup analyses of disability progression. RESULTS: Both groups showed equal rates of disability progression (hazard ratio, 0.96; 95% CI, 0.77 to 1.20; p = 0.73). In both groups the proportion of subjects with progression of disability by 36 months estimated from Kaplan-Meier curves was 37%. No dose effects were observed on any of the secondary clinical endpoints. Only one MRI measure at one time point, number of new or enlarging T2 lesions at month 36 compared with month 24, showed a difference favoring the 60- micro g dose. Both doses were well tolerated; however, slightly higher incidences of flulike symptoms and muscle weakness were observed in the 60- micro g group. The incidences of neutralizing antibodies (titers >/= 20) were 2.3% in the 30- micro g group and 5.8% in the 60- micro g group. CONCLUSION: There was no difference between IFNbeta-1a 30 micro g and 60 micro g IM in clinical or MRI measures.

Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.

Peduncular 'rubral' tremor and dopaminergic denervation: a PET study.

Lesions causing so-called rubral tremors frequently involve the substantia nigra or the nigrostriatal fibers, suggesting dopaminergic denervation as possibly contributory. We examined this hypothesis using PET and [18F]-fluorodopa in six patients with a contralateral tremor following a peduncular lesion. The denervation revealed by PET was even more marked than in severe parkinsonian patients. All patients showed partial to complete improvement with levodopa therapy. PET evaluation of D2-receptors with [76Br]bromolisuride showed no asymmetry of the D2 binding despite the important asymmetry of 18F-fluorodopa uptake. Our results indicate an important involvement of the nigral dopaminergic system in peduncular tremors that appears to be independent of postsynaptic dopamine receptors.

Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group.

BACKGROUND: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease. OBJECTIVE: To determine the contribution of familial factors to the clinical expression of MS. METHODS: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features). RESULTS: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03). CONCLUSION: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).