Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders

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

Decrease of blood anti-α1,3 Galactose Abs levels in multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients.

The etiology of multiple sclerosis (MS) remains elusive. Among the possible causes, the increase of anti-Neu5Gc antibodies during EBV primo-infection of Infectious mononucleosis (IMN) may damage the integrity of the blood-brain barrier facilitating the transfer of EBV-infected B cells and anti-EBV T cell clones in the brain. We investigated the change in titers of anti-Neu5Gc and anti-α1,3 Galactose antibodies in 49 IMN, in 76 MS, and 73 clinically isolated syndrome (CIS) patients, as well as age/gender-matched healthy individuals. Anti-Gal and anti-Neu5Gc are significantly increased during IMN (p=0.02 and p<1.10-4 respectively), but not in acute CMV primo-infection. We show that, whereas there was no change in anti-Neu5Gc in MS/CIS, the two populations exhibit a significant decrease in anti-Gal (combined p=2.7.10-3), in contrast with patients with non-MS/CIS central nervous system pathologies. Since anti-Gal result from an immunization against α1,3 Gal, lacking in humans but produced in the gut, our data suggest that CIS and MS patients have an altered microbiota or an altered response to this microbiotic epitope.

Efficacy of rituximab in refractory neuromyelitis optica.

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

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

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.

Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis.

BACKGROUND: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. OBJECTIVE: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. METHODS: We conducted differential analysis of the CSF proteome from control and relapsing-remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. RESULTS: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. CONCLUSIONS: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS.

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.

Multiple sclerosis and pregnancy.

The question of pregnancy in patients with multiple sclerosis is regularly raised due to the prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of pregnancy on the disease. As with topics of previous works, the formal expert consensus method was used. The working group was composed of hospital-based and private practice neurologists. The reading group was composed of neurologists, anaesthetists and obstetricians. Each recommendation is presented with the relevant level of consensus.

[Nosology and etiologies of acute longitudinally extensive transverse myelitis]. / Cadre nosologique et stratégie diagnostique de la myélite aiguë transverse longitudinalement étendue.

Acute transverse myelitis had many names and definitions, based primarily on clinical criteria. The role of MRI in the exploration of myelitis has increased recently after the individualization of neuromyelitis optica (NMO) in 2004. This approach has enabled clarification of the diagnostic and prognostic value of acute longitudinally extensive transverse myelitis (LETM), defined by an extensive T2 lesion affecting three vertebral segments in the sagittal plane. The limitations of this definition, the multiplicity of terms used to characterize it as well as the large number of etiologies associated with it led our group of experts to clarify its etiology and nosology. We conducted a national survey on this subject in order to propose a new definition of LETM. Additional first- and second-intention examinations were determined according to the clinical context. Infectious/para-infectious, inflammatory or paraneoplastic causes can thus be identified. To determine within a short time the cause of LETM is essential, since most of its causes are severe and require urgent treatment.

[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.

Recommendations for useful serum testing with suspected multiple sclerosis.

Several practical questions useful for management of patients with multiple sclerosis remain unanswered in the current scientific literature. Decisions are often made individually, without the support of solid scientific evidence. In order to facilitate concurring practices, we present guidelines concerning useful serum exams for the diagnosis of multiple sclerosis. The methodology used was that of a formal expert consensus. A working group performed a systematic analysis of the literature, taking into account both previously existing recommendations and original articles, and then drafted guideline proposals. These proposals were subjected to the critical review of a rating group. Three written drafts, followed by rating of the guideline proposals culminated in a consensual document, which was submitted for review to a second independent reading group. The final resulting document provided the material for the present article, in which each recommendation is presented with its grade according to the level of proof or its degree of consensus in the absence of scientific proof.

When does multiple sclerosis start? Three case reports and a review of the literature.

When does multiple sclerosis start? Multiple sclerosis (MS) is a major cause of disability in young adults. Its pathogenesis is not fully understood, although a large body of evidence suggests an autoimmune pattern. Autoreactive immune cells cross the blood-brain barrier to attack myelin and axons, thus leading to MS lesions. Considering the uncertainty concerning the mechanisms, however, it is hardly surprising that it is still not possible to pinpoint exactly when the disease starts. Yet, the question is of major importance for both patients and physicians. Faced with the impossibility of detecting the actual time of disease onset, the scientific community has nonetheless made great efforts to diagnose the disease as early as possible. In 1983, Poser defined relapsing-remitting MS as a chronic disease with at least two relapses. Further criteria (McDonald) allowed even earlier diagnosis. In the present review, which also includes three case reports, the earliest possible timepoint for making the MS diagnosis is discussed.

[Pathophysiology of spasticity]. / Physiopathologie de la spasticité

The term "spasticity" describes the velocity-dependent increase in tonic stretch reflexes. The symptom is commonly seen in patients with injury to the central nervous system. It is rarely isolated but, instead, part of a set of symptoms that is sometimes confusing. However, the pathophysiology of the symptom has evolved over the past three decades, and it is now considered part of a global process that includes not only spinal reflex loop modifications, but also changes in the biomechanical properties of muscle fibers. Finally, recent studies of changes in the membrane properties of motor neurons and the occurrence of plateau potential have opened new perspectives. This review aims to describe these new pathophysiological models.

Recommendations for the management of multiple sclerosis relapses.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes of useful serum testing with suspected multiple sclerosis, detection and management of cognitive disorders early in the course of the disease, and definition and early management of the disease, GRESEP wanted to develop recommendations on the management of multiple sclerosis (MS) relapse. Following a systematic analysis of the literature, the procedure of formal expert consensus enabled consensual recommendations among a working group, a rating group and a reading group to be written. Each recommendation is presented with its grade or the degree of consensus that it was accorded.

Recommendations for a definition of multiple sclerosis in support of early treatment.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques: GRESEP), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes on useful serum testing with suspected multiple sclerosis, as well as the detection and management of cognitive disorders early in the course of the disease, the subject of the present work is the early definition and early treatment of the disease. Following a systematic literature review, a RAND/UCLA appropriateness-derived method enabled consensual recommendations among a working group, a rating group and a reading group to be developed and formulated. Each recommendation is presented with the degree of consensus that it was accorded.

Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis.

The aim of the Multiple Sclerosis Think Tank (Groupe de réflexion sur la sclérose en plaques [GRESEP]) is to prescribe recommendations following a systematic literature search and using a Rand Corporation and California University (RAND/UCLA) appropriateness derived method, in response to practical questions that are raised in the management of patients with multiple sclerosis (MS). The topics of this working program were chosen because they were not addressed in the French recommendations and because of the few data in the literature that enabled practices to be based on validated data. Following the theme on useful serum testing with suspected multiple sclerosis, the subjects of the present work concern the detection and management of cognitive impairment in the beginning stages of the disease course. Two clinical questions were asked: which complementary exams (besides physical examination and neuropsychological tests) would help in the screening of cognitive impairment at the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? The recommendations are the result of a consensus amongst a working group, a rating group and a reading group comprised of hospital neurologists involved in the management of patients with multiple sclerosis. Each recommendation is presented with the degree of consensus that it was accorded.

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.

Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis.

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis.

Most of the published works so far have aimed at finding genes associated with multiple sclerosis (MS) susceptibility. Very few studies have attempted to correlate disease features with DNA variants. In a well-characterized sample (651 patients) representative of multiple sclerosis natural history, we engaged a comprehensive study of the role of human leukocyte antigen (HLA) in the course of the disease. We investigated the role of HLA-DRB1*15 allele in samples stratified according to severity evaluated by the Multiple Sclerosis Severity Score (MSSS), time to reach EDSS 6.0 and disease type. We found that HLA-DRB1*15 genotype does not influence MS severity even among patients presenting with a given type of the disease. However, we show for the first time that HLA-DRB1*15 allele modulates the course of MS for relapsing-remitting (RR) onset patients likely by precipitating the secondary progressive (SP) phase.

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.