Michel Clanet

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Neutralizing antibodies and efficacy of interferon beta-1a - A 4-year controlled study

Objective: To determine the incidence and clinical significance of neutralizing antibody (NAb) formation in patients with relapsing multiple sclerosis (MS) who participated in the European Interferon Beta-1a IM Dose-Comparison Study. Methods.: Patients were randomized to treatment with interferon β-1a (IFNβ-1a) 30 μg or 60 μg IM once weekly for up to 4 years. Serum samples obtained at baseline and every 3 months thereafter were screened for the presence of IFN binding antibodies by ELISA. Patients whose results were seropositive on ELISA were screened for the presence of NAbs using an antiviral cytopathic effect assay. Patients were considered to be positive for NAbs (NAb+) if the baseline NAb titer was 0 and two or more consecutive postbaseline titers were ≥20. Patients were considered to be negative for NAbs (NAb−) if the baseline NAb titer was 0 and all postbaseline NAb titers were <5. Results: The proportion of patients who became NAb+ was lower in patients who received 30 μg of IFNβ-1a than in those who received 60 μg (7/400 [1.8%] vs 19/395 [4.8%]; p = 0.02). The mean time to NAb+ status was 14.5 ± 6.2 months. Compared with patients who remained NAb−, NAb+ patients showed the following: higher relapse rates from months 12 to 48 (p = 0.04), higher rate of mean change (worsening) in Expanded Disability Status Scale score from baseline to month 48 (p = 0.01), greater number of T1 gadolinium-enhanced lesions at months 24 and 36 (p = 0.02 and 0.03), and greater accrual of new or enlarging T2 lesions from month 12 to months 24 and 36 (p = 0.05 and 0.09) Conclusions: Neutralizing antibodies (NAbs) to interferon β-1a (IFNβ-1a), as observed with other IFNβs used in the treatment of multiple sclerosis, reduce the therapeutic benefits measured by relapses and MRI activity. Data from this study also suggest NAbs to IFNβ-1a reduce treatment benefits as measured by change in Expanded Disability Status Scale score.

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 ≥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 ≤1/10. Conclusions: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

Square wave jerks in parkinsonian syndromes.

The frequency of square wave jerks (SWJ) was compared in eight patients with progressive supranuclear palsy (PSP), 25 patients with multiple system atrophy or Parkinsons disease plus (MSA/PP), 85 patients with idiopathic Parkinsons disease (PD) and 20 age-matched normal volunteers. In the control group, the mean (SD) SWJ frequency (SWJ larger than 1 degree amplitude) was 2.3 (2.4)/min. Abnormal ocular fixation (SWJ frequency greater than 10/min) was observed in a large proportion of PSP patients (7/8) and of MSA/PP patients (16/25) but in few PD patients (13/85). In the group of PD patients with abnormal ocular fixation, freezing of gait, falls and instability were more severe than in the group of PD patients with normal fixation. The study of ocular fixation may help to differentiate PD clinically from other Parkinsonian syndromes. SWJ are probably not related to the central degeneration of the dopaminergic nigrostriatal pathway observed in PD.

Rate of brain atrophy in relapsing MS decreases during treatment with IFNβ-1a

Objective: To determine the time course of brain atrophy during treatment with once-weekly IM interferon β-1a (IFNβ-1a). Methods: The MRI cohort (n = 386) of the European IFNβ-1a dose comparison study in relapsing multiple sclerosis (MS) was analyzed. In addition to baseline and three annual scans, a frequent subgroup (n = 138) had two scans before treatment initiation and scans at months 4, 5, 6, 10, and 11. Brain parenchymal fraction (BPF), a normalized measure of whole-brain atrophy, and volume of Gd-enhancing lesions (T1Gd) and T2 hyperintense lesions (T2LL) were evaluated. Results: BPF decrease was −0.686% (first year), −0.377% (second year), and −0.378% (third year). Analysis of the frequent subgroup showed that 68% of the first-year BPF decrease occurred during the first 4 months of treatment. This change was paralleled by a drop in T1Gd and T2LL. In the frequent subgroup, an annualized atrophy rate was determined by a regression slope for the pretreatment period and from month 4 of treatment onward. Annualized pretreatment rate (−1.06%) was significantly higher than the under-treatment rate (−0.33%). Conclusions: In the first year of treatment with anti-inflammatory agents, atrophy measurements are possibly confounded by resolution of inflammatory edema or more remote effects of previous damage to the CNS. The atrophy rate reduction observed after treatment month 4 may reflect a beneficial but partial effect of interferon β-1a and was sustained over the 3-year study period.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study

Background: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. Objective: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Methods: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5–7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6–7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. Results: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. Conclusion: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.

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.

Tumor necrosis factor polymorphisms in multiple sclerosis: No additional association independent of HLA

In order to investigate whether genes coding for tumor necrosis factors (TNF) contribute to the pathogenesis of multiple sclerosis (MS) and also whether they have a non-random association with the MS associated HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype, 40 MS patients and their parents were characterized at four polymorphic loci in the region of the TNF genes: a NcoI RFLP and three microsatellites. We were able to determine the parental haplotypes and used those which were not transmitted to the proband as controls. Fifty percent of the HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotypes carried the TNFc1-n2-a11-b4 allelic combination in both the patient and the control groups. However, there was no association of any of these TNF polymorphisms with MS, independent of that already described for the class II region. This, with the lack of association of DP alleles with MS, effectively marks the boundaries of the MS associated haplotype.