Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.

INTRODUCTION: No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS). OBJECTIVE: To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse. METHODS: Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. RESULTS: Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. CONCLUSIONS: A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.

BACKGROUND: Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. OBJECTIVE: To compare CPM to methylprednisolone (MP) in SPMS. METHODS: Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. RESULTS: Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. CONCLUSION: Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. TRIAL REGISTRATION: Clinicaltrials.gov NCT00241254.

Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.

Rituximab as first-line therapy in neuromyelitis optica: efficiency and tolerability.

Neuromyelitis optica (NMO) is a life-threatening disease without any validated treatment strategy. Recent retrospective studies suggested the efficacy of B cell depletion without any distinction between first-line or rescue therapy. To assess whether rituximab as first-line therapy in NMO could efficiently control the occurrence of relapses. A retrospective analysis of NMO patients from NOMADMUS network found 32 patients receiving rituximab as first-line therapy. Main measures were number of relapse-free patients, changes in the annualized relapse rate (ARR), and changes in the EDSS. Tolerance was reported. At baseline, NMO patients were 45 ± 12.1 years old, with a sex ratio of 5.4, and 87.5 % of them had AQP4 antibodies. The median disease duration was 6.5 months (1-410), the mean EDSS was 5.8 ± 2.4 and the mean ARR was 3.8 ± 4.3. After rituximab with a mean follow-up of 28.7 ± 21 months, twenty-seven patients (84.3 %) were relapse free. Patients presented a 97 % decrease of ARR (p = 0.00001). EDSS decreased significantly to 3.9 ± 2.6 (p = 0.01). No relevant side effect was noted. New retrospective data are presented on RTX use in NMOSD. When used as first-line therapy RTX is highly effective and well tolerated.

Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.

Neutralizing antibodies and fatigue as predictors of low response to interferon-beta treatment in patients with multiple sclerosis.

BACKGROUND: The clinical impact of neutralizing antibodies against interferon-beta (NAb) is controversial. Their presence can lead to a decrease in interferon-beta (IFNß) efficacy. Fatigue reported in patients with multiple sclerosis (MS) may be associated with an unfavorable clinical course. We conducted a prospective multicentre study to assess the association between response to IFNß, NAb and fatigue. METHODS: Patients with relapsing-remitting MS on IFNß treatment were included. During the second year of treatment, the patients were analyzed for NAb status and non-response criteria to IFNß (number of relapses ≥1 during the follow-up period, increase in the Expanded Disability Status Scale ≥0.5). The score on the Modified Fatigue Impact Scale (MFIS pathological if score ≥35) was noted for each patient. RESULTS: Of the 176 patients included: 22.3% were NAb positive, 54.5% presented non-response criteria to IFNß, and 57.4% had a pathological MFIS score. Fatigue was increased in NAb + patients (p = 0.0014) and they were more likely to present non-response criteria to IFNß (p = 0.041) than NAb- patients. Multivariate logistic regression analysis showed that the presence of NAb was related to fatigue (p = 0.0032) and denoted disease activity in these patients (p = 0.026). CONCLUSIONS: This study demonstrates the impact of NAb on the non-clinical response to IFNß. Fatigue assessment is an indicator of IFNß responsiveness and a predictive biomarker of deterioration on patient's neurological status.

Cognitive impairment among different clinical courses of multiple sclerosis.

BACKGROUND: As of yet, no consensus has been reached regarding cognitive impairment profiles in multiple sclerosis (MS) patients based on the MS type and disease duration. The main objective of this study was to describe cognitive impairment at the early stages of MS. The secondary objective was to compare cognitive performances in patients with relapsing remitting multiple sclerosis (RRMS), secondary progressive (SP) MS and primary progressive (PP) MS. METHODS: The study included 128 MS patients and 63 healthy controls (HC). The study constituted five groups: early RR (ERR) (<3 years); late RR (LRR) (>10 years), SP, PP, and healthy Controls (HC). A neuropsychological assessment was performed including information processing speed (IPS), working memory, verbal episodic memory and executive functions. RESULTS: Compared to HC, only impairment in phonemic fluency was observed in ERR. Slowing IPS, impairment in working memory and phonemic fluency were shown in LRR. In progressive forms, deficits were observed in verbal episodic memory, in working memory, in flexibility, in semantic and phonemic fluencies, with a slowing IPS. CONCLUSION: Verbal fluency is impaired at early stage of RRMS, in this form of MS, impairment increased with MS duration, and distinct cognitive profiles were observed between chronic and progressive forms.

Acute fulminant demyelinating disease: a descriptive study of 60 patients.

BACKGROUND: Acute demyelinating encephalomyelitis (ADEM) is characterized by a severe inflammatory attack, frequently secondary to infectious events or vaccinations. To date, no clear criteria exist for ADEM, and the risk of subsequent evolution to multiple sclerosis (MS) remains unknown. OBJECTIVE: To evaluate the risk of evolution to MS after a first episode of ADEM. DESIGN: Observational, retrospective case study. SETTING: Thirteen French MS centers. Patients We retrospectively studied 60 patients with ADEM who were older than 15 years with no history suggestive of an inflammatory event who presented to MS centers from January 1, 1995, through December 31, 2005. We excluded 6 patients with multiphasic ADEM because this is a rare condition and somewhat difficult to classify. After a mean follow-up of 3.1 years (range, 1-10 years), the remaining 54 patients were then classified into 2 groups: monophasic ADEM (ADEM group) (n = 35) and clinically definite MS (MS group) (n = 19). MAIN OUTCOME MEASURES: Clinical, laboratory, magnetic resonance imaging, and follow-up data were evaluated for each group. RESULTS: Patients in the ADEM group more frequently had atypical symptoms of MS (26 of 35 [74%]) than patients with MS (8 of 19 [42%]) (P = .02). Oligoclonal bands were more frequently observed in the MS group (16 of 19 [84%]) than in the ADEM group (7 of 35 [20%]) (P <.001). Patients in the ADEM group more frequently had gray matter involvement (21 of 35 [60%]) than those in the MS group (2 of 19 [11%]) (P <.001). On the basis of these results, we consider that the presence of any 2 of the following 3 criteria could be used to differentiate patients with ADEM from those with MS in our cohort: atypical clinical symptoms for MS, absence of oligoclonal bands, and gray matter involvement. On this basis, 29 of the 35 patients in the ADEM group (83%) and 18 of the 19 patients in the MS group (95%) were classified in the appropriate category. CONCLUSIONS: Our study found some differences concerning the risk of evolution to clinically definite MS after a first demyelinating episode suggestive of ADEM. These findings led us to propose criteria that should now be tested in a larger, prospective cohort study.