神经领域-神经系统自身免疫性疾病方向

METHODS::The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody-positive relapsing neuroinflammatory disease. This was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo [interquartile range {IQR} 7y 2mo-12y 5mo], median follow-up 2y 1mo [IQR 1y 7mo-2y 6mo]) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell-based methods. Median clinical follow-up after rituximab induction was 2 years (IQR 1y 7mo-2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0-0). After rituximab, two patients relapsed during B-cell suppression and four showed clinical or radiological disease recurrences at B-cell reconstitution. Mild-to-moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life-threatening events. Rituximab-induced B-cell suppression was associated with absence of relapses in 10 patients who were MOG-positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population. WHAT THIS PAPER ADDS: Rituximab appears to control disease in most anti-myelin oligodendrocyte glycoprotein-positive patients with relapsing neuroinflammatory disease. Rituximab was associated with transitory, mild-to-moderate infusion-related effects. Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia. No opportunistic infections were observed.

METHODS:OBJECTIVES:To examine the feasibility, reliability, granularity, and convergent validity of a video-based pairwise comparison technique that uses algorithmic support to enable automated rating of motor dysfunction in patients with multiple sclerosis (MS). DESIGN:Feasibility and larger cross-sectional cohort study. SETTING:The outpatient clinic of 2 specialist university medical centers. PARTICIPANTS:Selected sample from a cohort of patients with MS participating in the Assess MS study (N=42). Videos were randomly drawn from each strata of the ataxia severity-degrees as defined in the Expanded Disability Status Scale (EDSS). In Basel: 19 videos of 17 patients (mean age, 43.4±11.6y; 10 women). In Amsterdam: 50 videos of 25 patients (mean age, 50.0±10.0y; 15 women). INTERVENTIONS:Not applicable. MAIN OUTCOME MEASURES:In each center, neurologists (n=13; n=10) viewed pairs of videos of patients performing standardized movements (eg, finger-to-nose test) to assess relative performance. A comparative assessment score was calculated for each video using the TrueSkill algorithm and analyzed for intrarater (test-retest; ratio of agreement) and interrater reliability (intraclass correlation coefficient [ICC] for absolute agreement) and convergent validity (Spearman ρ). Granularity was estimated from the average difference in comparative assessment scores at which 80% of neurologists considered performance to be different. RESULTS:Intrarater reliability was excellent (median ratio of agreement≥0.87). The comparative assessment scores calculated from individual neurologists demonstrated good-excellent ICCs for interrater reliability (0.89; 0.71). The comparative assessment scores correlated (very) highly with their Neurostatus-EDSS equivalent (ρ=0.78, P<.001; ρ=0.91, P<.05), suggesting a more fine-grained rating. CONCLUSIONS:Video-based pairwise comparison of motor dysfunction allows for reliable and fine-grained capturing of clinical judgment about neurologic performance, which can contribute to the development of a consistent quantified metric of motor ability in MS.

METHODS:BACKGROUND:Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20-70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. CASE REPORT:A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. CONCLUSION:Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN.

METHODS:PURPOSE:To evaluate the associated factors of conversion of ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) among patients with seropositive acetylcholine receptor antibody (AchR Ab). DESIGN:Retrospective cohort study. METHODS:Setting: Retrospective chart review. PATIENT:Seventy-one OMG patients with seropositive AchR Ab presented during July 2009 and December 2016. The exclusion criteria were patients who (1) first presented with GMG, (2) were unable to identify the time of onset of OMG or GMG, (3) were unable to provide information about previous treatments before the onset of GMG, and (4) had incomplete or lost medical records. OBSERVATION PROCEDURE:We collected demographic and clinical characteristics, including onset of OMG and GMG, presence of other autoimmune disorders, history of smoking, presence of thymic abnormalities, and medications received. MAIN OUTCOME MEASURES:Conversion to GMG and time to conversion. RESULTS:Thirty-six patients experienced conversion to GMG. Overall incidence of GMG was 14 (95% confidence interval [CI] 10.09-19.4) per 100 patient-years. Probability of conversion at 2 years was .37 (95% CI .27-.49). Overall median conversion time was 4.97 years. Cox proportional hazard model showed that risk factors were female sex (HR 2.52, 95% CI 1.04-6.10), history of smoking (HR 3.42, 95% CI 1.40-8.45), and thymic abnormalities (HR 1.82, 95% CI 0.91-3.67). Protective factors against conversion to GMG were receiving immunosuppressive agents (HR 0.42, 95% CI 0.19-0.97) and pyridostigmine (HR 0.37, 95% CI 0.14-0.93). CONCLUSIONS:OMG patients with seropositive AchR Ab should be informed that taking pyridostigmine and/or immunosuppressive agents as well as smoking cessation might prevent conversion to GMG.

METHODS:OBJECTIVE:To investigate possible changes in the rate of conducted neuropsychological assessments and rehabilitation process for patients with multiple sclerosis (pwMS) during the last two decades. The change in the rate of vocational rehabilitation process was also evaluated. BACKGROUND:Cognitive deficits are frequent among pwMS and negatively affect patients' working ability and quality of life. Preliminary evidence suggests that neuropsychological rehabilitation positively affects cognitive symptoms. Vocational approaches are widely recommended for pwMS. METHODS:A retrospective survey of all multiple sclerosis (MS) patients diagnosed and treated at the Department of Neurology in Kanta-Häme Central Hospital over the period 1988-2013 was conducted using hospital records. The rate of neuropsychological assessment and rehabilitation processes as well as vocational rehabilitation processes were evaluated. RESULTS:A total of 417 pwMS were identified. A neuropsychological assessment was performed for 104 (24.9%) of these patients, of whom 21 (20.2%) were evaluated between 1988 and 1999 and 83 (79.8%) between 2000 and 2013. Of the 417 patients, eight (1.9%) received neuropsychological rehabilitation, each of these after the year 2000. Only 25 (6.0%) of the 417 pwMS received vocational rehabilitation. Fourteen (56.0%) of the 25 patients received vocational rehabilitation between 1988 and 1999 and 11 (44.0%) between 2000 and 2013. CONCLUSIONS:Neuropsychological assessment has been a rarity in MS in Finland, but a marked increase in frequency has occurred since the year 2000. Although understanding of MS-related cognitive impairment and its impact on working ability has increased, the rate of neuropsychological and vocational rehabilitation has remained low.

METHODS:OBJECTIVE:To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS:From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS:Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS:This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

METHODS:OBJECTIVES:We aimed to assess cortical damage in patients with relapsing-remitting multiple sclerosis (RRMS)/clinically isolated syndrome (CIS) with a multiparametric, surface-based quantitative MRI (qMRI) approach and to evaluate the correlation of imaging-derived parameters with cognitive scores, hypothesizing that qMRI parameters are correlated with cognitive abilities. METHODS:Multiparametric qMRI-data (T1, T2 and T2* relaxation times and proton density (PD)) were obtained from 34 patients/24 matched healthy control subjects. Cortical qMRI values were analyzed on the reconstructed cortical surface with Freesurfer. We tested for group differences of cortical microstructural parameters between the healthy and patient collectives and for partial Pearson correlations of qMRI parameters with cognitive scores, correcting for age. RESULTS:Cortical T2-/T2*-/PD values and four cognitive parameters differed between groups (p ≤ 0.046). These cognitive scores, reflecting information processing speed, verbal memory, visuospatial abilities, and attention, were correlated with cortical T2 (p ≤ 0.02) and T2* (p ≤ 0.03). Cortical changes appeared heterogeneous across the cortex and their distribution differed between the parameters. Vertex-wise correlation of T2 with neuropsychological parameters revealed specific patterns of cortical damage being related to distinct cognitive deficits. CONCLUSIONS:Microstructural changes are distributed heterogeneously across the cortex in RRMS/CIS. QMRI has the potential to provide surrogate parameters for the assessment of cognitive impairment in these patients for clinical studies. The characteristics of cognitive impairment in RRMS might depend on the distribution of cortical changes. KEY POINTS:• The goal of the presented study was to investigate cortical changes in RRMS/CIS and their relation to the cognitive status, using multiparametric quantitative MRI. • Cortical T2, T2*, and PD increases observed in patients appeared heterogeneous across the cortex and their distribution differed between the parameters. • Vertex-wise correlation of T2 with neuropsychological scores revealed specific patterns of cortical changes being related to distinct cognitive deficits.

METHODS::New so-called immune reconstitution therapies (IRTs) have the potential to induce long-term or even permanent drug-free remission in people with multiple sclerosis (MS). These therapies deplete components of the immune system with the aim of allowing the immune system to renew itself. Haematopoietic stem cell transplantation, the oral formulation cladribine and the monoclonal antibodies alemtuzumab, rituximab and ocrelizumab are frequently categorized as IRTs. However, the evidence that IRTs indeed renew adaptive immune cell repertoires and rebuild a healthy immune system in people with MS is variable. Instead, IRTs might foster the expansion of those cells that survive immunosuppression, and this expansion could be associated with acquisition of new functional phenotypes. Understanding immunological changes induced by IRTs and how they correlate with clinical outcomes will be instrumental in guiding the optimal use of immune reconstitution as a durable therapeutic strategy. This Perspectives article critically discusses the efficacy and potential mechanisms of IRTs in the context of immune system renewal and durable disease remission in MS.

METHODS:OBJECTIVES:Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS:Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS:Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS:Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.

METHODS:OBJECTIVE:Clinical outcomes in multiple sclerosis (MS) are highly variable. We aim to determine the long-term clinical outcomes in MS, and to identify early prognostic features of these outcomes. METHODS:One hundred thirty-two people presenting with a clinically isolated syndrome were prospectively recruited between 1984 and 1987, and followed up clinically and radiologically 1, 5, 10, 14, 20, and now 30 years later. All available notes and magnetic resonance imaging scans were reviewed, and MS was defined according to the 2010 McDonald criteria. RESULTS:Clinical outcome data were obtained in 120 participants at 30 years. Eighty were known to have developed MS by 30 years. Expanded Disability Status Scale (EDSS) scores were available in 107 participants, of whom 77 had MS; 32 (42%) remained fully ambulatory (EDSS scores ≤3.5), all of whom had relapsing-remitting MS (RRMS), 3 (4%) had RRMS and EDSS scores >3.5, 26 (34%) had secondary progressive MS (all had EDSS scores >3.5), and MS contributed to death in 16 (20%). Of those with MS, 11 received disease-modifying therapy. The strongest early predictors (within 5 years of presentation) of secondary progressive MS at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at 1 year. INTERPRETATION:Thirty years after onset, in a largely untreated cohort, there was a divergence of MS outcomes; some people accrued substantial disability early on, whereas others ran a more favorable long-term course. These outcomes could, in part, be predicted by radiological findings from within 1 year of first presentation. ANN NEUROL 2020;87:63-74.