Dimethyl fumarate treatment of primary progressive multiple sclerosis: results of an open-label extension study.

INTRODUCTION: Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL]). AIM: To investigate the effects of dimethyl fumarate treatment in the open-label extension phase of the trial (week 48-96), where all patients were treated with DMF. METHODS: Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new/enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures. RESULTS: Forty-two patients entered the open-label treatment phase, and 33 patients (61%) had complete data sets at week 96. The remaining 39% did not complete the trial and were not evaluated at week 96. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progression was observed for 14 patients (45%). Interestingly, another 15 patients (46%) had improvement in one or more of these domains. Applying a cut-off of 8 points, 2 (6%) patients worsened on SDMT, 25 (78%) did not change, and 5 (16%) improved. CONCLUSIONS: Dimethyl fumarate treatment showed no effects on neither clinical nor MRI outcomes or changes in serum concentrations of NFL. An expected number of patients showed evidence of progression on standard clinical scales; however, this was matched by an equal number of patients improving. The reasons for the physical improvement in an unexpectedly high proportion of patients must be addressed in future studies.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVE: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). METHODS: In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. RESULTS: Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. DISCUSSION: Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov identifier NCT02959658. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.

Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations.

We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left-sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.