Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune…

Alpha-Synchronized Stimulation of the Dorsolateral Prefrontal Cortex (DLPFC) in Major Depression: A Proof-of-Principle EEG-TMS Study

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) shows therapeutic potential in pharmaco-resistant patients with major depression. However, clinical efficacy is limited by high inter-individual variability and low response rates. One possible strategy to improve the effect size and consistency may be brain state dependent brain stimulation, i.e. coupling of TMS pulses to the endogenous brain states as reflected by the instantaneous oscillatory brain activity. Here we present findings from a proof-of-principle study of alpha-oscillation synchronized brain stimulation of the frontal cortex in patients with major depression (…

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.

TMS-EEG signatures of glutamatergic neurotransmission in human cortex

AbstractNeuronal activity in the brain is regulated by an excitation-inhibition balance. Glutamate is the main excitatory neurotransmitter. Transcranial magnetic stimulation (TMS) evoked electroencephalographic (EEG) potentials (TEPs) represent a novel way to quantify pharmacological effects on neuronal activity in the human cortex. Here we tested TEPs under the influence of a single oral dose of two anti-glutamatergic drugs, perampanel, an AMPA-receptor antagonist, and dextromethorphan, an NMDA-receptor antagonist, and nimodipine, an L-type voltage-gated calcium channel blocker in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled, crossover design. Single-pulse TM…

Supplement_TAND_050219 – Supplemental material for Longitudinal cortical network reorganization in early relapsing–remitting multiple sclerosis

Supplemental material, Supplement_TAND_050219 for Longitudinal cortical network reorganization in early relapsing–remitting multiple sclerosis by Vinzenz Fleischer, Nabin Koirala, Amgad Droby, René-Maxime Gracien, Ralf Deichmann, Ulf Ziemann, Sven G. Meuth, Muthuraman Muthuraman, Frauke Zipp and Sergiu Groppa in Therapeutic Advances in Neurological Disorders

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

Abstract Background We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. Methods In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. Findings Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (R…

Musical Sonification of Arm Movements in Stroke Rehabilitation Yields Limited Benefits.

Neurologic music therapy in rehabilitation of stroke patients has been shown to be a promising supplement to the often strenuous conventional rehabilitation strategies. The aim of this study was threefold: (i) replicate results from a previous study with a sample from one clinic (henceforth called Site 1; N = 12) using an already established recording system, and (ii) conceptually replicate previous findings with a less costly hand-tracking system in Site 2 (N = 30), and (iii) compare both sub-studies' outcomes to estimate the efficiency of neurologic music therapy. Stroke patients in both sites were randomly assigned to treatment or control groups and received daily training of guided sequ…

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been repor…

Effects of antiepileptic drugs on cortical excitability in humans: A TMS-EMG and TMS-EEG study.

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP a…

P 56 tDCS shows no effects on motor cortex excitability at rest

Introduction Transcranial direct current stimulation (tDCS) is a widely used technique in research and clinics. However, the underlying physiological mechanisms are not yet clear. Modeling studies suggest that the electric field during tDCS is dominated by a tangential component which predominantly modifies active synaptic connections ( Radman et al., 2007 ). We have previously shown that tDCS with an increased tangential compared to the conventional montage introduced by Nitsche and Paulus (2000) , suppresses the effects of paired associative stimulation of the supplementary motor area and the primary motor cortex (PASSMA-M1) independent of tDCS polarity (Faber et al., under submission). H…

Treatment choices and neuropsychological symptoms of a large cohort of early MS

ObjectiveTo assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS.MethodsThe German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms.ResultsOf 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06–40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded …

A degraded state of consciousness in healthy awake humans?

Low frequency and rare coding variation contributes to multiple sclerosis risk

AbstractMultiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including &gt;230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independe…

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatri…

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

AbstractBackgroundMultiple sclerosis (MS) disease risk is associated with reduced sun exposure. This study assessed the relationship between measures of sun-exposure (vitamin D (vitD), latitude) and MS disease severity, the mechanisms of action, and effect-modification by medication and sun-sensitivity associated MC1R variants.MethodsTwo multi-center cohort studies (nNationMS=946, nBIONAT=991). Outcomes were the multiple sclerosis severity score (MSSS) and the number of Gd-enhancing lesion (GELs). RNAseq of four immune cell populations before and after UV-phototherapy of five MS patients.ResultsHigh serum vitD was associated with reduced MSSS (PNationMS=0.021; PBIONAT=0.007) and reduced ris…