Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.

BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018. OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.

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 reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica.

BACKGROUND: In contrast to multiple sclerosis (MS), lesions in neuromyelitis optica (NMO) frequently contain neutrophils. However, the phenotypic profile of neutrophils in these two distinct pathologies remains unknown. OBJECTIVE: Our aim is to better understand the potential contribution of neutrophils to NMO and MS pathology. METHODS: We performed the first functional analysis of blood neutrophils in NMO and MS, including evaluation of neutrophil immune response (fMLP receptor, TLR2), chemotaxis and migration (CXCR1, CD62L, CD43), regulation of complement (CD46, CD55, CD59), respiratory burst, phagocytosis and degranulation. RESULTS: Compared with healthy controls (HC), neutrophils in NMO and MS show an activated phenotype characterized by an increased surface expression of TLR2 and fMLP receptor. However, contrary to MS neutrophils, NMO neutrophils show reduced adhesion and migratory capacity as well as decreased reduced production of reactive oxygen species (respiratory burst) and degranulation. CONCLUSION: Although NMO and MS neutrophils display an activated phenotype in comparison with HC, NMO neutrophils show a compromised functionality when compared with MS patients. These results suggest a distinct functional profile of neutrophils in MS and NMO.

Investigating the metabolite signature of an altered oral microbiota as a discriminant factor for multiple sclerosis: a pilot study.

In multiple sclerosis (MS), alterations of the gut microbiota lead to inflammation. However, the role of other microbiomes in the body in MS has not been fully elucidated. In a pilot case-controlled study, we carried out simultaneous characterization of faecal and oral microbiota and conducted an in-depth analysis of bacterial alterations associated with MS. Using 16S rRNA sequencing and metabolic inference tools, we compared the oral/faecal microbiota and bacterial metabolism pathways in French MS patients (n = 14) and healthy volunteers (HV, n = 21). A classification model based on metabolite flux balance was established and validated in an independent German cohort (MS n = 12, HV n = 38). Our analysis revealed decreases in diversity indices and oral/faecal compartmentalization, the depletion of commensal bacteria (Aggregatibacter and Streptococcus in saliva and Coprobacter and Roseburia in faeces) and enrichment of inflammation-associated bacteria in MS patients (Leptotrichia and Fusobacterium in saliva and Enterobacteriaceae and Actinomyces in faeces). Several microbial pathways were also altered (the polyamine pathway and remodelling of bacterial surface antigens and energetic metabolism) while flux balance analysis revealed associated alterations in metabolite production in MS (nitrogen and nucleoside). Based on this analysis, we identified a specific oral metabolite signature in MS patients, that could discriminate MS patients from HV and rheumatoid arthritis patients. This signature allowed us to create and validate a discrimination model on an independent cohort, which reached a specificity of 92%. Overall, the oral and faecal microbiomes were altered in MS patients. This pilot study highlights the need to study the oral microbiota and oral health implications in patients with autoimmune diseases on a larger scale and suggests that knowledge of the salivary microbiome could help guide the identification of new pathogenic mechanisms associated with the microbiota in MS patients.

Postural Sway in Parkinson's Disease and Multiple Sclerosis Patients During Tasks With Different Complexity.

Neurological diseases are associated with static postural instability. Differences in postural sway between neurological diseases could include "conceptual" information about how certain symptoms affect static postural stability. This information might have the potential to become a helpful aid during the process of finding the most appropriate treatment and training program. Therefore, this study investigated static postural sway performance of Parkinson's disease (PD) and multiple sclerosis (MS) patients, as well as of a cohort of healthy adults. Three increasingly difficult static postural tasks were performed, in order to determine whether the postural strategies of the two disease groups differ in response to the increased complexity of the balance task. Participants had to perform three stance tasks (side-by-side, semi-tandem and tandem stance) and maintain these positions for 10 s. Seven static sway parameters were extracted from an inertial measurement unit that participants wore on the lower back. Data of 47 healthy adults, 14 PD patients and 8 MS patients were analyzed. Both healthy adults and MS patients showed a substantial increase in several static sway parameters with increasingly complex stance tasks, whereas PD patients did not. In the MS patients, the observed substantial change was driven by large increases from semi-tandem and tandem stance. This study revealed differences in static sway adaptations between PD and MS patients to increasingly complex stance tasks. Therefore, PD and MS patients might require different training programs to improve their static postural stability. Moreover, this study indicates, at least indirectly, that rigidity/bradykinesia and spasticity lead to different adaptive processes in static sway.

Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging.

BACKGROUND: Mean kurtosis (MK), one of the parameters derived from diffusion kurtosis imaging (DKI), has shown increased sensitivity to tissue microstructure damage in several neurological disorders. METHODS: Thirty-seven patients with relapsing-remitting MS and eleven healthy controls (HC) received brain imaging on a 3T MR scanner, including a fast DKI sequence. MK and mean diffusivity (MD) were measured in the white matter of HC, normal-appearing white matter (NAWM) of MS patients, contrast-enhancing lesions (CE-L), FLAIR lesions (FLAIR-L) and black holes (BH). RESULTS: Overall 1529 lesions were analyzed, including 30 CE-L, 832 FLAIR-L and 667 BH. Highest MK values were obtained in the white matter of HC (0.814 ± 0.129), followed by NAWM (0.724 ± 0.137), CE-L (0.619 ± 0.096), FLAIR-L (0.565 ± 0.123) and BH (0.549 ± 0.12). Lowest MD values were obtained in the white matter of HC (0.747 ± 0.068 10-3mm2/sec), followed by NAWM (0.808 ± 0.163 10-3mm2/sec), CE-L (0.853 ± 0.211 10-3mm2/sec), BH (0.957 ± 0.304 10-3mm2/sec) and FLAIR-L (0.976 ± 0.35 10-3mm2/sec). While MK differed significantly between CE-L and non-enhancing lesions, MD did not. CONCLUSION: MK adds predictive value to differentiate between MS lesions and might provide further information about diffuse white matter injury and lesion microstructure.

Development of Cortical Lesion Volumes on Double Inversion Recovery MRI in Patients With Relapse-Onset Multiple Sclerosis.

Background and Objective: In multiple sclerosis (MS) patients, Double Inversion Recovery (DIR) magnetic resonance imaging (MRI) can be used to detect cortical lesions (CL). While the quantity and distribution of CLs seems to be associated with patients' disease course, literature lacks frequent assessments of CL volumes (CL-V) in this context. We investigated the reliability of DIR for the longitudinal assessment of CL-V development with frequent follow-up MRIs and examined the course of CL-V progressions in relation to white-matter lesions (WML), contrast enhancing lesions (CEL) and clinical parameters in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Methods: In this post-hoc analysis, image- and clinical data of a subset of 24 subjects that were part of a phase IIa clinical trial on the "Safety, Tolerability and Mechanisms of Action of Boswellic Acids in Multiple Sclerosis (SABA)" (ClinicalTrials.gov, NCT01450124) were included. The study was divided in three phases (screening, treatment, study-end). All patients received 12 MRI follow-up-examinations (including DIR) during a 16-months period. CL-Vs were assessed for each patient on each follow-up MRI separately by two experienced neuroradiologists. Results of neurological screening tests, as well as other MRI parameters (WML number and volume and CELs) were included from the SABA investigation data. Results: Inter-rater agreement regarding CL-V assessment over time was good-to-excellent (κ = 0.89). Mean intraobserver variability was 1.1%. In all patients, a total number of 218 CLs was found. Total CL-Vs of all patients increased during the 4 months of baseline screening followed by a continuous and significant decrease from month 5 until study-end (p < 0.001, Kendall'W = 0.413). A positive association between WML volumes and CL-Vs was observed during baseline screening. Decreased CL-V were associated with lower EDSS and also with improvements of SDMT- and SCRIPPS scores. Conclusion: DIR MRI seems to be a reliable tool for the frequent assessment of CL-Vs. Overall CL-Vs decreased during the follow-up period and were associated with improvements of cognitive and disability status scores. Our results suggest the presence of short-term CL-V dynamics in RRMS patients and we presume that the laborious evaluation of lesion volumes may be worthwhile for future investigations. Clinical Trial Numbers: www.ClinicalTrials.gov, "The SABA trial"; number: NCT01450124.

Metabolomic Profiles for Primary Progressive Multiple Sclerosis Stratification and Disease Course Monitoring.

Primary progressive multiple sclerosis (PPMS) shows a highly variable disease progression with poor prognosis and a characteristic accumulation of disabilities in patients. These hallmarks of PPMS make it difficult to diagnose and currently impossible to efficiently treat. This study aimed to identify plasma metabolite profiles that allow diagnosis of PPMS and its differentiation from the relapsing-remitting subtype (RRMS), primary neurodegenerative disease (Parkinson's disease, PD), and healthy controls (HCs) and that significantly change during the disease course and could serve as surrogate markers of multiple sclerosis (MS)-associated neurodegeneration over time. We applied untargeted high-resolution metabolomics to plasma samples to identify PPMS-specific signatures, validated our findings in independent sex- and age-matched PPMS and HC cohorts and built discriminatory models by partial least square discriminant analysis (PLS-DA). This signature was compared to sex- and age-matched RRMS patients, to patients with PD and HC. Finally, we investigated these metabolites in a longitudinal cohort of PPMS patients over a 24-month period. PLS-DA yielded predictive models for classification along with a set of 20 PPMS-specific informative metabolite markers. These metabolites suggest disease-specific alterations in glycerophospholipid and linoleic acid pathways. Notably, the glycerophospholipid LysoPC(20:0) significantly decreased during the observation period. These findings show potential for diagnosis and disease course monitoring, and might serve as biomarkers to assess treatment efficacy in future clinical trials for neuroprotective MS therapies.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis.

Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 10(9)) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.