71 research outputs found

    Neurocysticercosis with a single brain lesion in Germany: a case report

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    Neurocysticercosis is rare in Western Europe and a high degree of physician awareness is necessary for diagnosis. We describe a case of Neurocysticercosis with a single brain lesion acquired in Germany in which only surgical removal and subsequent histological examination allowed diagnosis whereas diagnostic investigation yielded no pathological findings

    Altered grey matter integrity and network vulnerability relate to epilepsy occurrence in patients with multiple sclerosis

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    Background and purpose: The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy. Methods: From 3-T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41‚ÄȬĪ‚ÄČ15‚ÄČyears, 21 females, disease duration 8‚ÄȬĪ‚ÄČ6‚ÄČyears, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41‚ÄȬĪ‚ÄČ12‚ÄČyears, 35 females, disease duration 6‚ÄȬĪ‚ÄČ4‚ÄČyears, EDSS score 2), and 60 healthy subjects (HS group; age 40‚ÄȬĪ‚ÄČ13‚ÄČyears, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver-operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients. Results: Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p‚ÄČ<‚ÄČ0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p‚ÄČ<‚ÄČ0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p‚ÄČ<‚ÄČ0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p‚ÄČ<‚ÄČ0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67‚Äď0.91]) in discriminating between MSE and MS patients. Conclusions: High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS

    Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis

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    BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing‚Äďremitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18¬†months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12¬†months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12¬†months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12¬†months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s42466-022-00219-3

    Association of obesity with disease outcome in multiple sclerosis

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    BackgroundObesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation.MethodsThis nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ‚Č•30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values.ResultsPresence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ‚Č•30 kg/m2‚ÄČand 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ‚Č•30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up.ConclusionsObesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS

    Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis

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    OBJECTIVE: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS). METHODS: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16‚ÄČ163) from Berlin/Northern Germany. RESULTS: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts. CONCLUSION: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS

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

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    Objective To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods The 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. Results Of 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 Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients

    The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

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    The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 √ó 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS

    K(2P)18.1 translates T cell receptor signals into thymic regulatory T cell development

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    It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca2+) is the most important second messenger, for which the potassium channel K(2P)18.1 is a relevant regulator. Here, we identify K(2P)18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-kappa B-mediated K(2P)18.1 upregulation in tTreg progenitors. K(2P)18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-kappa B- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K(2P)18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K(2P)18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K(2P)18.1 variant that is associated with poor clinical outcomes indicate that K(2P)18.1 also plays a role in human Treg development. Pharmacological modulation of K(2P)18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K(2P)18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K(2P)18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.Peer reviewe

    Genome-wide significant association with seven novel multiple sclerosis risk loci

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    Objective: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods: The lead SNPs of all 11 loci were genotyped in 10‚ÄÖ796 MS cases and 10‚ÄÖ793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21‚ÄÖ589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101‚ÄÖ683) revealed novel genome-wide significant association with MS susceptibility (p<5√ó10‚ąí8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03√ó10‚ąí12), CD28 (rs6435203, p=1.35√ó10‚ąí9), LPP (rs4686953, p=3.35√ó10‚ąí8), ETS1 (rs3809006, p=7.74√ó10‚ąí9), DLEU1 (rs806349, p=8.14√ó10‚ąí12), LPIN3 (rs6072343, p=7.16√ó10‚ąí12) and IFNGR2 (rs9808753, p=4.40√ó10‚ąí10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases

    Genome-wide significant association with seven novel multiple sclerosis risk loci

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    Objective: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods: The lead SNPs of all 11 loci were genotyped in 10‚ÄÖ796 MS cases and 10‚ÄÖ793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21‚ÄÖ589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101‚ÄÖ683) revealed novel genome-wide significant association with MS susceptibility (p<5√ó10‚ąí8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03√ó10‚ąí12), CD28 (rs6435203, p=1.35√ó10‚ąí9), LPP (rs4686953, p=3.35√ó10‚ąí8), ETS1 (rs3809006, p=7.74√ó10‚ąí9), DLEU1 (rs806349, p=8.14√ó10‚ąí12), LPIN3 (rs6072343, p=7.16√ó10‚ąí12) and IFNGR2 (rs9808753, p=4.40√ó10‚ąí10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases
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