Publications by authors named "Florian Then Bergh"

51 Publications

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue-Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers.

Biomolecules 2021 Mar 7;11(3). Epub 2021 Mar 7.

Department of Neurology, Universitätsmedizin Rostock, 18057 Rostock, Germany.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.
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http://dx.doi.org/10.3390/biom11030393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002075PMC
March 2021

Motor Sequence Learning across Multiple Sessions Is Not Facilitated by Targeting Consolidation with Posttraining tDCS in Patients with Progressive Multiple Sclerosis.

Neural Plast 2021 9;2021:6696341. Epub 2021 Feb 9.

Department of Neurology, University of Leipzig, Leipzig, Germany.

Compared to relapsing-remitting multiple sclerosis (MS), progressive MS is characterized by a lack of spontaneous recovery and a poor response to pharmaceutical immunomodulatory treatment. These patients may, therefore, particularly benefit from interventions that augment training-induced plasticity of the central nervous system. In this cross-sectional double-blind cross-over pilot study, effects of transcranial direct current stimulation (tDCS) on motor sequence learning were examined across four sessions on days 1, 3, 5, and 8 in 16 patients with progressive MS. Active or sham anodal tDCS of the primary motor cortex was applied immediately after each training session. Participants took part in two experiments separated by at least four weeks, which differed with respect to the type of posttraining tDCS (active or sham). While task performance across blocks of training and across sessions improved significantly in both the active and sham tDCS experiment, neither online nor offline motor learning was modulated by the type of tDCS. Accordingly, the primary endpoint (task performance on day 8) did not differ between stimulation conditions. In sum, patients with progressive MS are able to improve performance in an ecologically valid motor sequence learning task through training. However, even multisession posttraining tDCS fails to promote motor learning in progressive MS.
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http://dx.doi.org/10.1155/2021/6696341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984928PMC
February 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple 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 severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients.

Sci Rep 2020 09 4;10(1):14651. Epub 2020 Sep 4.

Department of Neurology, University of Leipzig, Leipzig, Germany.

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts anti-inflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[C]O-methylreboxetine in immunotherapy-naïve patients with relapsing-remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses.
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http://dx.doi.org/10.1038/s41598-020-70732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474089PMC
September 2020

Genetic determinants of the humoral immune response in MS.

Neurol Neuroimmunol Neuroinflamm 2020 09 16;7(5). Epub 2020 Jul 16.

From the Department of Neurology (C.G., T.F.M.A., A. Keating, B.K., A. Klein, V.P., A. Berthele, B.H.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich; Institute of Human Genetics (P.L.), Helmholtz Zentrum München, Neuherberg; Department of Neurology (R.G.), St. Josef Hospital, Ruhr-University Bochum; Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2) (F.Z.), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology and Translational Center for Regenerative Medicine (F.T.B.), University of Leipzig; Clinical Neuroimmunology and Neurochemistry (M.S.), Department of Neurology, Hannover Medical School, Hannover; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Department of Neurology (B.W.), University Hospital Heidelberg; Department of Neurology (H.W.), University of Münster; Department of Neurology (A. Bayas), University Hospital Augsburg; Institute of Clinical Neuroimmunology (T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Neurology (U.K.Z.), Neuroimmunological Section, University of Rostock; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology (R.A.L.), University of Regensburg; Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research (U.Z.), Eberhard-Karls-Universität Tübingen; Max Planck Institute of Psychiatry (M.K.), Munich; Department of Neurology (C.W.), Medical Faculty, Heinrich Heine University, Düsseldorf; Department of Neurology (C.W.), University Hospital Cologne; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F), University Medical Centre Hamburg-Eppendorf, Hamburg; NeuroCure Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health and Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Center of Neuroimmunology (B.T.), Philipps-University Marburg; and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Germany.

Objective: In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).

Methods: Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.

Results: The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted = 2.32 × 10), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], = 2.06 × 10) and A (β = -0.42 [-0.54 to -0.31], = 7.48 × 10) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest = 2.14 × 10) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], = 1.38 × 10) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], = 1.01 × 10) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], = 4.46 × 10). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.

Conclusion: Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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http://dx.doi.org/10.1212/NXI.0000000000000827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371373PMC
September 2020

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

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

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 (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

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

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany

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=16 163) 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.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

Hyperstable arousal regulation in multiple sclerosis.

Psychoneuroendocrinology 2019 12 28;110:104417. Epub 2019 Aug 28.

Department of Neurology, University of Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Germany. Electronic address:

Background: Fatigue is common in multiple sclerosis (MS) patients. Exhaustion of physiological reserves and mental stress are postulated causes, the latter supported by more pronounced hypothalamic-pituitary-adrenal (HPA) axis activation in fatigued patients. Divergent dysregulation of arousal appears to play important roles in depression- (hyperstable arousal) and in cancer-related (unstable arousal) fatigue, where HPA axis is hyperactive or hypoactive, respectively.

Objective: This study assessed arousal regulation in multiple sclerosis patients, explored if fatigue can be physiologically described by altered arousal regulation, and if HPA axis activity corresponds to the type(s) of arousal regulation.

Methods: 51 mildly-affected patients with relapsing-remitting MS (86% on disease-modifying treatment) and 20 healthy controls were analysed via Vigilance Algorithm Leipzig and combined dexamethasone/corticotropin releasing hormone test.

Results: Hyperstable arousal pattern was significantly more frequent in patients than in controls (62.7% vs. 45.0%, p = 0.011). Patients scored higher on all fatigue, but not on sleepiness scales. All patients combined showed mild activation of the hypothalamic-pituitary-adrenal axis (p < 0.05 for post-CRH ACTH and AUC ACTH; cortisol n.s.). While fatigue was numerically more pronounced in both hyperstable and unstable arousal, HPA axis activity was highest in hyperstable and lowest in unstable arousal (p = 0.013 for post-CRH ACTH; p = 0.087 for AUC ACTH; cortisol n.s.).

Conclusion: Frequency of arousal patterns are altered in MS. An association with HPA axis activity was weak, possibly because the present sample was stable on immunotherapy.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104417DOI Listing
December 2019

[Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany].

Nervenarzt 2019 Dec;90(12):1245-1253

Klinik für Neurologie, Forschungszentrum Translationale Neurowissenschaften (FTN), Forschungszentrum für Immuntherapie (FZI), Rhine Main Neuroscience Network (rmn2), Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Deutschland.

After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence.
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http://dx.doi.org/10.1007/s00115-019-0760-0DOI Listing
December 2019

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Acta Neuropathol 2019 08 27;138(2):237-250. Epub 2019 May 27.

Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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http://dx.doi.org/10.1007/s00401-019-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660501PMC
August 2019

Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis.

JAMA Neurol 2019 07;76(7):841-849

Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed.

Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome.

Design, Setting, And Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018.

Exposure: Patients were offered standard immunotherapies per national treatment guidelines.

Main Outcomes And Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated.

Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found.

Conclusions And Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
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http://dx.doi.org/10.1001/jamaneurol.2019.0905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583696PMC
July 2019

Custodiol-N™ cardioplegia lowers cerebral inflammation and activation of hypoxia-inducible factor-1α.

Interact Cardiovasc Thorac Surg 2019 06;28(6):884-892

Department of Cardiac Surgery, Heart Center, Helios Clinic, Leipzig, Germany.

Objectives: Cardioplegic solutions induce cardiac arrest and protect cardiac tissue from ischaemia-reperfusion injury. However, the effects on the brain, which is vulnerable to cardiopulmonary bypass (CPB) surgery and ischaemia-reperfusion injury, mostly remain unknown. We investigated if cardioplegic solutions differ in their effects in altered oxygen conditions and in their ability to induce cerebral inflammation.

Methods: Thirty pigs were subjected to a midline sternotomy and CPB at 34°C with 90 min cardiac arrest followed by 120 min reperfusion. Following randomization on a 1:1:1 basis, they received either a single shot of histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 10), histidine-tryptophan-α-ketoglutarate-N (HTK-N; n = 10) or HTK plus 1.2 mg/l cyclosporine A (HTK/CsA; n = 10). Brain regions of interest (frontal cortex, cerebellum, brain stem, diencephalon, colliculus superior) were analysed by real time quantitative reverse transcriptase polymerase chain reaction for hypoxia-inducible factor-1α (HIF-1α), tumour necrosis factor-α, interleukin (IL)-10, IL-1β and IL-1β receptor as well as by immunohistochemical analysis for HIF-1α. Blood gas and electrolyte analyses were performed.

Results: Comparisons between baseline and reperfusion period levels revealed that HTK-N cardioplegia induced a smaller reduction of the haemoglobin content and blood calcium concentrations (hbbaseline: 5.97 ± 0.63 mmol/l; hbreperfusion: 6.16 ± 0.66 mmol/l; P = 0.428; Cabaseline2+: 1.36 ± 0.05 mmol/l; Careperfusion2+: 1.28 ± 0.05 mmol/l; P < 0.001) compared to HTK (hbbaseline: 5.93 ± 0.45 mmol/l; hbreperfusion: 4.72 ± 0.79 mmol/l; P = 0.001; Cabaseline2+: 1.34 ± 0.07 mmol/l; Careperfusion2+: 1.24 ± 0.06 mmol/l; P = 0.004) and HTK/CsA cardioplegia (hbbaseline: 5.88 ± 0.44 mmol/l; hbreperfusion: 5.14 ± 0.87 mmol/l; P = 0.040; Cabaseline2+: 1.38 ± 0.04 mmol/l; Careperfusion2+: 1.20 ± 0.14 mmol/l; P = 0.001). Brain region-specific regulation of the HIF-1α expression, no general HIF-1α activation and a lower tumour necrosis factor-α expression (pto HTK = 0.050, pto HTK/CsA = 0.013) were documented for HTK-N cardioplegia.

Conclusions: HTK-N (Custodiol-N) induced fewer cerebral effects and less inflammation during CPB surgery than HTK and HTK/CsA cardioplegia. These data suggest that HTK-N exerts brain protective effects during and after CPB surgery.
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http://dx.doi.org/10.1093/icvts/ivy347DOI Listing
June 2019

Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).

J Neurol 2019 Feb 4;266(2):386-397. Epub 2018 Dec 4.

Department of Neurology, University Hospital Münster, Westfälische-Wilhelms-University Münster, Münster, Germany.

Background: Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis.

Methods: Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.

Results: At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.

Conclusions: Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
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http://dx.doi.org/10.1007/s00415-018-9142-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373354PMC
February 2019

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

Stress 2019 01 29;22(1):93-102. Epub 2018 Oct 29.

a Integrated Research and Treatment Center (IFB) Adiposity Diseases , Leipzig University Medical Center , Leipzig , Germany.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH r = 0.87, p = .001; cortisol r = 0.86, p = .002; amygdala: ACTH r = 0.86, p = .002; cortisol r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.
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http://dx.doi.org/10.1080/10253890.2018.1511698DOI Listing
January 2019

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 26;5(6):e504. Epub 2018 Sep 26.

Department of Neurology (I.K., A.G., K.H.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (N.B., F. Pache), Charité Universitätsmedizin Berlin, and Max Delbrueck Center for Molecular Medicine, Berlin; Department of Neurology (K.F., J.F.), Asklepios Fachklinikum Teupitz; CRO Sostana GmbH and Charité Universitätsmedizin Berlin (K.-D.W.); Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center (F.Pache, K.R.), Charité Universitätsmedizin Berlin; Institute of Clinical Neuroimmunology (J.H., T.K.), Ludwig Maximilians University, Munich; Department of Neurology (O.A., H.-P.H., M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (C.G., M. Schwab), Jena University Hospital; Department of Neurology (C.K.), University Hospital Essen; Department of Neurology (A.B.), Klinikum rechts der Isar, Technische Universität München, Munich; Department of Neurology (B.H.), Klinikum rechts der Isar, Technische Universität München and Munich Cluster for Systems Neurology (SyNergy); Department of Neurology (K.A.), University Hospital Regensburg; Institute of Neuroimmunology and MS (INIMS) and Department of Neurology (J.-P.S.), University Medical Centre Hamburg-Eppendorf, HamburgKlinik und Poliklinik für Neurologie (S.S.), Universitätsklinikum Hamburg-Eppendorf; Clinical Neuroimmunology and Neurochemistry (M. Stangel), Department of Neurology, Hannover Medical School; Department of Neurology (F.L., H.T.), University of Ulm; Fachklinik für Neurologie Dietenbronn (H.T.), Akademisches Krankenhaus der Universität Ulm, Schwendi; Department of Neurology (C.M.), Goethe University Frankfurt; Department of Neurology & Stroke (M.K., L.Z., U. Ziemann), and Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (R.L.), Friedrich-Alexander University Erlangen-Nuremberg; Department of Neurology and Neurological Intensive Care (M.M.), Isar-Amper-Clinic, Munich-East, Haar; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (U. Hofstadt-van Oy), Klinikum Westfalen, Dortmund; Department of Neurology (O.N.), SRH Krankenhaus Sigmaringen; Neuroimmunological Section (U. Zettl), Department of Neurology, University of Rostock; Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg; NeuroCure Clinical Research Center (F. Paul), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Department of Neurology (C.T.), Hannover Medical School, Germany.

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).

Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.

Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, = 0.046).

Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.

Classification Of Evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
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http://dx.doi.org/10.1212/NXI.0000000000000504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192689PMC
November 2018

Compromised tDCS-induced facilitation of motor consolidation in patients with multiple sclerosis.

J Neurol 2018 Oct 6;265(10):2302-2311. Epub 2018 Aug 6.

Department of Neurology, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany.

Objective: To investigate whether consolidation after motor learning can be facilitated by offline (post-training) transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS).

Methods: In this cross-sectional double-blind interventional study, effects of tDCS on motor consolidation were examined in 14 patients with relapsing remitting MS [median Expanded Disability Status Scale score 2.0 (range 1-4)] and 14 age- and sex-matched healthy controls. tDCS with the anode placed over the left primary motor cortex and the cathode placed over the right supraorbital region was applied immediately after a training session of an explicit sequential finger-tapping task that was performed with the right (dominant) hand. Task performance was retested after an interval of 8 h to assess consolidation. Participants took part in two experimental sessions separated by at least 7 days which differed with respect to type of post-training tDCS, i.e., sham and verum stimulation.

Results: Patients with MS performed worse than controls in functional motor tests and the motor sequence task. However, learning speed and magnitude of online performance increments during the training session were comparable to controls. While post-training tDCS facilitated motor consolidation in controls, patients with MS did not benefit from this type of intervention.

Conclusion: Absence of post-training tDCS-induced facilitation of consolidation in patients with MS suggests that the interaction of tDCS with the motor consolidation network is inefficient. Identification of the underlying disease-related mechanisms will have important implications for the design of studies aiming to promote motor recovery in MS by non-invasive brain stimulation.
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http://dx.doi.org/10.1007/s00415-018-8993-6DOI Listing
October 2018

Ischaemic preconditioning of the spinal cord to prevent spinal cord ischaemia during endovascular repair of thoracoabdominal aortic aneurysm: first clinical experience.

EuroIntervention 2018 Sep;14(7):828-835

Department of Vascular Surgery, University Hospital Leipzig, Germany.

Aims: The purpose of our study was to report our experience with minimally invasive segmental artery coil embolisation (MISACE) to prevent spinal cord ischaemia (SCI) after endovascular repair (ER) of thoracoabdominal aortic aneurysm (TAAA).

Methods And Results: A cohort of 57 patients with TAAAs was treated by MISACE followed by ER between October 2014 and December 2017. The TAAA Crawford classification was: type I, n=5; type II, n=12; type III, n=27; type IV, n=13. The average maximum aortic diameter was 62.7±8.8 mm. Patients had a median of 5 coiled SAs (range: 1-19). MISACE was completed in one (n=22), two (n=24), three (n=7), four (n=3) or five (n=1) sessions. The maximum number of coiled SAs per session was six. After completion of MISACE, 77.7% of direct segmental arterial flow was occluded. After a mean of 83±62 days, 55 of the patients received total ER of their TAAA. At 30 days after ER, no patient developed SCI and three patients had died.

Conclusions: MISACE to precondition the paraspinous collateral network prior to endovascular repair of thoracoabdominal aortic aneurysm is clinically feasible. The safety profile is promising and there is good reason to explore this new staging strategy further.
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http://dx.doi.org/10.4244/EIJ-D-18-00200DOI Listing
September 2018

Beyond the limbic system: disruption and functional compensation of large-scale brain networks in patients with anti-LGI1 encephalitis.

J Neurol Neurosurg Psychiatry 2018 11 9;89(11):1191-1199. Epub 2018 Jun 9.

Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objective: Hippocampal inflammation in anti-LGI1 encephalitis causes memory deficits, seizures and behavioural abnormalities. Recent findings suggest that extralimbic brain areas are additionally affected and that patients also suffer from non-limbic cognitive symptoms. Moreover, up to 60% of patients show no structural MRI abnormalities in the acute disease stage. We therefore investigated whether functional connectivity analyses can identify brain network changes underlying disease-related symptoms.

Methods: We studied 27 patients and a matched healthy control group using structural and functional MRI. Intrinsic functional networks were analysed using Independent Component Analysis and Dual Regression. Cognitive testing covered working memory, episodic memory, attention and executive function.

Results: Our analysis revealed functional connectivity alterations in several large-scale networks, including the default mode network (DMN) which showed an aberrant structure-function relationship with the damaged hippocampus. In addition, connectivity in the sensorimotor, salience and higher visual networks was impaired independent of hippocampal damage. Increased connectivity in ventral and dorsal DMN regions significantly correlated with better memory performance. In contrast, stronger connectivity of the insula with the salience network and DMN was linked to impaired memory function.

Conclusions: Anti-LGI1 encephalitis is associated with a characteristic pattern of widespread functional network alterations. Increased DMN connectivity seems to represent a compensatory mechanism for memory impairment induced by hippocampal damage. Network analyses may provide a key to the understanding of clinical symptoms in autoimmune encephalitis and reveal changes of brain function beyond apparent structural damage.
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http://dx.doi.org/10.1136/jnnp-2017-317780DOI Listing
November 2018

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

Ann Neurol 2018 04;83(4):863-869

Department of Neurology, Christian-Albrechts-University Kiel, Germany.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.
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http://dx.doi.org/10.1002/ana.25216DOI Listing
April 2018

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

Neurol Neuroimmunol Neuroinflamm 2018 May 1;5(3):e446. Epub 2018 Mar 1.

Department of Neurology (O.v.B., B.A., R.G., A.S.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biometry and Statistics (T.D., N.H., A.Z.), University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck; Central Information Office (CIO) (G.A.), Philipps-University Marburg, Germany; School of Mathematics (A.Z.), Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Department of Neurology (M.-M.H., L.A., B.H.), Klinikum rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (L.A., B.H.); Department of Neurology (F.L., S.G., F.Z.), University Medicine Mainz, Johannes Gutenberg University Mainz; Department of Neurology (L.K., S.G.M., H.W.), University Hospital Münster; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (M.Stoppe, F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (M.Stangel), Hannover Medical School; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Department of Neurology (B.W.), University of Heidelberg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité-University Medicine Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (A.B.), Klinikum Augsburg; Department of Neurology (C.W.), Heinrich-Heine-University, Düsseldorf; Department of Neurology (C.W.), University Hospital Köln; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), MATERNUS Kliniken AG, Bad Oeynhausen; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology & Stroke (U.Z.), Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen; Department of Neurology (U.K.Z.), University of Rostock, Germany; and Department of Neurology (A.S.), Inselspital Bern, University Hospital and University of Bern, Switzerland.

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.
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http://dx.doi.org/10.1212/NXI.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833336PMC
May 2018

Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study).

J Neurol 2017 Dec 23;264(12):2436-2449. Epub 2017 Oct 23.

Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital, Milan, Italy.

Cognitive impairment (CI) affects 40-65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN β-1b) on CI progression, magnetic resonance imaging (MRI) and clinical outcomes in relapsing-remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN β-1b (250 µg every other day). CI was assessed via Rao's Brief Repeatable Battery and Delis-Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN β-1b, 41.18%; p ≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN β-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN β-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN β-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit-risk profile of fingolimod reported in previous studies.
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http://dx.doi.org/10.1007/s00415-017-8642-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688215PMC
December 2017

Outcome of MS relapses in the era of disease-modifying therapy.

BMC Neurol 2017 Aug 7;17(1):151. Epub 2017 Aug 7.

Department of Neurology, University of Leipzig, Liebigstraße 20, 04103, Leipzig, Germany.

Background: In multiple sclerosis (MS), neurological disability results from incomplete remission of relapses and from relapse-independent progression. Intravenous high dose methylprednisolone (IVMP) is the established standard treatment to accelerate clinical relapse remission, although some patients do not respond. Most studies of relapse treatment have been performed when few patients received disease-modifying treatment and may no longer apply today.

Methods: We prospectively assessed, over one year, the course of patients who presented with a clinically isolated syndrome (CIS) or MS relapse, documenting demographic, clinical, treatment and outcome data. A standardized follow-up examination was performed 10-14 days after end of relapse treatment.

Results: We documented 119 relapses in 108 patients (31 CIS, 77 MS). 114 relapses were treated with IVMP resulting in full remission (29.2%), partial remission (38.7%), no change (18.2%) or worsening (4.4%). In 27 relapses (22.7%), escalating relapse treatment was indicated, and performed in 24, using double-dose IVMP (n = 18), plasmapheresis (n = 2) or immunoadsorption (n = 4).

Conclusions: Standardised follow-up visits and outcome documentation in treated relapses led to escalating relapse treatment in every fifth relapse. We recommend incorporating scheduled follow-up visits into routine relapse management. Our data facilitate the design of prospective trials addressing methods and timelines of relapse treatment.
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http://dx.doi.org/10.1186/s12883-017-0927-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547454PMC
August 2017

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.

J Neurol Neurosurg Psychiatry 2017 08 1;88(8):639-647. Epub 2017 Jun 1.

Department of Neurology, University of Münster, Münster, Germany.

Objective: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).

Design: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.

Results: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).

Conclusions: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.
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http://dx.doi.org/10.1136/jnnp-2017-315603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537514PMC
August 2017

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

Curr Med Res Opin 2017 May 2;33(5):877-890. Epub 2017 Mar 2.

ac Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.

Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes.

Methods: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included.

Findings: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches.

Conclusions: Several clinical niches have been identified that harbor patients at increased risk of NP-C.
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http://dx.doi.org/10.1080/03007995.2017.1294054DOI Listing
May 2017

Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity.

Psychoneuroendocrinology 2017 04 16;78:39-47. Epub 2017 Jan 16.

Department of Neurology, University of Leipzig, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany. Electronic address:

Context: Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear.

Objectives: To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC).

Methods: In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test.

Main Outcome Measures: Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100μg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration).

Results: Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, P<0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, P<0.01), driven by OB men (post-CRH ACTH: R=0.76, P<0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age.

Conclusions: The association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis.
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http://dx.doi.org/10.1016/j.psyneuen.2017.01.004DOI Listing
April 2017

Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies.

JAMA Neurol 2017 Jan;74(1):50-59

Department of Neurology, Memory Disorders and Plasticity Group, University Hospital Schleswig-Holstein, Kiel, Germany.

Importance: Limbic encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies is one of the most frequent variants of autoimmune encephalitis with antibodies targeting neuronal surface antigens. However, the neuroimaging pattern and long-term cognitive outcome are not well understood.

Objective: To study cognitive outcome and structural magnetic resonance imaging (MRI) alterations in patients with anti-LGI1 encephalitis.

Design, Setting, And Participants: A cross-sectional study was conducted at the Departments of Neurology at Charité-Universitätsmedizin Berlin and University Hospital Schleswig-Holstein, Kiel, Germany. Data on 30 patients with anti-LGI1 encephalitis and 27 healthy control individuals matched for age, sex, and educational level were collected from June 1, 2013, through February 28, 2015.

Main Outcomes And Measures: Clinical assessment, cognitive testing, and high-resolution MRI data, including whole-brain, hippocampal and basal ganglia volumetry; white matter integrity (diffusion tensor imaging); gray matter density (voxel-based morphometry); and hippocampal microstructural integrity (mean diffusivity and fractional anisotropy).

Results: Of the 30 patients included in the study, 19 were male (63%); mean (SD) age was 65.7 (12.3) years. Patients with anti-LGI1 encephalitis had incomplete recovery with significant and persisting verbal (mean [SE] Rey Auditory Verbal Learning Test [RAVLT], delayed recall: patients, 6.52 [1.05]; controls, 11.78 [0.56], P < .001) and visuospatial (Rey-Osterrieth Complex Figure Test [ROCF], delayed recall: patients, 16.0 [1.96]; controls, 25.86 [1.24]; P < .001) memory deficits. These deficits were accompanied by pronounced hippocampal atrophy, including subfields cornu ammonis 2/3 (CA2/3) and CA4/dentate gyrus (DG), as well as impaired hippocampal microstructural integrity. Higher disease severity correlated with larger verbal memory deficits (RAVLT delayed recall, r = -0.40; P = .049), decreased volumes of left hippocampus (r = -0.47; P = .02) and left CA2/3 (r = -0.41; P = .04) and CA4/DG (r = -0.43; P = .03) subfields, and impaired left hippocampal microstructural integrity (r = 0.47; P = .01). In turn, decreased volume of the left CA2/3 subfield (RAVLT delayed recall, r = 0.40; P = .047) and impaired left hippocampal microstructural integrity (RAVLT recognition, r = -0.41; P = .04) correlated with verbal memory deficits. Basal ganglia MRI signal abnormalities were observed in only 1 patient, but a longer duration of faciobrachial dystonic seizures correlated with a reduction of pallidum volume (r = -0.71; P = .03). In contrast, no abnormalities of cortical gray matter or white matter were found. The latency between disease onset and initiation of immunotherapy was significantly correlated with verbal (RAVLT recall after interference, r = -0.48; P = .02) and visuospatial (ROCF delayed recall, r = -0.46; P = .03) memory deficits.

Conclusions And Relevance: Anti-LGI1 encephalitis is associated with cognitive deficits and disability as a result of structural damage to the hippocampal memory system. This damage might be prevented by early immunotherapy.
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http://dx.doi.org/10.1001/jamaneurol.2016.4226DOI Listing
January 2017

Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study.

J Neurol 2017 Feb 25;264(2):304-315. Epub 2016 Nov 25.

McGill University, Montreal, QC, Canada.

Histamine H receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.
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http://dx.doi.org/10.1007/s00415-016-8341-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306088PMC
February 2017

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

Mult Scler 2017 Jul 6;23(8):1092-1103. Epub 2016 Oct 6.

Department of Neurology, Leipzig University, Leipzig, Germany.

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.

Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).

Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.

Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years.

Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
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http://dx.doi.org/10.1177/1352458516671203DOI Listing
July 2017