Publications by authors named "Ralf A Linker"

165 Publications

MuSK-antibodies are associated with worse outcome in myasthenic crisis requiring mechanical ventilation.

J Neurol 2021 May 10. Epub 2021 May 10.

Department of Neurology, University of Regensburg, Bezirksklinikum Regensburg, Universitaetsstraße 84, 93051, Regensburg, Germany.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Muscle-specific kinase-antibodies (MuSK-ABs) are detected in ~ 6% of MG, but data on outcome of MuSK-MCs are still lacking. We made a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody positive MG (AchR-MG) or MuSK-MG between 2006 and 2015 in a retrospective German multicenter study. We identified 19 MuSK-AB associated MCs in 15 patients and 161 MCs in 144 patients with AchR-ABs only. In contrast to patients with AchR-AB, MuSK-AB patients were more often female (p = 0.05, OR = 2.74) and classified as Myasthenia Gravis Foundation of America-class IV before crisis (p = 0.04, OR = 3.25). MuSK-AB patients suffer more often from multiple chronic disease (p = 0.016, OR = 4.87) and were treated more invasively in terms of plasma exchanging therapies (not significant). The number of days of mechanical ventilation (MV) (43.0 ± 53.1 vs. 17.4 ± 18; p < 0.0001), days on an intensive care unit (ICU) (45.3 ± 49.5 vs. 21.2 ± 19.7; p < 0.0001), and hospital-length of stay (LOS) (55.9 ± 47.6 vs. 28.8 ± 20.9 days; p < 0.0001) were significantly increased in MuSK-MC. Remarkable is that these changes were mainly due to patients with MusK-ABs only, whereas patients' outcome with both antibodies was similar to AchR-MCs. Furthermore, our data showed a shortened duration of MV after treatment with plasma exchanging therapies compared to treatment with intravenous immunoglobulin in MuSK-MCs. We conclude that MuSK-AB-status is associated with a longer need of MV, ICU-LOS, and hospital-LOS in MC, and therefore recommend early initiation of a disease-specific therapy.
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http://dx.doi.org/10.1007/s00415-021-10603-9DOI Listing
May 2021

Inflammation in multiple sclerosis.

Ther Adv Neurol Disord 2021 16;14:17562864211007687. Epub 2021 Apr 16.

Department of Neurology, University Hospital Regensburg, Regensburg, Germany.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterised pathologically by demyelination, gliosis, neuro-axonal damage and inflammation. Despite intense research, the underlying pathomechanisms driving inflammatory demyelination in MS still remain incompletely understood. It is thought to be caused by an autoimmune response towards CNS self-antigens in genetically susceptible individuals, assuming autoreactive T cells as disease-initiating immune cells. Yet, B cells were recognized as crucial immune cells in disease pathology, including antibody-dependent and independent effects. Moreover, myeloid cells are important contributors to MS pathology, and it is becoming increasingly evident that different cell types act in concert during MS immunopathology. This is supported by the finding that the beneficial effects of actual existing disease-modifying therapies cannot be attributed to one single immune cell-type, but rather involve immunological cooperation. The current strategy of MS therapies thus aims to shift the immune cell repertoire from a pro-inflammatory towards an anti-inflammatory phenotype, involving regulatory T and B cells and anti-inflammatory macrophages. Although no existing therapy actually exists that directly induces an enhanced regulatory immune cell pool, numerous studies identified potential net effects on these cell types. This review gives a conceptual overview on T cells, B cells and myeloid cells in the immunopathology of relapsing-remitting MS and discusses potential contributions of actual disease-modifying therapies on these immune cell phenotypes.
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http://dx.doi.org/10.1177/17562864211007687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053832PMC
April 2021

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Brain Sci 2021 Mar 14;11(3). Epub 2021 Mar 14.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, < 0.001). "Limb-onset" ALS (ALS) was associated with a better QoL than "bulbar-onset" ALS (ALS) (mean ALSAQ-5 total score 55.46 versus 60.99, = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, = 0.001), being tracheostomized (β = -14.80, = 0.004) and using non-invasive ventilation (β = -5.71, = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, = 0.007), and increasing age (β = 0.18, = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
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http://dx.doi.org/10.3390/brainsci11030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998410PMC
March 2021

Case report of a complicated neurologically manifesting acute porphyria treated successfully with Givosiran.

J Neurol Sci 2021 03 31;422:117334. Epub 2021 Jan 31.

Department of Neurology, University of Regensburg, Bezirksklinikum Regensburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2021.117334DOI Listing
March 2021

Cardiovascular fingolimod effects on rapid baroreceptor unloading are counterbalanced by baroreflex resetting.

Neurol Sci 2021 Jan 14;42(1):111-121. Epub 2021 Jan 14.

Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054, Erlangen, Germany.

Background And Purpose: Initial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation.

Patients And Methods: Twenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p < 0.05).

Results: RRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation.

Conclusions: VR-decreases 3-6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.
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http://dx.doi.org/10.1007/s10072-020-05004-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819912PMC
January 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

Oral Health, Oral Microbiota, and Incidence of Stroke-Associated Pneumonia-A Prospective Observational Study.

Front Neurol 2020 6;11:528056. Epub 2020 Nov 6.

Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany.

Stroke-associated pneumonia is a major cause for poor outcomes in the post-acute phase after stroke. Several studies have suggested potential links between neglected oral health and pneumonia. Therefore, the aim of this prospective observational study was to investigate oral health and microbiota and incidence of pneumonia in patients consecutively admitted to a stroke unit with stroke-like symptoms. This study involved three investigation timepoints. The baseline investigation (within 24 h of admission) involved collection of demographic, neurological, and immunological data; dental examinations; and microbiological sampling (saliva and subgingival plaque). Further investigation timepoints at 48 or 120 h after baseline included collection of immunological data and microbiological sampling. Microbiological samples were analyzed by culture technique and by 16S rRNA amplicon sequencing. From the 99 patients included in this study, 57 were diagnosed with stroke and 42 were so-called stroke mimics. From 57 stroke patients, 8 (14%) developed pneumonia. Stroke-associated pneumonia was significantly associated with higher age, dysphagia, greater stroke severity, embolectomy, nasogastric tubes, and higher baseline C-reactive protein (CRP). There were trends toward higher incidence of pneumonia in patients with more missing teeth and worse oral hygiene. Microbiological analyses showed no relevant differences regarding microbial composition between the groups. However, there was a significant ecological shift over time in the pneumonia patients, probably due to antibiotic treatment. This prospective observational study investigating associations between neglected oral health and incidence of SAP encourages investigations in larger patient cohorts and implementation of oral hygiene programs in stroke units that may help reducing the incidence of stroke-associated pneumonia.
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http://dx.doi.org/10.3389/fneur.2020.528056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677513PMC
November 2020

Living with secondary progressive multiple sclerosis in Europe: perspectives of multiple stakeholders.

Neurodegener Dis Manag 2021 02 25;11(1):9-19. Epub 2020 Nov 25.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland.

The transition from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS) remains a clinical challenge owing to the heterogeneous course of the disease, indistinct disease progression and lack of availability of validated biomarkers and diagnostic tools. This article summarizes the outcomes from an international expert group meeting conducted to validate the preliminary research findings gathered through interviews with primary healthcare stakeholders and pharmaceutical representatives, and to understand the current and future patient journey of SPMS across seven European countries. We highlight the uncertainty in SPMS diagnosis and management and, consequently, the need for uniform assessment guidelines, enhanced awareness and a collaborative effort between the stakeholders associated with SPMS patient care and the pharmaceutical industry.
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http://dx.doi.org/10.2217/nmt-2020-0054DOI Listing
February 2021

The role of the gut microbiota and microbial metabolites in neuroinflammation.

Eur J Immunol 2020 12 7;50(12):1863-1870. Epub 2020 Dec 7.

Department of Neurology, University Hospital Regensburg, Regensburg, Germany.

Recent literature indicates a potential importance of the gut microbiota for immune-mediated diseases. For instance, decreased diversity of commensals or an outgrowth of some bacterial strains, referred to as gut dysbiosis, was recently linked to hypertension, colitis, lupus, rheumatoid arthritis, and multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) as pivotal animal model of MS revealed a potential importance of microbial metabolites, including short-chain fatty acids or tryptophan metabolites. Both metabolites may influence the disease by modulation of the immune system, mainly by inducing Treg. These studies prompted researchers to investigate the contribution of the gut microbiota and microbial metabolites in the pathogenesis of MS. This review summarizes recent findings on the gut microbiota in MS patients and discusses the potential mechanisms how microbial metabolites may affect neuroinflammation. Many of these studies have been performed in the EAE model and were later reversely translated to humans. We also give a short summary on dietary high-salt effects on microbiota components and discuss the potential relevance of high-salt as a risk factor in MS.
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http://dx.doi.org/10.1002/eji.201847807DOI Listing
December 2020

Longer-term effects of intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: Who benefits?

J Neurol Sci 2020 Dec 4;419:117169. Epub 2020 Oct 4.

Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany; Department of Neurology, University Regensburg, Universitätsstr. 84, 93053 Regensburg, Germany. Electronic address:

Intravenous immunoglobulins (IVIg) represent an established cornerstone for the immunotherapy of chronic inflammatory demyelinating polyneuropathy (CIDP). Efficacy of IVIg for CIDP was proven in a large phase III trial. Yet, data on longer-term efficacy and effects in distinct subgroups are scarce. Our trial investigates the long-term efficacy of IVIg treatment in CIDP patients. In this observational real-world study, we retrospectively analyzed 49 CIDP patients receiving continuous IVIg treatment with a mean initial dosage of 87 g (1 g/kg body weight) every 4 weeks over a mean time of 45 months between 2010 and 2018. INCAT-Scores before the start of treatment and at the end of the observation period were compared. Over the observation period, IVIg treatment led to a median improvement of one INCAT score point. Subgroup analyses revealed a more pronounced improvement of INCAT scores in female CIDP patients, individuals with relapsing disease courses, patients with more pronounced motor impairment (higher initial INCAT scores) and in the cohort without need for concomitant other immunotherapies. These data argue for sustained beneficial effects of longer-term immunotherapy with IVIg in CIDP, particularly in females and relapsing disease forms with higher disease activity.
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http://dx.doi.org/10.1016/j.jns.2020.117169DOI Listing
December 2020

Normal Age- and Sex-Related Values of the Optic Nerve Sheath Diameter and Its Dependency on Position and Positive End-Expiratory Pressure.

Ultrasound Med Biol 2020 Dec 19;46(12):3279-3285. Epub 2020 Sep 19.

Department of Neurology, University of Regensburg, Medbo Bezirksklinikum Regensburg, Regensburg, Germany.

Optic nerve sheath diameter (ONSD) sonography is a reliable method for evaluation of intracranial pressure, yet there is a lack of reliable normal values. In the study described here, we established normal ONSD values in three different age groups and both sexes. One hundred eighty-seven volunteers without central nervous system disease were enrolled in this prospective study. ONSD measurements were taken in volunteers in the supine and upright positions and after application of positive end-expiratory pressure (PEEP). Normal ONSD values were 4.9-5.3 mm (patient age range: 20-85), with significant differences between men and women (p < 0.001). ONSD values increased with age (∆ = 0.34 mm, p < 0.001). There were no differences compared with the upright position but application of PEEP led to significantly increased ONSD values (∆ = 0.21 mm, p = 0.008). ONSD values increased with age, correlated well with the width of the third ventricle, were significantly lower in the female cohort and quickly responded to PEEP, especially in women.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.08.025DOI Listing
December 2020

Low stroke incidence in the TEMPiS telestroke network during COVID-19 pandemic - effect of lockdown on thrombolysis and thrombectomy.

J Telemed Telecare 2020 Aug 18:1357633X20943327. Epub 2020 Aug 18.

Department of Neurology, TEMPiS Telemedical Stroke Center, Academic Teaching Hospital of the University of Munich, München Klinik Harlaching, Munich, Germany.

Background: During the COVID-19 pandemic emergency departments have noted a significant decrease in stroke patients. We performed a timely analysis of the Bavarian telestroke TEMPiS "working diagnosis" database.

Methods: Twelve hospitals from the TEMPiS network were selected. Data collected for January through April in years 2017 through 2020 were extracted and analyzed for presumed and definite ischemic stroke (IS), amongst other disorders. In addition, recommendations for intravenous thrombolysis (rtPA) and endovascular thrombectomy (EVT) were noted and mobility data of the region analyzed. If statistically valid, group-comparison was tested with Fisher's exact test considering unpaired observations and ap-value < 0.05 was considered significant.

Results: Upon lockdown in mid-March 2020, we observed a significant reduction in recommendations for rtPA compared to the preceding three years (14.7% [2017-2019] vs. 9.2% [2020], p = 0.0232). Recommendations for EVT were significantly higher in January to mid-March 2020 compared to 2017-2019 (5.4% [2017-2019] vs. 9.3% [2020], p = 0.0013) reflecting its increasing importance. Following the COVID-19 lockdown mid-March 2020 the number of EVT decreased back to levels in 2017-2019 (7.4% [2017-2019] vs. 7.6% [2020], p = 0.1719). Absolute numbers of IS decreased in parallel to mobility data.

Conclusions: The reduced stroke incidence during the COVID-19 pandemic may in part be explained by patient avoidance to seek emergency stroke care and may have an association to population mobility. Increasing mobility may induce a rebound effect and may conflict with a potential second COVID-19 wave. Telemedical networks may be ideal databases to study such effects in near-real time.
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http://dx.doi.org/10.1177/1357633X20943327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441481PMC
August 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

Neuromonitoring Using Neurosonography and Pupillometry in A Weaning and Early Neurorehabilitation Unit.

J Neuroimaging 2020 09 27;30(5):631-639. Epub 2020 Jun 27.

Department of Neurology, University of Regensburg, Center for Vascular Neurology and Intensive Care, Regensburg, Germany.

Background And Purpose: Long-term surveillance of intracranial pressure (ICP) in neurological/neurosurgical patients during ventilator weaning and early neurorehabilitation currently relies on clinical observation because neuroimaging is rarely readily available. In this prospective study, multimodal neurosonography and pupillometry are evaluated for follow-up monitoring.

Methods: Sonographic neuromonitoring was used to noninvasively examine patients' ICP during weaning and early neurorehabilitation. It allowed assessments of third ventricle width, possible midline shift, middle cerebral artery flow velocities, and bilateral optic nerve sheath diameters. Quantitative pupillometry was used to determine pupil size and reactivity. Other neuroimaging findings, spinal tap ICP measurements, and clinical follow-up data served as controls.

Results: Seventeen patients-11 suffering from intracranial hemorrhage, four from encephalopathies, and two from ischemic stroke-were examined for ICP changes by using neurosonography and pupillometry during a mean observation period of 21 days. In total, 354 of 980 analyses (36.1%) yielded pathological results. In 15 of 17 patients (88.2%), pathological values were found during follow-up without a clear clinical correlate. In two patients (11.8%), clinically relevant changes in ICP occurred and were identified using neurosonography. Abnormal pupillometry findings displayed a high predictive value for absent clinical improvement.

Conclusion: Multimodal neurosonography may be a noninvasive means for long-term ICP assessment, whereas pupillometry may only detect rapid ICP changes during acute neurointensive care. The study also illustrates common pitfalls in neuromonitoring in general, with large numbers of pathological albeit nonsignificant findings. Additional controlled studies should validate the influence of detected subtle changes in ICP on neurological outcome.
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http://dx.doi.org/10.1111/jon.12742DOI Listing
September 2020

Real world application of ocrelizumab in multiple sclerosis: Single-center experience of 128 patients.

J Neurol Sci 2020 08 11;415:116973. Epub 2020 Jun 11.

Department of Neurology, University of Erlangen, Germany. Electronic address:

Background: Pivotal trials showed good clinical efficiency of the monoclonal antibody ocrelizumab while being well tolerated and manageable in multiple sclerosis (MS). However, data on adverse events in everyday practice are scarce. Hence, our study aims at investigating short-term tolerability of ocrelizumab in a "real-world" setting.

Methods: In this retrospective cohort study, data of 128 (86 relapsing-remitting, 42 progressive) MS patients at initiation of ocrelizumab were analyzed at the MS center of the University of Erlangen, Germany. Additionally, follow-up data of 68 patients at 6-months retreatment were analyzed. Structured phone interviews were applied after ocrelizumab initiation to report undocumented side effects.

Results: Patients predominantly switched from monoclonal antibodies (46%), orals (20%), injectables (10%), steroids or immunosuppressants (each 8%), with a mean interval of 9.0 months after the last application of the previous immunotherapy. Applying a combined premedication with steroids, antihistamines and antipyretics for >90% of patients, ocrelizumab treatment was well tolerated and mainly comprised mild (n = 59/128 at initiation, n = 5/68 at 6 months retreatment) and rarely moderate (n = 7/128 at initiation, n = 2/68 at 6 months) side effects. Predominantly mild infusion related reactions (IRR) were reported with a declining percentage over the follow-up applications. Infections occurred rarely. No severe side effects were observed. Secondary, treatment appeared efficient when looking at clinical surrogates of stable disease.

Discussion: Our study delineates good short-term tolerability of ocrelizumab in a miscellaneous "real-world" MS cohort. Additional studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.
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http://dx.doi.org/10.1016/j.jns.2020.116973DOI Listing
August 2020

The transitional phase of multiple sclerosis: Characterization and conceptual framework.

Mult Scler Relat Disord 2020 Sep 29;44:102242. Epub 2020 May 29.

Department of Neurology, University of Regensburg, Regensburg, Germany.

The conversion of relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) cannot be defined by a sharp threshold determined by event-based measures, but rather represents a gradual process. In consequence, there may exist a transitional phase between RRMS and clearly established SPMS. So far, transitional MS has been poorly characterized in terms of patient properties, course of disease and therapeutic interventions that may delay conversion to SPMS. Furthermore, the pathogenesis of transitional MS is incompletely understood, and no definitive imaging or laboratory test informs when exactly a patient has entered the transitional MS phase. Here we review the current knowledge and evidence characterizing the transitional phase of MS and propose potential designs and criteria for a prospective clinical study in patients with transitional MS.
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http://dx.doi.org/10.1016/j.msard.2020.102242DOI Listing
September 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

Functional role of endogenous Kv1.4 in experimental demyelination.

J Neuroimmunol 2020 06 24;343:577227. Epub 2020 Mar 24.

Department of Neurology, University of Regensburg, Regensburg, Germany. Electronic address:

During neuroinflammation, the shaker type potassium channel Kv1.4 is re-expressed in oligodendrocytes (Ol), but not immune cells. Here, we analyze the role of endogenous Kv1.4 in two demyelinating animal models of multiple sclerosis. While Kv1.4 deficiency in primary murine Ol led to a decreased proliferation rate in vitro, it did not exert an effect on Ol proliferation or on the extent of de- or remyelination in the cuprizone model in vivo. However, in experimental autoimmune encephalomyelitis, Kv1.4 mice exhibited a milder disease course and reduced Th1 responses. These data argue for an indirect effect of Kv1.4 on immune cells, possibly via glial cells.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577227DOI Listing
June 2020

alpha-Synuclein: a Modulator During Inflammatory CNS Demyelination.

J Mol Neurosci 2020 Jul 23;70(7):1038-1049. Epub 2020 Mar 23.

Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Neuroinflammation and demyelination are hallmarks of several neurological disorders such as multiple sclerosis and multiple system atrophy. To better understand the underlying mechanisms of de- and regeneration in respective diseases, it is critical to identify factors modulating these processes. One candidate factor is alpha-Synuclein (aSyn), which is known to be involved in the pathology of various neurodegenerative diseases. Recently, we have shown that aSyn is involved in the modulation of peripheral immune responses during acute neuroinflammatory processes. In the present study, the effect of aSyn deficiency on de- and regenerative events in the CNS was analyzed by using two different demyelinating animal models: chronic MOG-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. Histopathological analysis of spinal cord cross sections 8 weeks after EAE induction revealed a significant reduction of CNS inflammation accompanied by decreased myelin loss during late-stage inflammatory demyelination in aSyn-deficient mice. In contrast, after cuprizone-induced demyelination or remyelination following withdrawal of cuprizone, myelination and neuroinflammatory patterns were not affected by aSyn deficiency. These data provide further evidence for aSyn as regulator of peripheral immune responses under neuroinflammatory conditions, thereby also modulating degenerative events in late-stage demyelinating disease.
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http://dx.doi.org/10.1007/s12031-020-01498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334286PMC
July 2020

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

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism.

Cell 2020 03 10;180(6):1067-1080.e16. Epub 2020 Mar 10.

Department of Cell Morphology and Molecular Neurobiology, Ruhr University Bochum, Bochum 44801, Germany.

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
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http://dx.doi.org/10.1016/j.cell.2020.02.035DOI Listing
March 2020

Objective sensor-based gait measures reflect motor impairment in multiple sclerosis patients: Reliability and clinical validation of a wearable sensor device.

Mult Scler Relat Disord 2019 Dec 23;39:101903. Epub 2019 Dec 23.

Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany; Fraunhofer Institut für Integrierte Schaltungen, Erlangen, Germany. Electronic address:

Background: Gait deficits are common in multiple sclerosis (MS) and contribute to disability but may not be easily detected in the early stages of the disease.

Objectives: We investigated whether sensor-based gait analysis is able to detect gait impairments in patients with MS (PwMS).

Methods: A foot-worn sensor-based gait analysis system was used in 102 PwMS and 22 healthy controls (HC) that were asked to perform the 25-foot walking test (25FWT) two times in a self-selected speed (25FWT_pref), followed by two times in a speed as fast as possible (25FWT_fast). The Multiple Sclerosis Walking Scale (MSWS-12) was used as a subjective measure of patient mobility. Patients were divided into EDSS and functional system subgroups.

Results: Datasets between two consecutive measurements (test-retest-reliability) were highly correlated in all analysed mean gait parameters (e.g. 25FWT_fast: stride length r = 0.955, gait speed r = 0.969) Subgroup analysis between HC and PwMS with lower (EDSS≤3.5) and higher (EDSS 4.0-7.0) disability showed significant differences in mean stride length, gait speed, toe off angle, stance time and swing time (e.g. stride length of EDSS subgroups 25FWT_fast p ≤ 0.001, 25FWT_pref p = 0.003). The differences between EDSS subgroups were more pronounced in fast than in self-selected gait speed (e.g. stride length 25FWT_fast 33.6 cm vs. 25FWT_pref 16.3 cm). Stride length (25FWT_fast) highly correlated to EDSS (r=-0.583) and MSWS-12 (r=-0.668). We observed significant differences between HC and PwMS with (FS 0-1) and without (FS≥2) pyramidal or cerebellar disability (e.g. gait speed of FS subgroups p ≤ 0.001).

Conclusion: Sensor-based gait analysis objectively supports the clinical assessment of gait abnormalities even in the lower stages of MS, especially when walking with fast speed. Stride length and gait speed where identified as the most clinically relevant gait measures. Thus, it may be used to support the assessment of PwMS with gait impairment in the future, e.g. for more objective classification of disability. Its role in home-monitoring scenarios need to be evaluated in further studies.
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http://dx.doi.org/10.1016/j.msard.2019.101903DOI Listing
December 2019

Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999-2019: an epidemiological investigation.

Lancet Infect Dis 2020 04 7;20(4):467-477. Epub 2020 Jan 7.

Department of Neuropathology, Technical University of Munich, Munich, Germany.

Background: In 2018-19, Borna disease virus 1 (BoDV-1), the causative agent of Borna disease in horses, sheep, and other domestic mammals, was reported in five human patients with severe to fatal encephalitis in Germany. However, information on case frequencies, clinical courses, and detailed epidemiological analyses are still lacking. We report the occurrence of BoDV-1-associated encephalitis in cases submitted to the Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany, and provide a detailed description of newly identified cases of BoDV-1-induced encephalitis.

Methods: All brain tissues from 56 encephalitis cases from Bavaria, Germany, of putative viral origin (1999-2019), which had been submitted for virological testing upon request of the attending clinician and stored for stepwise diagnostic procedure, were systematically screened for BoDV-1 RNA. Two additional BoDV-1-positive cases were contributed by other diagnostic centres. Positive results were confirmed by deep sequencing, antigen detection, and determination of BoDV-1-reactive antibodies in serum and cerebrospinal fluid. Clinical and epidemiological data from infected patients were collected and analysed.

Findings: BoDV-1 RNA and bornavirus-reactive antibodies were detected in eight newly analysed encephalitis cases and the first human BoDV-1 isolate was obtained from an unequivocally confirmed human BoDV-1 infection from the endemic area. Six of the eight BoDV-1-positive patients had no record of immunosuppression before the onset of fatal disease, whereas two were immunocompromised after solid organ transplantation. Typical initial symptoms were headache, fever, and confusion, followed by various neurological signs, deep coma, and severe brainstem involvement. Seven of nine patients with fatal encephalitis of unclear cause were BoDV-1 positive within one diagnostic centre. BoDV-1 sequence information and epidemiological analyses indicated independent spillover transmissions most likely from the local wild animal reservoir.

Interpretation: BoDV-1 infection has to be considered as a potentially lethal zoonosis in endemic regions with reported spillover infections in horses and sheep. BoDV-1 infection can result in fatal encephalitis in immunocompromised and apparently healthy people. Consequently, all severe encephalitis cases of unclear cause should be tested for bornaviruses especially in endemic regions.

Funding: German Federal Ministry of Education and Research.
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http://dx.doi.org/10.1016/S1473-3099(19)30546-8DOI Listing
April 2020

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

Ther Adv Neurol Disord 2019 19;12:1756286419892077. Epub 2019 Dec 19.

Neurologische Klinik der Universität Regensburg, Universitätsstraße 84, Regensburg, 93053, Germany.

Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies.

Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded.

Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients.

Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.
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http://dx.doi.org/10.1177/1756286419892077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923693PMC
December 2019

Autoimmune diseases and immunosuppressive therapy in relation to the risk of glioma.

Cancer Med 2020 02 10;9(3):1263-1275. Epub 2019 Dec 10.

Wilhelm Sander-NeuroOncology Unit and Department of Neurology, Regensburg University Hospital, Regensburg, Germany.

Effectors from the immune system can modulate the course and possibly the early development of gliomas. We, therefore, hypothesized that autoimmune diseases associated with increased immune-surveillance may also modulate the risk of human glioma. To test this hypothesis, we used data from the well-validated Clinical Practice Research Datalink (CPRD) GOLD from the UK to analyze the association of immune-related disorders or use of immunosuppressive drugs and the risk of glioma. We identified 3112 incident glioma cases diagnosed between 1995 and 2017. We randomly selected up to 10 controls, matching them to glioma cases on age, sex, index date, general practice, and number of years of active history in the database prior to the index date. We performed conditional logistic regression analyses to estimate Odds Ratios (ORs) of glioma among those exposed to allergies, autoimmune diseases, and immunosuppressive drugs. Overall, we found no materially altered association between a history of any autoimmune disease (OR 0.98, 95% CI 0.86-1.11), allergy (OR 0.97, 95% CI 0.89-1.05), or use of immunosuppressive drugs and the risk of glioma. However, subgroup analyses among younger patients found a statistically significant increased risk of glioma in patients with a history of inflammatory bowel disease (IBD) (OR 2.59, 95% CI 1.31-5.12). There was also an inverse association between asthma and risk of glioma in patients with longer survival (OR 0.73, 95% CI 0.58-0.91) and between long-term duration diabetes and risk of glioma (OR 0.71, 95% CI 0.53-0.96).
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http://dx.doi.org/10.1002/cam4.2767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997055PMC
February 2020

Voxel-wise lesion mapping of self-reported urinary incontinence in multiple sclerosis.

Neurourol Urodyn 2020 01 29;39(1):295-302. Epub 2019 Oct 29.

Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Aims: Besides spinal lesions, urinary incontinence may be attributed to particular cerebral lesion sites in multiple sclerosis (MS) patients. We intended to determine the contribution of suprapontine lesions to urinary incontinence in MS using a voxel-wise lesion analysis.

Methods: In this retrospective study, we sought MS patients with documented urinary incontinence in a local database. We established a control group of MS-patients without documented urinary incontinence matched for gender, age, and disease severity. Patients with urinary incontinence due to local diseases of the urinary tract were excluded. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3T). After manual delineation and transformation into stereotaxic space, we determined the lesion overlap and compared the presence or absence of urinary incontinence voxel-wise between patients with and without lesions in a given voxel performing the Liebermeister test with 4000 permutations.

Results: A total of 56 patients with urinary incontinence and MS fulfilled the criteria and were included. The analysis yielded associations between urinary incontinence and MS in the frontal white matter, temporo-occipital, and parahippocampal regions.

Conclusions: Our voxel-wise analysis indicated associations between self-reported urinary incontinence and lesions in the left frontal white matter and right parahippocampal region. Thus, our data suggest that dysfunction of supraspinal bladder control due to cerebral lesions may contribute to the pathophysiology of urinary incontinence in MS.
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http://dx.doi.org/10.1002/nau.24194DOI Listing
January 2020

Interdisciplinary Decision Making in Hemorrhagic Stroke Based on CT Imaging-Differences Between Neurologists and Neurosurgeons Regarding Estimation of Patients' Symptoms, Glasgow Coma Scale, and National Institutes of Health Stroke Scale.

Front Neurol 2019 26;10:997. Epub 2019 Sep 26.

Department of Neurology, University of Regensburg, Regensburg, Germany.

Acute intracerebral hemorrhage (ICH) requires rapid decision making toward neurosurgery or conservative neurological stroke unit treatment. In a previous study, we found overestimation of clinical symptoms when clinicians rely mainly on cerebral computed tomography (cCT) analysis. The current study investigates differences between neurologists and neurosurgeons estimating specific scores and clinical symptoms. Overall, 14 neurologists and 15 neurosurgeons provided clinical estimates and National Institutes of Health Stroke Scale (NIHSS) as well as Glasgow Coma Scale (GCS) based on cCT images and basic information of 50 patients with hypertensive and lobar ICH. Subgroup analyses were performed for the different professions (neurologists vs. neurosurgeons) and bleeding subtypes (typical location vs. atypical). The differences between the actual GCS and NIHSS scores and the cCT-imaging-based estimated scores were depicted as Bland-Altman plots and negative and positive predictive value (NPV and PPV) for prediction of clinical relevant items. ΔNIHSS points (ΔGCS points) were calculated as the difference between actual and rated NIHSS (GCS) including 95% confidence interval (CI). Mean ΔGCS points for neurosurgeons was 1.16 (95% CI: -2.67-4.98); for neurologists, 0.99 (95% CI: -2.58-4.55), = 0.308; mean ΔNIHSS points for neurosurgeons was -2.95 (95% CI: -12.71-6.82); for neurologists, -0.33 (95% CI: -9.60-8.94), < 0.001. NPV and PPV for stroke symptoms were low, with large differences between different symptoms, bleeding subtypes, and professions. Both professions had more problems in proper rating of specific clinic-neurological symptoms than rating scores. Our results stress the need for joint decision making based on detailed neurological examination and neuroimaging findings also in telemedicine.
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http://dx.doi.org/10.3389/fneur.2019.00997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775244PMC
September 2019

Siponimod (BAF-312) Attenuates Perihemorrhagic Edema And Improves Survival in Experimental Intracerebral Hemorrhage.

Stroke 2019 11 27;50(11):3246-3254. Epub 2019 Sep 27.

From the Department of Neurology (T.B., A.M., P.B., V.B., M.I.S., S.S.R., R.A.L., S.S., H.B.H.), University of Erlangen, Germany.

Background and Purpose- Perihemorrhagic edema (PHE) is associated with poor outcome after intracerebral hemorrhage (ICH). Infiltration of immune cells is considered a major contributor of PHE. Recent studies suggest that immunomodulation via S1PR (sphingosine-1-phosphate receptor) modulators improve outcome in ICH. Siponimod, a selective modulator of sphingosine 1-phosphate receptors type 1 and type 5, demonstrated an excellent safety profile in a large study of patients with multiple sclerosis. Here, we investigated the impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH. Methods- ICH was induced by intracranial injection of 0.075 U of bacterial collagenase in 123 mice. Mice were randomly assigned to different treatment groups: vehicle, siponimod given as a single dosage 30 minutes after the operation or given 3× for 3 consecutive days starting 30 minutes after operation. The primary outcome of our study was evolution of PHE measured by magnetic resonance-imaging on T2-maps 72 hours after ICH, secondary outcomes included evolution of PHE 24 hours after ICH, survival and neurological deficits, as well as effects on circulating blood cells and body weight. Results- Siponimod significantly reduced PHE measured by magnetic resonance imaging (=0.021) as well as wet-dry method (=0.04) 72 hours after ICH. Evaluation of PHE 24 hours after ICH showed a tendency toward attenuated brain edema in the low-dosage group (=0.08). Multiple treatments with siponimod significantly improved neurological deficits measured by Garcia Score (=0.03). Survival at day 10 was improved in mice treated with multiple dosages of siponimod (=0.037). Mice treated with siponimod showed a reduced weight loss after ICH (=0.036). Conclusions- Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in our experimental ICH-model. Findings encourage further investigation of inflammatory modulators as well as the translation of BAF-312 to a human study of ICH patients.
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http://dx.doi.org/10.1161/STROKEAHA.119.027134DOI Listing
November 2019

Long-Term Follow-Up of Cerebral Amyloid Angiopathy-Associated Intracranial Hemorrhage Reveals a High Prevalence of Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2019 Nov 11;28(11):104342. Epub 2019 Sep 11.

Department of Neurology, University of Regensburg, Regensburg, Germany. Electronic address:

Goal: Cerebral amyloid angiopathy (CAA) is the second-most common cause of nontraumatic intracerebral hemorrhages (ICH), surpassed only by uncontrolled hypertension. We characterized the percentage, risk factors, and comorbidities of patients suffering from CAA-related ICH in relation to long-term outcomes.

Material And Methods: We performed retrospective analyses and clinical follow-ups of individuals suffering from ICH who were directly admitted to neurosurgery between 2002 and 2016.

Findings: Seventy-four of 174 (42%) spontaneous nontraumatic lobar ICH cases leastwise satisfied the modified Boston criteria definition for at least "possible CAA." Females suffered a higher risk of CAA-caused ICH (42 of 74, 56.8%, P= .035). Atrial fibrillation as a major comorbidity was observed in 19 patients (25.7%). Recovery (decrease of modified Rankin scale [mRS]) was highest during hospitalization in the acute clinic. One-year mortality was as follows: 14 of 25 patients (56%) with probable CAA without supporting pathology, 6 of 18, and 8 of 31 patients with supporting pathology and possible CAA, respectively. Only 10 of 74 (13.6%) had favorable long-term outcomes (mRS ≤2). Increasing numbers of lobar hemorrhages, low initial Glasgow Coma Scale, and subarachnoid hemorrhage were significantly associated with poor survivability, whereas statins, antithrombotic agents, an intraventricular hemorrhage, and midline shift played seemingly minor roles.

Conclusions: Symptomatic ICH is a serious stage in CAA progression with high mortality. The high incidence of concurrent atrial fibrillation in these patients may support data on more widespread vascular pathology in CAA.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104342DOI Listing
November 2019