Effect of the AMPA Receptor Inhibitor Perampanel in Combination Therapy with ionizing Radiation on Glioblastoma Cells and Fibroblasts - Knabe, A.; Stritzelberger, Jenny; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Effect of the German Act on the reform of the market for medicinal products (AMNOG) on the quality of neurological and psychiatric treatment - Hamer, Hajo; Meyer-Lindenberg, A. (Der Nervenarzt, 2016)
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Effects of a 4-Step Standard Operating Procedure for the Treatment of Fever in Patients With Acute Stroke - Lee, Hanna; Hedtmann, Günter; Schwab, Stefan; Kollmar, Rainer (Frontiers in Neurology, 2021)
Background and Purpose: Fever in the acute phase of stroke leads to an unfavorable clinical outcome and increased mortality. However, no specific form of effective fever treatment has been established, so far. We analyzed the effectiveness of our in-house standard operating procedure (SOP) of fever treatment. Methods: This SOP was analyzed for a period of 33 weeks. Patients with cerebral ischemia (ischemic stroke, transient ischemic attack) or cerebral hemorrhage (intracerebral, subarachnoid) and body temperature elevation of ≥ 37.5°C within the first 6 days after admission were eligible for inclusion in the analysis. The results of SOP group, who's data have been collected prospectively were then compared with a historical control group that had been treated conventionally 1 year earlier in the same period. The data of control group have been collected in retrospect. The primary endpoint was the total duration of the fever for the first 6 days after admission to the stroke unit. Results: A total of 130 patients (mean age of 78 ± 12) received 370 antipyretic interventions. Sequential application of paracetamol (n = 245), metamizole (n = 53) and calf compress (n = 15) led to significant reduction in body temperature. In patients who did not respond to these applications, normothermia could be achieved after infusion of the cooled saline solution. Normothermia could be achieved within 120 min in more than 90% of the cases treated by the SOP. The SOP reduced the fever duration in the 6 days significantly, from 12.2 ± 2.7 h [95% confidence interval (CI) for mean] in the control group to 3.9 ± 1.0 h (95% CI) in the SOP group (p < 0.001). The SOP was rated to be reasonable and effective. Conclusion: Our in-house SOP is cost-efficient and effective for fever treatment in stroke patients, that can be implemented by local health care professionals.
CRIS-Team Scopus Importer:2021-04-02
Keywords: acute stroke; fever; fever treatment; hyperthermia; standard operating procedure

Effects of clobazam for treatment of refractory status epilepticus - Madzar, Dominik; Geyer, Anna; Knappe, Ruben U.; Gollwitzer, Stephanie; Kuramatsu, Joji; Gerner, Stefan; Hamer, Hajo; Huttner, Hagen (BMC Neurology, 2016)
Clobazam (CLB) is a well characterized antiepileptic drug (AED) that differs from other benzodiazepines by its basic chemical structure and pharmacodynamic properties. Only one previous study examined the efficacy of CLB as add-on therapy in refractory status epilepticus (RSE).We analyzed RSE episodes treated in our institution between 2001 and 2012. Successful treatment with CLB was scored if CLB was the last AED added to therapy before RSE termination. We assessed the differences between patients with and without CLB and correlated CLB with outcome. Among patients treated with CLB, we studied responders and non-responders and compared our CLB cohort with recently published data.CLB was part of the AED regimen in 24/70 (34.3 %) RSE episodes. In six of these (25.0 %) RSE resolution was attributed to CLB. Baseline characteristics of episodes with and without CLB treatment showed no significant differences and RSE termination rates were very similar (83.3 % vs. 80.4 %). CLB was administered in clinically more complex RSE with longer RSE duration and worse outcome, but CLB was not related independently to outcome. Comparison of our results with previously published data revealed that baseline characteristics as well as CLB maintenance doses and time of treatment initiation were similar in both cohorts. CLB was less frequently the last AED added to RSE therapy in our patients indicating a lower treatment success rate than previously reported.CLB represents a reasonable AED and promising add-on agent for treatment of RSE. However, rates of successful CLB response were substantially lower than in a recently published study. Differing RSE characteristics and treatment strategies may account for the discrepancy between study results, as RSE etiologies and seizures types associated with unfavorable prognosis were more common in our cohort, while anesthetics tended to be less frequently applied to achieve seizure control.
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Effects of nature-based mindfulness training on resilience/symptom load in professionals with high work-related stress-levels: findings from the WIN-Study - Luecke, Caroline; Braumandl, Sylvia; Becker, Bernhard; Moeller, Sebastian; Custal, Christina; Philipsen, Alexandra; Mueller, Helge H. O. (Mental Illness, 2019)
Purpose - The levels of work-related stress and the incidence rates of subsequent related illnesses are increasing in our society, leading to high individual and socioeconomic burdens. Mindfulness training has been shown to be an effective method of improving stress resilience. This paper aims to investigate the efficacy of nature-based mindfulness training in professionals with high levels of work-related stress.
CRIS-Team WoS Importer:2020-04-17

Effects of perturbed treadmill training on Parkinsonian gait: time-course, sustainability, and transfer effects - Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Pasluosta, Cristian Federico; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Sportmotorik 2019. Adaptation, Lernen und virtuelle Welten. Abstractband zur 16. Jahrestagung der dvs-Sektion Sportmotorik vom 16.-18. Januar 2019 in Bern, 2019)

Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP) - Raccagni, Cecilia; Sidoroff, Victoria; Paraschiv-Ionescu, Anisoara; Roth, Nils; Schönherr, Gudrun; Eskofier, Björn; Gaßner, Heiko; Kluge, Felix; Teatini, Francesco; Seppi, Klaus; Goebel, Georg; Benninger, David H.; et al. (BMJ Open, 2024)
INTRODUCTION: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT). METHODS AND ANALYSIS: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention. ETHICS AND DISSEMINATION: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial. TRIAL REGISTRATION NUMBER: NCT04608604.
CRIS-Team Scopus Importer:2024-05-10
Keywords: Gait Analysis; Multiple System Atrophy; Parkinson-s disease; Rehabilitation medicine

Effects of tofersen treatment in patients with SOD1-ALS in a “real-world” setting – a 12-month multicenter cohort study from the German early access program - Wiesenfarth, Maximilian; Dorst, Johannes; Brenner, David; Elmas, Zeynep; Parlak, Özlem; Uzelac, Zeljko; Kandler, Katharina; Mayer, Kristina; Weiland, Ulrike; Herrmann, Christine; Schuster, Joachim; Freischmidt, Axel; et al. (EClinicalMedicine, 2024)
Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0–42.0) to 35.0 (IQR 29.0–42.0), corresponding to a median progression rate of 0.11 (IQR −0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0–147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0–65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061–6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521–2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.
CRIS-Team Scopus Importer:2024-03-01
Keywords: Amyotrophic lateral sclerosis; Antisense oligonucleotide; Early access program; SOD1; Tofersen

Efficacy and feasibility of home-based training for individuals with homonymous visual field defects - Aimola, Lina; Lane, Alison R.; Smith, Daniel T.; Kerkhoff, Georg; Ford, Gary A.; Schenk, Thomas (Neurorehabilitation and Neural Repair, 2014)
Homonymous visual field defects (HVFDs) are one of the most common consequences of stroke. Compensatory training encourages affected individuals to develop more efficient eye movements to improve function. However, training is typically supervised, which can be time consuming and costly.To develop and evaluate the efficacy and feasibility of an unsupervised reading and exploration computer training for individuals with HVFDs.Seventy individuals with chronic HVFDs were randomly assigned to 1 of 2 groups: intervention or control. The former received 35 hours of reading and exploration training, and the latter received 35 hours of control training. Visual and attentional abilities were assessed before and after training using perimetry, visual search, reading, activities of daily living, the Test of Everyday Attention, and a Sustained Attention to Response task.Eighteen individuals failed to complete the training; analyses were conducted on the remaining 28 intervention and 24 control group participants. Individuals in the intervention group demonstrated significant improvements in the primary outcomes of exploration (12.87%, 95% confidence interval [CI] = 8.44% to 17.30%) and reading (18.45%, 95% CI = 9.93% to 26.97%), which were significantly greater than those observed following the control intervention (exploration = 4.80%, 95% CI = 0.09% to 9.51%; reading = 1.95%, 95% CI = -4.78% to 8.68%). Participants in the intervention group also reported secondary subjective improvements, although these were not matched by objective gains in tasks simulating activities of daily living.Home-based compensatory training is an inexpensive accessible rehabilitation option for individuals with HVFDs, which can result in objective benefits in searching and reading, as well as improving quality of life.
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Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation - Pfeuffer, Steffen; Schmidt, Rene; Straeten, Frederike Anne; Pul, Refik; Kleinschnitz, Christoph; Wieshuber, Marinus; Lee, De-Hyung; Linker, Ralf; Doerck, Sebastian; Straeten, Vera; Windhagen, Susanne; Pawlitzki, Marc; et al. (Journal of Neurology, 2019)
Background: Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce. Objective: To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ. Methods: We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation. Results: 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12–4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04–57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26–4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74–13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time). Conclusion: Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Alemtuzumab; Fingolimod; Immunomodulatory therapy; Natalizumab; Progressive multifocal leukoencephalopathy; Remitting-relapsing multiple sclerosis

Efficacy and safety of combined intraventricular fibrinolysis with lumbar drainage for prevention of permanent shunt dependency after intracerebral hemorrhage with severe ventricular involvement: A randomized trial and individual patient data meta-analysi - Staykov, Dimitre; Kuramatsu, Joji; Bardutzky, Juergen; Volbers, Bastian; Gerner, Stefan; Kloska, Stephan; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen (Annals of Neurology, 2017)
Intraventricular hemorrhage (IVH) is a negative prognostic factor in intracerebral hemorrhage (ICH) and is associated with permanent shunt dependency in a substantial proportion of patients post-ICH. IVH treatment by intraventricular fibrinolysis (IVF) was recently linked to reduced mortality rates in the CLEAR III study and IVF represents a safe and effective strategy to hasten clot resolution that may reduce shunt rates. Additionally, promising results from observational studies reported reductions in shunt dependency for a combined treatment approach of IVF plus lumbar drains (LDs). The present randomized, controlled trial investigated efficacy and safety of a combined strategy-IVF plus LD versus IVF alone-on shunt dependency in patients with ICH and severe IVH.This randomized, open-label, parallel-group study included patients aged 18 to 85 years, prehospital modified Rankin Scale <=3, ICH volume < 60ml, Glasgow Coma Scale of <9, and severe IVH with tamponade of the third and fourth ventricles requiring placement of external ventricular drainage (EVD). Over a 3-year recruitment period, patients were allocated to either standard treatment (control group receiving IVF consisting of 1mg of recombinant human tissue plasminogen activator every 8 hours until clot clearance of third and fourth ventricles) or a combined treatment approach of IVF and-upon clot clearance of third and fourth ventricles-subsequent placement of an LD for drainage of cerebrospinal fluid (CSF; intervention group). The primary endpoint consisted of permanent shunt placement indicated after a total of three unsuccessful EVD clamping attempts or need for CSF drainage longer than 14 days in both groups. Secondary endpoints included IVF- and LD-related safety, such as bleeding or infections, and functional outcome at 90 and 180 days. Conducted endpoint analyses used individual patient data meta-analyses. The study was registered at clinicaltrials.gov (NCT01041950).The trial was stopped upon predefined interim analysis after 30 patients because of significant efficacy of tested intervention. The primary endpoint was analyzed without dropouts and was reached in 43% (7 of 16) of the control group versus 0% (0 of 14) of the intervention group (p = 0.007). Meta-analyses were based on overall 97 patients, 45 patients receiving IVF plus LD versus 42 with IVF only. Meta-analyses on shunt dependency showed an absolute risk reduction of 24% for the intervention (LD, 2.2% [1 of 45] vs no-LD, 26.2% [11 of 42]; odds ratio [OR] = 0.062; confidence interval [CI], 0.011-0.361; p = 0.002). Secondary endpoints did not show significant differences for CSF infections (OR = 0.869;CI, 0.445-1.695; p = 0.680) and functional outcome at 90 days (OR = 0.478; CI, 0.190-1.201; p = 0.116), yet bleeding complications were significantly reduced in favor of the intervention (OR = 0.401; CI, 0.302-0.532; p < 0.001).The present trial and individual patient data meta-analyses provide evidence that, in patients with severe IVH, as compared to IVF alone, a combined approach of IVF plus LD treatment is feasible and safe and significantly reduces rates of permanent shunt dependency for aresorptive hydrocephalus post-ICH. ANN NEUROL 2017;81:93-103.
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Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells - Lanfer, Jonas; Winner, Beate; Kaindl, Johanna; Krumm, Laura; Acera, Miguel Gonzalez; Neurath, Markus; Regensburger, Martin; Krach, Florian (International Journal of Molecular Sciences, 2022)
Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield. The protocol implemented a freezing step, thus allowing HPC biobanking and flexible timing of differentiation into iMGL. Our iMGL responded adequately to the inflammatory stimuli LPS, and iMGL RNAseq analysis matched those of other frequently used protocols. Comparing three different coating modalities, we increased the iMGL yield by culturing on uncoated glass surfaces, thereby retaining differentiation efficiency and functional hallmarks of iMGL. In summary, we provide a high-quality, easy-to-use protocol, rendering generation and functional studies on iMGL an accessible lab resource.
CRIS-Team Scopus Importer:2022-04-29
Keywords: cell differentiation; immunology; microglia; neurology; pluripotent stem cells

Einfluss von körperlicher Aktivität auf die psychische Verfassung von nicht behinderten MS-Patienten - Tallner, Alexander; Mäurer, Mathias Eckhard; Waschbisch, Anne; Hentschke, Christian; Pfeifer, Klaus (Der Nervenarzt, 2009)

Einfluss von körperlicher Aktivität auf Lebensqualität und psychische Gesundheit von Multiple Sklerose Patienten. - Tallner, Alexander; Mäurer, Mathias; Waschbisch, Anne; Hentschke, Christian; Pfeifer, Klaus (Innovation und Rehabilitation - Kommunikation und Vernetzung, 2010)

Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology - Cheshire, William P.; Freeman, Roy; Gibbons, Christopher H.; Cortelli, Pietro; Wenning, Gregor K.; Hilz, Max-Josef; Spies, Judith M.; Lipp, Axel; Sandroni, Paola; Wada, Naoki; Mano, Akiko; Ah Kim, Hyun; et al. (Clinical Neurophysiology, 2021)
Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Autonomic; Autonomic nervous system diseases; Denervation; Diabetic autonomic neuropathy; Hypotension; Orthostatic; Tilt table test; Valsalva Maneuver

Elevated VEGF-plasma levels in young patients with mild essential hypertension - Stumpf, Christian; Jukic, Jelena; Yilmaz, A.; Raaz, Dorette; Schmieder, Roland; Daniel, Werner; Garlichs, Christoph (European Journal of Clinical Investigation, 2009)
Background: Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Vascular endothelial cell growth factor (VEGF) is currently discussed as a possible mediator of inflammation. To investigate the hypothesis that VEGF plays a role as an inflammatory mediator in EH we performed the present pilot study of young patients in a very early stage of EH. Materials and methods: 15 young patients with mild EH [33.8 ± 7.3 years, systolic blood pressure (SBP): 143.8 ± 10.5 mmHg, diastolic blood pressure (DBP): 88.2 ± 11.1 mmHg, mean arterial pressure (MAP) 106.6 ± 10.4 mmHg] and 15 healthy controls (31.7 ± 10.6 years) were examined. Blood was drawn from a peripheral vein and serum levels of VEGF, monocyte-chemoattractant-protein (MCP)-1, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and tumour-necrosis-factor (TNF)-α were measured via commercially available enzyme-linked immunoassays. Results: Hypertensives showed increased plasma levels of VEGF (P < 0.05) and MCP-1 (P < 0.05). VEGF positively correlated with MAP (r = 0.46, P < 0.05) and MCP-1 (r = 0.63, P < 0.01). Multivariate analysis demonstrated VEGF to be an independent predictor of MCP-1 levels. Furthermore, hypertensives had higher levels of hsCRP (P < 0.01), IL-6 (P < 0.001) and TNF-α (P < 0.05). IL-6 levels correlated with SBP (r = 0.59, P < 0.001), DBP (r = 0.67, P < 0.001) and MAP (r = 0.46, P < 0.001). A significant positive correlation was also found between hsCRP levels and SBP (r = 0.39, P < 0.05). Conclusions: This pilot study demonstrates that in an early state of EH, inflammatory pathways have already been activated. Besides classical pro-inflammatory cytokines, VEGF serum levels are significantly elevated. The positive correlation of VEGF with MCP-1 is suggestive for the already described induction of MCP-1 via VEGF. © 2008 The Authors.
CRIS-Team Scopus Importer:2024-12-04
Keywords: Cytokines; Hypertension; Inflammation; VEGF

Emil Bratz (1868–1934): the life and work of an early German epileptologist Emil Bratz (1868–1934): Leben und Werk eines frühen deutschen Epileptologen - Kasper, Burkhard S.; Hebold, M.; Stockmann, J. P. (Clinical Epileptology, 2025)
Emil Bratz (1868–1934) was a German neuropsychiatrist who worked in Berlin institutions until 1933. From 1894 to 1910 he was affiliated with Berlin-Wuhlgarten, one of the first hospitals and colonies dedicated exclusively to epilepsy patients in Europe. From the beginning of his career, he actively researched the topic of epilepsy including pathoanatomical microscopic studies of Ammon’s horn starting before 1900. At the beginning of the 20th century, he wrote extensively on the topic of epilepsy. Furthermore, he represented Germany in the founding years of the International League Against Epilepsy (ILAE) and belonged to the group that established the journal Epilepsia. Here we commemorate Emil Bratz, an early but largely forgotten epileptologist, by presenting the first comprehensive synopsis of Bratz’s life and work including new information from first-hand materials, illustrating his professional career and research activities as an epileptologist, providing a full list of his publications on epilepsy, and describing his role in the founding years of ILAE and Epilepsia. As we show, Emil Bratz deserves to be remembered for his important contributions to the rise of epileptology at the turn of the 20th century.
CRIS-Team Scopus Importer:2025-03-28
Keywords: Ammon’s horn sclerosis; Epilepsy; Hebold; Pathoanatomy; Wuhlgarten

Emotional and Autonomic Processing of Olfactory Stimuli Is Compromised in Patients with a History of Mild Traumatic Brain Injury - Hilz, Max-Josef; Wang, Ruihao; Liu, Mao; Muresanu, Dafin; Flanagan, Steven; Winder, Klemens; Hoesl, Katharina; Hummel, Thomas (Journal of Neurotrauma, 2019)
Patients with a history of mild traumatic brain injury (post-mTBI patients) may have enduring cardiovascular-autonomic dysregulation and emotional problems. Olfactory stimulation (OS) triggers emotional and cardiovascular-autonomic responses that might be compromised in post-mTBI patients. We therefore evaluated these responses to OS in post-mTBI patients. In 17 post-mTBI patients (interval since mTBI: 32.4 +/- 6.8 months) and 17 age- and sex-matched controls, we recorded respiration, electrocardiographic RR intervals, and systolic and diastolic blood pressures (BPsys, BPdia) before and during pleasant vanilla stimulation and unpleasant hydrogen sulphide (H2S) stimulation. Participants rated OS-related pleasantness, arousal, intensity, and familiarity on 9-point Likert scales. Analyses of variance (ANOVAs) with post hoc analyses compared parameters within each group before and during OS. To assess associations between pleasantness, arousal, intensity, and familiarity, we correlated OS scores within groups (significance: p < 0.05). Baseline parameters were similar between groups. Only in controls, vanilla stimulation significantly lowered BPsys and BPdia, whereas H2S stimulation lowered RR intervals. Vanilla-related pleasantness scores were lower, intensity scores were higher in patients than controls. During vanilla stimulation, pleasantness scores correlated negatively with arousal scores in controls, whereas familiarity scores correlated positively with intensity scores in patients. During H2S stimulation, familiarity scores correlated negatively with pleasantness scores in controls, whereas pleasantness scores correlated negatively with arousal scores in mTBI patients. Post-mTBI patients could not change BP or RR intervals during OS but perceived vanilla stimuli as less pleasant and more intense than did controls. Associations between pleasantness, arousal, intensity, and familiarity differed between groups suggesting different activation of the olfactory network and the central autonomic network upon OS. Subtle lesions within these networks might cause persistent changes in emotional and cognitive odor perception and cardiovascular responses.
CRIS-Team WoS Importer:2019-08-30

Empfehlung zum differenzierten Einsatz nuklearmedizinischer Diagnostik bei Parkinson-Syndromen - van Eimeren, Thilo; Claßen, Joseph; Drzezga, Alexander; Eggers, Carsten; Hilker-Roggendorf, Rüdiger; Klucken, Jochen; Koschel, Jiri; Meyer, Philipp Tobias; Redecker, Christoph; Theis, Hendrik; Buhmann, Carsten (Fortschritte der Neurologie - Psychiatrie, 2020)
The present work provides an overview of the various nuclear medicine methods in the diagnosis of neurodegenerative parkinsonian syndromes and their respective evidence and is intended to enable practical decision-making aids in the application and interpretation of the methods and findings. The value of the procedures differs considerably in relation to the two relevant diagnostic questions. On the one hand, it is the question of whether there is a neurodegenerative parkinsonian syndrome at all, and on the other hand the question of which one. While the DAT-SPECT is undisputedly the method of choice for answering the first question (taking certain parameters into account), this method is not suitable for answering the second question. To categorise parkinsonian syndromes into idiopathic (i. e. Parkinson´s disease) or atypical, various procedures are used in everyday clinical practice including MIBG scintigraphy, and FDG-PET. We explain why FDG-PET currently is not only the most suitable of these methods to differentiate an idiopathic parkinsonian syndrome, from an atypical Parkinson's syndrome, but also enables sufficiently valid to distinguish the various atypical neurodegenerative Parkinson's syndromes (i. e. MSA, PSP and CBD) from each other and therefore should be reimbursed by health insurances.
CRIS-Team Scopus Importer:2020-10-02

Endogenous endophthalmitis complicating Streptococcus equi subspecies zooepidemicus meningitis: a case report - Madžar, Dominik; Hagge, Mareike; Möller, Sebastian; Regensburger, Martin; Lee, De Hyung; Schwab, Stefan; Jantsch, Jonathan (BMC Research Notes, 2015)
Streptococcus equi subspecies zooepidemicus (Streptococcus zooepidemicus) is a rare cause of meningitis in humans. Humans mainly get infected by contact with an animal source or by ingestion of unpasteurized dairy products. In rare cases, bacterial meningitis can be complicated by endogenous endophthalmitis which is frequently associated with a poor visual prognosis.A 73 year old male Caucasian patient presented with clinical signs indicative of bacterial meningitis. Blood and cerebrospinal fluid cultures yielded beta-hemolytic, catalase-negative cocci. The strain was identified as Streptococcus zooepidemicus. The patient was likely infected by contact with a sick horse. Under antibiotic treatment, his general condition improved rapidly. Early after hospital admission, however, he began seeing a black spot in his left eye's central visual field. An ophthalmological examination revealed signs of endogenous endophthalmitis and so the patient underwent vitrectomy. Despite treatment, the visual acuity of his left eye remained severely impaired. He showed no further neurological deficits at hospital discharge.Meningitis caused by Streptococcus zooepidemicus is rare with only 27 previously published adult cases in the literature. Of note, this report constitutes the third description of endogenous endophthalmitis associated with Streptococcus zooepidemicus meningitis. Thus, endogenous endophthalmitis may represent a comparatively common complication of meningitis caused by this microorganism.
EVALuna2:22366

Endovascular stroke treatment’s impact on malignant type of edema (ESTIMATE) - Fuhrer, Hannah; Schoenenberger, Silvia; Niesen, Wolf-Dirk; Seide, Svenja; Meyne, Johannes; Gerner, Stefan; Vollmuth, Christoph; Beck, Christopher; Meckel, Stephan; Schocke, Michael; Wodarg, Fritz; Huttner, Hagen; et al. (Journal of Neurology, 2019)
Background and purpose: In patients with acute ischemic stroke and large vessel occlusion, the prognosis has improved tremendously since the implementation of endovascular thrombectomy (EVT). The effect of EVT on the incidence of malignant middle cerebral artery infarctions (MMI) has not been studied before. Methods: ESTIMATE, a multicenter retrospective study, evaluates data of ischemic stroke patients with occlusion in the anterior circulation in the years of 2007–2015 comparing three treatment options (no therapy; IV-TPA; IV-TPA plus EVT or EVT only). Primary endpoint of the study was the incidence of MMI on follow-up imaging and mortality rates. Secondary endpoints were functional outcome, further clinical and imaging data. Logistic and Cox-regression models with a propensity score weighting approach were applied to evaluate differences between treatment groups. Results: In 2161 patients over 9 years, EVT reduced the MMI rates significantly: patients without acute stroke treatment had increased odds for MMI of 1.57 [95% confidence interval (CI) 1.49–1.65]. In contrast, after treatment with IV-TPA, only we observed an OR of 0.88 (95% CI 0.83–0.94, p < 0.001), and after EVT an OR of 0.80 (95% CI 0.76–0.85, p < 0.001). This was more pronounced in larger pretreatment infarctions (ASPECTS < 5, p < 0.01). IV-TPA also lowers the MMI rates but not to the same extent. EVT-treated patients had increased survival rates (p < 0.05) and the best functional outcome at discharge. Conclusions: The findings of this study illustrate that occurrence of MMI and mortality rates was significantly reduced in patients treated with EVT.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Brain ischemia; Infarction; Middle cerebral artery; Stroke; Thrombectomy; Treatment outcome

Endovascular therapy of isolated posterior cerebral artery occlusion stroke with and without general anesthesia - Berberich, Anne; Herweh, Christian; Qureshi, Muhammad M.; Strambo, Davide; Michel, Patrik; Räty, Silja; Abdalkader, Mohamad; Virtanen, Pekka; Olive Gadea, Marta; Ribo, Marc; Psychogios, Marios Nikos; Nguyen, Anh; et al. (Journal of Neurointerventional Surgery, 2024)
Background: The optimal anesthetic strategy for endovascular therapy (EVT) in acute ischemic stroke is still under debate. The aim of this study was to compare the clinical outcomes of patients with isolated posterior cerebral artery (PCA) occlusion stroke undergoing EVT by anesthesia modality with conscious sedation (non-GA) versus general anesthesia (GA). Methods: Patients from the Posterior CerebraL Artery Occlusion (PLATO) study were analyzed with regard to anesthetic strategy. GA was compared with non-GA using multivariable logistic regression and inverse probability of weighting treatment (IPTW) methods. The primary endpoint was the 90-day distribution of the modified Rankin Scale (mRS) score. Secondary outcomes included functional independence or return to Rankin at day 90, and successful reperfusion, defined as expanded Thrombolysis in Cerebral Infarction (eTICI) 2b to 3. Safety endpoints were symptomatic intracranial hemorrhage and mortality. Results: Among 376 patients with isolated PCA occlusion stroke treated with EVT, 183 (49%) had GA. The treatment groups were comparable, although the GA group contained more patients with severe stroke and lower posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS). On IPTW analysis, there was no difference between groups with regard to ordinal mRS shift analysis (common OR 0.89, 95% CI 0.53 to 1.51, P=0.67) or functional independence (OR 0.84, 95% CI 0.50 to 1.39, P=0.49). There were greater odds for successful reperfusion with GA (OR 1.70, 95% CI 1.17 to 2.47, P=0.01). Safety outcomes were comparable between groups. Conclusion: In patients with isolated PCA occlusion undergoing EVT, patients treated with GA had higher reperfusion rates compared with non-GA. Both GA and non-GA strategies were safe and functional outcomes were similar.
CRIS-Team Scopus Importer:2024-07-19
Keywords: Intervention; Stroke; Thrombectomy

Endovascular thrombectomy for ischemic stroke - Kallmünzer, Bernd; Koehrmann, M. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2017)
The standard of care for patients with acute stroke of the anterior circulation and large vessel occlusion is the combined treatment with intravenous rt-PA (recombinant tissue-type plasminogen activator) and endovascular thrombectomy. The therapy is highly effective while reducing functional deficits and long-term disability. International guidelines recommend thrombectomy during the first 6 h after symptom onset, but new evidence supports its use in selected patients within a time window of up to 24 h. Eligible patients show a clinical core mismatch, i. e. severe neurologic deficits contrasting to a small core of cerebral infarction. Future research questions regard the treatment of vessel occlusion at the M2 segments as well as the best anesthetic management during the intervention. The infrastructure of stroke care especially in rural areas is based on the drip-and-ship paradigm that implies emergency treatment with the start of intravenous thrombolysis at the nearest hospital followed by transport to an interventional center in case of large vessel occlusion.
EVALuna2:22559

Endovascular thrombectomy in patients with anterior circulation stroke: an emulated real-world comparison - Sembill, Jochen; Sprügel, Maximilian; Haupenthal, David; Kremer, Svenja; Knott, Michael; Mühlen, Iris; Kallmünzer, Bernd; Kuramatsu, Joji (Neurological Research and Practice, 2024)
Background: Endovascular thrombectomy (EVT) has been proven effective in anterior circulation stroke due to large vessel occlusion (LVO). However, translation from randomized clinical trials (RCTs) with highly selected patients to real-world requires confirmation, particularly to identify associations outside of strict selection criteria. Aims: This study aims to compare functional outcomes after EVT in real-world with those reported in RCTs, and to identify associations with functional outcome after EVT outside RCT-criteria. Methods: This study analyzed longitudinal German real-world data from the Stroke Research Consortium in Northern Bavaria (STAMINA) cohort from January, 2015 to June, 2019. We conducted a trial emulation, comparing patients with anterior circulation stroke and LVO meeting selection criteria for RCTs investigating EVT (1) predominantly within 6 hours with those from HERMES meta-analysis, and (2) within 6-24 hours with those from AURORA meta-analysis. We (3) analyzed treatment effects of EVT and association with functional outcome in patients treated outside RCT criteria. Results: Of 598 patients, 281 (47.0%) met RCT-criteria for treatment within 6 hours (hereinafter STAMINA-HERMES), 74 (12.4%) met RCT-criteria for treatment within 6–24 hours (STAMINA-AURORA), and 277 (46.3%) patients received EVT outside RCT-criteria. We observed no difference in rates of functional independence or mortality, comparing STAMINA-HERMES with HERMES meta-analysis (mRS 0-1: n=120/281 [43%] vs. 291/633 [46%], p=0.36; mortality: n=34/281 [12%] vs. 97/633 [15%], p=0.20), and STAMINA-AURORA with AURORA meta-analysis (mRS 0-1: n=26/74 [35%] vs. 122/266 [46%], p=0.10, mortality: n=10/74 [14%] vs. 45/266 [17%], p=0.48). Patients treated outside RCT-criteria had worse outcome (mRS 0-1: n=38/277 [14%], mortality: n=90/277 [32%], both p<0.001); possibly driven by pre-existing functional dependence (n=172/277 [62%]). Compared to matched controls, EVT outside of RCT-criteria was associated with lower mortality (absolute treatment effect: -14%, 95% Confidence Interval [CI] -23 to -5, p<0.01), but not with recovery to functional independence or premorbid functional status (treatment effect: 4%, CI -4 to 11, p=0.34), which was associated with lower NIHSS (Odds ratio [OR] 0.86, CI 0.80-0.92, p<0.001) and age (OR 0.95, CI 0.93-0.98, p=0.002). Conclusions: Translation of EVT outcomes reported in RCTs into real-world is possible, however, almost half of patients did not meet trial criteria. Identification of patients who functionally benefit from frequently performed EVT outside RCT-criteria requires further investigation. Trial registration: Clinicaltrials.gov, NCT04357899.
CRIS-Team Scopus Importer:2024-08-02
Keywords: Stroke; Thrombectomy; Treatment

Endovascular treatment in patients with large vessel occlusion: reduced mortality despite minimal penumbra - Schmidt, Manuel; Breuer, Lorenz; Kallmünzer, Bernd; Schwab, Stefan; Dörfler, Arnd; Engelhorn, Tobias; Hölter, Philip (Neuroradiology, 2019)
Purpose: In patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO), endovascular treatment (EVT) is highly effective for emergency revascularization. However, data on functional outcome are lacking for patients, which show no or minimal mismatch between ischemic core and penumbra. Methods: Forty-five patients with AIS due to LVO of the anterior circulation were retrospectively analyzed within 6 h since onset when administered to our department. In all patients, there was no relevant penumbra according to CT perfusion (CTP). Functional outcome, defined by the modified Rankin Scale (mRS) at 30 and 90 days, was analyzed according to LVO treatment (EVT versus non-EVT). Confounding was addressed by multivariable regression analyses. Results: mRS values at 30 days (p = 0.002) and 90 days (p = 0.005) after AIS occurrence were significantly lower in patients who had received EVT. There was no significant difference regarding good functional outcome, as measured by mRS of 0–2 at 30 (p = 0.432) and 90 days, respectively (p = 0.186). Mortality was significantly reduced in patients undergoing EVT at 30-day (p < 0.001) and at 90-day follow-up (p = 0.003), respectively. Multivariable regression analyses revealed that EVT was associated with reduced mortality at 30 (OR 0.091; CI (0.013–0.612); p = 0.014) and 90 days (OR 0.134; CI (0.021–0.857); p = 0.034) after AIS. Conclusions: Despite a small and highly selected patient collective, our study indicates that AIS patients with minimal penumbra in CTP might benefit from EVT in terms of reduced mortality at 30 and 90 days after AIS. However, in this group of patients, we could not prove favorable functional outcome at 30 and 90 days, despite receiving EVT.
CRIS-Team Scopus Importer:2019-09-17
Keywords: CTP; Endovascular treatment; Mortality; Penumbra; Stroke

Endovascular treatment of large vessel occlusion acute ischemic stroke: Is there a place for hypothermia? - Macha, Kosmas; Schwab, Stefan (European Journal of Neurology, 2021)
CRIS-Team WoS Importer:2021-06-25

Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study. - Nguyen, Thanh N.; Qureshi, Muhammad M.; Strambo, Davide; Strbian, Daniel; Räty, Silja; Herweh, Christian; Abdalkader, Mohamad; Olive-Gadea, Marta; Ribo, Marc; Psychogios, Marios; Fischer, Urs; Nguyen, Anh; et al. (Stroke, 2023)
BACKGROUND: The optimal management of patients with isolated posterior cerebral artery occlusion is uncertain. We compared clinical outcomes for endovascular therapy (EVT) versus medical management (MM) in patients with isolated posterior cerebral artery occlusion. METHODS: This multinational case-control study conducted at 27 sites in Europe and North America included consecutive patients with isolated posterior cerebral artery occlusion presenting within 24 hours of time last well from January 2015 to August 2022. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The coprimary outcomes were the 90-day modified Rankin Scale ordinal shift and ≥2-point decrease in the National Institutes of Health Stroke Scale. RESULTS: Of 1023 patients, 589 (57.6%) were male with median (interquartile range) age of 74 (64-82) years. The median (interquartile range) National Institutes of Health Stroke Scale was 6 (3-10). The occlusion segments were P1 (41.2%), P2 (49.2%), and P3 (7.1%). Overall, intravenous thrombolysis was administered in 43% and EVT in 37%. There was no difference between the EVT and MM groups in the 90-day modified Rankin Scale shift (aOR, 1.13 [95% CI, 0.85-1.50]; P=0.41). There were higher odds of a decrease in the National Institutes of Health Stroke Scale by ≥2 points with EVT (aOR, 1.84 [95% CI, 1.35-2.52]; P=0.0001). Compared with MM, EVT was associated with a higher likelihood of excellent outcome (aOR, 1.50 [95% CI, 1.07-2.09]; P=0.018), complete vision recovery, and similar rates of functional independence (modified Rankin Scale score, 0-2), despite a higher rate of SICH and mortality (symptomatic intracranial hemorrhage, 6.2% versus 1.7%; P=0.0001; mortality, 10.1% versus 5.0%; P=0.002). CONCLUSIONS: In patients with isolated posterior cerebral artery occlusion, EVT was associated with similar odds of disability by ordinal modified Rankin Scale, higher odds of early National Institutes of Health stroke scale improvement, and complete vision recovery compared with MM. There was a higher likelihood of excellent outcome in the EVT group despite a higher rate of symptomatic intracranial hemorrhage and mortality. Continued enrollment into ongoing distal vessel occlusion randomized trials is warranted.
EVALuna2:536990

Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry - Drexler, Richard; Ben-Haim, Sharona; Bien, Christian G.; Borger, Valeri; Cardinale, Francesco; Carpentier, Alexandre; Cendes, Fernando; Chandra, Sarat; Clusmann, Hans; Colon, Albert; Curtis, Marco De; Delev, Daniel; et al. (Frontiers in Neurology, 2021)
Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical Trial Registration:This study is indexed at clinicaltrials.gov (NT 04952298).
CRIS-Team WoS Importer:2022-01-28

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD - Nuber, Silke; Tadros, Daniel; Fields, Jerel; Overk, Cassia Rose; Ettle, Benjamin; Kosberg, Kori; Mante, Michael; Rockenstein, Edward; Trejo, Margarita; Masliah, Eliezer (Acta Neuropathologica, 2014)
The olfactory bulb (OB) is one of the first brain regions in Parkinson's disease (PD) to contain alpha-synuclein (?-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for ?-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory ?-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant ?-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory ?-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread ?-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of ?-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed ?-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble ?-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human ?-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.
EVALuna2:25321

Epidemiological, clinical and radiological characteristics of people with neurocysticercosis in Tanzania-A cross-sectional study - Stelzle, Dominik; Makasi, Charles; Schmidt, Veronika; Trevisan, Chiara; van Damme, Inge; Welte, Tamara; Ruether, Charlotte; Fleury, Agnes; Dorny, Pierre; Magnussen, Pascal; Zulu, Gideon; Mwape, Kabemba E.; et al. (Plos Neglected Tropical Diseases, 2022)
BACKGROUND: Neurocysticercosis (NCC) is common among people with epilepsy in low-resource settings. Prevalence of NCC and radiological characteristics of patients with NCC vary considerably even within small areas but differences have been poorly characterized so far. METHODS: We conducted a cross-sectional study between August 2018 and April 2020 in three district hospitals in southern Tanzania (Ifisi, Tukuyu and Vwawa). Patients with and without epileptic seizures were included in this study. All patients were tested with a novel antibody-detecting point-of-care test for the diagnosis of Taenia solium cysticercosis. All test positives and a subset of test negatives had a further clinical work-up including medical examination and computed tomography of the brain. NCC was defined according to the Del Brutto criteria. We assessed epidemiological, clinical and radiological characteristics of patients with NCC by presence of epileptic seizures and by serology status. RESULTS: In all three district hospitals, more than 30% of all people with epileptic seizures (PWE) had NCC lesions in their brain (38% in Vwawa, 32% in Tukuyu and 31% in Ifisi). Most PWE with NCC had multiple lesions and mostly parenchymal lesions (at least 85%). If patients were serologically positive, they had in the median more lesions than serologically negative patients (15 [interquartile range 8-29] versus 5 [1.8-11]), and only serologically positive patients had active stage lesions. Furthermore, serologically positive PWE had more lesions than serologically positive people without epileptic seizures (10.5 [7-23]), and more often had active lesions. PWE diagnosed with NCC (n = 53) were older, and more commonly had focal onset seizures (68% versus 44%, p = 0.03) and headache episodes (34% versus 14%, p = 0.06), which were also stronger than in PWE without NCC (p = 0.04). CONCLUSION: NCC is common among PWE. A combination of clinical and serological factors could help to establish an algorithm to identify patients potentially suffering from active NCC, who benefit from further clinical investigation including neuroimaging.
CRIS-Team Scopus Importer:2022-12-09

Epidemiology of epilepsy in old age – English Version Epidemiologie der Epilepsie im höheren Lebensalter – Englische Version - Lang, Johannes; Hamer, Hajo (Zeitschrift für Epileptologie, 2022)
Background: Epilepsy is a common neurological disease affecting all ages. The increasing frequency of symptomatic epilepsies with age is partly due to cerebrovascular and neurodegenerative diseases. Better knowledge of the epidemiology of epilepsy in old age improves our understanding of the disease as well as the therapeutic and sociomedical challenges for the individual and society. Objective: What do we currently know about the epidemiology of the epilepsies in old age and how should this be classified? Material and methods: A MEDLINE search in PubMed was conducted using the terms “epilepsy”, “elderly” and “incidence” or “prevalence” or “epidemiology” and relevant publications were analyzed. Results: The point prevalence of epilepsy of older age is 0.5–0.8% of the population and affects approximately 500,000 people in Germany. The highest age-adjusted prevalence is reported to lie beyond the age of 75 years. In recent decades, the prevalence climbed further among the 75-year-olds to be twice as high as among the adult working population. The incidence shows a significant increase among patients 65 years and older, reaches its maximum at around 80–85 years of age and is somewhat higher in men. Conclusion: Reasons for the high incidence and prevalence of epilepsy in old age are the age-related incidence of potentially epilepsy-associated diseases combined with a longer long-term survival for these diseases due to better medical care and an increase in life expectancy. The change in the age pyramid with a higher (and in the coming decades further increasing) proportion of old people, will further increase the rise of epilepsy of older age.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Aged; Elderly; Incidence; Prevalence; Seizures

Epidemiology of epilepsy in old age. German version Epidemiologie der Epilepsie im höheren Lebensalter - Lang, Johannes; Hamer, Hajo (Zeitschrift für Epileptologie, 2022)
Background: Epilepsy is a common neurological disease affecting all ages. The increasing frequency of symptomatic epilepsies with age is partly due to cerebrovascular and neurodegenerative diseases. Better knowledge of the epidemiology of epilepsy in old age improves our understanding of the disease as well as the therapeutic and sociomedical challenges for the individual and society. Objective: What do we currently know about the epidemiology of the epilepsies in old age and how should this be classified? Material and methods: A MEDLINE search in PubMed was conducted using the terms “epilepsy”, “elderly” and “incidence” or “prevalence” or “epidemiology” and relevant publications were analyzed. Results: The point prevalence of epilepsy of older age is 0.5–0.8% of the population and affects approximately 500,000 people in Germany. The highest age-adjusted prevalence is reported to lie beyond the age of 75 years. In recent decades, the prevalence climbed further among the 75-year-olds to be twice as high as among the adult working population. The incidence shows a significant increase among patients 65 years and older, reaches its maximum at around 80–85 years of age and is somewhat higher in men. Conclusion: Reasons for the high incidence and prevalence of epilepsy in old age are the age-related incidence of potentially epilepsy-associated diseases combined with a longer long-term survival for these diseases due to better medical care and an increase in life expectancy. The change in the age pyramid with a higher (and in the coming decades further increasing) proportion of old people, will further increase the rise of epilepsy of older age.
CRIS-Team Scopus Importer:2022-05-20
Keywords: Aged; Elderly; Incidence; Prevalence; Seizures

Epidemiology of ischemic stroke subtypes according to TOAST criteria: Incidence, recurrence, and long-term survival in ischemic stroke subtypes: A population-based study - Kolominsky-Rabas, Peter; Weber, Margarete; Gefeller, Olaf; Neundörfer, Bernhard; Heuschmann, Peter U. (Stroke, 2001)
Background and Purpose - The purpose of this study was to determine the incidence, recurrence, and long-term survival rates of ischemic stroke subtypes by a mechanism-based classification scheme (Trial of ORG 10172 in Acute Stroke Treatment, or TOAST). Methods - We identified all 583 residents of the city of Erlangen, Bavaria, Germany, with a first ischemic stroke between 1994 and 1998. Multiple overlapping sources of information were used to ensure completeness of case ascertainment. The cause of ischemic stroke was classified according to the TOAST criteria. Patients were followed up at 3 months and 1 and 2 years after stroke onset. Results - The age-standardized incidence rates for the European population (per 100 000) regarding ischemic stroke subtypes were as follows: cardioembolism, 30.2 (95% CI 25.6 to 35.7); small-artery occlusion, 25.8 (95% CI 21.5 to 30.9); and large-artery atherosclerosis, 15.3 (95% CI 12 to 19.3). When age-adjusted to the European population, the incidence rate for large-artery atherosclerosis was more than twice as high for men than for women (23.6/100 000 versus 9.2/100 000). Two years after onset, patients in the small-artery occlusion subgroup were 3 times more likely to be alive than those with cardioembolism. Ischemic stroke subtype according to the TOAST criteria was a significant predictor for long-term survival, whereas subtype was not a significant predictor of long-term recurrence up to 2 years, both before and after adjustment for age and sex. Conclusions - Epidemiological observational studies that possess wide access to appropriate diagnostic technologies and apply standardized etiologic classifications provide a much better understanding of underlying risk factors for initial stroke, recurrence, and mortality.
Created from Fastlane, Scopus look-up
Keywords: Epidemiology; Incidence; Recurrence; Stroke classification; Survival

Erectile dysfunction - Hilz, Max-Josef; Wang, Ruihao; Vodušek, David B. (Springer International Publishing, 2023)
Male erectile dysfunction (ED) increases with age and afflicts 52% of the 40-70 year old men. Neurological, endocrine, vascular, inflammatory, metabolic diseases, traumata, tumorous causes, illicit or "recreational "drugs, numerous prescription drugs, and psychological or psychiatric causes may induce ED. Diabetes mellitus is a leading cause of ED. ED can be the first sign of diabetes but also of coronary artery disease and thus requires a careful evaluation. In addition to a detailed history, ED patients need a general physical examination and may need additional urological, internal medicine, endocrinological-andrological, psychiatric and neurological assessment. Phosphodiesterase type 5 inhibitors should only be prescribed to patients at low cardiovascular risk. Various side effects and strict contraindications, such as treatment with nitrates, NO-donors, or alpha-blockers, and several others must be considered. Other ED treatments include lifestyle changes, where appropriate testosterone replacement, psychosexual counselling, intracavernous or intra-urethral prostaglandin E1 applications, vacuum erection pumps, constrictions rings, penile arterial reconstructive surgery, and penile prosthesis.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Cardiovascular disease; Diabetes mellitus; Erectile dysfunction; Impotence; Intracavernous prostaglandin E1 injections; Nitrates; Penile prosthesis; Phosphodiesterase type 5 inhibitors; Vacuum pumps

Erectile dysfunction (ED) after ischemic stroke: association between prevalence and site of lesion - Koehn, Julia; Crodel, Carl; Deutsch, Martina; Kolominsky-Rabas, Peter; Hoesl, Katharina M.; Köhrmann, Martin; Schwab, Stefan; Hilz, Max-Josef (Clinical Autonomic Research, 2015)
Stroke may cause or worsen erectile dysfunction (ED). Post-stroke ED prevalence and association with stroke location are not well established. Therefore, we assessed post-stroke ED prevalence in relation to ischemic lesion locations and stroke severity.In 57 men (62.6 ± 10.5 years) who had ischemic stroke within 24 months prior to evaluation, we used the five-item International Index of Erectile Function questionnaire (IIEF5) to evaluate ED prevalence after stroke and retrospectively 3 months prior to stroke. IIEF5 scores range from 5 to 25; scores below 22 indicate ED. We estimated stroke severity upon hospital admission, using the National Institute of Health Stroke Scale (NIHSS), and determined stroke location from cranial computed tomography or magnetic resonance imaging. We compared pre- and post-stroke results with those of 22 control persons (61.7 ± 11.2 years), calculated correlations between IIEF5 scores and NIHSS scores, and compared ED prevalence with stroke locations (significance: p < 0.05).ED was reported by 45/57 patients after stroke, 26/57 patients before stroke, and 6/22 control persons. Patients' IIEF5 values were significantly lower [median 16 interquartile range (IQR) 3.5-20.5] after than before stroke (median 23, IQR 19.0-24.0) and lower than in controls (median 24, IQR 19.8-25.0). Pre- and post-stroke IIEF5 scores did not correlate with the patients' NIHSS scores at stroke onset (p > 0.05). ED was associated with middle cerebral artery infarction in 27/34, posterior cerebral artery infarction in 4/5, anterior cerebral artery infarction in 1/1, basal ganglia infarction in 3/3, brain stem infarction in 8/10, cerebellar infarction in 2/5, and lesions in more than one region in 1/1 patients.Disruption of the central network assuring erection might contribute to increased ED severity and prevalence after stroke. Anti-erectile effects of functional and psychological impairment or medication added after stroke may also contribute to ED but must be evaluated in larger patients groups.
EVALuna2:22368

Erratum to 'Clinical/perfusion CT CBV mismatch as prognostic factor in intraarterial thrombectomy in acute anterior circulation stroke' (Clinical Neurology and Neurosurgery (2014) 121, (39-45)) - Saake, Marc; Breuer, Lorenz; Gölitz, Philipp; Köhrmann, Martin; Schwab, Stefan; Dörfler, Arnd; Kloska, Stephan (Clinical Neurology and Neurosurgery, 2014)
CRIS-Team Scopus Importer:2022-08-05

Ethanol consumption decreases autoantibody titers by blocking IL-21 secretion of Tfh cells during the development of arthritis - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, Jörg; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Sarter-Zaiss, Kerstin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Ethanol consumption inhibits the development of autoimmunity by blocking IL-21 secretion in T-FH cells - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, J.; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Herrmann, Martin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage - Goeldlin, Martina B.; Mueller, Achim; Siepen, Bernhard M.; Mueller, Madlaine; Strambo, Davide; Michel, Patrik; Schaerer, Michael; Cereda, Carlo W.; Bianco, Giovanni; Lindheimer, Florian; Berger, Christian; Medlin, Friedrich; et al. (Journal of Stroke, 2022)
Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. Methods We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). Results We included 2,650 patients (mean??standard deviation age 72??14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). Conclusions Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.
CRIS-Team WoS Importer:2022-07-08

Etomidate activates epileptic high frequency oscillations - Rampp, Stefan; Heers, M.; Schoenherr, M.; Schmitt, F. C.; Hopfengaertner, R.; Stefan, Hermann; et al. (Clinical Neurophysiology, 2014)
The short acting anesthetic etomidate has been shown to provoke epileptic spikes and rarely seizures. Influence of etomidate on the occurrence of epileptic HFO (high frequency oscillations) however is unknown. An HFO inducing effect of etomidate would allow further validation of the substance as a provocation measure in presurgical evaluation as well as provide insights into the common mechanisms of HFO, spike and seizure generation.We retrospectively analyzed EEG data from four patients who underwent etomidate activation during invasive video-EEG monitoring with subdural strip electrodes. Spikes were manually selected in raw data, HFO in band pass filtered data (80-250Hz). Rate and spatial distribution of HFO and spikes in three segments were compared: immediately after etomidate administration, as well as during slow wave sleep and while awake.Rates of HFO and spikes increased significantly after etomidate administration: Overall average rates of spikes were 9.7/min during sleep, 10/min while awake and 61.4/min after etomidate. Average HFO rates were 9.5/min during sleep, 8.3/min while awake and 24.4/min after etomidate (p<0.001, non-parametric ANOVA). Spatial distributions of HFO and spikes after administration of etomidate were consistent with the seizure onset zone (SOZ) and area of resection when available (SOZ: two patients; resection: one patient; no information: one patient). Except for spurious events, no additional HFO and spike foci were seen with activation.Etomidate administration activates spikes and HFO. Spatial distributions do not extend beyond electrodes showing spikes and HFO without Etomidate and seem consistent with the epileptic network.Etomidate activation is a safe procedure to provoke not only epileptic spikes but also HFO, which were shown to have a high specificity for the SO
EVALuna2:16662

EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke - Van Der Worp, H. Bart; Macleod, Malcolm R.; Bath, Philip M. W.; Demotes, Jacques; Durand-Zaleski, Isabelle; Gebhardt, Bernd; Gluud, Christian; Kollmar, Rainer; Krieger, Derk W.; Lees, Kennedy R.; Molina, Carlos; Montaner, Joan; et al. (International Journal of Stroke, 2014)
Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials.To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke.International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort.Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio.With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312.
EVALuna2:22308

EUROHYP-1: EUROPEAN, MULTICENTRE, RANDOMISED, PHASE III CLINICAL TRIAL OF THERAPEUTIC HYPOTHERMIA PLUS BEST MEDICAL TREATMENT VS BEST MEDICAL TREATMENT ALONE FOR ACUTE ISCHAEMIC STROKE - Petersson, J.; Van Der Worp, H. B.; Macleod, M. R.; Kollmar, R.; Krieger, D. W.; Staykov, D.; Szabo, I.; Kallmünzer, Bernd; Schwab, Stefan (2018)
EVALuna2:36384

European Academy of Neurology (EAN)/European Federation of Autonomic Societies (EFAS)/International Neuro-Urology Society (INUS) Guidelines for Practising Neurologists on the Assessment and Treatment of Neurogenic Urinary and Sexual Symptoms (NEUROGED Guidelines) - Panicker, Jalesh N.; Fanciulli, Alessandra; Skoric, Magdalena Krbot; Kaplan, Tamara; Aleksovska, Katina; Adamec, Ivan; Averbeck, Marcio Augusto; Campese, Nicole; Guaraldi, Pietro; Leys, Fabian; Moreno-Palacios, Jorge; Simeoni, Sara; et al. (European Journal of Neurology, 2025)
Background: Urinary and sexual symptoms are common following neurological disease, and we aimed to develop multidisciplinary inter-society evidence-based management guidelines. Methods: The ADAPTE framework was used, and a systematic search of guidelines published in different languages was performed. Guidelines, consensus statements, and systematic reviews were included, and guideline quality was appraised using AGREE II. Patient representatives reviewed the relevance and suitability of recommendations. A modified Delphi process integrating the Evidence to Decision framework adapted from GRADE and the Oxford Centre for Evidence Based Medicine system was used to reach consensus on recommendation wording and strength. Results: Recommendations were drafted, using guidelines/consensus statements (59 urinary, 50 sexual), systematic reviews (8 urinary, 2 sexual) and others (7 urinary,13 sexual), and wordings/strengths achieved at least 80% consensus through 2 Delphi rounds. Eleven evidence-based recommendations, 19 good practice statements, and 8 consensus-based recommendations were made. Individuals with neurological diseases should be asked about urogenital symptoms and undergo targeted physical examination when appropriate. Urinary symptom assessments include urinalysis, bladder diary completion, and post-void residual volume measurement. Treatments include fluid intake optimization, pelvic physiotherapy, tibial nerve stimulation, and oral medications. Urinary retention is managed by intermittent catheterization. Antibiotics should not be recommended to treat asymptomatic bacteriuria. Suprapubic catheterization is preferred for long-term catheterization. A comprehensive sexual history should be taken, focusing on multidimensional factors affecting sexual health. Treatments include lubricants, vibrators, and phosphodiesterase-5 inhibitors. Red flag symptoms warrant a shared-care approach with specialist colleagues. Conclusions: The 38 NEUROGED recommendations will guide neurologists to comprehensively manage urogenital symptoms reported by individuals with neurological diseases.
CRIS-Team Scopus Importer:2025-04-25
Keywords: guideline; neurogenic; sexual dysfunction; treatment; urinary dysfunction; urogenital

European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND - Amiri, Hemasse; Bluhmki, Erich; Bendszus, Martin; Eschenfelder, Christoph C.; Donnan, Geoffrey A.; Leys, Didier; Molina, Carlos; Ringleb, Peter A.; Schellinger, Peter D.; Schwab, Stefan; Toni, Danilo; Wahlgren, Nils; et al. (International Journal of Stroke, 2016)
Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4-26 and pre-stroke modified Rankin Scale (mRS) 0-1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo.The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0-1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0-1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.
EVALuna2:22431

European expert consensus recommendations for neurological therapeutic goals for patients with Fabry disease - Hilz, Max-Josef; Baron, R.; Elliott, P.; Germain, D.; Spada, M.; Viana-Baptista, M.; Wanner, C.; Burlina, A. P. (2018)
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European expert consensus statement on therapeutic goals in Fabry disease - Wanner, Christoph; Arad, Michael; Baron, Ralf; Burlina, Alessandro; Elliott, Perry M.; Feldt-Rasmussen, Ulla; Fomin, Victor V.; Germain, Dominique P.; Hughes, Derralynn A.; Jovanovic, Ana; Kantola, Ilkka; Linhart, Ales; et al. (Molecular Genetics and Metabolism, 2018)
Background: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation. Methods: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion. Results: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis. Conclusions: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.
EVALuna2:207471

Evaluation and treatment approaches for neurological post-acute sequelae of COVID-19: A consensus statement and scoping review from the global COVID-19 neuro research coalition - Frontera, Jennifer A.; Guekht, Alla; Allegri, Ricardo F.; Ashraf, Mariam; Baykan, Betül; Crivelli, Lucía; Easton, Ava; Garcia-Azorin, David; Helbok, Raimund; Joshi, Jatin; Köhn, Julia; Koralnik, Igor; et al. (Journal of the Neurological Sciences, 2023)
Post-acute neurological sequelae of COVID-19 affect millions of people worldwide, yet little data is available to guide treatment strategies for the most common symptoms. We conducted a scoping review of PubMed/Medline from 1/1/2020–4/1/2023 to identify studies addressing diagnosis and treatment of the most common post-acute neurological sequelae of COVID-19 including: cognitive impairment, sleep disorders, headache, dizziness/lightheadedness, fatigue, weakness, numbness/pain, anxiety, depression and post-traumatic stress disorder. Utilizing the available literature and international disease-specific society guidelines, we constructed symptom-based differential diagnoses, evaluation and management paradigms. This pragmatic, evidence-based consensus document may serve as a guide for a holistic approach to post-COVID neurological care and will complement future clinical trials by outlining best practices in the evaluation and treatment of post-acute neurological signs/symptoms.
CRIS-Team Scopus Importer:2023-11-03
Keywords: COVID-19; Diagnosis; Evaluation; Management; Neurologic; SARS-COV-2; Therapeutics; Therapy; Treatment

Evaluation of a laser-based sensor for the diagnosis of neurological disorders - Tenner, Felix; Regensburger, Martin; Schramm, A; Söhle, Mona; Schwarzkopf, Karen; Zalevsky, Zeev; Schmidt, Michael (2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2017)
Keywords: biomedical equipment; biomedical measurement; laser applications in medicine; muscle; neurophysiology; optical sensors; patient diagnosis; involuntary muscle activity; laser-based sensor; neurological disorder diagnosis; neurological disorders; remote quantification; ultrasound measurements; whole body measurement; Measurement by laser beam; Muscles; Skin; Speckle; Transducers; Ultrasonic imaging; Ultrasonic variables measurement

Evaluation of Functional Recovery Following Thrombectomy in Patients With Large Vessel Occlusion and Prestroke Disability - Sprügel, Maximilian; Sembill, Jochen; Kremer, Svenja; Gerner, Stefan; Knott, Michael; Hock, Stefan; Engelhorn, Tobias; Dörfler, Arnd; Huttner, Hagen; Schwab, Stefan (JAMA Network Open, 2022)
IMPORTANCE It is uncertain whether thrombectomy is associated with benefits in patients with prestroke disability.
CRIS-Team WoS Importer:2022-09-02

Evaluation of Orthostatic Reactions in Real-World Environments Using Wearable Sensors - Happold, Johanna; Richer, Robert; Küderle, Arne; Gaßner, Heiko; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (2021 43rd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), 2021)
As global life expectancy is constantly rising, the early detection of age-related, neurodegenerative diseases, such as Parkinson’s disease, is becoming increasingly important. Patients suffering from Parkinson’s disease often show autonomic nervous system dysfunction which is why its examination is an important diagnostic tool. Measuring the response of the heart rate (variability) to postural transitions and thereby assessing the orthostatic reaction is a common indicator of autonomic nervous system functioning. However, since these measurements are commonly performed in a clinical environment, results can be impaired by the white coat effect. To reduce this influence as well as inter- and intra-day variations, our work aims to investigate the assessment of orthostatic reactions in free-living environments. We collected IMU and ECG data of seven healthy participants over four days and evaluated differences in orthostatic reactions between standardized tests at lab, at home, as well as unsupervised recordings during real-world conditions. Except for the first lab recording, we detected significant changes in heart rate due to postural transitions in all recording settings, with the strongest response occurring during standardized tests at home. Our findings show that real-world assessment of orthostatic reactions is possible and provides comparable results to supervised assessments in lab settings. Additionally, our results indicate high inter- and intra-day variability which motivates the continuous orthostatic reaction measurement over the span of multiple days. We are convinced that our presented approach provides a first step towards unobtrusive assessment of orthostatic reactions in real-world environments, which might enable a more reliable early detection of disorders of the autonomic nervous system.
Keywords: Atmospheric measurements; Autonomic nervous system; Tools; Electrocardiography; Particle measurements; Biology; Reliability

Evaluation of simplified wireless EEG recordings in the neurological emergency room - Welte, Tamara; Janner, Felix; Lindner, Sara; Gollwitzer, Stephanie; Stritzelberger, Jenny; Lang, Johannes; Reindl, Caroline; Sprügel, Maximilian; Olmes, David; Schwab, Stefan; Blinzler, Christian; Hamer, Hajo (PLoS ONE, 2024)
Objective In the neurological emergency room (nER), timely electroencephalography (EEG) diagnostic is often crucial in patients with altered state of consciousness as well as in patients presenting with a first seizure. Yet, routine-EEG (rEEG) is often not available, especially during off-hours. Methods We analyzed the value of a commercially available, simplified wireless eight-channel EEG recording (swEEG, CerebAir® EEG headset, Nihon Kohden), applied by non-EEG-specialized medical students, in patients presenting in our nER with (suspicion of) epileptic seizures and/or loss of or altered state of consciousness between 08/2019 and 08/2022. We evaluated the feasibility and validity compared to a standard rEEG (21 electrodes according to the international 10/20 system) and also included the clinical follow-up of the patients. Results 100 patients were included in our analysis (mean age 57.6 ± 20.4 years; 61 male). Median time of electrode application was 7 minutes (range 4–20 minutes), with significantly longer duration in patients with altered level of consciousness (median 8 minutes, p = 0.035). Electrode impedances also differed according to state of consciousness (p = 0.032), and were higher in females (p<0.001). 55 patients received additional rEEG, either during their acute nER stay (25) and/or during the next days (38). Considering normal EEG findings vs. pathological slowing vs. epileptiform activity, swEEG matched first rEEG results in 48/55 cases (87.3%). Overall, swEEG detected the same or additional pathological EEG patterns in 52/ 55 cases (94.5%). In 7/75 patients (9.3%) who did not receive rEEG, or had their rEEG scheduled to a later time point during their hospital stay, swEEG revealed important additional pathological findings (e.g. status epilepticus, interictal epileptiform discharges), which would have triggered acute therapeutic consequences or led to further diagnostics and investigations. Conclusion The introduced swEEG represents a practicable, valuable technique to be quickly applied by non-EEG-specialized ER staff to initiate timely diagnostic and guide further investigations and treatment in the nER. Moreover, it may help to avoid under-diagnostic with potentially harmful consequences caused by skipped or postponed regular 10/20 EEG examinations, and ultimately improve the outcome of patients.
CRIS-Team Scopus Importer:2024-11-15

Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study - Stockinger, Jakob; Strzelczyk, Adam; Nemecek, Andrea; Cicanic, Michal; Bösebeck, Frank; Brandt, Christian; Hamer, Hajo; Intravooth, Tassanai; Steinhoff, Bernhard J. (Epilepsia, 2021)
Objective: There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice. Methods: We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (≥18 years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6 months. Results: A total of 45 subjects with a mean age of 31.6 ± 11.1 years at EVE start fulfilled the inclusion criteria. Retention rate after 6 months was 98% (43/44 evaluable subjects). Response rate (seizure reduction ≥ 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period. Significance: Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.
CRIS-Team Scopus Importer:2021-02-12
Keywords: disease-modifying therapy; epilepsy; everolimus; tuberous sclerosis complex

Evidence-based guidelines for the management of large hemispheric infarction : a statement for health care professionals from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine - Torbey, Michel T.; Boesel, Julian; Rhoney, Denise H.; Rincon, Fred; Staykov, Dimitre; Amar, Arun P.; Varelas, Panayiotis N.; Juettler, Eric; Olson, Daiwai; Huttner, Hagen; Zweckberger, Klaus; Sheth, Kevin N.; et al. (Neurocritical Care, 2015)
Large hemispheric infarction (LHI), also known as malignant middle cerebral infarction, is a devastating disease associated with significant disability and mortality. Clinicians and family members are often faced with a paucity of high quality clinical data as they attempt to determine the most appropriate course of treatment for patients with LHI, and current stroke guidelines do not provide a detailed approach regarding the day-to-day management of these complicated patients. To address this need, the Neurocritical Care Society organized an international multidisciplinary consensus conference on the critical care management of LHI. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. The panel devised a series of clinical questions related to LHI, and assessed the quality of data related to these questions using the Grading of Recommendation Assessment, Development and Evaluation guideline system. They then developed recommendations (denoted as strong or weak) based on the quality of the evidence, as well as the balance of benefits and harms of the studied interventions, the values and preferences of patients, and resource considerations.
EVALuna2:22397

Evidence for postnatal neurogenesis in the human amygdala - Röder, Sebastian; Burkardt, Petra; Rost, Fabian; Rode, Julian; Brusch, Lutz; Coras, Roland; Englund, Elisabet; Håkansson, Karl; Possnert, Göran; Salehpour, Mehran; Primetzhofer, Daniel; Csiba, László; et al. (Communications Biology, 2022)
The human amygdala is involved in processing of memory, decision-making, and emotional responses. Previous studies suggested that the amygdala may represent a neurogenic niche in mammals. By combining two distinct methodological approaches, lipofuscin quantification and 14C-based retrospective birth dating of neurons, along with mathematical modelling, we here explored whether postnatal neurogenesis exists in the human amygdala. We investigated post-mortem samples of twelve neurologically healthy subjects. The average rate of lipofuscin-negative neurons was 3.4%, representing a substantial proportion of cells substantially younger than the individual. Mass spectrometry analysis of genomic 14C-concentrations in amygdala neurons compared with atmospheric 14C-levels provided evidence for postnatal neuronal exchange. Mathematical modelling identified a best-fitting scenario comprising of a quiescent and a renewing neuronal population with an overall renewal rate of >2.7% per year. In conclusion, we provide evidence for postnatal neurogenesis in the human amygdala with cell turnover rates comparable to the hippocampus.
CRIS-Team Scopus Importer:2022-04-29

Excessive Use of Electrophysiologic Testing in Polyneuropathy? - Heuss, Dieter (Klinische Neurophysiologie, 2017)
EVALuna2:22592

Experimentelle Untersuchungen zum Laserstrahl-Punktschweißen metallischer Folien mittels kurzer Laserimpulse - Prechtl, Martin; Schmidt, Michael; Barth, J. (LEF 2004, Laser in der Elektronikproduktion und Feinwerktechnik, 2004)
LFT Import::2019-07-16 (1033)

Expertenempfehlung zur Magnetresonanztomographie bei Muskelerkrankungen - Zeng, Rachel; Schlaeger, Sarah; Türk, Matthias; Baum, Thomas; Deschauer, Marcus; Janka, Rolf Matthias; Karampinos, Dimitrios; Kassubek, Jan; Keller-Yamamura, Sarah; Kornblum, Cornelia; Lehmann, Helmar; Lichtenstein, Thorsten; et al. (Der Nervenarzt, 2024)
Background: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. Objectives: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. Methods: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. Results: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. Conclusions: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.
CRIS-Team Scopus Importer:2024-05-10
Keywords: Diagnostics; Muscle MRI; Myopathy; Myositis; Semi-quantitative assessment scales

Expertenempfehlung zur Magnetresonanztomographie bei Muskelerkrankungen - Zeng, Rachel; Schlaeger, Sarah; Türk, Matthias; Baum, Thomas; Deschauer, Marcus; Janka, Rolf Matthias; Karampinos, Dimitrios; Kassubek, Jan; Keller-Yamamura, Sarah; Kornblum, Cornelia; Lehmann, Helmar; Lichtenstein, Thorsten; et al. (Die Radiologie, 2024)
BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.
EVALuna2:566089

Expert opinion on the use of cladribine tablets in clinical practice. - Sorensen, Per Soelberg; Centonze, Diego; Giovannoni, Gavin; Montalban, Xavier; Selchen, Daniel; Vermersch, Patrick; Wiendl, Heinz; Yamout, Bassem; Salloukh, Hashem; Rieckmann, Peter (Therapeutic Advances in Neurological Disorders, 2020)
Background: Gaps in current product labels and a lack of detailed clinical guidelines leaves clinicians' questions on the practical management of patients receiving cladribine tablets for the treatment of relapsing multiple sclerosis (MS) unanswered. We describe a consensus-based programme led by international MS experts with the aim of providing recommendations to support the use of cladribine tablets in clinical practice. Methods: A steering committee (SC) of nine international MS experts led the programme and developed 11 clinical questions concerning the practical use of cladribine tablets. Statements to address each question were drafted using available evidence, expert experiences and perspectives from the SC and an extended faculty of 33 MS experts, representing 19 countries. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale. Results: Consensus was achieved on 46 out of 47 recommendations. Expert-agreed practical recommendations are provided on topics including: the definition of highly active disease; patterns of treatment response and suboptimal response with cladribine tablets; management of pregnancy planning and malignancy risk, infection risk and immune function, and switching to and from cladribine tablets. Conclusion: These expert recommendations provide up-to-date relevant guidance on the use of cladribine tablets in clinical practice.
EVALuna2:313710

Explicit and implicit timing in mesial temporal lobe epilepsy patients - Hellweg, Annika; Schwarz, Michael; Walther, Katrin; Hamer, Hajo; Visalli, Antonino; Mioni, Giovanna (Epilepsy and Behavior, 2025)
Objectives: The present study investigates the explicit and implicit timing abilities of patients with mesial temporal lobe epilepsy (MTLE). Based on previous studies, it was hypothesized that timing abilities were decreased in MTLE patients. Methods: The performance of 21 MTLE patients and 21 neurologically healthy probands was tested on two separate tasks. The time bisection task was used to investigate explicit timing and the foreperiod task to test implicit timing. Results: For the time bisection task, less precise temporal judgements were found in the patient group compared to the control group. This was indicated by a flatter psychophysical curve in the patients compared to controls. Moreover, participants did not differ in term of precision, but patients were more variable than controls. There was no statistical difference between the performance of the control and the patient group in the implicit timing task. Both groups demonstrated the foreperiod effect, meaning that the RTs of the participants became shorter with longer durations. Conclusions: MTLE patients showed less precise temporal judgments in explicit timing, while their implicit timing was largely preserved. This finding suggests that explicit time perception should be routinely investigated in MTLE patients.
CRIS-Team Scopus Importer:2025-04-25
Keywords: Epilepsy; Explicit timing; Foreperiod task; Implicit timing; Time bisection task

Exploring gait adaptations to perturbed and conventional treadmill training in Parkinson’s disease: Time-course, sustainability, and transfer - Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Pasluosta, Cristian Federico; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Human Movement Science, 2019)

Expression of brain-derived neurotrophic factor in astrocytes - Beneficial effects of glatiramer acetate in the R6/2 and YAC128 mouse models of Huntington's disease - Reick, Christiane; Ellrichmann, Gisa; Tsai, Teresa; Lee, De-Hyung; Wiese, Stefan; Gold, Ralf; Saft, Carsten; Linker, Ralf (Experimental Neurology, 2016)
Glatiramer acetate (GA) is a FDA-approved drug which is licensed for the treatment of relapsing-remitting multiple sclerosis and which may exert neuroprotective effects via brain-derived neurotrophic factor (BDNF). In this study, we investigate effects of GA on BDNF expression especially in astrocytes in vitro and in vivo in brains of R6/2 and YAC128 transgenic mouse models of Huntington's disease (HD) where a pathogenic role of astroglial cells has recently been shown. We show that GA increases the expression of functionally active BDNF in astrocyte culture and in astrocytes of GA treated HD mice. In the brains of these mice, GA decreases neurodegeneration and restores BDNF levels. The beneficial effect of GA in R6/2 mice also comprises reduced weight loss and prolonged life span and, for both models, also improved motor performance. Further studies with this safe and effective drug in HD are warranted.
EVALuna2:22500

Expression of Inflammatory Mediators in Biofilm Samples and Clinical Association in Multiple Sclerosis Patients in Remission—A Pilot Study - Fehlhofer, Jakob Paul; Ries, Jutta; Nickel, Florian; Rothhammer, Veit; Schwab, Stefan; Kesting, Marco Rainer; Buchbender, Mayte (Life, 2024)
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of unknown etiology that affects the central nervous system and can lead to neurological impairment. Our aim was to determine whether MS patients also show inflammatory changes in the oral cavity more frequently than healthy individuals. For this purpose, we examined plaque samples for various mediators and their correlation with clinical findings. A study group (MS) and a control group were examined and compared. The plaque samples were analyzed for the expression of interleukins (IL-2, -6, -10), matrix metalloproteinases (MMP-7, MMP-9), and a surface antigen CD90 by quantitative real-time PCR. The clinical parameters examined were the Mombelli plaque index; bleeding on probing (BOP) index; periodontal pocket depth; and decayed, missing, and filled tooth (DMFT) index. The expression of MMP9 was significantly (p = 0.035) higher in the control group. The expression of IL-2 was increased four-fold in the MS group; however, this difference was not statistically significant. The mean PD (p < 0.001) and BOP index (p = 0.029) values were increased in the study group. The clinical parameters of the BOP index and PD were significantly amplified in the MS patients. However, no causal relationship between the investigated inflammatory mediators and the clinical findings could be established in this case series.
CRIS-Team Scopus Importer:2024-05-24
Keywords: cytokine expression; multiple sclerosis; oral hygiene; periodontitis

Extended Multimodal Flat Detector CT Imaging in Acute Ischemic Stroke: A Pilot Study - Hölter, Philip; Lang, Stefan; Beuscher, Vanessa; Kallmünzer, Bernd; Manhart, Michael; Schwab, Stefan; Dörfler, Arnd (Journal of Digital Imaging, 2023)
By using Flat detector computed tomography (FD-CT), a one-stop-shop approach in the diagnostic workup of acute ischemic stroke (AIS) might be achieved. Although information on upstream vessels is warranted, dedicated FD-CT protocols which include the imaging of the cervical vasculature are still lacking. We aimed to prospectively evaluate the implementation of a new multimodal FD-CT protocol including cervical vessel imaging in AIS patients. In total, 16 patients were included in this study. Eight patients with AIS due to large vessel occlusion (LVO) prospectively received a fully multimodal FD-CT imaging, including non-enhanced flat detector computed tomography (NE-FDCT), dynamic perfusion flat detector computed tomography (FD-CTP) and flat detector computed tomography angiography (FD-CTA) including cervical imaging. For comparison of time metrics and image quality, eight AIS patients, which received multimodal CT imaging, were included retrospectively. Although image quality of NE-FDCT and FD-CTA was rated slightly lower than NE-CT and CTA, all FD-CT datasets were of diagnostic quality. Intracerebral hemorrhage exclusion and LVO detection was reliably possible. Median door-to-image time was comparable for the FD-CT group and the control group (CT:30 min, IQR27-58; FD-CT:44.5 min, IQR31-55, p = 0.491). Door-to-groin-puncture time (CT:79.5 min, IQR65-90; FD-CT:59.5 min, IQR51-67; p = 0.016) and image-to-groin-puncture time (CT:44 min, IQR30-50; FD-CT:14 min, IQR12-18; p < 0.001) were significantly shorter, when patients were directly transferred to the angiosuite, where FD-CT took place. Our study indicates that using a new fully multimodal FD-CT approach including imaging of cervical vessels for first-line imaging in AIS patients is feasible and comparable to multimodal CT imaging with substantial potential to streamline the stroke workflow.
CRIS-Team Scopus Importer:2023-02-03
Keywords: Flat Detector Computed Tomography; Interventional; Stroke; Workflow

Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection - Ringleb, Peter; Bendszus, Martin; Bluhmki, Erich; Donnan, Geoffrey; Eschenfelder, Christoph; Fatar, Marc; Kessler, Christof; Molina, Carlos; Leys, Didier; Muddegowda, Girish; Poli, Sven; Schellinger, Peter; et al. (International Journal of Stroke, 2019)
Background: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5–9 h after symptom onset benefit from intravenous thrombolysis compared to placebo. Methods: Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0–6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. Results: The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63–2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53). Conclusions: Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).
CRIS-Team Scopus Importer:2019-05-02
Keywords: Alteplase; endovascular; intravenous thrombolysis; magnetic resonance imaging; thrombolysis; time window

Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data - Johnston, C.; Burns, R.; McNeil, John; Tress, Brian M.; Campbell, Bruce C.V.; Williams, M.; Ma, Henry; Ringleb, Peter A.; Parsons, Mark W.; Churilov, Leonid; Bendszus, Martin; Hsu, Chung; et al. (Lancet, 2019)
Background: Stroke thrombolysis with alteplase is currently recommended 0–4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. Methods: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. Findings: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15–2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23–76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81–2·96, p=0·66). Interpretation: Patients with ischaemic stroke 4·5–9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. Funding: None.
CRIS-Team Scopus Importer:2019-07-16

Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose - Hoffmann, Anna-Carin; Minakaki, Georgia; Menges, Stefanie; Salvi, Rachele; Savitskiy, Sergey; Kazman, Aida; Miranda, Hugo Vicente; Mielenz, Dirk; Klucken, Jochen; Winkler, Jürgen; Xiang, Wei (Scientific Reports, 2019)
Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.
EVALuna2:36381

Extrinsic immune cell-derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis - Starost, Laura; Lindner, Maren; Herold, Martin; Xu, Yu Kang T.; Drexler, Hannes C.A.; Heß, Katharina; Ehrlich, Marc; Ottoboni, Linda; Ruffini, Francesca; Stehling, Martin; Röpke, Albrecht; Thomas, Christian; et al. (Acta Neuropathologica, 2020)
Multiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and defective remyelination in MS are currently unknown. To determine whether intrinsic oligodendroglial factors contribute to impaired remyelination in relapsing–remitting MS (RRMS), we compared induced pluripotent stem cell-derived oligodendrocytes (hiOL) from RRMS patients and controls, among them two monozygous twin pairs discordant for MS. We found that hiOL from RRMS patients and controls were virtually indistinguishable with respect to remyelination-associated functions and proteomic composition. However, while analyzing the effect of extrinsic factors we discovered that supernatants of activated peripheral blood mononuclear cells (PBMCs) significantly inhibit oligodendroglial differentiation. In particular, we identified CD4+ T cells as mediators of impaired oligodendroglial differentiation; at least partly due to interferon-gamma secretion. Additionally, we observed that blocked oligodendroglial differentiation induced by PBMC supernatants could not be restored by application of oligodendroglial differentiation promoting drugs, whereas treatment of PBMCs with the immunomodulatory drug teriflunomide prior to supernatant collection partly rescued oligodendroglial differentiation. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors but rather caused by the inflammatory environment in RRMS lesions which underlines the need for drug screening approaches taking the inflammatory environment into account. Combined, these findings may contribute to the development of new remyelination promoting strategies.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Ifnγ; Induced pluripotent stem cells; Oligodendrocytes; Proteome; Relapsing–remitting multiple sclerosis; Remyelination

Ex vivo radiosensitivity is increased in non-cancer patients taking valproate - Stritzelberger, Jenny; Lainer, Jennifer; Gollwitzer, Stefanie; Graf, Wolfgang; Jost, Tina; Lang, Johannes; Müller, Tamara; Schwab, Stefan; Fietkau, Rainer; Hamer, Hajo; Distel, Luitpold (BMC Neurology, 2020)
Background: Valproate (VPA) is a commonly prescribed antiepileptic drug for patients experiencing epileptic seizures due to brain tumors. VPA increases radiation sensitivity in various tumor cells in vitro due to complex mechanisms. This could make tumors more vulnerable to ionizing radiation or overcome radioresistance. Yet, clinical data on possible improvement of tumor control by adding VPA to tumor therapy is controversial. Potentially radiosensitizing effects of VPA on healthy tissue remain unclear. To determine individual radiosensitivity, we analyzed blood samples of individuals taking VPA. Methods: Ex vivo irradiated blood samples of 31 adult individuals with epilepsy were studied using 3-color fluorescence in situ hybridization. Aberrations in chromosomes 1, 2 and 4 were analyzed. Radiosensitivity was determined by the mean breaks per metaphase (B/M) and compared to age-matched (2:1) healthy donors. Results: The patient cohort (n = 31; female: 38.7%) showed an increase of their average B/M value compared to healthy individuals (n = 61; female: 56.9%; B/M: 0.480 ± 0.09 vs. 0.415 ± 0.07; p =.001). The portion of radiosensitive (B/M > 0.500) and distinctly radiosensitive individuals (B/M > 0.600) was increased in the VPA group (54.9% vs. 11.3 and 9.7% vs. 0.0%; p <.001). In 3/31 patients, radiosensitivity was determined prior to and after VPA treatment and radiosensitivity was increased by VPA-treatment. Conclusions: In our study, we confirmed that patients treated with VPA had an increased radiosensitivity compared to the control group. This could be considered in patients taking VPA prior to the beginning of radiotherapy to avoid toxic side effects of VPA-treatment.
CRIS-Team Scopus Importer:2020-11-06
Keywords: 3-colour fluorescence-in-situ-hybridization; Breaks per metaphase; Individual radiosensitivity; Valproate

Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury - Wang, Ruihao; Hoesl, Katharina M.; Ammon, Fabian; Markus, Jörg; Koehn, Julia; Roy, Sankanika; Liu, Mao; de Rojas Leal, Carmen; Muresanu, Dafin; Flanagan, Steven R.; Hilz, Max-Josef (Clinical Neurophysiology, 2018)
OBJECTIVE: After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. METHODS: In 51 post-moderate-severe-TBI patients (32.7 ± 10.5 years old, 43.1 ± 33.4 months post-injury), and 30 controls (29.1 ± 9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). RESULTS: At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. CONCLUSIONS: In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. SIGNIFICANCE: Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI.
EVALuna2:36357

Eyeball Pressure Stimulation Unveils Subtle Autonomic Cardiovascular Dysfunction in Persons with a History of Mild Traumatic Brain Injury - Hilz, Max-Josef; Aurnhammer, Felix; Flanagan, Steven R.; Intravooth, Tassanai; Wang, Ruihao; Hoesl, Katharina M.; Pauli, Elisabeth; Koehn, Julia (Journal of Neurotrauma, 2015)
After mild traumatic brain injury (mTBI), patients have increased long-term mortality rates, persisting even beyond 13 years. Pathophysiology is unclear. Yet, central autonomic network dysfunction may contribute to cardiovascular dysregulation and increased mortality. Purely parasympathetic cardiovascular challenge by eyeball pressure stimulation (EP), might unveil subtle autonomic dysfunction in post-mTBI patients. We investigated whether mild EP shows autonomic cardiovascular dysregulation in post-mTBI patients. In 24 patients (34 ± 12 years; 5-86 months post-injury) and 27 controls (30 ± 11 years), we monitored respiration, electrocardiographic RR intervals (RRI), systolic and diastolic blood pressure (BPsys, BPdia) before and during 2 min of 30 mm Hg EP, applied by an ophthalmologic ocular pressure device (Okulopressor(®)). We calculated spectral powers of RRI in the mainly sympathetic low frequency (LF; 0.04-0.15 Hz) and parasympathetic high frequency (HF; 0.15-0.5 Hz) ranges, and of BP in the sympathetic LF range, the RRI-LF/HF ratio as index of the sympathetic-parasympathetic balance, normalized (nu) RRI-LF- and HF-powers, and LF- and HF-powers after natural logarithmic transformation (ln). Parameters before and during EP in post-mTBI patients and controls were compared by repeated measurement analysis of variance with post hoc analysis (p < 0.05). During EP, BPsys and BPdia increased in post-mTBI patients. Only in controls but not in post-mTBI patients, EP increased RRI-HFnu-powers and decreased RRI-LF-powers, RRI-LFnu-powers, BPsys-LF-powers, BPsys-lnLF-powers and BPdia-lnLF-powers. RRI-LF/HF ratios slightly increased in post-mTBI patients but slightly decreased in controls upon EP. Even with only mild EP, our controls showed normal EP responses and shifted sympathetic-parasympathetic balance towards parasympathetic predominance. In contrast, our post-mTBI patients could not increase parasympathetic heart rate modulation but increased BP upon EP, indicating a paradox sympathetic activation. The findings support the hypothesis that central autonomic dysfunction might contribute to an increased cardiovascular risk, even years after mTBI.
EVALuna2:22373

Factors associated with occurrence and outcome of super-refractory status epilepticus - Madzar, Dominik; Knappe, Ruben U.; Reindl, Caroline; Giede-Jeppe, Antje; Sprügel, Maximilian; Beuscher, Vanessa; Gollwitzer, Stephanie; Hamer, Hajo; Huttner, Hagen (Seizure-European Journal of Epilepsy, 2017)
Super-refractory status epilepticus (SRSE) represents a challenging medical condition with high morbidity and mortality. In this study, we aimed to establish variables related to SRSE development and outcome.We retrospectively screened our databases for refractory SE (RSE) and SRSE episodes between January 2001 and January 2015. Baseline demographics, SE characteristics, and variables reflecting the clinical course were compared in order to identify factors independently associated with SRSE occurrence. Within the SRSE cohort, predictors of in-hospital mortality as well as good functional outcome in survivors to discharge were established through univariate and multivariable analyses.A total of 131 episodes were included, among those 46 (35.1%) meeting the criteria of SRSE. Comparison of RSE and SRSE episodes revealed a lower premorbid mRS score (odds ratio (OR) per mRS point, 0.769; p=0.039) and non-convulsive SE (NCSE) in coma (OR, 4.216; p=0.008) as independent predictors of SRSE. SRSE in-hospital mortality was associated with age (OR, 1.091 per increasing year; p=0.020) and worse premorbid functional status (OR, 1.938 per mRS point; p=0.044). Good functional outcome in survivors was independently related to shorter SRSE duration (OR, 0.714 per day; p=0.038).Better premorbid functional status and NCSE in coma as worst seizure type indicate a role of acute underlying etiologies in the development of SRSE. In-hospital mortality in SRSE is determined by nonmodifiable factors, while functional outcome in survivors depends on seizure duration underscoring the need of achieving rapid seizure termination.
EVALuna2:22567

FallRiskPD: Long-term fall risk classification for Parkinson’s disease via intelligent sensor-based gait analysis in the home environment (Talk) - Ullrich, Martin; Gladow, Till; Roth, Nils; Küderle, Arne; Ollenschläger, Malte; Gaßner, Heiko; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (European Falls Festival, 2nd and 3rd July 2018, Manchester, United Kingdom, ABSTRACT BOOKLET, 2018)

Fall Risk Prediction in Parkinson’s Disease Using Real-World Inertial Sensor Gait Data - Ullrich, Martin; Roth, Nils; Küderle, Arne; Richer, Robert; Gladow, Till; Gaßner, Heiko; Marxreiter, Franz; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (IEEE Transactions on Neural Systems and Rehabilitation Engineering, 2022)

Fall Risk Prediction in Parkinson's Disease Using Real-World Inertial Sensor Gait Data. - Ullrich, Martin; Roth, Nils; Küderle, Arne; Richer, Robert; Gladow, Till; Gaßner, Heiko; Marxreiter, Franz; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (IEEE Journal of Biomedical and Health Informatics, 2023)
Falls are an eminent risk for older adults and especially patients with neurodegenerative disorders, such as Parkinson's disease (PD). Recent advancements in wearable sensor technology and machine learning may provide a possibility for an individualized prediction of fall risk based on gait recordings from standardized gait tests or from unconstrained real-world scenarios. However, the most effective aggregation of continuous real-world data as well as the potential of unsupervised gait tests recorded over multiple days for fall risk prediction still need to be investigated. Therefore, we present a data set containing real-world gait and unsupervised 4x10-Meter-Walking-Tests of 40 PD patients, continuously recorded with foot-worn inertial sensors over a period of two weeks. In this prospective study, falls were self-reported during a three-month follow-up phase, serving as ground truth for fall risk prediction. The purpose of this study was to compare different data aggregation approaches and machine learning models for the prospective prediction of fall risk using gait parameters derived either from continuous real-world recordings or from unsupervised gait tests. The highest balanced accuracy of 74.0% (sensitivity: 60.0%, specificity: 88.0%) was achieved with a Random Forest Classifier applied to the real-world gait data when aggregating all walking bouts and days of each participant. Our findings suggest that fall risk can be predicted best by merging the entire two-week real-world gait data of a patient, outperforming the prediction using unsupervised gait tests (68.0% balanced accuracy) and contribute to an improved understanding of fall risk prediction.
EVALuna2:520585

Fatal intracranial haemorrhage occurring after oral anticoagulant treatment initiation for secondary stroke prevention in patients with atrial fibrillation - Tsivgoulis, G.; Katsanos, A. H.; Seiffge, D. J.; Paciaroni, M.; Wilson, D.; Koga, M.; Macha, Kosmas; Cappellari, M.; Kallmünzer, Bernd; Polymeris, A. A.; Toyoda, K.; Caso, V.; et al. (European Journal of Neurology, 2020)
Background and purpose: In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). Methods: Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed. Results: During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09–1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51–0.95). Conclusions: Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.
CRIS-Team Scopus Importer:2020-05-22
Keywords: anticoagulation; cerebral haemorrhage; cerebral infarction; cerebrovascular diseases and cerebral circulation; neurological disorders

Fatal Liver and Bone Marrow Toxicity by Combination Treatment of Dichloroacetate and Artesunate in a Glioblastoma Multiforme Patient: Case Report and Review of the Literature - Uhl, Martin; Schwab, Stefan; Efferth, Thomas (Frontiers in Oncology, 2016)
A 52-year-old male patient was treated with standard radiochemotherapy with temozolomide for glioblastoma multiforme (GBM). After worsening of his clinical condition, further tumor-specific treatment was unlikely to be successful, and the patient seeked help from an alternative practitioner, who administered a combination of dichloroacetate (DCA) and artesunate (ART). A few days later, the patient showed clinical and laboratory signs of liver damage and bone marrow toxicity (leukopenia, thrombocytopenia). Despite successful restoration of laboratory parameters upon symptomatic treatment, the patient died 10 days after the infusion. DCA bears a well-documented hepatotoxic risk, while ART can be considered as safe concerning hepatotoxicity. Bone marrow toxicity can appear upon ART application as reduced reticulocyte counts and disturbed erythropoiesis. It can be assumed that the simultaneous use of both drugs caused liver injury and bone marrow toxicity. The compassionate use of DCA/ART combination therapy outside of clinical trials cannot be recommended for GBM treatment.
EVALuna2:22527

Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman - Olmes, David G.; Agaimy, Abbas; Kloska, Stephan; Linker, Ralf (BMJ Case Reports, 2014)
An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide.
EVALuna2:6736

Feasibility and Diagnostic Accuracy of Ischemic Stroke Territory Recognition Based on Two-Dimensional Projections of Three-Dimensional Diffusion MRI Data. - Wrosch, Jana Katharina; Volbers, Bastian; Gölitz, Philipp; Gilbert, Daniel; Schwab, Stefan; Dörfler, Arnd; Kornhuber, Johannes; Groemer, Teja W. (Frontiers in Neurology, 2015)
This study was conducted to assess the feasibility and diagnostic accuracy of brain artery territory recognition based on geoprojected two-dimensional maps of diffusion MRI data in stroke patients. In this retrospective study, multiplanar diffusion MRI data of ischemic stroke patients was used to create a two-dimensional map of the entire brain. To guarantee correct representation of the stroke, a computer-aided brain artery territory diagnosis was developed and tested for its diagnostic accuracy. The test recognized the stroke-affected brain artery territory based on the position of the stroke in the map. The performance of the test was evaluated by comparing it to the reference standard of each patient’s diagnosed stroke territory on record. This study was designed and conducted according to Standards for Reporting of Diagnostic Accuracy (STARD). The statistical analysis included diagnostic accuracy parameters, cross-validation, and Youden Index optimization. After cross-validation on a cohort of 91 patients, the sensitivity of this territory diagnosis was 81% with a specificity of 87%. With this, the projection of strokes onto a two-dimensional map is accurate for representing the affected stroke territory and can be used to provide a static and printable overview of the diffusion MRI data. The projected map is compatible with other two-dimensional data such as EEG and will serve as a useful visualization tool.
Keywords: computer-aided detection and diagnosis; diffusion-weighted imaging; dimensionality reduction; magnetic resonance imaging; stroke territories; validation; visualization

Feasibility of certified quality management in a comprehensive stroke care network using telemedicine: STENO project - Handschu, Rene; Scibor, Mateusz; Wacker, Angela; Stark, David Rianto; Köhrmann, Martin; Erbguth, Frank; Oschmann, Patrick; Schwab, Stefan; Marquardt, Lars (International Journal of Stroke, 2014)
Stroke care networks with and without telemedicine have been established in several countries over the last decade to provide specialized stroke expertise to patients in rural areas. Acute consultation is a first step in the management of stroke, but not the only one. Methods of standardization of care and treatment are much needed. So far, quality management systems have only been used for single stroke units. To the best of our knowledge, we are the first stroke network worldwide to aim for certification of a network-wide quality management system.The Stroke Network Using Telemedicine in Northern Bavaria (STENO), currently with 20 associated medical institutions, is one of the world's largest stroke networks, caring for over 5000 stroke patients each year. In 2010, we initiated the implementation of a network-wide 'total' quality management system according to ISO standard 9001:2008 in cooperation with the German Stroke Society and a third-party certification organization (LGA InterCert).Certification according to ISO 9001:2008 was awarded in March 2011 and maintained over a complete certification cycle of 3 years without major deviation from the norm in three external third-party audits. Thrombolysis rate significantly increased from 8·2% (2009) to 12·8% (2012).Certified quality management within a large stroke network using telemedicine is possible and might improve stroke care procedures and thrombolysis rates. Outcome studies comparing conventional stroke care and telestroke care are inevitable.
EVALuna2:22263

Fenfluramine in clinical practice: new therapy option for Dravet and Lennox–Gastaut syndromes - Muhle, Hiltrud; Kurlemann, Gerhard; Lehmann, Irene; Hamer, Hajo; Mayer, Thomas; Potschka, Heidrun; Schubert-Bast, Susanne; Strzelczyk, Adam; Pringsheim, Milka (Clinical Epileptology, 2024)
Fenfluramine is an antiseizure medication for the treatment of Dravet and Lennox–Gastaut syndromes. This review summarizes the literature on the efficacy and tolerability of fenfluramine and presents recommendations for practical therapeutic management. With regular monitoring, this medication is generally well tolerated and to date has shown no cardiac side effects such as valve insufficiency or pulmonary hypertension in the clinical development program. However, children may experience a loss of appetite and should be closely monitored for weight loss, and sedation was observed in several overweight patients due to rapid dosage titration; therefore, a slower dosage increase than recommended might be needed for children and adults. Drug interactions should be considered before and during therapy, and dosage reductions are necessary when the medication is used in combination with stiripentol. Furthermore, bromide levels could increase with this medication. Contact with the patient or their relatives is important to determine the general state of health, potential movement disturbances, and seizure frequency so as to allow for timely dosage adjustments during the titration phase.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Anti-seizure medication; Developmental and epileptic encephalopathy; Drug interactions; Epilepsy

Fibrinolysis Treatment for Cerebral Intraventricular Hemorrhage: A Temporal and Spatial Voxel-Based Analysis - Strinitz, Marc; Kuramatsu, Joji; Kaschka, Iris; Kloska, Stephan; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen; Seifert, Frank (Journal of Neuroimaging, 2016)
A voxel-based statistical approach on computer tomographic data in patients with intracerebral hemorrhage (ICH) and acute intraventricular hemorrhage (IVH) was used to evaluate spatial and temporal patterns of intraventricular blood in patients treated with intraventricular fibrinolysis (IVF) or without.IVH shapes were systematically assessed three dimensionally in patients with supratentorial ICH at three intervals of time (day of admission, day 4 ± 1, day 7+). The boundaries of the intraventricular blood clot were delineated on computed tomography (CT) scans using dedicated software. The CT scan and the IVH shape were transferred into stereotaxic space. In a second step, voxel-based statistics on group level were used to correlate the distribution of intraventricular blood with the interval and the treatment group.Altogether 45 patients, 29 with IVF therapy and 16 without, were eligible to be included into this study. We found significant (false discovery rate [FDR] correction, q < .05) reduction of the intraventricular blood between day of admission and day 7 + for the third and fourth ventricle and parts of both lateral ventricles. In addition, we were able to show a significant difference between the IVF therapy and the conventionally treated group at day 4 ± 1 for the third ventricle.The data indicate that voxel-based analysis on group level can be used to compare the time course and the distribution of intraventricular hemorrhage. This technique could be an interesting tool for future research on ICH with IVH.
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Fingolimod does not seem to alter autonomic modulation of bladder in patients with relapsing-remitting multiple sclerosis - Hilz, Max-Josef; Winder, Klemens; Linker, Ralf; Lee, De-Hyung; Wang, Ruihao (NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-08-02

Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters? - Lee, De-Hyung; Seubert, Silvia; Huhn, Konstantin; Brecht, Lukas; Rötger, Caroline; Waschbisch, Anne; Schlachetzki, Johannes; Klausmeyer, Alice; Melms, Arthur; Wiese, Stefan; Winkler, Jürgen; Linker, Ralf (PLoS ONE, 2017)
Fingolimod is an oral sphingosine-1-phosphate-receptor modulator which reduces the recirculation of immune cells and may also directly target glial cells. Here we investigate effects of fingolimod on expression of astroglial glutamate transporters under pro-inflammatory conditions. In astrocyte cell culture, the addition of pro-inflammatory cytokines led to a significant downregulation of glutamate transporters glutamate transporter-1 (slc1a2/SLC1A2) and glutamate aspartate transporter (slc1a3/SLC1A3) expression on the mRNA or protein level. In this setting, the direct application of fingolimod-1 phosphate (F1P) on astrocytes did not change expression levels of slc1a2 and slc1a3 mRNA. The analysis of both transporters on the protein level by Western Blot and immunocytochemistry did also not reveal any effect of F1P. On a functional level, the addition of conditioned supernatants from F1P treated astrocytes to neuronal cell culture did not result in increased neurite growth. In experimental autoimmune encephalomyelitis as a model of multiple sclerosis, fingolimod treatment reduced T cell and macrophages/microglia mediated inflammation and also diminished astrocyte activation. At the same time, fingolimod restored the reduced expression of slc1a2 and slc1a3 in the inflamed spinal cord on the mRNA level and of SLC1A2 and SLC1A3 on the protein level, presumably via indirect, anti-inflammatory mechanisms. These findings provide further evidence for a predominantly peripheral effect of the compound in neuroinflammation.
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Fingolimod induced reduction in cardiac autonomic regulation is fully reversible after lingolimod discontinuation - Hilz, Max-Josef; Wang, Ruihao; Roy, Sankanika; de Rojas Leal, Carmen; Liu, Mao; Hoesl, K.; Lee, De-Hyung; Linker, Ralf (2017)
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Fingolimod initiation in multiple sclerosis patients is associated with potential beneficial cardiovascular autonomic effects - Hilz, Max J.; Wang, Ruihao; de Rojas Leal, Carmen; Liu, Mao; Canavese, Francesca; Roy, Sankanika; Hoesl, Katharina M.; Winder, Klemens; Lee, De-Hyung; Linker, Ralf (Therapeutic Advances in Neurological Disorders, 2017)
Fingolimod slows heart rate (HR) due to vagomimetic effects and might cause additional cardiovascular autonomic changes. While the time course of HR changes is well described, the extent and course of cardiovascular autonomic changes upon fingolimod initiation has not yet been evaluated. This study, therefore, intended to assess cardiovascular autonomic changes during the first 6 h after fingolimod initiation.In 21 patients with relapsing-remitting multiple sclerosis (RRMS), we recorded respiration (RESP), electrocardiographic RR interval (RRI), systolic and diastolic blood pressure (BPsys, BPdia) at rest, before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. We calculated parameters of total autonomic modulation [RRI standard deviation (RRI-SD), RRI coefficient of variation (RRI-CV), RRI-total powers], mainly sympathetic cardiac modulation [RRI low frequency (LF) powers], sympathetic BP modulation (BPsys-LF powers), parasympathetic modulation [square root of the mean squared difference of successive RRIs (RMSSD), RRI high frequency (HF) powers], sympatho-vagal cardiac balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). We compared parameters between the eight measurements [analysis of variance (ANOVA) or Friedman test with post-hoc analysis; significance: p < 0.05].After fingolimod initiation, RESP, BPsys, and BPsys-LF powers remained unchanged while RRIs, RRI-CV, RRI-SD, RRI-total powers, RRI-LF powers, RMSSD, RRI-HF powers, and BRS increased after 1 h and rose to peak values occurring after 5, 1, 2, 2, 1, 4, 4, and 4 h, respectively. After 3 h, BPdia had decreased significantly and was lowest after 5 h. RRI-LF/HF ratios decreased to a nadir after 4 h.The increases in parasympathetic and overall cardiac autonomic modulation and in BRS seen with fingolimod initiation are theoretically beneficial for the MS patient's cardiovascular system. However, long-term studies must show whether these effects persist or are attenuated (e.g. due to S1P1 receptor down-regulation upon continued fingolimod therapy).
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First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: A retrospective observational multicentre study - Menzler, Katja; Mross, Peter Michael; Rosenow, Felix; Schubert-Bast, Susanne; Willems, Laurent Maximilian; Zahnert, Felix; Immisch, Ilka; Fuest, Sven; Von Podewils, Felix; Kunz, Rhina; Hirsch, Martin; Müller, Tamara; et al. (BMJ Open, 2019)
Objectives Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting. Design Retrospective, observational multicentre study. Setting We retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist. Participants Data of 615 epilepsy patients treated with BRV were included in the study. Primary and secondary outcome measures Efficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X 2 contingency tests and effect sizes were performed. Results Overall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV. Conclusions The present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.
CRIS-Team Scopus Importer:2019-11-15
Keywords: adverse events; brivaracetam; efficacy; levetiracetam; monotherapy; tolerability

First epileptic Seizure - Strzelczyk, Adam; Hamer, Hajo (Deutsche Medizinische Wochenschrift, 2022)
Epileptische Anfalle sind ein haufiges klinisches Phanomen und die Lebenszeitpravalenz betragt bis zu 5%. Hierbei kommt es zu einer abnormalen exzessiven oder synchronen neuronalen Aktivitat im Gehirn, die sich klinisch in einer Sprachstorung, vermindertem Bewusstsein oder motorischen Entau ss erungen manifestieren kann.
CRIS-Team WoS Importer:2022-04-01

Flow-diverting stents allow efficient treatment of unruptured, intradural dissecting aneurysms of the vertebral artery: An explanatory approach using in vivo flow analysis - Gölitz, Philipp; Struffert, Tobias; Eyüpoglu, Ilker Yasin; Knossalla, Frauke; Dörfler, Arnd; Hölter, Philip (Interventional Neuroradiology, 2016)
Our study aimed to evaluate the efficiency of flow-diverting stents (FDS) in treating unruptured, intradural dissecting aneurysms of the vertebral artery (VADAs). Additionally, the effect of FDS on the aneurysmal flow pattern was investigated by performing in vivo flow analysis using parametric color coding (PCC).We evaluated 11 patients with unruptured, intradural VADAs, treated with FDS. Pre- and postinterventional DSA-series were postprocessed by PCC, and time-density curves were calculated. The parameters aneurysmal inflow-velocity, outflow-velocity and relative time-to-peak (rTTP) were calculated. Pre- and postinterventional values were compared and correlated with the occlusion rate after six months.Follow-up DSA detected 10 aneurysms occluded, meaning an occlusion rate of 91%. No procedure-related morbidity and mortality was found. Flow analyses revealed a significant reduction of aneurysmal inflow- velocity and prolongation of rTTP after FDS deployment. Concerning aneurysm occlusion, the postinterventional outflow-velocity turned out to be a marginally statistically significant predictor. A definite threshold value (-0.7 density change/s) could be determined for the outflow-velocity that allows prediction of complete aneurysm occlusion with high sensitivity and specificity (100%).Using FDS can be considered an efficient and safe therapy option in treating unruptured, intradural VADA. From in vivo flow analyses the postinterventional aneurysmal outflow-velocity turned out to be a potential predictor for later complete aneurysm occlusion. Here, it might be possible to determine a threshold value that allows prediction of aneurysm occlusion with high specificity and sensitivity. As fast, applicable and easy-to-handle tool, PCC could be used for procedural monitoring and might contribute to further treatment optimization.
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Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. - Kohl, Zacharias; Winner, Beate; Ubhi, Kiren; Rockenstein, Edward; Mante, Michael; Muench, Martina; Barlow, Carolee; Carter, Todd; Masliah, Eliezer; Winkler, Jürgen (European Journal of Neuroscience, 2012)
The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD.
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FOCAL CORTICAL DYSPLASIA TYPE II IS MEG, MULTIMODAL NEURONAVIGATION AND INTRAOPERATIVE MR IMAGING HELPFUL FOR SURGERY? - Roessler, K.; Kasper, Burkhard; Heynold, Elisabeth; Coras, R.; Rampp, Stefan; Sommer, B.; Hamer, Hajo; Blümcke, Ingmar; Buchfelder, Michael (2017)
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Foreword - Linker, Ralf (Neurodegenerative Disease Management, 2017)
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FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis - Schäffner, Iris; Minakaki, Georgia; Khan, M. Amir; Balta, Elli-Anna; Schlötzer-Schrehardt, Ursula; Schwarz, Tobias J.; Beckervordersandforth, Ruth; Winner, Beate; Webb, Ashley E.; Depinho, Ronald A.; Paik, Jihye; Wurst, Wolfgang; et al. (Neuron, 2018)
Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.
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Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss - Grötsch, Bettina; Lux, Anja; Rombouts, Yoann; Hoffmann, Alana; Andreev, Darja; Nimmerjahn, Falk; Xiang, Wei; Scherer, Hans Ulrich; Schett, Georg; Bozec, Aline (Journal of Bone and Mineral Research, 2019)
Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG-rheumatoid factor (IgG-RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG-RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG-RF production by plasma cells and regulates autoimmune-mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell ) led to increased IgG1-producing bone marrow plasma cells, enhanced IgG-RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG-RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T-cell-dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast-mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG-RF production and autoimmune-mediated bone loss. © 2019 American Society for Bone and Mineral Research.
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Frameless stereotactic functional neuronavigation combined with intraoperative magnetic resonance imaging as a strategy in highly eloquent located tumors causing epilepsy - Sommer, Bjoern; Grummich, Peter; Hamer, Hajo; Blümcke, Ingmar; Coras, Roland; Buchfelder, Michael; Roessler, Karl (Stereotactic and Functional Neurosurgery, 2014)
Background: Intractable epilepsy due to tumors located in highly eloquent brain regions is often considered surgically inaccessible because of a high risk of postoperative neurological deterioration. Intraoperative MRI and functional navigation contribute to overcome this problem. Objectives: To retrospectively investigate the long-term results and impact of functional neuronavigation and 1.5-tesla intraoperative MRI on patients who underwent surgery of tumors associated with epilepsy located close to or within eloquent brain areas. Methods: Nineteen patients (9 female, 10 male, mean age 41.4 ± 13.4 years, 11 low-grade and 8 high-grade glial tumors) were evaluated preoperatively using BOLD imaging, diffusion-tensor imaging tractography and magnetoencephalography. Functional data were implemented into neuronavigation in this multimodal approach. Results: In 14 of 19 patients (74%), complete resection was achieved, and in 5 patients significant tumor volume reduction was accomplished. Eight of 14 (57%) complete resections were achieved only by performing an intraoperative image update. Neurological deterioration was found permanently in 2 patients. After a mean follow-up of 43.8 ± 23.8 months, 15 patients (79%) became seizure free (Engel class Ia). Conclusions: Despite the highly eloquent location of tumors causing intractable epilepsy, our multimodal approach led to complete resection in more than two-thirds of patients with an acceptable neurological morbidity and excellent long-term seizure control. © 2013 S. Karger AG, Basel.
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Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia - Schüle, R.; Schlipf, N.; Synofzik, M.; Klebe, S.; Klimpe, S.; Hehr, U.; Winner, Beate; Lindig, T.; Dotzer, A.; Rieß, O.; Winkler, Jürgen; Schöls, L.; et al. (Journal of Neurology Neurosurgery and Psychiatry, 2009)
Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently, two novel genes, SPG11 (spatacsin) and SPG15 (spastizin), associated with autosomal recessive HSP, were identified. Clinically, both are characterised by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. Objective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterise the phenotype of SPG11 and SPG15. Results: A sample of 36 index patients with early onset complicated HSP and a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5/36) but was considerably higher in patients with TCC (42%). One patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene. Conclusions: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore, priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.
CRIS-Team Scopus Importer:2024-08-07

From amaurotic idiocy to biochemically defined lipid storage diseases: the first identification of GM1-Gangliosidosis - Kasper, Burkhard S.; Thomas, Christian; Albers, Anne; Kasper, Ekkehard M.; Sandhoff, Konrad (Free Neuropathology, 2023)
On February 23rd 1936, a boy-child (“Kn”) died in an asylum near Munich after years of severe congenital disease, which had profoundly impaired his development leading to inability to walk, talk and see as well as to severe epilepsy. While a diagnosis of “Little’s disease” was made during life, his postmortem brain investigation at Munich neuropathology (“Deutsche Forschungsanstalt für Psychiatrie”) revealed the diagnosis of “amaurotic idiocy” (AI). AI, as exemplified by Tay-Sachs-Disease (TSD), back then was not yet understood as a specific inborn error of metabolism encompassing several disease entities. Many neuropathological studies were performed on AI, but the underlying processes could only be revealed by new scientific techniques such as biochemical analysis of nervous tissue, deciphering AI as nervous system lipid storage diseases, e.g. GM2-gangliosidosis. In 1963, Sandhoff & Jatzkewitz published an article on a “biochemically special form of AI” reporting striking differences when comparing their biochemical observations of hallmark features of TSD to tissue composition in a single case: the boy Kn. This was the first description of “GM1-Gangliosidosis”, later understood as resulting from genetically determined deficiency in beta-galactosidase. Here we present illustrative materials from this historic patient, including selected diagnostic slides from the case “Kn” in virtual microscopy, original records and other illustrative material available. Finally, we present results from genetic analysis performed on archived tissue proving beta-galactosidase-gene mutation, verifying the 1963 interpretation as correct. This synopsis shall give a first-hand impression of this milestone finding in neuropathology.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Amaurotic idiocy; Beta-galactosidase; GM1-gangliosidosis; Lipid storage disease; Tay-Sachs-Disease

From Lysosomal Storage Disorders to Parkinson's Disease – Challenges and Opportunities - Mächtel, Rebecca; Boros, Fanni Annamaria; Dobert, Jan; Arnold, Philipp; Zunke, Friederike (Journal of Molecular Biology, 2023)
Lysosomes are specialized organelles with an acidic pH that act as recycling hubs for intracellular and extracellular components. They harbour numerous different hydrolytic enzymes to degrade substrates like proteins, peptides, and glycolipids. Reduced catalytic activity of lysosomal enzymes can cause the accumulation of these substrates and loss of lysosomal integrity, resulting in lysosomal dysfunction and lysosomal storage disorders (LSDs). Post-mitotic cells, such as neurons, seem to be highly sensitive to damages induced by lysosomal dysfunction, thus LSDs often manifest with neurological symptoms. Interestingly, some LSDs and Parkinson's disease (PD) share common cellular pathomechanisms, suggesting convergence of aetiology of the two disease types. This is further underlined by genetic associations of several lysosomal genes involved in LSDs with PD. The increasing number of lysosome-associated genetic risk factors for PD makes it necessary to understand functions and interactions of lysosomal proteins/enzymes both in health and disease, thereby holding the potential to identify new therapeutic targets. In this review, we highlight genetic and mechanistic interactions between the complex lysosomal network, LSDs and PD, and elaborate on methodical challenges in lysosomal research.
CRIS-Team Scopus Importer:2023-03-24
Keywords: lysosomal enzymes; lysosomal storage disorder; lysosome; neurodegeneration; Parkinson's disease

From pullout-techniques to modular elastic stable chest repair: the evolution of an open technique in the correction of pectus excavatum - Schulz-Drost, Stefan; Syed, Julia; Luber, Anna-Maria; Carbon, Roman T.; Besendörfer, Manuel (Journal of Thoracic Disease, 2019)
Background: Traditionally open procedures have been replaced by minimally invasive techniques in the correction of pectus excavatum. Efforts to improve the extent of mobilization of the chest wall and its stabilization have led to constant modifications. There is currently no consensus about the best procedure for correction of pectus excavatum.
CRIS-Team WoS Importer:2019-08-13

From theory to practice: Critical points in the 2017 ILAE classification of epileptic seizures and epilepsies - Palmini, André; Akamatsu, Naoki; Bast, Thomas; Bauer, Sebastian; Baumgartner, Christoph; Benbadis, Selim; Bermeo-Ovalle, Adriana; Beyenburg, Stefan; Bleasel, Andrew; Bozorgi, Alireza; Brázdil, Milan; Carreño, Mar; et al. (Epilepsia, 2020)
CRIS-Team Scopus Importer:2020-02-28

Functional dissociation between cognitive estimation and object naming in focal temporal and frontal lobe epilepsies - Braun, Isabella; Schwarz, Michael; Walther, Katrin; Stemmler, Mark; Kasper, Burkhard; Hamer, Hajo (International Journal of Epilepsy, 2018)

Functional gait measures correlate to fear of falling, and quality of life in patients with Hereditary Spastic Paraplegia: A cross-sectional study - Gaßner, Heiko; List, Julia; Martindale, Christine; Regensburger, Martin; Klucken, Jochen; Winkler, Jürgen; Kohl, Zacharias (Clinical Neurology and Neurosurgery, 2021)
Objective: Gait impairment is the cardinal motor symptom in hereditary spastic paraplegias (HSPs) possibly linked to increased fear of falling and reduced quality of life (QoL). Disease specific symptoms in HSP are rated using the Spastic Paraplegia Rating Scale (SPRS). However, limited studies evaluated more objectively easy-to-apply gait measures by comparing these standardized assessments with patients’ self-perceived impairment and clinically established scores. Therefore, the aim of this study was to correlate functional gait measures with self-rating questionnaires for fear of falling and QoL, and with the SPRS as clinical gold standard. Methods: HSP patients (“pure” phenotype, n = 22) fulfilling the clinical diagnostic criteria for HSP and age-and gender-matched healthy subjects (n = 22) were included in this study. Motor impairment was evaluated using the SPRS, fear of falling by the Falls Efficacy Scale-International (FES-I), and QoL by SF-12. Functional gait measures included gait speed and step length (10-meter-walk-test), the Timed up and go test (TUG), and maximum walking distance (2-min-walking-test). Results: Functional gait measures correlated to fear of falling (gait speed: r = −0.726; step length: r = −0.689; TUG: r = 0.721; 2-min: r = −0.709) and the physical component of QoL (gait speed: r = 0.541; step length: r = 0.531; TUG: r = −0.512; 2-min: r = 0.548). Furthermore, FES-I (r = 0.767) and QoL (r = -0.728) correlated with the clinical gold standard (SPRS). Gait measures strongly correlated with SPRS (gait speed: r = −0.787; step length: r = −0.821; TUG: r = 0.756; 2-min: r = −0.791). Conclusion: Functional gait measures reflect fear of falling, QoL, and mobility in HSP. The metric, semi-quantitative gait measures complement the clinician's evaluation and support the clinical workup by more objective parameters.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Fear of falling; Gait analysis; Hereditary spastic paraplegia; Patient-reported outcome; Quality of life

Functional Long-Term Outcome after Left- versus Right-Sided Intracerebral Hemorrhage - Beuscher, Vanessa D.; Kuramatsu, Joji; Gerner, Stefan; Kohn, Julia; Lücking, Hannes; Kloska, Stephan; Huttner, Hagen (Cerebrovascular Diseases, 2017)
Hemispheric location might influence outcome after intracerebral hemorrhage (ICH). INTERACT suggested higher short-term mortality in right hemispheric ICH, yet statistical imbalances were not addressed. This study aimed at determining the differences in long-term functional outcome in patients with right- vs. left-sided ICH with a priori-defined sub-analysis of lobar vs. deep bleedings.Data from a prospective hospital registry were analyzed including patients with ICH admitted between January 2006 and August 2014. Data were retrieved from institutional databases. Outcome was assessed using the modified Rankin Scale (mRS) score. Outcome measures (long-term mortality and functional outcome at 12 months) were correlated with ICH location and hemisphere, and the imbalances of baseline characteristics were addressed by propensity score matching.A total of 831 patients with supratentorial ICH (429 left and 402 right) were analyzed. Regarding clinical baseline characteristics in the unadjusted overall cohort, there were differences in disfavor of right-sided ICH (antiplatelets: 25.2% in left ICH vs. 34.3% in right ICH; p < 0.01; previous ischemic stroke: 14.7% in left ICH vs. 19.7% in right ICH; p = 0.057; and presence/extent of intraventricular hemorrhage: 45.0% in left ICH vs. 53.0% in right ICH; p = 0.021; Graeb-score: 0 [0-4] in left ICH vs. 1 [0-5] in right ICH; p = 0.017). While there were no differences in mortality and in the proportion of patients with favorable vs. unfavorable outcome (mRS 0-3: 142/375 [37.9%] in left ICH vs. 117/362 [32.3%] in right ICH; p = 0.115), patients with left-sided ICH showed excellent outcome more frequently (mRS 0-1: 64/375 [17.1%] in left ICH vs. 43/362 [11.9%] in right ICH; p = 0.046) in the unadjusted analysis. After adjusting for confounding variables, a well-balanced group of patients (n = 360/hemisphere) was compared showing no differences in long-term functional outcome (mRS 0-3: 36.4% in left ICH vs. 33.9% in right ICH; p = 0.51). Sub-analyses of patients with deep vs. lobar ICH revealed also no differences in outcome measures (mRS 0-3: 53/151 [35.1%] in left deep ICH vs. 53/165 [32.1%] in right deep ICH; p = 0.58).Previously described differences in clinical end points among patients with left- vs. right-hemispheric ICH may be driven by different baseline characteristics rather than by functional deficits emerging from different hemispheric functions affected. After statistical corrections for confounding variables, there was no impact of hemispheric location on functional outcome after ICH.
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Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial - Barow, Ewgenia; Boutitie, Florent; Cheng, Bastian; Cho, Tae-Hee; Ebinger, Martin; Endres, Matthias; Fiebach, Jochen B.; Fiehler, Jens; Ford, Ian; Galinovic, Ivana; Nickel, Alina; Puig, Josep; et al. (JAMA Neurology, 2019)
IMPORTANCE The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.
CRIS-Team WoS Importer:2019-07-26

Functional role of endogenous Kv1.4 in experimental demyelination - Gonzalez Alvarado, Maria; Rötger, Caroline; Berger, Laura; London, Barry; Haase, Stefanie; Kuhbandner, Kristina; Lee, De Hyung; Linker, Ralf A. (Journal of Neuroimmunology, 2020)
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.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Cuprizone; EAE; Kv1.4; Multiple sclerosis; Oligodendrocytes; Remyelination

Further evidence for plasma progranulin as a biomarker in bipolar disorder - Kittel-Schneider, Sarah; Weigl, Johannes; Volkert, Julia; Gessner, Alexandra; Schmidt, Brigitte; Hempel, Susanne; Kiel, Tilman; Olmes, David G.; Bartl, Jasmin; Weber, Heike; Kopf, Juliane; Reif, Andreas (Journal of Affective Disorders, 2014)
A recent study suggested that progranulin (encoded by the fronto-temporal dementia risk gene GRN) plasma levels are decreased in bipolar disorder (BD). Replication of this finding is however lacking.Progranulin plasma levels of bipolar patients (n=104) and healthy controls (n=80) were measured by enzyme-linked immunosorbent assay (ELISA). Participants were also genotyped for three single nucleotide polymorphisms (SNPs) in the GRN gene (rs2879096, rs4792938 and rs5848), and the effect of genetic variation on progranulin levels was examined.Plasma progranulin levels were decreased in BD (ANCOVA, p=0.001). Furthermore, age was significantly and positively correlated with plasma progranulin (Pearson?s correlation, r=0.269, p<0.001). Also, lithium treatment but no other medication had a significant effect on progranulin plasma levels (ANCOVA, p=0.007). Specifically in BD, the GRN SNP rs5848 was associated with progranulin plasma levels (Kruskal-Wallis test, p<0.005).Subgroup analysis regarding bipolar I vs. bipolar II subtype and polarity of the episode at sampling (manic vs. depressed vs. mixed vs. rapid cycling vs. euthymic) could only be performed with limited validity due to the relatively small sample size. The suitability of peripheral progranulin as a biomarker for BD is limited due to the overlap between patients and controls.The findings strengthen the evidence for progranulin being involved in pathomechanisms of bipolar disorder, and suggest a genetic determinant of progranulin concentrations that is relevant specifically in bipolar patients.
EVALuna2:22294

GABA transmission via ATP-dependent K+ channels regulates α-synuclein secretion in mouse striatum - Emmanouilidou, Evangelia; Minakaki, Georgia; Keramioti, Maria V.; Xylaki, Mary; Balafas, Evangelos; Chrysanthou-Piterou, Margarita; Kloukina, Ismini; Vekrellis, Kostas (Brain, 2016)
α-Synuclein is readily released in human and mouse brain parenchyma, even though the normal function of the secreted protein has not been yet elucidated. Under pathological conditions, such as in Parkinson's disease, pathologically relevant species of α-synuclein have been shown to propagate between neurons in a prion-like manner, although the mechanism by which α-synuclein transfer induces degeneration remains to be identified. Due to this evidence extracellular α-synuclein is now considered a critical target to hinder disease progression in Parkinson's disease. Given the importance of extracellular α-synuclein levels, we have now investigated the molecular pathway of α-synuclein secretion in mouse brain. To this end, we have identified a novel synaptic network that regulates α-synuclein release in mouse striatum. In this brain area, the majority of α-synuclein is localized in corticostriatal glutamatergic terminals. Absence of α-synuclein from the lumen of brain-isolated synaptic vesicles suggested that they are unlikely to mediate its release. To dissect the mechanism of α-synuclein release, we have used reverse microdialysis to locally administer reagents that locally target specific cellular pathways. Using this approach, we show that α-synuclein secretion in vivo is a calcium-regulated process that depends on the activation of sulfonylurea receptor 1-sensitive ATP-regulated potassium channels. Sulfonylurea receptor 1 is distributed in the cytoplasm of GABAergic neurons from where the ATP-dependent channel regulates GABA release. Using a combination of specific agonists and antagonists, we were able to show that, in the striatum, modulation of GABA release through the sulfonylurea receptor 1-regulated ATP-dependent potassium channels located on GABAergic neurons controls α-synuclein release from the glutamatergic terminals through activation of the presynaptic GABAB receptors. Considering that sulfonylurea receptors can be selectively targeted, our study highlights the potential use of the key molecules in the α-synuclein secretory pathway to aid the discovery of novel therapeutic interventions for Parkinson's disease.
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GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient: A CARE-Compliant Case Report and Review of the Literature - Maier, Andrea; Mannartz, Vera; Wasmuth, Hermann; Trautwein, Christian; Neumann, Ulf-Peter; Weis, Joachim; Grosse, Joachim; Fuest, Matthias; Hilz, Max-Josef; Schulz, Joerg B.; Haubrich, Christina (Medicine, 2015)
Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life-threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome.In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases.The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed.The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy.
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Gait adaptations to treadmill training in Parkinson’s patients: effects of perturbation, sustainability, and moderators - Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Pasluosta, C. F.; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Book of Abstracts, 2018)

Gait and cognition in Parkinson’s disease: cognitive impairment is inadequately reflected by gait performance during dual task - Gaßner, Heiko; Marxreiter, Franz; Steib, Simon; Kohl, Zacharias; Schlachetzki, Johannes; Adler, Werner; Eskofier, Björn; Pfeifer, Klaus; Winkler, Jürgen; Klucken, Jochen (Frontiers in Neurology, 2017)
Introduction: Cognitive and gait deficits are common symptoms in Parkinson's disease (PD). Motor-cognitive dual tasks (DTs) are used to explore the interplay between gait and cognition. However, it is unclear if DT gait performance is indicative for cognitive impairment. Therefore, the aim of this study was to investigate if cognitive deficits are reflected by DT costs of spatiotemporal gait parameters.Methods: Cognitive function, single task (ST) and DT gait performance were investigated in 67 PD patients. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) followed by a standardized, sensor-based gait test and the identical gait test while subtracting serial 3's. Cognitive impairment was defined by a MoCA score <26. DT costs in gait parameters [(DT ST)/ST x 100] were calculated as a measure of DT effect on gait. Correlation analysis was used to evaluate the association between MoCA performance and gait parameters. In a linear regression model, DT gait costs and clinical confounders (age, gender, disease duration, motor impairment, medication, and depression) were correlated to cognitive performance. In a subgroup analysis, we compared matched groups of cognitively impaired and unimpaired PD patients regarding differences in ST, DT, and DT gait costs.Results: Correlation analysis revealed weak correlations between MoCA score and DT costs of gait parameters (r/r(Sp) <= 0.3). DT costs of stride length, swing time variability, and maximum toe clearance (vertical bar r/r(Sp)vertical bar > 0.2) were included in a regression analysis. The parameters only explain 8% of the cognitive variance. In combination with clinical confounders, regression analysis showed that these gait parameters explained 30% of MoCA performance. Group comparison revealed strong DT effects within both groups (large effect sizes), but significant between-group effects in DT gait costs were not observed.Conclusion: These findings suggest that DT gait performance is not indicative for cognitive impairment in PD. DT effects on gait parameters were substantial in cognitively impaired and unimpaired patients, thereby potentially overlaying the effect of cognitive impairment on DT gait costs. Limits of the MoCA in detecting motor-function specific cognitive performance or variable individual response to the DT as influencing factors cannot be excluded. Therefore, DT gait parameters as marker for cognitive performance should be carefully interpreted in the clinical context.
Keywords: Parkinson's disease; gait; cognition; dual task; gait analysis; Montreal Cognitive Assessment

Gait variability as digital biomarker of disease severity in Huntington’s disease - Gaßner, Heiko; Jensen, Dennis; Marxreiter, Franz; Kletsch, Anja; Bohlen, Stefan; Schubert, Robin; Muratori, Lisa M.; Eskofier, Björn; Klucken, Jochen; Winkler, Jürgen; Reilmann, Ralf; Kohl, Zacharias (Journal of Neurology, 2020)
Background Impaired gait plays an important role for quality of life in patients with Huntington's disease (HD). Measuring objective gait parameters in HD might provide an unbiased assessment of motor deficits in order to determine potential beneficial effects of future treatments. Objective To objectively identify characteristic features of gait in HD patients using sensor-based gait analysis. Particularly, gait parameters were correlated to the Unified Huntington's Disease Rating Scale, total motor score (TMS), and total functional capacity (TFC). Methods Patients with manifest HD at two German sites (n = 43) were included and clinically assessed during their annual ENROLL-HD visit. In addition, patients with HD and a cohort of age- and gender-matched controls performed a defined gait test (4 x 10 m walk). Gait patterns were recorded by inertial sensors attached to both shoes. Machine learning algorithms were applied to calculate spatio-temporal gait parameters and gait variability expressed as coefficient of variance (CV). Results Stride length (- 15%) and gait velocity (- 19%) were reduced, while stride (+ 7%) and stance time (+ 2%) were increased in patients with HD. However, parameters reflecting gait variability were substantially altered in HD patients (+ 17% stride length CV up to + 41% stride time CV with largest effect size) and showed strong correlations to TMS and TFC (0.416 <= r(Sp) <= 0.690). Objective gait variability parameters correlated with disease stage based upon TFC. Conclusions Sensor-based gait variability parameters were identified as clinically most relevant digital biomarker for gait impairment in HD. Altered gait variability represents characteristic irregularity of gait in HD and reflects disease severity.
CRIS-Team Scopus Importer:2020-02-25
Keywords: Gait analysis; Gait variability; Huntington’s disease; Regularity of gait; Wearable sensors

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes - Hoffmann, Lucas; Coras, Roland; Kobow, Katja; López-Rivera, Javier A.; Lal, Dennis; Leu, Costin; Najm, Imad; Nürnberg, Peter; Herms, Jochen; Harter, Patrick N.; Bien, Christian G.; Kalbhenn, Thilo; et al. (Acta Neuropathologica, 2023)
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
CRIS-Team Scopus Importer:2023-04-07
Keywords: Brain; DNA methylation; Epilepsy; Seizure; Summary plots

Gap Analysis Regarding Prognostication in Neurocritical Care: A Joint Statement from the German Neurocritical Care Society and the Neurocritical Care Society - Wartenberg, Katja E.; Hwang, David Y.; Häusler, Karl Georg; Muehlschlegel, Susanne; Sakowitz, Oliver W.; Madžar, Dominik; Hamer, Hajo; Rabinstein, Alejandro A.; Greer, David M.; Hemphill, J. Claude; Meixensberger, Juergen; Varelas, Panayiotis N. (Neurocritical Care, 2019)
Background/Objective: Prognostication is a routine part of the delivery of neurocritical care for most patients with acute neurocritical illnesses. Numerous prognostic models exist for many different conditions. However, there are concerns about significant gaps in knowledge regarding optimal methods of prognostication. Methods: As part of the Arbeitstagung NeuroIntensivMedizin meeting in February 2018 in Würzburg, Germany, a joint session on prognostication was held between the German NeuroIntensive Care Society and the Neurocritical Care Society. The purpose of this session was to provide presentations and open discussion regarding existing prognostic models for eight common neurocritical care conditions (aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, acute ischemic stroke, traumatic brain injury, traumatic spinal cord injury, status epilepticus, Guillain–Barré Syndrome, and global cerebral ischemia from cardiac arrest). The goal was to develop a qualitative gap analysis regarding prognostication that could help inform a future framework for clinical studies and guidelines. Results: Prognostic models exist for all of the conditions presented. However, there are significant gaps in prognostication in each condition. Furthermore, several themes emerged that crossed across several or all diseases presented. Specifically, the self-fulfilling prophecy, lack of accounting for medical comorbidities, and absence of integration of in-hospital care parameters were identified as major gaps in most prognostic models. Conclusions: Prognostication in neurocritical care is important, and current prognostic models are limited. This gap analysis provides a summary assessment of issues that could be addressed in future studies and evidence-based guidelines in order to improve the process of prognostication.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Comorbidities; Outcome predictors; Prognostication; Self-fulfilling prophecy

Gaps Between Aims and Achievements in Therapeutic Modification of Neuronal Damage ("Neuroprotection") - Wiendl, Heinz; Elger, Christian; Foerstl, Hans; Hartung, Hans-Peter; Oertel, Wolfgang; Reichmann, Heinz; Schwab, Stefan (Neurotherapeutics, 2015)
The term "neuroprotection" is often misused, overused, or misunderstood. A reasonable definition of neuroprotection refers to the preservation of "neuronal structure and/or function." Although our knowledge about the cellular and molecular mechanisms of neurodegeneration has expanded, experimental systems and animal models that mimic the process or allow translation into clinical success remain limited. This editorial discusses reasons for this gap and strategies to close it. Experimental models can only mirror certain aspects of disease mechanisms in humans. Therefore, findings in these models need to be linked with patient data to improve real-life relevance. Successful neuroprotection depends on finding the right "window of opportunity" which varies from very short (stroke) to very long (Alzheimer's disease), necessitating the need to focus on strategies for very early disease recognition. This need challenges the strategies to be chosen, trial approaches and methodologies, and the allocation of resources. Additionally, outcome measures are often not well suited to assess neuroprotection. To this end, surrogate measures, including biomarkers, are useful endpoints to demonstrate evidence of target directed therapeutic utility. Finally, studies have shown that neuroprotection is not likely to succeed when targeting only one pathway. These obstacles have reduced the level of enthusiasm for neuroprotection in certain disease areas (e.g., stroke). Academia, industry, regulatory authorities, funding agencies and patient organizations have to cooperate to a greater extent in order to overcome these impediments and to encourage nonclassical concepts. These concepts will be interdisciplinary in order to achieve meaningful disease modification.
EVALuna2:22435

Gastrointestinal microbiome in Parkinson's disease in a Bavarian cohort - Marxreiter, Franz; Cosma-Grigorov, Alexandra; Gaßner, Heiko; Meixner, Holger; Kohl, Zacharias; Neurath, Markus; Wirtz, Stefan; Winkler, Jürgen (2019)
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Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons - Havlicek, Steven; Kohl, Zacharias; Mishra, Himanshu Kumar; Prots, Iryna; Eberhardt, Esther; Denguir, Naime; Wend, Holger; Ploetz, Sonja; Boyer, Leah; Marchetto, Maria C. N.; Aigner, Stefan; Sticht, Heinrich; et al. (Human Molecular Genetics, 2014)
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients.
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General Trends in Prices and Prescription Patterns of Anticonvulsants in Germany between 2000 and 2017: Analysis of National and Cohort-Based Data - Willems, Laurent M.; Hamer, Hajo; Knake, Susanne; Rosenow, Felix; Reese, Jens Peter; Strzelczyk, Adam (Applied Health Economics and Health Policy, 2019)
Objective: Our aim was to explore trends in price evolution and prescription volumes of anticonvulsants (AEDs, antiepileptic drugs) in Germany between 2000 and 2017. Method: This study used data from annual reports on mean prescription frequency and prices of defined daily doses (DDD) of AEDs in Germany to analyze nationwide trends. Interrupted time series (ITS) analysis was employed to test for significant effects of several statutory healthcare reforms in Germany on AED price evolution. These data were compared to cohort-based prescription patterns of four German cohort studies from 2003, 2008, 2013, and 2016 that included a total of 1368 patients with focal and generalized epilepsies. Results: Analysis of national prescription data between 2000 and 2017 showed that mean prices per DDD of third-generation AEDs decreased by 65% and mean prices of second-generation AEDs decreased by 36%, whereas mean prices of first-generation AEDs increased by 133%. Simultaneously, mean prescription frequency of third- generation AEDs increased by 2494%, while there was a substantial decrease in the use of first- (− 55%) and second- (− 16%) generation AEDs. ITS analysis revealed that in particular the introduction of mandatory rebates on drugs in 2003 affected prices of frequently used newer AEDs. These findings are consistent with data from cohort studies of epilepsy patients showing a general decrease of prices for frequently used AEDs in monotherapy by 62% and in combination therapies by 68%. The analysis suggests that overall expenses for AEDs remained stable despite an increase in the prescription of “newer” and “non-enzyme-inducing” AEDs for epilepsy patients. Conclusion: Between 2000 and 2017, a distinct decline in AED prices can be observed that seems predominately caused by a governmentally obtained price decline of third- and second-generation drugs. These observations seem to be the result of a German statutory cost containment policy applied across all health-care sectors. The increasing use of third-generation AEDs to the disadvantage of “old” and “enzyme-inducing” AEDs reflects the preferences of physicians and patients with epilepsy and follows national treatment guidelines.
CRIS-Team Scopus Importer:2019-06-18

Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in - Winner, Beate; Krumm, Laura; Pozner, Tatyana; Kaindl, Johanna; Regensburger, Martin; Günther, Claudia; Turan, Sören; Asadollahi, Reza; Rauch, Anita (Stem Cell Research, 2021)
Pathogenic bi-allelic variants in the SPG11 gene result in rare motor neuron disorders such as Hereditary Spastic Paraplegia type 11, Charcot-Marie Tooth, and Juvenile Amyotrophic Lateral Sclerosis-5. The main challenge in SPG11-linked disease research is the lack of antibodies against SPG11 encoded spatacsin. Here, we describe the CRISPR/Cas9 mediated generation and validation of an endogenously tagged SPG11- human iPSC line that contains an HA tag at the C-terminus of SPG11. The line exhibits multi-lineage differentiation potential and holds promise for studying the role of spatacsin and for the elucidation of SPG11-associated pathogenesis. Resource Table.

Generation of a homozygous and a heterozygous SNCA gene knockout human-induced pluripotent stem cell line by CRISPR/Cas9 mediated allele-specific tuning of SNCA expression - Schneider, Yanni; Turan, Soeren; Koller, Aron; Krumbiegel, Mandy; Farrell, Michaela; Plotz, Sonja; Winkler, Jürgen; Xiang, Wei (Stem Cell Research, 2022)
Aggregation of alpha-synuclein (aSyn) is closely linked to Parkinson's disease, probably due to the loss of physiological functions and/or gain of toxic functions of aggregated aSyn. Significant efforts have been made elucidating the physiological structure and function of aSyn, however, with limited success thus far in human -derived cells, partly because of restricted resources. Here, we developed two human-induced pluripotent stem cell lines using CRISPR/Cas9-mediated allele-specific frame-shift deletion of the aSyn encoding gene SNCA, resulting in homo-and heterozygous SNCA knockout. The generated cell lines are promising cellular tools for studying aSyn dosage-dependent functions and structural alterations in human neural cells.
CRIS-Team WoS Importer:2022-11-18

Genetically Single Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in - Krumm, Laura; Pozner, Tatyana; Kaindl, Johanna; Regensburger, Martin; Günther, Claudia; Turan, Sören; Asadollahi, Reza; Rauch, Anita; Winner, Beate (Stem Cell Research, 2021)
Pathogenic bi-allelic variants in the SPG11 gene result in rare motor neuron disorders such as Hereditary Spastic Paraplegia type 11, Charcot-Marie Tooth, and Juvenile Amyotrophic Lateral Sclerosis-5. The main challenge in SPG11-linked disease research is the lack of antibodies against SPG11 encoded spatacsin. Here, we describe the CRISPR/Cas9 mediated generation and validation of an endogenously tagged SPG11- human iPSC line that contains an HA tag at the C-terminus of SPG11. The line exhibits multi-lineage differentiation potential and holds promise for studying the role of spatacsin and for the elucidation of SPG11-associated pathogenesis.
CRIS-Team Scopus Importer:2021-09-10

Genetic determinants of the humoral immune response in MS - Gasperi, Christiane; Andlauer, Till F. M.; Keating, Ana; Knier, Benjamin; Klein, Ana; Pernpeintner, Verena; Lichtner, Peter; Gold, Ralf; Zipp, Frauke; Bergh, Florian Then; Stangel, Martin; Tumani, Hayrettin; et al. (Neurology, Neuroimmunology and Neuroinflammation, 2020)
Objective
CRIS-Team WoS Importer:2020-10-09

Genetic testing for Parkinson's disease: Indication and practical implementation - Tönges, Lars; Ip, Chi Wang; Dresel, Christian; Lingor, Paul; Csoti, Ilona; Kohl, Zacharias; Winkler, Jürgen; Klebe, Stephan (Fortschritte der Neurologie - Psychiatrie, 2020)
More than 20 years have passed since the first description of a monogenic cause of Parkinson's disease. Despite the tremendous advances of genetic testing these techniques are rarely used in Parkinson's disease. However, genetic tests in patients with Parkinson's syndrome will play an important role in the future. This is not only to ensure the diagnosis of Parkinson's patients with a young onset and/or a positive family history, but also in the context of personalised medicine with new therapeutic options. In the following we would like to give an overview of the basics of genetic testing, the legal requirements, the procedure for genetic testing and an outlook into the future for hereditary Parkinson's diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Genetic testing; Genetics; Parkinson's disease

Genital ulcers as diagnostic clue for acute myeloid leukaemia - Schröder, Sina; Krause, Stefan; Erfurt-Berge, Cornelia (International Wound Journal, 2018)
Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions.
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Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia - Kobow, Katja; Ziemann, Mark; Kaipananickal, Harikrishnan; Khurana, Ishant; Mühlebner, Angelika; Feucht, Martha; Hainfellner, Johannes A.; Czech, Thomas; Aronica, Eleonora; Pieper, Tom; Holthausen, Hans; Kudernatsch, Manfred; et al. (Epilepsia, 2019)
Objectives: Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation–based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes. Methods: DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls. Results: Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway–related genes. Significance: Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.
CRIS-Team Scopus Importer:2019-06-18
Keywords: diagnostic biomarker; epigenetic; focal cortical dysplasia; focal epilepsy; mTOR pathway

German Validation of the Composite Autonomic Symptom Score 31 - Wang, Ruihao; Canavese, Francesca; Intravooth, Tassanai; Singer, Wolfgang; Hilz, Max-Josef (NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-08-02

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice - Winner, Beate; Marxreiter, Franz; Ettle, Benjamin; May, Verena Elisabeth Luise; Patrick, Christina; Klucken, Jochen; Winkler, Jürgen; Masliah, Eliezer; Nuber, Silke; et al. (Neurobiology of Disease, 2013)
In Parkinson's disease (PD) patients, alpha-synuclein (alpha-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of alpha-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how alpha-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood.We used a tetracycline-suppressive (Let-off) transgenic mouse model that restricts overexpression of human A30P alpha-syn to neurons owing to usage of the neuron-specific CaMKIla promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P alpha-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P alpha-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P alpha-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P alpha-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior. (C) 2013 Elsevier Inc. All rights reserved.
Keywords: Ghosts; Parkinson's disease; S1008; Transgenic; A30P alpha-synuclein; Conditional; Propagation

Glucocorticoid modulation of synaptic plasticity in the human temporal cortex of epilepsy patients: Does chronic stress contribute to memory impairment? - Brandner, Sebastian; Schröter, Sarah; Çalışkan, Gürsel; Salar, Seda; Kobow, Katja; Coras, Roland; Blümcke, Ingmar; Hamer, Hajo; Schwarz, Michael; Buchfelder, Michael; Maslarova, Anna (Epilepsia, 2021)
Objective: Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients. Methods: We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators. Results: LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS. Significance: Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of GRs. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.
CRIS-Team Scopus Importer:2021-10-29
Keywords: dexamethasone; epilepsy; human cortex; long-term potentiation; stress

Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis - Lee, De-Hyung; Roetger, Caroline; Appeldoorn, Chantal C. M.; Reijerkerk, Arie; Gladdines, Werner; Gaillard, Pieter J.; Linker, Ralf (Journal of Neuroimmunology, 2014)
Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS. After disease onset, mice were randomized to receive either saline, three injections of free MP (high dose MP, 100mg/kg i.v.), two injections of free MP (low dose MP, 10mg/kg; i.v.), or two injections of 2B3-201 (10mg/kg i.v.). Treatment with a low dose of 2B3-201 significantly reduced the severity of EAE as compared to saline control, similar to treatment with high dose free MP, while a low dose of free MP was not effective. In a histological analysis of the spinal cord, treatment with 2B3-201 significantly decreased T cell as well as macrophage/microglia infiltration in the CNS by about 50%. Moreover, application of a low dose of 2B3-201 or a high dose of free MP reduced the amount of astrocyte activation as well as the extent of axonal loss and also demyelination in spinal cord lesions as compared to low dose MP or sham treatment. In summary, in the murine MOG-EAE model of MS, a glutathione PEGylated liposomal formulation of MP (2B3-201) is clinically and histologically as effective as free MP at one tenth of the dosage as well as at a lower application frequency and clearly more effective than the same dosage of free MP. These positive proof-of-concept efficacy studies warrant further development of 2B3-201 for the treatment of neuroinflammatory conditions such as MS.
EVALuna2:22300

GMP-production of purified human B lymphocytes for the adoptive transfer in patients after allogeneic hematopoietic stem cell transplantation - Tittlbach, Hannes; Schneider, Andrea; Strobel, Joachim; Zimmermann, Robert; Maas, Stefanie; Gebhardt, Bernd; Rauser, Georg; Mach, Michael; Mackensen, Andreas; Winkler, Thomas; Winkler, Jürgen (Journal of Translational Medicine, 2017)
We have recently shown that memory B cells from murine CMV immune donor animals adoptively transferred into immunodeficient mice were highly effective in protecting from a viral infection indicating a therapeutic potential of virus specific memory B cells. These preclinical data provided evidence that a cell-based strategy supporting the humoral immune response might be effective in a clinical setting of immunodeficiency after allogeneic hematopoietic stem cell transplantation. As adoptive transfer of B cells has not been used before in a clinical setting it was necessary to establish a technology for the generation of good manufacturing practice (GMP)-grade B cell products.Starting from the leukapheresis product of healthy blood donors, B cells were purified by two different separation strategies using GMP-grade microbeads and the CliniMACS system. A one-step protocol was used for positive enrichment of B lymphocytes with anti-CD19 microbeads. In a two-step enrichment protocol, first T lymphocytes were depleted by anti-CD3 microbeads and the remaining fraction was positively selected by anti-CD19 microbeads.The purity and recovery after enrichment of B lymphocytes from the leukapheresis material in both separations strategies was not statistically different. However, contamination of the B-cell product with T cells was significantly lower after the two-step protocol (0.16%, range 0.01-0.43% after two-step separation and 0.55%, range 0.28-0.85% after one-step separation, p < 0.05). Therefore, a combined CD3 depletion and CD19 enrichment was used for the production of GMP-conform B-cell products from the leukapheresis material of 17 healthy stem cell donors. The absolute B-cell numbers obtained in the final product was 4.70 ± 3.64 × 108 with a purity of 95.98 ± 3.31% B lymphocytes and a recovery of 18.9 ± 10.6%. Importantly, the contamination with CD3+ T cells was extremely low in the final B- cell products (0.10 ± 0.20%). Purified B cells exhibited normal antibody production after in vitro stimulation and showed excellent viability after cryopreservation.A GMP-grade B-cell product can be obtained with high purity and very low T-cell contamination using the two-step enrichment protocol based on CliniMACS® technology.
EVALuna2:25773

Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution - Sauer, Rolf; Gölitz, Philipp; Jacobi, Johannes; Schwab, Stefan; Linker, Ralf; Lee, De-Hyung (Journal of the Neurological Sciences, 2017)
Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.
EVALuna2:22499

Granulocyte colony-stimulating factor does not promote neurogenesis after experimental intracerebral haemorrhage - Kallmünzer, Bernd; Tauchi, Miyuki; Schlachetzki, Johannes; Machold, Kristin; Schmidt, Ariana; Winkler, Jürgen; Schwab, Stefan; Kollmar, Rainer (International Journal of Stroke, 2014)
Hematopoietic growth factors have been suggested to induce neuroprotective and regenerative effects in various animal models of cerebral injury. However, the pathways involved remain widely unexplored.This study aimed to investigate effects of local and systemic administration of granulocyte colony-stimulating factor on brain damage, functional recovery, and cerebral neurogenesis in an intracerebral haemorrhage whole blood injection model in rats.Eight-week-old male Wistar rats (n = 100) underwent induction of striatal intracerebral haemorrhage by autologous whole blood injection or sham procedure and were randomly assigned to either (a) systemic treatment with granulocyte colony-stimulating factor (60 ?g/kg) for five-days; (b) single intracerebral injection of granulocyte colony-stimulating factor (60 ?g/kg) into the cavity; or (c) application of vehicle for five-days. Bromodeoxyuridine-labelling and immunohistochemistry were used to analyze proliferation and survival of newly born cells in the sub-ventricular zone and the hippocampal dentate gyrus. Moreover, functional deficits and lesion volume were assessed until day 42 after intracerebral haemorrhage.Differences in lesion size or hemispheric atrophy between granulocyte colony-stimulating factor-treated and control groups did not reach statistical significance. Neither systemic, nor local granulocyte colony-stimulating factor administration induced neurogenesis within the dentate gyrus or the sub-ventricular zone. The survival of newborn cells in these regions was prevented by intracerebral granulocyte colony-stimulating factor application. A subtle benefit in functional recovery at day 14 after intracerebral haemorrhage induction was observed after granulocyte colony-stimulating factor treatment.There was a lack of neuroprotective or neuroregenerative effects of granulocyte colony-stimulating factor in the present rodent model of intracerebral haemorrhage. Conflicting results from functional outcome assessment require further research.
EVALuna2:22279

GSK3ss-Dependent Dysregulation of Neurodevelopment in SPG11-Patient Induced Pluripotent Stem Cell Model - Mishra, Himanshu Kumar; Prots, Iryna; Havlicek, Steven; Kohl, Zacharias; Pérez-Brangulí, Francesc; Börstler, Tom; Anneser, Lukas; Minakaki, Georgia; Wend, Holger; Hampl, Martin; Leone, Marina; Brückner, Martina; et al. (Annals of Neurology, 2016)
Objective: Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC)-derived cortical neural progenitor cells (NPCs).Methods: We generated and characterized iPSC-derived NPCs and neurons from 3 SPG11 patients and 2 age-matched controls.Results: Gene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell-cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ss-signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation.Interpretation: This iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ss as a potential novel target to reverse the disease phenotype.

Guest editorial: Enabling technologies for Parkinson's disease management - Klucken, Jochen; Friedl, K. E.; Eskofier, Björn; Hausdorff, J. M. (IEEE Journal of Biomedical and Health Informatics, 2015)

Guidelines on dermatomyositis–excerpt from the interdisciplinary S2k guidelines on myositis syndromes by the German Society of Neurology - Sunderkoetter, Cord; Nast, Alexander; Worm, Margitta; Dengler, Reinhard; Doerner, Thomas; Ganter, Horst; Hohlfeld, Reinhard; Melms, Arthur; Melzer, Nico; Roesler, Kai; Schmidt, Jens; Sinnreich, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
The present guidelines on dermatomyositis (DM) represent an excerpt from the interdisciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30% of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic workup. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5-20% of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30% of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1-2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of intravenous immunoglobulins is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for one to three years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include antimalarial agents (also in combination), methotrexate, and corticosteroids. Intravenous immunoglobulins or rituximab may also be helpful. UV protection is an important prophylactic measure.
EVALuna2:22517

Gunshot Injuries to the Head - Kasper, Ekkehard M.; Algethami, Hanan; Takroni, Radwan; Kasper, Burkhard S. (Springer International Publishing, 2024)
Traumatic brain injury (TBI) remains a major cause of death and disability worldwide, and missile-induced TBI remains the deadliest of all traumas since first reported and has always been associated with high mortality and morbidity. It also results in significant socioeconomic burden to the health care system. The prevalence of TBI secondary to gunshots is geographically strikingly variable and reflects the global scenery of violence as well as access to weaponry. Injuries from gunshot wounds (GSW) to the head place an extreme economic burden on the public while disabling most victims in the zenith of their life and imposing enormous medical, legal, and emotional costs. Since every gun/projectile combination is associated with a typical pattern of injury, war injuries differ significantly from others. We will focus here on predominantly penetrating civilian gunshot wounds with low muzzle velocity (<1000 f/s) as they occur in the setting of homicide, and suicide attempts or during domestic and hunting accidents as well as during legal interventions. Many surgeons rushed patients to the OR over the last 30 years, and they have achieved a remarkable reduction in morbidity from well above 50% to less than 25%, even in patients admitted with severe brain injury. However, in the setting of increasingly limited resources, recent research focus has shifted toward more precise prediction of survival as well as on better functional outcome.
CRIS-Team Scopus Importer:2025-02-04

Gut–Brain Interactions and Their Impact on Astrocytes in the Context of Multiple Sclerosis and Beyond - Zißler, Julia; Rothhammer, Veit; Linnerbauer, Mathias (Cells, 2024)
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to physical and cognitive impairment in young adults. The increasing prevalence of MS underscores the critical need for innovative therapeutic approaches. Recent advances in neuroimmunology have highlighted the significant role of the gut microbiome in MS pathology, unveiling distinct alterations in patients’ gut microbiota. Dysbiosis not only impacts gut-intrinsic processes but also influences the production of bacterial metabolites and hormones, which can regulate processes in remote tissues, such as the CNS. Central to this paradigm is the gut–brain axis, a bidirectional communication network linking the gastrointestinal tract to the brain and spinal cord. Via specific routes, bacterial metabolites and hormones can influence CNS-resident cells and processes both directly and indirectly. Exploiting this axis, novel therapeutic interventions, including pro- and prebiotic treatments, have emerged as promising avenues with the aim of mitigating the severity of MS. This review delves into the complex interplay between the gut microbiome and the brain in the context of MS, summarizing current knowledge on the key signals of cross-organ crosstalk, routes of communication, and potential therapeutic relevance of the gut microbiome. Moreover, this review places particular emphasis on elucidating the influence of these interactions on astrocyte functions within the CNS, offering insights into their role in MS pathophysiology and potential therapeutic interventions.
CRIS-Team Scopus Importer:2024-04-05
Keywords: dysbiosis; gut–brain interactions; microbiome; multiple sclerosis; neuroinflammation

Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation - Zundler, Sebastian; Günther, Claudia; Kremer, Andreas E.; Rothhammer, Veit; Neurath, Markus; Zaiss, Mario (Nature Reviews Gastroenterology & Hepatology, 2022)
Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body’s fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut–liver, gut–joint and gut–brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.
CRIS-Team Scopus Importer:2022-08-26

Gut-to-brain spreading of pathology in synucleinopathies: A focus on molecular signalling mediators - Schmitt, Verena; Masanetz, Rebecca Katharina; Weidenfeller, Martin; Ebbinghaus, Lara Savannah; Süß, Patrick; Rosshart, Stephan Patrick; von Hörsten, Stephan; Zunke, Friederike; Winkler, Jürgen; Xiang, Wei (Behavioural Brain Research, 2023)
Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Alpha synuclein; Gut-to-brain communication; Inflammatory bowel disease; Multiple system atrophy; Parkinson's disease

Have attitudes toward epilepsy improved in Germany over the last 50 years? - Thorbecke, Rupprecht; Pfäfflin, Margarete; Bien, Christian G.; Hamer, Hajo; Holtkamp, Martin; Rating, Dietz; Schulze-Bonhage, Andreas; Straub, Hans Beatus; Strzelczyk, Adam; May, Theodor W. (Epilepsy and Behavior, 2023)
Objective: In Germany, six previous representative surveys on attitudes toward epilepsy (AE) have been conducted between 1967 and 2008 using the four original Caveness questions (CQs) from 1949 to 1980. The aims of this study were (1) to investigate changes in AE over the time span of 50 years, including the current survey in 2018 (2) to investigate the first-time emotional reactions measured with the Scales of Attitudes toward People with Epilepsy (SAPE) (3) to identify predictors of AE. Methods: A representative face-to-face survey with CQ, in addition with the SAPE scales of Social Distance, Stereotypes, Personal Concerns, and Emotional Reactions was carried out in Germany in 2018. One thousand and twenty-six persons who ever had heard of epilepsy participated. Respondents who answered “don't know” in the CQs were subsequently asked to answer only yes/no. The analysis of trends from 1967 to 2018 was based on the pooled data of the surveys. The four CQs in the 2018 survey were included in the SAPE item pool and an exploratory principal axis factor analysis was performed. General linear models were performed to identify predictors. Results: For all four CQs, the trend of improved AE was significant over the past 50 years. In the 2018 survey, excluding the “don't know” answer option increased the proportion of negative responses for contact of one's own children with a person with epilepsy (PWE) from 6.9% to 11.4% and for the marriage of one's own children with a PWE from 13.9% to 23.8%. When encountering a PWE, 30.1% would feel insecure or uncomfortable and nearly 60% were concerned that the PWE might be injured in case of a seizure. Knowing what to do in case of a seizure, knowing that seizures can be treated successfully, personal contact with a PWE along with younger age, and higher education were found to be the strongest predictors for positive AE identified by multivariate analyses. Exploratory principal axis factor analysis revealed that three of the four CQs items loaded > 0.30 at the factors of Social Distance and Stereotypes of SAPE but none on the factors measuring emotional reactions. Significance: AE measured by CQs have markedly improved in Germany over the last 50 years. Germany is to our knowledge the only country with such a long-term trend investigation in AE. Negative AE may be underestimated by survey questions with “don't know” answer option. Emotional aspects of attitudes are underexposed resp. neglected in the CQs, which are used worldwide for measuring AE. Additional tools like SAPE can close this gap. The identified predictors may help to derive interventions against negative AE.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Caveness; Emotional reaction; Long-term trends; Social distance; Stereotypes

Heart Failure in Ischemic Stroke: Relevance for Acute Care and Outcome - Siedler, Gabriela; Sommer, Kim; Macha, Kosmas; Marsch, Armin; Breuer, Lorenz; Stoll, Svenja; Engelhorn, Tobias; Dörfler, Arnd; Schwab, Stefan; Kallmünzer, Bernd; Arnold, Martin (Stroke, 2019)
Background and Purpose- Heart failure (HF) in patients with acute ischemic stroke constitutes the source of various detrimental pathophysiologic mechanisms including prothrombotic and proinflammatory states, worsening of cerebral tissue oxygenation, and hemodynamic impairment. In addition, HF might affect the safety and efficacy of the acute recanalization stroke therapies. Methods- Patients treated with intravenous recombinant tissue-type plasminogen activator or mechanical recanalization at a universitary stroke center were included into a prospective registry. Patients received cardiological evaluation, including echocardiography, during acute care. Functional outcome was assessed after 90 days by structured telephone interviews. Safety and efficacy of intravenous thrombolysis and mechanical thrombectomy were investigated among patients with HF and compared with patients with normal cardiac function after propensity score matching. Results- One thousand two hundred nine patients were included. HF was present in 378 patients (31%) and an independent predictor of unfavorable functional outcome. Recanalization rates were equal among patients with HF after intravenous thrombolysis and after mechanical recanalization or combined treatment. The rate of secondary intracranial hemorrhage was not different (7% versus 8%; P=0.909 after thrombolysis and 15% versus 20%, P=0.364 after mechanical recanalization or combined therapy). Early mortality within 48 hours after admission was equal (<1.5% in both groups). Conclusions- In this real-world cohort of patients with stroke, HF was an independent predictor of unfavorable functional long-term outcome, while the safety and efficacy of intravenous thrombolysis and mechanical recanalization appeared unaffected.
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Hematoma Characteristics and Functional Outcome Do Not Differ in NOAC- Versus VKA-Associated Intracerebral Hemorrhage - Gerner, Stefan; Lücking, Hannes; Köhrmann, Martin; Huttner, Hagen (2016)
EVALuna2:22585

Hematoma enlargement characteristics in deep versus lobar intracerebral hemorrhage - Sembill, Jochen; Kuramatsu, Joji; Gerner, Stefan; Sprügel, Maximilian; Röder, Sebastian; Madžar, Dominik; Hagen, Manuel; Lücking, Hannes; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen; Hölter, Philip (Annals of Clinical and Translational Neurology, 2020)
Objective: Hematoma enlargement (HE) is associated with clinical outcomes after supratentorial intracerebral hemorrhage (ICH). This study evaluates whether HE characteristics and association with functional outcome differ in deep versus lobar ICH. Methods: Pooled analysis of individual patient data between January 2006 and December 2015 from a German-wide cohort study (RETRACE, I + II) investigating ICH related to oral anticoagulants (OAC) at 22 participating centers, and from one single-center registry (UKER-ICH) investigating non-OAC-ICH patients. Altogether, 1954 supratentorial ICH patients were eligible for outcome analyses, which were separately conducted or controlled for OAC, that is, vitamin-K-antagonists (VKA, n = 1186) and non-vitamin-K-antagonist-oral-anticoagulants (NOAC, n = 107). Confounding was addressed using propensity score matching, cox regression modeling and multivariate modeling. Main outcomes were occurrence, extent, and timing of HE (>33%/>6 mL) and its association with 3-month functional outcome. Results: Occurrence of HE was not different after deep versus lobar ICH in patients with non-OAC-ICH (39/356 [11.0%] vs. 36/305 [11.8%], P = 0.73), VKA-ICH (249/681 [36.6%] vs. 183/505 [36.2%], P = 0.91), and NOAC-ICH (21/69 [30.4%] vs. 12/38 [31.6%], P = 0.90). HE extent did not differ after non-OAC-ICH (deep:+59% [40–122] vs. lobar:+74% [37–124], P = 0.65), but both patients with VKA-ICH and NOAC-ICH showed greater HE extent after deep ICH [VKA-ICH, deep: +94% [54–199] vs. lobar: +56% [35–116], P < 0.001; NOAC-ICH, deep: +74% [56–123] vs. lobar: +40% [21–49], P = 0.001). Deep compared to lobar ICH patients had higher HE hazard during first 13.5 h after onset (Hazard ratio [HR]: 1.85 [1.03–3.31], P = 0.04), followed by lower hazard (13.5–26.5 h, HR: 0.46 [0.23–0.89], P = 0.02), and equal hazard thereafter (HR: 0.96 [0.56–1.65], P = 0.89). Odds ratio for unfavorable outcome was higher after HE in deep (4.31 [2.71–6.86], P < 0.001) versus lobar ICH (2.82 [1.71–4.66], P < 0.001), and only significant after small-medium (1st volume-quarter, deep: 3.09 [1.52–6.29], P < 0.01; lobar: 3.86 [1.35–11.04], P = 0.01) as opposed to large-sized ICH (4th volume-quarter, deep: 1.09 [0.13–9.20], P = 0.94; lobar: 2.24 [0.72–7.04], P = 0.17). Interpretation: HE occurrence does not differ among deep and lobar ICH. However, compared to lobar ICH, HE after deep ICH is of greater extent in OAC-ICH, occurs earlier and may be of greater clinical relevance. Overall, clinical significance is more apparent after small–medium compared to large-sized bleedings.
CRIS-Team Scopus Importer:2020-03-17

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracereoral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care - Huttner, Hagen; Gerner, Stefan; Kuramatsu, Joji; Connolly, Stuart J.; Beyer-Westendorf, Jan; Demchuk, Andrew M.; Middeldorp, Saskia; Zotova, Elena; Altevers, Julia; Andersohn, Frank; Christoph, Mary J.; Yue, Patrick; et al. (Stroke, 2022)
BACKGROUND AND PURPOSE: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor-related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor-related ICH.
CRIS-Team WoS Importer:2022-02-04

Hematoma expansion in intracerebral hemorrhage – the right target? - Haupenthal, David; Schwab, Stefan; Kuramatsu, Joji (Neurological Research and Practice, 2023)
Background: The avoidance of hematoma expansion is the most important therapeutic goal during acute care of patients with intracerebral hemorrhage. Hematoma expansion occurs in up to 20–40% of patients and leads to poorer patient outcome in one of the most severe sub-types of stroke. Main text: At current, randomized controlled trials have failed to provide evidence for interventions that effectively improve functional outcome in patients with intracerebral hemorrhage. Hence, hematoma expansion may serve as important surrogate target that appears causally linked with a poorer prognosis. Therefore, reduction of hematoma expansion rates will eventually translate to improved patient outcome overall. Recent years have shed light on the importance of early and aggressive treatment in order to reduce the risk for hematoma expansion in these patients. Time measures and imaging markers have been identified that may allow patient selection at very high risk for hematoma expansion. Conclusions: Refinements in patient selection may increase chance for randomized trials to show true benefit. Therefore, this current review article will critically evaluate and discuss available evidence associated with hematoma expansion in patients with intracerebral hemorrhage.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Blood pressure management; Hematoma enlargement; Hematoma expansion; Hemostatic therapies; Intracerebral hemorrhage

Henry Head (1861–1940) und seine Bedeutung für die Neurologie - Rheinländer, Andreas; Weih, Markus (Der Nervenarzt, 2024)
Nowadays, Henry Head is best known for his Head zones. The concept was understood very differently by Head in comparison to what current medical books falsely describe them to be. In reality, there is no direct relationship between one particular skin zone and one single organ. It is certain that the drawings considered depictions of the Head zones in today’s medical textbooks were actually not created by Head. From a neurological point of view, Head is important for two reasons: his self-experiment in 1909 to damage one of his own peripheral nerves followed by regeneration was heroic. It has helped generations of neurologists to have a better understanding of the pathophysiology of peripheral nerve damage and thus make a better assessment of the prognosis of such injuries. Head’s second contribution pertains to the radicular organization at the level of the spinal cord. The pathophysiology of herpes zoster radiculitis enabled him to develop the concept of the dermatomes on the basis of preliminary work around 1900. Henry Head’s contribution was the systematic compilation of the existing publications of the time and amendment of his own cases. As he was the most important neurologist at that time, at least in the English speaking world, and was well connected with people in the German neurology community, it was probably easy for him to make his dermatome maps well known. In retrospect, Head was less successful in neuropsychology with holistic concepts for higher cognitive functions which were in vogue during his lifetime. His late work on aphasia is now considered refuted. Head’s criticism of the strict localization was well in syncronization with the zeitgeist of the early twentieth century. Establishing the fact that Broca’s aphasia and Wernicke’s aphasia are not easily diagnostically distinguishable from each other was more an achievement of subsequent generations of neurologists and neuropsychologists as well as technical advances.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Aphasie; Dermatome mapping; Head zones; Psychosomatic medicine; Referred pain

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage - Sprügel, Maximilian; Sembill, Jochen; Kuramatsu, Joji; Gerner, Stefan; Hagen, Manuel; Röder, Sebastian; Endres, Matthias; Haeusler, Karl Georg; Sobesky, Jan; Schurig, Johannes; Zweynert, Sarah; Bauer, Miriam; et al. (Journal of Neurology Neurosurgery and Psychiatry, 2019)
Objective: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. Methods: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. Results: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. Conclusions: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.
CRIS-Team Scopus Importer:2019-05-02
Keywords: cerebrovascular disease; critical care; intracerebral heamorrhage; stroke

Herbal detox – Benzodiazepine withdrawal treatment with the help of St. John's Wort? - Moeller, Sebastian; Sitter, Aileen; Darrelmann, Ute gr; Philipsen, Alexandra; Müller, Helge H.O.; Wang, Ruihao; Olek, Alexander (Asian Journal of Psychiatry, 2019)
CRIS-Team Scopus Importer:2019-09-03

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients - Schuele, Rebecca; Wiethoff, Sarah; Martus, Peter; Karle, Kathrin N.; Otto, Susanne; Klebe, Stephan; Klimpe, Sven; Gallenmueller, Constanze; Kurzwelly, Delia; Henkel, Dorothea; Rimmele, Florian; Stolze, Henning; et al. (Annals of Neurology, 2016)
OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.
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Herz-Kreislauftraining zur Optimierung motorischer Lernprozesse in der Neurorehabilitation - Wanner, Philipp; Adler, Werner; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (Neurologie & Rehabilitation, 2018)
Einleitung: Positive Anpassungen an regelmäßiges motorisches Üben bei Morbus Parkinson (PD) sind auf zentralnervöse Anpassungsprozesse zurückzuführen (Neuroplastizität), weshalb die Bewegungstherapie auch als motorischer Lernprozess zu verstehen ist (Abbruzzese et al., 2016). Die motorische Lernfähigkeit von PD Patienten ist im Vergleich zu gesunden altersgleichen Personen reduziert, was sich in einer verminderten Aneignungs- und Behaltensleistung (Konsolidierung) darstellt. Neuere Studien an jungen Erwachsenen deuten darauf hin, dass motorische Lernprozesse durch akute Herz-Kreislauf-Beanspruchungen in unmittelbarer zeitlicher Nähe zum motorischen Üben optimiert werden können (Roig et al., 2016; Taubert et al., 2015). Ziel dieser Studie war es, diesen Zusammenhang bei PD Patienten zu untersuchen. Material/Methode: 17 Patienten mit idiopathischem Parkinson Syndrom (Hoehn & Yahr:1-2,5; Alter: 64,4±6,2) nahmen an dieser Crossover-Studie teil. Unmittelbar vor dem Üben einer Gleichgewichtsaufgabe absolvierten die Patienten eine von zwei Versuchskonditionen für 30 Minuten: i) aerobes Radfahren mit mäßiger Intensität (60-70% VO2max), oder ii) Ruhephase im Sitzen. Die motorische Aufgabe bestand darin, eine Gleichgewichtsplattform (Stabilometer) in horizontaler Position zu stabilisieren. Die Patienten führten 15 Übungsversuche (jeweils 30 Sekunden) durch, gefolgt von einem Retentionstest 24 Stunden später. Zur Beurteilung der Aneignungsleistung sowie der Konsolidierung der motorischen Aufgabe wurde die Zeit im Gleichgewicht (Plattform innerhalb von ±5° von der Horizontalen) für jeden Übungsdurchgang berechnet und mittels Messwiederholungs-ANOVA innerhalb und zwischen den Versuchsbedingungen verglichen. Ergebnisse: Die Ergebnisse zeigten, dass das aerobe Radfahren keinen Einfluss auf das Performanzniveau während der Aneignung hatte (F1,31 < 1, p = .842), obwohl es den zeitlichen Verlauf des Lernanstiegs beeinflusste (größere anfängliche und geringere späte Steigerung). Im Gegensatz dazu verbesserte das aerobe Radfahren die Konsolidierung signifikant (F1,32 = 10.734, p = .003). Demnach kam es in der Ruhe-Kondition zu einem Leistungsabfall nach 24 Stunden, wohingegen das Niveau in der Experimentalkondition stabil blieb. Diskussion: Die Ergebnisse dieser Studie deuten darauf hin, dass eine einzelne Herz-Kreislauf-Beanspruchung mit moderater Intensität zu einer Verbesserung der motorischen Lernleistung bei Parkinsonpatienten führen kann. Weitere Arbeiten sind notwendig, um die zugrundeliegenden Mechanismen, die optimale Trainingssteuerung und die Anwendbarkeit auf andere motorische Aufgaben zu überprüfen. Außerdem muss das Potenzial für Patienten in späteren Krankheitsstadien untersucht werden. Literatur Abbruzzese, G., Marchese, R., Avanzino, L., et al. (2016). Parkinsonism Relat Disord, 22 Suppl 1, 60-4. Roig, M., Thomas, R., Mang, C. S., Snow, N. J. et al. (2016). Exerc Sport Sci Rev, 44 (2), 81-8. Taubert, M., Villringer, A., & Lehmann, N. (2015). Front Hum Neurosci, 9, 69

Hidden Markov Model based stride segmentation on unsupervised free-living gait data in Parkinson’s disease patients - Roth, Nils; Küderle, Arne; Ullrich, Martin; Gladow, Till; Marxreiter, Franz; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (Journal of neuroEngineering and rehabilitation, 2021)
Background: To objectively assess a patient’s gait, a robust identification of stride borders is one of the first steps in inertial sensor-based mobile gait analysis pipelines. While many different methods for stride segmentation have been presented in the literature, an out-of-lab evaluation of respective algorithms on free-living gait is still missing. Method: To address this issue, we present a comprehensive free-living evaluation dataset, including 146.574 semi-automatic labeled strides of 28 Parkinson’s Disease patients. This dataset was used to evaluate the segmentation performance of a new Hidden Markov Model (HMM) based stride segmentation approach compared to an available dynamic time warping (DTW) based method. Results: The proposed HMM achieved a mean F1-score of 92.1% and outperformed the DTW approach significantly. Further analysis revealed a dependency of segmentation performance to the number of strides within respective walking bouts. Shorter bouts (< 30 strides) resulted in worse performance, which could be related to more heterogeneous gait and an increased diversity of different stride types in short free-living walking bouts. In contrast, the HMM reached F1-scores of more than 96.2% for longer bouts (> 50 strides). Furthermore, we showed that an HMM, which was trained on at-lab data only, could be transferred to a free-living context with a negligible decrease in performance. Conclusion: The generalizability of the proposed HMM is a promising feature, as fully labeled free-living training data might not be available for many applications. To the best of our knowledge, this is the first evaluation of stride segmentation performance on a large scale free-living dataset. Our proposed HMM-based approach was able to address the increased complexity of free-living gait data, and thus will help to enable a robust assessment of stride parameters in future free-living gait analysis applications.
CRIS-Team Scopus Importer:2021-06-11
Keywords: HMM; IMU; Machine learning; Mobile gait analysis; Stride borders; Wearable sensors

High-resolution diffusion tensor-imaging indicates asymmetric microstructural disorganization within substantia nigra in early Parkinson's disease - Knossalla, Frauke; Kohl, Zacharias; Winkler, Jürgen; Schwab, Stefan; Schenk, Thomas; Engelhorn, Tobias; Dörfler, Arnd; Gölitz, Philipp (Journal of Clinical Neuroscience, 2018)
BACKGROUND AND PURPOSE: Parkinson's disease (PD) is characterised by neuropathological degenerative changes in the substantia nigra (SN). Our study aimed to evaluate whether high-resolution diffusion tensor-imaging (DTI) can detect anatomical biomarkers in early-stage PD, and has the potential to visualize asymmetry effects comparable to the 123I-FP-CIT SPECT (DaTSCAN). METHODS: Ten early-stage PD patients with mild disease severity and ten age- and gender-matched healthy controls were examined with a high-resolution DTI protocol at a 3 Tesla MRI scanner to assess fractional anisotropy (FA) values in the ventral, middle and dorsal region of SN. In addition, a subgroup of 5 PD patients underwent a DaTSCAN. RESULTS: PD subjects showed reduced FA values in all SN regions compared to controls, but post hoc analysis revealed a significant reduction (p = .032) in the dorsal region. There was no significant correlation between clinical data and FA values. Subgroup analysis of PD patients with asymmetric radioligand uptake in the DaTSCAN demonstrated also significant asymmetric FA values (p = .027) in the dorsal region of SN. CONCLUSIONS: Our results provide preliminary evidence that high-resolution DTI can detect in early-stage PD patients with mild disease severity an anatomical biomarker in the dorsal region of SN, indicating microstructural disorganization. This biomarker, discriminating potentially in vivo between patients and healthy people, could be valuable for early PD diagnosis. If asymmetric radioligand uptake in the DaTSCAN was present, also asymmetry effects in the dorsal region of SN were obtained by DTI. These findings might contribute to improve effectiveness in diagnosing and monitoring PD.
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High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells - Joerg, Stefanie; Kissel, Jan; Manzel, Arndt; Kleinewietfeld, Markus; Haghikia, Aiden; Gold, Ralf; Mueller, Dominik N.; Linker, Ralf (Experimental Neurology, 2016)
Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiation. During the initiation phase of MOG35-55 EAE, we did not observe altered DC frequencies or co-stimulatory capacities in lymphoid organs, while IL-17A production and Th17 cells in the spleen were significantly increased. Complementary ex vivo analyses of the spinal cord during the effector phase of EAE showed increased frequencies of Th17 cells, but did not reveal differences in phenotypes of CNS invading DCs. Finally, adaption of transgenic mice harboring a MOG specific T cell receptor to a high-salt diet led to aggravated clinical disease only after active immunization. Wild-type mice adapted to a high-salt diet in the effector phase of EAE, bypassing the priming phase of T cells, only displayed mildly aggravated disease. In summary, our data argue for a direct effect of NaCl on Th17 cells in neuroinflammation rather than an effect primarily exerted via DCs. These data may further fuel our understanding on the dietary impact on different immune cell subsets in autoimmune diseases, such as multiple sclerosis.
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Hippocampal neurons code individual episodic memories in humans - Kolibius, Luca D.; Roux, Frederic; Parish, George; Ter Wal, Marije; Van Der Plas, Mircea; Chelvarajah, Ramesh; Sawlani, Vijay; Rollings, David T.; Lang, Johannes; Gollwitzer, Stephanie; Walther, Katrin; Hopfengärtner, Rüdiger; et al. (Nature Human Behaviour, 2023)
The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode.
CRIS-Team Scopus Importer:2023-10-20

Hippocampal structure and function are maintained despite severe innate peripheral inflammation - Süß, Patrick; Kalinichenko, Liubov; Baum, Wolfgang; Reichel, Martin; Kornhuber, Johannes; Loskam, Sandra; Ettle, Benjamin; Distler, Jörg; Schett, Georg; Winkler, Jürgen; Müller, Christian P.; Schlachetzki, Johannes (Brain Behavior and Immunity, 2015)
Chronic peripheral inflammation mediated by cytokines such as TNF?, IL-1?, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-? transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1? and IL-6 expression in tarsal joints with highly elevated human TNF-? levels in the serum. Intriguingly, IL-1? and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.
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Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery - Blümcke, Ingmar; Spreafico, R.; Haaker, G.; Coras, R.; Kobow, K.; Bien, C. G.; Pfaefflin, M.; Elger, C.; Widman, G.; Schramm, J.; Becker, Albert; Braun, K. P.; et al. (New England Journal of Medicine, 2017)
Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy.We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%).The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients.In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).
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Historical and memorable aspects in epileptology Historisches und Denkwürdiges in der Epileptologie - Krämer, Günter; Kasper, Burkhard S. (Clinical Epileptology, 2025)
CRIS-Team Scopus Importer:2025-05-16

Home-based telerehabilitation after stroke - Keidel, M.; Vauth, F.; Richter, J.; Hoffmann, B.; Soda, H.; Griewing, B.; Scibor, M. (Der Nervenarzt, 2017)
The use of modern information and telecommunication technologies enables telerehabilitation of neurological deficits in the domestic environment. The current state of studies on rehabilitative teletherapy for improvement of motor function and mobility deficits due to stroke is reviewed. Two neurolinguistic proof of concept studies investigating the efficacy of online interactive telespeech therapy are reported, which compared virtual screen to screen interactive telerehabilitation of aphasia after stroke and dysarthrophonia in Parkinson's disease to conventional face to face rehabilitation. The results of the studies indicate that the neurological rehabilitation of motor and communicative deficits in the domestic environment of patients by means of teletherapy is just as efficient as conventional rehabilitation. Under home-based telerehabilitation patient transfer becomes unnecessary. Rehabilitative Teletherapy is a posthospital component of a cross-sector supply chain for patients with handicaps or impairments due to stroke and other neurological diseases.
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Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy - Mészáros, Lisa; Riemenschneider, Markus J.; Gaßner, Heiko; Marxreiter, Franz; von Hörsten, Stephan; Hoffmann, Alana; Winkler, Jürgen (Acta Neuropathologica Communications, 2021)
Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.[Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2021-04-30
Keywords: Cerebellar ataxia; Cerebellar pathology; Gait analysis; Multiple system atrophy

Human Induced Pluripotent Stem Cell-Derived Pericytes as Scalable and Editable Source to Study Direct Lineage Reprogramming Into Induced Neurons - Menon, Radhika; Petrucci, Linda; Lohrer, Benjamin; Zhang, Jingzhong; Schulze, Markus; Schichor, Christian; Winner, Beate; Winkler, Jürgen; Riemenschneider, Markus J.; Kühn, Ralf; Falk, Sven; Karow, Marisa (Cellular Reprogramming, 2023)
Studying human somatic cell-to-neuron conversion using primary brain-derived cells as starting cell source is hampered by limitations and variations in human biopsy material. Thus, delineating the molecular variables that allow changing the identity of somatic cells, permit adoption of neuronal phenotypes, and foster maturation of induced neurons (iNs) is challenging. Based on our previous results that pericytes derived from the adult human cerebral cortex can be directly converted into iNs (Karow et al., 2018; Karow et al., 2012), we here introduce human induced pluripotent stem cell (hiPSC)-derived pericytes (hiPSC-pericytes) as a versatile and more uniform tool to study the pericyte-to-neuron conversion process. This strategy enables us to derive scalable cell numbers and allows for engineering of the starting cell population such as introducing reporter tools before differentiation into hiPSC-pericytes and subsequent iN conversion. Harvesting the potential of this approach, we established hiPSC-derived human-human neuronal cocultures that not only allow for independent manipulation of each coculture partner but also resulted in morphologically more mature iNs. In summary, we exploit hiPSC-based methods to facilitate the analysis of human somatic cell-to-neuron conversion.
CRIS-Team Scopus Importer:2023-11-03
Keywords: direct lineage reprogramming; induced neurons; organoids; pericytes

Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease - Winner, Beate; Marchetto, Maria C.; Winkler, Jürgen; Gage, Fred H. (Human Molecular Genetics, 2014)
While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease-relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia and spinal muscular atrophy.
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Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, Jil; Lehmann, Christian; Heger, Lukas; Eissing, Nathalie; Baranska, Anna; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (Science immunology, 2016)
In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammatio
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Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, J.; Lehmann, C. H. K.; Heger, Lukas; Eissing, N.; Baranska, A.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (2017)
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Human SPG11 cerebral organoids reveal cortical neurogenesis impairment - Pérez-Brangulí, Francesc; Buchsbaum, Isabel; Pozner, Tatyana; Regensburger, Martin; Fan, Wenqiang; Schray, Annika; Börstler, Tom; Mishra, Himanshu Kumar; Gräf, Daniela; Kohl, Zacharias; Winkler, Jürgen; Berninger, Benedikt; et al. (Human Molecular Genetics, 2018)
SPG11 linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of neural progenitor cells leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3-inhibititors including the FDA-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.
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Huntingtin lowering strategies - Marxreiter, Franz; Stemick, Judith; Kohl, Zacharias (International Journal of Molecular Sciences, 2020)
Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.
CRIS-Team Scopus Importer:2020-04-03
Keywords: Antisense oligonucleotides; Chorea; Disease modification; HD; Huntingtin-lowering; Huntington’s Disease; RNA interference

Hydrogen inhibits microglial activation and regulates microglial phenotype in a mouse middle cerebral artery occlusion model - Huang, Jun Long; Liu, Wen Wu; Manaenko, Anatol; Sun, Xue Jun; Mei, Qi Yong; Hu, Qin (Medical Gas Research, 2019)
Microglia participate in bi-directional control of brain repair after stroke. Previous studies have demonstrated that hydrogen protects brain after ischemia/reperfusion (I/R) by inhibiting inflammation, but the specific mechanism of anti-inflammatory effect of hydrogen is poorly understood. The goal of our study is to investigate whether inhalation of high concentration hydrogen (HCH) is able to attenuate I/R-induced microglia activation. Eighty C57B/L male mice were divided into four groups: sham, I/R, I/R + HCH and I/R + N2/O2 groups. Assessment of animals happened in 'blind' matter. I/R was induced by occlusion of middle cerebral artery for one hour). After one hour, filament was withdrawn, which induced reperfusion. Hydrogen treated I/R animals inhaled mix of 66.7% H2 balanced with O2 for 90 minutes, starting immediately after initiation of reperfusion. Control animals (N2/O2) inhaled mix in which hydrogen was replaced with N2 for the same time (90 minutes). The brain injury, such as brain infarction and development of brain edema, as well as neurobehavioral deficits were determined 23 hours after reperfusion. Effect of HCH on microglia activation in the ischemic penumbra was investigated by immunostaining also 23 hours after reperfusion. mRNA expression of inflammation related genes was detected by PCR. Our results showed that HCH attenuated brain injury and consequently reduced neurological dysfunction after I/R. Furthermore, we demonstrated that HCH directed microglia polarization towards anti-inflammatory M2 polarization. This study indicates hydrogen may exert neuroprotective effects by inhibiting the microglial activation and regulating microglial polarization. This study was conducted in agreement with the Animal Care and Use Committee (IACUC) and Institutional Animal Care guidelines regulation (Shanghai Jiao Tong University, China (approval No. A2015-011) in November 2015.
CRIS-Team Scopus Importer:2019-10-01
Keywords: hydrogen; inflammation; ischemic stroke; macrophages; microglial phenotype; neuroprotection; polarization; reperfusion

Hyponatremia is an independent predictor of in-hospital mortality in spontaneous intracerebral hemorrhage - Kuramatsu, Joji; Bobinger, Tobias; Volbers, Bastian; Staykov, Dimitre; Lücking, Hannes; Kloska, Stephan; Köhrmann, Martin; Huttner, Hagen (Stroke, 2014)
Hyponatremia is the most frequent electrolyte disturbance in critical care. Across various disciplines, hyponatremia is associated with increased mortality and longer hospital stay, yet in intracerebral hemorrhage (ICH) no data are available. This the first study that investigated the prevalence and clinical associations of hyponatremia in patients with ICH.This observational study included all consecutive spontaneous ICH patients (n=464) admitted during a 5-year period to the Department of Neurology. Patient characteristics, in-hospital measures, mortality, and functional outcome (90 days and 1 year) were analyzed to determine the effects of hyponatremia (Na<135 mEq/L). Multivariable regression analyses were calculated for factors associated with hyponatremia and predictors of in-hospital mortality.The prevalence of hyponatremia on hospital admission was 15.6% (n=66). Normonatremia was achieved and maintained in almost all hyponatremia patients<48 hours. In-hospital mortality was roughly doubled in hyponatremia compared with nonhyponatremia patients (40.9%; n=27 versus 21.1%; n=75), translating into a 2.5-fold increased odds ratio (P<0.001). Multivariable analyses identified hyponatremia as an independent predictor of in-hospital mortality (odds ratio, 2.2; 95% confidence interval, 1.05-4.62; P=0.037). Within 90 days after ICH, hyponatremia patients surviving hospital stay were also at greater risk of death (odds ratio, 4.8; 95% confidence interval, 2.1-10.6; P<0.001); thereafter, mortality rates were similar.Hyponatremia was identified as an independent predictor of in-hospital mortality with a fairly high prevalence in spontaneous ICH patients. The presence of hyponatremia at hospital admission is related to an increased short-term mortality in patients surviving acute care, possibly reflecting a preexisting condition that is linked to worse outcome due to greater comorbidity. Correction of hyponatremia does not seem to compensate its influence on mortality, which strongly warrants future research.
EVALuna2:22304

Ictal semiology, functional anatomy and multimodal diagnostic in patients with insular epilepsies - Stefan, Hermann; Gollwitzer, Stephanie (Acta Epileptologica, 2019)
Background: The insula is a hidden part in the cerebral cortex. Insular epilepsy is underrecognized and it bears a special risk for misdiagnosis with regard to nonepileptic seizures or wrong localization of epileptic seizures. Case presentations: The manuscript describes 2 cases with ictal semiology of paresthesia and pain followed by hyperkinetic movements, noninvasive findings of source localization and/or invasive SEEG exploration. Conclusion: Magnetic source imaging, ictal SPECT as noninvasive and invasive recordings with depth electrodes (SEEG) can provide important preoperative information for the involvement of insular and periinsular regions in focal pharmacoresistant epilepsies. The optimal use of these methods presupposes extensive knowledge of ictal semiology and other clinical characteristics. The clinical localization hypothesis can be optimally proofed by SEEG exploration.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Ictal semiology; Insular epilepsy; MEG/EEG; SEEG; Source localization

Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization - Bauer, Peter; Winner, Beate; Schüle, Rebecca; Bauer, Claudia; Häfele, Veronika; Hehr, Ute; Bonin, Michael; Walter, Michael; Karle, Kathrin; Ringer, Thomas M.; Rieß, Olaf; Winkler, Jürgen; et al. (Neurogenetics, 2009)
Mutations in the spatacsin gene have recently been identified as the genetic cause of autosomal-recessive spastic paraplegia (SPG) with thin corpus callosum, mapping to chromosome 15p13-21. While several nonsense and frameshift mutations as well as splice mutations have been identified, large genomic deletions have not yet been found, potentially due to the absence of an efficient analysis tool. After complete sequencing of 12 autosomal recessive hereditary spastic paraplegia patients with suggestive clinical signs, we were able to define nine SPG11 cases but were left with three patients in which only one SPG11 mutation could be identified by direct sequencing. In these patients, we performed high-resolution comparative genomic hybridization using a predesigned human chromosome 15 tiling array with an average spacing of 100 bp. Data analysis suggested heterozygous genomic deletion within the spatacsin gene in all three patients. In one patient, a relatively small genomic deletion (8.2 kb) could be validated by quantitative polymerase chain reaction (PCR) and long-range PCR, allowing the diagnosis of the deletion of exons 31 through 34. For two patients, quantitative PCR validation could not confirm a genomic deletion. As high density tiling arrays are available for the entire human genome, we suggest this approach for the screening of heterozygous genomic deletions in candidate genes down to a few kilobases. © 2008 Springer-Verlag.
CRIS-Team Scopus Importer:2024-08-07
Keywords: Genomic deletions; Hereditary spastic paraplegia type 11; High resolution; Tiling array

Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-β processing effects - Vöglein, Jonathan; Willem, Michael; Trambauer, Johannes; Schönecker, Sonja; Dieterich, Marianne; Biskup, Saskia; Giudici, Camilla; Utz, Kathrin; Oberstein, Timo; Brendel, Matthias; Rominger, Axel; Danek, Adrian; et al. (Neurobiology of Aging, 2019)
We report the novel presenilin 1 (PSEN1) single amino acid deletion mutation F175del. Comprehensive clinical work-up, including cerebral MRI, FDG-PET, and CSF analysis, was performed in a male who had developed forgetfulness at the age of 39. Alzheimer's disease dementia was diagnosed according to established criteria. The index patient manifested rapid progressive dementia, seizures, and myoclonus, and a Pisa syndrome as a side effect of donepezil treatment. The PSEN1 mutation F175del was found on genetic testing. It was rendered very likely pathogenic as amyloid-β (Aβ) peptide 42 was elevated in a cell culture model compared to presenilin 1 wild-type controls. An additional, unusual increase in Aβ39 indicates a rarely observed product line deviation in the generation of the shorter Aβ species. Our observations extend the range of PSEN1 mutations to be considered in familial dementia. We demonstrate that deletion of a single conserved amino acid, which is very rare compared to missense mutations as the common cause for PSEN1-associated Alzheimer's disease, can lead to an unusual profile of Aβ species.
CRIS-Team Scopus Importer:2019-10-25
Keywords: Alzheimer's disease; Autosomal dominant; Genetics; Novel mutation; PSEN1

Identification of DAPK as a scaffold protein for the LIMK/cofilin complex in TNF-induced apoptosis - Ivanovska, Jelena; Tregubova, Alexandra; Mahadevan, Vijayalakshmi; Chakilam, Saritha; Gandesiri, Muktheshwar; Benderska, Natalya; Ettle, Benjamin; Hartmann, Arndt; Söder, Stephan; Ziesche, Elisabeth; Fischer, Thomas; Lautscham, Lena; et al. (International Journal of Biochemistry and Cell Biology, 2013)
The role of cytoskeleton-associated proteins during TNF-induced apoptosis is not fully understood. A potential candidate kinase that might connect TNF signalling to actin reorganization is the death-associated protein kinase (DAPK). To identify new DAPK interaction partners in TNF-induced apoptosis, we performed a peptide array screen. We show that TNF-treatment enhanced the phosphorylation of LIMK at threonine508 and its downstream target cofilin at serine3 (p-cofilin(Ser3)). Modulation of DAPK activity and expression by DAPK inhibitor treatment, siRNA knockdown, and overexpression affected the phosphorylation of both proteins. We propose a 3D structural model where DAPK functions as a scaffold for the LIMK/cofilin complex and triggers a closer interaction of both proteins under TNF stimulation. Upon TNF a striking redistribution of LIMK, DAPK, and cofilin to the perinuclear compartment was observed. The pro-apoptotic DAPK/LIMK/cofilin multiprotein complex was abrogated in detached cells, indicating that its signaling was no longer needed if cells committed to apoptosis. P-cofilin(Ser3) was strongly accumulated in cells with condensed chromatin, pronounced membrane blebs and Annexin V up-regulation. From studying different cofilin(Ser3) mutants we suggest that p-cofilin(Ser3) is an indicator of TNF-induced apoptosis. Collectively, our findings identify a novel molecular cytoskeleton-associated mechanism in TNF-induced DAPK-dependent apoptosis.

Identification of symbol digit modality test score extremes in Huntington's disease - Braisch, Ulrike; Muche, Rainer; Rothenbacher, Dietrich; Landwehrmeyer, Georg Bernhard; Long, Jeffrey D.; Orth, Michael; Bachoud-Levi, Anne-Catherine; Bentivoglio, Anna-Rita; Biunno, Ida; Bonelli, Raphael M.; Burgunder, Jean-Marc; Dunnett, Stephen B.; et al. (American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 2019)
Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers.
CRIS-Team WoS Importer:2019-03-29

ILAE neuroimaging task force highlight: Subcortical laminar heterotopia - Kasper, Burkhard S.; Archer, John; Bernhardt, Boris C.; Caciagli, Lorenzo; Cendes, Fernando; Chinvarun, Yotin; Concha, Luis; Federico, Paolo; Gaillard, William; Kobayashi, Eliane; Ogbole, Godwin; Vaudano, Anna Elisabetta; et al. (Epileptic Disorders, 2024)
The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Subcortical laminar heterotopia, also known as subcortical band heterotopia (SBH) or “double cortex,” is an intriguing and rare congenital malformation of cortical development. SBH lesions are part of a continuum best designated as agyria-pachygyria-band-spectrum. The malformation is associated with epilepsy that is often refractory, as well as variable degrees of developmental delay. Moreover, in an increasing proportion of cases, a distinct molecular-genetic background can be found. Diagnosing SBH can be a major challenge for many reasons, including more subtle lesions, and “non-classic” or unusual MRI-appearances. By presenting an illustrative case, we address the challenges and needs of diagnosing and treating SBH patients in epilepsy, especially the value of high-resolution imaging and specialized MRI-protocols.<br
Keywords: double cortex; epilepsy; neuroimaging; subcortical band heterotopia; subcortical laminar heterotopia

Immediate effects of perturbation treadmill training on gait and postural control in patients with Parkinson’s disease - Klamroth, Sarah; Steib, Simon; Gaßner, Heiko; Goßler, Julia; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus (Gait & Posture, 2016)
EVALuna2:33512

Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity. - Müller-Jensen, Leonie; Schulz, Axel R.; Mei, Henrik E.; Mohr, Raphael; Ulrich, Claas; Knape, Philipp; Frost, Nikolaj; Frischbutter, Stefan; Kunkel, Desiree; Schinke, Christian; Ginesta Roque, Lorena; Maierhof, Smilla K.; et al. (Neuro-Oncology, 2024)
BACKGROUND: Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount. METHODS: In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay. RESULTS: During acute illness, patients with irAE-n presented higher frequencies of cluster of differentiation (CD)8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multiorgan immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered C-X-C motif chemokine ligand (CXCL)10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n. CONCLUSIONS: We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.
EVALuna2:541088

Immunological and clinical consequences of splenectomy in a multiple sclerosis patient treated with natalizumab - Lee, De-Hyung; Waschbisch, Anne; Laemmer, Alexandra B.; Dörfler, Arnd; Schwab, Stefan; Linker, Ralf (Journal of Neuroinflammation, 2013)
Objective: Here we report a case of a splenectomized white woman with natalizumab-associated progressive multifocal leukoencephalopathy (PML), occurring as early as after 11 infusions and provide blood fluorescence-activated cell sorting (FACS) analyses before and after natalizumab treatment.Design: This is a report of a single case with immunological studies.Methods: Methods comprised neurologic examination, magnetic resonance imaging, and cerebrospinal fluid (CSF) studies as well as immune cell FACS analyses from blood.Results: Diagnosis of PML was established after positive John Cunningham virus (JCV) DNA was detected in the CSF. An immune reconstitution inflammatory syndrome was treated with repeated cycles of steroid pulses and intravenous immunoglobulins. Reduced numbers of memory B cells, which might play an important role in antiviral immune response, were detected in the blood. Moreover the percentage of CD19+ B cells was elevated in our post-splenectomy patient as compared to a control cohort of multiple sclerosis (MS) patients under natalizumab therapy.Conclusion: Splenectomy may increase the risk for the development of natalizumab-associated PML via effects on the B cell compartment. It may be regarded as a risk factor in MS patients independent from the duration of disease. © 2013 Lee et al.; licensee BioMed Central Ltd.
CRIS-Team Scopus Importer:2022-08-05
Keywords: CD19 positive B cells; Multiple sclerosis; Natalizumab; Progressive multifocal leukoencephalopathy; Splenectomy

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response - Stellmann, Jan-Patrick; Krumbholz, Markus; Friede, Tim; Gahlen, Anna; Borisow, Nadja; Fischer, Katrin; Hellwig, Kerstin; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Kuempfel, Tania; Aktas, Orhan; et al. (Journal of Neurology Neurosurgery and Psychiatry, 2017)
To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).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.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-? (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-?, 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).Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-?.
EVALuna2:22505

Immunotherapy Improves Cognitive Function in Secondary Progressive Multiple Sclerosis - Kinner, Markus; Hoepner, Robert; Klotz, Peter; Prehn, Christian; Faissner, Simon; Salmen, Anke; Linker, Ralf; Gold, Ralf; Chan, Andrew (Cns Neuroscience & Therapeutics, 2016)
EVALuna2:22504

Impact of antimuscarinic molecules on MAPK-mediated signal transduction in oligodendroglial myelination - Meszaros, Lisa; Hoffmann, Alana; Wihan, Jeanette; Reiprich, Simone; Winkler, Jürgen (GLIA, 2019)
CRIS-Team WoS Importer:2020-01-10

Impact of combined sodium chloride and saturated long-chain fatty acid challenge on the differentiation of T helper cells in neuroinflammation - Hammer, Anna; Schliep, Anne; Joerg, Stefanie; Haghikia, Aiden; Gold, Ralf; Kleinewietfeld, Markus; Mueller, Dominik N.; Linker, Ralf (Journal of Neuroinflammation, 2017)
BACKGROUND: There has been a marked increase in the incidence of autoimmune diseases like multiple sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Here, growing evidence suggests that ingredients of a Western diet like high intake of sodium chloride (NaCl) or saturated fatty acids may impact systemic immune responses, thus increasing disease susceptibility. Recently, we have shown that high dietary salt or long-chain fatty acid (LCFA) intake indeed aggravates T helper (Th) cell responses and neuroinflammation. METHODS: Naïve CD4+ T cells were treated with an excess of 40 mM NaCl and/or 250 μM lauric acid (LA) in vitro to analyze effects on Th cell differentiation, cytokine secretion, and gene expression. We employed ex vivo analyses of the model disease murine experimental autoimmune encephalomyelitis (EAE) to investigate whether salt and LCFA may affect disease severity and T cell activation in vivo. RESULTS: LCFA, like LA, together with NaCl enhance the differentiation of Th1 and Th17 cells as well as pro-inflammatory cytokine and gene expression in vitro. In cell culture, we observed an additive effect of LA and hypertonic extracellular NaCl (NaCl + LA) in Th17 differentiation assays as well as on IL-17, GM-CSF, and IL-2 gene expression. In contrast, NaCl + LA reduced Th2 frequencies. We employed EAE as a model of Th1/Th17 cell-mediated autoimmunity and show that the combination of a NaCl- and LA-rich diet aggravated the disease course and increased T cell infiltration into the central nervous system (CNS) to the same extent as dietary NaCl. CONCLUSIONS: Our findings demonstrate a partially additive effect of NaCl and LA on Th cell polarization in vitro and on Th cell responses in autoimmune neuroinflammation. These data may help to better understand the pathophysiology of autoimmune diseases such as MS.
EVALuna2:35525

Impact of early benefit assessment on patients with epilepsy in Germany: Current healthcare provision and therapeutic needs - Strzelczyk, Adam; Hamer, Hajo (Der Nervenarzt, 2016)
Epilepsy is one of the most common chronic neurological diseases and represents a significant burden for patients, their families and society. In more than 75 % of patients anticonvulsant therapy consists of valproate, carbamazepine, lamotrigine or levetiracetam. There is a need for polytherapy in drug-refractory patients and they suffer from negative effects on quality of life and employment that is associated with high indirect costs. To allow a comprehensive treatment in this patient group, access to new anticonvulsants with novel modes of action is needed; however, all applications for new antiepileptic drugs failed to prove added benefits during the Pharmaceutical Market Restructuring Act (AMNOG) in Germany. One of the main reasons is the mandatory definition of a standard comparative therapy. It remains unclear whether there will be studies in the future which will fulfill the requirements of the current version of AMNOG. Observational studies after approval and marketing of new antiepileptic drugs could be better alternatives to prove added benefits for individual patients in the current German healthcare system.
EVALuna2:22465

Impact of heart rate dynamics on mortality in the early phase after ischemic stroke: a prospective observational trial - Kallmünzer, Bernd; Bobinger, Tobias; Kopp, Markus; Kurka, Natalia; Hilz, Max-Josef; Schwab, Stefan; Köhrmann, Martin; Arnold, Martin (Journal of Stroke and Cerebrovascular Diseases, 2015)
Growing evidence suggests that the heart rate (HR) at rest is an independent predictor of cardiovascular mortality. In ischemic stroke, continuous monitoring of HR is the standard of care, but systematic data on its dynamics and prognostic value during the acute phase are limited.In this prospective observational study, HR was measured by continuous electrocardiographic monitoring on admission and during the first 72 hours of care among patients who were awake with ischemic stroke and survived until discharge. Functional outcome was assessed after 90 days.Data from 702 consecutive patients were analyzed (median age, 73 years, 54% men). The time course of HR was initially characterized by a rapid decline during the first 12 hours after admission. Among patients who survived until day 90, this was followed by a continuous downward trend in HR, whereas death after discharge was associated with a secondary increase and a reversal point 12 hours after admission. After adjustment for established risk factors, this secondary increase during the acute period was an independent predictor of death (hazard ratio, 3.73; 95% confidence interval, 1.47-9.43; P = .005).A secondary rise of HR during care for acute ischemic stroke is an early sign of fatality and may represent a surrogate for an unfavorable sympathetic disinhibition. Further research is warranted to clarify the role of targeted HR reduction after ischemic stroke (http://clinicaltrials.gov/, unique identifier NCT01858779).
EVALuna2:12023

Impact of Hypothermia Initiation and Duration on Perihemorrhagic Edema Evolution After Intracerebral Hemorrhage - Volbers, Bastian; Herrmann, Sabrina; Willfarth, Wolfgang; Lücking, Hannes; Kloska, Stephan; Dörfler, Arnd; Huttner, Hagen; Kuramatsu, Joji; Schwab, Stefan; Staykov, Dimitre (Stroke, 2016)
Intracerebral hemorrhage (ICH) causes high morbidity and mortality. Recently, perihemorrhagic edema (PHE) has been suggested as an important prognostic factor. Therapeutic hypothermia may be a promising therapeutic option to treat PHE. However, no data exist about the optimal timing and duration of therapeutic hypothermia in ICH. We examined the impact of therapeutic hypothermia timing and duration on PHE evolution.In this retrospective, single-center, case-control study, we identified patients with ICH treated with mild endovascular hypothermia (target temperature 35°C) from our institutional database. Patients were grouped according to hypothermia initiation (early: days 1-2 and late: days 4-5 after admission) and hypothermia duration (short: 4-8 days and long: 9-15 days). Patients with ICH matched for ICH volume, age, ICH localization, and intraventricular hemorrhage were identified as controls. Relative PHE, temperature, and intracranial pressure course were analyzed. Clinical outcome on day 90 was assessed using the modified Rankin scale (0-3=favorable and 4-6=poor).Thirty-three patients with ICH treated with hypothermia and 37 control patients were included. Early hypothermia initiation led to relative PHE decrease between admission and day 3, whereas median relative PHE increased in control patients (-0.05 [interquartile range, -0.4 to 0.07] and 0.07 [interquartile range, -0.07 to 0.26], respectively; P=0.007) and patients with late hypothermia initiation (0.22 [interquartile range 0.12-0.27]; P=0.037). After day 3, relative PHE increased in all groups without difference. Outcome was not different between patients treated with hypothermia and controls.Early hypothermia initiation after ICH onset seems to have an important impact on PHE evolution, whereas our data suggest only limited impact later than day 3 after onset.
EVALuna2:22477

Impact of Microbiome–Brain Communication on Neuroinflammation and Neurodegeneration - Stolzer, Iris; Scherer, Eveline; Süß, Patrick; Rothhammer, Veit; Winner, Beate; Neurath, Markus; Günther, Claudia (International Journal of Molecular Sciences, 2023)
The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly affect the development and progression of various immune-mediated diseases affecting both the digestive tract and the central nervous system (CNS). This complex interplay between the microbiota, the gut, and the CNS is referred to as the gut–brain axis. The role of the gut microbiota in the pathogenesis of neurodegenerative diseases has gained increasing attention in recent years, and evidence suggests that gut dysbiosis may contribute to disease development and progression. Clinical studies have shown alterations in the composition of the gut microbiota in multiple sclerosis patients, with a decrease in beneficial bacteria and an increase in pro-inflammatory bacteria. Furthermore, changes within the microbial community have been linked to the pathogenesis of Parkinson’s disease and Alzheimer’s disease. Microbiota–gut–brain communication can impact neurodegenerative diseases through various mechanisms, including the regulation of immune function, the production of microbial metabolites, as well as modulation of host-derived soluble factors. This review describes the current literature on the gut–brain axis and highlights novel communication systems that allow cross-talk between the gut microbiota and the host that might influence the pathogenesis of neuroinflammation and neurodegeneration.
CRIS-Team Scopus Importer:2023-11-03
Keywords: gut–brain-axis; microbial dysbiosis; neurodegenerative diseases

Impact of Perihemorrhagic Edema on Short-Term Outcome After Intracerebral Hemorrhage - Volbers, Bastian; Willfarth, Wolfgang; Schwab, Sibylle; Kuramatsu, J. B.; Huttner, Hagen; Struffert, Tobias; Dörfler, Arnd; Staykov, S. (Neurocritical Care, 2016)
Intracerebral hemorrhage (ICH) is a devastating disease with ICH volume being the main predictor of poor outcome. The prognostic role of perihemorrhagic edema (PHE) is still unclear; however, available data are mainly derived from analyses during the first days after symptom onset. As PHE growth may continue up to 14 days after ICH, we evaluated PHE over a longer period of time and investigated its impact on short-term clinical outcome.In this monocentric retrospective cohort study, patients with spontaneous supratentorial ICH were identified from our institutional data base. Different time points of CT scans were merged to time clusters for better comparison (day 1, 2-3, 4-6, 7-9, 10-12). Absolute volumes of ICH and PHE were obtained using a validated semiautomatic volumetric algorithm. Clinical outcome at discharge was assessed using the modified Rankin Scale (0-3 = favorable, 4-6 = poor).220 patients (83 with favorable, 137 with poor outcome) were included in the final analysis. Mean ICH volume on admission was 22.8 [standard deviation (SD) 24.6] cm(3). Mean absolute PHE volume on admission was 22.5 (SD 20.8) cm(3) and increased to a mean peak volume of 38.1 (SD 31.4) cm(3) during 6.7 (SD 4.1) days on average. Besides GCS on admission, functional status before ICH, peak hematoma volume, lobar localization and fever burden, and high peak PHE volume predicted poor outcome at discharge [OR 0.977 (95 % CI 0.957-0.998)] in the multivariable analysis.PHE may have a negative impact on short-term functional outcome after ICH and therefore represent a possible treatment target.
EVALuna2:22273

Impact of pre-stroke dependency on outcome after endovascular therapy in acute ischemic stroke - Oesch, Lisa; Arnold, Marcel; Bernasconi, Corrado; Kaesmacher, Johannes; Fischer, Urs; Mosimann, Pascal J.; Jung, Simon; Meinel, Thomas; Goeldlin, Martina; Heldner, Mirjam; Volbers, Bastian; Gralla, Jan; et al. (Journal of Neurology, 2020)
Background and purpose Current demographic changes indicate that more people will be care-dependent due to increasing life expectancy. Little is known about impact of preexisting dependency on stroke outcome after endovascular treatment (EVT).
CRIS-Team WoS Importer:2020-09-18

Impact of Recent Studies for the Treatment of Intracerebral Hemorrhage - Sembill, Jochen; Huttner, Hagen; Kuramatsu, Joji (Current Neurology and Neuroscience Reports, 2018)
PURPOSE OF REVIEW: The present review will cover most recent and important studies on acute treatment of intracerebral hemorrhage (ICH). RECENT FINDINGS: Overly pessimistic prognostication in ICH may deny meaningful recovery achieved by specialized neurocritical care. Hematoma enlargement represents the most important target of acute ICH care, which is reduced by aggressive blood pressure management (targeting a systolic blood pressure of 140 mmHg) and appropriate hemostatic treatment especially in anticoagulation-associated ICH (INR reversal using prothrombin complex concentrates, eventually idarucizumab, andexanet, or tranexamic acid). Surgical treatment strategies involving fibrinolytics either used for direct hematoma lysis or used for intraventricular clot removal with/without additional lumbar drainage show great promise. Further novel treatment strategies are underway and need validation or evaluation strongly warranting well-designed future ICH research. Several randomized and large-sized observational studies have considerably expanded the field and the evidence on how to treat acute ICH patients. Yet, the one breakthrough intervention to improve functional outcome is still missing, though various treatment concepts possibly interacting with one another have been evaluated and such treatment bundle may improve patients' outcome.
EVALuna2:201936

IMPACT OF STATINS ON HEMATOMA CHARACTERISTICS, PERIHEMORRHAGIC EDEMA, SEIZURES AND FUNCTIONAL RECOVERY AFTER INTRACEREBRAL HEMORRHAGE - Sprügel, Maximilian; Kuramatsu, Joji; Volbers, Bastian; Sembill, Jochen; Saam, Justina; Gerner, Stefan; Balk, Stefanie; Hamer, Hajo; Lücking, Hannes; Hölter, Philip; Nolte, C.; Scheitz, J.; et al. (INTERNATIONAL JOURNAL OF STROKE, 2020)
CRIS-Team WoS Importer:2021-01-22

Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage - Sprügel, Maximilian; Kuramatsu, Joji; Volbers, Bastian; Saam, Justina; Sembill, Jochen; Gerner, Stefan; Balk, Stefanie; Hamer, Hajo; Lücking, Hannes; Hölter, Philip; Nolte, Christian H.; Scheitz, Jan F.; et al. (Stroke, 2021)
BACKGROUND AND PURPOSE: The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied. METHODS: Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH. RESULTS: A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03-2.40]; P=0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06, P=0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (P>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80-1.66]; P=0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09-2.56]; P=0.019). CONCLUSIONS: Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.
CRIS-Team Scopus Importer:2021-03-19
Keywords: edema; hematoma; incidence; odds ratio; seizures

Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020 - Vollmuth, Christoph; Miljukov, Olga; Abu-Mugheisib, Mazen; Angermaier, Anselm; Barlinn, Jessica; Busetto, Loraine; Grau, Armin J.; Guenther, Albrecht; Gumbinger, Christoph; Hubert, Nikolai; Hüttemann, Katrin; Klingner, Carsten; et al. (European Journal of Neurology, 2021)
Background and purpose: The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany. Methods: In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted. Results: Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018–2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care. Conclusions: Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany.
CRIS-Team Scopus Importer:2021-04-02
Keywords: COVID-19; SARS-CoV-2; stroke; survey; telemedicine

Impact of timing of continuous intravenous anesthetic drug treatment on outcome in refractory status epilepticus - Madzar, Dominik; Reindl, Caroline; Giede-Jeppe, Antje; Bobinger, Tobias; Sprügel, Maximilian; Knappe, Ruben U.; Hamer, Hajo; Huttner, Hagen (Critical Care, 2018)
BACKGROUND: Patients in refractory status epilepticus (RSE) may require treatment with continuous intravenous anesthetic drugs (cIVADs) for seizure control. The use of cIVADs, however, was recently associated with poor outcome in status epilepticus (SE), raising the question of whether cIVAD therapy should be delayed for attempts to halt seizures with repeated non-anesthetic antiepileptic drugs. In this study, we aimed to determine the impact of differences in therapeutic approaches on RSE outcome using timing of cIVAD therapy as a surrogate for treatment aggressiveness. METHODS: This was a retrospective cohort study over 14 years (n = 77) comparing patients with RSE treated with cIVADs within and after 48 h after RSE onset, and functional status at last follow-up was the primary outcome (good = return to premorbid baseline or modified Rankin Scale score of less than 3). Secondary outcomes included discharge functional status, in-hospital mortality, RSE termination, induction of burst suppression, use of thiopental, duration of RSE after initiation of cIVADs, duration of mechanical ventilation, and occurrence of super-refractory SE. Analysis was performed on the total cohort and on subgroups defined by RSE severity according to the Status Epilepticus Severity Score (STESS) and by the variables contained therein. RESULTS: Fifty-three (68.8%) patients received cIVADs within the first 48 h. Early cIVAD treatment was independently associated with good outcome (adjusted risk ratio [aRR] 3.175, 95% confidence interval [CI] 1.273-7.918; P = 0.013) as well as lower chance of both induction of burst suppression (aRR 0.661, 95% CI 0.507-0.861; P = 0.002) and use of thiopental (aRR 0.446, 95% CI 0.205-0.874; P = 0.043). RSE duration after cIVAD initiation was shorter in the early cIVAD cohort (hazard ratio 1.796, 95% CI 1.047-3.081; P = 0.033). Timing of cIVAD use did not impact the remaining secondary outcomes. Subgroup analysis revealed early cIVAD impact on the primary outcome to be driven by patients with STESS of less than 3. CONCLUSIONS: Patients with RSE treated with cIVADs may benefit from early initiation of such therapy.
EVALuna2:201933

Impacts of microbiome metabolites on immune regulation and autoimmunity - Haase, Stefanie; Haghikia, Aiden; Wilck, Nicola; Mueller, Dominik N.; Linker, Ralf (Immunology, 2018)
A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro-inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T-cells (Treg), contributing to immune suppression. Short-chain fatty acids may induce Treg either by G-protein-coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T-cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long-chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host-microbiota interaction and the immune system with a special focus on MS as a prototype T-cell-mediated autoimmune disease of the CNS.
EVALuna2:201904

Impaired adult olfactory bulb neurogenesis in the R6/2 mouse model of Huntington's disease - Winner, Beate; Kohl, Zacharias; Regensburger, Martin; Kandasamy, Mahesh; Winkler, Jürgen; et al. (BMC Neuroscience, 2010)
Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to expanded CAG-triplet nucleotide repeats within the huntingtin gene. Intracellular huntingtin aggregates are present in neurons of distinct brain areas, among them regions of adult neurogenesis including the hippocampus and the subventricular zone/olfactory bulb system. Previously, reduced hippocampal neurogenesis has been detected in transgenic rodent models of HD. Therefore, we hypothesized that mutant huntingtin also affects newly generated neurons derived from the subventricular zone of adult R6/2 HD mice.Results: We observed a redirection of immature neuroblasts towards the striatum, however failed to detect new mature neurons. We further analyzed adult neurogenesis in the granular cell layer and the glomerular layer of the olfactory bulb, the physiological target region of subventricular zone-derived neuroblasts. Using bromodeoxyuridine to label proliferating cells, we observed in both neurogenic regions of the olfactory bulb a reduction in newly generated neurons.Conclusion: These findings suggest that the striatal environment, severely affected in R6/2 mice, is capable of attracting neuroblasts, however this region fails to provide sufficient signals for neuronal maturation. Moreover, in transgenic R6/2 animals, the hostile huntingtin-associated microenvironment in the olfactory bulb interferes with the survival and integration of new mature neurons. Taken together, endogenous cell repair strategies in HD may require additional factors for the differentiation and survival of newly generated neurons both in neurogenic and non-neurogenic regions.

Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein - May, Verena Elisabeth Luise; Nuber, S.; Marxreiter, Franz; Riess, O.; Winner, Beate; Winkler, Jürgen (Neuroscience, 2012)
Synucleinopathies including Parkinson's disease (PD) are characterized by the accumulation of alpha-synuclein (?-syn) within neural cell bodies and their processes. Transgenic mice overexpressing human wild-type or mutant forms of ?-syn under the control of different promoters were developed to analyse the underlying neuropathology of PD. One of the earliest clinical symptoms associated with PD is olfactory impairment. The generation of new neurons persists up to adulthood in mammals, in particular the olfactory bulb (OB). In order to assess this process in relation to ?-syn accumulation, we used mice overexpressing human wild-type ?-syn under the regulatable control (tet-off) of the calcium/calmodulin-dependent protein kinase II?-promoter (CaMKII). We observed a decrease in OB neurogenesis in transgenic animals compared to controls using 5-bromo-2'-deoxyuridine (BrdU) to label newly generated cells (neuron-specific nuclear protein; NeuN). After cessation of transgene expression we detected an increase in newly generated cells both in granular (GCL) and glomerular (GLOM) layers of the OB. This led to a rescue of newly generated neurons (BrdU(+)/NeuN(+)) within the GLOM with a distinct specificity for the dopaminergic subpopulation. In contrast, we did not detect a cell-specific rescue of neuronal cells in the GCL suggesting diverse effects of alpha-synucleinopathy in both interneuronal layers of the OB. Colabelling of BrdU with glial markers showed that a differentiation into neither astroglia nor microglia attributed to the observed phenotype in the GCL. In particular, BrdU(+) particles located within microglial cells were predominantly associated close to the membrane therefore the resembling phagocytosed nuclear fragments of BrdU(+) cells. Thus, our study further contributes insights into ?-syn accumulation as a causative player in the impairment of adult neurogenesis and emphasizes its diverse role in cell renewal of distinct OB cell layers.
EVALuna2:22048

Impaired renal function in stroke patients with atrial fibrillation - Sauer, Eva-Maria; Sauer, Rolf; Kallmuenzer, Bernd; Blinzler, Christian; Breuer, Lorenz; Huttner, Hagen; Schwab, Stefan; Köhrmann, Martin (Journal of Stroke and Cerebrovascular Diseases, 2014)
Stroke patients with atrial fibrillation (AF) are prone to have comorbidities such as impaired renal function. Because poly-pharmacotherapy is often required in those patients, renal function is important to consider in light of renally cleared medications such as direct oral anticoagulants. In this study, we analyzed frequency and predictors for impaired renal function and its impact on functional outcome in stroke patients with underlying AF.We analyzed 272 patients with acute ischemic stroke and AF of our prospective, observational stroke database. Estimated glomerular filtration rate (eGFR) was calculated on admission and during hospitalization from the equation of the Modification Diet for Renal Disease. Outcome measures included mortality and functional outcome at 90 days, assessed as modified Rankin Scale (mRS) score.On admission, impaired renal function was found in 41.5% (n = 113) and was associated with worse 90-day outcome (mRS score <= 2: 26.5% versus 45.9%, P = .001) and a higher mortality rate (23.9% versus 14.5%, P = .043). Multivariate logistic regression identified older age and history of myocardial infarction as independent predictors of renal dysfunction on admission (P < .05). Normalization of eGFR during hospitalization was achieved in 55.8%.In patients with acute ischemic stroke and AF, impaired renal function on admission is frequent and associated with worse outcome. Normalization of eGFR can often be achieved during hospitalization, but in everyday life, fluctuations of renal function because of infection or dehydration have to be considered. Careful monitoring of renal status is indispensable and should influence drug treatment decisions.
EVALuna2:22248

Impairment of autonomic cardiovascular modulation is more pronounced in focal epilepsy patients with than without limbic system lesions - Zhuravlev, D.; Lebedeva, M.; Lebedeva, A.; Teplyshova, A.; Rider, F.; Semenovykh, N.; Yakovlev, A.; Guekht, A.; Hilz, Max-Josef (EUROPEAN JOURNAL OF NEUROLOGY, 2020)
CRIS-Team WoS Importer:2020-06-16

Implant for Augmentation of Cerebral Blood Flow Trial-1 (ImpACT-1). A single-arm feasibility study evaluating the safety and potential benefit of the Ischemic Stroke System for treatment of acute ischemic stroke - Khurana, Dheeraj; Kaul, Subhash; Schneider, Dietmar; Csanyi, Attila; Adam, Ilona; Ichaporia, Nasli R.; Griewing, Bernd; Csiba, Laszlo; Valikovics, Attila; Puri, Vinod; Diener, Hans Christoph; Schwab, Stefan; et al. (PLoS ONE, 2019)
BACKGROUND: The Ischemic Stroke System is a novel device designed to deliver stimulation to the sphenopalatine ganglion(SPG).The SPG sends parasympathetic innervations to the anterior cerebral circulation. In rat stroke models, SPG stimulation results in increased cerebral blood flow, reduced infarct volume, protects the blood brain barrier, and improved neurological outcome. We present here the results of a prospective, multinational, single-arm, feasibility study designed to assess the safety, tolerability, and potential benefit of SPG stimulation inpatients with acute ischemic stroke(AIS). METHODS: Patients with anterior AIS, baseline NIHSS 7-20 and ability to initiate treatment within 24h from stroke onset, were implanted and treated with the SPG stimulation. Patients were followed up for 90 days. Effect was assessed by comparing the patient outcome to a matched population from the NINDS rt-PA trial placebo patients. RESULTS: Ninety-eight patients were enrolled (mean age 57years, mean baseline NIHSS 12 and mean treatment time from stroke onset 19h). The observed mortality rate(12.2%), serious adverse events (SAE)incidence(23.5%) and nature of SAE were within the expected range for the population. The modified intention to treat cohort consisted of 84 patients who were compared to matched patients from the NINDS placebo arm. Patients treated with SPG stimulation had an average mRS lower by 0.76 than the historical controls(CMH test p = 0.001). CONCLUSION: The implantation procedure and the SPG stimulation, initiated within 24hr from stroke onset, are feasible, safe, and tolerable. The results call for a follow-up randomized trial (funded by BrainsGate; clinicaltrials.gov number, NCT03733236).
CRIS-Team Scopus Importer:2019-07-30

Improved resection in lesional temporal lobe epilepsy surgery using neuronavigation and intraoperative MR imaging: Favourable long term surgical and seizure outcome in 88 consecutive cases - Roessler, Karl; Sommer, Bjoern; Grummich, Peter; Coras, Roland; Kasper, Burkhard; Hamer, Hajo; Blümcke, Ingmar; Stefan, Hermann; Buchfelder, Michael (Seizure-European Journal of Epilepsy, 2014)
To investigate the value of intraoperative MR imaging (iopMRI) combined with neuronavigation to avoid intraoperative underestimation of the resection amount during surgery of lesional temporal lobe epilepsy (LTLE) patients.We retrospectively investigated 88 patients (40 female, 48 male, mean age 37.2yrs, from 12 to 69yrs, 41 left sided lesions) with LTLE operated at our department, including 40.9% gangliogliomas (GG), 26.1% cavernomas (CM), 10.2% dysembryoplastic neuroepithelial tumours (DNT) and 11.4% focal cortical dysplasias (FCD), excluding hippocampal sclerosis.Complete resection was achieved in 85 of 88 patients (96.6%), as proven by postoperative MRI 6 months after surgery. In contrast, the routine first iopMR imaging before closure revealed radical resection in only 66 of these 88 patients (75%). After re-intervention, the second iopMR imaging demonstrated complete resection in 19 more patients. Thus, as a direct effect of iopMRI and neuronavigation, overall resection rate was increased by 21.6%. An excellent seizure outcome Engel Class I was found in 76.1% of patients during a mean follow-up of 26.4 months, irrespective of histological entity (74% in CM, 75% in GG, 78% in DNT and 60% in FCD). No severe postoperative complications occurred; permanent superior visual field defects were detected in 10.2% and permanent dysphasia/dyscalculia in 1.1%.Refined surgery using neuronavigation combined with iopMR imaging in LTLE surgery led to radical resection in 96.6% of the patients, due to immediate correction of underestimated resection in 21.6% of patients. This protocol resulted in a favourable seizure outcome and a low complication rate.
EVALuna2:7229

Improvement and stabilization of cardiovascular autonomic modulation three months after acute ischemic stroke - Wang, Ruihao; Macha, Kosmas; Köhn, Julia; Marsch, Armin; Winder, K.; Gerner, Stefan; Koehrmann, M.; Schwab, Stefan; Kallmünzer, Bernd; Hilz, Max-Josef (EUROPEAN JOURNAL OF NEUROLOGY, 2020)
CRIS-Team WoS Importer:2020-06-16

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study - Pechmann, Astrid; Behrens, Max; Dörnbrack, Katharina; Tassoni, Adrian; Wenzel, Franziska; Stein, Sabine; Vogt, Sibylle; Zöller, Daniela; Bernert, Günther; Hagenacker, Tim; Schara-Schmidt, Ulrike; Walter, Maggie C.; et al. (Journal of Neuromuscular Diseases, 2023)
BACKGROUND AND OBJECTIVES: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. METHODS: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. RESULTS: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. CONCLUSION: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.
CRIS-Team Scopus Importer:2023-01-20
Keywords: ambulant; nusinersen; SMArtCARE; Spinal muscular atrophy; walker

Improving the Robustness of IMU-based Sit-To-Stand Detection during Simulated Real-World Activities for Different Sensor Positions - Seifer, Ann-Kristin; Popp, Friederike; Richer, Robert; Gaßner, Heiko; Eskofier, Björn (IEEE Biomedical and Health Informatics Conference, 2023)