Transcutaneous vagus nerve stimulation - A brief introduction and overview - Hilz, Max-Josef (Autonomic Neuroscience-Basic & Clinical, 2022)
Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity, and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily available. Consequently, transcutaneous VNS (tVNS) has been developed 20 years ago as non-invasive, less expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and many more. tVNS might become a standard tool to enhance autonomic balance and function in various autonomic, neurological, psychiatric, rheumatologic, as well as other diseases.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Auricular branch of the vagus nerve; Concha cymba; Locus coeruleus; Nucleus tractus solitarii; Tragus; Transcutaneous vagus nerve stimulation

Transcutaneous vagus nerve stimulation and the realm of its therapeutic hopes and physiologic enigmas - Hilz, Max-Josef; Bolz, Armin (Autonomic Neuroscience-Basic & Clinical, 2022)
Vagus nerve stimulation (VNS) is an established treatment option for patients with treatment resistant epilepsy and depression. However, the procedure is invasive and has side-effects. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive alternative. Particularly transcutaneous stimulation at the outer ear is gaining increasing interest. While the scope of therapeutic tVNS applications is expanding, there are still questions regarding the optimal stimulation parameters and site as well as the physiology and pathways of auricular tVNS. This Special Issue of Autonomic Neuroscience: Basic & Clinical provides an introduction and overview on basic aspects as well as special topics of tVNS.
CRIS-Team Scopus Importer:2022-11-25
Keywords: Auricular branch of the vagus nerve; Concha cymba; Locus coeruleus; Nucleus tractus solitarii; Tragus; Transcutaneous vagus nerve stimulation

Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02) - Bauer, S.; Baier, H.; Baumgartner, C.; Bohlmann, K.; Fauser, S.; Graf, Wolfgang; Hillenbrand, B.; Hirsch, M.; Last, C.; Lerche, H.; Mayer, T.; Schulze-Bonhage, A.; et al. (Brain Stimulation, 2016)
Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch.We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy.Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation.Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related.tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.
EVALuna2:22447

Transforming growth factor-beta 1 is a negative modulator of adult neurogenesis - Winner, Beate; Couillard-Despres, Sebastien; Winkler, Jürgen; Bogdahn, Ulrich; et al. (Journal of Neuropathology and Experimental Neurology, 2006)
Transforming growth factor (TGF)-beta 1 has multiple functions in the adult central nervous system (CNS). It modulates inflammatory responses in the CNS and controls proliferation of microglia and astrocytes. In the diseased brain, TGF-beta 1 expression is upregulated and, depending on the cellular context, its activity can be beneficial or detrimental regarding regeneration. We focus on the role of TGF-beta 1 in adult neural stem cell biology and neurogenesis. In adult neural stem and progenitor cell cultures and after intracerebroventricular infusion, TGF-beta 1 induced a long-lasting inhibition of neural stem and progenitor cell proliferation and a reduction in neurogenesis. In vitro, although TGF-beta 1 specifically arrested neural stem and progenitor cells in the G0/1 phase of the cell cycle, it did not affect the self-renewal capacity and the differentiation fate of these cells. Also, in vivo, TGF-beta 1 did not influence the differentiation fate of newly generated cells as shown by bromo-deoxyuridine incorporation experiments. Based on these data, we suggest that TGF-beta 1 is an important signaling molecule involved in the control of neural stem and progenitor cell proliferation in the CNS. This might have potential implications for neurogenesis in a variety of TGF-beta 1-associated CNS diseases and pathologic conditions.
Keywords: brain repair; cell fate; differentiation; doublecortin; neurodegenerative diseases

Transglutaminase 6 is colocalized and interacts with mutant huntingtin in huntington disease rodent animal models - Schulze-Krebs, Anja; Canneva, Fabio; Stemick, Judith; Plank, Anne-Christine; Harrer, Julia; Bates, Gillian P.; Aeschlimann, Daniel; Steffan, Joan S.; von Hörsten, Stephan (International Journal of Molecular Sciences, 2021)
Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different transglutaminases are found in many different tissues, the TG6 isoform is mostly expressed in the CNS. The present study was embarked on/undertaken to investigate expression, distribution and activity of transglutaminases in Huntington disease transgenic rodent models, with a focus on analyzing the involvement of TG6 in the age-and genotype-specific pathological features relating to disease progression in HD transgenic mice and a tgHD transgenic rat model using biochemical, histological and functional assays. Our results demonstrate the physical interaction between TG6 and (mutant) huntingtin by co-immunoprecipitation analysis and the contribution of its enzymatic activity for the total aggregate load in SH-SY5Y cells. In addition, we identify that TG6 expression and activity are especially abundant in the olfactory tubercle and piriform cortex, the regions displaying the highest amount of mHTT aggregates in transgenic rodent models of HD. Furthermore, mHTT aggregates were colocalized within TG6-positive cells. These findings point towards a role of TG6 in disease pathogenesis via mHTT aggregate formation.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Huntington disease; Neurodegeneration; Rodent transgenic animal models; Transglutaminase isoform 6

Transient decrease in circulating dendritic cell precursors after acute stroke: Potential recruitment into the brain - Yilmaz, Atilla; Fuchs, Tanja; Dietel, Barbara; Altendorf, Regina; Cicha, Iwona; Stumpf, Christian; Schellinger, Peter D.; Blümcke, Ingmar; Schwab, Stefan; Daniel, Werner; Garlichs, Christoph; Kollmar, Rainer (Clinical Science, 2010)
The role of DCs (dendritic cells) as potent mediators of inflammation has not been sufficiently investigated in stroke. Therefore, in the present study, circulating mDCPs (myeloid DC precursors), pDCPs (plasmacytoid DCPs) and tDCPs (total DCPs) were analysed by flow cytometry in (i) healthy controls (n = 29), (ii) patients with ACI-S (asymptomatic cerebral infarction stenosis; n = 46), (iii) patients with TIA (transient ischaemic attack; n = 39), (iv) patients with AIS (acute ischaemic stroke; n = 73), and (v) patients with AHS (acute haemorrhagic stroke; n = 31). The NIHSS (National Institutes of Health Stroke Scale) and infarction size on a CT (computer tomography) scan were evaluated after stroke. In a patient subgroup, post-mortem immunohistochemical brain analyses were performed to detect mDCs (CD209), pDCs (CD123), T-cells (CD3) and HLA-DR. In AIS and AHS, the numbers of circulating mDCPs (P < 0.005), pDCPs (P < 0.005) and tDCPs (P < 0.001) were significantly reduced. A significant inverse correlation was found between the NIHSS and circulating DCPs (P < 0.02), as well as between hsCRP (high-sensitivity C-reactive protein) and circulating DCPs (P < 0.001). Patients with large stroke sizes on a CT scan had significantly lower numbers of mDCPs (P = 0.007), pDCPs (P = 0.05) and tDCPs (P = 0.01) than those with smaller stroke sizes. Follow-up analysis showed a significant recovery of circulating DCPs in the first few days after stroke. In the infarcted brain, a dense infiltration of mDCs co-localized with T-cells, single pDCs and high HLA-DR expression were observed. In conclusion, acute stroke leads to a decrease in circulating DCPs. Potentially, circulating DCPs are recruited from the blood into the infarcted brain and probably trigger cerebral immune reactions there. © The Authors Journal compilation © 2010 Biochemical Society.
CRIS-Team Scopus Importer:2024-12-04
Keywords: Dendritic cell; Inflammation; Ischaemic brain injury; Leucocyte infiltration; Stroke; T-cell activation

Transient naming deficits associated with insular lesions in a patient with encephalitis - Marxreiter, Franz; Utz, Kathrin; Schlachetzki, Johannes; Seifert, Frank; Schmidt, Manuel; Dörfler, Arnd; Schwab, Stefan; Schenk, Thomas (Neurocase, 2019)
We describe a patient with acute herpes simplex encephalitis with left-hemispheric hippocampal, parahippocampal and insular lesions. Although prototypic language areas were unaffected, the patient suffered from an inability to name objects or animals displayed on pictures. This deficit was transient and gradually disappeared 8 weeks after the initial diagnosis. Our findings are in line with a previous report showing similar deficits in a patient with a comparable lesion pattern and support the hypothesis that left insular lesions can produce severe naming deficits. Using FDG-PET we ruled out that functional deactivation in classical language areas account for the observed naming deficits.
EVALuna2:204482

Translational research in geriatrics? A plea based on current biomedical key publications - Bollheimer, Cornelius; Volkert, Dorothee; Bertsch, T.; Bauer, J.; Klucken, Jochen; Sieber, Cornel; Buettner, R. (Zeitschrift für Gerontologie und Geriatrie, 2013)
Contemporary geriatric research focuses mainly on observational clinical studies and epidemiological surveys and the translation of basic scientific results from biogerontology into a clinical context is often neglected. Following a definition of translational research the article gives an overview of recent key publications in experimental biogerontology with a special emphasis on their relevance for clinical geriatrics. The topics dealt with include age-induced loss of skeletal muscle (sarcopenia), the aging immune system (immunosenescence) and neurodegenerative disorders (Alzheimer's and Parkinson's disease).
Keywords: Translational research; Sarcopenia; Immunosenescence; Alzheimer disease; Parkinson disease

Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation - Pieger, Katharina; Schmitt, Verena; Gauer, Carina; Gießl, Nadja; Prots, Iryna; Winner, Beate; Winkler, Jürgen; Brandstätter, Johann Helmut; Xiang, Wei (Biomolecules, 2022)
Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson's disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood. Current knowledge suggests the existence of various aSyn species with distinct structural and biochemical properties. Here, we identified a C-terminal-targeting aSyn antibody (Nu-aSyn-C), which has a high immunoaffinity towards aSyn in the nucleus. Comparing the Nu-aSyn-C antibody to aSyn antibodies developed against phosphorylated or aggregated forms, we observed that nuclear aSyn differs from cytosolic aSyn by an increased phosphorylation and assembly level in proliferating cells. Employing Nu-aSyn-C, we characterized aSyn distribution during neuronal differentiation in midbrain dopaminergic neurons (mDANs) derived from human-induced pluripotent stem cells (hiPSCs) and Lund human mesencephalic cells, and in primary rat hippocampal neurons. We detected a specific translocation pattern of aSyn during neuronal differentiation from the nucleus to the soma and finally to neuronal processes. Interestingly, a remarkable shift of Nu-aSyn-C-positive species towards neurites was detected in hiPSC mDANs from a PD patient carrying aSyn gene duplication. Together, our results reveal distinct nuclear and cytosolic aSyn species that redistribute during neuronal differentiation-a process that is altered in PD-derived neurons.
CRIS-Team WoS Importer:2022-09-09

Treadmill exercise intervention improves gait and postural control in alpha-synuclein mouse models without inducing cerebral autophagy - Minakaki, Georgia; Canneva, Fabio; Chevessier, Frederic; Bode, Frederik; Menges, Stefanie; Timotius, Ivanna; Kalinichenko, Liubov; Meixner, Holger; Müller, Christian P.; Eskofier, Björn; Casadei, Nicolas; Riess, Olaf; et al. (Behavioural Brain Research, 2019)
Gait and postural control dysfunction are prototypical symptoms compromising quality of life for patients with Parkinson’s disease (PD). Hallmarks of cellular pathology are dopaminergic degeneration and accumulation of the cytosolic protein alpha-synuclein, linked to impaired autophagy-lysosome pathway (ALP) clearance. Physical exercise improves gait in PD patients and motor function in rodent lesion models. Moreover, exercise is considered neuroprotective and ALP induction has been reported, e.g. in human skeletal muscle, rodent peripheral and cerebral tissues. A combined analysis of how distinct exercise paradigms affect motor and central biochemical aspects of PD could maximize benefits for patients. Here we examine the effect of 4 weeks treadmill exercise intervention in 7-8 month non-lesioned mice on a) distinct gait categories, b) ALP activity, c) dopaminergic and alpha-synuclein homeostasis. The study includes wild type, alpha-synuclein knockout, and mice exclusively expressing human alpha-synuclein. Parameters of gait regularity and stability, activity, and dynamic postural control during unforced walk, were assessed by an automated system (CatWalk XT). At baseline, alpha-synuclein mouse models exhibited irregular and less active gait, with impaired dynamic postural control, compared to wild type mice. Treadmill exercise particularly improved speed and stride length, while increasing dual diagonal versus three-paw body support in both the alpha-synuclein knockout and transgenic mice. Biochemical analyses showed higher striatal tyrosine hydroxylase immuno-reactivity and reduced higher-order alpha-synuclein species in the cerebral cortex. However, no significant cerebral ALP induction was measured. In summary, treadmill exercise improved gait activity and postural stability, and promoted dopaminergic and alpha-synuclein homeostasis, without robustly inducing cerebral ALP.<br
Keywords: alpha-synuclein; autophagy; instrumented gait analysis; mouse gait pattern; Parkinson´s disease; treadmill exercise

Treadmill training and physiotherapy similarly improve dual task gait performance: a randomized-controlled trial in Parkinson's disease - Gaßner, Heiko; Trutt, Elmar; Seifferth, Sarah; Friedrich, Jana; Zucker, Diana; Salhani, Ziad; Adler, Werner; Winkler, Jürgen; Jost, Wolfgang H. (Journal of Neural Transmission, 2022)
Motor-cognitive dual tasks are used to investigate the interplay between gait and cognition. Dual task walking in patients with Parkinson's disease (PD) results in decreased gait speed and more importantly in an increased fall risk. There is evidence that physical training may improve gait during dual task challenge. Physiotherapy and treadmill walking are known to improve single task gait. The aim of this study was to investigate the impact of individualized physiotherapy or treadmill training on gait during dual task performance. 105 PD patients were randomly assigned to an intervention group (physiotherapy or treadmill). Both groups received 10 individual interventional sessions of 25 min each and additional group therapy sessions for 14 days. Primary outcome measure was the dual task gait speed. Secondary outcomes were additional gait parameters during dual task walking, UPDRS-III, BBS and walking capacity. All gait parameters were recorded using sensor-based gait analysis. Gait speed improved significantly by 4.2% (treadmill) and 8.3% (physiotherapy). Almost all secondary gait parameters, UPDRS-III, BBS, and walking capacity improved significantly and similarly in both groups. However, interaction effects were not observed. Both interventions significantly improved gait in patients with mild to moderate PD. However, treadmill walking did not show significant benefits compared to individualized physiotherapy. Our data suggest that both interventions improve dual task walking and therefore support safe and independent walking. This result may lead to more tailored therapeutic preferences.
CRIS-Team WoS Importer:2022-06-24

Treatment and Outcome in Stroke Patients With Acute M2 Occlusion and Minor Neurological Deficits - Dobrocky, Tomas; Piechowiak, Eike I.; Volbers, Bastian; Slavova, Nedelina; Kaesmacher, Johannes; Meinel, Thomas R.; Arnold, Marcel; Fischer, Urs; Jung, Simon; Gralla, Jan; Mordasini, Pasquale; Heldner, Mirjam R. (Stroke, 2021)
BACKGROUND AND PURPOSE: Treatment in stroke patients with M2 segment occlusion of the middle cerebral artery presenting with mild neurological deficits is a matter of debate. The main purpose was to compare the outcome in patients with a minor stroke and a M2 occlusion. METHODS: Consecutive intravenous thrombolysis (IVT) eligible patients admitted to the Bernese stroke center between January 2005 and January 2020 with acute occlusion of the M2 segment and National Institutes of Health Stroke Scale score ≤5 were included. Outcome was compared between IVT only versus endovascular therapy (EVT) including intra-arterial thrombolysis and mechanical thrombectomy (MT; ±IVT) and between IVT only versus MT only. RESULTS: Among 169 patients (38.5% women, median age 70.2 years), 84 (49.7%) received IVT only and 85 (50.3%) EVT (±IVT), the latter including 39 (45.9%) treated with MT only. Groups were similar in sex, age, vascular risk factors, event cause, or preevent independency. Compared with IVT only, there was no difference in favorable outcome (modified Rankin Scale score, 0-2) for EVT (adjusted odds ratio, 0.96; adjusted P=0.935) or for MT only (adjusted odds ratio, 1.12; adjusted P=0.547) groups. Considering only patients treated after 2015, there was a significantly better 3-month modified Rankin Scale shift (adjusted P=0.032) in the EVT compared with the IVT only group. CONCLUSIONS: Our study demonstrates similar effectiveness of IVT only versus EVT (±IVT), and of IVT only versus MT only in patients with peripheral middle cerebral artery occlusions and minor neurological deficits and indicates a possible benefit of EVT considering only patients treated after 2015. There is an unmet need for randomized controlled trials in this stroke field, including imaging parameters, and more sophisticated evaluation of National Institutes of Health Stroke Scale score subitems, neurocognition, and quality of life neglected by the standard outcome scales such as modified Rankin Scale and National Institutes of Health Stroke Scale score.
CRIS-Team Scopus Importer:2021-03-19
Keywords: middle cerebral artery; National Institutes of Health; quality of life; risk factors; thrombectomy

Treatment escalation in patients not responding to pharmacotherapy, psychotherapy, and electro-convulsive therapy: experiences from a novel regimen using intravenous S-ketamine as add-on therapy in treatment-resistant depression - Kallmünzer, Bernd; Volbers, Bastian; Karthaus, Anne; Tektas, Ozan Yueksel; Kornhuber, Johannes; Mueller, Helge H. (Journal of Neural Transmission, 2016)
A lack of response despite maximum therapy is common in patients fulfilling criteria of treatment-resistant depression. Therefore, innovative strategies for treatment escalation are warranted. Here, we report the clinical experiences associated with a novel therapeutic regimen combining electroconvulsive therapy and repeated intravenous S-ketamine treatment in three patients. The combined therapy was feasible and had no serious side effects. All patients responded to the new treatment option. The augmentative effect of sub-anesthetic S-ketamine on ECT is discussed.
EVALuna2:22270

Treatment of established status epilepticus in the elderly - a study protocol for a prospective multicenter double-blind comparative effectiveness trial (ToSEE) - Müller, Annekatrin; Schmiedeknecht, Anett; Mende, Meinhard; Awissus, Carolin; Rosenow, Felix; Hamer, Hajo; Classen, Joseph (BMC Neurology, 2020)
Background: Status epilepticus (SE) is a common neurological emergency condition that especially affects the elderly and old population. Older people with SE frequently have non-convulsive SE (NCSE) and are also at special risk of suffering a poor outcome. The application of benzodiazepines fails to control SE in about one third of the cases. For benzodiazepine refractory SE (BRSE) in elderly, there is little evidence that would justify the choice of one of the commonly used antiepileptic drugs. The present study aims to generate evidence for the treatment of BRSE in this age group. Methods: We will conduct a prospective, randomized, double-blind comparative effectiveness study in more than twenty hospitals in Germany over a four-year period. Four hundred and seventy-seven elderly patients (≥ 65 years old) diagnosed with BRSE will be allocated by 1:1 randomization to receive either levetiracetam or valproate. All types of SE will be considered. For the diagnosis NCSE a verification by EEG is required. Levetiracetam or valproate will be administered in one single infusion. The primary endpoint is the stable cessation of ictal activity 15 min after the start of infusion persisting for the following 45 min of observation. EEG recording is maintained over the whole observation period, clinical examinations are conducted in predefined intervals. In case of treatment success patients and study staff remain blinded until 60 min after the start of the infusion. Adverse events will be recorded until the end of the study. EEG data will be reviewed by two external independent experts. To obtain data about the further treatment of SE, intrahospital complications and the functional outcome in the short term the study participants will be observed until the day of discharge or day 30 whichever is earliest. Discussion: ToSEE is the first study which shall deliver evidence for the SE-therapy in the elderly and old population in a controlled prospective comparator study. By design it also shall collect information about therapy regimes and outcome aspects of this disease. Trial registration: The trial has been registered at the German Clinical Trials Register on 3 July, 2020 (DRKS00022308, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022308).
CRIS-Team Scopus Importer:2020-12-11
Keywords: Benzodiazepine refractory status epilepticus; Elderly; Levetiracetam; Valproate

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol - Diem, Ricarda; Molnar, Fanni; Beisse, Flemming; Gross, Nikolai; Drueschler, Katharina; Heinrich, Sven P.; Joachimsen, Lutz; Rauer, Sebastian; Pielen, Amelie; Suehs, Kurt-Wolfram; Linker, Ralf; Huchzermeyer, Cord; et al. (BMJ Open, 2016)
Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function.Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to <= 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months.TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP.NCT01962571.
EVALuna2:21279

Trends in resource utilization and cost of illness in patients with active epilepsy in Germany from 2003 to 2020 - Willems, Laurent M.; Hochbaum, Maja; Zöllner, Johann Philipp; Schulz, Juliane; Menzler, Katja; Langenbruch, Lisa; Kovac, Stjepana; Knake, Susanne; von Podewils, Felix; Hamacher, Mario; Hamer, Hajo; Reese, Jens Peter; et al. (Epilepsia, 2022)
Objective: This study was undertaken to calculate epilepsy-related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008, and 2013. This analysis was part of the Epi2020 study. Methods: Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom-up design and human capital approach over a 3-month period in late 2020. Epilepsy-specific costs in the German health care sector from 2003, 2008, and 2013 were corrected for inflation to allow for a valid comparison. Results: Data on the disease-specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at €5551 (±€5805, median = €2611, range = €274–€21 667) per 3 months, comprising mean direct costs of €1861 (±€1905, median = €1276, range = €327–€13 158) and mean indirect costs of €3690 (±€5298, median = €0, range = €0–€11 925). The main direct cost components were hospitalization (42.4%), antiseizure medication (42.2%), and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part-time work or unemployment (30.8%), and seizure-related off-days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (−10.0%), and indirect costs significantly increased (p <.028, +35.1%), resulting in a significant increase in total epilepsy-related costs (p <.047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p =.047). Significance: The present study shows that disease-related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction, and seizure-related days off.
CRIS-Team Scopus Importer:2022-04-15
Keywords: antiseizure medication; cost of illness; economic burden; health care; seizure

Trends in the neurological emergency room, focusing on persons with seizures - Welte, Tamara; Ernst, Sebastian; Stritzelberger, Jenny; Gollwitzer, Stephanie; Lang, Johannes; Reindl, Caroline; Sprügel, Maximilian; Olmes, David; Schwab, Stefan; Blinzler, Christian; Hamer, Hajo (European Journal of Neurology, 2023)
Background and purpose: Previous studies in neurological emergency rooms (nERs) have reported many non-acute, self-presenting patients, patients with delayed presentation of stroke, and frequent visits of persons with seizures (PWS). The aim of this study was to evaluate trends during the last decade, with special focus on PWS. Methods: We retrospectively analyzed patients who presented to our specialized nER during the course of 5 months in 2017 and 2019, and included information on admission/referral, hospitalization, discharge diagnosis, and diagnostic tests/treatment in the nER. Results: A total of 2791 patients (46.6% male, mean age 57 ± 21 years) were included. The most common diagnoses were cerebrovascular events (26.3%), headache (14.1%), and seizures (10.5%). Most patients presented with symptoms lasting >48 h (41.3%). The PWS group included the largest proportion of patients presenting within 4.5 h of symptom onset (171/293, 58.4%), whereas only 37.1% of stroke patients presented within this time frame (273/735). Self-presentation was the most common admission pathway (31.1%), followed by emergency service referral (30.4%, including the majority of PWS: 197/293, 67.2%). Despite known diagnosis of epilepsy in 49.2%, PWS more often underwent accessory diagnostic testing including cerebral imaging, compared to the overall cohort (accessory diagnostics 93.9% vs. 85.4%; cerebral imaging 70.1% vs. 64.1%). Electroencephalography in the nER was only performed in 20/111 patients (18.0%) with a first seizure. Nearly half of the patients (46.7%) were discharged home after nER work-up, including most self-presenters (632/869, 72.7%) and headache patients (377/393, 88.3%), as well as 37.2% (109/293) of PWS. Conclusion: After 10 years, nER overuse remains a problem. Stroke patients still do not present early enough, whereas PWS, even those with known epilepsy, often seek acute and extensive assessment, indicating gaps in pre-hospital management and possible over-assessment.
CRIS-Team Scopus Importer:2023-09-15
Keywords: epilepsy; headache; neurological emergency room; seizures; stroke

Turning analysis during standardized test using on-shoe wearable sensors in parkinson’s disease - Haji Ghassemi, Nooshin; Hannink, Julius; Roth, Nils; Gaßner, Heiko; Marxreiter, Franz; Klucken, Jochen; Eskofier, Björn (Sensors, 2019)
Mobile gait analysis systems using wearable sensors have the potential to analyze and monitor pathological gait in a finer scale than ever before. A closer look at gait in Parkinson’s disease (PD) reveals that turning has its own characteristics and requires its own analysis. The goal of this paper is to present a system with on-shoe wearable sensors in order to analyze the abnormalities of turning in a standardized gait test for PD. We investigated turning abnormalities in a large cohort of 108 PD patients and 42 age-matched controls. We quantified turning through several spatio-temporal parameters. Analysis of turn-derived parameters revealed differences of turn-related gait impairment in relation to different disease stages and motor impairment. Our findings confirm and extend the results from previous studies and show the applicability of our system in turning analysis. Our system can provide insight into the turning in PD and be used as a complement for physicians’ gait assessment and to monitor patients in their daily environment.
CRIS-Team Scopus Importer:2019-08-20
Keywords: Mobile gait analysis; Parkinson’s disease; Pathological gait; Turning analysis; Wearable sensors

Twenty-Year Time Trends in Long-Term Case-Fatality and Recurrence Rates After Ischemic Stroke Stratified by Etiology - Rücker, Viktoria; Heuschmann, Peter U.; O'Flaherty, Martin; Weingärtner, Michael; Hess, Manuela; Sedlak, Claudia; Schwab, Stefan; Kolominsky-Rabas, Peter (Stroke, 2020)
BACKGROUND AND PURPOSE: Data on long-term survival and recurrence after stroke are lacking. We investigated time trends in ischemic stroke case-fatality and recurrence rates over 20-years stratified by etiological subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification within a population-based stroke register in Germany. METHODS: Data was collected within the Erlangen Stroke Project, a prospective, population-based stroke register covering a source population of 105 164 inhabitants (2010). Case fatality and recurrence rates for 3 months, 1 year, and 5 years were estimated with Kaplan-Meier estimates. Sex-specific time trends for case-fatality and recurrence rates were estimated with Cox regression. We adjusted for age, sex, and year of event and stratified for etiological subtypes. A sensitivity analysis with competing risk analysis for time trends in recurrence were performed. RESULTS: Between 1996 and 2015, 3346 patients with first ischemic stroke were included; age-standardized incidence per 100 000 was 75.8 in women and 131.6 in men (2015). Overall, 5-year survival probabilities were 50.4% (95% CI, 47.9-53.1) in women and 59.2% (95% CI, 56.4-62.0) in men; 5-year survival was highest in patients with first stroke due to small-artery occlusion (women, 71.8% [95% CI, 67.1-76.9]; men, 75.9% [95% CI, 71.3-80.9]) and lowest in cardioembolic stroke (women, 35.7% [95% CI, 31.0-41.1]; men, 47.8% [95% CI, 42.2-54.3]). Five-year recurrence rates were 20.1% (95% CI, 17.5-22.6) in women and 20.1% (95% CI, 17.5-22.7) in men; 5-year recurrence rate was lowest in women in stroke due to small artery occlusion 16.0% (95% CI, 11.7-20.1) and in men in large-artery atherosclerosis 16.6% (95% CI, 8.7-23.9); highest risk of recurrence was observed in undefined strokes (women, 22.3% [95% CI, 17.8-26.6]; men, 21.4% [95% CI, 16.7-25.9]). Cox regression revealed improvements in case-fatality rates over time with differences in stroke causes. No time trends in recurrence rates were observed. CONCLUSIONS: Long-term survival and recurrence varied substantially by first stroke cause. Survival probabilities improved over the past 2 decades; no major trends in stroke recurrence rates were observed.
CRIS-Team Scopus Importer:2020-09-04
Keywords: arteries; atherosclerosis; incidence; mortality; recurrence

Ultraearly assessed reperfusion status after middle cerebral artery recanalization predicting clinical outcome - Gölitz, Philipp; Mühlen, Iris; Gerner, Stefan; Knossalla, F.; Dörfler, Arnd (Acta Neurologica Scandinavica, 2018)
Objectives: Mechanical thrombectomy has high evidence in stroke therapy; however, successful recanalization guarantees not a favorable clinical outcome. We aimed to quantitatively assess the reperfusion status ultraearly after successful middle cerebral artery (MCA) recanalization to identify flow parameters that potentially allow predicting clinical outcome. Materials and Methods: Sixty-seven stroke patients with acute MCA occlusion, undergoing recanalization, were enrolled. Using parametric color coding, a post-processing algorithm, pre-, and post-interventional digital subtraction angiography series were evaluated concerning the following parameters: pre- and post-procedural cortical relative time to peak (rTTP) of MCA territory, reperfusion time, and index. Functional long-term outcome was assessed by the 90-day modified Rankin Scale score (mRS; favorable: 0-2). Results: Cortical rTTP was significantly shorter before (3.33 +/- 1.36seconds; P = .03) and after intervention (2.05 +/- 0.70seconds; P=.003) in patients with favorable clinical outcome. Additionally, age (P=.005) and initial National Institutes of Health Stroke Scale score (P = .02) were significantly different between the patients, whereas reperfusion index and time as well as initially estimated infarct size were not. In multivariate analysis, only post-procedural rTTP (P=.005) was independently associated with favorable clinical outcome. 2.29seconds for post-procedural rTTP might be a threshold to predict favorable clinical outcome. Conclusions: Ultraearly quantitative assessment of reperfusion status after successful MCA recanalization reveals post-procedural cortical rTTP as possible independent prognostic value in predicting favorable clinical outcome, even determining a threshold value might be possible. In consequence, focusing stroke therapy on microcirculatory patency could be valuable to improve outcome.
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Ultra-early Detection of Microcirculatory Injury as Predictor of Developing Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage - Gölitz, Philipp; Rösch, Julie; Roessler, Karl; Knossalla, Frauke; Dörfler, Arnd; Hölter, Philip (Clinical Neuroradiology, 2018)
Purpose Delayed cerebral ischemia (DCI) still remains amajor complication after subarachnoid hemorrhage (SAH). The aim of our study was to evaluate whether flow analysis of admission digital subtraction angiography (DSA) using parametric color coding (PCC), apostprocessing algorithm, allows ultra-early identification of SAH patients at risk for developing subsequent symptomatic vasospasm. Methods In this study 52patients who suffered SAH from aneurysm rupture, were retrospectively enrolled. Of the patients 26 developed DCI and angiographically proven cerebral vasospasm and 26age, gender-and clinical status-matched SAH patients without DCI served as controls. Using PCC, the following flow parameters were calculated: cerebral circulation time (CirT), cortical relative time to peak (rTTP) and microvascular transit time (TT). Results Mean cerebral CirT and cortical rTTP were longer in the DCI group (6.42s +/- 1.54 and 3.16s +/- 0.86, respectively) than in the non-DCI group (5.77s +/- 1.86 and 3.11s +/- 1.41, respectively), but without statistical significance. The mean microvascular TT was statistically significantly (p = 0.04) longer in the DCI group (3.19s +/- 0.78) than in the non-DCI group (2.67s +/- 0.73). Conclusion Angiographic flow analysis might be suitable for ultra-early detection and quantitative assessment of microcirculatory injury in SAH patients, predictive of developing subsequent DCI. Prolonged microvascular TT seems to be asignificant independent factor positively associated with DCI development. Identifying SAH patients at risk for DCI ultra-early after ictus might contribute to initiate prophylactic therapies before clinical deterioration.
EVALuna2:34933

Ultra high-field SWI of the substantia nigra at 7T: reliability and consistency of the swallow-tail sign - Schmidt, Manuel; Engelhorn, Tobias; Marxreiter, Franz; Winkler, Jürgen; Lang, Stefan; Kloska, Stephan; Gölitz, Philipp; Dörfler, Arnd (BMC Neurology, 2017)
BACKGROUND: The loss of the swallow-tail sign of the substantia nigra has been proposed for diagnosis of Parkinson's disease. Aim was to evaluate, if the sign occurs consistently in healthy subjects and if it can be reliably detected with high-resolution 7T susceptibility weighted imaging (SWI). METHODS: Thirteen healthy adults received SWI at 7T. 3 neuroradiologists, who were blinded to patients' diagnosis, independently classified subjects regarding the swallow-tail sign to be present or absent. Accuracy, positive and negative predictive values (PPV and NPV) as well as inter- and intra-rater reliability and internal consistency were analyzed. RESULTS: The sign could be detected in 81% of the cases in consensus reading. Accuracy to detect the sign compared to the consensus was 100, 77 and 96% for the three readers with PPV reader 1/2/3 = 1/0.45/0.83 and NPV = 1/1/1. Inter-rater reliability was excellent (inter-class correlation coefficient = 0.844, alpha = 0.871). Intra-rater reliability was good to excellent (reader 1 R/L = 0.625/0.786; reader 2 = 0.7/0.64; reader 3 = 0.9/1). CONCLUSION: The swallow-tail sign can be reliably detected. However, our data suggest its occurrence is not consistent in healthy subjects. It may be possible that one reason is an individually variable molecular organization of nigrosome 1 so that it does not return a uniform signal in SWI.
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Ultrasound and electrophysiologic findings in patients with Guillain-Barré syndrome at disease onset and over a period of six months - Grimm, Alexander; Decard, Bernhard F.; Schramm, Axel; Proebstel, Anne-Katrin; Rasenack, Maria; Axer, Hubertus; Fuhr, Peter (Clinical Neurophysiology, 2016)
To investigate cross-sectional areas (CSAs) of several peripheral nerves including the vagus nerve and the diameter of spinal nerves as measured by nerve ultrasound (NUS) and nerve conduction studies (NCS) in Guillain-Barré syndrome (GBS) patients over at least six months compared to healthy controls.NUS and/or NCS of several nerves, the vagus nerve, and the 5th/6th cervical spinal nerves were performed in patients with GBS at days 2-3 after symptom onset, at days 10-14 after immunoglobulin therapy and after six months compared to healthy controls.27 GBS-patients and 31 controls were included. Using NUS significant enlargement was found in all measured nerves (P<0.001), except the sural nerve (P=0.086) compared to the controls at onset. The vagus (median 3.0mm(2) vs. 2.0mm(2), P<0.0001) and the cervical spinal nerves were significantly enlarged (median 3.5/4.0mm vs. 2.6/3.2mm, p<0.0001), the vagus most obviously in patients with autonomic dysregulation (AD, 4.0mm(2)). Six months later, NCS showed persisting pathology in CMAP-amplitudes with amelioration of F-wave pathology. NUS showed restitution in the spinal nerves (median 2.6/3.2mm) and the vagus (median 2.0mm(2)) in all patients excluding the vagus in those with persistent AD (median 4.0mm(2)). The peripheral nerves did not change significantly (P>0.05).Ultrasonographic detection of cervical spinal nerve enlargement supports the diagnosis of GBS in the early phase. Its regression may be a good parameter for the clinical restitution over time. Vagus enlargement may be a risk marker for development of AD.Ultrasound is a reliable diagnostic follow-up tool in early GBS.
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Ultrasound in dual nerve impairment after proximal radial nerve lesion - Laemmer, Alexandra B.; Schwab, Stefan; Schramm, Axel (PLoS ONE, 2015)
Sonography in classical nerve entrapment syndromes is an established and validated method. In contrast, few publications highlight lesions of the radial nerve, particularly of the posterior interosseus nerve (PIN).Five patients with a radial nerve lesion were investigated by electromyography, nerve conduction velocity and ultrasound. Further normative values of 26 healthy subjects were evaluated.Four patients presented a clinical and electrophysiological proximal axonal radial nerve lesion and one patient showed a typical posterior interosseous nerve syndrome (PINS). The patient with PINS presented an enlargement of the PIN anterior to the supinator muscle. However four patients with proximal lesions showed an unexpected significant enlargement of the PIN within the supinator muscle.High-resolution sonography is a feasible method to demonstrate the radial nerve including its distal branches. At least in axonal radial nerve lesions, sonography might reveal abnormalities far distant from a primary proximal lesion site clearly distinct from the appearance in classical PINS.
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Unaltered Responses of Distal Motor Neurons to Non-Targeted Thoracic Spinal Cord Stimulation in Chronic Pain Patients - Riera, Carolyn; Souza de Oliveira, Daniela; Borutta, Matthias; Regensburger, Martin; Zhao, Yining; Brenner, Steffen; Del Vecchio, Alessandro; Kinfe, Thomas Mehari (Pain and Therapy, 2024)
Introduction: Spinal cord stimulation (SCS) represents an established interventional pain therapeutic; however, the SCS effects of SCS waveforms on motor neuron recruitment of the lower limbs of chronic pain patients remain largely unknown. Methods: We investigated these effects by performing isometric ankle-dorsal flexions at varying force levels under four SCS conditions: SCS Off (1 week), burst SCS (40 Hz), SCS Off (acute), and tonic SCS (130 Hz). Muscle activity was recorded via high-density surface electromyography (64-electrode grid) on the tibialis anterior muscle. Motor unit action (MUs) potentials were analyzed for recruitment and de-recruitment thresholds, discharge rate, inter-spike interval, and common synaptic input. Results: In this prospective study, we included nine patients (five females; four males; mean age 59 years) with chronic pain treated with thoracic (Th7–Th8) epidural spinal stimulation. A total of 97 MUs were found for 15% maximal voluntary torque (MVT) and 83 for 30%MVT, an average of 10.8 ± 3.7 for 15%MVT and 10.4 ± 3.5 for 30%MVT. While a few subject-specific variations were observed, our study suggests that the different SCS frequencies applied do not significantly influence motor unit discharge characteristics in the TA muscle among the participants (p values at 15%MVT were 0.586 (Chi2 = 1.933), 0.737 (Chi2 = 1.267), 0.706 (Chi2 = 1.4) and 0.586 (Chi2 = 1.933), respectively. The p values of the Friedman test at 30%MVT were 0.896 (Chi2 = 0.6), 0.583 (Chi2 = 1.95), 0.896 (Chi2 = 0.6) and 0.256 (Chi2 = 4.05). No significant difference was found for the different stimulation types for the delta (0–5 Hz), alpha (5–12 Hz), and beta (15–30 Hz) bands at both force levels. Conclusions: In summary, we did not observe any changes in motor unit oscillatory activity at any low and high bandwidths, indicating that SCS using different waveforms (tonic/burst) does not significantly influence motor neuron recruitment for non-motor individuals with chronic pain.
CRIS-Team Scopus Importer:2024-11-01
Keywords: Burst/tonic stimulation waveforms; Chronic pain; High-density surface electromyogram (HD-EMG); Motor unit recruitment (MUR); Spinal cord stimulation (SCS)

Unbiased and Mobile Gait Analysis Detects Motor Impairment in Parkinson's Disease - Klucken, Jochen; Barth, Jens; Kugler, Patrick; Schlachetzki, Johannes; Henze, Thore; Marxreiter, Franz; Kohl, Zacharias; Steidl, Ralph; Hornegger, Joachim; Eskofier, Björn; Winkler, Jürgen (PLoS ONE, 2013)
Motor impairments are the prerequisite for the diagnosis in Parkinson's disease (PD). The cardinal symptoms (bradykinesia, rigor, tremor, and postural instability) are used for disease staging and assessment of progression. They serve as primary outcome measures for clinical studies aiming at symptomatic and disease modifying interventions. One major caveat of clinical scores such as the Unified Parkinson Disease Rating Scale (UPDRS) or Hoehn&Yahr (H&Y) staging is its rater and time-of-assessment dependency. Thus, we aimed to objectively and automatically classify specific stages and motor signs in PD using a mobile, biosensor based Embedded Gait Analysis using Intelligent Technology (eGaIT). eGaIT consist of accelerometers and gyroscopes attached to shoes that record motion signals during standardized gait and leg function. From sensor signals 694 features were calculated and pattern recognition algorithms were applied to classify PD, H&Y stages, and motor signs correlating to the UPDRS-III motor score in a training cohort of 50 PD patients and 42 age matched controls. Classification results were confirmed in a second independent validation cohort (42 patients, 39 controls). eGaIT was able to successfully distinguish PD patients from controls with an overall classification rate of 81%. Classification accuracy increased with higher levels of motor impairment (91% for more severely affected patients) or more advanced stages of PD (91% for H&Y III patients compared to controls), supporting the PD-specific type of analysis by eGaIT. In addition, eGaIT was able to classify different H&Y stages, or different levels of motor impairment (UPDRS-III). In conclusion, eGaIT as an unbiased, mobile, and automated assessment tool is able to identify PD patients and characterize their motor impairment. It may serve as a complementary mean for the daily clinical workup and support therapeutic decisions throughout the course of the disease. © 2013 Klucken et al.
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Uncertainty-aware deep learning for trustworthy prediction of long-term outcome after endovascular thrombectomy - Martín Vicario, Celia; Rodriguez Salas, Dalia; Maier, Andreas; Hock, Stefan; Kuramatsu, Joji; Kallmünzer, Bernd; Thamm, Florian; Taubmann, Oliver; Ditt, Hendrik; Schwab, Stefan; Dörfler, Arnd; Mühlen, Iris (Scientific Reports, 2024)
Acute ischemic stroke (AIS) is a leading global cause of mortality and morbidity. Improving long-term outcome predictions after thrombectomy can enhance treatment quality by supporting clinical decision-making. With the advent of interpretable deep learning methods in recent years, it is now possible to develop trustworthy, high-performing prediction models. This study introduces an uncertainty-aware, graph deep learning model that predicts endovascular thrombectomy outcomes using clinical features and imaging biomarkers. The model targets long-term functional outcomes, defined by the three-month modified Rankin Score (mRS), and mortality rates. A sample of 220 AIS patients in the anterior circulation who underwent endovascular thrombectomy (EVT) was included, with 81 (37%) demonstrating good outcomes (mRS≤2). The performance of the different algorithms evaluated was comparable, with the maximum validation under the curve (AUC) reaching 0.87 using graph convolutional networks (GCN) for mRS prediction and 0.86 using fully connected networks (FCN) for mortality prediction. Moderate performance was obtained at admission (AUC of 0.76 using GCN), which improved to 0.84 post-thrombectomy and to 0.89 a day after stroke. Reliable uncertainty prediction of the model could be demonstrated.
CRIS-Team Scopus Importer:2024-05-17

Uncovering the role of Sox2 in oligodendroglia - Kuhbandner, Kristina (Journal of Neuroscience, 2018)
Created from Fastlane, Scopus look-up

Unique signatures of stress-induced senescent human astrocytes - Simmnacher, Katrin; Krach, Florian; Schneider, Yanni; Alecu, Julian E.; Mautner, Lena; Klein, Paulina; Roybon, Laurent; Prots, Iryna; Xiang, Wei; Winner, Beate (Experimental Neurology, 2020)
Senescence was recently linked to neurodegeneration and astrocytes are one of the major cell types to turn senescent under neurodegenerative conditions. Senescent astrocytes were detected in Parkinson's disease (PD) patients' brains besides reactive astrocytes, yet the difference between senescent and reactive astrocytes is unclear. We aimed to characterize senescent astrocytes in comparison to reactive astrocytes and investigate differences and similarities. In a cell culture model of human fetal astrocytes, we determined a unique senescent transcriptome distinct from reactive astrocytes, which comprises dysregulated pathways. Both, senescent and reactive human astrocytes activated a proinflammatory pattern. Astrocyte senescence was at least partially depending on active mechanistic-target-of-rapamycin (mTOR) and DNA-damage response signaling, both drivers of senescence. To further investigate how PD and senescence connect to each other, we asked if a PD-linked environmental factor induces senescence and if senescence impairs midbrain neurons. We could show that the PD-linked pesticide rotenone causes astrocyte senescence. We further delineate, that the senescent secretome exaggerates rotenone-induced neurodegeneration in midbrain neurons differentiated from human induced pluripotent stem cells (hiPSC) of PD patients with alpha-synuclein gene (SNCA) locus duplication.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Alpha synuclein; Astrocyte neuron interplay; iPSC derived neurons; Parkinson's disease; Reactive astrocyte; Rotenone; Senescence

Unmeasured Confounding in Observational Studies of Management of Cerebellar Intracranial Hemorrhage-Reply - Kuramatsu, Joji; Sheth, Kevin N.; Huttner, Hagen (Journal of the American Medical Association, 2020)
CRIS-Team Scopus Importer:2020-02-28

Unobtrusive Real-time Heart Rate Variability Analysis for the Detection of Orthostatic Dysregulation - Richer, Robert; Groh, Benjamin; Blank, Peter; Dorschky, Eva; Martindale, Christine; Klucken, Jochen; Eskofier, Björn (2016 IEEE 13th International Conference on Wearable and Implantable Body Sensor Networks (BSN), 2016)
The possibilities for wearable health care technology to improve the quality of life for chronic disease patients has been increasing within recent years. For instance, unobtrusive cardiac monitoring can be applied to people suffering from a disorder of the autonomic nervous system (ANS) which show a significantly lower heart rate variability (HRV) than healthy people. Although recent work presented solutions to analyze this relationship, they did not perform it during daily life situations. For that reason, this work presents a system for a real-time analysis of the user's HRV on an Android-based mobile device throughout the day. The system was used for the detection of an orthostatic dysregulation which can be an indicator for a disorder of the ANS. Measures for HRV analysis were computed from acquired ECG data and compared before and after a posture change. For triggering the HRV analysis, an IMU-based algorithm which detects stand up events was developed. As a proof of concept for an automatic assessment of an orthostatic dysregulation, a classification based on the derived HRV measures was performed. The performance of the stand up detection was evaluated in the first part of this study. The second part was conducted for the evaluation of the derived HRV measures and involved healthy subjects as well as patients with idiopathic Parkinson's Disease. The results of the evaluation showed a recognition rate of 90.0% for the stand up detection algorithm. Furthermore, a clear difference in the change of HRV measures between the two groups before and after standing up was observed. The classification provided an accuracy of 96.0%, and a sensitivity of 93.3%. The results demonstrated the possibility of unobtrusive HRV monitoring during daily life situations.

Unraveling progression subtypes in people with Huntington’s disease - Raschka, Tamara; Li, Zexin; Gaßner, Heiko; Kohl, Zacharias; Jukic, Jelena; Marxreiter, Franz; Fröhlich, Holger (EPMA Journal, 2024)
Background: Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a CAG trinucleotide expansion in the huntingtin gene. The length of the CAG repeat is inversely correlated with disease onset. HD is characterized by hyperkinetic movement disorder, psychiatric symptoms, and cognitive deficits, which greatly impact patient’s quality of life. Despite this clear genetic course, high variability of HD patients’ symptoms can be observed. Current clinical diagnosis of HD solely relies on the presence of motor signs, disregarding the other important aspects of the disease. By incorporating a broader approach that encompasses motor as well as non-motor aspects of HD, predictive, preventive, and personalized (3P) medicine can enhance diagnostic accuracy and improve patient care. Methods: Multisymptom disease trajectories of HD patients collected from the Enroll-HD study were first aligned on a common disease timescale to account for heterogeneity in disease symptom onset and diagnosis. Following this, the aligned disease trajectories were clustered using the previously published Variational Deep Embedding with Recurrence (VaDER) algorithm and resulting progression subtypes were clinically characterized. Lastly, an AI/ML model was learned to predict the progression subtype from only first visit data or with data from additional follow-up visits. Results: Results demonstrate two distinct subtypes, one large cluster (n = 7122) showing a relative stable disease progression and a second, smaller cluster (n = 411) showing a dramatically more progressive disease trajectory. Clinical characterization of the two subtypes correlates with CAG repeat length, as well as several neurobehavioral, psychiatric, and cognitive scores. In fact, cognitive impairment was found to be the major difference between the two subtypes. Additionally, a prognostic model shows the ability to predict HD subtypes from patients’ first visit only. Conclusion: In summary, this study aims towards the paradigm shift from reactive to preventive and personalized medicine by showing that non-motor symptoms are of vital importance for predicting and categorizing each patients’ disease progression pattern, as cognitive decline is oftentimes more reflective of HD progression than its motor aspects. Considering these aspects while counseling and therapy definition will personalize each individuals’ treatment. The ability to provide patients with an objective assessment of their disease progression and thus a perspective for their life with HD is the key to improving their quality of life. By conducting additional analysis on biological data from both subtypes, it is possible to gain a deeper understanding of these subtypes and uncover the underlying biological factors of the disease. This greatly aligns with the goal of shifting towards 3P medicine.
CRIS-Team Scopus Importer:2024-06-07
Keywords: Artificial intelligence; Cognition; Huntington’s disease; Non-motor symptoms; Patient stratification; Precision medicine; Predictive preventive personalized medicine; Progression

Unraveling the complexity of alpha-synucleinopathies: Insights from the special issue “alpha synuclein and synucleinopathies” - Xiang, Wei; Vicente Miranda, Hugo (Behavioural Brain Research, 2024)
CRIS-Team Scopus Importer:2024-01-19

Unsupervised harmonic frequency-based gait sequence detection for Parkinson’s disease - Ullrich, Martin; Hannink, Julius; Gaßner, Heiko; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI), 2019)
Sensor-based gait analysis is a valuable tool in diagnosis and assessment of Parkinson’s disease. Especially for large data sets, efficient analysis pipelines are required. Presegmentation of long time series into chunks of interest is a possible approach to increase efficiency. Therefore, we developed an unsupervised algorithm for the detection of gait sequences from continuous sensor signals. In the proposed method, gyroscope signals representing the angular rate of the feet are analyzed in the frequency domain using moving windows. A gait sequence was detected, if the frequency spectrum of a given window contained harmonic frequencies. The approach was tested on two data sets that differed in the ratio of clinical gait and cyclic movement tests. Sensitivity in both data sets was higher than 99% in a stride-to-stride comparison with ground truth. The specificity was measured with 76.1% (data set 1) and 94.5% (data set 2) for tests against sequences of other cyclic movements. In conclusion, the algorithm offers a reliable and efficient approach for the detection of gait sequences in time series data and is also promising for the application in long-term home-monitoring scenarios.<br
Keywords: gait analysis; inertial sensors; harmonics; Parkinson’s disease

Update: Muscle and Nerve Sonography - Schminke, Ulf; Allendoerfer, Jens; Grimm, Alexander; Kramer, Heidrun H.; Walter, Uwe (Klinische Neurophysiologie, 2021)
Die Sonografie von Nerven und Muskeln hat sich zu einem essenziellen Baustein der Diagnostik von Erkrankungen des peripheren Nervensystems und der Muskulatur entwickelt. Haufig gelingt eine umfassende Aufklarung einer Lasion erst durch die Kombination aus Kenntnissen uber eine elektrophysiologisch nachgewiesene gestorte Funktion des Nervs und uber sonografisch festgestellte morphologische Veranderungen des Nervs und des angrenzenden Gewebes.
CRIS-Team WoS Importer:2021-12-10

Upregulation of sicam-1 and svcam-1 levels in the cerebrospinal fluid of patients with schizophrenia spectrum disorders - Meixensberger, Sophie; Kuzior, Hanna; Fiebich, Bernd L.; Süß, Patrick; Runge, Kimon; Berger, Benjamin; Nickel, Kathrin; Denzel, Dominik; Schiele, Miriam A.; Michel, Maike; Maier, Simon; Bechter, Karl; et al. (Diagnostics, 2021)
Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age-and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), and PAI-1 (p < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indi-cate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Blood-brain barrier; Cerebrospinal fluid; Depression; ICAM-1; Neuroinflammation; Schizophrenia; VCAM-1

Usage of antiepileptic drugs in different diseases in Germany – A retrospective study - Scholten, Jerome; Hamer, Hajo; Kostev, Karel (Epilepsy & Behavior, 2020)
Aim: The goal of this study was to analyze and quantify the usage of antiepileptic drugs (AEDs) in different diseases and settings in Germany. Methods: This retrospective study, based on data from the Disease Analyzer database (IQVIA), included patients from 550 general practices (GP) and 73 neurological practices. Patients who had received at least one prescription for AED from one of these practices between January 2009 and December 2011 (time period 1, n = 39,434) or between January 2016 and December 2018 (time period 2, n = 49,128) were analyzed. Results: In patients who received AED prescriptions from neurologists, epilepsy (43%) was the most common diagnosis and did not change over time. The proportion of pain diagnoses slightly decreased from 35% in the period from 2009 to 2011 to 34% in the period from 2016 to 2018, while psychiatric disorders increased from 13% to 15%. In GPs, 58% of patients received their AED prescriptions for pain disorders, followed by epilepsy (29%) in the period from 2009 to 2011. The proportion of pain patients slightly increased to 60%, while that of patients with epilepsy slightly decreased to 27%. Conclusions: The main indications for which AEDs are prescribed vary with the type of medical practice. The different indications for different AEDs changed between the two time periods, which is in line with the state of the research.
CRIS-Team Scopus Importer:2020-06-23
Keywords: Antiepileptic drugs; Epilepsy; Pain; Psychiatric condition

Use of a German longitudinal prescription database (LRx) in pharmacoepidemiology - Richter, Hartmut; Dombrowski, Silvia; Hamer, Hajo; Hadji, Peyman; Kostev, Karel (GMS German Medical Science, 2015)
Large epidemiological databases are often used to examine matters pertaining to drug utilization, health services, and drug safety. The major strength of such databases is that they include large sample sizes, which allow precise estimates to be made. The IMS® LRx database has in recent years been used as a data source for epidemiological research. The aim of this paper is to review a number of recent studies published with the aid of this database and compare these with the results of similar studies using independent data published in the literature. In spite of being somewhat limited to studies for which comparative independent results were available, it was possible to include a wide range of possible uses of the LRx database in a variety of therapeutic fields: prevalence/incidence rate determination (diabetes, epilepsy), persistence analyses (diabetes, osteoporosis), use of comedication (diabetes), drug utilization (G-CSF market) and treatment costs (diabetes, G-CSF market). In general, the results of the LRx studies were found to be clearly in line with previously published reports. In some cases, noticeable discrepancies between the LRx results and the literature data were found (e.g. prevalence in epilepsy, persistence in osteoporosis) and these were discussed and possible reasons presented. Overall, it was concluded that the IMS® LRx database forms a suitable database for pharmacoepidemiological studies.
EVALuna2:22376

Use of a telestroke service for evaluation of non-stroke neurological cases - Handschu, Rene; Wacker, Angela; Scibor, Mateusz; Sancu, Camelia; Schwab, Stefan; Erbguth, Frank; Oschmann, Patrick; Stark, David Rianto; Marquardt, Lars (Journal of Neurology, 2015)
Telemedicine is a growing field in many medical specialties. Within clinical neurosciences one of its largest applications is in acute stroke care. However, little is known about its value and effect in general neurology, despite stroke. In a retrospective survey of 1500 teleconsultations over a time period of 12 months from October 2008 to September 2009, from a large telestroke network in Germany, we evaluated 352 cases with a non-stroke diagnosis. Duration and methods of teleconsultation as well as neurological consultations at bedside and discharge diagnosis were analyzed and compared to stroke cases. Discharge diagnosis was not identical to teleconsultation diagnosis in 48.9% of all non-stroke cases compared to 12.5% of all stroke cases. Duration of teleconsultation was 26.5 min in non-stroke cases compared to 14.3 min for stroke cases. In non-stroke cases other parts of the neurological examination were added to the pure administration of a stroke scale. There were no significant differences between non-stroke cases with correct and incorrect consultation diagnoses concerning in-hospital mortality (4.6 vs. 5.0%) and length of hospital stay (8.3 vs. 7.6 days). We conclude that diagnostic accuracy and protocol routine is not as exact in non-stroke cases compared to acute stroke cases. Other neurologic conditions may need different algorithms for a telemedicine service. Thus experience from a telestroke service cannot be transferred to other neurologic conditions on a routine basis.
EVALuna2:22364

Using wearable inertial sensors to compare different versions of the dual task paradigm during walking - Witchel, Harry J.; Needham, Robert; Healy, Aoife; Guppy, Joseph H.; Bush, Jake; Oberndorfer, Cäcilia; Herberz, Chantal; Westling, Carina E.I.; Kim, Dawit; Roggen, Daniel; Barth, Jens; Eskofier, Björn; et al. (ACM International Conference Proceeding Series, 2017)
The dual task paradigm (DTP), where performance of a walking task co-occurs with a cognitive task to assess performance decrement, has been controversially mooted as a more suitable task to test safety from falls in outdoor and urban environments than simple walking in a hospital corridor. There are a variety of different cognitive tasks that have been used in the DTP, and we wanted to assess the use of a secondary task that requires mental tracking (the alternate letter alphabet task) against a more automatic working memory task (counting backward by ones). In this study we validated the x-io x-IMU wearable inertial sensors, used them to record healthy walking, and then used dynamic time warping to assess the elements of the gait cycle. In the timed 25 foot walk (T25FW) the alternate letter alphabet task lengthened the stride time significantly compared to ordinary walking, while counting backward did not. We conclude that adding a mental tracking task in a DTP will elicit performance decrement in healthy volunteers.
CRIS-Team Scopus Importer:2023-03-07
Keywords: Accelerometer; Accelerometry; Ambulation; Ambulatory; Gyroscope; Inertial; MEMS; T25FW; X-io; XIMU; Xio

uTUG: An unsupervised Timed Up and Go test for Parkinson's disease - da Rosa Tavares, João Elison; Ullrich, Martin; Roth, Nils; Kluge, Felix; Eskofier, Björn; Gaßner, Heiko; Klucken, Jochen; Gladow, Till; Marxreiter, Franz; da Costa, Cristiano André; da Rosa Righi, Rodrigo; Victória Barbosa, Jorge Luis (Biomedical Signal Processing and Control, 2023)
Inertial measurement units (IMU) are used diagnostically in the movement analysis of Parkinson's disease (PD) patients, allowing an objective way to assess biomechanical motion and gait parameters. The Timed Up and Go (TUG) is a standardized clinical gait test widely used in the monitoring of patient fall risk and disease progression. Gait tests performed at home have been applied as part of movement monitoring protocols, enabling a link to clinical supervised reference assessments. However, unsupervised gait tests in a real-world data context present challenges, mainly regarding the interaction between participants and the recording system. Therefore, we developed and evaluated a novel algorithmic pipeline called unsupervised TUG (uTUG). Our contribution is the automatic detection and decomposition of TUG tests into their subphases, performed at home with no clinician supervision. In contrast to related studies, we used only foot-mounted IMU with no additional markers or manual annotations, allowing the detection of TUG test frames for subsequent classification by machine learning Support Vector Machine (SVM), Random Forest (RF) and Naïve Bayes Classifier (NBC) algorithms. The evaluation comprised 96 daily recordings of real-world gait data and 81 clinical visits accumulating 300 real TUG test samples processed from 32 PD patients. A prefiltering sensitivity of 98.6%, followed by the precision of 90.6%, recall of 88.5%, and Fl-score of 89.6% for TUG test detection were achieved using RF for the automatic classification in continuous real-world gait data. Thus, uTUG simplifies the test for patients and avoids manual annotations for clinicians, automatically detecting TUG tests.
CRIS-Team Scopus Importer:2022-12-09
Keywords: Gait analysis; Gait test; IMU; Machine learning; TUG; Wearable sensors

Vaccination after Allogenic Stem Cell Transplantation: Diminished Memory B Cell Response and High Number of Spontaneously IgG Secreting Plasmablasts - Tittlbach, Hannes; Schneider, Andrea; Buchstaller, Corinna; Mayr, Andreas; Vasova, Ingrid; Rösler, Wolf; Mackensen, Andreas; Mach, Michael; Winkler, Thomas; Winkler, Jürgen (BLOOD, 2018)
CRIS-Team WoS Importer:2019-02-27

Vagomimetic Fingolimod effects are compensated by central up-regulation of cardiovagal withdrawal upon rapid blood pressure decrease - Roy, Sankanika; Wang, Ruihao; de Rojas Leal, Carmen; Liu, Mao; Hoesl, K.; Lee, De-Hyung; Linker, Ralf; Hilz, Max-Josef (2018)
EVALuna2:201951

Validation of a sensor-based gait analysis system with a gold-standard motion capture system in patients with parkinson’s disease - Jakob, Verena; Küderle, Arne; Klucken, Jochen; Eskofier, Björn; Winkler, Jürgen; Winterholler, Martin; Gaßner, Heiko; Kluge, Felix (Sensors, 2021)
Digital technologies provide the opportunity to analyze gait patterns in patients with Par-kinson’s Disease using wearable sensors in clinical settings and a home environment. Confirming the technical validity of inertial sensors with a 3D motion capture system is a necessary step for the clinical application of sensor-based gait analysis. Therefore, the objective of this study was to com-pare gait parameters measured by a mobile sensor-based gait analysis system and a motion capture system as the gold standard. Gait parameters of 37 patients were compared between both systems after performing a standardized 5 × 10 m walking test by reliability analysis using intra-class correlation and Bland–Altman plots. Additionally, gait parameters of an age-matched healthy control group (n = 14) were compared to the Parkinson cohort. Gait parameters representing bradykinesia and short steps showed excellent reliability (ICC > 0.96). Shuffling gait parameters reached ICC > 0.82. In a stridewise synchronization, no differences were observed for gait speed, stride length, stride time, relative stance and swing time (p > 0.05). In contrast, heel strike, toe off and toe clearance significantly differed between both systems (p < 0.01). Both gait analysis systems distinguish Parkinson patients from controls. Our results indicate that wearable sensors generate valid gait parameters compared to the motion capture system and can consequently be used for clinically relevant gait recordings in flexible environments.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Inertial sensors; Machine learning algorithm; Parkinson’s disease; Spatiotemporal gait parameters; Three-dimensional gait analysis; Wearables

Validation of automatic MRI hippocampal subfield segmentation by histopathological evaluation in patients with temporal lobe epilepsy - Menzler, Katja; Hamer, Hajo; Mross, Peter; Rosenow, Felix; Deichmann, Ralf; Wagner, Marlies; Gracien, René Maxime; Dörfler, Arnd; Blümcke, Ingmar; Coras, Roland; Belke, Marcus; Knake, Susanne (Seizure-European Journal of Epilepsy, 2021)
Objective: The present study validates the results of automated hippocampal subfield segmentation with histopathology in epilepsy patients undergoing epilepsy surgery. Methods: We performed an automated hippocampal subfield segmentation on presurgical three-dimensional, T1-weighted magnetization Prepared Rapid Acquisition of Gradient Echoes Magnetic Resonance Imaging (MRI) data of 25 patients with unilateral mesial temporal lobe epilepsy due to hippocampal sclerosis (HS), using Freesurfer Version 6.0. The resulting volumes of cornu ammonis (CA) subfields CA1, CA2/3, CA4 and the dentate gyrus (DG) were compared to the histopathological cell count. Results: We found a significant correlation between histopathology in subregion CA2 and automated segmentation of subregion CA1 (p = 0.0062), CA2/3 (p = 0.004), CA4 (p = 0.0062) and the DG (p = 0.0054), between histopathology in CA3 and automated segmentation of CA1 (p = 0.0132), CA2/3 (p = 0.0004), CA4 (p = 0.0032) and the DG (p = 0.0037), as well as between histopathology in the DG and automated segmentation of CA1 (p = 0.0115), CA2/3 (p < 0.0001), CA4 (p < 0.0001) and the DG (p = 0.0001). The histopathological finding of HS type 1 could correctly be classified in all cases on MRI. Significance: The present study shows significant correlations between histopathological evaluation and results of the automated segmentation of the hippocampus, thereby validating the automated segmentation method. As the differential involvement of different hippocampal subfields may be associated with clinical parameters and the outcome after epilepsy surgery, the automated segmentation is also promising for prognostic purposes.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Automated segmentation; Hippocampal subfields; Mesiotemporal sclerosis; Mri

Validation of the Composite Autonomic Symptom Score 31 in the German language - Hilz, Max-Josef; Wang, Ruihao; Singer, Wolfgang (Neurological Sciences, 2021)
Background The Composite Autonomic Symptom Score 31 (COMPASS 31) is a validated, 31-item self-assessment questionnaire assessing autonomic symptoms in six domains, orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor function. So far, there is no validated German COMPASS 31 version. This study aimed at developing and validating a German COMPASS 31. Methods Two autonomic experts with command of German and English independently translated the English COMPASS 31 into German. One agreed-upon German version was translated back into English to assure conformity with the original version. Twenty patients with possible autonomic symptoms and 20 age- and gender-matched healthy persons completed the English and German COMPASS 31 in a randomized order with a 4-week interval. To evaluate reliability of the German COMPASS 31, total scores and sub-scores of the domains assessed with the German version were correlated with corresponding scores of the English version using Pearson's or Spearman's test. The Cronbach alpha-coefficient evaluated the internal consistency of the questions. Total- and sub-scores of both COMPASS 31 versions were compared between patients and controls by analysis of variance with post-hoc analysis (significance: p < 0.05). Results Total scores and sub-scores of the German and English COMPASS 31 correlated significantly (p < 0.001) and closely (correlation coefficients: 0.757-0.934). Cronbach alpha-coefficients were above 0.7 in all domains except for the secretomotor domain. In the German and English COMPASS 31, total scores were significantly higher in patients than controls. Conclusions The German COMPASS 31 is reliable, internally consistent, and valid to detect and quantify autonomic symptoms in patients with neurological disorders.
CRIS-Team WoS Importer:2021-12-03

Validity of an inertial sensor-based system for the assessment of spatio-temporal parameters in people with multiple sclerosis - Zahn, Annalena; Koch, Veronika; Schreff, Lucas; Oschmann, Patrick; Winkler, Jürgen; Gaßner, Heiko; Müller, Roy (Frontiers in Neurology, 2023)
Background: Gait variability in people with multiple sclerosis (PwMS) reflects disease progression or may be used to evaluate treatment response. To date, marker-based camera systems are considered as gold standard to analyze gait impairment in PwMS. These systems might provide reliable data but are limited to a restricted laboratory setting and require knowledge, time, and cost to correctly interpret gait parameters. Inertial mobile sensors might be a user-friendly, environment- and examiner-independent alternative. The purpose of this study was to evaluate the validity of an inertial sensor-based gait analysis system in PwMS compared to a marker-based camera system. Methods: A sample N = 39 PwMS and N = 19 healthy participants were requested to repeatedly walk a defined distance at three different self-selected walking speeds (normal, fast, slow). To measure spatio-temporal gait parameters (i.e., walking speed, stride time, stride length, the duration of the stance and swing phase as well as max toe clearance), an inertial sensor system as well as a marker-based camera system were used simultaneously. Results: All gait parameters highly correlated between both systems (r > 0.84) with low errors. No bias was detected for stride time. Stance time was marginally overestimated (bias = −0.02 ± 0.03 s) and gait speed (bias = 0.03 ± 0.05 m/s), swing time (bias = 0.02 ± 0.02 s), stride length (0.04 ± 0.06 m), and max toe clearance (bias = 1.88 ± 2.35 cm) were slightly underestimated by the inertial sensors. Discussion: The inertial sensor-based system captured appropriately all examined gait parameters in comparison to a gold standard marker-based camera system. Stride time presented an excellent agreement. Furthermore, stride length and velocity presented also low errors. Whereas for stance and swing time, marginally worse results were observed.
CRIS-Team Scopus Importer:2023-05-19
Keywords: different walking speeds; gait-parameter; multiple sclerosis (MS); three-dimensional gait analysis; walking human; wearable sensors

Valsalva maneuver unveils central baroreflex dysfunction with altered blood pressure control in persons with a history of mild traumatic brain injury - Hilz, Max-Josef; Liu, Mao; Koehn, Julia; Wang, Ruihao; Ammon, Fabian; Flanagan, Steven R.; Hoesl, Katharina M. (BMC Neurology, 2016)
Patients with a history of mild TBI (post-mTBI-patients) have an unexplained increase in long-term mortality which might be related to central autonomic dysregulation (CAD). We investigated whether standardized baroreflex-loading, induced by a Valsalva maneuver (VM), unveils CAD in otherwise healthy post-mTBI-patients.In 29 healthy persons (31.3 ± 12.2 years; 9 women) and 25 post-mTBI-patients (35.0 ± 13.2 years, 7 women, 4-98 months post-injury), we monitored respiration (RESP), RR-intervals (RRI) and systolic blood pressure (BP) at rest and during three VMs. At rest, we calculated parameters of total autonomic modulation [RRI-coefficient-of-variation (CV), RRI-standard-deviation (RRI-SD), RRI-total-powers], of sympathetic [RRI-low-frequency-powers (LF), BP-LF-powers] and parasympathetic modulation [square-root-of-mean-squared-differences-of-successive-RRIs (RMSSD), RRI-high-frequency-powers (HF)], the index of sympatho-vagal balance (RRI LF/HF-ratios), and baroreflex sensitivity (BRS). We calculated Valsalva-ratios (VR) and times from lowest to highest RRIs after strain (VR-time) as indices of parasympathetic activation, intervals from highest systolic BP-values after strain-release to the time when systolic BP had fallen by 90 % of the differences between peak-phase-IV-BP and baseline-BP (90 %-BP-normalization-times), and velocities of BP-normalization (90 %-BP-normalization-velocities) as indices of sympathetic withdrawal. We compared patient- and control-parameters before and during VM (Mann-Whitney-U-tests or t-tests; significance: P < 0.05).At rest, RRI-CVs, RRI-SDs, RRI-total-powers, RRI-LF-powers, BP-LF-powers, RRI-RMSSDs, RRI-HF-powers, and BRS were lower in patients than controls. During VMs, 90 %-BP-normalization-times were longer, and 90 %-BP-normalization-velocities were lower in patients than controls (P < 0.05).Reduced autonomic modulation at rest and delayed BP-decrease after VM-induced baroreflex-loading indicate subtle CAD with altered baroreflex adjustment to challenge. More severe autonomic challenge might trigger more prominent cardiovascular dysregulation and thus contribute to increased mortality risk in post-mTBI-patients.
EVALuna2:22445

Value of Flat-detector Computed Tomography Angiography with Intravenous Contrast Media Injection in the Evaluation and Treatment of Acutely Ruptured Aneurysms of the AcomA complex: A Single Center Experience in 15 Cases - Rösch, Julie; Lang, Stefan; Gölitz, Philipp; Kallmünzer, Bernd; Roessler, Karl; Dörfler, Arnd; Struffert, Tobias (Clinical Neuroradiology, 2018)
Objective To illustrate the added value of flat-detector computed tomography angiography with intravenous contrast media injection (intravenous FDCTA) in the evaluation of complex A1/A2/AcomA aneurysms. Patients and Methods We retrospectively reviewed 15patients with ruptured aneurysms. In each patient, an intravenous FDCTA was performed and its diagnostic value investigated. Results In all patients, FDCTA contributed relevant additional information concerning the anatomy of the A1/A2/AcomA complex and the relationship of the aneurysm neck to these vascular structures, which could not be gained by 2D- and 3D-DSA, and changed the management in 33% of the patients (5 out of 15). In an additional 5cases, knowledge of the detailed anatomy was helpful to plan the exact stent position. Conclusion In case of complex A1/A2/AcomA aneurysms, intravenous FDCTA is an effective option to visualize the exact location of the aneurysm neck and the relationship between the aneurysm and the adjacent vessels. Thus, it is of significant added value in the precise planning of atherapeutic strategy.
EVALuna2:34934

Value of initial C-reactive protein levels in status epilepticus outcome prediction - Madzar, Dominik; Reindl, Caroline; Mrochen, Anne; Hamer, Hajo; Huttner, Hagen (Epilepsia, 2021)
The role of neuroinflammation in the pathophysiology of seizures is increasingly recognized, and the evaluation of potential biochemical markers of inflammatory processes in seizures and status epilepticus (SE), such as C-reactive protein (CRP), has gained attention. The present study assessed the first CRP level obtained in an SE episode regarding its value for SE outcome prediction. Among 362 admissions for SE during the study period, 231 episodes satisfied the inclusion criteria. Higher initial CRP concentrations were independently associated with in-hospital mortality and poor functional outcome at discharge in logistic regression models adjusting for SE severity, severity of SE etiology, and development of treatment refractoriness. Therefore, initial CRP levels may add to the prediction of SE prognosis. The pathomechanisms through which CRP is linked with the prognosis of SE, however, remain to be established.
CRIS-Team Scopus Importer:2021-03-05
Keywords: acute phase proteins; C-reactive protein; inflammation; laboratory parameters; outcome; status epilepticus

Vanilla-stimulation suggests subtle central autonomic dysfunction in patients with a history of mild traumatic brain injury - Liu, Mao; Roy, Sankanika; Wang, Ruihao; de Rojas Leal, Carmen; Hoesl, K.; Hummel, T.; Hilz, M. J. (2017)
EVALuna2:22571

Variation of membrane particle–bound CD133 in cerebrospinal fluid of patients with subarachnoid and intracerebral hemorrhage - Bobinger, Tobias; Röder, Sebastian; Sprügel, Maximilian; Fröhlich, Kilian; Beuscher, Vanessa; Hölter, Philip; Lücking, Hannes; Corbeil, Denis; Huttner, Hagen (Journal of Neurosurgery, 2021)
OBJECTIVE Previous studies have demonstrated that human CSF contains membrane particles carrying the stem cell antigenic marker CD133 (prominin-1). Here, the authors analyzed the variation of the amount of these CD133-positive particles in the CSF of patients with subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). METHODS Consecutive CSF samples from 47 patients with SAH or ICH were compared to 14 healthy control patients. After differential ultracentrifugation of CSF, the membrane particle fraction was separated on gel electrophoresis and its CD133 content was probed by immunoblotting using the mouse monoclonal antibody 80B258 directed against human CD133. The antigen-antibody complexes were detected by chemiluminescence reagents and quantified using human Caco-2 cell extract as positive control with a standardized curve. RESULTS As compared to healthy controls (6.3 ± 0.5 ng of bound CD133 antibody; n = 14), the amount of membrane particle–associated CD133 immunoreactivities was significantly elevated in patients with SAH and ICH (38.2 ± 6.6 ng and 61.3 ± 11.0 ng [p < 0.001] for SAH [n = 18] and ICH [n = 29], respectively). In both groups the CD133 level dropped during the first 7 days (i.e., day 5–7: SAH group, 24.6 ± 10.1 ng [p = 0.06]; ICH group, 25.0 ± 4.8 ng [p = 0.002]). Whereas changes in the amount of CD133-positive membrane particles between admission and day 5–7 were not associated with clinical outcomes in patients with ICH (modified Rankin Scale [mRS] scores 0–3, −30.9 ± 12.8 ng vs mRS scores 4–6, −21.8 ± 10.7 ng; p = 0.239), persistent elevation of CD133 in patients with SAH was related to impaired functional outcome 3 months after ictus (mRS scores 0–2, −29.9 ± 8.1 ng vs mRS scores 3–6, 7.6 ± 20.3 ng; p = 0.027). These data are expressed as the mean ± standard error of the mean (SEM). CONCLUSIONS Levels of membrane particle–associated CD133 in the CSF of patients with SAH and ICH are significantly increased in comparison to healthy patients, and they decline during the hospital stay. Specifically, the persistent elevation of CD133-positive membrane particles within the first week may represent a possible surrogate measure for impaired functional outcome in patients with SAH.
CRIS-Team Scopus Importer:2021-04-09
Keywords: CD133; Intracerebral hemorrhage; Membrane particles; Prominin-1; Stem cells; Subarachnoid hemorrhage; Vascular disorders

Varicella Zoster Virus-Specific Hyperimmunoglobulin in the Adjuvant Treatment of Immunocompromised Herpes Zoster Patients: A Case Series - Terheyden, Patrick; Sunderkötter, Cord; Söhngen, Franz Dietmar; Golle, Linda; Schimo, Sonja; Baron, Ralf; Maihöfner, Christian; Binder, Andreas; Pönisch, Wolfram (Dermatology and Therapy, 2023)
Introduction: Immunocompromised patients are at increased risk for herpes zoster (HZ)-associated complications. Despite standard therapy with systemic antiviral drugs and analgesics, complications are frequently encountered, including generalization of lesions or persistent neuropathic pain, so-called post-herpetic neuralgia (PHN). Given the scarcity of literature and awareness of therapeutic options to improve patient outcomes, especially for vulnerable patient groups, here we describe a strategy based on early intensification of treatment with a varicella zoster virus-specific hyperimmunoglobulin (VZV-IgG), which is approved in the adjuvant treatment of HZ. Methods: For this case series, we selected four cases of HZ in patients with impaired immunity due to hemato-oncologic disease or immunosuppressive treatment who presented with either existing generalized lesions and/or severe pain or with other risk factors for a complicated HZ course such as PHN. They were considered to be representative examples of different patient profiles eligible for intensification of treatment by the addition of VZV-IgG to virostatic therapy. Case Report: All patients showed a rapid response to combined treatment with VZV-IgG and a virostatic agent. In two patients who had generalized lesions, the formation of new lesions ceased 1 day after VZV-IgG infusion. One patient, with mantle cell lymphoma, achieved complete healing of the lesions 9 days after diagnosis of HZ, a rare occurrence compared to similar cases or cohorts. A patient with HZ in the cervical region showed a good response after a single dose of VZV-IgG. None of the patients developed post-zoster-related complications. Combination therapy of a virostatic agent and VZV-IgG was well tolerated in these four cases. Conclusion: This case series demonstrates highly satisfactory treatment effectiveness and tolerability for VZV-IgG in the adjuvant treatment of immunocompromised HZ patients and supports early intensification of HZ therapy in patients at high risk of severe disease progression.
CRIS-Team Scopus Importer:2023-09-22
Keywords: Generalized lesions; Herpes zoster; Hyperimmunoglobulin; Immunocompromised; Varitect CP; VZV; VZV-IgG

Vascular Parkinson's Disease (= Parkinsonism in vascular Encephalopathy) - Marxreiter, Franz; Winkler, Jürgen (Fortschritte der Neurologie - Psychiatrie, 2016)
Parkinsonism may result from cerebral vascular disorders that feature white matter lesions and small vessel pathology. Vascular Parkinsonism typically presents as lower body Parkinsonism with predominant gait impairment. Urinary incontinence and cognitive decline are additional features of the disease. There is a considerable overlap between vascular Parkinsonism and vascular dementia. We review the clinical characteristics of vascular Parkinsonism and discuss the current treatment approaches, as well as the role of brain imaging for the diagnostic workup.
EVALuna2:33518
Keywords: vascular parkinsonism; vascular dementia; subcortical arteriosclerotic encephalopathy (SAE); lower body parkinsonism; frontal lobe gait

Vasospasm in intracerebral hemorrhage with ventricular involvement: a prospective pilot transcranial Doppler sonography study - Kiphuth, Ines C.; Huttner, Hagen; Breuer, Lorenz; Engelhorn, Tobias; Schwab, Stefan; Köhrmann, Martin (Cerebrovascular Diseases, 2011)
Cerebral vasospasm (VSP) is a common complication after subarachnoid hemorrhage (SAH), but has rarely been reported after intracerebral hemorrhage (ICH) without subarachnoidal bleeding. The underlying pathophysiological mechanism is mainly mediated by circulating heme products within the cerebrospinal fluid, and thus patients with ICH and ventricular involvement (IVH) may also be in danger of developing VSP. The incidence and role of VSP in IVH, however, have not been systematically studied.We prospectively enrolled 115 patients with ICH with or without IVH into the study between April 2009 and April 2010. All patients received serial extracranial and transcranial Doppler sonography (TCD) at baseline, on days 3-5 and 7-9 to detect and monitor VSP. In addition, CT scans taken on admission, after 24 h and before discharge were evaluated for the occurrence of delayed cerebral ischemia.Three out of 53 patients (5.7%) with IVH showed a significant elevation of flow velocities over the examined timeframe. One of these patients developed severe VSP resulting in secondary ischemic infarction. None of the ICH patients without IVH showed significantly elevated flow velocities or secondary infarction.Cerebral VSP with secondary infarction may occur in patients with spontaneous IVH, though far less frequently than in SAH; thus, systematic screening of all patients with IVH may not be warranted. However, serial TCD should be considered in patients with secondary clinical worsening or extensive IVH.
EVALuna2:21961

VCP-related multisystem proteinopathy presenting as early-onset Parkinson disease - Regensburger, Martin; Türk, Matthias; Pagenstecher, Axel; Schröder, Rolf; Winkler, Jürgen (Neurology, 2017)
EVALuna2:7395

Versorgung von Parkinson-Patienten in Deutschland: Status quo und Perspektiven im Spiegel des digitalen Wandels - Eggers, Carsten; Wellach, Ingmar; Groppa, Sergiu; Strothjohann, Martin; Klucken, Jochen (Der Nervenarzt, 2020)
As a chronic neurodegenerative disease, Parkinson’s disease requires a close cooperation between different specialist disciplines in order to ensure the best possible quality of life for patients. A problem that has been identified is the inadequate communication between the protagonists (e.g. caregivers, physicians and therapists), especially at the sectoral interfaces. Due to structural hurdles, the current process and supply chains for Parkinson’s disease do not reflect successful cross-sectoral care. Against the background of the new Digital Care Act in Germany that refunds patient-centered digital healthcare applications (DiGA), innovative, digital care and communication structures can now be established and thus comprehensively revolutionize the care of chronic diseases, such as Parkinson’s disease. In this review examples and case application scenarios are presented and critically discussed.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Digital health; Digital health application; Integrated care; Networks; Telemedicine

Violations of Weber's law tell us more about methodological challenges in sensorimotor research than about the neural correlates of visual behaviour - Schenk, Thomas; Utz, Kathrin S.; Hesse, Constanze (Vision research, 2017)
The violation of Weber's law in grasping has been presented as evidence for the claim that grasping is guided by visual information which is distinct from the information used in perceptual tasks. Previously, we contested this claim and argued that biomechanical constraints of the hand might explain why Weber's law cannot be reliably uncovered in grasping movements. In a recent article Manzone and colleagues (2017) show that pantomime grasping follows Weber's law even with objects whose width is close to the hand's biomechanical limit. In this commentary we explain why the biomechanical account does not necessarily predict the violation of Weber's law in a pantomime grasping task and why it seems problematic to use adherence or violation of Weber's law as a criterion to assign tasks to different anatomical pathways.
EVALuna2:35712

"Virtual stent" - clinical evaluation and user experience of on-the-fly stent simulation in treatment of cerebral aneurysms - Lücking, Hannes; Birkhold, Annette; Hölter, Philip; Lang, Stefan; Gölitz, Philipp; Schmidt, Manuel; Mrochen, Anne; Brandner, Sebastian; Dörfler, Arnd (Interventional Neuroradiology, 2021)
Background Predicting final stent position can be challenging when treating cerebral aneurysms. Third-Party software proved helpful in selecting proper stents in treatment planning. Recent angiographic systems provide basic stent simulation capabilities integrated in the post-processing software to simulate stent position. Goal of this analysis was to evaluate the simulation process and correlation with definite stent position. Materials and Methods Thirty-three datasets with fusiform (n = 10) and saccular (n = 23) aneurysms, treated with stent or flow-diverter, were processed. A "virtual stent" of the same (nominal) size was simulated and its position was compared to the treatment result. Simulated length was rated in five grades (too short, shorter, equal, longer, too long), with regard to side-branches, anchoring zone etc. Simulation quality (centerline recognition/adherence to vessel margins) was rated in three grades (no, minor or major corrections required). Results Simulation was successful in 32/33 cases (97%), with one abortive attempt (3%). In 27/33 simulations (82%), there was no need for centerline refinement. Minor corrections were necessary in four and major corrections in two cases. Simulated nominal length was rated "equal" in 14/33 (42%) cases and "shorter" or "longer" - but within acceptable range - in each 9/33 (27%) cases. Conclusion Basic stent simulation tools available with genuine angiographic workplace software can provide good simulation capabilities without need for third-party equipment. They can facilitate treatment planning and help to avoid shortage of devices. Yet, lack of calculation of foreshortening in large vessel diameters leaves the user to rely on their experience to account for device-specific properties.
CRIS-Team WoS Importer:2021-11-12

Visual and semiautomated evaluation of epileptogenicity in focal cortical dysplasias - An intracranial EEG study - Gollwitzer, Stephanie; Valente, Ivan; Rodionov, Roman; Scott, Catherine; Ritter, Laura Mantoan; Wehner, Tim; Hamer, Hajo; Bartolomei, Fabrice; Diehl, Beate (Epilepsy and Behavior, 2016)
The aim of the study was the evaluation of the added value of depth to subdural electrodes in delineating epileptogenicity of focal cortical dysplasias (FCDs) and to test the Epileptogenicity Index (EI) in this setting.Fifteen patients with FCD underwent iEEG with subdural and depth electrodes. Visual/EI analysis was performed in up to three habitual seizures per patient.Visual analysis: Grid onset seizures (n=10) started in electrodes overlying the lesion in 7 and remote from it in 3 cases. Depth onset seizures (n=7) affected only intralesional contacts in 4, intra- and extralesional in 2, and exclusively extralesional in 1 patient. Seizures started in depth and grid contacts simultaneously in 2 cases. EI analysis: The EI completely confirmed visual localization of seizure onset in 8 cases and depicted ictal onset-time accurately in 13. Beta/gamma ictal patterns were most reliably captured. Impact on surgical decision: Resection outline differed from MRI lesion in 7 patients based on grid and in three based on depth electrode information.In FCD, seizures can be generated within gyral/deep tissue appearing normal on imaging.Investigating FCD with subdural and depth electrodes is efficient to outline the seizure onset zone. The EI is a helpful additional tool to quantify epileptogenicity. Specific ictal patterns are prerequisite for reliable results.
EVALuna2:22453

Visual feedback explains why propointing is better than antipointing in spatial neglect - Utz, Kathrin S.; Hesse, Constanze; Hintz, Annika; Grüneberger, Daniela; Kulke, Hartwig; Roth, Inga; Klos, Thomas; Kromichal, Vaclav; Melms, Arthur; Schupp, Wilfried; Kohl, Detlef; Schenk, Thomas (Cortex, 2017)
Rossit et al. (2011) showed that neglect patients perform normally in a propointing task but not in an antipointing task which requires pointing towards the mirrored position of a target. It is assumed that antipointing relies on information from the perceptual pathway of our visual brain. Therefore, this finding supports the notion that neglect is a disorder that primarily affects perceptual spatial representations within the brain leaving spatial maps used for visuomotor guidance intact. Alternatively, performance of patients might be compromised in both tasks, but only obviously so in tasks in which online corrections are made more difficult. It can be argued that online-corrections via visual feedback are less effective in antipointing because a direct comparison between hand and target is not possible in this condition. Secondly, it is also known that neglect patients have a pronounced egocentric bias which is assumed to be associated with a deviation of the perceived body midline. Since the midline is used to compute the end-position in the antipointing task this could also explain why patients are worse in antipointing. We investigated the influence of visual feedback on pro- and antipointing and the effect of providing a visual reference line for the antipointing task in right-brain damaged patients with neglect (n = 20), right-brain damaged patients without neglect (n = 23) and in a group of healthy participants (n = 22). The withdrawal of visual feedback had a stronger effect on propointing compared to antipointing. This effect was stronger in neglect patients than in patients without neglect or healthy controls. The introduction of a reference line reduced errors in antipointing performance, particularly in neglect patients with a strong egocentric bias. The results support our alternative account and challenge the hypothesis that the spatial disorder in neglect affects primarily perceptual maps within the visual system.
EVALuna2:22443

Visualization of large vessel occlusion, clot extent, and collateral supply using volume perfusion flat detector computed tomography in acute stroke patients - Gölitz, Philipp; Lang, Stefan; Lücking, Hannes; Kalmuenzer, Bernd; Struffert, Tobias; Dörfler, Arnd; Hölter, Philip (Acta Radiologica, 2019)
Background: Flat detector computed tomography angiography (FDCTA) can be reconstructed from volume perfusion flat detector computed tomography (VP-FDCT). Thus, CTA equivalent stroke imaging might be feasible within the angio suite. Purpose: To evaluate the diagnostic accuracy of FDCTA in detecting large vessel occlusion (LVO) and collateral supply in acute stroke patients. Material and Methods: Sixteen patients with LVO of the anterior circulation were analyzed retrospectively. Each patient underwent a multimodal CT stroke protocol, subsequent VP-FDCT, and digital subtraction angiography (DSA) for endovascular stroke therapy. Angiographic images reconstructed secondarily from VP-FDCT were evaluated with regard to visualization of LVO, Collateral Score (CS), Clot Burden Score (CBS), and image quality. Results: Image quality of FDCTA was sufficient for diagnosis with a strong correlation between CTA and FDCTA (median score: CTA = 4 ± 0.447; FDCTA = 4 ± 0.5). Detection of LVO could be achieved with high sensitivity and specificity for FDCTA and CTA (97.9%, 95% confidence interval [CI] = 96.0–99.9; 92.6%, 95% CI = 84.3–100.0 vs. 96.8%, 95% CI = 93.2–100.0; 86.3%, 95% CI = 88.2–95.2). CBS and CS assessment showed no significant difference between FDCTA and CTA for both readers (reader1 CBS : P = 0.751, reader1 CS : P = 0.718; reader2 CBS : P = 0.164; reader2 CS : P = 0.582) and an excellent interrater agreement (CTA CBS ICC = 0.984, FDCTA CBS ICC = 0.951; CTA CS ICC = 0.754, FDCTA CS ICC = 0.789). Conclusion: FDCTA, reconstructed from VP-FDCT data, allows reliable detection of ICA or MCA M1 segment occlusion comparable to CTA and may provide information concerning the clot extent with sufficient image quality.
CRIS-Team Scopus Importer:2019-10-11
Keywords: Central nervous system; flat detector computed tomography; interventional; stroke

Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo - Bittel, Miriam; Reichert, Patrick; Sarfati, Ilann; Dressel, Anja; Leikam, Stefanie; Uderhardt, Stefan; Stolzer, Iris; Phu, Tuan Anh; Ng, Martin; Vu, Ngan K.; Tenzer, Stefan; Distler, Ute; et al. (Journal of Extracellular Vesicles, 2021)
The intestinal microbiota influences mammalian host physiology in health and disease locally in the gut but also in organs devoid of direct contact with bacteria such as the liver and brain. Extracellular vesicles (EVs) or outer membrane vesicles (OMVs) released by microbes are increasingly recognized for their potential role as biological shuttle systems for inter-kingdom communication. However, physiologically relevant evidence for the transfer of functional biomolecules from the intestinal microbiota to individual host cells by OMVs in vivo is scarce. By introducing Escherichia coli engineered to express Cre-recombinase (E. coliCre) into mice with a Rosa26.tdTomato-reporter background, we leveraged the Cre-LoxP system to report the transfer of bacterial OMVs to recipient cells in vivo. Colonizing the intestine of these mice with E. coliCre, resulted in Cre-recombinase induced fluorescent reporter gene-expression in cells along the intestinal epithelium, including intestinal stem cells as well as mucosal immune cells such as macrophages. Furthermore, even far beyond the gut, bacterial-derived Cre induced extended marker gene expression in a wide range of host tissues, including the heart, liver, kidney, spleen, and brain. Together, our findings provide a method and proof of principle that OMVs can serve as a biological shuttle system for the horizontal transfer of functional biomolecules between bacteria and mammalian host cells.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Cre-Loxp; extracellular vesicles; inflammation; intestinal stem cells; microbiome; outer membrane vesicles

Visual search as a tool for a quick and reliable assessment of cognitive functions in patients with multiple sclerosis - Utz, Kathrin S.; Hankeln, Thomas; Jung, Lena; Laemmer, Alexandra; Waschbisch, Anne; Lee, De-Hyung; Linker, Ralf; Schenk, Thomas (PLoS ONE, 2013)
Despite the high frequency of cognitive impairment in multiple sclerosis, its assessment has not gained entrance into clinical routine yet, due to lack of time-saving and suitable tests for patients with multiple sclerosis.The aim of the study was to compare the paradigm of visual search with neuropsychological standard tests, in order to identify the test that discriminates best between patients with multiple sclerosis and healthy individuals concerning cognitive functions, without being susceptible to practice effects.Patients with relapsing remitting multiple sclerosis (n = 38) and age-and gender-matched healthy individuals (n = 40) were tested with common neuropsychological tests and a computer-based visual search task, whereby a target stimulus has to be detected amongst distracting stimuli on a touch screen. Twenty-eight of the healthy individuals were re-tested in order to determine potential practice effects.Mean reaction time reflecting visual attention and movement time indicating motor execution in the visual search task discriminated best between healthy individuals and patients with multiple sclerosis, without practice effects.Visual search is a promising instrument for the assessment of cognitive functions and potentially cognitive changes in patients with multiple sclerosis thanks to its good discriminatory power and insusceptibility to practice effects.
EVALuna2:22182

Voxel-wise lesion mapping of restless legs syndrome in multiple sclerosis - Fröhlich, Kilian; Knott, Michael; Hock, Stefan; Dörfler, Arnd; Seifert, Frank; Winder, Klemens (Neurological Sciences, 2022)
Objective Restless legs syndrome (RLS) is known to be associated with multiple sclerosis (MS) and may be caused by MS lesions in specific cerebral brain regions. Applying a voxel-wise lesion analysis, we tried to identify the contribution of cerebral MS lesions to RLS. Methods In this retrospective study, we established a cohort of people with MS with documented RLS and controls of people with MS without RLS matched disease severity. Diagnosis of MS and RLS was based on the current guidelines. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3 T). After manual delineation, lesion maps were converted into stereotaxic space. We generated a lesion overlap and performed a Liebermeister test with 4000 permutations to compare the absence or presence of RLS voxel-wise between patients with and without lesions in a given voxel. Results Forty of the patients with RLS and MS fulfilled the inclusion criteria. The voxel-wise analysis yielded associations between RLS and MS in the subcortex of the left gyrus precentralis. Conclusion Our voxel-wise analysis shows associations in the subcortex of the left gyrus precentralis. Thus, our data suggests that a dysfunction of the efferent motor system due to cerebral lesions may contribute to the pathophysiology of RLS in MS.
CRIS-Team WoS Importer:2022-05-20

Voxel-wise lesion mapping of self-reported urinary incontinence in multiple sclerosis - Fröhlich, Katharina; Wang, Ruihao; Bobinger, Tobias; Schmidt, Manuel; Dörfler, Arnd; Nickel, Franziska; Hilz, Max-Josef; Lee, De-Hyung; Linker, Ralf A.; Seifert, Frank; Winder, Klemens (Neurourology and Urodynamics, 2019)
Aims Besides spinal lesions, urinary incontinence may be attributed to particular cerebral lesion sites in multiple sclerosis (MS) patients. We intended to determine the contribution of suprapontine lesions to urinary incontinence in MS using a voxel-wise lesion analysis. Methods In this retrospective study, we sought MS patients with documented urinary incontinence in a local database. We established a control group of MS-patients without documented urinary incontinence matched for gender, age, and disease severity. Patients with urinary incontinence due to local diseases of the urinary tract were excluded. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3T). After manual delineation and transformation into stereotaxic space, we determined the lesion overlap and compared the presence or absence of urinary incontinence voxel-wise between patients with and without lesions in a given voxel performing the Liebermeister test with 4000 permutations. Results A total of 56 patients with urinary incontinence and MS fulfilled the criteria and were included. The analysis yielded associations between urinary incontinence and MS in the frontal white matter, temporo-occipital, and parahippocampal regions. Conclusions Our voxel-wise analysis indicated associations between self-reported urinary incontinence and lesions in the left frontal white matter and right parahippocampal region. Thus, our data suggest that dysfunction of supraspinal bladder control due to cerebral lesions may contribute to the pathophysiology of urinary incontinence in MS.
CRIS-Team WoS Importer:2019-11-12

WADA test for postoperative memory prediction in left TLE. Is it still useful in the 21st century? - Bruzsa, Ann Kathrin; Walther, Katrin; Kasper, Burkhard; Gollwitzer, Stefanie; Hamer, Hajo; Schwarz, Michael (Clinical Neurology and Neurosurgery, 2023)
Background: Epilepsy surgery offers an effective treatment to achieve seizure freedom in refractory temporal lobe epilepsy. Since left temporal lobe surgery can be associated with verbal memory deterioration, control of cognitive decline is a main goal of therapy. This study analyzes the prognostic value of intracarotid amobarbital procedure (Wada test) in addition to specific neuropsychological and clinical variables for postoperative memory changes. Method: Between 2013 and 2021 thirty-six patients (18 females, 18 males, mean age 41.0 years) from the Epilepsy Center Erlangen (ECE) with left hemispheric temporal lobe epilepsy underwent neuropsychological assessment preoperatively – including the Wada test – and six months postoperatively. In addition, a group of 92 patients (40 females, 52 males, mean age 36.1 years) with left or right hemispheric focus who underwent Wada test and surgery before 2013 was included as a standardization group. In all patients Wada test was carried out preoperatively to determine language dominance and memory capacity. Results: Postoperative verbal memory scores showed no significant difference from preoperative performance. Preoperative verbal memory performance as well as the hippocampal resection extent is particularly important in predicting postoperative verbal memory change. After left temporal lobe surgery, a significantly higher postoperative functional level was shown for figural memory. Specifically, a good contralateral hemispheric performance level assessed by the Wada test proved to be a compensatory factor for postoperative losses. Conclusion: The Wada test is no longer necessary as a diagnostic tool for a broad group of patients with temporal lobe epilepsy. However, it can be useful for a subgroup of patients with clinical indicators such as nonspecific or incongruent preoperative verbal and figural memory impairments. In this study, Wada test data about the functional level of the contralateral hemisphere specifically allowed estimation of postoperative figural memory changes.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Epilepsy surgery; Memory changes; Temporal lobe epilepsy; Wada test

Walking on common ground: a cross-disciplinary scoping review on the clinical utility of digital mobility outcomes - Polhemus, Ashley; Ortiz, Laura Delgado; Brittain, Gavin; Chynkiamis, Nikolaos; Salis, Francesca; Gaßner, Heiko; Gross, Michaela; Kirk, Cameron; Rossanigo, Rachele; Taraldsen, Kristin; Balta, Diletta; Breuls, Sofie; et al. (npj Digital Medicine, 2021)
Physical mobility is essential to health, and patients often rate it as a high-priority clinical outcome. Digital mobility outcomes (DMOs), such as real-world gait speed or step count, show promise as clinical measures in many medical conditions. However, current research is nascent and fragmented by discipline. This scoping review maps existing evidence on the clinical utility of DMOs, identifying commonalities across traditional disciplinary divides. In November 2019, 11 databases were searched for records investigating the validity and responsiveness of 34 DMOs in four diverse medical conditions (Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, hip fracture). Searches yielded 19,672 unique records. After screening, 855 records representing 775 studies were included and charted in systematic maps. Studies frequently investigated gait speed (70.4% of studies), step length (30.7%), cadence (21.4%), and daily step count (20.7%). They studied differences between healthy and pathological gait (36.4%), associations between DMOs and clinical measures (48.8%) or outcomes (4.3%), and responsiveness to interventions (26.8%). Gait speed, step length, cadence, step time and step count exhibited consistent evidence of validity and responsiveness in multiple conditions, although the evidence was inconsistent or lacking for other DMOs. If DMOs are to be adopted as mainstream tools, further work is needed to establish their predictive validity, responsiveness, and ecological validity. Cross-disciplinary efforts to align methodology and validate DMOs may facilitate their adoption into clinical practice.
CRIS-Team WoS Importer:2021-10-29

Walking-related digital mobility outcomes as clinical trial endpoint measures: protocol for a scoping review - Polhemus, Ashley Marie; Bergquist, Ronny; Bosch de Basea, Magda; Brittain, Gavin; Buttery, Sara Catherine; Chynkiamis, Nikolaos; Dalla Costa, Gloria; Delgado Ortiz, Laura; Demeyer, Heleen; Emmert, Kirsten; Garcia Aymerich, Judith; Gaßner, Heiko; et al. (BMJ Open, 2020)
INTRODUCTION: Advances in wearable sensor technology now enable frequent, objective monitoring of real-world walking. Walking-related digital mobility outcomes (DMOs), such as real-world walking speed, have the potential to be more sensitive to mobility changes than traditional clinical assessments. However, it is not yet clear which DMOs are most suitable for formal validation. In this review, we will explore the evidence on discriminant ability, construct validity, prognostic value and responsiveness of walking-related DMOs in four disease areas: Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease and proximal femoral fracture. METHODS AND ANALYSIS: Arksey and O'Malley's methodological framework for scoping reviews will guide study conduct. We will search seven databases (Medline, CINAHL, Scopus, Web of Science, EMBASE, IEEE Digital Library and Cochrane Library) and grey literature for studies which (1) measure differences in DMOs between healthy and pathological walking, (2) assess relationships between DMOs and traditional clinical measures, (3) assess the prognostic value of DMOs and (4) use DMOs as endpoints in interventional clinical trials. Two reviewers will screen each abstract and full-text manuscript according to predefined eligibility criteria. We will then chart extracted data, map the literature, perform a narrative synthesis and identify gaps. ETHICS AND DISSEMINATION: As this review is limited to publicly available materials, it does not require ethical approval. This work is part of Mobilise-D, an Innovative Medicines Initiative Joint Undertaking which aims to deliver, validate and obtain regulatory approval for DMOs. Results will be shared with the scientific community and general public in cooperation with the Mobilise-D communication team. REGISTRATION: Study materials and updates will be made available through the Center for Open Science's OSFRegistry (https://osf.io/k7395).
CRIS-Team Scopus Importer:2020-07-31
Keywords: chronic airways disease; geriatric medicine; multiple sclerosis; orthopaedic & trauma surgery; Parkinson-s disease; telemedicine

Weaning and extubation failure in myasthenic crisis: a multicenter analysis - Neumann, Bernhard; Angstwurm, Klemens; Dohmen, Christian; Mergenthaler, Philipp; Kohler, Siegfried; Schönenberger, Silvia; Lee, De Hyung; Gerner, Stefan; Huttner, Hagen; Thieme, Andrea; Steinbrecher, Andreas; Dunkel, Juliane; et al. (Journal of Neurology, 2023)
Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.
CRIS-Team Scopus Importer:2023-12-01
Keywords: Extubation failure; Myasthenia gravis; Myasthenic crisis; Weaning failure

Wearables als unterstützendes Tool für den Paradigmenwechsel in der Versorgung von Parkinson Patienten - Thun-Hohenstein, Caroline; Klucken, Jochen (Klinische Neurophysiologie, 2021)
Wearables are portable sensors that are suitable for collecting data on functional disturbances in patients with Parkinson's disease and are used for prevention, prediction, diagnosis and therapy. In research applications, they increase the reliability of the collected data and represent better study endpoints than traditional subjective and non-quantitative ratings and self-report scales. In this study, we examine motor symptoms such as tremor, bradykinesia and gait disturbances as well as non-motor symptoms. Home diagnostics can be used to examine the patient's condition in real life, monitor therapy, improve adherence, and check compliance. Additionally, wearables can be used in interventions such as cueing, gamification or coaching in order to improve symptoms. Transfer from laboratory conditions to everyday life at home is a medical-technical challenge, optimized care models have to be developed and the actual benefit for the individual patient needs to be demonstrated in further studies.
CRIS-Team Scopus Importer:2021-03-19
Keywords: care effect; gait analysis; Parkinson's disease; value-based medicine; wearables

Wearable sensor-based objective assessment of motor symptoms in Parkinson's disease - Ossig, Christiana; Antonini, Angelo; Buhmann, Carsten; Classen, Joseph; Csoti, Ilona; Falkenburger, Bjoern; Schwarz, Michael; Winkler, Jürgen; Storch, Alexander (Journal of Neural Transmission, 2016)
Effective management and development of new treatment strategies of motor symptoms in Parkinson's disease (PD) largely depend on clinical rating instruments like the Unified PD rating scale (UPDRS) and the modified abnormal involuntary movement scale (mAIMS). Regarding inter-rater variability and continuous monitoring, clinical rating scales have various limitations. Patient-administered questionnaires such as the PD home diary to assess motor stages and fluctuations in late-stage PD are frequently used in clinical routine and as clinical trial endpoints, but diary/questionnaire are tiring, and recall bias impacts on data quality, particularly in patients with cognitive dysfunction or depression. Consequently, there is a strong need for continuous and objective monitoring of motor symptoms in PD for improving therapeutic regimen and for usage in clinical trials. Recent advances in battery technology, movement sensors such as gyroscopes, accelerometers and information technology boosted the field of objective measurement of movement in everyday life and medicine using wearable sensors allowing continuous (long-term) monitoring. This systematic review summarizes the current wearable sensor-based devices to objectively assess the various motor symptoms of PD.
EVALuna2:33524

Wearable sensors objectively measure gait parameters in Parkinson's disease - Schlachetzki, Johannes; Barth, Jens; Marxreiter, Franz; Goßler, Julia; Kohl, Zacharias; Reinfelder, Samuel; Gaßner, Heiko; Aminian, Kamiar; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen (PLoS ONE, 2017)
Distinct gait characteristics like short steps and shuffling gait are prototypical signs commonly observed in Parkinson's disease. Routinely assessed by observation through clinicians, gait is rated as part of categorical clinical scores. There is an increasing need to provide quantitative measurements of gait, e.g. to provide detailed information about disease progression. Recently, we developed a wearable sensor-based gait analysis system as diagnostic tool that objectively assesses gait parameter in Parkinson's disease without the need of having a specialized gait laboratory. This system consists of inertial sensor units attached laterally to both shoes. The computed target of measures are spatiotemporal gait parameters including stride length and time, stance phase time, heel-strike and toe-off angle, toe clearance, and inter-stride variation from gait sequences. To translate this prototype into medical care, we conducted a cross-sectional study including 190 Parkinson's disease patients and 101 age-matched controls and measured gait characteristics during a 4x10 meter walk at the subjects' preferred speed. To determine intraindividual changes in gait, we monitored the gait characteristics of 63 patients longitudinally. Cross-sectional analysis revealed distinct spatiotemporal gait parameter differences reflecting typical Parkinson's disease gait characteristics including short steps, shuffling gait, and postural instability specific for different disease stages and levels of motor impairment. The longitudinal analysis revealed that gait parameters were sensitive to changes by mirroring the progressive nature of Parkinson's disease and corresponded to physician ratings. Taken together, we successfully show that wearable sensor-based gait analysis reaches clinical applicability providing a high biomechanical resolution for gait impairment in Parkinson's disease. These data demonstrate the feasibility and applicability of objective wearable sensor-based gait measurement in Parkinson's disease reaching high technological readiness levels for both, large scale clinical studies and individual patient care.
EVALuna2:33508

Wearable sensors provide objective gait parameters correlating to clinical scores in Parkinson’s disease - Gaßner, Heiko; Schlachetzki, Johannes; Marxreiter, Franz; Kohl, Zacharias; Barth, Jens; Goßler, Julia; Reinfelder, Samuel; Pasluosta, Cristian Federico; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen (89th Congress of the Deutschen Gesellschaft für Neurologie mit Fortbildungsakademie (DGN), 2016)

„Wearables“ in der Behandlung neurologischer Erkrankungen – wo stehen wir heute? - Klucken, Jochen; Gladow, Till; Hilgert, Johannes G.; Stamminger, Marc; Weigand, Christian; Eskofier, Björn (Der Nervenarzt, 2019)
Fitness and lifestyle trackers raise the awareness for wearable sensors in medical applications for clinical trials and healthcare. Various functional impairments of patients with neurological diseases are an ideal target to generate wearable-derived and patient-centered parameters that have the potential to support prevention, prediction, diagnostic procedures and therapy monitoring during the clinical work-up; however, substantial differences between clinical grade wearables and fitness trackers have to be acknowledged. For the application in clinical trials or individualized patient care distinct technical and clinical validation trials have to be conducted. The different test environments under laboratory conditions during standardized tests or under unsupervised home monitoring conditions have to be included in the algorithmic processing of sensor raw data in order to enable a clinical decision support under real-life conditions. This article presents the general understanding of the technical application for the most relevant functional impairments in neurology. While wearables used for sleep assessment have already reached a high level of technological readiness due to the defined test environment (bed, sleep), other wearable applications, e.g. for gait and mobility during home monitoring require further research in order to transfer the technical capabilities into real-life patient care.
CRIS-Team Scopus Importer:2019-07-23
Keywords: Big Data; Gait analysis; Home-monitoring; Mobile sensors; Movement disorder

Wearable Static Posturography Solution Using a Novel Pressure Sensor Sole - Reinfelder, Samuel; Durlak, Felix; Barth, Jens; Klucken, Jochen; Eskofier, Björn (Engineering in Medicine and Biology Society (EMBC), 2014 36th Annual International Conference of the IEEE, 2014)
UnivIS-Import:2015-04-16:Pub.2014.tech.IMMD.IMMD5.wearab

Western lifestyle and immunopathology of multiple sclerosis - Matveeva, Olga; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.; Linker, Ralf; Haghikia, Aiden; Kleinewietfeld, Markus (Annals of the New York Academy of Sciences, 2018)
There is increasing evidence for a sudden and unprecedented rise in the incidence of multiple sclerosis (MS) in Westernized countries over the past decades, emphasizing the role of environmental factors. Among many candidates, rapid changes in dietary habits seem to play a role in the pathogenesis of MS. Here, we summarize and discuss the available evidence for the role of dietary nutrients, such as table salt, fatty acids, and flavonoids, in the development and pathogenesis of MS. We also discuss new and emerging risk factors accompanying Western lifestyle, such as shift work, sleep, and circadian disruption.
EVALuna2:207129

What is the hemodynamic effect of the Woven EndoBridge? An in vivo quantification using time-density curve analysis - Gölitz, Philipp; Lücking, Hannes; Hölter, Philip; Knossalla, Frauke; Dörfler, Arnd (Neuroradiology, 2020)
Purpose: Using the Woven EndoBridge (WEB) for aneurysm treatment has emerged as endovascular approach aiming for flow disruption in aneurysm sac. Since quantifiable data confirming the hemodynamic effect are lacking, we investigated in vivo aneurysmal flow alterations using time-density curve (TDC) analysis. Additionally, we evaluated whether flow parameters could be identified as independent factor to predict aneurysm occlusion. Methods: Forty cerebral aneurysm patients treated with WEB were enrolled. Pre- and postinterventional digital subtraction angiography series were postprocessed and TDCs generated. TDCs were quantified calculating the parameters aneurysmal inflow velocity, outflow velocity, mean flow velocity, and relative time-to-peak (rTTP) of aneurysm filling. Pre- and postinterventional values were compared and related to occlusion rate. Results: WEB implanting induced highly significant rTTP prolongation by 52% (p = 0.001) and highly significant decrease of aneurysmal inflow, outflow, and mean flow velocity (p < 0.001). While outflow velocity was reduced by 49%, inflow velocity was reduced by 33% only. No statistically significant difference between the occluded and the non-occluded group was observed. No flow parameter reached significance level concerning predicting aneurysm occlusion. Conclusion: Flow quantification confirms a significant flow-disrupting effect of WEB reducing more the outflow than the inflow velocity. In our small cohort, no flow parameter reached statistical significance to show predictive value regarding complete aneurysm occlusion. The hemodynamic effect of WEB is on comparable level to flow-diverting stents meaning that aneurysm closure can be delayed. In case of only slight inflow changes and high aneurysmal hemodynamic stress, some aneurysms might not be adequately protected in the short term.
CRIS-Team Scopus Importer:2020-03-27
Keywords: Aneurysm; Digital subtraction angiography; Hemodynamics; Image postprocessing; Intrasaccular flow diverter; Time-density curve

What's new in multiple sclerosis spasticity research? Poster session highlights - Linker, Ralf (Neurodegenerative Disease Management, 2017)
Each year at the Multiple Sclerosis Experts Summit, relevant research in the field of multiple sclerosis spasticity is featured in poster sessions. The main studies presented at this year's meeting are summarized herein.
EVALuna2:36316

Which Comprehensive Geriatric Assessment (CGA) instruments are currently used in Germany: a survey - Kudelka, Jennifer; Ollenschläger, Malte; Dodel, Richard; Eskofier, Björn; Hobert, Markus A.; Jahn, Klaus; Klucken, Jochen; Labeit, Bendix; Polidori, M. Cristina; Prell, Tino; Warnecke, Tobias; von Arnim, Christine A.F.; et al. (BMC Geriatrics, 2024)
Background: The Comprehensive Geriatric Assessment (CGA) records geriatric syndromes in a standardized manner, allowing individualized treatment tailored to the patient’s needs and resources. Its use has shown a beneficial effect on the functional outcome and survival of geriatric patients. A recently published German S1 guideline for level 2 CGA provides recommendations for the use of a broad variety of different assessment instruments for each geriatric syndrome. However, the actual use of assessment instruments in routine geriatric clinical practice and its consistency with the guideline and the current state of literature has not been investigated to date. Methods: An online survey was developed by an expert group of geriatricians and sent to all licenced geriatricians (n = 569) within Germany. The survey included the following geriatric syndromes: motor function and self-help capability, cognition, depression, pain, dysphagia and nutrition, social status and comorbidity, pressure ulcers, language and speech, delirium, and frailty. Respondents were asked to report which geriatric assessment instruments are used to assess the respective syndromes. Results: A total of 122 clinicians participated in the survey (response rate: 21%); after data cleaning, 76 data sets remained for analysis. All participants regularly used assessment instruments in the following categories: motor function, self-help capability, cognition, depression, and pain. The most frequently used instruments in these categories were the Timed Up and Go (TUG), the Barthel Index (BI), the Mini Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Visual Analogue Scale (VAS). Limited or heterogenous assessments are used in the following categories: delirium, frailty and social status. Conclusions: Our results show that the assessment of motor function, self-help capability, cognition, depression, pain, and dysphagia and nutrition is consistent with the recommendations of the S1 guideline for level 2 CGA. Instruments recommended for more frequent use include the Short Physical Performance Battery (SPPB), the Montreal Cognitive Assessment (MoCA), and the WHO-5 (depression). There is a particular need for standardized assessment of delirium, frailty and social status. The harmonization of assessment instruments throughout geriatric departments shall enable more effective treatment and prevention of age-related diseases and syndromes.
CRIS-Team Scopus Importer:2024-04-26
Keywords: Activities of daily living; CGA; Cognition; Comorbidities; Comprehensive geriatric assessment; Delirium; Depression; Dysphagia; Frailty; Self-help capability

Which kinds of fasciculations are missed by ultrasonography in ALS? - Regensburger, Martin (Clinical Neurophysiology, 2019)
CRIS-Team Scopus Importer:2019-12-03

Why Does It Shine?-A Prognostic Analysis about Predisposing Factors for Blood-Brain Barrier Damage after Revascularisation of Cerebral Large-Vessel Occlusion. - Knott, Michael; Hock, Stefan; Soder, Liam; Mühlen, Iris; Kremer, Svenja; Sprügel, Maximilian; Sembill, Jochen; Kuramatsu, Joji; Schwab, Stefan; Engelhorn, Tobias; Dörfler, Arnd (Journal of Cardiovascular Development and Disease, 2023)
BACKGROUND: Hyperdense lesions in CT after EVT of LVO are common. These lesions are predictors for haemorrhages and an equivalent of the final infarct. The aim of this study based on FDCT was the evaluation of predisposing factors for these lesions. METHODS: Using a local database, 474 patients with mTICI ≥ 2B after EVT were recruited retrospectively. A postinterventional FDCT after recanalisation was analysed regarding such hyperdense lesions. This was correlated with a variety of items (demographics, past medical history, stroke assessment/treatment and short-/long-term follow-up). RESULTS: Significant differences were present in NHISS at admission, regarding time window, ASPECTS in initial NECT, location of the LVO, CT-perfusion (penumbra, mismatch ratio), haemostatic parameters (INR, aPTT), duration of EVT, number of EVT attempts, TICI, affected brain region, volume of demarcation and FDCT-ASPECTS. The ICH-rate, the volume of demarcation in follow-up NECT and the mRS at 90 days differed in association with these hyperdensities. INR, the location of demarcation, the volume of demarcation and the FDCT-ASPECTS could be demonstrated as independent factors for the development of such lesions. CONCLUSION: Our results support the prognostic value of hyperdense lesions after EVT. We identified the volume of the lesion, the affection of grey matter and the plasmatic coagulation system as independent factors for the development of such lesions.
EVALuna2:536989

Why systematic literature reviews in Fabry disease should include all published evidence - Elliott, Perry M.; Germain, Dominique P.; Hilz, Max-Josef; Spada, Marco; Wanner, Christoph; Falissard, Bruno (European Journal of Medical Genetics, 2019)
Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.
CRIS-Team Scopus Importer:2019-07-19
Keywords: Enzyme replacement therapy; Fabry disease; Systematic literature review

Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann – Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation - Gerschel, Tanita; Prokop, Scally; Schulze, Lara; Feige, Tim; Zschieschang, Anja; Barbe, Michael Thomas; Bitterlich, Robert; Caffier, Julian; Csoti, Ilona; Eggers, Carsten; Gaßner, Heiko; Gülke, Eileen; et al. (Der Nervenarzt, 2024)
Background: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson’s disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson’s disease with skills to manage the disease better and to participate in shared decision making. Material and methods: To prepare the implementation of a concept for patient education for people with Parkinson’s disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. Results: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6–8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. Discussion: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.
CRIS-Team Scopus Importer:2024-06-21
Keywords: Chronic disease; Expert panel; Patient participation; Quality management; Self-management education

Woman with sudden-onset speech difficulties. - To, Vi Tuong Daniel; Marterstock, Dominique; Madžar, Dominik (Journal of the American College of Emergency Physicians Open, 2023)
EVALuna2:540367

Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study) - Kretschmer, Julian Reza; Tkachenko, Daria; Kümpfel, Tania; Havla, Joachim; Engels, Daniel; Paul, Friedemann; Schindler, Patrick; Bellmann-Strobl, Judith; Berthele, Achim; Giglhuber, Katrin; Zappe, Clarissa; Klotz, Luisa; et al. (Frontiers in Immunology, 2025)
Objective: This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD. Methods: This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes. Results: Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81–3.84). Interpretation: LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.
CRIS-Team Scopus Importer:2025-05-16
Keywords: aging; immunoscenecence; late onset; myelitis; NMOSD = neuromyelitis optica spectrum disorder

yEFIS with EFIS Lead the Way to ECR Engagement at ECI2024 - Pallett, Mitchell A.; Benešová, Iva; Masanetz, Rebecca Katharina; van Gool, Melissa M.J.; Diefenbach-Wilke, Marie Louise; Hausmann, Annika; Nabhan, Myriam (European Journal of Immunology, 2025)
CRIS-Team Scopus Importer:2025-04-18
Keywords: career; conference; EFIS; symposium

Young human alpha synuclein transgenic (BAC-SNCA) mice display sex- and gene-dose-dependent phenotypic disturbances - Moceri, Sandra; Bäuerle, Natascha; Habermeyer, Johanna; Ratz-Wirsching, Veronika; Harrer, Julia; Distler, Jörg; Schulze-Krebs, Anja; Timotius, Ivanna K.; Bluhm, Alexandra; Hartlage-Rübsamen, Maike; Roßner, Steffen; Winkler, Jürgen; et al. (Behavioural Brain Research, 2024)
Parkinson's disease (PD) is a common neurodegenerative movement disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of aggregated alpha synuclein (aSyn). The disease often presents with early prodromal non-motor symptoms and later motor symptoms. Diagnosing PD based purely on motor symptoms is often too late for successful intervention, as a significant neuronal loss has already occurred. Furthermore, the lower prevalence of PD in females is not well understood, highlighting the need for a better understanding of the interaction between sex and aSyn, the crucial protein for PD pathogenesis. Here, we conducted a comprehensive phenotyping study in 1- to 5-month-old mice overexpressing human aSyn gene (SNCA) in a bacterial artificial chromosome (BAC-SNCA). We demonstrate a SNCA gene-dose-dependent increase of human aSyn and phosphorylated aSyn, as well as a decrease in tyrosine hydroxylase expression in BAC-SNCA mice, with more pronounced effects in male mice. Phosphorylated aSyn was already found in the dorsal motor nucleus of the vagus nerve of 2-month-old mice. This was time-wise associated with significant gait altrations in BAC-SNCA mice as early as 1 and 3 months of age using CatWalk gait analysis. Furthermore, anxiety-related behavioral tests revealed an increase in anxiety levels in male BAC-SNCA mice. Finally, 5-month-old male BAC-SNCA mice exhibited a SNCA gene-dose-dependent elevation in energy expenditure in automated home-cage monitoring. For the first time, these findings describe early-onset, sex- and gene-dose-dependent, aSyn-mediated disturbances in BAC-SNCA mice, providing a model for sex-differences, early-onset neuropathology, and prodromal symptoms of PD.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Alpha synuclein; Behavioral phenotyping; Gait analysis; Parkinson's disease; Sex difference; SNCA gene-dose

Zooming in on Cryopreservation of hiPSCs and Neural Derivatives: A Dual-Center Study Using Adherent Vitrification - Kaindl, Johanna; Meiser, Ina; Majer, Julia; Sommer, Annika; Krach, Florian; Katsen-Globa, Alisa; Winkler, Jürgen; Zimmermann, Heiko; Neubauer, Julia C.; Winner, Beate (Stem Cells Translational Medicine, 2019)
Human induced pluripotent stem cells (hiPSCs) are an important tool for research and regenerative medicine, but their efficient cryopreservation remains a major challenge. The current gold standard is slow-rate freezing of dissociated colonies in suspension, but low recovery rates limit immediate post-thawing applicability. We tested whether ultrafast cooling by adherent vitrification improves post-thawing survival in a selection of hiPSCs and small molecule neural precursor cells (smNPCs) from Parkinson's disease and controls. In a dual-center study, we compared the results by immunocytochemistry (ICC), fluorescence-activated cell sorting analysis, and RNA-sequencing (RNA-seq). Adherent vitrification was achieved in the so-called TWIST substrate, a device combining cultivation, vitrification, storage, and post-thawing cultivation. Adherent vitrification resulted in preserved confluency and significantly higher cell numbers, and viability at day 1 after thawing, while results were not significantly different at day 4 after thawing. RNA-seq and ICC of hiPSCs revealed no change in gene expression and pluripotency markers, indicating that physical damage of slow-rate freezing disrupts cellular membranes. Scanning electron microscopy showed preserved colony integrity by adherent vitrification. Experiments using smNPCs demonstrated that adherent vitrification is also applicable to neural derivatives of hiPSCs. Our data suggest that, compared to the state-of-the-art slow-rate freezing in suspension, adherent vitrification is an improved cryopreservation technique for hiPSCs and derivatives. Stem Cells Translational Medicine 2019;8:247&259.
EVALuna2:36383

α-Synuclein deficiency promotes neuroinflammation by increasing Th1 cell-mediated immune responses - Ettle, Benjamin; Kuhbandner, Kristina; Joerg, Stefanie; Hoffmann, Alana; Winkler, Jürgen; Linker, Ralf (Journal of Neuroinflammation, 2016)
Increased ?-synuclein immunoreactivity has been associated with inflammatory activity in multiple sclerosis (MS) lesions, but the function of ?-synuclein in neuroinflammation remains unknown. The aim of this study was to examine the role of ?-synuclein in immunological processes in murine experimental autoimmune encephalomyelitis (EAE) as a model of MS.We studied EAE in wildtype (aSyn(+/+)) and ?-synuclein knockout (aSyn(-/-)) mice on a C57BL/6N background. In the spleen and spinal cord of aSyn(+/+) mice, we observed a gradual reduction of ?-synuclein expression during EAE, starting already in the pre-symptomatic disease phase. Compared to aSyn(+/+) mice, aSyn(-/-) mice showed an earlier onset of symptoms but no differences in symptom severity at the peak of disease. Earlier symptom onset was accompanied by increased spinal cord infiltration of CD4(+) T cells, predominantly of interferon-?-producing T helper 1 (Th1) cells, and reduced infiltration of regulatory T cells, whereas antigen-presenting cells were unaltered. Pre-symptomatically, aSyn(-/-) mice exhibited hyperproliferative CD4(+) splenocytes consistent with increased splenic interleukin-2 mRNA expression, resulting in increased numbers of Th1 cells in the spleen at the onset of symptoms.Our findings indicate a functional role of ?-synuclein in early EAE by increasing Th1 cell-mediated immune response.
EVALuna2:22458

α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. - Winner, Beate; May, Verena Elisabeth Luise; Ettle, Benjamin; Pöhler, Anne-Maria; Nuber, Silke; Ubhi, Kiren; Rockenstein, Edward; Wegner, Michael; Masliah, Eliezer; Winkler, Jürgen (Neurobiology of Aging, 2014)
Multiple system atrophy (MSA), an atypical parkinsonian disorder, is characterized by α-synuclein (α-syn(+)) cytoplasmatic inclusions in mature oligodendrocytes. Oligodendrocyte progenitor cells (OPCs) represent a distinct cell population with the potential to replace dysfunctional oligodendrocytes. However, the role of OPCs in MSA and their potential to replace mature oligodendrocytes is still unclear. A postmortem analysis in MSA patients revealed α-syn within OPCs and an increased number of striatal OPCs. In an MSA mouse model, an age-dependent increase of dividing OPCs within the striatum and the cortex was detected. Despite of myelin loss, there was no reduction of mature oligodendrocytes in the corpus callosum or the striatum. Dissecting the underlying molecular mechanisms an oligodendroglial cell line expressing human α-syn revealed that α-syn delays OPC maturation by severely downregulating myelin-gene regulatory factor and myelin basic protein. Brain-derived neurotrophic factor was reduced in MSA models and its in vitro supplementation partially restored the phenotype. Taken together, efficacious induction of OPC maturation may open the window to restore glial and neuronal function in MSA.

α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. - Desplats, Paula; Spencer, Brian; Crews, Leslie; Pathel, Pruthul; Morvinski-Friedmann, Dinorah; Kosberg, Kori; Roberts, Scott; Patrick, Christina; Winner, Beate; Winkler, Jürgen; Masliah, Eliezer (Journal of Biological Chemistry, 2012)
Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that α-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that α-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for α-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.

α-Synuclein in Parkinson’s disease: causal or bystander? - Riederer, Peter; Berg, Daniela; Casadei, Nicolas; Cheng, Fubo; Classen, Joseph; Dresel, Christian; Jost, Wolfgang; Krüger, Rejko; Müller, Thomas; Reichmann, Heinz; Rieß, Olaf; Storch, Alexander; et al. (Journal of Neural Transmission, 2019)
Parkinson’s disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.
CRIS-Team Scopus Importer:2019-07-09
Keywords: Autophagy; Gene expression; Lysosome; Neuroinflammation; Neuromelanin; Parkinson’s disease; Proteasome; Protein interactions; SNCA gene; Synucleinopathy; Therapy; α-Synuclein

α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies - Prots, Iryna; Grosch, Janina; Brazdis, Razvan-Marius; Simmnacher, Katrin; Veber, Vanesa; Havlicek, Steven; Hannappel, Christian; Krach, Florian; Krumbiegel, Mandy; Schuetz, Oliver; Reis, André; Wrasidlo, Wolfgang; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2018)
α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson's disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.
EVALuna2:34623
Keywords: alpha-synuclein; oligomers; axonal transport; synucleinopathies; neurodegeneration

α-Synuclein Seed Amplification Assays from Blood-Based Extracellular Vesicles in Parkinson's Disease: An Evaluation of the Evidence - Bernhardt, Alexander Maximilian; Nemati, Mojtaba; Boros, Fanni Annamaria; Hopfner, Franziska; Levin, Johannes; Mollenhauer, Brit; Winkler, Jürgen; Zerr, Inga; Zunke, Friederike; Höglinger, Günter (Movement Disorders, 2024)
CRIS-Team Scopus Importer:2024-07-19

β-Secretase BACE1 Is Required for Normal Cochlear Function - Dierich, Marlen; Hartmann, Stephanie; Dietrich, Nadine; Möser, Philip; Brede, Franziska; Johnson Chacko, Lejo; Tziridis, Konstantin; Schilling, Achim; Krauß, Patrick; Heßler, Sabine; Karch, Sandra; Schrott-Fischer, Anneliese; et al. (The Journal of Neuroscience, 2019)
Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1-/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1-/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1-/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1-/- mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype.SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Alzheimer's disease; auditory function; BACE1; BACE1 inhibitor NB-360; BACE1 knock-out mice; Neuregulin-1

Acupuncture-induced differentiation of stem cells into neuron-like cells in patients with spinal cord injuries - Wu, Mingyuan; Moldenhauer, Sonja; Dütsch, Matthias; Scheffel, Thomas; Hellweg, Rainer; Holloschi, Andreas; Abel, Frank Rainer; Han, Wei; Moldenhauer, Anja (Acupuncture in Medicine, 2019)
EVALuna2:206753

Acute ischemic stroke, atrial fibrillation and early DOAC-treatment: 30-day risk of recurrent ischemic stroke, intracranial hemorrhage in a multi-centre individual patient data meta-analysis - De Marchis, G. M.; Seiffge, D.; Schaedelin, S.; Wilson, D.; Caso, V.; Acciarresi, M.; Tsivgoulis, G.; Koga, M.; Yoshimura, S.; Toyoda, K.; Cappellari, M.; Bonetti, B.; et al. (EUROPEAN JOURNAL OF NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-07-30

Akute und chronische Bewusstseinsstörungen bei schwerer Gehirnschädigung - Erbguth, Frank (Zeitschrift für Palliativmedizin, 2019)
CRIS-Team WoS Importer:2019-09-20

Autonomic dysfunction in hereditary sensory and autonomic neuropathies and Fabry disease - Hilz, Max-Josef (2018)
EVALuna2:201953

Benefit-risk Assessment of Cladribine Using Multi-criteria Decision Analysis (MCDA) for Patients With Relapsing-remitting Multiple Sclerosis - Vermersch, Patrick; Martinelli, Vittorio; Pfleger, Claudia; Rieckmann, Peter; Alonso-Magdalena, Lucia; Galazka, Andrew; Dangond, Fernando; Phillips, Lawrence (Clinical Therapeutics, 2019)
Purpose: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit-risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS).
CRIS-Team WoS Importer:2019-04-04

Choroid plexus-derived miR-204 regulates the number of quiescent neural stem cells in the adult brain - Lepko, Tjasa; Pusch, Melanie; Mueller, Tamara; Schulte, Dorothea; Ehses, Janina; Kiebler, Michael; Hasler, Julia; Huttner, Hagen; Vandenbroucke, Roosmarijn E.; Vandendriessche, Charysse; Modic, Miha; Martin-Villalba, Ana; et al. (EMBO Journal, 2019)
Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post-transcriptional control mechanism, centered around the microRNA 204 (miR-204), to control the maintenance of quiescent (q)NSCs. miR-204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR-204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre-mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche-specific miRNA repressing activation and differentiation of stem cells.
CRIS-Team WoS Importer:2019-08-02

Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-ER): design and methodology of a multinational phase 3 trial - Schellinger, Peter D.; Alexandrov, Andrei V.; Barreto, Andrew D.; Demchuk, Andrew M.; Tsivgoulis, Georgios; Köhrmann, Martin; Alleman, John; Howard, Virginia; Howard, George; Alexandrov, Anne W.; Brandt, Gordon; Molina, Carlos A. (International Journal of Stroke, 2015)
We designed a Phase 3 clinical trial to determine the safety and efficacy of adding transcranial ultrasound using an operator-independent headframe to recombinant tissue-plasminogen-activator for the treatment of acute ischemic stroke.Combined lysis of thrombus with ultrasound and systemic tissue-plasminogen-activator for emergent revascularization in acute ischemic stroke is a randomized, double-blind, placebo-controlled clinical trial that will enroll subjects with the following main inclusion criteria: less than 4·5 hours from symptom onset (three-hours in US and Canada), age 18-80 years, baseline National Institutes of Health Stroke Scale score >= 10, and premorbid modified-Rankin-score of 0-1, eligibility for full dose recombinant tissue-plasminogen-activator. Subjects will receive two-hours of 2-MHz pulsed wave transcranial ultrasound (target group) or sham ultrasound (control group). The projected sample size is approximately 824 subjects.The primary endpoint, based on intention-to-treat criteria of patients enrolled within three-hours of symptom onset is the comparison between target and control groups of modified-Rankin-score scores at day 90 poststroke assessed using the proportional odds method. The study will have two planned interim analyses after approximately one-third and two-thirds of subjects have reached the 90-day modified-Rankin-score evaluation. Safety outcomes are symptomatic intracranial hemorrhage within 24 h and an overall analysis of adverse events.Since intravenous recombinant tissue-plasminogen-activator remains the only medical therapy to reverse ischemic stroke applicable in the emergency department, our trial will determine if the additional use of transcranial ultrasound improves functional outcomes in patients with severe acute ischemic stroke (NCT#01098981).
EVALuna2:22372

Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis - Comi, Giancarlo; Cook, Stuart; Giovannoni, Gavin; Rieckmann, Peter; Sorensen, Per Soelberg; Vermersch, Patrick; Galazka, Andrew; Nolting, Axel; Hicking, Christine; Dangond, Fernando (Multiple Sclerosis and Related Disorders, 2019)
Background: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19(+) B cells and T cells, followed by reconstitution of adaptive immune function.
CRIS-Team WoS Importer:2019-03-29

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke - Alexandrov, Andrei V.; Tsivgoulis, Georgios; Köhrmann, Martin; Katsanos, Aristeidis H.; Soinne, Lauri; Barreto, Andrew D.; Rothlisberger, Travis; Sharma, Vijay K.; Mikulik, Robert; Muir, Keith W.; Levi, Christopher R.; Molina, Carlos A.; et al. (Therapeutic Advances in Neurological Disorders, 2019)
Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.
CRIS-Team Scopus Importer:2019-07-23
Keywords: endovascular; equipoise shift; intracranial hemorrhage; mechanical thrombectomy; outcome; recanalization; sonothrombolysis; stroke; ultrasound-enhanced thrombolysis

Epilepsy in the elderly: restrictions, fears, and quality of life - May, T. W.; Pfaefflin, M.; Brandt, Christian; Fueratsch, N.; Schmitz, B.; Wandschneider, B.; Kretz, R.; Runge, U.; Geithner, J.; Karakizlis, H.; Rosenow, F.; Kerling, F.; et al. (Acta Neurologica Scandinavica, 2015)
Due to demographic change and high incidence of epilepsy in elderly, the number of elderly with epilepsies is increasing. However, only few studies investigated the impact of epilepsy on quality of life (QoL). We investigated how epilepsy affects different aspects of QoL dependent on the age of the patients and the age of onset of epilepsy.In a multicenter, cross-sectional study, three patient groups were recruited from five centers: Group A1: 45 elderly (>=65 years.) with late onset of epilepsy (>=65 years), group A2: 51 elderly (>=65 years.) with early-onset, long-lasting epilepsy (<=50 years), group B: 41 young adults (<=50 years) with epilepsy. Statistical analysis of differences between groups was performed using generalized linear models.Elderly with late-onset epilepsy (group A1) had a significantly lower seizure frequency, were treated with less anti-epileptic drugs (AEDs), and reported a better tolerability of AED treatment, but had more comorbidities compared with groups A2 and B. After adjusting for seizure frequency, tolerability of AEDs and comorbidity, young adults (group B) reported the highest overall QoL, whereas patients of group A1 and A2 did not differ significantly. Epilepsy-related fears, especially fears of stigmatization, were significantly higher in elderly with long-lasting epilepsy compared with groups A1 and B.Seizure-related variables, tolerability of AEDs and comorbidity have a stronger impact on QoL and on restrictions due to epilepsy than age, age at onset of epilepsy or duration of epilepsy. However, some results indicate group-specific patterns of impairment and epilepsy-related fears.
EVALuna2:22415

Evidence for the Role of Magnetic Source Imaging in the Presurgical Evaluation of Refractory Epilepsy Patients - Carrette, Evelien; Stefan, Hermann (Frontiers in Neurology, 2019)
Magnetoencephalography (MEG) in the field of epilepsy has multiple advantages; just like electroencephalography (EEG), MEG is able to measure the epilepsy specific information (i.e., the brain activity reflecting seizures and/or interictal epileptiform discharges) directly, non-invasively and with a very high temporal resolution (millisecond-range). In addition MEG has a unique sensitivity for tangential sources, resulting in a full picture of the brain activity when combined with EEG. It accurately allows to perform source imaging of focal epileptic activity and functional cortex and shows a specific high sensitivity for a source in the neocortex. In this paper the current evidence and practice for using magnetic source imaging of focal interictal and ictal epileptic activity during the presurgical evaluation of drug resistant patients is being reviewed.
CRIS-Team WoS Importer:2019-09-24

Expert opinion paper on atrial fibrillation detection after ischemic stroke - Haeusler, Karl Georg; Groeschel, Klaus; Koehrmann, Martin; Anker, Stefan D.; Brachmann, Johannes; Boehm, Michael; Diener, Hans-Christoph; Doehner, Wolfram; Endres, Matthias; Gerloff, Christian; Huttner, Hagen; Kaps, Manfred; et al. (Clinical Research in Cardiology, 2018)
This expert opinion paper on atrial fibrillation detection after ischemic stroke includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. This paper was endorsed by the Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork. In patients with ischemic stroke, detection of atrial fibrillation should usually lead to a change in secondary stroke prevention, since oral anticoagulation is superior to antiplatelet drugs. The detection of previously undiagnosed atrial fibrillation can be improved in patients with ischemic stroke to optimize stroke prevention. This paper summarizes the present knowledge on atrial fibrillation detection after ischemic stroke. We propose an interdisciplinary standard for a "structured analysis of ECG monitoring" on the stroke unit as well as a staged diagnostic scheme for the detection of atrial fibrillation. Since the optimal duration and mode of ECG monitoring has not yet been finally established, this paper is intended to give advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on the expert opinion, reported case series and clinical experience. Therefore, this paper is not intended as a guideline.
EVALuna2:51605

Impact of Lesion Load Thresholds on Alberta Stroke Program Early Computed Tomographic Score in Diffusion-Weighted Imaging - Schroeder, Julian; Cheng, Bastian; Malherbe, Caroline; Ebinger, Martin; Köhrmann, Martin; Wu, Ona; Kang, Dong-Wha; Liebeskind, David S.; Tourdias, Thomas; Singer, Oliver C.; Campbell, Bruce; Luby, Marie; et al. (Frontiers in Neurology, 2018)
Background and aims: Assessment of ischemic lesions on computed tomography or MRI diffusion-weighted imaging (DWI) using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to guide acute stroke treatment. However, it has never been defined how many voxels need to be affected to label a DWI-ASPECTS region ischemic. We aimed to assess the effect of various lesion load thresholds on DWI-ASPECTS and compare this automated analysis with visual rating. Materials and methods: We analyzed overlap of individual DWI lesions of 315 patients from the previously published predictive value of fluid-attenuated inversion recovery study with a probabilistic ASPECTS template derived from 221 CT images. We applied multiple lesion load thresholds per DWI-ASPECTS region (>0, >1, >10, and >20% in each DWI-ASPECTS region) to compute DWI-ASPECTS for each patient and compared the results to visual reading by an experienced stroke neurologist. Results: By visual rating, median ASPECTS was 9, 84 patients had a DWI-ASPECTS score ≤7. Mean DWI lesion volume was 22.1 (±35) ml. In contrast, by use of >0, >1-, >10-, and >20%-thresholds, median DWI-ASPECTS was 1, 5, 8, and 10; 97.1% (306), 72.7% (229), 41% (129), and 25.7% (81) had DWI-ASPECTS ≤7, respectively. Overall agreement between automated assessment and visual rating was low for every threshold used (>0%: κw = 0.020 1%: κw = 0.151; 10%: κw = 0.386; 20% κw = 0.381). Agreement for dichotomized DWI-ASPECTS ranged from fair to substantial (≤7: >10% κ = 0.48; >20% κ = 0.45; ≤5: >10% κ = 0.528; and >20% κ = 0.695). Conclusion: Overall agreement between automated and the standard used visual scoring is low regardless of the lesion load threshold used. However, dichotomized scoring achieved more comparable results. Varying lesion load thresholds had a critical impact on patient selection by ASPECTS. Of note, the relatively low lesion volume and lack of patients with large artery occlusion in our cohort may limit generalizability of these findings.
EVALuna2:213465

Inflammation, edema, hematoma and etiology – a rectangular relationship? - Volbers, B.; Fischer, U.; Huttner, Hagen (European Journal of Neurology, 2019)
CRIS-Team Scopus Importer:2019-05-07
Keywords: hyperthermia; inflammation; intracerebral hemorrhage; perihemorrhagic edema

Inhibition of stress fiber formation preserves blood-brain barrier after intracerebral hemorrhage in mice - Manaenko, Anatol; Yang, Peng; Nowrangi, Derek; Budbazar, Enkhjargal; Hartman, Richard E.; Obenaus, Andre; Pearce, William J.; Zhang, John H.; Tang, Jiping (Journal of Cerebral Blood Flow and Metabolism, 2018)
Intracerebral hemorrhage (ICH) represents the deadliest subtype of all strokes. The development of brain edema, a consequence of blood-brain barrier (BBB) disruption, is the most life-threatening event after ICH. Pathophysiological conditions activate the endothelium, one of the components of BBB, inducing rearrangement of the actin cytoskeleton. Upon activation, globular actin assembles into a filamentous actin resulting in the formation of contractile actin bundles, stress fibers. The contraction of stress fibers leads to the formation of intercellular gaps between endothelial cells increasing the permeability of BBB. In the present study, we investigated the effect of ICH on stress fiber formation in CD1 mice. We hypothesized that ICH-induced formation of stress fiber is triggered by the activation of PDGFR-β and mediated by the cortactin/RhoA/LIMK pathway. We demonstrated that ICH induces formation of stress fibers. Furthermore, we demonstrated that the inhibition of PDGFR-β and its downstream reduced the number of stress fibers, preserving BBB and resulting in the amelioration of brain edema and improvement of neurological functions in mice after ICH.
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Intensive Blood Pressure Reduction and Perihematomal Edema Expansion in Deep Intracerebral Hemorrhage - Leasure, Audrey C.; Qureshi, Adnan I.; Murthy, Santosh B.; Kamel, Hooman; Goldstein, Joshua N.; Walsh, Kyle B.; Woo, Daniel; Shi, Fu Dong; Huttner, Hagen; Ziai, Wendy C.; Hanley, Daniel F.; Matouk, Charles C.; et al. (Stroke, 2019)
Background and Purpose- It is unknown whether blood pressure (BP) reduction influences secondary brain injury in spontaneous intracerebral hemorrhage (ICH). We tested the hypothesis that intensive BP reduction is associated with decreased perihematomal edema expansion rate (PHER) in deep ICH. Methods- We performed an exploratory analysis of the ATACH-2 randomized trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2). Patients with deep, supratentorial ICH were included. PHER was calculated as the difference in perihematomal edema volume between baseline and 24-hour computed tomography scans divided by hours between scans. We used regression analyses to determine whether intensive BP reduction was associated with PHER and if PHER was associated with poor outcome (3-month modified Rankin Scale score 4-6). We then used interaction analyses to test whether specific deep location (basal ganglia versus thalamus) modified these associations. Results- Among 1000 patients enrolled in ATACH-2, 870 (87%) had supratentorial, deep ICH. Of these, 780 (90%) had neuroimaging data (336 thalamic and 444 basal ganglia hemorrhages). Baseline characteristics of the treatment groups remained balanced (P>0.2). Intensive BP reduction was associated with a decrease in PHER in univariable (β= -0.15; 95% CI, -0.26 to -0.05; P=0.007) and multivariable (β=-0.12; 95% CI, -0.21 to -0.02; P=0.03) analyses. PHER was not independently associated with outcome in all deep ICH (odds ratio, 1.14; 95% CI, 0.93-1.41; P=0.20), but this association was modified by the specific deep location involved (multivariable interaction P=0.02); in adjusted analyses, PHER was associated with poor outcome in basal ganglia (odds ratio, 1.42; 1.05-1.97; P=0.03) but not thalamic (odds ratio, 1.02; 95% CI, 0.74-1.40; P=0.89) ICH. Conclusions- Intensive BP reduction was associated with decreased 24-hour PHER in deep ICH. PHER was not independently associated with outcome in all deep ICH but was associated with poor outcome in basal ganglia ICH. PHER may be a clinically relevant end point for clinical trials in basal ganglia ICH.
CRIS-Team Scopus Importer:2019-08-13
Keywords: basal ganglia; blood pressure; cerebral hemorrhage; edema; thalamus

Ischemic stroke despite oral anticoagulant therapy in patients with AF: recurrence risk and optimal anticoagulation strategy - Seiffge, D.; De Marchis, G. M.; Koga, M.; Paciaroni, M.; Wilson, D.; Cappellari, M.; Macha, Kosmas; Tsivgoulis, G.; Ambler, G.; Arihiro, S.; Bonati, L.; Bonetti, B.; et al. (EUROPEAN JOURNAL OF NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-07-30

Myalgia with the presence of pathologic EMG correlates with perimysial inflammatory infiltrates - Johannssen, Kirsten; Schwab, Nicholas; Wessig, Carsten P.; Reiners, Karlheinz; Wiendl, Heinz; Sommer, Claudia (Neurology, Neuroimmunology and Neuroinflammation, 2019)
ObjectiveWe aimed to define normal numbers of inflammatory cells in muscle biopsies and to identify the predictive value of isolated muscle pain and increased creatine kinase regarding the diagnosis of myositis.MethodsWe analyzed muscle biopsies of 71 patients using immunostains for CD3 + , CD4 + , CD8 + , CD68 + , major histocompatibility complex class I, perforin, and myeloid-related protein (MRP) 8. Patients were categorized as follows-group 1: Myalgia without further clinical or laboratory abnormalities (n = 24); group 2: Asymptomatic elevation of creatine kinase (hyperCKemia, n = 26); group 3: Myalgia and pathologic EMG findings (n = 9); and group 4: Otherwise healthy controls who had malignant hyperthermia susceptibility testing (n = 12).ResultsIn the normal muscle biopsy specimens from group 4, mean endomysial macrophage (CD68 + ) density was 21.7 ± 5.6/mm 2 , and perimysial density was 13.0 ± 5.6/mm 2 . Numbers of T-lymphocytes (CD3 + ) were 5 ± 3.5 endomysially and 2.2 ± 3.9/mm 2 perimysially. This was not different from groups 1 and 2. Only group 3 patients had increased mean numbers of perimysial macrophages (24.1 ± 6.3/mm 2 ; p = 0.0005), CD3 + (7.6 ± 4.9/mm 2 ; p = 0.0056), and CD8 + T-lymphocytes (5.4 ± 3.1/mm 2 ; p = 0.0008) and displayed the activation marker MRP8 in all cases. Although inflammatory cells were increased in the perimysium in group 3, histology did not fulfill the criteria for dermatomyositis, polymyositis, or inclusion body myositis.ConclusionsNormal muscle contains a considerable number of macrophages and T-lymphocytes. Muscle biopsy is likely to detect inflammatory changes in patients with myalgia or hyperCKemia only if pathologic EMG findings are present.
CRIS-Team Scopus Importer:2019-05-09

Neuro-Ophthalmology at the Bedside: A Clinical Guide - Heckmann, Josef G.; Vachalova, Ivana; Lang, Christoph; Pitz, Susanne (Journal of Neurosciences in Rural Practice, 2018)
Neuro-ophthalmological signs and symptoms are common in the emergency department but are a frequent source of diagnostic uncertainties. However, neuro-ophthalmological signs often allow a precise neuro-topographical localization of the clinical problem. A practical concept is presented how to perform a neuro-ophthalmological examination at the bedside and to interpret key findings under the aspect of emergency medicine with limited resources.
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Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status - Hildebrandt, Wulf; Sauer, Roland; Bonaterra, Gabriel; Dugi, Klaus A.; Edler, Lutz; Kinscherf, Ralf (American Journal of Clinical Nutrition, 2015)
Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy.We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers.We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL.NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% ± 3.0% (placebo: 4.1% ± 3.6%) while increasing those of cysteine by 28.1% ± 5.7% (placebo: 4.0% ± 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction.Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men, with significant diastolic blood pressure reductions in the HYL group only. Increased oral intake of cysteine may therefore be considered for primary or secondary prevention of vascular events with regard to the 2 independent risk factors of hyperhomocysteinemia and arterial hypertension.
EVALuna2:22427

Psychopharmacological Treatment of Schizophrenia Over Time in 30 908 Inpatients: Data From the AMSP Study - Toto, Sermin; Grohmann, Renate; Bleich, Stefan; Frieling, Helge; Maier, Hannah B.; Greil, Waldemar; Cordes, Joachim; Schmidt-Kraepelin, Christian; Kasper, Siegfried; Stübner, Susanne; Degner, Detlef; Druschky, Katrin; et al. (International Journal of Neuropsychopharmacology, 2019)
BACKGROUND: Psychotropic drugs are the cornerstone of schizophrenia treatment, often requiring lifelong treatment. Data on pharmacotherapy in inpatient settings are lacking. METHODS: Prescription data of schizophrenic inpatients within the time period 2000-2015 were obtained from the database of the Drug Safety Program in Psychiatry (AMSP). Data were collected at 2 index dates per year; the prescription patterns and changes over time were analyzed. RESULTS: Among 30 908 inpatients (mean age 41.6 years, 57.8% males), the drug classes administered most often were antipsychotics (94.8%), tranquilizers (32%), antidepressants (16.5%), antiparkinsonians (16%), anticonvulsants (14.1%), hypnotics (8.1%), and lithium (2.1%). The use of second-generation antipsychotics significantly increased from 62.8% in 2000 to 88.9% in 2015 (P < .001), whereas the prescription of first-generation antipsychotics decreased from 46.6% in 2000 to 24.7% in 2015 (P < .001). The administration of long-acting injectable antipsychotics decreased from 15.2% in 2000 to 11.7% in 2015 (P = .006). Clopazine was the most often used antipsychotic, having been used for 21.3% of all patients. Polypharmacy rates (≥5 drugs) increased from 19% in 2000 to 26.5% in 2015. Psychiatric polypharmacy (≥3 psychotropic drugs) was present in 44.7% of patients. CONCLUSIONS: Combinations of antipsychotics and augmentation therapies with other drug classes are frequently prescribed for schizophrenic patients. Though treatment resistance and unsatisfactory functional outcomes reflect clinical necessity, further prospective studies are needed on real-world prescription patterns in schizophrenia to evaluate the efficacy and safety of this common practice.
CRIS-Team Scopus Importer:2019-10-01
Keywords: AMSP; antipsychotics; pharmacotherapy; prescription; schizophrenia

Seizure rates under treatment with antipsychotic drugs: Data from the AMSP project - Druschky, Katrin; Bleich, Stefan; Grohmann, Renate; Engel, Rolf R.; Neyazi, Alexandra; Stuebner, Susanne; Toto, Sermin (World Journal of Biological Psychiatry, 2019)
Objectives: The study aimed to assess seizure rates related to different antipsychotic drugs (APDs) in a clinical setting using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie (AMSP). Methods: Psychotropic drug use data and reports of APD-related seizures were collected in 89 psychiatric hospitals in Austria, Germany and Switzerland from 1993 to 2015. Results: Of 475,096 patients under surveillance, 320,383 patients were treated with APDs for the main indications of schizophrenic disorders, mood disorders and organic disorders. A total of 144 APD-related tonic clonic seizures were identified (0.04%). The butyrophenones ranked slightly lower (0.03%) compared to the phenothiazines, thioxanthenes and second-generation APDs (0.05% each). No significant differences were observed when comparing first- and second-generation APDs. Clozapine was related to the highest seizure rate (0.18%). In 107 cases (74.3%), more than one drug was considered responsible for seizure induction. With the exception of clozapine, seizures imputed to a single APD were in the clear minority. Seizure rates under the combinations of APDs with tricyclic antidepressants or lithium, as well as under triple combinations of APDs, were increased approximately two-fold. Young age (<= 30 years), the male gender, and diagnosis of schizophrenic disorder were associated with significantly higher seizure rates (P < 0.05). Conclusions: Closely reflecting daily clinical practice, the present results provide supplementary information regarding APD therapy for patients not only at risk for seizures but also seizure-unaffected psychiatric inpatients.
CRIS-Team WoS Importer:2020-02-11

Severe drug-induced liver injury in patients under treatment with antipsychotic drugs: Data from the AMSP study - Druschky, Katrin; Toto, Sermin; Bleich, Stefan; Baumgaertner, Jessica; Engel, Rolf R.; Grohmann, Renate; Maier, Hannah B.; Neyazi, Alexandra; Rudolph, Yannick J.; Ruether, Eckart; Schwoerer, Harald; Seifert, Johanna; et al. (World Journal of Biological Psychiatry, 2020)
Objectives Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available. Methods Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016. Results Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (>= 65 years old) were significantly less often affected. Conclusions In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.
CRIS-Team WoS Importer:2020-10-09

Single-dose intravenous administration of antiepileptic drugs induces rapid and reversible remodeling in the brain: Evidence from a voxel-based morphometry evaluation of valproate and levetiracetam in rhesus monkeys - Tang, Y.; Yu, X.; Zhang, X.; Xia, W.; Wu, X.; Zou, X.; Li, H.; Huang, X.; Stefan, Hermann; Chen, Q.; Gong, Q.; Zhou, D. (Neuroscience, 2015)
Effects of the long-term use of antiepileptic drugs (AEDs) on the brains of patients with epilepsy have been previously reported. The aim of this study was to determine the rapid brain structure remodeling induced by single-dose intravenous AED administration that rules out the potential effects of epilepsy.Ten rhesus monkeys were randomly divided into two groups and were intravenously administered a single dose of valproic acid (VPA) or levetiracetam (LEV) at treatment dosages. Magnetic resonance imaging (MRI) data were recorded from every subject prior to AED administration and at 2h and 1 week after administration. Using optimized voxel-based morphometry (VBM) analysis, we measured changes in regional gray matter volume (GMV) and white matter volume (WMV) in each group over time following medication and directly compared the differences between the two groups.Both AEDs induced brain volume alterations at 2h after their administration, but these changes had reverted at 1 week. The VPA group exhibited increased GMV in the right geniculate nucleus and the right pulvinar, whereas the LEV group exhibited WMV reductions in the right pulvinar, the right parietal lobe and the right occipital lobe. Directly compared with the LEV group, the VPA group exhibited a temporally constant GMV increase in the bilateral temporal cortex and a WMV reduction in the left pedunculus cerebri.Single-dose intravenous administration of a level of VPA or LEV that mimics clinical use is associated with rapid and reversible VBM-detected GMV or WMV alterations in rhesus monkeys. This finding may provide new insights into the understanding of AED-induced brain structure remodeling and may contribute to our understanding of the brain-level mechanisms and targets of AED action.
EVALuna2:22417

The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial - Joussen, Antonia M.; Wolf, Sebastian; Kaiser, Peter K.; Boyer, David; Schmelter, Thomas; Sandbrink, Rupert; Zeitz, Oliver; Deeg, Gesa; Richter, Annett; Zimmermann, Torsten; Hoechel, Joachim; Buetehorn, Ulf; et al. (British Journal of Clinical Pharmacology, 2019)
Aims This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). Methods Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 mu l, 30 mg ml(-1)) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12. Results In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, respectively. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).
CRIS-Team WoS Importer:2019-02-21

The Utility of Routine Intensive Care Admission for Patients Undergoing Intracranial Neurosurgical Procedures: A Systematic Review - De Almeida, Cesar Cimonari; Boone, M. Dustin; Laviv, Yosef; Kasper, Burkhard; Chen, Clark C.; Kasper, Ekkehard M. (Neurocritical Care, 2018)
BACKGROUND: Patients who have undergone intracranial neurosurgical procedures have traditionally been admitted to an intensive care unit (ICU) for close postoperative neurological observation. The purpose of this study was to systematically review the evidence for routine ICU admission in patients undergoing intracranial neurosurgical procedures and to evaluate the safety of alternative postoperative pathways. METHODS: We were interested in identifying studies that examined selected patients who presented for elective, non-emergent intracranial surgery whose postoperative outcomes were compared as a function of ICU versus non-ICU admission. A systematic review was performed in July 2016 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist of the Medline database. The search strategy was created based on the following key words: "craniotomy," "neurosurgical procedure," and "intensive care unit." RESULTS: The nine articles that satisfied the inclusion criteria yielded a total of 2227 patients. Of these patients, 879 were observed in a non-ICU setting. The most frequent diagnoses were supratentorial brain tumors, followed by patients with cerebrovascular diseases and infratentorial brain tumors. Three percent (30/879) of the patients originally assigned to floor or intermediate care status were transferred to the ICU. The most frequently observed neurological complications leading to ICU transfer were delayed postoperative neurological recovery, seizures, worsening of neurological deficits, hemiparesis, and cranial nerves deficits. CONCLUSION: Our systematic review demonstrates that routine postoperative ICU admission may not benefit carefully selected patients who have undergone elective intracranial neurosurgical procedures. In addition, limiting routine ICU admission may result in significant cost savings.
EVALuna2:213471

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels, CSF clotting, and communicating hydrocephalus: a comprehensive review - Laviv, Yosef; Kasper, Burkhard; Kasper, Ekkehard M. (Neurosurgical Review, 2018)
Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a "pro-inflammatory state" of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.
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