Incidence and relative risk of stroke in the diabetic and the non-diabetic population between 1998 and 2014: A community-based stroke register - Icks, Andrea; Claessen, Heiner; Kvitkina, Tatjana; Narres, Maria; Weingaertner, Michael; Schwab, Stefan; Kolominsky-Rabas, Peter (PLoS ONE, 2017)
One major objective of the St. Vincent Declaration was to reduce excess risk of stroke in people with diabetes mellitus. The aim of this study is to estimate the trend of incidence and relative risk of stroke in the diabetic and the non-diabetic populations in Germany over a 17-year period. We estimated age-sex standardised incidence rates of all stroke and ischaemic stroke in people with and without diabetes based on an ongoing prospective community-based stroke register covering 105,000 inhabitants. Time trends were analysed using Poisson regression. In total, 3,111 individuals (diabetes: 28.4%, men 46.9%, mean age 73.1 years (SD 13.2)) had a first stroke, 84.9% of which were ischaemic stroke. Among people with diabetes we observed a significant reduction in all stroke incidence by 1.5% per year (relative risk: 0.985; 95% confidence interval 0.972-0.9995) Likewise, this incidence tended to decrease for ischaemic stroke by 1% per year (0.993; 0.979-1.008). In contrast, the incidence rate for all stroke remained nearly stable among people without diabetes (1.003; 0.993-1.013) and for ischaemic stroke (1.002; 0.991-1.013). The relative risk comparing diabetic and non-diabetic population decreased for all stroke (two percent annual reduction) but not for ischaemic stroke. Time trends were similar for both sexes regarding all and ischaemic strokes. We found a reduction in risk of stroke in the diabetic population while this rate did not materially change in the non-diabetic population.
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Incidence, temporal profile and neuroanatomic correlates of poststroke epilepsy - Winder, Klemens; Bobinger, Tobias; Seifert, Frank; Mrochen, Anne; Haupenthal, David; Knott, Michael; Dörfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Fröhlich, Kilian (Journal of Neuroimaging, 2023)
Background and Purpose: The relationship between ischemic stroke site and occurrence of poststroke epilepsy (PSE) is incompletely understood. This study intended to evaluate incidence and temporal profiles of seizures and to correlate ischemic lesion sites with PSE using voxel-based lesion symptom mapping (VLSM). Methods: Patients with imaging-confirmed first-ever ischemic stroke without prior history of epilepsy were prospectively included. Demographic data, cardiovascular risk factors, and National Institute of Health Stroke Scale (NIHSS) scores were assessed. Data on seizures and modified Rankin scale scores were determined within a 90-day period after stroke onset. Ischemic lesion sites were correlated voxel wise with occurrence of PSE using nonparametric permutation test. Age- and sex-matched patients with first-ever ischemic strokes without PSE after 90 days served as controls for the VLSM analysis. Results: The stroke database contained 809 patients (mean age: 68.4 ± 14.2 years) with first-ever imaging-confirmed ischemic strokes without history of epilep. Incidence of PSE after 90-day follow-up was 2.8%. Five additional patients were admitted to the emergency department with a seizure after 90-day follow-up. Fifty percent of the seizures occurred in the acute phase after stroke. PSE patients had higher NIHSS scores and infarct volumes compared to controls without PSE (p <.05). PSE patients had infarcts predominantly involving the cerebral cortex. The hemisphere-specific VLSM analysis shows associations between PSE and damaged voxels in the left-hemispheric temporo-occipital transition zone. Conclusions: The data indicate that PSE occurs in a small proportion of patients with rather large ischemic strokes predominantly involving the cerebral cortex. Especially patients with ischemic lesions in the temporo-occipital cortex are vulnerable to develop PSE.
CRIS-Team Scopus Importer:2023-05-19
Keywords: ischemic stroke; poststroke epilepsy; voxel-based lesion symptom mapping

Incorporating respiratory signals for machine learning-based multimodal sleep stage classification: a large-scale benchmark study with actigraphy and heart rate variability - Krauß, Daniel; Richer, Robert; Küderle, Arne; Jukic, Jelena; German, Alexander; Leutheuser, Heike; Regensburger, Martin; Winkler, Jürgen; Eskofier, Björn (Sleep, 2025)
Insufficient sleep quality is directly linked to various diseases, making reliable sleep monitoring crucial for prevention, diagnosis, and treatment. As sleep laboratories are cost- and resource-prohibitive, wearable sensors offer a promising alternative for long-term unobtrusive sleep monitoring at home. Current unobtrusive sleep detection systems are mostly based on actigraphy (ACT) that tend to overestimate sleep due to a lack of movement in short periods of wakefulness. Previous research established sleep stage classification by combining ACT with cardiac information but has not investigated the incorporation of respiration in large-scale studies. For that reason, this work aims to systematically compare ACT-based sleep-stage classification with multimodal approaches combining ACT, heart rate variability (HRV) as well as respiration rate variability (RRV) using state-of-the-art machine- and deep learning algorithms. The evaluation is performed on a publicly available sleep dataset including more than 1000 recordings. Respiratory information is introduced through ECG-derived respiration features, which are evaluated against traditional respiration belt data. Results show that including RRV features improves the Matthews Correlation Coefficient (MCC), with long short-term memory (LSTM) algorithms performing best. For sleep staging based on AASM standards, the LSTM achieved a median MCC of 0.51 (0.16 IQR). Respiratory information enhanced classification performance, particularly in detecting wake and rapid eye movement (REM) sleep epochs. Our findings underscore the potential of including respiratory information in sleep analysis to improve sleep detection algorithms and, thus, help to transfer sleep laboratories into a home monitoring environment. The code used in this work can be found online at https://github.com/mad-lab-fau/sleep_analysi
Keywords: machine learning; deep learning; wearable electronic devices; multimodal sensing; neural networks; sleep; sleep-stage

Increased IL-8 concentrations in the cerebrospinal fluid of patients with unipolar depression - Kuzior, Hanna; Fiebich, Bernd L.; Yousif, Nizar M.; Saliba, Soraya W.; Ziegler, Christiane; Nickel, Kathrin; Maier, Simon J.; Süß, Patrick; Runge, Kimon; Matysik, Miriam; Dersch, Rick; Berger, Benjamin; et al. (Comprehensive Psychiatry, 2020)
Introduction: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. Materials and methods: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. Results: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). Limitations: The significance of the results is limited by the retrospective design and methodological aspects. Discussion: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Depression; IL-8; Interleukin 8; Neuroinflammation

Increased intima-media thickness in rayon workers after long-term exposure to carbon disulfide - Schramm, Axel; Uter, Wolfgang; Brandt, Meike; Göen, Thomas; Köhrmann, Martin; Baumeister, Thomas; Drexler, Hans (International Archives of Occupational and Environmental Health, 2016)
Long-term exposure to carbon disulfide (CS2) is associated with increased cardiovascular mortality. However, previous studies on actual vascular changes showed heterogeneous results. Intima-media thickness of the carotid arteries (IMT) represents an established marker of atherosclerosis and a reasonable surrogate marker for cardiovascular risk. IMT was examined in a large cohort of CS2 exposed workers and the association with cumulative CS2 exposure analysed.In a cross-sectional examination, 290 exposed and 137 non-exposed workers in a German rayon-manufacturing plant were assessed. Individual cumulative exposure was calculated from this assessment combined with the results of two cross-sectional studies in 1992 and 1999 and department-specific annual means of ambient (CECS2) and individual biological (CETTCA) monitoring results obtained 1992-2009. Furthermore, cumulative duration of working in CS2-exposed departments (CEYEARS) was calculated. Examination included assessment of a broad set of known cardiovascular risk factors and IMT measurement of the carotid arteries on both sides. Multiple linear regression analyses were performed with IMT as outcome and three variants of cumulative exposure (duration of exposure, cumulative CS2, and cumulative TTCA) as well as categorised maximum CS2 exposure, all adjusted for cardiovascular risk factors.All models of cumulative exposure showed a significant increase in IMT in the group with the highest level of exposure: CEYEARS > 20 years, ? = 0.045 mm; CECS2 > 270 ppm × years, ? = 0.052 mm; CETTCA > 33 mg/g creatinine × years, ? = 0.038 mm. Alternatively, addressing maximum exposure, workers with CS2 exposure of >10 ppm in at least 3 years exhibited a significant IMT increase (? = 0.068 mm).Long-term CS2 exposure is an independent risk factor concerning IMT changes. The amount of IMT increase, in a similar range as that associated with other cardiovascular risk factors, might be clinically relevant.
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Increased Neutrophil-to-Lymphocyte Ratio is Associated with Unfavorable Functional Outcome in Acute Ischemic Stroke - Giede-Jeppe, Antje; Madzar, Dominik; Sembill, Jochen; Sprügel, Maximilian; Atay, Selim; Lücking, Hannes; Huttner, Hagen; Bobinger, Tobias; Hölter, Philip (Neurocritical Care, 2019)
Background Inflammatory response is the hallmark of secondary brain injury in stroke patients. Neutrophil-to-lymphocyte ratio (NLR) emerged as a marker for functional outcome in several diseases. Objectives To investigate the association between NLR on admission and during hospital stay and functional outcome in acute ischemic stroke (AIS). Methods This observational study included all consecutive AIS patients admitted at a German stroke center covering 2011-2013. Patient characteristics and clinical data were retrieved from institutional databases. Multivariate analysis was conducted to investigate parameters associated with functional outcome. Receiver operating characteristic (ROC) analysis was performed to identify the best cutoff for NLR to discriminate between favorable and unfavorable functional outcome. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on functional outcome. Results A total of 807 patients with AIS were included for analysis. Patients with worse functional outcome at 3 months were older and had worse clinical status on admission, higher rates of infectious complications, and an increased NLR. ROC analysis identified a NLR of 3.3 as best cutoff value to discriminate between favorable and unfavorable functional outcomes (area under the curve 0.693, p < 0.001, Youden's index = 0.318; p < 0.001; sensitivity 68.5%, specificity 63.9%). Propensity-matched analysis still demonstrated a higher rate of unfavorable functional outcome at 3 months in patients with NLR >= 3.3 [modified Rankin scale 3-6 at 3 months: NLR >= 3.3 51.5% vs. NLR < 3.3 36.4%; p = 0.002]. Conclusions In AIS patients we identified NLR as an important predictor for unfavorable functional outcome.
CRIS-Team WoS Importer:2019-10-25

Increased prevalence of posttraumatic stress disorder in patients after transient ischemic attack - Kiphuth, Ines C.; Utz, Kathrin S.; Noble, Adam J.; Köhrmann, Martin; Schenk, Thomas (Stroke, 2014)
A transient ischemic attack (TIA) involves temporary neurological symptoms but leaves a patient symptom-free. Patients are faced with an increased risk for future stroke, and the manifestation of the TIA itself might be experienced as traumatizing. We aimed to investigate the prevalence of posttraumatic stress disorder (PTSD) after TIA and its relation to patients' psychosocial outcome.Patients with TIA were prospectively studied, and 3 months after the diagnosis, PTSD, anxiety, depression, quality of life, coping strategies, and medical knowledge were assessed via self-rating instruments.Of 211 patients with TIA, data of 108 patients were complete and only those are reported. Thirty-two (29.6%) patients were classified as having PTSD. This rate is 10× as high as in the general German population. Patients with TIA with PTSD were more likely to show signs of anxiety and depression. PTSD was associated with the use of maladaptive coping strategies, subjectively rated high stroke risk, as well as with younger age. Finally, PTSD and anxiety were associated with decreased mental quality of life.The experience of TIA increases the risk for PTSD and associated anxiety, depression, and reduced mental quality of life. Because a maladaptive coping style and a subjectively overestimated stroke risk seem to play a crucial role in this adverse progression, the training of adaptive coping strategies and cautious briefing about the realistic stroke risk associated with TIA might be a promising approach. Despite the great loss of patients to follow-up, the results indicate that PTSD after TIA requires increased attention.
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Increased tyrosine hydroxylase expression accompanied by glial changes within the non-lesioned hemisphere in the 6-hydroxydopamine model of Parkinson's disease - Schlachetzki, Johannes; Marxreiter, Franz; Regensburger, Martin; Kulinich, Anna; Winner, Beate; Winkler, Jürgen (Restorative Neurology and Neuroscience, 2014)
Parkinson's disease (PD) is characterized by striatal synaptic deafferentation followed by dopaminergic cell death in the substantia nigra pars compacta. Not only degenerative, but also regenerative, compensatory changes at distant sites of the primary lesion may occur in PD. The aim of the study was to analyze the temporal pattern of axonal and glial responses over a time course of six weeks post-lesioning.For this aim, 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle and both lesioned and non-lesioned striata were analyzed.We detected increased tyrosine hydroxylase (TH) immunoreactivity within the non-lesioned striatum six weeks after injection indicative either of increased TH expression or compensatory neuritic changes. An increased number of microglial cells was present in both lesioned and unlesioned striata. There was no obvious change in microglial phenotype or in pro-inflammatory cytokine gene expression within the striatum without any apparent switch into a pro-inflammatory phenotype. No changes were observed in the number of mature oligodendrocytes.This temporal pattern shows, that the non-lesioned striatum undergoes profound changes, involving increased TH expression accompanied by a glial response. A better understanding of this complex interplay of neuronal as well as glial components not only within the lesioned, but also non-lesioned striatum may help to restore local neural circuits in PD.
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Increase of angiotensin II type 1 receptor auto-antibodies in Huntington's disease - Lee, De-Hyung; Heidecke, Harald; Schroeder, Alexandra; Paul, Friedemann; Wachter, Rolf; Hoffmann, Rainer; Ellrichmann, Gisa; Dragun, Duska; Waschbisch, Anne; Stegbauer, Johannes; Klotz, Peter; Gold, Ralf; et al. (Molecular Neurodegeneration, 2014)
In the recent years, a role of the immune system in Huntington's disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease.As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers >= 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection.These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking.
EVALuna2:22303

Increase of Reproductive Life Span Delays Age of Onset of Parkinson's Disease - Frentzel, Dominik; Judanin, Grigorij; Borozdina, Olga; Klucken, Jochen; Winkler, Jürgen; Schlachetzki, Johannes (Frontiers in Neurology, 2017)
One striking observation in Parkinson's disease (PD) is the remarkable gender difference in incidence and prevalence of the disease. Data on gender differences with regard to disease onset, motor and non-motor symptoms, and dopaminergic medication are limited. Furthermore, whether estrogen status affects disease onset and progression of PD is controversially discussed. In this retrospective single center study, we extracted clinical data of 226 ambulatory PD patients and compared age of disease onset, disease stage, motor impairment, non-motor symptoms, and dopaminergic medication between genders. We applied a matched-pairs design to adjust for age and disease duration. To determine the effect of estrogen-related reproductive factors including number of children, age at menarche, and menopause on the age of onset, we applied a standardized questionnaire and performed a regression analysis. The male to female ratio in the present PD cohort was 1.9:1 (147 men vs. 79 women). Male patients showed increased motor impairment than female patients. The levodopa equivalent daily dose was increased by 18.9% in male patients compared to female patients. Matched-pairs analysis confirmed the increased dose of dopaminergic medication in male patients. No differences were observed in age of onset, type of medication, and non-motor symptoms between both groups. Female reproductive factors including number of children, age at menarche, and age at menopause were positively associated with a delay of disease onset up to 30 months. The disease-modifying role of estrogen-related outcome measures warrants further clinical and experimental studies targeting gender differences, specifically hormone-dependent pathways in PD.
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Individual participant data analysis comparing acute stroke patients with anterior versus posterior circulation dissections - Zhang, Yanan; Zhang, Yang; Fröhlich, Kilian; Mrochen, Anne; Mühlen, Iris; Lang, Stefan; Lehmann, Sophie; Gerner, Stefan T.; Huttner, Hagen B.; Schwab, Stefan; He, Li; Bobinger, Tobias (Clinical Neurology and Neurosurgery, 2024)
Background: Cervical artery dissection (CAD) is a relevant etiology of transient ischemic attacks and strokes. Several trials explored the significance of specific antithrombotic treatments, i.e. oral anticoagulation (OAC) versus antiplatelet treatment (APT), on recurrent ischemic complications and clinical outcomes. As overall incidence rates of complications were low there is still controversy which antithrombotic treatment should be used. However, up to now there has been no systematic investigation among CAD-patients with ischemic stroke specifically comparing clinical course and outcome of patients with anterior versus posterior CAD. Methods: We performed an individual participant data analysis of patients with CAD and ischemic stroke. Over a five-year period we pooled data from three sites (i.e. West China Hospital, Chengdu, China as well as Erlangen and Giessen University Hospitals, Germany) and enrolled patients with CAD-associated ischemic stroke. Patient demographics, clinical and in-hospital measures as well as radiological data were retrieved from institutional databases. Clinical follow-up was over 6 months and included data on recurrent ischemic strokes and hemorrhages as well as clinical functional outcome assessed by the modified Rankin Scale dichotomized into favourable (mRS=0–2) and unfavourable. Results: A total of 203 patients with CAD were included of which n=112 had anterior and n=91 had posterior CAD. Patients with posterior CAD were younger (46.0 vs. 41.0 y; p<0.001) than patients with anterior CAD and showed less often arterial hypertension. (42.0 % vs. 28.6 %; p<0.048). Antithrombotic treatment with APT and OAC was similarily distributed among patients with anterior and posterior CAD and not significantly differently related to ischemic or hemorrhagic complications during follow-up (all p=n.s.). Main difference between Chinese and German patients were mode of antithrombotic treatment consisting predominantly of APT in China compared to OAC in Germany. Functional outcome overall was good, yet worse in patients with anterior CAD compared to posterior CAD (80.2 % favorable in anterior CAD vs. 92.2 % in posterior CAD (p=0.014). Conclusion: This study provides evidence that anterior and posterior CAD show baseline imbalances regarding age and comorbidity which may affect clinical outcome. There are no signals of superiority or harm of any specific mode of antithrombotic treatment nor relevant discrepancies in clinical outcome among Chinese and German CAD-associated stroke patients.
CRIS-Team Scopus Importer:2024-06-21
Keywords: Acute ischemic stroke; Antiplatelet treatment; Cervical artery dissections; Clinical outcome; Oral anticoagulation

Individuelle Therapieeffekte: Analyse interindividueller Unterschiede in der Anpassung der Gleichgewichtsfähigkeit nach Laufbandtherapie bei Parkinsonpatienten - Klamroth, Sarah; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (3. Symposium Physiotherapiewissenschaft, 2018)

Inertial Gait Sensors to Measure Mobility and Functioning in Hereditary Spastic Paraplegia A Cross-sectional Multicenter Clinical Study - Regensburger, Martin; Spatz, Imke; Ollenschläger, Malte; Martindale, Christine; Lindeburg, Philipp; Kohl, Zacharias; Eskofier, Björn; Klucken, Jochen; Schuele, Rebecca; Klebe, Stephan; Winkler, Jürgen; Gaßner, Heiko (Neurology, 2022)
Background and Objectives Hereditary spastic paraplegia (HSP) causes progressive spasticity and weakness of the lower limbs. As neurologic examination and the clinical Spastic Paraplegia Rating Scale (SPRS) are subject to potential patient-dependent and clinician-dependent bias, instrumented gait analysis bears the potential to objectively quantify impaired gait. The aim of this study was to investigate gait cyclicity parameters by application of a mobile gait analysis system in a cross-sectional cohort of patients with HSP and a longitudinal fast progressing subcohort. Methods Using wearable sensors attached to the shoes, patients with HSP and controls performed a 4 x 10 m walking test during regular visits in 3 outpatient centers. Patients were also rated according to the SPRS, and in a subset, questionnaires on quality of life and fear of falling were obtained. An unsupervised segmentation algorithm was used to extract stride parameters and respective coefficients of variation. Results Mobile gait analysis was performed in a total of 112 ambulatory patients with HSP and 112 age-matched and sex-matched controls. Although swing time was unchanged compared with controls, there were significant increases in the duration of the total stride phase and the duration of the stance phase, both regarding absolute values and coefficients of variation values. Although stride parameters did not correlate with age, weight, or height of the patients, there were significant associations of absolute stride parameters with single SPRS items reflecting impaired mobility (|r| > 0.50), with patients' quality of life (|r| > 0.44), and notably with disease duration (|r| > 0.27). Sensor-derived coefficients of variation, on the other hand, were associated with patient-reported fear of falling (|r| > 0.41) and cognitive impairment (|r| > 0.40). In a small 1-year follow-up analysis of patients with complicated HSP and fast progression, the absolute values of mobile gait parameters had significantly worsened compared with baseline. Discussion The presented wearable sensor system provides parameters of stride characteristics which seem clinically valid to reflect gait impairment in HSP. Owing to the feasibility regarding time, space, and costs, this study forms the basis for larger scale longitudinal and interventional studies in HSP.
CRIS-Team WoS Importer:2022-09-23

Inertial sensor acquired foot elevation parameters validated by Motion capture in a cohort of patients with Hereditary Spastic Paraplegias - Koch, Veronika; Jakob, Verena; Küderle, Arne; Ollenschläger, Malte; Kotter, Kathrin; Ibrahim, Alzhraa; Winkler, Jürgen; Eskofier, Björn; Regensburger, Martin; Gaßner, Heiko (Gait & Posture, 2023)
CRIS-Team WoS Importer:2023-03-24

Inertial sensor-based estimation of peak accelerations during heel-strike and loading as markers of impaired gait patterns in PD patients - Hannink, Julius; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen (10. Deutscher Kongress für Parkinson und andere Bewegungsstörungen, 2017)

Inertial Sensor based Gait Analysis Discriminates Subjects with and without Visual Impairment Caused by Simulated Macular Degeneration - Kanzler, Christoph M.; Barth, Jens; Klucken, Jochen; Eskofier, Björn (Proceedings of the 38th IEEE Engineering in Medicine and Biology Society Conference, 2016)
Macular degeneration is the third leading cause of blindness worldwide and the leading cause of blindness in the developing world. The analysis of gait parameters can be used to assess the influence of macular degeneration on gait. This study examines the effect of macular degeneration on gait using inertial sensor based 3D spatio-temporal gait parameters. We acquired gait data from 21 young and healthy subjects during a 40m obstacle walk. All subjects had to perform the gait trial with and without macular degeneration simulation glasses. The order of starting with or without glasses alternated between each subject in order to test for training effects. Multiple 3D spatio-temporal gait parameters were calculated for the normal vision as well as the impaired vision groups. The parameters trial time, stride time, stride time coefficient of variation (CV), stance time, stance time CV, stride length, cadence, gait velocity and angle at toe off showed statistically significant differences between the two groups. Training effects were visible for the trials which started without vision impair- ment. Inter-group differences in the gait pattern occurred due to an increased sense of insecurity related with the loss of visual acuity from the simulation glasses. In summary, we showed that 3D spatio-temporal gait pa- rameters derived from inertial sensor data are viable to detect differences in the gait pattern of subjects with and without a macular degeneration simulation. We believe that this study provides the basis for an in-depth analysis regarding the impact of macular degeneration on gait.
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Inertial sensor-based gait parameters reflect patient-reported fatigue in multiple sclerosis - Ibrahim, Alzhraa; Küderle, Arne; Gaßner, Heiko; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (Journal of neuroEngineering and rehabilitation, 2020)
Background: Multiple sclerosis (MS) is a disabling disease affecting the central nervous system and consequently the whole body’s functional systems resulting in different gait disorders. Fatigue is the most common symptom in MS with a prevalence of 80%. Previous research studied the relation between fatigue and gait impairment using stationary gait analysis systems and short gait tests (e.g. timed 25 ft walk). However, wearable inertial sensors providing gait data from longer and continuous gait bouts have not been used to assess the relation between fatigue and gait parameters in MS. Therefore, the aim of this study was to evaluate the association between fatigue and spatio-temporal gait parameters extracted from wearable foot-worn sensors and to predict the degree of fatigue. Methods: Forty-nine patients with MS (32 women; 17 men; aged 41.6 years, EDSS 1.0–6.5) were included where each participant was equipped with a small Inertial Measurement Unit (IMU) on each foot. Spatio-temporal gait parameters were obtained from the 6-min walking test, and the Borg scale of perceived exertion was used to represent fatigue. Gait parameters were normalized by taking the difference of averaged gait parameters between the beginning and end of the test to eliminate inter-individual differences. Afterwards, normalized parameters were transformed to principle components that were used as input to a Random Forest regression model to formulate the relationship between gait parameters and fatigue. Results: Six principal components were used as input to our model explaining more than 90% of variance within our dataset. Random Forest regression was used to predict fatigue. The model was validated using 10-fold cross validation and the mean absolute error was 1.38 points. Principal components consisting mainly of stride time, maximum toe clearance, heel strike angle, and stride length had large contributions (67%) to the predictions made by the Random Forest. Conclusions: The level of fatigue can be predicted based on spatio-temporal gait parameters obtained from an IMU based system. The results can help therapists to monitor fatigue before and after treatment and in rehabilitation programs to evaluate their efficacy. Furthermore, this can be used in home monitoring scenarios where therapists can monitor fatigue using IMUs reducing time and effort of patients and therapists.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Accelerometer; Digital biomarker; Fatigue; Gait; IMU; Machine learning; MS

Influence of antithrombotic pre-treatment and time window on hemorrhagic complications of ivt in ischemic stroke - Macha, Kosmas; Hölter, Philip; Sembill, Jochen; Hock, Stefan; Siedler, Gabriela; Mühlen, Iris; Haupenthal, David; Schwab, Stefan; Kallmünzer, Bernd; Dörfler, Arnd (EUROPEAN JOURNAL OF NEUROLOGY, 2022)
CRIS-Team WoS Importer:2022-07-22

Influence of bundled care treatment on functional outcome in patients with intracerebral hemorrhage - Mrochen, Anne; Song, Yu; Harders, Verena; Sembill, Jochen; Sprügel, Maximilian; Hock, Stefan; Lang, Stefan; Engelhorn, Tobias; Kallmünzer, Bernd; Volbers, Bastian; Kuramatsu, Joji (Frontiers in Neurology, 2024)
Background and aims: General guideline recommendations in patients with intracerebral hemorrhage (ICH) include blood pressure-, temperature- and glucose management. The therapeutic effect of such a “care bundle” (blood pressure lowering, glycemic control, and treatment of pyrexia) on clinical outcomes becomes increasingly established. For the present study, we aimed to investigate associations of strict bundled care treatment (BCT) with clinical outcomes and characterize associations with key outcome effectors such as hematoma enlargement (HE) and peak perihemorrhagic edema (PHE). Methods: We screened consecutive ICH patients (n = 1,322) from the prospective UKER-ICH cohort study. BCT was defined as achieving and maintaining therapeutic ranges for systolic blood pressure (110–160 mmHg), glucose (80–180 mg/dL), and body temperature (35.5–37.5°C) over the first 72 h. The primary outcome was the functional outcome at 12 months (modified Rankin Scale (mRS) 0–3). Secondary outcomes included mortality at 12 months, the occurrence of hematoma enlargement, and the development of peak perihemorrhagic edema. Confounding was addressed by a doubly robust methodology to calculate the absolute treatment effect (ATE) and by calculating e-values. Results: A total of 681 patients remained for analysis, and 182 patients fulfilled all three BCT criteria and were compared to 499 controls. The ATE of BCT to achieve the primary outcome was 9.3%, 95% CI (1.7 to 16.9), p < 0.001; e-value: 3.1, CI (1.8). Mortality at 12 months was significantly reduced by BCT [ATE: −12.8%, 95% CI (−19.8 to −5.7), p < 0.001; e-value: 3.8, CI (2.2)], and no association was observed for HE or peak PHE. Significant drivers of BCT effect on the primary outcome were systolic blood pressure control (ATE: 15.9%) and maintenance of normothermia (ATE: 10.9%). Conclusion: Strict adherence to this “care bundle” over the first 72 h during acute hospital care in patients with ICH was independently associated with improved functional long-term outcome, driven by systolic blood pressure control and maintenance of normothermia. Our findings strongly warrant prospective validation to determine the generalizability especially in Western countries. Clinical trial registration:ClinicalTrials.gov, identifier [ID: NCT03183167].
CRIS-Team Scopus Importer:2024-08-30
Keywords: bundle; HE; ICH; PHE; treatment

Influence of Early Enteral Nutrition on Clinical Outcomes in Neurocritical Care Patients With Intracerebral Hemorrhage - Peng, Jianhua; Volbers, Bastian; Sprugel, Maximilian I.; Hölter, Philip; Engelhorn, Tobias; Jiang, Yong; Kuramatsu, Joji; Huttner, Hagen; Dörfler, Arnd; Schwab, Stefan; Gerner, Stefan (Frontiers in Neurology, 2021)
Objective: Early enteral nutrition (EEN) represents the current standard of care for patients treated in general intensive care units (ICU). Specific nutritional recommendations for patients receiving dedicated neurocritical care are not established. This study investigated associations of EEN with clinical outcomes for patients suffering from intracerebral hemorrhage treated at a neurological ICU (NICU).
CRIS-Team WoS Importer:2021-05-14

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders - Borisow, Nadja; Kleiter, Ingo; Gahlen, Anna; Fischer, Katrin; Wernecke, Klaus-Dieter; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Krumbholz, Markus; Kuempfel, Tania; Aktas, Orhan; Ringelstein, Marius; et al. (Multiple sclerosis journal, 2017)
Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ?40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years.Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
EVALuna2:22502

Influence of image reconstruction parameters on diagnostic performance of on-site CT-derived FFR: Comparison with invasively measured FFR - Ammon, Fabian; Röther, Jens; Hell, M.; Schuhbaeck, A.; Achenbach, Stephan; Schlundt, Christian; Marwan, Mohamed (EUROPEAN HEART JOURNAL, 2018)
CRIS-Team WoS Importer:2019-03-15

Influence of new versus traditional antiepileptic drugs on course and outcome of status epilepticus - Reindl, Caroline; Sprügel, Maximilian; Sembill, Jochen; Müller, Tamara; Hagen, Manuel; Gerner, Stefan; Kuramatsu, Joji; Hamer, Hajo; Huttner, Hagen; Madžar, Dominik (Seizure-European Journal of Epilepsy, 2020)
Purpose: New antiepileptic drugs (AEDs) are increasingly applied in second-line therapy of status epilepticus (SE). In our study, we analyzed the impact of the choice of second-line AEDs on the course and prognosis of SE. Methods: This retrospective single- center study used data of an 8 year cohort of SE in adults from 2007 to 2014. Based on the year of market introduction with a cutoff at 1990, we classified AEDs as traditional or new. Prescription pattern associated differences in prognosis were measured through univariate and multivariable analysis of 3 endpoints: occurrence of refractory SE (RSE), functional outcome in survivors to discharge (good: mRS at discharge <3 or identical to admission mRS; otherwise poor), and in-hospital mortality. Results: From 362 SE episodes during the study period, 222 episodes were included into the study, among those 150 episodes treated with new and 72 with traditional AEDs. Use of new AEDs increased during the study period. After adjustment for confounders, treatment with new AEDs was on the one hand associated with higher rate of RSE occurrence (OR 1.95, 95 % CI 1.05–3.62, p = 0.03), but, on the other hand, also with better functional outcome at discharge (OR 2.64, 95 % CI 1.16–6.00, p = 0.02), while it was not an independent predictor of in- hospital mortality (OR 0.88, 95 % CI 0.33–2.33, p = 0.80). Conclusion: Our observation that new AEDs may be associated with a higher rate of RSE development and relatively better functional outcome when adjusted for the premorbid mRS needs confirmation in prospective studies.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Anticonvulsant; Antiepileptic drug; Established status epilepticus; Functional outcome; Mortality; Refractoriness; Status epilepticus; Treatment

Influence of Prior Nicotine and Alcohol Use on Functional Outcome in Patients after Intracerebral Hemorrhage - Sembill, Jochen; Sprügel, Maximilian; Gerner, Stefan; Beuscher, Vanessa D.; Giede-Jeppe, Antje; Stocker, Margarete; Lücking, Hannes; Kuramatsu, Joji; Huttner, Hagen; Hölter, Philip (Journal of Stroke and Cerebrovascular Diseases, 2018)
Background: The influence of prior nicotine or alcohol use (legal drug use [LDU]) on outcome measures after intracerebral hemorrhage (ICH) is insufficiently established. We investigated drug-specific associations with (1) neuroradiologic and clinical parameters and (2) functional long-term outcome after ICH. Methods: This observational cohort study analyzed consecutive spontaneous patients with ICH (n = 554) from our prospective institutional registry over a 5-year study period (January 2010 to December 2014). We compared no-LDU patients with LDU patients, and patients using only nicotine, only alcohol, or both. To account for baseline imbalances, we reanalyzed cohorts after propensity score matching. Results: Prevalence of prior LDU was 197 of 554 (35.6%), comprising 94 of 554 (17.0%) with only nicotine use, 33 of 554 (6.0%) with only alcohol use, and 70 of 554 (12.6%) with alcohol and nicotine use. LDU patients were younger (65 [56-73] versus 75 [67-82], P < .01), less often female (n = 61 of 197 [31.0%] versus n = 188 of 357 [52.7%], P < .01), had more often prior myocardial infarction (n = 29 of 197 [14.7%] versus n = 24 of 357 [6.7%], P < .01), and in-hospital complications (sepsis or systemic inflammatory response syndrome: n = 95 of 197 [48.2%] versus n = 98 of 357 [27.5%], P < .01; pneumonia: n = 89 of 197 [45.2%] versus n = 110 of 357 [30.8%], P < .01). Except for an increased risk of pneumonia (odds ratio 2.22, confidence interval [1.04-4.75], P = .04) in patients using both nicotine and alcohol, we detected no significant differences upon reanalysis after propensity score matching of neuroradiologic or clinical parameters, complications, or long-term outcome between patients with and without LDU (mortality: n = 48 of 150 [32.0%] versus n = 45 of 150 [30.0%], P = .71; favorable outcome [modified Rankin Scale 0-3]: n = 56 of 150 [37.3%] versus n = 53 of 150 [35.3%], P = .72). Conclusions: Prior nicotine use, alcohol use, and their combination were associated with significant differences in baseline characteristics. However, adjusting for unevenly balanced baseline parameters revealed no differences in functional long-term outcome after ICH.
EVALuna2:34918

Influence of Residual Quadrupolar Interaction on Quantitative Sodium Brain Magnetic Resonance Imaging of Patients With Multiple Sclerosis - Wilferth, Tobias; Mennecke, Angelika; Huhn, Konstantin; Uder, Michael; Doerfler, Arnd; Schmidt, Manuel; Nagel, Armin M. (Investigative Radiology, 2023)
OBJECTIVES: The purpose of this work was to evaluate the influence of residual quadrupolar interaction on the determination of human brain apparent tissue sodium concentrations (aTSCs) using quantitative sodium magnetic resonance imaging ( 23 Na MRI) in healthy controls (HCs) and patients with multiple sclerosis (MS). Especially, it was investigated if the more detailed examination of residual quadrupolar interaction effects enables further analysis of the observed 23 Na MRI signal increase in MS patients. MATERIALS AND METHODS: 23 Na MRI with a 7 T MR system was performed on 21 HC and 50 MS patients covering all MS subtypes (25 patients with relapsing-remitting MS, 14 patients with secondary progressive MS, and 11 patients with primary progressive MS) using 2 different 23 Na pulse sequences for quantification: a commonly used standard sequence (aTSC Std ) as well as a sequence with shorter excitation pulse length and lower flip angle for minimizing signal loss resulting from residual quadrupolar interactions (aTSC SP ). Apparent tissue sodium concentration was determined using the same postprocessing pipeline including correction of the receive profile of the radiofrequency coil, partial volume correction, and relaxation correction. Spin dynamic simulations of spin-3/2 nuclei were performed to aid in the understanding of the measurement results and to get deeper insight in the underlying mechanisms. RESULTS: In normal-appearing white matter (NAWM) of HC and all MS subtypes, the aTSC SP values were approximately 20% higher than the aTSC Std values ( P < 0.001). In addition, the ratio aTSC SP /aTSC Std was significantly higher in NAWM than in normal-appearing gray matter (NAGM) for all subject cohorts ( P < 0.002). In NAWM, aTSC Std values were significantly higher in primary progressive MS compared with HC ( P = 0.01) as well as relapsing-remitting MS ( P = 0.03). However, in contrast, no significant differences between the subject cohorts were found for aTSC SP . Spin simulations assuming the occurrence of residual quadrupolar interaction in NAWM were in good accordance with the measurement results, in particular, the ratio aTSC SP /aTSC Std in NAWM and NAGM. CONCLUSIONS: Our results showed that residual quadrupolar interactions in white matter regions of the human brain have an influence on aTSC quantification and therefore must be considered, especially in pathologies with expected microstructural changes such as loss of myelin in MS. Furthermore, the more detailed examination of residual quadrupolar interactions may lead to a better understanding of the pathologies themselves.
CRIS-Team Scopus Importer:2023-09-15

Influence of the Extent of Intraventricular Hemorrhage on Functional Outcome and Mortality in Intracerebral Hemorrhage - Röder, Sebastian; Sprügel, Maximilian; Sembill, Jochen; Giede-Jeppe, Antje; Macha, Kosmas; Madžar, Dominik; Lücking, Hannes; Gerner, Stefan; Kuramatsu, Joji; Huttner, Hagen; Hölter, Philip (Cerebrovascular Diseases, 2019)
Background and Objective: Intraventricular hemorrhage (IVH) is a verified independent prognostic parameter in patients with intracerebral hemorrhage (ICH). However, the impact of the extent of IVH on clinical outcomes is unestablished. Methods: We analyzed 1,112 consecutive primary ICH patients of the UKER-ICH cohort (NCT03183167) and hypothesized that there is no difference in outcome between patients without IVH and patients with minor IVH not leading to obstructive hydrocephalus. Propensity score matching and multivariable analyses were performed to account for imbalances in baseline characteristics. Primary outcome was defined as functional outcome 3 months after ICH -assessed using the modified Rankin Scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable outcome (mRS = 4-6). Secondary outcomes included mortality at 3 months and a Graeb score-based threshold analysis for association of the extent of IVH with unfavorable clinical outcome. Results: Among the 461 out of 1,112 (41.5%) ICH patients with IVH, 191 out of 461 (41.4%) showed IVH without obstructive hydrocephalus and no requirement of external ventricular drain (EVD) placement. After adjusting for baseline imbalances we found no difference in functional outcome at 3 months between patients without IVH (No-IVH) and patients with IVH not requiring EVD (IVH-w/o-EVD): mRS 0-3: No-IVH 64/161 (39.8%) vs. IVH-w/o-EVD 53/170 (31.2%); p = 0.103. However, there was a trend toward a higher mortality in IVH-w/o-EVD patients (mRS 6: No IVH 40/161 [24.8%] vs. IVH-w/o-EVD 57/170 [33.5%]; p = 0.083). Multivariable analysis revealed that a Graeb score >2 was independently associated with unfavorable outcome (mRS 4-6: OR 3.16 [1.54-6.48]; p = 0.002), and higher mortality (mRS 6: OR 2.57 [1.40-4.74]; p = 0.002) in IVH patients. Conclusions: Small amounts of intraventricular blood (Graeb score ≤2) not leading to obstructive hydrocephalus are not associated with unfavorable outcome or death after ICH. Thus, IVH per se should not be considered a binary variable in outcome prediction for ICH patients.
CRIS-Team Scopus Importer:2019-07-02

Influence on Outcome and Treatment of Intracerebral Hematoma in Patients with Atraumatic Subarachnoid Hemorrhage - Gerner, Stefan; Kuramatsu, Joji; Reichl, Jonathan; Eyüpoglu, Ilker Yasin; Dörfler, Arnd; Engelhorn, Tobias; Schwab, Stefan; Huttner, Hagen (CEREBROVASCULAR DISEASES, 2019)
CRIS-Team WoS Importer:2020-02-21

In-hospital management of intracerebral hemorrhage Innerklinische Versorgung von intrazerebralen Blutungen - Sembill, Jochen; Schwab, Stefan (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2024)
Background: Intracerebral hemorrhage (ICH) is a medical emergency with high morbidity and mortality. General and specific therapeutic approaches aim to improve the patient’s outcome. Objectives: The objective of this article is to present the current scientific state regarding the in-hospital care of patients with ICH. Materials and methods: This narrative review presents and analyzes the current evidence regarding treatment options for ICH. Results: The primary focus of acute therapy is to prevent the prognostically unfavorable enlargement of the hematoma. This is associated with specific computed tomographic markers, as well as the initial hematoma volume, the use of anticoagulants, and a shorter time from symptom onset. An elevated blood pressure should be promptly and precisely lowered to a systolic value below 140 mm Hg, and the inhibition of coagulation must be immediately antagonized. This should be constituted into a treatment bundle with optimal adjustment of vital parameters and implementation of basic intensive care measures. Intraventricular hemorrhage can be effectively treated by external ventricular drainage and intraventricular fibrinolysis, with or without additional lumbar drainage. Minimally invasive procedures for hematoma removal have the potential to improve outcomes in lobar ICH. A realistic prognostic assessment forms the basis for informed treatment decisions regarding ICH. Conclusions: In recent years, the evidence supporting aggressive therapeutic approaches in ICH has become increasingly robust, with reliable results now available regarding the efficacy of individual or combined measures.
CRIS-Team Scopus Importer:2025-02-04
Keywords: Anticoagulants; Cerebral intraventricular hemorrhage; Critical care; Hypertension; Prognosis

Initiating anticoagulant therapy after ICH is associated with patient characteristics and treatment recommendations - Sembill, Jochen; Wieser, Claudia; Sprügel, Maximilian; Gerner, Stefan; Giede-Jeppe, Antje; Reindl, Caroline; Eyüpoglu, Ilker Yasin; Lücking, Hannes; Kuramatsu, Joji; Huttner, Hagen; Hölter, Philip (Journal of Neurology, 2018)
The proportion of patients with intracerebral hemorrhage (ICH) and concomitant indication for oral anticoagulant (OAC) therapy is increasing. Although recent studies documented a favorable risk-benefit profile of OAC initiation, deciding whether, when, and which OAC should be started remains controversial. We investigated (1) OAC recommendations, its implementation, and adherence and (2) factors associated with OAC initiation after ICH. This prospective observational study analyzed consecutive ICH patients (n = 246) treated at the neurological and neurosurgical department of the University-Hospital Erlangen, Germany over a 21-month inclusion period (05/2013-01/2015). We analyzed the influence of patient characteristics, in-hospital measures, and functional status on treatment recommendations and on OAC initiation during 12-month follow-up. In-hospital mortality of 24.8% (n = 61/246) left 185 patients discharged alive of which 34.1% (n = 63/185) had OAC indication. In these patients, OAC initiation was clearly recommended in only 49.2% (n = 31/63) and associated with favorable [modified Rankin Scale (mRS) = 0-3] functional discharge status [OR 7.18, CI (1.05-49.13), p = 0.04], less frequent heart failure [OR 0.19, CI (0.05-0.71), p = 0.01], and younger age [OR 0.95, CI (0.90-1.00), p = 0.05]. OAC was more often started if clearly recommended [n = 19/31 (61.3%) versus (no recommendation) n = 4/26 (15.4%), p < 0.001; (clearly not recommended, n = 6)] and associated with younger age [67 (58-74) versus 79 (73-83), p < 0.001], favorable functional outcome [n = 10/23 (43.5%) versus n = 5/40 (12.5%), p = 0.01], decreased mortality [n = 6/23 (26.1%) versus n = 19/40 (47.5%), p = 0.06], and functional improvement [n = 13/17 (76.5%) versus n = 7/21 (33.3%), p = 0.01]. We observed no differences in rates of intracranial complications [thromboembolism, n = 3/23 (13.0%) versus n = 4/40 (10.0%), p = 1.00; hemorrhage, n = 1/23 (4.3%) versus n = 3/40 (7.5%), p = 1.00]. Clear treatment recommendations by attending stroke physicians significantly influence OAC initiation after ICH. OAC were more frequently recommended and started in younger patients with better functional recovery independent from intracranial complications. This might represent an important determinant of observed beneficial associations, hinting towards an indication bias which might affect observational analyses.
EVALuna2:34916

In response to commentary on cavernoma-related epilepsy: review and recommendations for management-report of the surgical task force of the ILAE commission on therapeutic strategies - Rosenow, Felix; Alonso-Vanegas, Mario A.; Baumgartner, Christoph; Blümcke, Ingmar; Carreno, Mar; Gizewski, Elke R.; Hamer, Hajo; Knake, Susanne; Kahane, Philippe; Lueders, Hans O.; Mathern, Gary W.; Menzler, Katja; et al. (Epilepsia, 2014)
EVALuna2:7236

Insular multiple sclerosis lesions are associated with erectile dysfunction - Winder, Klemens; Linker, Ralf; Seifert, Frank; Deutsch, Martina; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Hoesl, Katharina M.; Hilz, Max-Josef (Journal of Neurology, 2018)
Erectile function (EF) is frequently compromised in men with multiple sclerosis (MS). Functional neuroimaging in healthy men identified a network of brain areas, such as the insula, visual and somatosensory association areas, cingulate gyrus, prefrontal cortex, as well as subcortical regions, contributing to EF. This study intended to determine associations between EF deterioration during MS and cerebral MS-associated lesion sites. In 31 men with MS (mean age 38.2 ± 11.2 years), we evaluated MS-related EF deterioration by comparing scores of the 5-item International Index of Erectile Function-5 questionnaire (IIEF5) at the time of study and retrospectively, 3 months prior to MS diagnosis, by calculating score differences as DeltaIIEF5 (DeltaIIEF5 score < 0 indicated EF deterioration). To assess the impact of confounding factors of EF, patient age, disease duration, disease severity, depressiveness, bladder and bowel symptoms, and total cerebral MS lesion volume were correlated with DeltaIIEF5 scores (Spearman rank correlation) and compared between patients with and without EF deterioration (t tests or Mann-Whitney U test). MS lesions were assessed on T2-weighted magnetic resonance imaging (MRI; 1.5 or 3 T). We determined the lesion overlap (prevalence of identical lesion sites among patients), subtracted lesion overlaps in patients without EF deterioration from overlaps in patients with EF deterioration, and compared DeltaIIEF5 scores voxel-wise between patients with and without lesions in a given voxel (t test; significance: p < 0.05). In 14 patients (45.2%), DeltaIIEF5 scores indicated EF deterioration. DeltaIIEF5 scores were not associated with age (ρ = 0.06; p = 0.74), disease duration (ρ = 0.26; p = 0.15), disease severity (ρ = - 0.19; p = 0.31), depressiveness (ρ = 0.07; p = 0.72), bladder symptoms (ρ = - 0.11; p = 0.57), bowel symptoms (ρ = 0.17; p = 0.37), and total lesion volume (ρ = - 0.13; p = 0.47). The voxel-wise analysis showed associations between EF deterioration and MS lesions primarily in the bilateral, and predominantly left juxtacortical insular region. In conclusion, MS lesions particularly in the left insular region, which is activated with sexual arousal, contribute to erectile dysfunction.
EVALuna2:34021

Integration of functional neuronavigation and intraoperative MRI in surgery for drug-resistant extratemporal epilepsy close to eloquent brain areas - Sommer, Bjoern; Grummich, Peter; Coras, Roland; Kasper, Burkhard S.; Blümcke, Ingmar; Hamer, Hajo; Stefan, Hermann; Buchfelder, Michael; Roessler, Karl (Neurosurgical Focus, 2013)
Object. The authors performed a retrospective study to assess the impact of functional neuronavigation and intraoperative MRI (iMRI) on surgery of extratemporal epileptogenic lesions on postsurgical morbidity and seizure control. Methods. Twenty-five patients (14 females and 11 males) underwent extratemporal resections for drug-resistant epilepsy close to speech/motor brain areas or adjacent to white matter tracts. The mean age at surgery was 34 years (range 12-67 years). The preoperative mean disease duration was 13.2 years. To avoid awake craniotomy, cortical motor-sensory representation was mapped during preoperative evaluation in 14 patients and speech representation was mapped in 15 patients using functional MRI. In addition, visualization of the pyramidal tract was performed in 11 patients, of the arcuate fascicle in 7 patients, and of the visual tract in 6 patients using diffusion tensor imaging. The mean minimum distance of tailored resection between the eloquent brain areas was 5.6mm. During surgery, blood oxygen level-dependent imaging and diffusion tensor imaging data were integrated into neuronavigation and displayed through the operating microscope. The postoperative mean follow-up was 44.2 months. Results. In 20% of these patients, further intraoperative resection was performed because of intraoperatively documented residual lesions according to iMRI findings. At the end of resection, the final iMRI scans confirmed achievement of total resection of the putative epileptogenic lesion in all patients. Postoperatively, transient complications and permanent complications were observed in 20% and 12% of patients, respectively. Favorable postoperative seizure control (Engel Classes I and II) was achieved in 84% and seizure freedom in 72% of these consecutive surgical patients. Conclusions. By using functional neuronavigation and iMRI for treatment of epileptogenic brain lesions, the authors achieved a maximum extent of resection despite the lesions' proximity to eloquent brain cortex and fiber tracts in all cases. The authors' results underline possible benefits of this technique leading to a favorable seizure outcome with acceptable neurological deficit rates in difficult-to-treat extratemporal epilepsy. © AANS, 2013.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Eloquent brain area; Extratemporal epilepsy; Functional neuronavigation; Intraoperative MRI; Seizure outcome; Surgery

INTEGRATION OF MULTIMODAL IMAGING AND INTRAOPERATIVE MR IN RESECTIVE SURGERY FOR MEDICALLY REFRACTORY EPILEPSY: THE ERLANGEN EXPERIENCE OF 415 PATIENTS - Sommer, B.; Roessler, K.; Hofmann, Andrea; Coras, R.; Kasper, Burkhard; Hamer, Hajo; Blümcke, Ingmar; Buchfelder, Michael (2016)
EVALuna2:33851

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells - Schneider, Yanni; Drobny, Alice; Prots, Iryna; Zunke, Friederike; Xiang, Wei; Seebauer, Lukas; Schneider, Yanni; Drobny, Alice; Ploetz, Sonja; Koudelka, Tomas; Tholey, Andreas; Prots, Iryna; et al. (International Journal of Molecular Sciences, 2022)
Parkinson’s disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by sev-eral studies using cell-free model systems. In this study, we investigate the impact of aSyn on mi-crotubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCA-Dupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.
CRIS-Team Scopus Importer:2022-02-11
Keywords: Alpha-synuclein; IPSC; Microtubule; Neurite; Neurodegeneration; Parkinson’s disease; SNCA duplication

Interferon Beta and vitamin d synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients - Waschbisch, Anne; Sanderson, Nicholas; Krumbholz, Markus; Vlad, George; Theil, Diethilde; Schwab, Stefan; Mäurer, Mathias Eckhard; Derfuss, Tobias (PLoS ONE, 2014)
Immunoglobulin-like transcript (ILT) 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D.
EVALuna2:22287

Interictal Electrical Source Imaging. - Rampp, Stefan; Müller-Voggel, Nadia; Hamer, Hajo; Dörfler, Arnd; Brandner, Sebastian; Buchfelder, Michael (Journal of Clinical Neurophysiology, 2024)
Interictal electrical source imaging (ESI) determines the neuronal generators of epileptic activity in EEG occurring outside of seizures. It uses computational models to take anatomic and neuronal characteristics of the individual patient into account. The presented article provides an overview of application and clinical value of interictal ESI in patients with pharmacoresistant focal epilepsies undergoing evaluation for surgery. Neurophysiological constraints of interictal data are discussed and technical considerations are summarized. Typical indications are covered as well as issues of integration into clinical routine. Finally, an outlook on novel markers of epilepsy for interictal source analysis is presented. Interictal ESI provides diagnostic performance on par with other established methods, such as MRI, PET, or SPECT. Although its accuracy benefits from high-density recordings, it provides valuable information already when applied to EEG with only a limited number of electrodes with complete coverage. Novel oscillatory markers and the integration of frequency coupling and connectivity may further improve accuracy and efficiency.
EVALuna2:547206

Interictal epileptiform discharges affect memory in an Alzheimer's disease mouse model - Soula, Marisol; Maslarova, Anna; Harvey, Ryan E.; Valero, Manuel; Brandner, Sebastian; Hamer, Hajo; Fernández-Ruiz, Antonio; Buzsáki, György (Proceedings of the National Academy of Sciences of the United States of America, 2023)
Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Alzheimer model; interictal epileptiform discharges; memory; replay; sharp wave ripples

Interictal magnetoencephalography used in magnetic resonance imaging-negative patients with epilepsy - Wu, Xueqing; Rampp, Stefan; Buchfelder, Michael; Kuwert, Torsten; Blümcke, Ingmar; Zhou, D.; Stefan, Herrmann; Dörfler, Arnd (Acta Neurologica Scandinavica, 2013)
Purpose: This study aims to investigate the contributions of magnetoencephalography (MEG) in magnetic resonance imaging (MRI)-negative patients. Methods: A total of 18 MRI-negative patients diagnosed with refractory epilepsy, subjected to MEG investigation, and subsequently underwent surgery were selected for retrospective analysis. A 1.5-tesla Magnetom Sonata with an eight-channel head array coil was used. MEG data were obtained using a 74/248-channel system. Results: A total of 16 patients (16/18) had positive MEG results, comprising 12 patients with monofocal localizations, five with multifocal localizations, and one with unremarkable results in MEG. In addition, 12 patients had indicative single photon-emission computed tomography (SPECT), five had indicative fluorodeoxyglucose positron emission tomography (FDG-PET), and all the patients had intracranial electroencephalography (EEG) (14 with subdural electrodes and four with electrocorticography). The intracranial EEG recordings of nine patients were guided by MEG informative results. Among these 18 patients, 10 exhibited good postoperative outcomes (Engel I and II), four of which were completely seizure-free. All these ten patients had clear monofocal localization in MEG, including nine with accordant indicative metabolic changes in either SPECT or FDG-PET, or both. None of the five patients with multifocal localizations achieved good postoperative outcomes. Conclusion: For cases with negative MRI findings, epilepsy surgery may be an alternative option for pharmaco-resistant patients if epileptogenic focus localizations by MEG are present in multimodal evaluation. © 2012 John Wiley & Sons A/S.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Magnetic resonance imaging; Magnetoencephalography; Non-lesional epilepsy; Outcome

Interindividual Balance Adaptations in Response to Perturbation Treadmill Training in Persons With Parkinson Disease - Klamroth, Sarah; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (Journal of Neurologic Physical Therapy, 2019)
BACKGROUND AND PURPOSE: Perturbation training is a promising approach to reduce fall incidence in persons with Parkinson disease (PwPD). This study aimed to evaluate interindividual differences in balance adaptations in response to perturbation treadmill training (PTT) and identify potential outcome predictors. METHODS: PwPD (n = 43, Hoehn & Yahr stage 1-3.5) were randomly assigned to either 8 weeks of PTT or conventional treadmill training (CTT) without perturbations. At baseline and following intervention, data from 4 domains of balance function (reactive, anticipatory, dynamic postural control, and quiet stance) were collected. Using responder analysis we investigated interindividual differences (responder rates and magnitude of change) and potential predictive factors. RESULTS: PTT showed a significantly higher responder rate in the Mini Balance Evaluation Systems Test (Mini-BESTest) subscore reactive postural control, compared with CTT (PTT = 44%; CTT = 10%; risk ratio = 4.22, confidence interval = 1.03-17.28). Additionally, while between-groups differences were not significant, the proportion of responders in the measures of dynamic postural control was higher for PTT compared with CTT (PTT: 22%-39%; CTT: 5%-10%). The magnitude of change in responders and nonresponders was similar in both groups. PTT responders showed significantly lower initial balance performance (4/8 measures) and cognitive function (3/8 measures), and were older and at a more advanced disease stage, based on descriptive evaluation. DISCUSSION AND CONCLUSIONS: Our findings suggest that PTT is beneficial to improve reactive balance in PwPD. Further, PTT appeared to be effective only for a part of PwPD, especially for those with lower balance and cognitive function, which needs further attention.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A1).
CRIS-Team Scopus Importer:2019-09-20

International consensus guidance for management of myasthenia gravis: Executive summary - Sanders, Donald B.; Wolfe, Gil I.; Benatar, Michael; Evoli, Amelia; Gilhus, Nils E.; Illa, Isabel; Kuntz, Nancy; Massey, Janice M.; Melms, Arthur; Murai, Hiroyuki; Nicolle, Michael; Palace, Jacqueline; et al. (Neurology, 2016)
To develop formal consensus-based guidance for the management of myasthenia gravis (MG).In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input.Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy.This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.
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Interrelation of depression, sexual dysfunction and disease severity in patients with multiple sclerosis - Hoesl, K.; Roy, Sankanika; Wang, Ruihao; Intravooth, Tassanai; Deutsch, Martina; Winder, K.; Lee, De-Hyung; Linker, Ralf; Hilz, M. J. (2017)
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Intracellular A53T Mutant alpha-Synuclein Impairs Adult Hippocampal Newborn Neuron Integration - Winner, Beate; Regensburger, Martin; Stemick, Judith; Masliah, Eliezer; Kohl, Zacharias (Frontiers in Cell and Developmental Biology, 2020)
Dendritic dysfunction is an early event in alpha-synuclein (alpha-syn) mediated neurodegeneration. Altered postsynaptic potential and loss of dendritic spines have been observed in different in vitro and in vivo models of synucleinopathies. The integration of newborn neurons into the hippocampus offers the possibility to study dendrite and spine formation in an adult environment. Specifically, survival of hippocampal adult newborn neurons is regulated by synaptic input and was reduced in a mouse model transgenic for human A53T mutant alpha-syn. We thus hypothesized that dendritic integration of newborn neurons is impaired in the adult hippocampus of A53T mice. We analyzed dendritic morphology of adult hippocampal neurons 1 month after retroviral labeling. Dendrite length was unchanged in the dentate gyrus of A53T transgenic mice. However, spine density and mushroom spine density of newborn neurons were severely decreased. In this mouse model, transgenic alpha-syn was expressed both within newborn neurons and within their environment. To specifically determine the cell autonomous effects, we analyzed cell-intrinsic overexpression of A53T alpha-syn using a retrovirus. Since A53T alpha-syn overexpressing newborn neurons exhibited decreased spine density 1 month after labeling, we conclude that cell-intrinsic A53T alpha-syn impairs postsynaptic integration of adult hippocampal newborn neurons. Our findings further support the role of postsynaptic degeneration as an early feature in synucleinopathies and provide a model system to study underlying mechanisms.
Keywords: A53T alpha-synuclein; cell autonomous; adult neurogenesis; hippocampus; spines

Intracellular A53T Mutant α-Synuclein Impairs Adult Hippocampal Newborn Neuron Integration - Regensburger, Martin; Stemick, Judith; Masliah, Eliezer; Kohl, Zacharias; Winner, Beate (Frontiers in Cell and Developmental Biology, 2020)
Dendritic dysfunction is an early event in α-synuclein (α-syn) mediated neurodegeneration. Altered postsynaptic potential and loss of dendritic spines have been observed in different in vitro and in vivo models of synucleinopathies. The integration of newborn neurons into the hippocampus offers the possibility to study dendrite and spine formation in an adult environment. Specifically, survival of hippocampal adult newborn neurons is regulated by synaptic input and was reduced in a mouse model transgenic for human A53T mutant α-syn. We thus hypothesized that dendritic integration of newborn neurons is impaired in the adult hippocampus of A53T mice. We analyzed dendritic morphology of adult hippocampal neurons 1 month after retroviral labeling. Dendrite length was unchanged in the dentate gyrus of A53T transgenic mice. However, spine density and mushroom spine density of newborn neurons were severely decreased. In this mouse model, transgenic α-syn was expressed both within newborn neurons and within their environment. To specifically determine the cell autonomous effects, we analyzed cell-intrinsic overexpression of A53T α-syn using a retrovirus. Since A53T α-syn overexpressing newborn neurons exhibited decreased spine density 1 month after labeling, we conclude that cell-intrinsic A53T α-syn impairs postsynaptic integration of adult hippocampal newborn neurons. Our findings further support the role of postsynaptic degeneration as an early feature in synucleinopathies and provide a model system to study underlying mechanisms.
CRIS-Team Scopus Importer:2020-12-04
Keywords: A53T alpha-synuclein; adult neurogenesis; cell autonomous; hippocampus; spines

Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells - Ettle, Benjamin; Reiprich, Simone; Deußer, Janina; Schlachetzki, Johannes; Xiang, Wei; Prots, Iryna; Masliah, Eliezer; Winner, Beate; Wegner, Michael; Winkler, Jürgen (Molecular and Cellular Neuroscience, 2014)
Myelin loss is a widespread neuropathological hallmark of the atypical parkinsonian disorder multiple system atrophy (MSA). On a cellular level, MSA is characterized by alpha-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCIs) within mature oligodendrocytes leading to demyelination as well as axonal and neuronal loss. Oligodendrocyte progenitor cells (OPCs) represent a proliferative cell population distributed throughout the adult mammalian central nervous system. During remyelination, OPCs are recruited to sites of demyelination, differentiate, and finally replace dysfunctional mature oligodendrocytes. However, comprehensive studies investigating OPCs and remyelination processes in MSA are lacking. In the present study, we therefore investigate the effect of human aSyn (h-aSyn) on early primary rat OPC maturation. Upon lentiviral transduction, h-aSyn expressing OPCs exhibit fewer and shorter primary processes at the initiation of differentiation. Until day 4 of a 6day differentiation paradigm, h-aSyn expressing OPCs further show a severely delayed maturation evidenced by reduced myelin gene expression and increased levels of the progenitor marker platelet derived growth factor receptor-alpha (PDGFR?). Matching these results, OPCs that take up extracellular recombinant h-aSyn exhibit a similar delayed differentiation. In both experimental setups however, myelin gene expression is restored at day 6 of differentiation paralleled by decreased intracellular h-aSyn levels indicating a reverse correlation of h-aSyn and the differentiation potential of OPCs. Taken together, these findings suggest a tight link between the intracellular level of h-aSyn and maturation capacity of primary OPCs.
EVALuna2:4696

Intracerebral haemorrhage volume, haematoma expansion and 3-month outcomes in patients on antiplatelets. A systematic review and meta-analysis. - Goeldlin, Martina B.; Siepen, Bernhard M.; Mueller, Madlaine; Volbers, Bastian; Z'Graggen, Werner; Bervini, David; Raabe, Andreas; Sprigg, Nikola; Fischer, Urs; Seiffge, David J. (European Stroke Journal, 2021)
AIMS: We assessed the association of prior antiplatelet therapy (APT) at onset of intracerebral haemorrhage (ICH) with haematoma characteristics and outcome. METHODS: We performed a systematic review and meta-analysis of studies comparing ICH outcomes of patients on APT (APT-ICH) with patients not taking APT (non-APT-ICH). Primary outcomes were haematoma volume (mean difference and 95% CI), haematoma expansion (HE), in-hospital 3-month mortality rates and good functional outcome (modified Rankin Scale score 0-2). We provide odds ratios (ORs) from random effects models and subgroup analyses for haematoma expansion and short-term mortality rates. RESULTS: We included 23 of 1551 studies on 30,949 patients with APT-ICH and 62,018 with non-APT-ICH. Patients on APT were older (Δmean 6.27 years, 95% CI 5.44-7.10), had larger haematoma volume (Δmean 5.74 mL, 95% CI 1.93-9.54), higher short-term mortality rates (OR 1.44, 95% CI 1.14-1.82), 3-month mortality rates (OR 1.58, 95% CI 1.14-2.19) and lower probability of good functional outcome (OR 0.61, 95% CI 0.49-0.77). While there was no difference in HE in the overall analysis (OR 1.32, 95% CI 0.85-2.06), HE occurred more frequently when assessed within 24 h (OR 2.58, 95% CI 1.18-5.67). We found insufficient data for comparison of single versus dual APT-ICH. Heterogeneity was substantial amongst studies. DISCUSSION: APT is associated with larger baseline haematoma volume, early (<24 h) haematoma expansion, mortality rates and morbidity in patients with ICH. Data on differences in single and dual APT-ICH are scarce and warrant further investigation. New treatment options for APT-ICH are urgently needed.
EVALuna2:527467

Intracerebral haemorrhage volume, haematoma expansion and 3-month outcomes in patients on antiplatelets. A systematic review and meta-analysis - Goeldlin, Martina B.; Siepen, Bernhard M.; Mueller, Madlaine; Volbers, Bastian; Z’Graggen, Werner; Bervini, David; Raabe, Andreas; Sprigg, Nikola; Fischer, Urs; Seiffge, David J. (European Stroke Journal, 2021)
Aims: We assessed the association of prior antiplatelet therapy (APT) at onset of intracerebral haemorrhage (ICH) with haematoma characteristics and outcome. Methods: We performed a systematic review and meta-analysis of studies comparing ICH outcomes of patients on APT (APT-ICH) with patients not taking APT (non–APT-ICH). Primary outcomes were haematoma volume (mean difference and 95% CI), haematoma expansion (HE), in-hospital 3-month mortality rates and good functional outcome (modified Rankin Scale score 0–2). We provide odds ratios (ORs) from random effects models and subgroup analyses for haematoma expansion and short-term mortality rates. Results: We included 23 of 1551 studies on 30,949 patients with APT-ICH and 62,018 with non-APT-ICH. Patients on APT were older (Δmean 6.27 years, 95% CI 5.44–7.10), had larger haematoma volume (Δmean 5.74 mL, 95% CI 1.93–9.54), higher short-term mortality rates (OR 1.44, 95% CI 1.14–1.82), 3-month mortality rates (OR 1.58, 95% CI 1.14–2.19) and lower probability of good functional outcome (OR 0.61, 95% CI 0.49–0.77). While there was no difference in HE in the overall analysis (OR 1.32, 95% CI 0.85–2.06), HE occurred more frequently when assessed within 24 h (OR 2.58, 95% CI 1.18–5.67). We found insufficient data for comparison of single versus dual APT-ICH. Heterogeneity was substantial amongst studies. Discussion: APT is associated with larger baseline haematoma volume, early (<24 h) haematoma expansion, mortality rates and morbidity in patients with ICH. Data on differences in single and dual APT-ICH are scarce and warrant further investigation. New treatment options for APT-ICH are urgently needed.
CRIS-Team Scopus Importer:2021-09-10
Keywords: 3-month outcome; antiplatelets; haematoma expansion; haematoma volume; Intracerebral haemorrhage

Intracerebroventricular administration of nerve growth factor induces gliogenesis in sensory ganglia, dorsal root, and within the dorsal root entry zone - Schlachetzki, Johannes; Pizzo, Donald P.; Morrissette, Debbi A.; Winkler, Jürgen (BioMed Research International, 2014)
Previous studies indicated that intracerebroventricular administration of nerve growth factor (NGF) leads to massive Schwann cell hyperplasia surrounding the medulla oblongata and spinal cord. This study was designed to characterize the proliferation of peripheral glial cells, that is, Schwann and satellite cells, in the trigeminal ganglia and dorsal root ganglia (DRG) of adult rats during two weeks of NGF infusion using bromodeoxyuridine (BrdU) to label dividing cells. The trigeminal ganglia as well as the cervical and lumbar DRG were analyzed. Along the entire neuraxis a small number of dividing cells were observed within these regions under physiological condition. NGF infusion has dramatically increased the generation of new cells in the neuronal soma and axonal compartments of sensory ganglia and along the dorsal root and the dorsal root entry zone. Quantification of BrdU positive cells within sensory ganglia revealed a 2.3- to 3-fold increase in glial cells compared to controls with a similar response to NGF for the different peripheral ganglia examined. Immunofluorescent labeling with S100? revealed that Schwann and satellite cells underwent mitosis after NGF administration. These data indicate that intracerebroventricular NGF infusion significantly induces gliogenesis in trigeminal ganglia and the spinal sensory ganglia and along the dorsal root entry zone as well as the dorsal root.
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Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation - Linnerbauer, Mathias; Lößlein, Lena; Vandrey, Oliver; Tsaktanis, Thanos; Beer, Alexander; Naumann, Ulrike; Panier, Franziska; Beyer, Tobias; Nirschl, Lucy; Kuramatsu, Joji; Winkler, Jürgen; Quintana, Francisco J.; et al. (JCI Insight, 2022)
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.
CRIS-Team Scopus Importer:2022-04-22

Intraoperative Magnetic-Resonance Tomography and Neuronavigation During Resection of Focal Cortical Dysplasia Type II in Adult Epilepsy Surgery Offers Better Seizure Outcomes - Roessler, Karl; Kasper, Burkhard; Heynold, Elisabeth; Coras, Roland; Sommer, Bjoern; Rampp, Stefan; Hamer, Hajo; Blümcke, Ingmar; Buchfelder, Michael (World Neurosurgery, 2018)
Focal cortical dysplasia (FCD) is one important cause of drug-resistant epilepsy potentially curable by epilepsy surgery. We investigated the options of using neuronavigation and intraoperative magnetic-resonance tomographical imaging (MRI) to avoid residual epileptogenic tissue during resection of patients with FCD II to improve seizure outcome.Altogether, 24 patients with FCD II diagnosed by MRI (16 female, 8 male; mean age 34 ± 10 years) suffered from drug-resistant electroclinical and focal epilepsy for a mean of 20.7 ± 5 years. Surgery was performed with preoperative stereoelectroencephalography (in 15 patients), neuronavigation, and intraoperative 1.5T-iopMRI in all 24 investigated patients.In 75% of patients (18/24), a complete resection was performed. In 89% (16/18) of completely resected patients, we documented an Engel I seizure outcome after a mean follow-up of 42 months. All incompletely resected patients had a worse outcome (Engel II-III, P < 0.0002). Patients with FCD IIB had also significant better seizure outcome compared with patients diagnosed as having FCD IIA (82% vs. 28%, P < 0.02). In 46% (11/24) of patients, intraoperative second-look surgeries due to residual lesions detected during the intraoperative MRI were performed. In these 11 patients, there were significant more completely seizure free patients (73% vs. 38% Engel IA), compared with 13 patients who finished surgery after the first intraoperative MRI (P < 0.05).Excellent seizure outcome after surgery of patients with FCD II positively correlated with the amount of resection, histologic subtype, and the use of intraoperative MRI, especially when intraoperative second-look surgeries were performed.
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Intraoperative use of high-field MRI in hypothalamic hamartomas associated with epilepsy: clinico-pathological presentation of five adult patients - Sommer, Bjoern; Schlaffer, Sven-Martin; Coras, Roland; Blümcke, Ingmar; Hamer, Hajo; Stefan, Hermann; Buchfelder, Michael (Acta Neurochirurgica, 2014)
Hypothalamic harmartomas (HHs) are either occasionally associated with medically intractable epileptic syndromes or precocious puberty. Due to the extraordinary location and the expansive intra-axial growth, surgical resection is difficult and challenging without causing severe neurological, hypothalamic or endocrinological deficits, which account for higher mortality and morbidity.We present a series of five adult patients with drug-resistant epilepsy who had been operated on for HH using neuronavigation and intraoperative 1.5-T magnetic resonance imaging (MRI). In this retrospective investigation, we compared our surgical strategy and postoperative results to existing series.During surgery, we identified remnant HH in the first intraoperative MRI control scan in three out of five patients. After re-segmentation of the residual lesion using neuronavigation, complete resection was achieved in two of the three patients as confirmed by final intraoperative and late follow-up MRI, raising the rate of total resections to four out of five patients. Two patients died during the observation period. One patient suffered from a permanent third nerve palsy and one from a transient monoparesis of the left arm. New endocrinological disturbances included diabetes insipidus centralis in two and secondary hypothyroidism and hypogonadism in one patient. Four out of five patients had favourable seizure control (Engel I or II) after 64.8 (34-83) months of mean follow-up.Neuronavigation and intraoperative MRI are valuable tools to encounter difficulties while performing surgery in patients with HHs. Intraoperative resection control increases the amount of maximum resection.
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Intraprocedural angiographic CT as a valuable tool in the course of endovascular treatment of direct sinus cavernous fistulas - Gölitz, Philipp; Struffert, Tobias; Saake, Marc; Knossalla, F.; Dörfler, Arnd (Interventional Neuroradiology, 2012)
This investigation aimed to demonstrate the potential of intraprocedural angiographic CT in monitoring complex endovascular coil embolization of direct carotid cavernous fistulas. Angiographic CT was performed as a dual rotational 5 s run with intraarterial contrast medium injection in two patients during endovascular coil embolization of direct carotid cavernous fistulas. Intraprocedural angiographic CT was considered helpful if conventional 2D series were not conclusive concerning coil position or if a precise delineation of the parent artery was impossible due to a complex anatomy or overlying coil material. During postprocessing multi-planar reformatted and dual volume images of angiographic CT were reconstructed. Angiographic CT turned out to be superior in the intraprocedural visualization of accidental coil migration into the parent artery where conventional 2D-DSA series failed to reliably detect coil protrusion. The delineation of coil protrusion by angiographic CT allowed immediate correct coil repositioning to prevent parent artery compromising. Angiographic CT can function as a valuable intraprocedurally feasible tool during complex coil embolizations of direct carotid cavernous fistulas. It allows the precise visualization of the cerebral vasculature and any accidental coil protrusion can be determined accurately in cases where conventional 2D-DSA series are unclear or compromised. Thus angiographic CT might contribute substantially to reduce procedural complications and to increase safety in the management of endovascular treatment of direct carotid cavernous fistulas.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Carotid cavernous fistula; Endovascular approach; Intraprocedural angiographic CT; Transarterial coil embolization

Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants - Meinel, Thomas R.; Wilson, Duncan; Gensicke, Henrik; Scheitz, Jan F.; Ringleb, Peter; Goganau, Ioana; Kaesmacher, Johannes; Bae, Hee-Joon; Kim, Do Yeon; Kermer, Pawel; Suzuki, Kentaro; Kimura, Kazumi; et al. (JAMA Neurology, 2023)
IMPORTANCE International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). OBJECTIVE To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. DESIGN, SETTING, AND PARTICIPANTS This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. EXPOSURES Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. MAIN OUTCOMES AND MEASURES The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. RESULTS Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. CONCLUSIONS AND RELEVANCE In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.
CRIS-Team WoS Importer:2023-02-10

Intraventricular fibrinolysis does not increase perihemorrhagic edema after intracerebral hemorrhage - Volbers, Bastian; Wagner, Irina; Willfarth, Wolfgang; Dörfler, Arnd; Schwab, Stefan; Staykov, Dimitre (Stroke, 2013)
BACKGROUND AND PURPOSE - : Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator (rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume. METHODS - : Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF, matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days 4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio of PHE volume and initial ICH volume. RESULTS - : The matching algorithm resulted in similar mean ICH volumes in both groups (20.01±17.5 mL, IVF vs 20.08±17.1 mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8±19.2 mL vs 9.2±13.4 mL). The mean total rtPA dose used for IVF was 8±6 mg. PHE increased over time in both groups until day 12. At all investigated time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39; P=0.844). CONCLUSIONS - : IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem to be safe regarding PHE. © 2013 American Heart Association, Inc.
CRIS-Team Scopus Importer:2022-08-05
Keywords: intracerebral hemorrhage; intraventricular fibrinolysis; intraventricular hemorrhage; perihemorrhagicedema; recombinant tissue-type plasminogen activator; semiautomatic volumetry; X-ray computed tomography

Intraventricular fibrinolysis has no effects on shunt dependency and functional outcome in endovascular-treated aneurysmal SAH - Gerner, Stefan; Kuramatsu, Joji; Abel, Henning; Kloska, Stephan; Lücking, Hannes; Eyüpoglu, Ilker Yasin; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen (Neurocritical Care, 2014)
Intraventricular fibrinolysis (IVF) in subarachnoid hemorrhage (SAH) is an emerging strategy aiming to hasten clot lysis, treat hydrocephalus, and reduce permanent shunt rates. Because of clinical heterogeneity of investigated patient effects of IVF on permanent shunt incidence and functional outcome are widely debated. The present study is the first to investigate solely endovascular-treated SAH patients.Overall, 88 consecutive patients with aneurysmal SAH requiring external ventricular drain placement and endovascular aneurysm closure were included. Functional outcome and shunt dependency were assessed 90 days after event. A matched controlled sub-analysis was carried out to investigate the effects of IVF treatment (n = 14; matching criteria: age, neuro-status and imaging). Multivariate modeling was performed to identify independent predictors for permanent shunt dependency.In IVF-patients neurological status was significantly poorer [Hunt&Hess: IVF = 4(3-5) vs. non-IVF = 3(1-5); p = 0.035] and the extent of ventricular hemorrhage was increased [Graeb Score: IVF = 7(6-8) vs. non-IVF = 3(1-4); p <= 0.001]. Consecutive matched controlled sub-analysis revealed no significant therapeutic effect of IVF with respect to shunt dependency rate and functional outcome. Multivariate analysis revealed Graeb score [OR = 1.34(1.02-1.76); p = 0.035] and sepsis [OR = 11.23(2.28-55.27); p = 0.003] as independent predictors for shunt dependency, whereas IVF did not exert significant effects (p = 0.820).In endovascular-treated SAH patients IVF neither reduced permanent shunt dependency nor influenced functional outcome. Despite established effects on intraventricular clot resolution IVF appears less powerful in SAH as compared to ICH. Given the reported positive effects of lumbar drainage (LD) in SAH, a prospective analysis of a combined treatment approach of IVF and subsequent lumbar drain sOeems warranted aiming to reduce permanent shunting and improve functional outcome.
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Intrazerebrale Blutung: „hot topics“ - Sprügel, Maximilian; Huttner, Hagen (Der Nervenarzt, 2019)
Significant advances in the acute treatment of patients with intracerebral hemorrhage (ICH) have been achieved in recent years. While many randomized trials have provided neutral results, important findings have been generated for the design of follow-up studies. Furthermore, a number of observational studies have been published, which in turn provide the basis for further methodologically stronger investigations. The focus is on avoidance of early bleeding progression, which can be influenced by blood pressure management and hemostasis. Furthermore, ICH surgery may experience a renaissance through minimally invasive techniques. In addition, perihemorrhagic edema and its pharmacological modulation are becoming increasingly more important. Optimal treatment of ventricular involvement is continuing to develop dynamically. Finally, long-term antithrombotic treatment has been intensely studied in observational analyses and is currently being investigated in randomized trials. This article addresses these most relevant topics in acute and long-term treatment of ICH patients and provides an overview of current debates in these areas of treatment.
CRIS-Team Scopus Importer:2019-08-27
Keywords: Anticoagulation; Hematoma growth; Minimally invasive surgery; Perihemorrhagic edema; Ventricular hemorrhage

Invasiveness and Clinical Outcomes of Off-Hour Admissions in Patients with Intracerebral Hemorrhage - Mrochen, Anne; Sprügel, Maximilian; Gerner, Stefan; Madžar, Dominik; Kuramatsu, Joji; Lücking, Hannes; Schwab, Stefan; Huttner, Hagen; Hölter, Philip (Journal of Stroke and Cerebrovascular Diseases, 2019)
BACKGROUND: Whether time of hospital admission-during or outside regular working hours-affects functional outcome in intracerebral hemorrhage (ICH) is unestablished as previous analyses have focused on mortality only. We here investigate whether on- versus off-hour hospital admission in ICH is associated with levels of invasiveness and clinical outcomes. METHODS: Based on the UKER registry (NCT03183167) we grouped ICH-patients according to on- versus off-hour hospital admission. Primary outcome measures was functional outcome after 3 months using the modified Rankin scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6). Multivariate regression analyses were used to adjust for baseline imbalances, and subgroup analyses were performed to explore associations of on- versus off-hour admission with invasiveness of therapeutic interventions. RESULTS: A total of 438/1269 (34.5%) of ICH-patients were admitted during regular working hours. Mortality rates were not significantly different among patients with on- versus off-hour admission. On-hour patients showed a significantly larger proportion of patients with favorable outcome (on-hour: mRS = 0-3 after 3 months: 176/416 (42.3%) versus off-hour: 265/784 (33.8%); P = .004). Analysis of invasive therapeutic interventions revealed that likelihood of favorable outcome was significantly increased among on-hour admitted patients who did not require neurosurgical interventions (no external ventricular drain n = 349, OR: 1.67[1.13-2.48], P < .05; no hematoma evacuation surgery n = 423, OR: 1.51[1.07-2.14], P < .05). CONCLUSION: This study verified an "off-hour effect" in ICH that relates to functional outcome, rather than mortality, and which may be linked to different levels of invasive therapeutic interventions in patients admitted during off-hour.
EVALuna2:206735

Invasive stimulation procedures and EEG diagnostics in epilepsy - Schulze-Bonhage, A.; Hamer, Hajo; Hirsch, M.; Hagge, Mareike (Der Nervenarzt, 2016)
Stimulation has been performed experimentally and in small case series to treat epilepsy since the 1970s. Since the introduction of vagus nerve stimulation in 1997 and intracranial stimulation methods in 2011 into patient care, invasive stimulation has become a rapidly developing but infrequently used therapeutic option in Europe. Whereas vagus nerve stimulation is frequently used, particularly in the USA, intracranial stimulation differs in its regional availability. In order to improve the efficacy of stimulation, develop criteria for its use and assure low complication rates, a concentration on experienced centers and multicenter data acquisition and sharing are needed.Invasive electroencephalographic (EEG) monitoring with subdural electrodes and especially with stereotactically implanted depth electrodes have been used increasingly more often for presurgical evaluation in recent years. They are applied when non-invasive diagnostics show insufficient results to exactly identify the location and extent of the epileptogenic zone or cannot be adequately distinguished from eloquent cortex areas. Complications include intracranial hemorrhage, infections and increased intracranial pressure but lasting deficits or even death are rare (<=2 %). The outcome of invasive monitoring is inferior to non-invasive monitoring because of the higher degree of complexity of the cases; however, it is far superior to the seizure-free rates achieved by anticonvulsant drug treatment alone.
EVALuna2:22470

Invasive stroke treatment - Study results and clinical routine : Lost in translation? - Breuer, L.; Schwab, Sibylle; Köhrmann, Martin (Der Nervenarzt, 2016)
How can the overwhelmingly positive results of the five randomized thrombectomy trials published in 2015 be transferred to the clinical routine?Analysis of trial-specific characteristics with regard to implementation of mechanical thrombectomy into clinical routine.Stroke patients with symptomatic proximal artery occlusion are principally eligible for mechanical thrombectomy; however, the stroke patients included in the thrombectomy trials are not representative of all stroke patients. They were carefully selected according to clinical and imaging criteria as well as to the time window from symptom onset. Furthermore, they were treated in highly selected specialized stroke centers. Analysis of the five trials and the Catalan population-based SONIIA registry revealed that the observed number needed to treat (NNT) of 5 to reach a modified Rankin scale (mRS) score of 0-2 only applies to approximately 1 % of all stroke patients. The NNT for the remaining patients who are principally eligible for thrombectomy requires further study. Currently, centralization seems to be useful to facilitate mechanical thrombectomy in routine care leading to several problems that have to be dealt with in particular regions. Secondary transport to thrombectomy centers plays a major role in this context and has to be provided with highest priority.Only careful analysis of study results and the background circumstances will enable adequate organization and successful practical implementation of this highly effective therapy in the clinical routine. Regional conditions have to be considered and will be crucial in this context.
EVALuna2:22469

Investigation of subdural electrode displacement in invasive epilepsy surgery workup using neuronavigation and intraoperative MRI - Sommer, Bjoern; Rampp, Stefan; Dörfler, Arnd; Stefan, Hermann; Hamer, Hajo; Buchfelder, Michael; Roessler, Karl (Neurological Research, 2018)
OBJECTIVES: One of the main obstacles of electrode implantation in epilepsy surgery is the electrode shift between implantation and the day of explantation. We evaluated this possible electrode displacement using intraoperative MRI (iopMRI) data and CT/MRI reconstruction. METHODS: Thirteen patients (nine female, four male, median age 26 ± 9.4 years) suffering from drug-resistant epilepsy were examined. After implantation, the position of subdural electrodes was evaluated by 3.0 T-MRI and thin-slice CCT for 3D reconstruction. Localization of electrodes was performed with the volume-rendering technique. Post-implantation and pre-explantation 1.5 T-iopMRI scans were coregistered with the 3D reconstructions to determine the extent of electrode dislocation. RESULTS: Intraoperative MRI at the time of explantation revealed a relevant electrode shift in one patient (8%) of 10 mm. Median electrode displacement was 1.7 ± 2.6 mm with a coregistration error of 1.9 ± 0.7 mm. The median accuracy of the neuronavigation system was 2.2 ± 0.9 mm. Six of twelve patients undergoing resective surgery were seizure free (Engel class 1A, median follow-up 37.5 ± 11.8 months). CONCLUSION: Comparison of pre-explantation and post-implantation iopMRI scans with CT/MRI data using the volume-rendering technique resulted in an accurate placement of electrodes. In one patient with a considerable electrode dislocation, the surgical approach and extent was changed due to the detected electrode shift. ABBREVIATIONS: ECoG: electrocorticography; EZ: epileptogenic zone; iEEG: invasive EEG; iopMRI: intraoperative MRI; MEG: magnetoencephalography; PET: positron emission tomography; SPECT: single photon emission computed tomography; 3D: three-dimensional.
EVALuna2:201939

Involvement of obliquus capitis inferior muscle in dystonic head tremor - Schramm, Axel; Huber, D.; Möbius, Cornelia; Muenchau, A.; Kohl, Zacharias; Baeumer, T. (Parkinsonism & Related Disorders, 2017)
Head tremor is a common feature in cervical dystonia (CD) and often less responsive to botulinum neurotoxin (BoNT) treatment than dystonic posturing. Ultrasound allows accurate targeting of deeper neck muscles.In 35 CD patients with dystonic head tremor the depth and thickness of the splenius capitis (SPL), semispinalis capitis and obliquus capitis inferior muscles (OCI) were assessed using ultrasound. Ultrasound guided EMG recordings were performed from the SPL and OCI.Burst-like tremor activity was present in both OCI in 25 and in one in 10 patients. In 18 patients, tremor activity was present in one SPL and in 2 in both SPL. Depth and thickness of OCI, SPL and semispinalis capitis muscles were very variable.Muscular activity underlying tremulous CD is most commonly present in OCI. Due to the variability of muscle thickness, we suggest ultrasound guided BoNT injections into OCI.
EVALuna2:22566

Ischaemic stroke and Clostridium septicum sepsis and meningitis in a patient with occult colon carcinoma - a case report and review of the literature - Macha, Kosmas; Giede-Jeppe, Antje; Lücking, Hannes; Coras, Roland; Huttner, Hagen; Held, Jürgen (BMC Neurology, 2016)
Clostridium septicum is a rare cause of meningitis and brain abscess in children and adults. Gas production by the pathogen can lead to pneumocephalus and the overall mortality rate of Clostridium septicum CNS infection is as high as 74%. The most common entry site of the pathogen is the gastrointestinal tract.We describe a 74-year-old man who presented with a left-sided cerebral infarction in the middle cerebral artery territory. In addition the patient showed signs of Systemic Inflammatory Response Syndrome and Disseminated Intravascular Coagulation. Examination of blood cultures and cerebrospinal fluid led to the diagnosis of sepsis and meningitis caused by Clostridium septicum. Despite appropriate antibiotic therapy the condition of the patient deteriorated rapidly and he died on day 2 after admission. Autopsy revealed a previously unknown adenocarcinoma of the colon ascendens as entry site of the pathogen.Clostridium septicum should be considered as potential pathogen in patients with sepsis and meningitis. Gram stain morphology in conjunction with severe sepsis can rapidly point into the direction of this pathogen. CNS infections manifest either as meningoencephalitis/cerebritis or as brain abscess. Entry site of the pathogen is almost uniquely the gastrointestinal tract. In adults more than 50% suffer from colorectal carcinoma, therefore survivors of Clostridium septicum infections should be examined for underlying occult colorectal malignancy.
EVALuna2:7346

Ischemic stroke and dose adjustment of oral Factor Xa inhibitors in patients with atrial fibrillation - Stoll, Svenja; Macha, Kosmas; Marsch, Armin; Gerner, Stefan; Siedler, Gabriela; Fröhlich, Kilian; Volbers, Bastian; Strasser, Erwin; Schwab, Stefan; Kallmünzer, Bernd (Journal of Neurology, 2020)
Background: Oral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common. Methods: Data from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as “appropriate”, “underdosed” and “overdosed” in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated. Results: 254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA2DS2–Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0–121.6) vs. 129.2 ng/ml (65.5–207.2); p < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1–10) vs. 3 (1–7); p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025). Conclusion: One in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome.
CRIS-Team Scopus Importer:2020-03-31
Keywords: Atrial fibrillation; Direct oral anticoagulants; Dose reduction; Plasma levels; Stroke

Ischemic stroke associated with the use of a synthetic cannabinoid (spice) - Möller, Sebastian; Luecke, Caroline; Struffert, Tobias; Schwarze, Bernhard; Gerner, Stefan; Schwab, Stefan; Köhrmann, Martin; Machold, Kristin; Philipsen, Alexandra; Mueller, Helge H. (Asian Journal of Psychiatry, 2017)
Synthetic cannabinoids, i.e. "spice", are psychoactive drugs with increasing use worldwide. Spice may have harmful neuropsychiatric and physical side effects. Here, we present the case of a 25-year-old man with ischemic stroke after smoking spice on the previous evening. Diagnostic work-up was negative for other common causes of stroke. Toxicology screen unveiled the cannabimimetic ADB-FUBINACA in the drug sample and in patient's urine. The cardiac sympathomimetic effect of spice might have triggered an unnoticed episode of tachyarrhythmia and resulted in stroke via cardioembolic etiology. Thus, in absence of other risk factors, a careful patient history of spice use is recommended for patients with acute neurological deficits.
EVALuna2:22545

Ischemic Stroke Despite Oral Anticoagulant Therapy in Patients With AF - What is the Risk of Recurrence and How to Prevent Further Events?. - Seiffge, David J.; De Marchis, Gian Marco; Koga, Masatoshi; Paciaroni, Maurizio; Cappellari, Manuel; Kallmünzer, Bernd; Macha, Kosmas; Wilson, Duncan; Engelter, Stefan; Werring, David J. (STROKE, 2019)
CRIS-Team WoS Importer:2019-08-23

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation - Seiffge, David J.; De Marchis, Gian Marco; Koga, Masatoshi; Paciaroni, Maurizio; Wilson, Duncan; Cappellari, Manuel; Macha, Kosmas; Tsivgoulis, Georgios; Ambler, Gareth; Arihiro, Shoji; Bonati, Leo H.; Bonetti, Bruno; et al. (Annals of neurology, 2020)
Objective: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. Methods: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior) with those without prior oral anticoagulation (OACnaive). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged) with those who continued the same anticoagulation as secondary prevention (OACunchanged). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine–Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71–84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2–12]). The median CHA2DS2-Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65–74 years, sex category) was 5 (IQR = 4–6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2–5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2–2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7–2.1, p = 0.415) compared with OACunchanged (n = 585). Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2DS2-Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.
CRIS-Team Scopus Importer:2020-03-10

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia - Kuramatsu, Joji; Kollmar, Rainer; Gerner, Stefan; Madzar, Dominik; Pisarcikova, Andrea; Staykov, Dimitre; Kloska, Stephan; Dörfler, Arnd; Eyüpoglu, Ilker Yasin; Schwab, Stefan; Huttner, Hagen (Cerebrovascular Diseases, 2015)
Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated.This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome.Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06).Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact.
EVALuna2:22357

Isolated meningomyeloradiculitis following infection with tick borne encephalitis virus - Racz, Attila; Schaller, Gerd; Lunkenheimer, Jens; Engelhorn, Tobias; Dörfler, Arnd; Sperling, Wolfgang; Schwab, Stefan; Maihöfner, Christian (Clinical Neurology and Neurosurgery, 2012)
CRIS-Team Scopus Importer:2022-08-05
Keywords: Meningomyeloradiculitis; Myelitis; Polyradiculitis; Tick borne encephalitis virus

It is all about timing: decompressive hemicraniectomy for malignant middle-cerebral-artery infarction - Macha, Kosmas; Schwab, Stefan (Arquivos De Neuro-Psiquiatria, 2023)
CRIS-Team Scopus Importer:2023-06-30

IV Thrombolysis for Acute Ischemic Stroke with Unknown Onset in Patients on Oral Anticoagulation - Macha, Kosmas; Sembill, Jochen; Mühlen, Iris; Engelhorn, Tobias; Dörfler, Arnd; Schwab, Stefan; Kallmünzer, Bernd (Cerebrovascular Diseases, 2024)
Introduction: IV thrombolysis (IVT) is established in the unknown or extended time window based on multimodal imaging. Further, increasing evidence exists regarding IVT in patients on oral anticoagulation including direct oral anticoagulants (DOACs). However, data on IVT in ischemic stroke patients on oral anticoagulation with unknown time of stroke onset are sparse. Methods: This study bases on the longitudinal cohort study Stroke Research Consortium in Northern Bavaria (STAMINA; ClinicalTrials.gov Identifier: NCT04357899). Acute ischemic stroke patients treated with IVT in the unknown or extended time window from January 2015 to December 2019 were included. Patient selection was based on multimodal CT or MRI. Patients on oral anticoagulation (vitamin-K antagonist [VKA] or DOAC within 48 h) were eligible for IVT based on INR measurement (VKA) or plasma levels (DOAC) according to an institutional protocol. Primary outcomes were the incidence of any and symptomatic intracranial hemorrhage. Results: Of 170 ischemic stroke patients treated with IVT in the unknown or extended time window, 151 had no oral anticoagulation at stroke onset and 19 were on oral anticoagulation (6 on VKA and 13 on DOAC). The risk of symptomatic ICH according to ECASS II criteria was similar between the patients with and without oral anticoagulation (1 [5.3%] vs. 4 [2.7%], p = 0.453). After adjustment for confounding factors, pre-medication with oral anticoagulation was not associated with symptomatic ICH (aOR 1.02 [0.09-11.02], p = 0.988). Conclusion: IVT for ischemic stroke with unknown onset appeared safe in selected patients on oral anticoagulation with both DOAC and VKA.
CRIS-Team Scopus Importer:2024-12-06
Keywords: Direct oral anticoagulant; Ischemic stroke; IV thrombolysis; Unknown onset; Vitamin-K antagonist

IV-Thrombolysis in Ischemic Stroke With Unknown Time of Onset—Safety and Outcomes in Posterior vs. Anterior Circulation Stroke - Macha, Kosmas; Hölter, Philip; Siedler, Gabriela; Wang, Ruihao; Knott, Michael; Stoll, Svenja; Engelhorn, Tobias; Dörfler, Arnd; Schwab, Stefan; Mühlen, Iris; Kallmünzer, Bernd (Frontiers in Neurology, 2021)
Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce. Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors. Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5–15) vs. 14 (9–18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, −18.9% (−39.8 to −2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, −10.4% (−20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, −2.9% (−10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients. Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS.
CRIS-Team Scopus Importer:2021-10-01
Keywords: anterior circulation stroke; extended time window; IV-thrombolysis; posterior circulation stroke; wake-up stroke

Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration - Pozner, Tatyana; Regensburger, Martin; Engelhorn, Tobias; Winkler, Jürgen; Winner, Beate (Brain, 2020)
Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP. The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery. In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.
CRIS-Team Scopus Importer:2020-09-04
Keywords: autophagy; hereditary spastic paraplegia; neurodegeneration; neurodevelopment; SPG11

Kennwertermittlung für Streck-Biege-Beanspruchungen - Merklein, Marion; Hezler, Christian; Kopp, C.; Hecht, J.; Schaller, L. (Proceedings Tagung Werkstoffprüfung, 2010)
LFT Import::2019-08-05 (719)

Körperliche Aktivität und Prävention der Alzheimerdemenz: Übersicht über aktuelle Evidenz und Überlegungen zur Machbarkeit einer Interventionsstudie - Weih, Markus; Abu-Omar, Karim; Esselmann, H; Gelbrich, Götz; Lewczuk, Piotr; Rütten, Alfred; Wiltfang, Jens; Kornhuber, Johannes (Fortschritte der Neurologie - Psychiatrie, 2009)

Lacosamide in patients with intellectual disability and refractory epilepsy - Kleist, Anika; Kerling, Frank; Hamer, Hajo; Winterholler, Martin (Acta Neurologica Belgica, 2019)
The objective of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in residential patients at our epilepsy centre. We assessed retrospectively 80 patients (mean age 36.2 years, range 18–63 years; 29 female) with intellectual disability (ID) and drug-resistant epilepsy using an industry-independent, non-interventional study design based on standardised seizure records. Evaluation, including calculation of retention rate, was carried out for the intervals 3–6, 9–12 and 21–24 months after LCM initiation. The Clinical Global Impression scale (CGI) was used to allow assessment of qualitative changes in seizure severity and clinical status. CGI improved for 61% of the patients. The responder rate was 48%; ten patients (13%) became seizure free. The response was not related to the degree of ID. The retention rates after 12 and 24 months were 71% and 65%, and were significantly lower in patients taking other sodium-channel blockers (SCBs; 76% vs. 55%). The occurrence of adverse events (AEs) was related to the administration of concomitant SCBs (48% with SCBs vs. 26% without). Sedation (15%), ataxia (13%), vertigo (11%), and nausea (9%) were the commonest AEs. While 60% of our patients had concomitant psychiatric diagnosis, we found no relevant effect of this on challenging behaviour. Adjunctive LCM may provide an antiepileptic treatment option for patients with ID with or without additional psychiatric diagnosis. The occurrence of AEs and the LCM retention rate were affected by concomitant SCB use but not by psychiatric comorbidity.
CRIS-Team Scopus Importer:2019-09-10
Keywords: Antiepileptic drug; Intellectual disability; Lacosamide; Refractory epilepsy

Laquinimod in the treatment of multiple sclerosis: a review of the data so far - Thoene, Jan; Linker, Ralf (Drug Design, Development and Therapy, 2016)
Laquinimod (ABR-215062) is a new orally available carboxamide derivative, which is currently developed for relapsing remitting (RR) and chronic progressive (CP) forms of multiple sclerosis (MS; RRMS or CPMS) as well as neurodegenerative diseases. Its mechanism of action may comprise immunomodulatory effects on T-cells, monocytes, and dendritic cells as well as neuroprotective effects with prominent actions on astrocytes. Laquinimod was tested in Phase II and III clinical trials in RRMS at different dosages ranging from 0.1 to 0.6 mg/day. The compound was well tolerated, yet at the dosages tested only led to moderate effects on the reduction of relapse rates as primary study endpoint in Phase III trials. In contrast, significant effects on brain atrophy and disease progression were observed. While there were no significant safety signals in the clinical trials, the Committee for Medicinal Products for Human Use (CHMP) refused marketing authorization for RRMS based on the assessment of the risk-benefit ratio with regard to data from animal studies. At present, the compound is further tested in RRMS as well as CPMS and Huntington's disease at different concentrations. Results from these trials will further inform about the clinical benefit of laquinimod in patient cohorts with a persisting, but still insufficiently met need for safe and at the same time effective oral compounds with neuroprotective effects.
EVALuna2:22451

Large diameter hemicraniectomy does not improve long-term outcome in malignant infarction - Lehrieder, Dominik; Müller, Hans Peter; Kassubek, Jan; Hecht, Nils; Thomalla, Götz; Michalski, Dominik; Gattringer, Thomas; Wartenberg, Katja E.; Schultze-Amberger, Jörg; Huttner, Hagen; Kuramatsu, Joji; Wunderlich, Silke; et al. (Journal of Neurology, 2023)
Introduction: In malignant cerebral infarction decompressive hemicraniectomy has demonstrated beneficial effects, but the optimum size of hemicraniectomy is still a matter of debate. Some surgeons prefer a large-sized hemicraniectomy with a diameter of more than 14 cm (HC > 14). We investigated whether this approach is associated with reduced mortality and an improved long-term functional outcome compared to a standard hemicraniectomy with a diameter of less than 14 cm (HC ≤ 14). Methods: Patients from the DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) registry who received hemicraniectomy were dichotomized according to the hemicraniectomy diameter (HC ≤ 14 cm vs. HC > 14 cm). The primary outcome was modified Rankin scale (mRS) score ≤ 4 after 12 months. Secondary outcomes were in-hospital mortality, mRS ≤ 3 and mortality after 12 months, and the rate of hemicraniectomy-related complications. The diameter of the hemicraniectomy was examined as an independent predictor of functional outcome in multivariable analyses. Results: Among 130 patients (32.3% female, mean (SD) age 55 (11) years), the mean hemicraniectomy diameter was 13.6 cm. 42 patients (32.3%) had HC > 14. There were no significant differences in the primary outcome and mortality by size of hemicraniectomy. Rate of complications did not differ (HC ≤ 14 27.6% vs. HC > 14 36.6%, p = 0.302). Age and infarct volume but not hemicraniectomy diameter were associated with outcome in multivariable analyses. Conclusion: In this post-hoc analysis, large hemicraniectomy was not associated with an improved outcome or lower mortality in unselected patients with malignant middle cerebral artery infarction. Randomized trials should further examine whether individual patients could benefit from a large-sized hemicraniectomy. Clinical trial registration information: German Clinical Trials Register (URL: https://www.drks.de ; Unique Identifier: DRKS00000624).
CRIS-Team Scopus Importer:2023-05-26
Keywords: Functional outcome; Hemicraniectomy; Malignant stroke; Middle cerebral artery infarction; Size of hemicraniectomy

Late-onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D - Mächtel, Rebecca; Dobert, Jan; Hehr, Ute; Weiß, Alexander; Kettwig, Matthias; Laugwitz, Lucia; Groeschel, Samuel; Schmidt, Manuel; Arnold, Philipp; Regensburger, Martin; Zunke, Friederike (Annals of Clinical and Translational Neurology, 2024)
Objective: Krabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late-onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late-onset KD (LOKD). Methods: Additionally to cerebral MRI, protein structural analyses of the β-galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β-glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts. Results: Exome sequencing revealed biallelic likely pathogenic variants: GALC exons 11–17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected. Interpretation: The presented LOKD case underlines the age-dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.
CRIS-Team Scopus Importer:2024-06-14
Keywords: cathepsin B; cathepsin D; enzymatic activity; Krabbe disease; late-onset; β-glucocerebrosidase

Laufbandtherapie in der Neurorehabilitation: Evidenz und Anwendungsspektrum - Klamroth, Sarah; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (Neurologie & Rehabilitation, 2018)

Laufbandtraining mit Perturbation verbessert Gang- und Gleichgewichtskontrolle bein Parkinsonpatienten: Eine randomisiert-kontrollierte Pilotstudie - Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Pasluosta, Cristian Federico; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Innovation & Technologie im Sport. Abstractband des 23. dvs-Hochschultags vom 13. bis 15. September 2017 in München, 2017)
Keywords: Morbus Parkinson; Laufbandtraining; Gehfähigkeit; Balance

Layer-specific axonal degeneration of serotonergic fibers in the prefrontal cortex of aged A53T α-synuclein–expressing mice - Wihan, Jeanette; Grosch, Janina; Kalinichenko, Liubov; Müller, Christian P.; Winkler, Jürgen; Kohl, Zacharias (Neurobiology of Aging, 2019)
Axonal pathology precedes dopaminergic cell loss in Parkinson's disease (PD), indicating a dying back axonopathy of nigrostriatal projections. Although most attention focused on the dopaminergic system, increasing evidence implies a compromised serotonergic system in PD as well. By combining immunohistological and biochemical approaches, a profound layer-specific reduction of the serotonergic input to the prefrontal cortex (PFC)layers II and V/VI in aged mutant A53T α-synuclein–expressing mice (A53T mice)was detected. In addition, the altered fiber network was characterized by swollen axons and enlarged axonal varicosities within all PFC layers, but most pronounced in PFC layer I. Although prefrontal serotonin levels and synaptic protein expression were preserved, aged A53T mice showed increased levels of kinesin family member 1a and vesicular monoamine transporter 2. Together with increased tryptophan hydroxylase 2 mRNA levels in the raphe nuclei and an elevated serotonin receptor 1b expression in the PFC, these findings point to compensatory mechanisms within the serotonergic system to overcome the reduced neuritic input to the PFC in this transgenic animal model for PD.
CRIS-Team Scopus Importer:2019-05-16
Keywords: Alpha-synuclein; Parkinson's disease; Prefrontal cortex; Serotonin; Serotonin transporter

Lesion correlates of secondary paroxysmal dyskinesia in multiple sclerosis - Fröhlich, Katharina; Winder, Klemens; Linker, Ralf; Huhn, Konstantin; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Schwab, Stefan; Seifert, Frank (Journal of Neurology, 2018)
Secondary paroxysmal dyskinesia is a rare but life-quality-compromising symptom in multiple sclerosis (MS) and might be associated with particular MS lesions. The present study intended to determine associations between paroxysmal dyskinesia and the MS-associated lesion site using a voxelwise lesion analysis. We conducted a retrospective study and sought MS patients with documented paroxysmal dyskinesia and controls without paroxysmal dyskinesia matched for age, disease severity, and disease duration in a local database. The MS lesions were analysed on T2-weighted magnetic resonance imaging scans (1.5 or 3 T), manually outlined, and transformed into stereotaxic space. We determined the lesion overlap and compared the absence or presence of paroxysmal dyskinesia voxelwise between patients with and without lesions in a given voxel using the Liebermeister test with 4000 permutations. From 15,869 MS patient records screened, we identified 25 patients with paroxysmal dyskinesia. The voxelwise analysis in 22 subjects yielded associations between paroxysmal dyskinesia and MS lesions in the internal capsule, the basal ganglia, and another prominent lesion cluster in the posterior periventricular white matter. Our voxelwise analysis shows associations between paroxysmal dyskinesia and MS lesions in the internal capsule and basal ganglia, areas contributing to motor sequence programming. This association in another lesion site located in the posterior thalamic radiation suggests that lesions in subcortical sensory pathways may also contribute to paroxysmal dyskinesia in MS.
EVALuna2:34912

Lesion mapping of stroke-related erectile dysfunction - Winder, Klemens; Seifert, Frank; Köhrmann, Martin; Crodel, Carl; Kloska, Stephan; Dörfler, Arnd; Hoesl, Katharina M.; Schwab, Stefan; Hilz, Max-Josef (Brain, 2017)
Acute ischaemic stroke in brain areas contributing to male sexual function may impair erectile function depending on the lesion site. This study intended to determine associations between stroke-related erectile dysfunction and cerebral ischaemic lesion sites using voxel-based lesion mapping. In 52 males (mean age 60.5 ± 10.5 years) with first-ever ischaemic strokes, we assessed erectile function after and retrospectively 3 months prior to the stroke using scores of the 5-item International Index of Erectile Function-5 questionnaire. We assessed cardiovascular risk factors and determined clinical stroke severity and infarct volumes as well as total brain volume by neuroimaging. We calculated correlations between patient age, clinical stroke severity, infarct volumes as well as brain volumes and the difference between erectile dysfunction scores before and after stroke. Moreover, we compared patient age, prevalence of cardiovascular risk factors, clinical stroke severity, infarct volumes and brain volumes of patients with unchanged and deteriorated erectile function after stroke. The infarcts were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed subtraction analyses of lesions. In a voxel-based lesion analysis, the difference between erectile dysfunction scores before and after stroke was correlated with the lesion site using t-test statistics. Finally, we conducted a region of interest-based multivariate linear regression analysis that was adjusted for potential confounding factors including patient age, clinical stroke severity, imaging modality, lesion size and brain volume. In 32 patients (61.5%) erectile dysfunction scores declined after the stroke and therefore had stroke-related erectile dysfunction. Deterioration of erectile dysfunction scores was not associated with patient age, clinical stroke severity, infarct volume, brain volume, and cardiovascular risk factors. The voxel-wise subtraction analysis showed associations between stroke-related erectile dysfunction and lesion sites in the right occipito-parietal cortex and thalamus, as well as in the left insula and adjacent temporo-parietal areas. Using voxel-wise t-test statistics, we showed associations between deterioration of erectile function and lesion sites in the right occipital and thalamic region, and the left parietal association area. The linear regression analysis showed that stroke-related erectile dysfunction remained associated with lesions of the right occipital and left parietal association areas after adjusting for confounding factors. In conclusion, our voxel-wise analysis indicates that deteriorating erectile function after stroke is associated with lesions in the right occipito-parietal and thalamic areas integrating visual and somatosensory information, as well as lesions in the left insular and adjacent parieto-temporal areas contributing to generating and mapping visceral arousal states.
EVALuna2:22497

Lessons learned from transcutaneous vagus nerve stimulation (tVNS) - Hamer, Hajo; Bauer, Sebastian (Epilepsy Research, 2019)
Transcutaneous vagus nerve stimulation (tVNS) is a newly developed method which intends to overcome the disadvantage of surgical implantation of the stimulation device. The tVNS device is designed to stimulate the auricular branch of the vagus nerve via a bipolar electrode attached to the skin of the left ear conch. A randomized, double-blind controlled trial assessed efficacy and safety over 20 weeks of tVNS (n=39) vs. active control tVNS (n=37) in patients with drug-resistant epilepsy. While the mean seizure reduction per 28 days at end of treatment (2.9% reduction from baseline in the control group vs 23.4% in the active group) did not reach statistical significance, there was a significant reduction in seizure frequency (34 %) in patients in the tVNS group at the end of the treatment period (20 weeks). TVNS was well-tolerated. The results justify further trials with longer observation periods and possibly at earlier stages of epilepsy.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Epilepsy; Seizures; Transcutaneous vagus nerve stimulation; Treatment

Letter by Kallmünzer et al Regarding Article, "safety of Intravenous Thrombolysis among Patients Taking Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis" - Kallmünzer, Bernd; Pott, Michael; Schwab, Stefan (Stroke, 2020)
CRIS-Team Scopus Importer:2020-07-17

Leveraging the Potential of Digital Technology for Better Individualized Treatment of Parkinson's Disease - Froehlich, Holger; Bontridder, Noemi; Petrovska-Delacreta, Dijana; Glaab, Enrico; Kluge, Felix; El Yacoubi, Mounim; Marin Valero, Mayca; Corvol, Jean-Christophe; Eskofier, Björn; Van Gyseghem, Jean-Marc; Lehericy, Stephane; Winkler, Jürgen; et al. (Frontiers in Neurology, 2022)
Recent years have witnessed a strongly increasing interest in digital technology within medicine (sensor devices, specific smartphone apps) and specifically also neurology. Quantitative measures derived from digital technology could provide Digital Biomarkers (DMs) enabling a quantitative and continuous monitoring of disease symptoms, also outside clinics. This includes the possibility to continuously and sensitively monitor the response to treatment, hence opening the opportunity to adapt medication pathways quickly. In addition, DMs may in the future allow early diagnosis, stratification of patient subgroups and prediction of clinical outcomes. Thus, DMs could complement or in certain cases even replace classical examiner-based outcome measures and molecular biomarkers measured in cerebral spinal fluid, blood, urine, saliva, or other body liquids. Altogether, DMs could play a prominent role in the emerging field of precision medicine. However, realizing this vision requires dedicated research. First, advanced data analytical methods need to be developed and applied, which extract candidate DMs from raw signals. Second, these candidate DMs need to be validated by (a) showing their correlation to established clinical outcome measures, and (b) demonstrating their diagnostic and/or prognostic value compared to established biomarkers. These points again require the use of advanced data analytical methods, including machine learning. In addition, the arising ethical, legal and social questions associated with the collection and processing of sensitive patient data and the use of machine learning methods to analyze these data for better individualized treatment of the disease, must be considered thoroughly. Using Parkinson's Disease (PD) as a prime example of a complex multifactorial disorder, the purpose of this article is to critically review the current state of research regarding the use of DMs, discuss open challenges and highlight emerging new directions.
CRIS-Team WoS Importer:2022-04-29

Life style and Parkinson's disease - Reichmann, Heinz; Csoti, Ilona; Koschel, Jiri; Lorenzl, Stefan; Schrader, Christoph; Winkler, Jürgen; Wuellner, Ullrich (Journal of Neural Transmission, 2022)
The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson's disease.
CRIS-Team WoS Importer:2022-06-03

Limbic encephalitis with mGluR5 antibodies and immunotherapy-responsive prosopagnosia - Pruess, Harald; Rothkirch, Marcus; Kopp, Ute; Hamer, Hajo; Hagge, Mareike; Sterzer, Phillipp; Saschenbrecker, Sandra; Stoecker, Winfried; Harms, Lutz; Endres, Matthias (Neurology, 2014)
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Limited versus Whole-Brain Perfusion for the Indication of Thrombolysis in the Extended Time Window of Acute Cerebral Ischemia - Breuer, Lorenz; Knott, Michael; Struffert, Tobias; Kloska, Stephan; Kurka, Natalia; Schwab, Stefan; Dörfler, Arnd; Köhrmann, Martin; Engelhorn, Tobias (Journal of Stroke and Cerebrovascular Diseases, 2015)
Perfusion computed tomography (PCT) has emerged as alternative to magnetic resonance imaging (MRI) for assessment of patients clinically qualifying for off-label thrombolysis within 4.5 to 9 hours after onset of ischemic stroke. However, disadvantage of PCT is its often limited anatomic coverage with only 2 or 3 slices when using a 4- to 64-section scanner. Our purpose was therefore to evaluate the value of 2- and 3-slice perfusion compared to whole-brain perfusion.One hundred twenty-five patients undergoing MRI beyond 4.5 hours after symptom onset with supratentorial perfusion deficit were selected retrospectively. Accordingly to PCT slice positioning, 2 or 3 slices of the whole-brain perfusion weighted imaging data set were depicted. Volumes of infarct (using cerebral blood volume) and penumbra (using time-to-peak and cerebral blood volume) were calculated, and results were compared with 2- and 3-slice-derived volumes, respectively.Whole-brain imaging revealed a mismatch of more than 20% in 68.8% of patients (defined as 100%). Two-slice imaging detected a perfusion deficit in 72% and a mismatch in 48.8% (sensitivity = 70.9%). Three-slice imaging detected a perfusion deficit in 76% and a mismatch in 50.4% (sensitivity = 73.3%). Although there was no significant difference between 2- and 3-slice imaging (P > .23), both techniques revealed significantly less patients with mismatch compared to whole-brain coverage (P < .01).Two- and 3-slice imaging like obtained with PCT on most installed CT systems to assess perfusion deficits with subsequent mismatch calculation in acute stroke outside the 4.5-hour time window is significantly inferior to whole-brain coverage and, hence, has to be considered as a less-than-ideal solution.
EVALuna2:22358

Linear projection-based CEST parameter estimation - Glang, Felix; Zaiss, Moritz; Laun, Frederik Bernd; Fabian, Moritz S.; German, Alexander; Khakzar, Katrin; Mennecke, Angelika; Liebert, Andrzej; Herz, Kai; Liebig, Patrick; Kasper, Burkhard S.; Schmidt, Manuel; et al. (NMR in Biomedicine, 2022)
Isolated evaluation of multi-parametric in vivo CEST MRI often requires complex computational processing for both correction of B0 and B1 inhomogeneity and contrast generation. For that, sufficiently densely sampled Z-spectra need to be acquired. The list of acquired frequency offsets largely determines the total CEST acquisition time, while potentially representing redundant information. In this work, a linear projection-based multi parametric CEST evaluation method is introduced that offers fast B0 and B1 inhomogeneity correction, contrast generation and feature selection for CEST data, enabling reduction of the overall measurement time. To that end, CEST data acquired at 7T in 6 healthy subjects and in one brain tumor patient were conventionally evaluated by interpolation-based inhomogeneity correction and Lorentzian curve fitting. Linear regression was used to obtain coefficient vectors that directly map uncorrected data to corrected Lorentzian target parameters. L1 regularization was applied to find subsets of the originally acquired CEST measurements that still allow for such a linear projection mapping. The linear projection method allows fast and interpretable mapping from acquired raw data to contrast parameters of interest, generalizing from healthy subject training data to unseen healthy test data and to the tumor patient dataset. The L1 regularization method shows that a fraction of the acquired CEST measurements is sufficient to preserve tissue contrasts, offering up to 2.8-fold reduction of scan time. Similar observations as for the 7T data can be made for data from a clinical 3T scanner. Being a fast and interpretable computation step, the proposed method is complementary to neural networks, which have been recently employed for similar purposes. The scan time acceleration offered by the L1 regularization (‘CEST-LASSO’) constitutes a step towards better applicability of multi parametric CEST protocols in clinical context.<br
Keywords: chemical exchange saturation transfer (CEST); feature selection; LASSO; APT; NOE; linear projection

Liquorpunktion – Schritt für Schritt - Siedler, Gabriela; Kallmünzer, Bernd; Schwab, Stefan (Deutsche Medizinische Wochenschrift, 2019)
Performing a diagnostic lumbar puncture is an essential clinical skill for the clinician. The procedure is of high importance for both, the emergency care for patients with suspected infection of the cerebral nervous system or subarachnoidal hemorrhage, as well as the elective diagnostic work up of chronic disease including multiple sclerosis and dementia. Furthermore the technique's principles are applied for spinal anesthesia or the intrathecal administration of drugs. This article describes a Standard Operating Procedure for the lumbar puncture step by step. Based on the latest evidence, it particularly focusses on clinically relevant questions and practical aspects.
CRIS-Team Scopus Importer:2019-10-08
Keywords: atraumatic needle; cerebrospinal fluid analysis; diagnostic lumbar puncture; post-lumbar; puncture headache

Localization of beta power decrease as measure for lateralization in pre-surgical language mapping with magnetoencephalography, compared with functional magnetic resonance imaging and validated by Wada test - Herfurth, Kirsten; Harpaz, Yuval; Rösch, Julie; Müller, Nadia; Walther, Katrin; Kaltenhaeuser, Martin; Pauli, Elisabeth; Goldstein, Abraham; Hamer, Hajo; Buchfelder, Michael; Dörfler, Arnd; Prell, Julian; et al. (Frontiers in Human Neuroscience, 2022)
Objective: Atypical patterns of language lateralization due to early reorganizational processes constitute a challenge in the pre-surgical evaluation of patients with pharmaco-resistant epilepsy. There is no consensus on an optimal analysis method used for the identification of language dominance in MEG. This study examines the concordance between MEG source localization of beta power desynchronization and fMRI with regard to lateralization and localization of expressive and receptive language areas using a visual verb generation task. Methods: Twenty-five patients with pharmaco-resistant epilepsy, including six patients with atypical language lateralization, and ten right-handed controls obtained MEG and fMRI language assessment. Fourteen patients additionally underwent the Wada test. We analyzed MEG beta power desynchronization in sensor (controls) and source space (patients and controls). Beta power decrease between 13 and 35 Hz was localized applying Dynamic Imaging of Coherent Sources Beamformer technique. Statistical inferences were grounded on cluster-based permutation testing for single subjects. Results: Event-related desynchronization of beta power in MEG was seen within the language-dominant frontal and temporal lobe and within the premotor cortex. Our analysis pipeline consistently yielded left language dominance with high laterality indices in controls. Language lateralization in MEG and Wada test agreed in all 14 patients for inferior frontal, temporal and parietal language areas (Cohen’s Kappa = 1, p < 0.001). fMRI agreed with Wada test in 12 out of 14 cases (85.7%) for Broca’s area (Cohen’s Kappa = 0.71, p = 0.024), while the agreement for temporal and temporo-parietal language areas were non-significant. Concordance between MEG and fMRI laterality indices was highest within the inferior frontal gyrus, with an agreement in 19/24 cases (79.2%), and non-significant for Wernicke’s area. Spatial agreement between fMRI and MEG varied considerably between subjects and brain regions with the lowest Euclidean distances within the inferior frontal region of interest. Conclusion: Localizing the desynchronization of MEG beta power using a verb generation task is a promising tool for the identification of language dominance in the pre-surgical evaluation of epilepsy patients. The overall agreement between MEG and fMRI was lower than expected and might be attributed to differences within the baseline condition. A larger sample size and an adjustment of the experimental designs are needed to draw further conclusions.
CRIS-Team Scopus Importer:2022-11-25
Keywords: beta power decrease; epilepsy; epilepsy surgery; functional magnetic resonance imaging (fMRI); intracarotid sodium amobarbital procedure (IAT); language lateralization; magnetoencephalography (MEG); Wada test

Location and Timing of Recurrent, Nontraumatic Intracerebral Hemorrhage - Goeldlin, Martina B.; Fandler-Höfler, Simon; Pezzini, Alessandro; Manikantan, Anusha; Rauch, Janis; Hald, Stine Munk; Kristensen, Mona Løgtholt; Obergottsberger, Lena; Sembill, Jochen; Haupenthal, David; Larsen, Kristin Tveitan; Avramiotis, Nikolaos S.; et al. (JAMA Neurology, 2025)
Importance:: The spatial and temporal distribution of intracerebral hemorrhage (ICH) recurrence are largely unknown. Objective: To assess timing and location of recurrent ICH events in relation to the index ICH event (adjacent ICH [adjICH] vs remote ICH [remICH]). Design, Setting, and Participants: This cohort study was a pooled analysis of individual cohort studies from 2002 to 2021 among hospital-based European cohorts. Patients with 2 or more clinically distinguishable (≥1 recurrent) small vessel disease-related ICH events were included. Data analysis was performed from December 2023 to December 2024. Exposures: ICH location and underlying small vessel disease type. Main Outcomes and Measures: The primary outcome was adjICH, defined by anatomical ICH location and side, and the secondary outcome was time to recurrence. Multivariable regression analyses were conducted adjusting for ICH location, cerebral amyloid angiopathy according to Boston 2.0 or simplified Edinburgh criteria, convexity subarachnoid hemorrhage extension, hypertension, and antihypertensive treatment, including an interaction term for hypertension and antihypertensive treatment. Results: Among 733 patients (median [IQR] age, 72.4 [65.2 to 79.0] years; 346 female [47.2%]), there were 1616 ICH events, including 733 index and 883 recurrent ICH events (range, 1 to 6 recurrences) over a median (IQR) follow-up of 2.53 (0.66 to 4.92) years. There were 340 patients (46.4%) with adjICH and 393 patients (53.6%) with remICH. Among recurrent ICH events, there were 476 adjICH events and 407 remICH events. In multivariable regression analyses, lobar index ICH (adjusted odds ratio [aOR], 2.08; 95% CI, 1.32 to 3.27) and cerebral amyloid angiopathy at index ICH (aOR, 2.21; 95% CI, 1.57 to 3.11) were associated with higher odds of adjICH, while cerebellar index ICH was associated with lower odds of adjICH (aOR, 0.25; 95% CI, 0.07 to 0.89). The median (IQR) time to recurrence was 1.25 (0.36 to 3.38) years for adjICH and 2.21 (0.66 to 4.85) years for remICH. Previous lobar or convexity subarachnoid hemorrhage (coefficient, -0.75; 95% CI, -1.25 to -0.25; P =.003), adjICH (coefficient, -0.60; 95% CI, -1.02 to -0.18; P =.005), and the number of previous ICH events (coefficient per 1-event increase, -0.62; 95% CI, -0.93 to -0.32; P <.001) were independently associated with a shorter time to recurrence. Conclusions and relevance: This study found that early recurrence and cerebral amyloid angiopathy were associated with adjICH. These findings suggest that regional, tissue-based factors may facilitate recurrence and that identifying and targeting local vasculopathic changes may represent potential novel treatment targets..
CRIS-Team Scopus Importer:2025-03-28

LOMUSTINE/TEMOZOLOMIDE CHEMOTHERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED IDHWT GLIOBLASTOMA ACCORDING TO CETEG/NOA-09: REAL-WORLD EXPERIENCE IN A MULTICENTER COHORT - Weller, Johannes; Zeyen, Thomas; Schlegel, Uwe; Lazaridis, Lazaros; Werner, Jan-Michael; Onken, Julia; Zeiner, Pia; Drexler, Richard; Hau, Peter; Seidel, Clemens; Grosse, Lucia; Clusmann, Hans; et al. (NEURO-ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-30

Longer-term effects of intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: Who benefits? - Terhoeven, Pauline; Seybold, Julia; Utz, Katrin; Nickel, Franziska; Lee, De-Hyung; Linker, Ralf (Journal of the Neurological Sciences, 2020)
Intravenous immunoglobulins (IVIg) represent an established cornerstone for the immunotherapy of chronic inflammatory demyelinating polyneuropathy (CIDP). Efficacy of IVIg for CIDP was proven in a large phase III trial. Yet, data on longer-term efficacy and effects in distinct subgroups are scarce. Our trial investigates the long-term efficacy of IVIg treatment in CIDP patients. In this observational real-world study, we retrospectively analyzed 49 CIDP patients receiving continuous IVIg treatment with a mean initial dosage of 87 g (1 g/kg body weight) every 4 weeks over a mean time of 45 months between 2010 and 2018. INCAT-Scores before the start of treatment and at the end of the observation period were compared. Over the observation period, IVIg treatment led to a median improvement of one INCAT score point. Subgroup analyses revealed a more pronounced improvement of INCAT scores in female CIDP patients, individuals with relapsing disease courses, patients with more pronounced motor impairment (higher initial INCAT scores) and in the cohort without need for concomitant other immunotherapies. These data argue for sustained beneficial effects of longer-term immunotherapy with IVIg in CIDP, particularly in females and relapsing disease forms with higher disease activity.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Chronic inflammatory demyelinating polyneuropathy; Immunotherapy; Intravenous immunoglobulins; Long-term effect; Polyneuritis

Longitudinal Sodium MRI of Multiple Sclerosis Lesions: Is there Added Value of Sodium Inversion Recovery MRI - Mennecke, Angelika; Nagel, Armin Michael; Huhn, Konstantin; Linker, Ralf; Schmidt, Manuel; Rothhammer, Veit; Wilferth, Tobias; Linz, Peter; Wegmann, Julius; Eisenhut, Felix; Engelhorn, Tobias; Dörfler, Arnd (Journal of Magnetic Resonance Imaging, 2021)
Background Sodium enhancement has been demonstrated in multiple sclerosis (MS) lesions. Purpose To investigate sodium MRI with and without an inversion recovery pulse in acute MS lesions in an MS relapse and during recovery. Study Type Prospective. Subjects Twenty-nine relapsing-remitting MS patients with an acute relapse were included. Field Strength/Sequence A 3D density-adapted radial sodium sequence at 3 T using a dual-tuned (Na-23/H-1) head coil. Assessment Full-brain images of the tissue sodium concentration (TSC1, n = 29) and a sodium inversion recovery sequence (SIR1, n = 20) at the beginning of the anti-inflammatory therapy and on medium-term follow-up visits (days 27-99, n = 12 [TSC], n = 5 [SIR]) were measured. Regions of interest (RoIs) with contrast enhancement (T1CE+) and without change in T1-weighted imaging (FL + T1n) were normalized (nTSC and nSIR). To gain insight on the origin of the TSC enhancement at time point 1, it is investigated whether the nTSC enhancement of the lesions is accompanied by a change of the respective nSIR. Potential prognostic value of nSIR1 is examined referring to the nTSC progression. Statistical Tests nTSC and nSIR were compared regarding the type of lesion and the time point using a one-way ANOVA. Pearson's correlation coefficient was calculated for nTSC over nSIR and for nTSC1-nTSC2 over nSIR1. A P-value At the first measurement, all lesion types showed increased nTSC, while nSIR was decreased in the FL + T(1)n and the T1CE+ lesions in comparison to the normal-appearing white matter. For acute lesions, the difference between nTSC at baseline and nTSC at time point 2 showed a significant correlation with the baseline nSIR. Data Conclusion At time point 1, nTSC is increased, while nSIR is unchanged or decreased in the lesions. The mean sodium IR signal at baseline correlates with recovery or progression of an acute lesion. Evidence Level 2 Technical Efficacy Stage 4
CRIS-Team WoS Importer:2021-07-23

Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation - Korompoki, Eleni; Filippidis, Filippos T.; Nielsen, Peter B.; Del Giudice, Angela; Lip, Gregory Y. H.; Kuramatsu, Joji; Huttner, Hagen; Fang, Jiming; Schulman, Sam; Marti-Fabregas, Joan; Gathier, Celine S.; Viswanathan, Anand; et al. (Neurology, 2017)
To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up.A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for >=3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method.Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84).In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.
EVALuna2:22565

Long-Term Complications and Influence on Outcome in Patients Surviving Spontaneous Subarachnoid Hemorrhage - Gerner, Stefan; Reichl, Jonathan; Custal, Christina; Brandner, Sebastian; Eyüpoglu, Ilker Yasin; Lücking, Hannes; Hölter, Philip; Kallmünzer, Bernd; Huttner, Hagen (Cerebrovascular Diseases, 2020)
BACKGROUND: While the short-term clinical outcome of patients with subarachnoid hemorrhage (SAH) is well described, there are limited data on long-term complications and their impact on social reintegration. This study aimed to assess the frequency of complications post-SAH and to investigate whether these complications attribute to functional and self-reported outcomes as well as the ability to return to work in these patients. METHODS: This retrospective single-center study included patients with atraumatic SAH over a 5-year period at a tertiary care center. Patients received a clinical follow-up for 12 months. In addition to demographics, imaging data, and parameters of acute treatment, the rate and extent of long-term complications after SAH were recorded. The functional outcome was assessed using the modified Rankin Scale (mRS; favorable outcome defined as mRS = 0-2). Further outcomes comprised self-reported subjective health measured by the EQ-5D and return to work for SAH patients with appropriate age. Multivariable analyses including in-hospital parameters and long-term complications were conducted to identify parameters independently associated with outcomes in SAH survivors. RESULTS: This study cohort consisted of 505 SAH patients of whom 405 survived the follow-up period of 12 months (i.e., mortality rate of 19.8%). Outcome data were available in 359/405 (88.6%) patients surviving SAH. At 12 months, a favorable functional outcome was achieved in 287/359 (79.9%) and 145/251 (57.8%) SAH patients returned to work. The rates of post-acute complications were headache (32.3%), chronic hydrocephalus requiring permanent ventriculoperitoneal shunting (VP shunt 25.4%) and epileptic seizures (9.5%). Despite patient's and clinical characteristics, both presence of epilepsy and need for VP shunt were independently and negatively associated with a favorable functional outcome (epilepsy: adjusted odds ratio [aOR] (95% confidence interval [95% CI]): 0.125 [0.050-0.315]; VP shunt: 0.279 [0.132-0.588]; both p < 0.001) as well as with return to work (aOR [95% CI]: epilepsy 0.195 [0.065-0.584], p = 0.003; VP shunt 0.412 [0.188-0.903], p = 0.027). Multivariable analyses revealed presence of headache, VP shunt, or epilepsy to be significantly related to subjective health impairment (aOR [95% CI]: headache 0.248 [0.143-0.430]; epilepsy 0.223 [0.085-0.585]; VP shunt 0.434 [0.231-0.816]; all p < 0.01). CONCLUSIONS: Long-term complications occur frequently after SAH and are associated with an impairment of functional and social outcomes. Further studies are warranted to investigate if treatment strategies specifically targeting these complications, including preventive aspects, may improve the outcomes after SAH.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Long-term complications; Post-stroke outcomes; Social participation; Subarachnoid hemorrhage

Long-term course of anterior spinal cord herniation presenting with an upper motor neuron syndrome: Case report illustrating diagnostic and therapeutic implications - Regensburger, Martin; Schlachetzki, Johannes; Klekamp, Jörg; Dörfler, Arnd; Winkler, Jürgen (BMC Neurology, 2020)
Background: Anterior spinal cord herniation (aSCH) is a rare cause of myelopathy which may present as pure motor syndrome and mimic other degenerative diseases of the spinal cord. In slowly progressive cases, diagnosis may be impeded by equivocal imaging results and mistaken for evolving upper motor neuron disease. As early imaging studies are lacking, we aimed to provide a detailed description of imaging and neurophysiology findings in a patient with aSCH, focusing on the early symptomatic stages. Case presentation: We here present the case of a 51-year old male patient with an episode of pain in the right trunk and a normal spinal MRI. After a symptom-free interval of 8 years, spasticity and paresis evolved in the right leg. There was subtle ventral displacement and posterior indentation of the thoracic spinal cord on MRI which, in retrospect, was missed as an early sign of aSCH. After another 3 years, symptoms spread to the left leg and a sensory deficit of the trunk became evident. Follow-up MRI now clearly showed an aSCH. Neurosurgical intervention consisted of remobilization of the herniated spinal cord and patch closure of the dura defect. Over the following years, motor and sensory symptoms partially improved. Conclusions: The history of this patient with aSCH illustrates the importance of careful longitudinal clinical follow-up with repeated imaging studies in progressive upper motor neuron syndromes. Specific attention should be paid to a history of truncal pain and to MRI findings of a ventrally displaced spinal cord. Neurosurgical intervention may halt the progression of herniation.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Case Report; Evoked potentials; Spasticity; Spinal cord herniation

Long-term effects of zonisamide in adult patients with intellectual disability - Eck, Kattrinna; Rauch, Christophe; Kerling, Frank; Hamer, Hajo; Winterholler, Martin (Acta Neurologica Scandinavica, 2021)
Objective This study aimed to evaluate the tolerability and efficacy of zonisamide (ZNS) in adult patients with drug-resistant epilepsy and intellectual disability (ID) at our epilepsy centre.
CRIS-Team WoS Importer:2021-05-21

Long-term Fingolimod therapy increases sympathetic cardiovascular modulation - Wang, Ruihao; Hilz, Max-Josef; Roy, Sankanika; Liu, Mao; de Rojas Leal, Carmen; Hoesl, Katharina M.; Winder, Klemens; Lee, De-Hyung; Linker, Ralf (2018)
EVALuna2:35519

Long-term outcome after epilepsy surgery in older adults - Lang, Johannes D.; Grell, Laura; Hagge, Mareike; Onugoren, Muejgan Dogan; Gollwitzer, Stephanie; Graf, Wolfgang; Schwarz, Michael; Coras, Roland; Blümcke, Ingmar; Sommer, Bjoern; Roessler, Karl; Buchfelder, Michael; et al. (Seizure-European Journal of Epilepsy, 2018)
PURPOSE: The incidence of epilepsy in older adults is growing, as does the incidence of comorbidities. Therefore, when it comes to epilepsy surgery in medically intractable epilepsy, age is often seen as a limiting factor. To investigate the outcome after epilepsy surgery in a population of older adults, we compared the benefit for patients aged 50-59 years with those aged 60 years and older in respect of efficacy and safety. METHOD: Patients aged ≥50 years with medically intractable epilepsy who underwent epilepsy surgery from 1990 to 2013 were selected from the database of a German epilepsy center. All of them received a standardised and detailed presurgical diagnostic evaluation. Follow-up included at least four scheduled visits with EEG, MRI and neuropsychological testing. Outcome was assessed using the Engel outcome scale. RESULTS: 79 patients aged between 50 and 67 years were followed-up for a median of 4.7 years (2-16 years). 68% of patients were free of disabling seizures (Engel class I, ≥60 years: 75%) and 58% were seizure-free (Engel class IA, ≥60 years: 70%). 90% of our patients suffered from temporal lobe epilepsy (TLE), 9% from frontal lobe epilepsy (FLE) and one occipital lobe epilepsy (OLE). After surgery, 9% discontinued or tapered their medication. Permanent surgical complications occurred in 10% of cases and transient neurological deficits were seen in 11%. Older patients had a higher risk for postoperative hygroma (≥60 years 15%; <60 years 8%) and were more prone to postoperative memory deficits (≥60 years 45%), especially after resection of the dominant temporal lobe. Verbal and figural memory testing did not differ significantly between the groups. CONCLUSIONS: The results support the view that in selected older patients, epilepsy surgery shows equal or even higher success rates as compared to younger patients. However, patients of older age may be at greater risk for postoperative hygroma and memory deficits, especially after dominant temporal lobe resections.
EVALuna2:34593

Long term propionic acid supplementation leads to modulation of T effector cell balance/function and a decrease in annual relapse rate - Duscha, A.; Hasse, S.; Berg, J.; Schneider, R.; Lukas, C.; Linker, Ralf; Gold, R.; Haghikia, A. (2018)
EVALuna2:201947

Long-Term Survival, Burden of Disease, and Patient-Centered Outcomes in Maximally Treated Intracerebral Hemorrhage - Mrochen, Anne; Sprügel, Maximilian; Sekita, Alexander; Balk, Stefanie; Haupenthal, David; Gerner, Stefan; Lücking, Hannes; Dörfler, Arnd; Macha, Kosmas; Schwab, Stefan; Kuramatsu, Joji; Sembill, Jochen (Annals of Clinical and Translational Neurology, 2025)
Objective: Increasing evidence shows that patients with intracerebral hemorrhage (ICH) can achieve better-than-expected outcomes with aggressive therapy. However, real-world long-term data, patient-centered outcomes, and societal measures after maximal ICH treatment are lacking. This study aimed to analyze 5-year survival, utility-weighted functional outcomes, and burden of disease in maximally treated ICH patients, stratified by max-ICH Score. Methods: This study investigated consecutive patients with spontaneous ICH included in the single-center Longitudinal Cohort Study on ICH Care (UKER-ICH, NCT03183167, 2006–2015). We included all patients without early care limitations, hereinafter referred to as maximally treated. We analyzed the stratification by max-ICH Score of cumulative 5-year survival using Kaplan–Meier estimates and COX regression modeling, disease burden using disability-adjusted life years (DALYs), and patient-centered outcome at 12 months using the Utility-Weighted modified Rankin Scale (UW-mRS). Results: The 5-year survival rate of the included 1022 maximally treated patients was 53%, stratified by max-ICH Score (0 points: 85%, 1: 91%, 2: 69%, 3: 59%, 4: 47%, 5: 32%, 6: 29%, 7: 18%, ≥ 8: 0%, log-rank p < 0.001). The mean number of DALYs was 8.94 (±8.15, standard deviation [SD]), consisting of 4.27 years of life lost (±7.79, SD) and 4.67 years lived with disability (±6.38, SD). Patients with a max-ICH Score of 5 had the highest burden of disease (12.76 [±9.43, SD]). The mean UW-mRS at 12 months was 0.45 (±0.37, SD) and decreased with increasing max-ICH Score (0: 0.80 [±0.23], 1: 0.73 [±0.29], 2: 0.67 [±0.29], 3: 0.50 [±0.34], 4: 0.39 [±0.34], 5: 0.25 [±0.30], 6: 0.19 [±0.28], 7: 0.16 [±0.26], ≥ 8: 0.08 [±0.22], p < 0.001). Interpretation: These observational data, stratified by max-ICH Score, provide patients and treating physicians with an initial severity assessment in terms of potential long-term patient-centered outcomes and burden of disease following maximal treatment.
CRIS-Team Scopus Importer:2025-04-25
Keywords: intracerebral hemorrhage prognosis; patient-centered outcomes; stroke disability burden

Lost in Transition: The Long and Winding Road Toward Epilepsy Surgery-An Analysis of Obstacles Prior to Surgery and Call for Orchestrated Health Care Efforts in Epilepsy - Kasper, Burkhard; Graf, Wolfgang; Sharma, Sunjay; Kasper, Ekkehard M. (Journal of Pediatric Neurology, 2020)
Difficult-to-treat epilepsy is defined as ongoing seizures despite adequate pharmacological treatment. This condition is affecting a significant percentage of epilepsy patients and is estimated to be as high as one-third of all patients. Epilepsy surgery, targeting the removal of the key parts of cerebral convolutions responsible for seizure generation and often including a structural lesion, can be a very successful approach. However, this necessitates careful patient selection by comprehensive investigations, proving the localization of the epileptogenic zone as well as measures to make such surgeries safe. With careful selection as a prerequisite, the percentage of patients achieving seizure freedom by neurosurgical intervention is high, approximating two-thirds of all epilepsy surgeries performed. In contrast, the average duration of a patient's pharmacoresistant focal epilepsy prior to surgery anywhere around the globe is around 20 years. Given that typical patients are similar to 30 to 40 years of age at the time of surgery, many patients have been living with chronic seizures since childhood or adolescence. This means that most of these patients have been going through several stages of medical care for years or even decades, both as children and adults, without ever being fully investigated and/or selected for surgery which is concerning. Yet, there is no set standard for a timeline leading toward successful surgery in epilepsy. It is obvious that the average transit period from the moment of first seizure manifestation until the day of successful surgery takes much too long. This is the reason why we see these patients lost in transition.
CRIS-Team WoS Importer:2020-09-04

Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans - Coras, Roland; Siebzehnrübl, Florian; Pauli, Elisabeth; Huttner, Hagen; Njunting, Marleisje; Kobow, Katja; Villmann, Carmen; Hahnen, Eric; Neuhuber, Winfried; Weigel, Daniel; Buchfelder, Michael; Stefan, Herrmann; et al. (Brain, 2010)
The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 +/- 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 +/- 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R-adjusted(2) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R-adjusted(2) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.
Keywords: stem cells; neurogenesis; hippocampus; memory; learning; epilepsy; doublecortin

Lymphocytopenia Is an Independent Predictor of Unfavorable Functional Outcome in Spontaneous Intracerebral Hemorrhage - Giede-Jeppe, Antje; Bobinger, Tobias; Gerner, Stefan; Madzar, Dominik; Sembill, Jochen; Lücking, Hannes; Kloska, Stephan; Keil, Toni; Kuramatsu, Joji; Huttner, Hagen (Stroke, 2016)
Stroke-associated immunosuppression is an increasingly recognized factor triggering infections and thus potentially influencing outcome after stroke. Specifically, lymphocytopenia after intracerebral hemorrhage (ICH) has only been addressed in small-sized retrospective studies of mixed intracranial bleedings. This cohort study investigated the natural course of lymphocytopenia, parameters associated with lymphocytopenia on admission (LOA) and during stay, and evaluated the clinical impact of lymphocytopenia in solely ICH patients.This observational study included 855 consecutive patients with ICH. Patient demographics, clinical and neuroradiological data as well as laboratory and in-hospital measures were retrieved from institutional prospective databases. Functional 3-month outcome was assessed by mailed questionnaires. Lymphocytopenia was defined as <1.0 (10(9)/L) and was correlated with patient's characteristics and outcome.Prevalence of LOA was 27.3%. Patients with LOA showed significant associations with poorer neurological status (18 [10-32] versus 13 [5-24]; P<0.001), larger hematoma volume (18.5 [6.2-46.2] versus 12.8 [4.4-37.8]; P=0.006), and unfavorable outcome (74.7% versus 63.3%; P=0.0018). Natural course of lymphocyte count during hospital stay revealed a lymphocyte nadir of 1.1 (0.80-1.53 [10(9)/L]) at day 5. Focusing on patients with day-5-lymphocytopenia, compared with patients with LOA, revealed increased rates of infections (63 [71.6] versus 113 [48.5]; P<0.001) and poorer functional outcome at 3 months (76 [86.4] versus 175 [75.1); P=0.029). Adjusting for baseline confounders, multivariable logistic and receiver operating characteristics analyses documented independent associations of day-5-lymphocytopenia with unfavorable outcome (day-5-lymphocytopenia: odds ratio, 2.017 [95% confidence interval, 1.029-3.955], P=0.041; LOA: odds ratio, 1.391 [0.795-2.432], P=0.248; receiver operating characteristics: day-5-lymphocytopenia: area under the curve=0.673, P<0.0001, Youden's index=0.290; LOA: area under the curve=0.513, P=0.676, Youden's index=0.084), whereas receiver operating characteristics analyses revealed no association of age or hematoma volume with day-5-lymphocytopenia (age: area under the curve=0.540, P=0.198, Youden's index=0.106; volume: area under the curve=0.550, P=0.0898, Youden's index=0.1224).Lymphocytopenia is frequently present in patients with ICH and may represent an independent parameter associated with unfavorable functional outcome. Developing lymphocytopenia affected outcome even stronger than LOA, a finding that may open up new therapeutic avenues in specific subsets of patients with ICH.
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Macrophages in neuroinflammation: role of the renin-angiotensin-system - Hammer, Anna; Stegbauer, Johannes; Linker, Ralf (Pflügers Archiv: European Journal of Physiology, 2017)
Macrophages are essential players of the innate immune system which are involved in the initiation and progression of various inflammatory and autoimmune diseases including neuroinflammation. In the past few years, it has become increasingly clear that the regulation of macrophage responses by the local tissue milieu is also influenced by mediators which were first discovered as regulators in the nervous or also cardiovascular system. Here, the renin-angiotensin system (RAS) is a major focus of current research. Besides its classical role in blood pressure control, body fluid, and electrolyte homeostasis, the RAS may influence (auto)immune responses, modulate T cells, and particularly act on macrophages via different signaling pathways. Activation of classical RAS pathways including angiotensin (Ang) II and AngII type 1 (AT1R) receptors may drive pro-inflammatory macrophage responses in neuroinflammation via regulation of chemokines. More recently, alternative RAS pathways were described, such as binding of Ang-(1-7) to its receptor Mas. Signaling via Mas pathways may counteract some of the AngII/AT1R-mediated effects. In macrophages, the Ang-(1-7)/Mas exerts beneficial effects on neuroinflammation via modulating macrophage polarization, migration, and T cell activation in vitro and in vivo. These data delineate a pivotal role of the RAS in inflammation of the nervous system and identify RAS modulation as a potential new target for immunotherapy with a special focus on macrophages.
EVALuna2:22498

MAdCAM-1-Mediated Intestinal Lymphocyte Homing Is Critical for the Development of Active Experimental Autoimmune Encephalomyelitis - Kuhbandner, Kristina; Hammer, Anna; Haase, Stefanie; Terbrack, Elisa; Hoffmann, Alana; Schippers, Angela; Wagner, Norbert; Hussain, Rehana Z.; Miller-Little, William A.; Koh, Andrew Y.; Stoolman, Joshua S.; Segal, Benjamin M.; et al. (Frontiers in Immunology, 2019)
Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite of intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-) inflammatory disease conditions remains to be clarified. This prompted us to investigate the role of MAdCAM-1 in immunological processes in the intestine during T cell-mediated autoimmunity of the central nervous system (CNS). Using the experimental autoimmune encephalomyelitis model of MS, we show that MAdCAM-1-deficient (MAdCAM-1-KO) mice are less susceptible to actively MOG35-55-induced disease. Protection from disease was accompanied by decreased numbers of immune cells in the lamina propria and Peyer's patches as well as reduced immune cell infiltration into the spinal cord. MOG35-55-recall responses were intact in other secondary lymphoid organs of MAdCAM-1-KO mice. The composition of specific bacterial groups within the microbiome did not differ between MAdCAM-1-KO mice and controls, while MAdCAM-1-deficiency severely impaired migration of MOG35-55-activated lymphocytes to the gut. Our data indicate a critical role of MAdCAM-1 in the development of CNS inflammation by regulating lymphocyte homing to the intestine, and may suggest a role for the intestinal tract in educating lymphocytes to become encephalitogenic.
CRIS-Team WoS Importer:2019-05-03

MaD GUI: An Open-Source Python Package for Annotation and Analysis of Time-Series Data - Ollenschläger, Malte; Küderle, Arne; Mehringer, Wolfgang; Seifer, Ann-Kristin; Winkler, Jürgen; Gaßner, Heiko; Eskofier, Björn; Kluge, Felix (Sensors, 2022)
Developing machine learning algorithms for time-series data often requires manual annotation of the data. To do so, graphical user interfaces (GUIs) are an important component. Existing Python packages for annotation and analysis of time-series data have been developed without addressing adaptability, usability, and user experience. Therefore, we developed a generic open-source Python package focusing on adaptability, usability, and user experience. The developed package, Machine Learning and Data Analytics (MaD) GUI, enables developers to rapidly create a GUI for their specific use case. Furthermore, MaD GUI enables domain experts without programming knowledge to annotate time-series data and apply algorithms to it. We conducted a small-scale study with participants from three international universities to test the adaptability of MaD GUI by developers and to test the user interface by clinicians as representatives of domain experts. MaD GUI saves up to 75% of time in contrast to using a state-of-the-art package. In line with this, subjective ratings regarding usability and user experience show that MaD GUI is preferred over a state-of-the-art package by developers and clinicians. MaD GUI reduces the effort of developers in creating GUIs for time-series analysis and offers similar usability and user experience for clinicians as a state-of-the-art package.
CRIS-Team WoS Importer:2022-08-26

Magnetoencephalography for epileptic focus localization in a series of 1000 cases. - Rampp, Stefan; Stefan, Hermann; Wu, Xintong; Kaltenhäuser, Martin; Maess, Burkhard; Schmitt, Friedhelm C.; Wolters, Carsten H.; Hamer, Hajo; Kasper, Burkhard S.; Schwab, Stefan; Blümcke, Ingmar; Rössler, Karl; et al. (Brain, 2019)
The aim of epilepsy surgery in patients with focal, pharmacoresistant epilepsies is to remove the complete epileptogenic zone to achieve long-term seizure freedom. In addition to a spectrum of diagnostic methods, magnetoencephalography focus localization is used for planning of epilepsy surgery. We present results from a retrospective observational cohort study of 1000 patients, evaluated using magnetoencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecutive cases were included in the study, evaluated at the University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to 20 years. Sensitivity for interictal epileptic activity was evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar level. We evaluate magnetoencephalography characteristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In operated patients, resection of magnetoencephalography localizations were related to postsurgical seizure outcomes, including long-term results after several years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic accuracy were calculated for magnetoencephalography resection and lesionectomy. Sensitivity for interictal epileptic activity was 72% with significant differences between temporal and extra-temporal lobe epilepsy. Magnetoencephalography was concordant with the presurgical consensus in 51% and showed additional or more focal involvement in an additional 32%. Patients who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography results. Complete magnetoencephalography resection was associated with significantly higher chances to achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and extra-temporal lobe cases, but was significantly higher in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-lesional versus lesional cases (42.0 versus 6.2). The results show that magnetoencephalography provides non-redundant information, which significantly contributes to patient selection, focus localization and ultimately long-term seizure freedom after epilepsy surgery. Specifically in extra-temporal lobe epilepsy and non-lesional cases, magnetoencephalography provides excellent accuracy.
EVALuna2:204465

Magnetoencephalography for epileptic focus localization in a series of 1000 cases - Rampp, Stefan; Stefan, Hermann; Wu, Xueqing; Kaltenhäuser, Martin; Maess, Burkhard; Schmitt, Friedhelm C.; Wolters, Carsten H.; Hamer, Hajo; Kasper, Burkhard; Schwab, Stefan; Dörfler, Arnd; Blümcke, Ingmar; et al. (Brain, 2019)
The aim of epilepsy surgery in patients with focal, pharmacoresistant epilepsies is to remove the complete epileptogenic zone to achieve long-term seizure freedom. In addition to a spectrum of diagnostic methods, magnetoencephalography focus localization is used for planning of epilepsy surgery. We present results from a retrospective observational cohort study of 1000 patients, evaluated using magnetoencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecutive cases were included in the study, evaluated at the University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to 20 years. Sensitivity for interictal epileptic activity was evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar level. We evaluate magnetoencephalography characteristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In operated patients, resection of magnetoencephalography localizations were related to postsurgical seizure outcomes, including long-term results after several years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic accuracy were calculated for magnetoencephalography resection and lesionectomy. Sensitivity for interictal epileptic activity was 72% with significant differences between temporal and extra-temporal lobe epilepsy. Magnetoencephalography was concordant with the presurgical consensus in 51% and showed additional or more focal involvement in an additional 32%. Patients who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography results. Complete magnetoencephalography resection was associated with significantly higher chances to achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and extra-temporal lobe cases, but was significantly higher in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-lesional versus lesional cases (42.0 versus 6.2). The results show that magnetoencephalography provides non-redundant information, which significantly contributes to patient selection, focus localization and ultimately long-term seizure freedom after epilepsy surgery. Specifically in extra-temporal lobe epilepsy and non-lesional cases, magnetoencephalography provides excellent accuracy.
CRIS-Team Scopus Importer:2019-10-08
Keywords: epilepsy; epilepsy surgery; long-term outcome; magnetic source imaging; magnetoencephalography

Magnetoencephalography-guided surgery in frontal lobe epilepsy using neuronavigation and intraoperative MR imaging - Sommer, Bjoern; Roessler, Karl; Rampp, Stefan; Hamer, Hajo; Blümcke, Ingmar; Stefan, Hermann; Buchfelder, Michael (Epilepsy Research, 2016)
Especially in hidden lesions causing drug-resistant frontal lobe epilepsy (FLE), the localization of the epileptic zone EZ can be a challenge. Magnetoencephalography (MEG) can raise the chances for localization of the (EZ) in combination with electroencephalography (EEG). We investigated the impact of MEG-guided epilepsy surgery with the aid of neuronavigation and intraoperative MR imaging (iopMRI) on seizure outcome of FLE patients.Twenty-eight patients (15 females, 13 males; mean age 31.0±11.1 years) underwent surgery in our department. All patients underwent presurgical MEG monitoring (two-sensor Magnes II or whole head WH3600 MEG system; 4-D Neuroimaging, San Diego, CA, USA). Of those, six patients (group 1) with MRI-negative FLE were operated on before 2002 with intraoperative electrocorticography (ECoG) and invasive EEG mapping only. Eleven patients with MRI-negative FLE (group 2) and eleven with lesional FLE (group 3) underwent surgery using 1.5T-iopMRI and neuronavigation, including intraoperative visualization of the MEG localizations in 22 and functional MR imaging (for motor and speech areas) as well as DTI fiber tracking (for language and pyramidal tracts) in 13 patients.In the first group, complete resection of the defined EZ including the MEG localization according to the latest postoperative MRI was achieved in four out of six patients. Groups two and three had complete removal of the MEG localizations in 20/22 (91%, 10 of 11 each). Intraoperative MRI revealed incomplete resection of the MEG localizations of four patients (12%; two in both groups), leading to successful re-resection. Transient and permanent neurological deficits alike occurred in 7.1%, surgery-associated complications in 11% of all patients. In the first group, excellent seizure outcome (Engel Class IA) was achieved in three (50%), in the second in 7 patients (61%) and third group in 8 patients (64%, two iopMRI-based re-resections). Mean follow-up was 70.3 months (from 12 to 284 months).In our series, MEG-guided resection using neuronavigation and iopMR imaging led to promising seizure control rates. Even in non-lesional FLE, seizure control rates and the probability of complete resection of the MEG localizations was similar to lesional FLE using multimodal navigation.
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Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment - Schubert, Julia; Braemer, Dirk; Huttner, Hagen; Gerner, Stefan; Fuhrer, Hannah; Melzer, Nico; Dik, Andre; Pruess, Harald; Ly, Lam-Than; Fuchs, Kornelius; Leypoldt, Frank; Nissen, Gunnar; et al. (Neurology, Neuroimmunology and Neuroinflammation, 2019)
To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge.Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.
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MANAGEMENT OF INSUFFICIENT FUNCTIONAL ANTITHROMBOTIC ACTIVITY DURING TREATMENT WITH DIRECT ORAL ANTICOAGULANTS FOR STROKE PREVENTION - Macha, Kosmas; Stoll, Svenja; Siedler, Gabriela; Volbers, Bastian; Strasser, Erwin; Schwab, Stefan; Kallmünzer, Bernd (INTERNATIONAL JOURNAL OF STROKE, 2020)
CRIS-Team WoS Importer:2021-01-22

Management of oral anticoagulation after intracerebral hemorrhage - Kuramatsu, Joji; Huttner, Hagen (International Journal of Stroke, 2019)
Background The most recent years have significantly expanded knowledge regarding risks and benefits of resuming oral anticoagulation (OAC) after intracerebral hemorrhage (ICH). No randomized data is yet available, though several large observational studies and meta-analyses have investigated the impact of resuming OAC on thromboembolic versus hemorrhagic complications in these high-risk patients after ICH. Aims The present review will summarize the most important studies conducted over the last years and will focus on relevant factors help guiding on decision-making on whether to start OAC after ICH. Summary of review Several important factors (demographic, co-morbidities, clinical characteristics) need to be considered before individual decision-making for or against OAC is employed. Existing observational data suggest that patients after ICH with indication for long-term oral anticoagulation benefit from OAC given significant reductions of thromboembolic events without significantly increasing bleeding complications. Studies even suggest that thereby also clinical outcomes may be improved. Prospective trials currently recruiting patients will clarify whether OAC after ICH - or left atrial appendage closure as a meaningful alternative - is of clinical net-benefit. Conclusions Large sized and well-executed investigations (moderate quality of evidence) are showing that OAC resumption after ICH decreases thromboembolic complications and long-term mortality without significantly increasing bleeding complications. Further, data suggest that resumption may be safer in non-lobar ICH compared to lobar ICH, but overall, thoughtful selection, strict blood pressure control, and precise communication are paramount before starting a patient on OAC after ICH.
CRIS-Team WoS Importer:2019-04-02

Management of Parkinson's Disease 20 Years from Now: Towards Digital Health Pathways - Klucken, Jochen; Kruger, Rejko; Schmidt, Peter; Bloem, Bastiaan R. (Journal of Parkinson's Disease, 2018)
Current best medical treatment for patients with Parkinson's disease (PD) involves a medical professional who applies state-of-the-art knowledge of diagnostics and treatment- as derived from cohort studies and clinical trials- to the healthcare process of individual patients. Thus, the much-needed personalization of medicine depends on the abilities, experience and intuition of medical professionals to adjust group-based knowledge to individual decision making. Within 20 years from now, such personal clinical decisions will be largely supported by digital means, also defining a new ecosystem of healthcare often referred to as "digital medicine". We expect that the next phase of digitalization will include new "digital health pathways": data-driven personalized decision support that is based on a combination of multimodal data sources, including evidence-based medical knowledge (e.g., clinical guidelines), personal disease profiles (including genetic determinants of disease progression and treatment response), insights into individual disease trajectories (thereby defining subgroups of patients) and individual patients' needs. Here, we illustrate the potential of this development by sketching the contours of a digitally supported care pathway for gait disability and falls. Such digital health pathways will support the introduction of personalized medicine for PD patients, allowing patients to benefit optimally from individually tailored treatments. This should result in a better quality of life for patients and lower costs for society.
EVALuna2:213410

Management of Stroke in Patients with Left Ventricular Assist Devices - Giede-Jeppe, Antje; Röder, Sebastian; Macha, Kosmas; Huttner, Hagen; Gerner, Stefan; Fröhlich, Kilian; Heim, Christian; Schwab, Stefan; Kallmünzer, Bernd (Journal of Stroke and Cerebrovascular Diseases, 2020)
Introduction: The number of patients with left ventricular assist devices (LVAD) is rapidly growing in industrialized countries. While cerebrovascular events comprise a significant complication, data on stroke etiology, clinical management and functional outcome are scarce. Methods: Consecutive LVAD patients with ischemic or hemorrhagic stroke receiving treatment at an university stroke center between 2010 and 2018 were included into an institutional registry. Clinical characteristics, causes, management and functional outcome of stroke occurring within this cohort are reported. Acceptable functional outcome was defined as mRS 0-3. Results: N = 30 acute strokes occurred in 20 patients (77% ischemic, 23% hemorrhagic, mean age 57 ± 13 years, 10% female, 8 patients (40%) had more than one event). 87% of all events happened with non-pulsatile devices, on average 9 (IQR 3-22) months after the implantation. All patients used oral anticoagulation with a Vitamin-K antagonist in combination with anti-platelets. The international normalized ratio (INR)-values were outside the therapeutic range in 39% of ischemic strokes and in 57% of hemorrhagic strokes. Ischemic strokes were predominantly of cardioembolic origin (92%) and of mild to moderate clinical severity (median NIHSS 6 (IQR 4-10). None qualified to receive intravenous thrombolysis or intra-arterial endovascular therapy. 61% of IS-patients showed an acceptable functional outcome after three months. 4/7 patients with hemorrhagic stroke received immediate reversal of anticoagulation without any thrombotic complications. Conclusion: The majority of LVAD patients with ischemic stroke had an acceptable functional outcome after three months. Future clinical research is warranted to improve therapeutic strategies for acute care and stroke prevention.
CRIS-Team Scopus Importer:2020-08-21
Keywords: Functional outcome; Intracerebral hemorrhage; Ischemic stroke; Left ventricular assist devices

Management of supine hypertension in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension - Jordan, Jens; Fanciulli, Alessandra; Tank, Jens; Calandra-Buonaura, Giovanna; Cheshire, William P.; Cortelli, Pietro; Eschlboeck, Sabine; Grassi, Guido; Hilz, Max-Josef; Kaufmann, Horacio; Lahrmann, Heinz; Mancia, Giuseppe; et al. (Journal of Hypertension, 2019)
: Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.
CRIS-Team Scopus Importer:2019-07-26

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves - Kuramatsu, Joji; Sembill, Jochen; Gerner, Stefan; Sprügel, Maximilian; Hagen, Manuel; Röder, Sebastian; Endres, Matthias; Haeusler, Karl Georg; Sobesky, Jan; Schurig, Johannes; Zweynert, Sarah; Bauer, Miriam; et al. (European Heart Journal, 2018)
Aims Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results We pooled individual patient- data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). Conclusion Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.
EVALuna2:34917

Management von intrazerebralen Blutungen unter oraler Antikoagulation - Sembill, Jochen; Kuramatsu, J. B.; Hohnloser, S. H.; Huttner, Hagen (Herz, 2019)
The incidence of intracerebral hemorrhage (ICH) in patients using oral anticoagulation (OAC) will continue to increase with the demographic change of an aging population. As compared to primary spontaneous ICH, OAC-ICH is characterized by larger hematoma volumes, more frequent hematoma enlargement and intraventricular hemorrhage resulting in an even worse prognosis. Specific treatment should focus on immediate reversal of anticoagulation in addition to the basic acute management of ICH. In ICH patients using vitamin K antagonists (VKA), complete anticoagulant reversal with an international normalized ratio (INR) <1.3 should be achieved as quickly as possible using prothrombin complex concentrate (PCC) with additional substitution of vitamin K. Patients with ICH under dabigatran treatment should receive idarucizumab. In ICH patients using factor-Xa inhibitors, andexanet should be administered as soon as approved in Europe or within clinical studies and if unavailable alternatively high-dose PCC administration. Regarding OAC resumption, results from randomized trials are pending. In comprehensive observational studies and meta-analyses ICH patients resuming OAC showed a reduced incidence of thromboembolic events and mortality without significantly increased rates of hemorrhagic complications. Non-vitamin K dependent oral anticoagulants (NOAC) might further increase the safety of OAC resumption, which should be initiated after 4–8 weeks for patients with atrial fibrillation. In contrast, VKA resumption in patients with mechanical heart valves should not take place earlier than 1 week after ICH. Generally, safety of OAC resumption appears to be affected by ICH localization along with the presence of cerebral microbleeding, cortical superficial siderosis and cortical/convexity subarachnoid hemorrhage, making it crucial to weigh up the individual patient risk with respect to thromboembolic versus hemorrhagic events.
CRIS-Team Scopus Importer:2019-06-25
Keywords: Anticoagulant reversal; Atrial fibrillation; Intracranial hemorrhages; Mechanical heart valves; Oral anticoagulation

Manufacturer switch of anti-seizure drugs may not increase the risk of seizure recurrence in Children: A nationwide study of prescription data in Germany - Lang, Johannes; Kostev, Karel; Reindl, Caroline; Müller, Tamara; Stritzelberger, Jenny; Gollwitzer, Stephanie; Westermayer, Vivien; Trollmann, Regina; Hamer, Hajo (Epilepsy & Behavior, 2021)
Objective: Several publications on the exchangeability of antiepileptic drugs in clinical settings revealed an increased risk for seizure recurrence after changing the manufacturer of anti-seizure drugs (ASD) in adults, possibly due to a decline of adherence. It is unclear whether this holds true in children and adolescents. Methods: Patient data of children and adolescents (<18 years) were collected anonymously from 236 German pediatricians and pediatric neurologists between January 2011 and December 2018 using the IMS® Disease Analyzer database (IQVIA, Frankfurt, Germany). Patients with epilepsy were included if at least 2 prescriptions within 360 days and 1 within 180 days prior to the index date were available. The cohort was separated into a seizure group and seizure-free controls. Both groups were matched 1:1 according to age, gender, insurance status, and treating pediatrician. The risk for seizure recurrence after a manufacturer switch of the same ASD at the last prescription before the index date was analyzed using a multivariate regression model. Results: A total of 678 children and adolescents with epilepsy were included (each group: n = 339; age: 9.6 ± 4.4 years). Comparing both groups, the risk for seizures recurrence was not increased after a manufacturer switch had occurred. Albeit changes during the last prescription before the index date had occurred more often in the seizure-free group, neither change of branded and generic products nor substances reached significance. Only change of ASD strength showed a significantly reduced odds ratio for seizures (OR 0.40, 95% CI 0.24–0.65, p < 0.001). Significance: In contrast to the available evidence in adults, changing the manufacturer did not appear to increase the risk for seizure recurrence in previously seizure-free children and adolescents with epilepsy.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Anti-seizure drugs; Manufacturer changes; Relapse seizures

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia - Newton, Timothy; Allison, Rachel; Edgar, James R.; Lumb, Jennifer H.; Rodger, Catherine E.; Manna, Paul T.; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O. H.; Arning, Larissa; Schuele, Rebecca; Depienne, Christel; et al. (Brain, 2018)
Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.
EVALuna2:35784

MEG in frontal epilepsy - Rampp, Stefan; Kasper, Burkhard; Brandner, Sebastian; Hamer, Hajo; Buchfelder, Michael (Zeitschrift für Epileptologie, 2022)
Magnetoencephalography (MEG) offers considerable advantages for presurgical localization diagnostics of frontal and generalized extratemporal epilepsy. A number of retrospective and prospective studies show a significant impact on the planning of invasive recordings and epilepsy surgical procedures with marked improvement of postoperative seizure control. This article provides a concise overview of the current state of the evidence.
CRIS-Team WoS Importer:2022-02-04

MEG in MRI-Negative Patients with Focal Epilepsy - Kreidenhuber, Rudolf; Poppert, Kai-Nicolas; Mauritz, Matthias; Hamer, Hajo; Delev, Daniel; Schnell, Oliver; Rampp, Stefan (Journal of Clinical Medicine, 2024)
Objectives: To review the evidence on the clinical value of magnetic source imaging (MSI) in patients with refractory focal epilepsy without evidence for an epileptogenic lesion on magnetic resonance imaging (“MRI-negative” or “non-lesional MRI”). Methods: We conducted a systematic literature search on PUBMED, which was extended by researchrabbit.ai using predefined criteria to identify studies that applied MSI in MRI-negative patients with epilepsy. We extracted data on patient characteristics, MSI methods, localization results, surgical outcomes, and correlation with other modalities. Results: We included 23 studies with a total of 512 non-lesional epilepsy patients who underwent MSI. Most studies used equivalent current dipole (ECD) models to estimate the sources of interictal epileptic discharges (IEDs). MEG detected IEDs in 32–100% of patients. MSI results were concordant with other modalities, such as EEG, PET, and SPECT, in 3892% of cases. If MSI concordant surgery was performed, 52–89% of patients achieved seizure freedom. MSI contributed to the decision-making process in 28–75% of cases and altered the surgical plan in 5–33% of cases. Conclusions: MSI is a valuable diagnostic tool for MRI-negative patients with epilepsy, as it can detect and localize IEDs with high accuracy and sensitivity, and provides useful information for surgical planning and predicts outcomes. MSI can also complement and refine the results of other modalities, such as EEG and PET, and optimize the use of invasive recordings. MSI should be considered as part of the presurgical evaluation, especially in patients with non-lesional refractory epileps
CRIS-Team Scopus Importer:2024-10-25
Keywords: magnetic source imaging; non-lesional; epilepsy; magnetoencephalography; negative MRI; normal MRI; refractory epilepsy; presurgical

MEG Node Degree Differences in Patients with Focal Epilepsy vs. Controls-Influence of Experimental Conditions - Vogel, Stephan; Kaltenhaeuser, Martin; Kim, Cora; Müller-Voggel, Nadia; Rössler, Karl; Dörfler, Arnd; Schwab, Stefan; Hamer, Hajo; Buchfelder, Michael; Rampp, Stefan (Brain Sciences, 2021)
Drug-resistant epilepsy can be most limiting for patients, and surgery represents a viable therapy option. With the growing research on the human connectome and the evidence of epilepsy being a network disorder, connectivity analysis may be able to contribute to our understanding of epilepsy and may be potentially developed into clinical applications. In this magnetoencephalographic study, we determined the whole-brain node degree of connectivity levels in patients and controls. Resting-state activity was measured at five frequency bands in 15 healthy controls and 15 patients with focal epilepsy of different etiologies. The whole-brain all-to-all imaginary part of coherence in source space was then calculated. Node degree was determined and parcellated and was used for further statistical evaluation. In comparison to controls, we found a significantly higher overall node degree in patients with lesional and non-lesional epilepsy. Furthermore, we examined the conditions of high/reduced vigilance and open/closed eyes in controls, to analyze whether patient node degree levels can be achieved. We evaluated intraclass-correlation statistics (ICC) to evaluate the reproducibility. Connectivity and specifically node degree analysis could present new tools for one of the most common neurological diseases, with potential applications in epilepsy diagnostics.
CRIS-Team WoS Importer:2022-01-07

MEG Node Degree for Focus Localization: Comparison with Invasive EEG - Rampp, Stefan; Kaltenhaeuser, Martin; Müller-Voggel, Nadia; Dörfler, Arnd; Kasper, Burkhard S.; Hamer, Hajo; Brandner, Sebastian; Buchfelder, Michael (Biomedicines, 2023)
Epilepsy surgery is a viable therapy option for patients with pharmacoresistant focal epilepsies. A prerequisite for postoperative seizure freedom is the localization of the epileptogenic zone, e.g., using electro- and magnetoencephalography (EEG/MEG). Evidence shows that resting state MEG contains subtle alterations, which may add information to the workup of epilepsy surgery. Here, we investigate node degree (ND), a graph-theoretical parameter of functional connectivity, in relation to the seizure onset zone (SOZ) determined by invasive EEG (iEEG) in a consecutive series of 50 adult patients. Resting state data were subjected to whole brain, all-to-all connectivity analysis using the imaginary part of coherence. Graphs were described using parcellated ND. SOZ localization was investigated on a lobar and sublobar level. On a lobar level, all frequency bands except alpha showed significantly higher maximal ND (mND) values inside the SOZ compared to outside (ratios 1.11-1.20, alpha 1.02). Area-under-the-curve (AUC) was 0.67-0.78 for all expected alpha (0.44, ns). On a sublobar level, mND inside the SOZ was higher for all frequency bands (1.13-1.38, AUC 0.58-0.78) except gamma (1.02). MEG ND is significantly related to SOZ in delta, theta and beta bands. ND may provide new localization tools for presurgical evaluation of epilepsy surgery.
CRIS-Team WoS Importer:2023-03-24
Keywords: MEG; epilepsy; epilepsy surgery; connectivity; graph theory; focus localization

Meningioma growth dynamics assessed by radiocarbon retrospective birth dating - Huttner, Hagen B.; Bergmann, Olaf; Salehpour, Mehran; El Cheikh, Raouf; Nakamura, Makoto; Tortora, Angelo; Heinke, Paula; Coras, Roland; Englund, Elisabet; Eyüpoglu, Ilker Yasin; Kuramatsu, Joji; Röder, Sebastian; et al. (EBioMedicine, 2018)
It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n=6 with meningothelial and n=6 with fibrous subtype, as well as n=2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1±6.5years, whereas atypical WHO grade II meningiomas originated 1.5±0.1years prior to surgery (p<0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.
EVALuna2:34031

Meningitis and intracranial abscess due to Mycoplasma pneumoniae in a B cell-depleted patient with multiple sclerosis - Madžar, Dominik; Nickel, Florian; Rothhammer, Veit; Gölitz, Philipp; Geißdörfer, Walter; Dumke, Roger; Lang, Roland (European Journal of Clinical Microbiology & Infectious Diseases, 2024)
Mycoplasma pneumoniae, a frequent respiratory pathogen, can cause neurological disease manifestations. We here present a case of M. pneumoniae as cause of meningitis and occurrence of an intracranial abscess as a complication of mastoiditis with septic cerebral venous sinus thrombosis in a patient with multiple sclerosis on anti-CD20 therapy.
CRIS-Team Scopus Importer:2024-09-20
Keywords: Abscess; Anti-CD20 antibody; Complication; Mastoiditis; Multiple sclerosis; Mycoplasma pneumoniae; Ocrelizumab; Rituximab; Septic cerebral venous sinus thrombosis

Mental Health in Multiple Sclerosis Patients without Limitation of Physical Function: The Role of Physical Activity. - Tallner, Alexander; Waschbisch, Anne; Hentschke, Christian; Pfeifer, Klaus; Mäurer, Mathias (International Journal of Molecular Sciences, 2015)
Multiple sclerosis (MS) patients, in general, show reduced physical function, physical activity, and quality of life. Positive associations between physical activity and quality of life have been reported. In particular, we were interested in the relation between physical activity and mental health in MS patients without limitation of physical function, since limitations of physical function may influence both physical activity and quality of life. Assessment comprised the Baecke questionnaire on physical activity, the Short Form 36 Health Survey (SF-36), and Beck Depression Inventory (BDI). We ranked our sample according to physical activity into four groups and performed an ANOVA to analyze the relationship between levels of physical activity and health-related quality of life (HRQoL). Then we performed a subgroup analysis and included patients with unlimited walking distance and a score of less than 18 in the BDI. Most active vs. inactive patients were compared for the mental subscales of the SF-36 and depression scores. From 632 patients, 265 met inclusion criteria and hence quartiles were filled with 67 patients each. Active and inactive patients did not differ considerably in physical function. In contrast, mental subscales of the SF-36 were higher in active patients. Remarkable and significant differences were found regarding vitality, general health perception, social functioning and mental health, all in favor of physically active patients. Our study showed that higher physical activity is still associated with higher mental health scores even if limitations of physical function are accounted for. Therefore, we believe that physical activity and exercise have considerable health benefits for MS patients.

Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin - Seliger, Corinna; Meyer, Anne-Louise; Leidgens, Verena; Rauer, Lisa; Moeckel, Sylvia; Jachnik, Birgit; Proske, Judith; Dettmer, Katja; Rothhammer-Hampl, Tanja; Kaulen, Leon D.; Riemenschneider, Markus J.; Oefner, Peter J.; et al. (International Journal of Molecular Sciences, 2022)
Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.
CRIS-Team Scopus Importer:2022-10-28
Keywords: glioma; metabolism; metformin

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-?2 - Seliger, Corinna; Meyer, Anne-Louise; Renner, Kathrin; Leidgens, Verena; Moeckel, Sylvia; Jachnik, Birgit; Dettmer, Katja; Tischler, Ulrike; Gerthofer, Valeria; Rauer, Lisa; Uhl, Martin; Proescholdt, Martin; et al. (Cell Cycle, 2016)
To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor ? 2 (TGF-?2) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-?2-signaling. Functional investigation of proliferation and migration of primary BTICs after treatment with metformin+/-TGF-?2 revealed that metformin doses as low as 0.01 mM metformin thrice a day were able to inhibit proliferation of susceptible cell lines, whereas migration was impacted only at higher doses. Known cellular mechanisms of metformin, such as increased lactate secretion, reduced oxygen consumption and activated AMPK-signaling, could be confirmed. However, TGF-?2 and metformin did not act as functional antagonists, but both rather inhibited proliferation and/or migration, if significant effects were present. We did not observe a relevant influence of metformin on TGF-?2 mRNA expression (qRT-PCR), TGF-?2 protein expression (ELISA) or SMAD-signaling (Western blot). Therefore, it seems that metformin does not exert its inhibitory effects on GBM BTIC proliferation and migration by altering TGF-?2-signaling. Nonetheless, as low doses of metformin are able to reduce proliferation of certain GBM cells, further exploration of predictors of BTICs' susceptibility to metformin appears justified.
EVALuna2:22529

Methods for integrating postural control into biomechanical human simulations: a systematic review - Shanbhag, Julian; Wolf, Alexander; Wechsler, Iris; Fleischmann, Sophie; Winkler, Jürgen; Leyendecker, Sigrid; Eskofier, Björn; Koelewijn, Anne; Wartzack, Sandro; Miehling, Jörg (Journal of neuroEngineering and rehabilitation, 2023)
Understanding of the human body’s internal processes to maintain balance is fundamental to simulate postural control behaviour. The body uses multiple sensory systems’ information to obtain a reliable estimate about the current body state. This information is used to control the reactive behaviour to maintain balance. To predict a certain motion behaviour with knowledge of the muscle forces, forward dynamic simulations of biomechanical human models can be utilized. We aim to use predictive postural control simulations to give therapy recommendations to patients suffering from postural disorders in the future. It is important to know which types of modelling approaches already exist to apply such predictive forward dynamic simulations. Current literature provides different models that aim to simulate human postural control. We conducted a systematic literature research to identify the different approaches of postural control models. The different approaches are discussed regarding their applied biomechanical models, sensory representation, sensory integration, and control methods in standing and gait simulations. We searched on Scopus, Web of Science and PubMed using a search string, scanned 1253 records, and found 102 studies to be eligible for inclusion. The included studies use different ways for sensory representation and integration, although underlying neural processes still remain unclear. We found that for postural control optimal control methods like linear quadratic regulators and model predictive control methods are used less, when models’ level of details is increasing, and nonlinearities become more important. Considering musculoskeletal models, reflex-based and PD controllers are mainly applied and show promising results, as they aim to create human-like motion behaviour considering physiological processes.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Biomechanical human model; Biomechanics; Forward dynamics; Musculoskeletal model; Postural control; Simulation; Systematic review

Microcatheters with extra-long detachable tip: A promising treatment option in dural arteriovenous fistulas - Gölitz, Philipp; Lücking, Hannes; Knott, Michael; Hock, Stefan; Brandner, Sebastian; Knossalla, Frauke; Dörfler, Arnd (Interventional Neuroradiology, 2022)
Purpose Treating cerebral dural arteriovenous fistulas (dAVFs) by transarterial embolization is an established endovascular approach but no data exist regarding the utility of using the newly introduced microcatheters with extra-long detachable tip. Aim of our study was to evaluate the value of these microcatheters and, additionally, of combining them with the simplified pressure cooker technique. Methods Twenty-nine patients treated for dAVF with transarterial embolization were enrolled. In a subgroup of fifteen patients the simplified pressure cooker technique was additionally applied. Demographics and characteristics were collected for patients and dAVFs and procedural details reviewed. The association between covariates and binary-coded occlusion status was evaluated. Results Microcatheter navigation into the target pedicle as well as application of the simplified pressure cooker technique were successful in all cases. Complete dAVF occlusion was reached in 69.0% at a single stage. In case of complete dAVF occlusion, embolization via only one pedicle was enough. Subgroup analysis revealed a higher occlusion status (80%) if using the simplified pressure cooker technique than if not (57%) but reached not significance level. Conclusion Using microcatheters with extra-long detachable tip for dAVF embolization seems to offer a safe and effective treatment option with exceptional high occlusion rate at a single stage. The high navigability facilitates catheterization of a single selected target pedicle that is often enough to reach complete dAVF occlusion. Combining these microcatheters with the simplified pressure cooker technique turned out to be safe and easy to handle and might allow an increasing dAVF occlusion rate.
CRIS-Team WoS Importer:2022-10-14

Microcystic adnexal carcinoma (MAC)-like squamous cell carcinoma as a differential diagnosis to Bell´s palsy: review of guidelines for refractory facial nerve palsy - Müller, Sandra; Iro, Heinrich; Lell, M.; Seifert, F.; Bohr, Christopher; Scherl, C.; Agaimy, Abbas; Traxdorf, Maximilian (Journal of Otolaryngology-Head & Neck Surgery, 2017)
Bell´s palsy is the most common cause of facial paralysis worldwide and the most common disorder of the cranial nerves. It is a diagnosis of exclusion, accounting for 60-75% of all acquired peripheral facial nerve palsies. Our case shows the first case of a microcystic adnexal carcinoma-like squamous cell carcinoma as a cause of facial nerve palsy.The patient, a 70-year-old Caucasian male, experienced subsequent functional impairment of the trigeminal and the glossopharyngeal nerve about 1½ years after refractory facial nerve palsy. An extensive clinical work-up and tissue biopsy of the surrounding parotid gland tissue was not able to determine the cause of the paralysis. Primary infiltration of the facial nerve with subsequent spreading to the trigeminal and glossopharyngeal nerve via neuroanastomoses was suspected. After discussing options with the patient, the main stem of the facial nerve was resected to ascertain the diagnosis of MAC-like squamous cell carcinoma, and radiochemotherapy was subsequently started.This case report shows that even rare neoplastic etiologies should be considered as a cause of refractory facial nerve palsy and that it is necessary to perform an extended diagnostic work-up to ascertain the diagnosis. This includes high-resolution MRI imaging and, as perilesional parotid biopsies might be inadequate for rare cases like ours, consideration of a direct nerve biopsy to establish the right diagnosis.
EVALuna2:6836

Microglia in Alzheimer's Disease - Süß, Patrick; Schlachetzki, Johannes (Current Alzheimer Research, 2020)
Alzheimer's Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.
CRIS-Team Scopus Importer:2020-04-03
Keywords: Alzheimer's disease; Aβ plaques; genetics; Microglia; neurofibrillary tangles; transcriptomics.

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis - Sinner, Pia; Peckert-Maier, Katrin; Mohammadian, Hashem; Kuhnt, Christine; Draßner, Christina; Panagiotakopoulou, Vasiliki; Rauber, Simon; Linnerbauer, Mathias; Haimon, Zhana; Royzman, Dmytro; Kronenberg-Versteeg, Deborah; Ramming, Andreas; et al. (Nature Communications, 2023)
Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
CRIS-Team Scopus Importer:2023-08-11

MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice - Zuo, Xiaokun; Lu, Jianfei; Manaenko, Anatol; Qi, Xin; Tang, Jiping; Mei, Qiyong; Xia, Ying; Hu, Qin (Experimental Neurology, 2019)
MicroRNAs (miRNAs) have been widely reported to induce posttranscriptional gene silencing and led to an explosion of new strategies for the treatment of human disease. It has been reported that the expression of MicroRNA-132 (miR-132) are altered both in the blood and brain after stroke. However, the effect of miR-132 on blood-brain barrier (BBB) disruption in ischemia stroke has not been studied. Here we will investigate the effects of miR-132 on the permeability of BBB after ischemic stroke and explore the potential mechanism underlying observed protection. Eight week-old mice were injected intracerebroventricularly with miR-132, antagomir-132 or agomir negative control (agomir-NC) 2 h before middle cerebral artery occlusion (MCAO), followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. BBB permeability and integrity were measured by Evan's blue extravasation and brain water content. The expression of tight junction proteins was detected by immnostaining and Western blots. The level of MiR-132 and its targeted gene Mmp9 were assayed. Treatment with exogenous MiR-132 (agomir-132) decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control mice. Agomir-132 increased the level of MiR-132 in brain tissue, suppressed the expression of MMP-9 mRNA and decreased the degradation of tight junction proteins VE-cadherin and β-Catenin in ischemic stroke mice. Inhibition of MMP-9 has a similar protective effect to agomir-132 on infraction volume, brain edema, and tight-junction protein expression after MCAO. Our results indicated that miR-132/MMP-9 axis might be a novel therapeutic target for BBB protection in ischemic stroke.
CRIS-Team Scopus Importer:2019-05-02
Keywords: BBB integrity; Ischemic stroke; MicroRNA-132; MMP-9

MicroRNAs in epilepsy: pathophysiology and clinical utility - Henshall, David C.; Hamer, Hajo; Pasterkamp, R. Jeroen; Goldstein, David B.; Kjems, Jorgen; Prehn, Jochen H. M.; Schorge, Stephanie; Lamottke, Kai; Rosenow, Felix (Lancet Neurology, 2016)
Temporal lobe epilepsy is a common and frequently intractable seizure disorder. Its pathogenesis is thought to involve large-scale alterations to the expression of genes controlling neurotransmitter signalling, ion channels, synaptic structure, neuronal death, gliosis, and inflammation. Identification of mechanisms coordinating gene networks in patients with temporal lobe epilepsy will help to identify novel therapeutic targets and biomarkers. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy.In the past 5 years, studies have found changes in miRNA levels in the hippocampus of patients with temporal lobe epilepsy and in neural tissues from animal models of epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using antisense oligonucleotides (antagomirs) had potent antiseizure effects in animal models, whereas genetic deletion of miR-128 produced fatal epilepsy in mice. Levels of certain miRNAs were also found to be altered in the blood of rodents after seizures. In the past 18 months, functional studies have identified nine novel miRNAs that appear to influence seizures or hippocampal pathology. Their targets include transcription factors, neurotransmitter signalling components, and modulators of neuroinflammation. New approaches to manipulate miRNAs have been tested, including injection of mimics (agomirs) to enhance brain levels of miRNAs. Altered miRNA expression has also been reported in other types of refractory epilepsy and our understanding of how miRNA levels are controlled has grown, with studies on DNA methylation indicating epigenetic regulation. Biofluids (blood) of patients with epilepsy have shown differences in quantity of circulating miRNAs, implying diagnostic biomarker potential. WHERE NEXT?: Recent functional studies need to be replicated to build a robust evidence base. The specific cell types in which miRNAs execute their functions and their primary targets have to be identified, to fully explain the phenotypic effects of modulating miRNAs. Delivery of large molecules such as antisense inhibitors or mimics to the brain poses a challenge, and the multi-targeting effects of miRNAs create additional risks of unanticipated side effects. Potential genetic variation in miRNAs should be explored as the basis for disease susceptibility. The latest findings provide a rich source of new miRNA targets, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of epilepsy can be translated into clinical practice.
EVALuna2:22485

Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS - Sauer, Eva-Maria; Schliep, Stefan; Manger, Bernhard; Lee, De-Hyung; Linker, Ralf (Neurology, Neuroimmunology and Neuroinflammation, 2018)
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Mild prolonged hypothermia for large intracerebral hemorrhage - Staykov, Dimitre; Wagner, Irina; Volbers, Bastian; Dörfler, Arnd; Schwab, Stefan; Kollmar, Rainer (Neurocritical Care, 2013)
Background: Perihemorrhagic edema (PHE) develops after intracerebral hemorrhage (ICH). It can worsen the clinical situation by its additional mass effect. Therapeutic hypothermia (TH) might be an effective method to control PHE, but has not been sufficiently studied in ICH patients. Methods: We report data on n = 25 consecutive patients with large supratentorial ICH (volume > 25 ml) who were treated by mild TH of 35 C for 8-10 days. Body temperature was controlled by endovascular cooling catheters. We followed the clinical course during hospital stay and measured volumes of ICH and PHE in regularly performed serial cranial computed tomography. Outcome was assessed after 3 and 12 months. These data were compared to a historical group of n = 25 patients with large ICH. Results: While PHE continuously increased in the historical control group up to day 10, PHE volumes in the hypothermia group remained stable. There was a significant difference from day 3 after symptom onset. Shivering (36 %) and pneumonia (96 %) were the most frequent complications during TH. Mortality rate was 8.3 % in TH versus 16.7 % in the control group after 3 months and 28 versus 44 % after 1 year. Conclusions: These data support the promising results of our first case series on TH in large ICH. TH prevents the development of PHE and its complications. Side effects of TH appeared often, but could be treated sufficiently. Therefore, TH might represent a new therapy for PHE after large ICH, but has to be further tested in randomized trials. © 2012 Springer Science+Business Media, LLC.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Hypothermia; Intracerebral hemorrhage; Perihemorrhagic edema

Misdiagnosis of polymyositis in a young female patient with occult limb-girdle muscular dystrophy - Valor-Mendez, Lara; Türk, Matthias; Schett, Georg; Manger, Bernhard; Knitza, Johannes (Rheumatology Advances in Practice, 2023)
CRIS-Team Scopus Importer:2023-08-11

Mitochondria in Ischemic Stroke: New Insight and Implications - Liu, Fan; Lu, Jianfei; Manaenko, Anatol; Tang, Junjia; Hu, Qin (Aging and Disease, 2018)
Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction has been regarded as one of the hallmarks of ischemia/reperfusion (I/R) induced neuronal death. Maintaining the function of mitochondria is crucial in promoting neuron survival and neurological improvement. In this article, we review current progress regarding the roles of mitochondria in the pathological process of cerebral I/R injury. In particular, we emphasize on the most critical mechanisms responsible for mitochondrial quality control, as well as the recent findings on mitochondrial transfer in acute stroke. We highlight the potential of mitochondria as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.
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Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile - Kim, Yongsung; Zheng, Xinde; Ansari, Zoya; Bunnell, Mark C.; Herdy, Joseph R.; Traxler, Larissa; Lee, Hyungjun; Paquola, Apua C. M.; Blithikioti, Chrysanthi; Ku, Manching; Schlachetzki, Johannes; Winkler, Jürgen; et al. (Cell Reports, 2018)
Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging. Kim et al. compared mitochondrial features in aging human fibroblasts and directly induced neurons (iNs). They find that only iNs display severe signs of mitochondrial aging defects and show that the metabolic shift during fibroblast-to-neuron conversion renders iNs particularly vulnerable to mitochondrial aging.
CRIS-Team Scopus Importer:2021-07-19
Keywords: aging; directly converted induced neurons; glycolysis; metabolic shift; mitochondria; mitochondrial aging; neurodegenerative disease; oxidative phosphorylation

Mobile biometrische Ganganalyse - Klucken, Jochen; Barth, Jens; Maertens, Katharina; Eskofier, Björn; Kugler, Patrick; Steidl, Ralph; Hornegger, Joachim; Winkler, Jürgen (Nervenarzt, 2011)

Mobile biosensor-based gait analysis: A diagnostic and therapeutic tool in Parkinson's disease - Klucken, Jochen; Barth, Jens; Maertens, Katharina; Eskofier, Björn; Kugler, Patrick; Steidl, Ralph; Hornegger, Joachim; Winkler, Jürgen; Klucken, Jochen (Nervenarzt, 2011)
Summary: Parkinson's disease (PD) is characterized by progressive motor and non-motor symptoms, leading to distinct diagnostic and therapeutic challenges in all stages of the disease. This study investigated a mobile biosensor-based gait analysis system for patients in early and intermediate stages of PD compared to controls. Subjects wearing a motion sensor-equipped shoe performed a standardized gait exercise. Accelerometer-and gyroscope-based signals were analysed using a complex set of pattern recognition algorithms. The analysis was able (1) to distinguish between PD patients and controls, (2) to identify patients at an early stage of the disease and (3) to distinguish between early and intermediate stage patients. Thus, using this mobile biosensor-based analysis system we were able to obtain objective classifications of gait characteristics in PD. Future studies will show that mobile biosensor-based movement detection technology will support identification of early PD stages and allow objective characterization of motor fluctuations in advanced stages of the disease. This will provide an important and supportive tool for patients, caregivers and therapists. © 2011 Springer-Verlag.

Mobile digital gait analysis captures effects of botulinum toxin in hereditary spastic paraplegia - Ibrahim, Alzhraa; Ollenschläger, Malte; Klebe, Stephan; Schüle, Rebecca; Jeschonneck, Nicole; Kellner, Melanie; Loris, Evelyn; Greinwalder, Teresa; Eskofier, Björn; Winkler, Jürgen; Gaßner, Heiko; Regensburger, Martin (European Journal of Neurology, 2024)
Background and purpose: Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient-reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response. Methods: We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters. Results: A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1-month and declining by the 3-month follow-up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response. Conclusions: Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response.
CRIS-Team Scopus Importer:2024-06-28
Keywords: botulinum toxin; gait analysis; lower extremity; muscle spasticity; spastic paraplegia; hereditary

Mobile digital gait analysis objectively measures progression in hereditary spastic paraplegia - Loris, Evelyn; Ollenschläger, Malte; Greinwalder, Teresa; Eskofier, Björn; Winkler, Jürgen; Gaßner, Heiko; Regensburger, Martin (Annals of Clinical and Translational Neurology, 2023)
Progressive spasticity and gait impairment is the functional hallmark of hereditary spastic paraplegia (HSP), but due to inter-individual variability, longitudinal studies on its progression are scarce. We investigated the progression of gait deficits via mobile digital measurements in conjunction with clinical and patient-reported outcome parameters. Our cohort included adult HSP patients (n = 55) with up to 77 months of follow-up. Gait speed showed a significant association with SPRS progression. Changes in stride time and gait variability correlated to fear of falling and quality of life, providing evidence that gait parameters are meaningful measures of HSP progression.
CRIS-Team Scopus Importer:2023-01-20

Mobile Gait Analysis Using Personalised Hidden Markov Models for Hereditary Spastic Paraplegia Patients - Martindale, Christine; Roth, Nils; Gaßner, Heiko; Jensen, Dennis; Kohl, Zacharias; Eskofier, Björn (2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2018)
Gait analysis provides a quantitative method to assess disease progression or intervention effect on gait disorders. While mobile gait analysis enables continuous monitoring in free living conditions, state of the art gait analysis for diseases such as hereditary spastic paraplegia (HSP) is currently limited to motion capture systems which are large and expensive. The challenge with HSP is its heterogeneous nature and rarity, leading to a wide range of ages, severity and gait patterns as well as small patient numbers. We propose a sensor-based mobile solution, based on a personalised hierarchical hidden Markov Model (hHMM) to extract spatio-temporal gait parameters. This personalised hHMM achieves a mean absolute error of 0.04 s pm 0.03 s for stride time estimation with respect to a GAITRite® reference system. We use the successful extraction of initial ground contact to explore the limits of the double integration method for such heterogeneous diseases. While our personalised model compensates for the heterogeneity of the disease, it would require a new model per patient. We observed that the general model was sufficient for some of the less severely affected patient

Mobiles Ganglabor: Sensorbasierte Ganganalyse optimiert Diagnostik und Therapiemonitoring bei Bewegungserkrankungen - Herberz, Chantal; Klucken, Jochen; Eskofier, Björn (medical future verlag, 2015)
UnivIS-Import:2015-04-02:Pub.2015.tech.IMMD.IMMD5.mobile

Modeling Cell-Cell Interactions in Parkinson's Disease Using Human Stem Cell-Based Models. - Rizo Garza, Tania; Simmnacher, Katrin; Lanfer, Jonas; Rizo, Tania; Kaindl, Johanna; Winner, Beate (Frontiers in Cellular Neuroscience, 2019)
models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models - Simmnacher, Katrin; Lanfer, Jonas; Rizo, Tania; Kaindl, Johanna; Winner, Beate (Frontiers in Cellular Neuroscience, 2020)
Parkinson’s disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.
CRIS-Team Scopus Importer:2020-02-14
Keywords: disease modeling; dopaminergic neuron; glia; inflammation; iPSC; neurodegeneration; organoid; Parkinson’s disease

Modelling human neurodegeneration using induced pluripotent stem cells - Prots, Iryna; Winner, Beate; Winkler, Jürgen (The Matrix of Stem Cell Research. An Approach to Rethinking Science in Society, 2019)
Neurodegeneration is a process of neuronal damage and death. A progressive loss of neurons is a common pathological feature of many neurodegenerative diseases, including motor neuron diseases (MND) and Parkinson's disease (PD). Neurodegenerative diseases are incurable and the only therapies possible are to this date symptomatic. Discovering the mechanisms that either lead to the disease occurrence or that influence the disease progression (together called 'pathomechanisms') would open up possibilities for developing new therapeutic approaches. Cellular material for research in the field of human neurodegeneration is very limited and mostly available as a post-mortem tissue derivate. Therefore, stem cells, as a source of different types of somatic cells, are a very promising tool for developing suitable human models to investigate neurodegeneration. With the discovery of induced pluripotent stem cells (iPSC), researchers now have access to otherwise difficult-to-obtain patient-specific cellular material to investigate the mechanisms that cause neuronal loss and that lead to the development of a neurodegenerative disease. In other words, iPSC-based technology allows the retrieving of disease-specific neurons and thereby allows the observation of the disease development in a dish. In this article, we first describe the symptomatic and current management of two big groups of neurodegenerative diseases: MND and PD. We next explain the advantages of using iPSC technology for the investigation of human neurodegeneration. Then, we highlight a number of pathomechanisms underlying neuronal degeneration in MND and PD, which have been uncovered in iPSC-based models. We finally show that some disease-related phenotypes could already be rescued on a cellular level in the laboratory and discuss the iPSC-based research as a promising tool, fuelling hope that new successful therapies for neurodegenerative disorders can be developed.
CRIS-Team Scopus Importer:2024-08-07
Keywords: Bioscience; Humanities; Medicine; Dentistry; Nursing & Allied Health; Social Sciences

Modelling postural control of upright standing during translational perturbations - Shanbhag, Julian; Fleischmann, Sophie; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Koelewijn, Anne; Wartzack, Sandro; Miehling, Jörg (29th Congress of the European Society of Biomechanics, 2024)

Model Testing of PluriTest with Next-Generation Sequencing Data - Schulze, Markus; Hoja, Sabine; Winner, Beate; Winkler, Jürgen; Edenhofer, Frank; Riemenschneider, Markus J. (Stem Cells and Development, 2016)
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MODIFIED SUBPIAL - Roessler, K.; Kasper, Burkhard; Coras, R.; Sommer, B.; Blümcke, Ingmar; Hamer, Hajo; Buchfelder, Michael (2017)
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Modulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3- and anti-Cd40-stimulated blood in vitro - Himmerich, Hubertus; Bartsch, Stefanie; Hamer, Hajo; Mergl, Roland; Schönherr, Jeremias; Petersein, Charlotte; Munzer, Alexander; Kirkby, Kenneth Clifford; Bauer, Katrin; Sack, Ulrich (Oxidative Medicine and Cellular Longevity, 2014)
Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA) report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL)-6 and tumor necrosis factor (TNF)-?. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), VPA, oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), and lithium on the production of the following cytokines in vitro: interleukin (IL)-1?, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-?. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1?, IL-2, IL-4, IL-6, IL-17, and TNF-? production, which substantiates and adds knowledge to current hypotheses on VPA's anti-inflammatory properties.
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Modulator of VRAC Current 1 Is a Potential Target Antigen in Multiple Sclerosis - Dahl, Johannes Raffael; Weier, Alicia; Winter, Christopher; Hintze, Maik; Rothhammer, Veit; Tsaktanis, Thanos; Proebstel, Anne-Katrin; Neziraj, Tradite; Poessnecker, Elisabeth; Oechtering, Johanna; Kuhle, Jens; Kallmann, Boris-Alexander; et al. (Neurology, Neuroimmunology and Neuroinflammation, 2025)
Background and Objectives Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the CNS. Highlighted by the success of B-cell–depleting therapies such as the monoclonal anti-CD20 antibodies rituximab, ocrelizumab, and ofatumumab, B cells have been shown to play a central role in the immunopathology of the disease. Yet, the target antigens of the pathogenic B-cell response in MS remain unclear. Methods We combined polyclonal B-cell stimulation of peripheral blood mononuclear cells with a human proteome-wide protein microarray to identify target antigens of MS by comparing samples from 20 patients with MS with 9 age-matched and sex-matched healthy controls. Results were verified by enzyme-linked immunosorbent assay (ELISA) in 3 independent validation cohorts (N = 47 patients with MS in remission; N = 20 patients with MS during relapse; N = 25 HCs; N = 30 patients with other noninflammatory neurologic diseases; N = 9 patients with other inflammatory neurologic diseases). Experimental autoimmune encephalomyelitis (EAE) was used as an animal model to evaluate the pathogenicity of the antibodies of choice. Results Our results corroborate the existing concept of a highly diverse autoimmune response in MS. Yet, a significantly elevated antibody response against the membrane protein modulator of VRAC current 1 (MLC1) was noted in B-cell culture supernatants and serum samples of patients with MS. Furthermore, significantly elevated titers to MLC1 were observed in the CSF of patients with neuroinflammatory diseases other than MS. Neurons and astrocytes were identified as the main cell types expressing MLC1 in the brain of a patient with MS. Injection of anti-MLC1 antibodies into mice with EAE led to strong in vivo binding to cerebral cortical neurons and to the death of 4 of the 7 injected mice. Discussion Future studies will have to address the diagnostic and prognostic value of MLC1-specific antibodies in neuroinflammatory disorders such as MS and characterize the functional role of MLC1 expression in neurons and astrocytes. Trial Registration Information The study has been registered in the German Clinical Trials Register (study number DRKS00015528

Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease - Drobny, Alice; Ngo, Phuong A.; Neurath, Markus; Zunke, Friederike; Lopez-Posadas, Rocio (Frontiers in Medicine, 2021)
Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
CRIS-Team WoS Importer:2021-09-03

Monitoring in the follow up of patients after EVT. Could pupillometry replace repetitive CT-control? - Köhn, Julia; Borutta, Matthias; Giede-Jeppe, Antje; Hagen, Manuel; Kuramatsu, Joji; Schwab, Stefan; Huttner, Hagen (Journal für Anasthesie und Intensivbehandlung, 2021)
CRIS-Team Scopus Importer:2024-12-16

Monitoring medication optimization in patients with Parkinson’s disease - Moradi, Hamid; Hannink, Julius; Stallforth, Sabine; Gladow, Till; Ringbauer, Stefan; Mayr, Martin; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (2023 45th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), 2023)
Medication optimization is a common component of the treatment strategy in patients with Parkinson’s disease. As the disease progresses, it is essential to compensate for the movement deterioration in patients. Conventionally, examining motor deterioration and prescribing medication requires the patient’s onsite presence in hospitals or practices. Home-monitoring technologies can remotely deliver essential information to physicians and help them devise a treatment decision according to the patient’s need. Additionally, they help to observe the patient’s response to these changes. In this regard, we conducted a longitudinal study to collect gait data of patients with Parkinson’s disease while they received medication changes. Using logistic regression classifier, we could detect the annotated motor deterioration during medication optimization with an accuracy of 92%. Moreover, an in-depth examination of the best features illustrated a decline in gait speed and swing phase duration in the deterioration phases due to suboptimal medication.Clinical relevance— Our proposed gait analysis method in this study provides objective, detailed, and punctual information to physicians. Revealing clinically relevant time points related to the patient’s need for medical adaption alleviates therapy optimization for physicians and reduces the duration of suboptimal treatment for patients. As the home-monitoring system acts remotely, embedding it in the medical care pathways could improve patients’ quality of life.<br

Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action - Klotz, L.; Berthele, A.; Brueck, W.; Chan, A.; Flachenecker, P.; Gold, R.; Haghikia, A.; Hellwig, K.; Hemmer, B.; Hohlfeld, R.; Korn, T.; Kuempfel, T.; et al. (Der Nervenarzt, 2016)
With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.
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Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention - Siedler, Gabriela; Macha, Kosmas; Stoll, Svenja; Plechschmidt, Johannes; Wang, Ruihao; Gerner, Stefan; Strasser, Erwin; Schwab, Stefan; Kallmünzer, Bernd (Journal of Thrombosis and Haemostasis, 2022)
Background: Patients with atrial fibrillation have a relevant risk for ischemic stroke despite the recommended use of direct oral anticoagulants (DOAC). The risk correlates with the functional DOAC plasma levels in clinical trials, but the value of their measurement in community use remains undetermined. Objectives: We aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state. Methods: In this observational clinical cohort study among patients with ischemic stroke and atrial fibrillation, 397 individuals on oral anticoagulants for secondary stroke prevention were included between 2016 and 2020. The functional DOAC plasma levels were measured during steady state. Early stroke recurrence within 3 months was recorded as the main outcome parameter. Results: Three hundred ninety-seven patients (201 female, mean age 78 [±9] years, median CHA2DS2VASc-Score 6 [interquartile range 5–7]) were included. Mean DOAC plasma trough level was 95.9 (±66.9) ng/ml. A high glomerular filtration rate (GFR) was an independent predictor of lower levels in a multivariate model (R coefficient: −0.174, P =.014). During follow-up, 10 patients (3%) suffered from early ischemic stroke recurrence despite the use of DOAC, while 10 clinically relevant bleeding complications occurred (3%). Ischemic stroke recurrence was associated with numerical lower plasma levels for patients on apixaban and dabigatran after propensity score matching. Conclusions: Monitoring of DOAC plasma levels could help to identify patients with increased risk for stroke recurrence and should be considered for certain subgroups, including patients with high GFR.
CRIS-Team Scopus Importer:2022-03-18
Keywords: atrial fibrillation; cardioembolic stroke; direct oral anticoagulants; ischemic stroke; secondary prevention

Monitoring of hematopoietic chimerism by real-time quantitative PCR of micro insertions/deletions in samples with low DNA quantities - Bach, Christian; Tomova, Elmira; Goldmann, Katja; Weisbach, Volker Günter; Rösler, Wolf; Mackensen, Andreas; Winkler, Jürgen; Spriewald, Bernd M. (Transfusion Medicine and Hemotherapy, 2015)
Sensitive and accurate methods to detect hematopoietic chimerism after hematopoietic stem cell transplantation (HSCT) are essential to evaluate engraftment and to monitor response to therapeutic procedures such as donor lymphocyte infusion. Continuous long-term follow up, however, requires large amounts of pre-HSCT samples limiting the application of many widely used techniques for sensitive chimerism monitoring.DNAs from 42 normal healthy donors and 16 HSCT donor/recipient pairs were employed to validate the use of allele-specific insertion/deletion (indel) quantitative real-time polymerase chain reaction (qPCR) to quantify chimerism in samples with low amounts of DNA. Consequently, indel-qPCR analyses of samples from 16 HSCT patients were compared to short-tandem repeat (STR) specific PCR analyses.Typing with reduced amounts of input DNA (15 vs. 60 ng) allowed for the reliable distinction of positive (mean threshold cycle (ct) 28.05) and negative (ct >36) signals. The high informativity of primer/probe sets, with 12 out of 19 markers exceeding 20% informativity, was confirmed in our cohort (n = 74). Importantly, a fourfold reduction of input DNA compared to published protocols did not alter PCR efficiencies and allowed for a more sensitive detection of chimerism in 7 of 16 HSCT patients compared to results obtained by STR-PCR.Our data suggest that indel-qPCR is a more sensitive technique for the detection of hematopoietic chimerism compared to STR-PCR and works efficiently for samples with low amounts of DNA.
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Monozygotic twins with a new compound heterozygous SPG11 mutation and different disease expression - Schneider-Gold, Christiane; Dekomien, Gabriele; Regensburger, Martin; Schneider, Ruth; Trampe, Nadine; Krogias, Christos; Lukas, Carsten; Bellenberg, Barbara (Journal of the Neurological Sciences, 2017)
BACKGROUND: A pair of monozygotic 22-year-old twins with complicated hereditary spastic paraplegia caused by a novel SPG11 mutation is described. METHODS: Genetic testing and thorough clinical examination, magnetic resonance imaging (MRI) and MR-spectroscopy were performed. RESULTS: The twins were compound heterozygous for a known frameshift as well as a novel splice site mutation in the SPG11 gene. Clinically the patients showed a similar spectrum of symptoms but different disease presentation. MRI studies including morphometry and regional microstructural analysis by diffusion tensor imaging (DTI) of the corpus callosum (CC) by 3T MRI revealed marked thinning and corresponding increases of radial diffusivity (RD) and apparent diffusion coefficient (ADC) and reduction of the fractional anisotropy (FA) as compared to controls in all CC sections, particularly in the anterior callosal body. There was marked mainly supratentorial white matter reduction and to a lesser extent grey matter reduction in both patients. Involvement of the cortico-spinal tracts was reflected by FA and RD alterations. The more strongly affected patient showed a higher degree of callosal microstructural damage and cervical cord atrophy. CONCLUSIONS: This study shows a similar symptom spectrum, but distinct clinical and imaging findings in monozygotic twins suffering from SPG 11, suggesting individual downstream genetic effects and/or non-genetic modifiers.
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Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay - Kobow, Katja; Jabari, Samir; Pieper, Tom; Kudernatsch, Manfred; Polster, Tilman; Woermann, Friedrich G.; Kalbhenn, Thilo; Hamer, Hajo; Roessler, Karl; Muhlebner, Angelika; Spliet, Wim G. M.; Feucht, Martha; et al. (Acta Neuropathologica, 2020)
Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases, about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Brain development; Chromosome 1; Copy number variation; Cortical malformation; ID; Seizures

MotionLab@Home: Complementary Measurement of Gait Characteristics Using Wearable Technology and Markerless Video Tracking - A Study Protocol - Kluge, Felix; Pasluosta, Cristian Federico; Gaßner, Heiko; Klucken, Jochen; Eskofier, Björn (Advanced Engineering Forum, 2016)
Keywords: Accelerometers; Gyroscopes; Individualized Movement Analysis; Inertial Measurement Units; Signal Analysis; Validation; Video Tracking

Motor neuron diseases. Clinical and genetic differential diagnostics - Regensburger, Martin; Weidner, N.; Kohl, Zacharias (Der Nervenarzt, 2018)
The causes of degenerative disease of the upper and lower motor neurons are incompletely understood. In this review the current concepts in the clinical and genetic differential diagnostics of motor neuron diseases are presented. Hereditary spastic paraplegia, primary lateral sclerosis, spinal muscular atrophy and amyotrophic lateral sclerosis are explained, structured according to the affection of the upper and/or lower motor neuron. The substantial variability in the presentation and course of motor neuron diseases as well as the lack of specific laboratory tests hinder an early diagnosis. The precise description of the clinical picture, thorough testing of possible differential diagnoses as well as monitoring of the clinical course are essential. Genetic analyses should be offered to patients with a positive family history. Early identification of clinical and genetic subentities of the individual motor neuron diseases is a prerequisite for future neuroprotective interventions.
EVALuna2:35783

Motor output complexity in Parkinson's disease during quiet standing and walking: Analysis of short-term correlations using the entropic half-life. - Pasluosta, C. F.; Hannink, Julius; Gaßner, Heiko; von Tscharner, Vinzenz; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (Human movement science, 2018)
Parkinson's disease (PD) is associated with alterations in motor outputs such as center of pressure (CoP) adjustments during quiet standing and foot kinematics during walking. Previous research suggests that the complexity of motor outputs reflects the number of control processes stabilizing a specific movement, providing a measure that is linked to the neurological control of the movement. The Entropic Half Life (EnHL) represents a new method for assessing motor output complexity. We hypothesized that there will be a lack of neuromuscular control pathways for PD patients, resulting in a decrease in motor output complexity. We computed the EnHL of CoP adjustments during quiet standing and foot kinematics during walking of 70 PD patients and 33 age-matched controls. Patients with PD showed longer EnHL values compared to controls, suggesting a tighter motor control. Excluding vision led to a decrease of EnHL of CoP in both groups. EnHL was correlated with spatio-temporal gait parameters. We compared EnHL with the pull test and the timed up-and-go test. No significant differences were present in the pull test, yet motor output complexity was correlated with the timed up-and-go test. The results suggest a reduced complexity in motor outputs of PD patients affecting distinct motor functions.

Motor Output Complexity in Parkinson's disease Patients during Acute Treadmill Intervention - Pasluosta, Cristian Federico; Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Hannink, Julius; Von Tscharner, Vinzenz; Pfeifer, Klaus; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (International Symposium on the Neuromechanics of Human Movement, 2016)

Mucosal addressin cell adhesion molecule 1 mediated intestinal lymphocyte homing is critical for the development of experimental autoimmune encephalomyelitis - Kuhbandner, Kristina; Hammer, A.; Haase, S.; Terbrack, E.; Schippers, A.; Wagner, N.; Hussain, R. Z.; Miller-Little, W. A.; Stoolman, J. S.; Segal, B. M.; Linker, Ralf; Stuve, O. (2018)
EVALuna2:34762

Multicenter Validation of the max-ICH Score in Intracerebral Hemorrhage - Sembill, Jochen; Castello, Juan P.; Sprügel, Maximilian; Gerner, Stefan; Lücking, Hannes; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen; Biffi, Alessandro; Kuramatsu, Joji; Hölter, Philip (Annals of Neurology, 2020)
Objective: Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to determine whether the max-ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long-term outcomes after ICH. Methods: This multicenter validation study compared the prognostication of the max-ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German-wide studies (RETRACE I + II; anticoagulation-associated ICH only) conducted at 22 participating centers, one German prospective single-center study (UKER-ICH; nonanticoagulation-associated ICH only), and 1 US-based prospective longitudinal single-center study (MGH; both anticoagulation- and nonanticoagulation-associated ICH), treated between January 2006 and December 2015. Results: Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% [440 of 2,377]; MGH: 31.0% [577 of 1,283]). Validation of long-term functional outcome prognostication by the max-ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve [AUROC], German cohort: 0.81 [0.78–0.83] vs 0.74 [0.72–0.77], p < 0.01; MGH: 0.85 [0.81–0.89] vs 0.78 [0.74–0.82], p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 [0.82–0.86] vs 0.80 [0.77–0.82], p < 0.01; MGH: 0.83 [0.81–0.85] vs 0.77 [0.75–0.79], p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false-positive poor outcome attribution), that the max-ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients). Interpretation: The max-ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2020.
CRIS-Team Scopus Importer:2020-12-25

Multimodal assessment of Parkinson's disease: a deep learning approach - Vasquez Correa, Juan; Arias Vergara, Tomás; Rafael Orozco-Arroyave, Juan; Eskofier, Björn; Klucken, Jochen; Nöth, Elmar (IEEE Journal of Biomedical and Health Informatics, 2018)
Keywords: Parkinson's Disease; Deep Learning; Convolutional Neural Networks; Speech; Handwriting; Gait

Multimodal CT or MRI for IV thrombolysis in ischemic stroke with unknown time of onset - Macha, Kosmas; Hölter, Philip; Siedler, Gabriela; Knott, Michael; Schwab, Stefan; Dörfler, Arnd; Kallmünzer, Bernd; Engelhorn, Tobias (Neurology, 2020)
OBJECTIVE: To investigate differences in procedure times, safety, and efficacy outcomes comparing 2 different protocols to enable thrombolysis in the extended or unknown time window after stroke onset with either multimodal CT or MRI. METHODS: Patients with ischemic stroke in the extended or unknown time window who received IV thrombolysis between January 2011 and May 2019 were identified from an institutional registry. Imaging-based selection was done by multimodal CT or MRI according to institutional treatment algorithms. RESULTS: IV thrombolysis was performed in 100 patients (54.3%) based on multimodal CT imaging and in 84 patients (45.7%) based on MRI. Baseline clinical data, including stroke severity and time from last seen normal to hospital admission, were similar in patients with CT and MRI. Door-to-needle times were shorter in patients with CT-based selection (median [interquartile range] 45 [37-62] minutes vs 75 [59-90] minutes; mean difference [95% confidence interval (CI)] -28 minutes [-35 to -21]). No differences were detected regarding the incidence of symptomatic intracranial hemorrhage (2 [2.0%] vs 4 [4.8%]; adjusted odds ratio [aOR] [95% CI] 0.47 [0.08-2.83]) and favorable outcome at day 90 (25 [33.8%] vs 33 [42.9%]; aOR 0.95 [0.45-2.02]). CONCLUSION: IV thrombolysis in ischemic stroke in the unknown or extended time window appeared safe in CT- and MRI-selected patients, while the use of CT imaging led to faster door-to-needle times. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with ischemic stroke in the extended or unknown time window, imaging-based selection for IV thrombolysis by multimodal CT compared to MRI led to shorter door-to-needle times.
CRIS-Team Scopus Importer:2020-12-11

Multiple sclerosis in families: risk factors beyond known genetic polymorphisms - Akkad, Denis A.; Lee, De-Hyung; Bruch, Kathrin; Haghikia, Aiden; Epplen, Jorg T.; Hoffjan, Sabine; Linker, Ralf (Neurogenetics, 2016)
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by genome wide association studies and independent replication studies. A weighted genetic risk score (wGRS) was recently established using the identified MS risk loci in order to predict MS outcome including clinical and paraclinical features. Here, we present the results on a family with several affected siblings including a monozygotic triplet. The individuals were genotyped for 57 non-MHC risk loci as well as the HLA DRB1*1501 tagging SNP rs3135388 with subsequent calculation of the wGRS. Additionally, SNP array based analyses for aberrant chromosomal regions were performed for all individuals.
EVALuna2:22471

Multiple Sclerosis relapses are not associated with exercise - Tallner, Alexander; Waschbisch, Anne; Wenny, Ingrid; Schwab, Stefan; Hentschke, Christian; Pfeifer, Klaus; Mäurer, Mathias (Multiple Sclerosis Journal, 2012)

Multiple Sklerose und körperliche Aktivität - Bewegungsmangel verschlechtert den Zustand - Tallner, Alexander; Waschbisch, Anne; Mäurer, Mathias Eckhard; Pfeifer, Klaus (Der Neurologe & Psychiater, 2009)

Multiple Sklerose und Sport - Waschbisch, Anne; Tallner, Alexander; Pfeifer, Klaus; Mäurer, Mathias Eckhard (Der Nervenarzt, 2009)

Multisensory deficit of hedonic perception in Parkinson's Disease - Martini, Max; Utz, Katrin; Mrochen, Anne; Klucken, Jochen; Renner, Bertold; Winkler, Jürgen; Marxreiter, Franz (2019)
EVALuna2:213355

Music induces different cardiac autonomic arousal effects in young and older persons - Hilz, Max-Josef; Stadler, Peter; Gryc, Thomas; Nath, Juliane; Habib-Romstoeck, Leila; Stemper, Brigitte; Buechner, Susanne; Wong, Samuel; Koehn, Julia (Autonomic Neuroscience-Basic & Clinical, 2014)
Autonomic arousal-responses to emotional stimuli change with age. Age-dependent autonomic responses to music-onset are undetermined.To determine whether cardiovascular-autonomic responses to "relaxing" or "aggressive" music differ between young and older healthy listeners.In ten young (22.8±1.7 years) and 10 older volunteers (61.7±7.7 years), we monitored respiration (RESP), RR-intervals (RRI), and systolic and diastolic blood pressure (BPsys, BPdia) during silence and 180second presentations of two "relaxing" and two "aggressive" classical-music excerpts. Between both groups, we compared RESP, RRI, BPs, spectral-powers of mainly sympathetic low-frequency (LF: 0.04-0.15Hz) and parasympathetic high-frequency (HF: 0.15-0.5Hz) RRI-oscillations, RRI-LF/HF-ratios, RRI-total-powers (TP-RRI), and BP-LF-powers during 30s of silence, 30s of music-onset, and the remaining 150s of music presentation (analysis-of-variance and post-hoc analysis; significance: p<0.05).During silence, both groups had similar RRI, LF/HF-ratios and LF-BPs; RESP, LF-RRI, HF-RRI, and TP-RRI were lower, but BPs were higher in older than younger participants. During music-onset, "relaxing" music decreased RRI in older and increased BPsys in younger participants, while "aggressive" music decreased RRI and increased BPsys, LF-RRI, LF/HF-ratios, and TP-RRI in older, but increased BPsys and RESP and decreased HF-RRI and TP-RRI in younger participants. Signals did not differ between groups during the last 150s of music presentation.During silence, autonomic modulation was lower - but showed sympathetic predominance - in older than younger persons. Responses to music-onset, particularly "aggressive" music, reflect more of an arousal- than an emotional-response to music valence, with age-specific shifts of sympathetic-parasympathetic balance mediated by parasympathetic withdrawal in younger and by sympathetic activation in older participants.
EVALuna2:22324

Myasthenic crisis demanding mechanical ventilation: A multicenter analysis of 250 cases - Neumann, Bernhard; Angstwurm, Klemens; Mergenthaler, Philipp; Kohler, Siegfried; Schönenberger, Silvia; Boesel, Julian; Neumann, Ursula; Vidal, Amelie; Huttner, Hagen; Gerner, Stefan; Thieme, Andrea; Steinbrecher, Andreas; et al. (Neurology, 2019)
OBJECTIVE: To determine demographic characteristics, clinical features, treatment regimens, and outcome of myasthenic crisis (MC) requiring mechanical ventilation (MV). METHODS: Analysis of patients who presented with MC between 2006 and 2015 in a German multicenter retrospective study. RESULTS: We identified 250 cases in 12 participating centers. Median age at crisis was 72 years. Median duration of MV was 12 days. Prolonged ventilation (>15 days) depended on age (p = 0.0001), late-onset myasthenia gravis (MG), a high Myasthenia Gravis Foundation of America Class before crisis (p = 0.0001 for IVb, odds ratio [OR] = infinite), number of comorbidities (>3 comorbidities: p = 0.002, OR 2.99), pneumonia (p = 0.0001, OR 3.13), and resuscitation (p = 0.0008, OR 9.15). MV at discharge from hospital was necessary in 20.5% of survivors. Patients with early-onset MG (p = 0.0001, OR 0.21), thymus hyperplasia (p = 0.002, OR 0), and successful noninvasive ventilation trial were more likely to be ventilated for less than 15 days. Noninvasive ventilation in 92 cases was sufficient in 38%, which was accompanied by a significantly shorter duration of ventilation (p = 0.001) and intensive care unit (ICU) stay (p = 0.01). IV immunoglobulins, plasma exchange, and immunoadsorption were more likely to be combined sequentially if the duration of MV and the stay in an ICU extended (p = 0.0503, OR 2.05). Patients who received plasma exchange or immunoadsorption as first-line therapy needed invasive ventilation significantly less often (p = 0.003). In-hospital mortality was 12%, which was significantly associated with the number of comorbidities (>3) and complications such as acute respiratory distress syndrome and resuscitation. Main cause of death was multiorgan failure, mostly due to sepsis. CONCLUSION: Mortality and duration of MC remained comparable to previous reports despite higher age and a high disease burden in our study. Prevention and treatment of complications and specialized neurointensive care are the cornerstones in order to improve outcome.
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Na-23-MRI reveals sodium accumulation in skin of patients with relapsing-remitting multiple sclerosis - Huhn, K.; Linz, Peter; Pemsel, F.; Waschbisch, Anne; Lee, De-Hyung; Kopp, C.; Uder, Michael; Titze, J.; Mueller, D. N.; Linker, Ralf (2015)
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Neck cooling induces blood pressure increase and peripheral vasoconstriction in healthy persons - Koehn, Julia; Wang, Ruihao; de Rojas Leal, Carmen; Kallmünzer, Bernd; Winder, Klemens; Köhrmann, Martin; Kollmar, Rainer; Schwab, Stefan; Hilz, Max-Josef (Neurological Sciences, 2020)
Introduction: Noninvasive temperature modulation by localized neck cooling might be desirable in the prehospital phase of acute hypoxic brain injuries. While combined head and neck cooling induces significant discomfort, peripheral vasoconstriction, and blood pressure increase, localized neck cooling more selectively targets blood vessels that supply the brain, spares thermal receptors of the face and skull, and might therefore cause less discomfort cardiovascular side effects compared to head- and neck cooling. The purpose of this study is to assess the effects of noninvasive selective neck cooling on cardiovascular parameters and cerebral blood flow velocity (CBFV). Methods: Eleven healthy persons (6 women, mean age 42 ± 11 years) underwent 90 min of localized dorsal and frontal neck cooling (EMCOOLS Brain.Pad™) without sedation. Before and after cooling onset, and after every 10 min of cooling, we determined rectal, tympanic, and neck skin temperatures. Before and after cooling onset, after 60- and 90-min cooling, we monitored RR intervals (RRI), systolic, diastolic blood pressures (BPsys, BPdia), laser Doppler skin blood flow (SBF) at the index finger pulp, and CBFV at the proximal middle cerebral artery (MCA). We compared values before and during cooling by analysis of variance for repeated measurements with post hoc analysis (significance: p < 0.05). Results: Neck skin temperature dropped significantly by 9.2 ± 4.5 °C (minimum after 40 min), while tympanic temperature decreased by only 0.8 ± 0.4 °C (minimum after 50 min), and rectal temperature by only 0.2 ± 0.3 °C (minimum after 60 min of cooling). Index finger SBF decreased (by 83.4 ± 126.0 PU), BPsys and BPdia increased (by 11.2 ± 13.1 mmHg and 8.0 ± 10.1 mmHg), and heart rate slowed significantly while MCA-CBFV remained unchanged during cooling. Conclusions: While localized neck cooling prominently lowered neck skin temperature, it had little effect on tympanic temperature but significantly increased BP which may have detrimental effects in patients with acute brain injuries.
CRIS-Team Scopus Importer:2020-04-03
Keywords: Blood pressure increase; Cerebral blood flow velocity; Hypothermia; Neck cooling

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium - Popp, Bernt; Krumbiegel, Mandy; Grosch, Janina; Sommer, Annika; Uebe, Steffen; Kohl, Zacharias; Ploetz, Sonja; Farrell, Michaela; Trautmann, Udo; Kraus, Cornelia; Ekici, Arif Bülent; Asadollahi, Reza; et al. (Scientific Reports, 2018)
Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.
EVALuna2:34839

Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney - Domenig, Oliver; Manzel, Arndt; Grobe, Nadja; Koenigshausen, Eva; Kaltenecker, Christopher C.; Kovarik, Johannes J.; Stegbauer, Johannes; Gurley, Susan B.; Van Oyen, Dunja; Antlanger, Marlies; Bader, Michael; Motta-Santos, Daisy; et al. (Scientific Reports, 2016)
Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.
EVALuna2:22474

Neue Klassifikation epileptischer Anfälle: Eine kritische Bewertung der Änderungen - Schulze-Bonhage, Andreas; Hamer, Hajo; Krämer, Günter (Der Nervenarzt, 2019)
In the new classification of epileptic seizures by the International League Against Epilepsy (ILAE), a multitude of changes are recommended particularly for seizures of focal origin. In addition to aspects of the nomenclature, this involves the introduction of different levels of classification with respect to the state of consciousness and the evolution to a bilateral tonic-clonic seizure, the inclusion of the first semiological seizure element in the classification and a new operationalization of the state of consciousness. This leads partly to specification in the description but in some areas also to counterintuitive changes in the classification. The advantages and disadvantages of this reorganization for the clinical practice are critically discussed with reference to the most important modifications.
CRIS-Team Scopus Importer:2019-11-01
Keywords: Bilateral tonic-clonic seizure; Consciousness; Focal origin; Generalized origin; Semiology

Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy - Kilo, Sonja; Berghoff, Martin; Hilz, Max-Josef; Freeman, Roy L. (Neurology, 2000)
Objective: To examine the role played by endothelium-dependent and endothelium-independent vasodilation of the cutaneous microcirculation and their relationship to neural microcirculatory control in type 1 and type 2 diabetic patients. Methods: Acetylcholine and sodium nitroprusside were iontophoresed using a dose-response technique. Endothelium-dependent, endothelium-independent, and C-fiber-mediated vasodilation were measured with a laser Doppler device. Results: Endothelium-dependent vasodilation of the forearm cutaneous microcirculation was attenuated in diabetic subjects. The response was less in type 2 diabetic subjects than in controls (p < 0.005). In contrast, there was no significant difference between type 1 diabetic subjects and controls. There was no significant abnormality in endothelium-independent vasodilation in either diabetic group. The C-fiber-mediated axon reflex in the forearm was impaired in both type 1 and type 2 diabetics, which is consistent with a small-fiber neuropathy (p < 0.005). The duration of diabetes in type 2 diabetics was a significant predictor of the maximum endothelium-mediated vasodilation. Conclusion: Changes in cutaneous blood flow are seen relatively early in the course of diabetic peripheral neuropathy and are characterized by endothelial and neural but not smooth muscle dysfunction. The presence of significant C-fiber impairment in both diabetic groups, together with significantly greater dysfunction in endothelium-dependent vasodilation in type 2 diabetics, suggests that the endothelial function and nitric oxide may play a greater role in the pathogenesis of diabetic peripheral neuropathy in type 2 diabetic patients.
Keywords: diabetic neuropathy; nitric oxide; endothelium; axon reflex

Neuroanatomical correlates of severe cardiac arrhythmias in acute ischemic stroke - Seifert, Frank; Kallmünzer, Bernd; Gutjahr, Isabell; Breuer, Lorenz; Winder, Klemens; Kaschka, Iris; Kloska, Stephan; Dörfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Köhrmann, Martin (Journal of Neurology, 2015)
Neurocardiological interactions can cause severe cardiac arrhythmias in patients with acute ischemic stroke. The relationship between the lesion location in the brain and the occurrence of cardiac arrhythmias is still discussed controversially. The aim of the present study was to correlate the lesion location with the occurrence of cardiac arrhythmias in patients with acute ischemic stroke. Cardiac arrhythmias were systematically assessed in patients with acute ischemic stroke during the first 72 h after admission to a monitored stroke unit. Voxel-based lesion-symptom mapping (VLSM) was used to correlate the lesion location with the occurrence of clinically relevant severe arrhythmias. Overall 150 patients, 56 with right-hemispheric and 94 patients with a left-hemispheric lesion, were eligible to be included in the VLSM study. Severe cardiac arrhythmias were present in 49 of these 150 patients (32.7%). We found a significant association (FDR correction, q < 0.05) between lesions in the right insular, right frontal and right parietal cortex as well as the right amygdala, basal ganglia and thalamus and the occurrence of cardiac arrhythmias. Because left- and right-hemispheric lesions were analyzed separately, the significant findings rely on the 56 patients with right-hemispheric lesions. The data indicate that these areas are involved in central autonomic processing and that right-hemispheric lesions located to these areas are associated with an elevated risk for severe cardiac arrhythmias.
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Neuroanatomic Correlates of Angioedema in stroke patients with thrombolysis - Winder, K.; Kallmünzer, Bernd; Dörfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Seifert, F.; Fröhlich, Kilian (EUROPEAN JOURNAL OF NEUROLOGY, 2020)
CRIS-Team WoS Importer:2020-06-16

Neuroanatomic Correlates of Female Sexual Dysfunction in Multiple Sclerosis - Winder, Klemens; Linker, Ralf; Seifert, Frank; Deutsch, Martina; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Hoesl, Katharina M.; Hilz, Max-Josef (Annals of Neurology, 2016)
This study intended to determine associations between alterations of female sexual arousal as well as vaginal lubrication and the site of cerebral multiple sclerosis (MS) lesions.In 44 women with MS (mean age: 36.5 ± 9.9 years), we assessed their medical history and evaluated sexual function using the Female Sexual Function Index scores for arousal and vaginal lubrication. We determined potential confounding factors of sexual dysfunction: age; disease duration; physical disability; depression; bladder or urinary dysfunction; and total volume of cerebral lesions. Arousal and lubrication scores were correlated with one another and with potential confounding factors. Cerebral MS lesions were recorded on imaging scans. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating cerebral sites of MS lesions with arousal and lubrication scores.Decreased arousal scores correlated with decreased lubrication scores; decreased lubrication scores were associated with bladder or urinary symptoms. Arousal and lubrication scores were not associated with any other variables. Multivariate VLSM analysis, including arousal and lubrication scores as covariables of interest, showed right occipital lesions associated with impaired arousal and left insular lesions associated with decreased lubrication. Impaired lubrication remained associated with left insular lesions after adjustment for bladder or urinary dysfunction.Our data indicate that impaired female sexual arousal is associated with MS lesions in the occipital region, integrating visual information and modulating attention toward visual input. Impaired lubrication correlated with lesions in the left insular region, contributing to mapping and generating visceral arousal states. Ann Neurol 2016;80:490-498.
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Neuroanatomic correlates of poststroke hyperglycemia - Winder, Klemens; Seifert, Frank; Ohnemus, Tessa; Sauer, Eva-Maria; Kloska, Stephan; Dörfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Köhrmann, Martin (Annals of Neurology, 2015)
A study was undertaken to determine associations between ischemic stroke sites and poststroke hyperglycemia (PSH).Nondiabetic patients with first ever ischemic stroke confirmed by imaging were prospectively included. Blood glucose level (BGL), National Institute of Health Stroke Scale (NIHSS) score, and clinical parameters were assessed on admission. BGL was dichotomized for elevated versus normal levels using a cutoff value of >7.0 mmol/l. Clinical parameters were correlated with BGL and were compared between patient groups with elevated versus normal glucose values. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating sites of ischemic lesions with PSH.Of 1,281 stroke patients screened, 229 (mean age = 66.3 ± 15.9 years) met the inclusion criteria. Patients with elevated BGL were older, had higher NIHSS scores, and had larger infarcts compared to those without elevated glucose levels. Spearman rank analysis showed correlations between BGL and age, infarct size, heart rate (HR), and NIHSS scores (p <= 0.05). The VLSM analysis adjusted for these confounding factors demonstrated associations between PSH and damaged voxels in right hemispheric insular and opercular areas.The data indicate that damage in the right insulo-opercular areas contributes to PSH. The association between sympathetically mediated increase of HR and BGL suggests disinhibition of sympathetic outflow as a possible mechanism for PSH.
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Neurocritical care in Germany: need for guidance - Huttner, Hagen; Schwab, Stefan (Neurocritical Care, 2014)
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Neuroendocrine changes in patients with spontaneous supratentorial intracerebral hemorrhage - Huttner, Hagen; Kiphuth, Ines-Christine; Teuber, Linda; Lücking, Hannes; Kloska, Stephan; Staykov, Dimitre; Kuramatsu, Joji; Mauer, Christoph; Breuer, Lorenz; Dörfler, Arnd; Köhrmann, Martin (Neurocritical Care, 2013)
Background: Neuroendocrine changes have been reported after ischemic stroke, subarachnoid hemorrhage, and brain trauma. As there are no corresponding data in patients with intracerebral hemorrhage (ICH) we analyzed various neuroendocrine parameters to investigate possible alterations in hormone profiles of patients with ICH. Methods: Twenty patients with ICH were prospectively enrolled in the study. Patients were a priori parted into two groups: Ten non-ventilated patients treated on the stroke-unit (hemorrhage volumes <20 ml, "small ICH"), and 10 ventilated patients treated on the neurocritical care unit (hematoma volumes >20 ml with possible additional ventricular involvement ("large ICH"). Neuroendocrine parameters were compared between both groups referring to reference values. The following parameters were obtained over a period of 9 days in 20 patients with spontaneous supratentorial ICH: thyrotropin, free thiiodothyronine and thyroxine, human growth hormone, insulin-like growth factor 1, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone, and cortisol. Results: Small ICH patients were in a median 71 (54-88) years old and had a mean ICH volume of 9.5 ± 6.5 ml, whereas large ICH patients were 65 (47-80) years old and showed a mean volume of 56 ± 30.2 ml. None of the patients revealed pathological alterations for thyrotropin, free thiiodothyronine, thyroxine, human growth hormone, insulin-like growth factor 1, and testosterone. There was only a mild decrease of adrenocorticotropic hormone and cortisol on day 3 in large ICH patients. Small ICH patients showed pathologically elevated levels of luteinizing and follicle-stimulating hormone throughout the observation period. Large ICH patients showed a marked increase of prolactin that developed during the course. Conclusions: Overall, neuroendocrine changes in ICH patients are not as profound as reported for ischemic stroke or subarachnoid hemorrhage. The clinical significance of increased LH and FSH levels in small ICH is unclear, whereas elevation of prolactin in large ICH was anticipated. Future randomized controlled trials should also focus on neuroendocrine parameters to clarify the impact of possible hormonal alterations on functional outcome. © 2011 Springer Science+Business Media, LLC.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Hormone profile; Intracerebral hemorrhage; Neuroendocrine

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities - Jacobs, Andreas H.; Emmert, Kirsten; Baron, Ralf; Bartsch, Thorsten; Bauer, Juergen; Becker, Clemens; Berg, Daniela; Bergmann, Philipp; Boetzel, Kai; Bollheimer, Cornelius; Deuschl, Guenther; Djukic, Marija; et al. (Zeitschrift für Gerontologie und Geriatrie, 2020)
Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.
CRIS-Team WoS Importer:2020-05-29

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients. - Krumm, Laura; Pozner, Tatyana; Zagha, Naime; Coras, Roland; Arnold, Philipp; Tsaktanis, Thanos; Scherpelz, Kathryn; Davis, Marie Y.; Kaindl, Johanna; Stolzer, Iris; Süß, Patrick; Khundadze, Mukhran; et al. (Acta Neuropathologica, 2024)
Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11-/- mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
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Neurointensive care medicine-from where, where to? - Stummer, W.; Schwab, Stefan; Fink, G. R. (Der Nervenarzt, 2018)
EVALuna2:201956

Neurological diseases after lightning strike : Lightning strikes twice - Gruhn, K. M.; Knossalla, Frauke; Schwenkreis, Peter; Hamsen, Uwe; Schildhauer, Thomas A.; Tegenthoff, Martin; Sczesny-Kaiser, Matthias (Der Nervenarzt, 2016)
Lightning strikes rarely occur but 85 % of patients have lightning-related neurological complications. This report provides an overview about different modes of energy transfer and neurological conditions related to lightning strikes. Moreover, two case reports demonstrate the importance of interdisciplinary treatment and the spectrum of neurological complications after lightning strikes.
EVALuna2:22519

Neurometabolic Dysfunction in SPG11 Hereditary Spastic Paraplegia. - Winner, Beate; Marterstock, Dominique; Kopp, Christoph; Dörfler, Arnd; Regensburger, Martin; Krumm, Laura; Schmidt, Manuel; Schmid, Andreas; Spatz, Imke; Marterstock, Dominique; Kopp, Christoph; Kohl, Zacharias; et al. (Nutrients, 2022)
Body composition, adipokine levels, and hypothalamic volume are altered in SPG11. Our data indicate a link between obesity and hypothalamic neurodegeneration in SPG11 and imply that specific metabolic interventions may prevent obesity despite severely impaired mobility in SPG11. Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking. In order to characterize metabolic alterations, a cross-sectional analysis was performed comparing SPG11 patients (n = 16) and matched healthy controls (n = 16). We quantified anthropometric parameters, body composition as determined by bioimpedance spectroscopy, and serum metabolic biomarkers, and we measured hypothalamic volume by high-field MRI. Compared to healthy controls, SPG11 patients exhibited profound changes in body composition, characterized by increased fat tissue index, decreased lean tissue index, and decreased muscle mass. The presence of lymphedema correlated with increased extracellular fluid. The serum levels of the adipokines leptin, resistin, and progranulin were significantly altered in SPG11 while adiponectin and C1q/TNF-related protein 3 (CTRP-3) were unchanged. MRI volumetry revealed a decreased hypothalamic volume in SPG11 patients. CONCLUSIONS BACKGROUND METHODS RESULTS
Keywords: SPG11; adipokines; bioimpedance spectroscopy; hypothalamus; leptin; obesity

Neuromodulation of Electrically Induced Hyperalgesia in the Trigeminocervical System - Reindl, Caroline; Seifert, Frank; Nickel, Franziska; Maihoefner, Christian (Pain Practice, 2016)
Trigeminal and cervical afferents converge on neurons of the trigeminocervical complex and may significantly alter the function of these neurons. This interaction may have implications for the pathophysiology and treatment of primary headache disorders. Therefore, the aim of this work was to study pain modulatory mechanisms within the trigeminocervical complex.We used an electrical pain model challenging pro- and antinociceptive systems in 19 healthy volunteers.Transcutaneous supraorbital noxious electrical low-frequency stimulation (0.5 Hz), known to induce both hyperalgesia due to central sensitization (as a marker of pain facilitation) and habituation (as a marker of pain inhibition), was combined with different noxious stimulation paradigms applied to the innervation territory of upper cervical afferents. We investigated the effects of concurrent stimulation in the cervical/extratrigeminal system on habituation profiles, hyperalgesic area, pain, and detection thresholds in the trigeminal system.It was previously shown that conditioning 20-Hz noxious electrical stimuli may provoke centrally mediated sensory decline that possesses heterotopic antihyperalgesic properties. Occipital and forearm costimulation at a frequency of 20 Hz had no significant modulating effect on supraorbital pain adaptation, hyperalgesic area, or pain perception. Effects for trigeminal stimulation were independent of occipital stimulus intensity. Furthermore, for single occipital stimulation at 0.5 and 20 Hz, no somatosensory changes could be demonstrated within the trigeminal system.Trigeminal nociception stayed unchanged despite of occipital costimulation.
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Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses - Kleiter, Ingo; Gahlen, Anna; Borisow, Nadja; Fischer, Katrin; Wernecke, Klaus-Dieter; Wegner, Brigitte; Hellwig, Kerstin; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Krumbholz, Markus; Kuempfel, Tania; et al. (Annals of Neurology, 2016)
Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach.A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006).Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.
EVALuna2:22444

Neuromyelitis optica presenting with relapses under treatment with natalizumab: a case report - Lee, De Hyung; Laemmer, Alexandra B.; Waschbisch, Anne; Struffert, Tobias; Maihöfner, Christian; Schwab, Stefan; Linker, Ralf (Journal of Medical Case Reports, 2014)
Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system. To date, optimal therapeutic approaches for neuromyelitis optica have yet to be defined. Natalizumab is highly effective in relapsing-remitting multiple sclerosis and might be considered as an option.Here, we describe a 67-year-old Caucasian man with definite neuromyelitis optica with detection of anti-aquaporin-4 antibodies over the course of the disease. After initially discussing the diagnosis of multiple sclerosis at an outside hospital, our patient received interferon beta 1a as well as repeated corticosteroid pulses without success. Under subsequent therapy with natalizumab, he continued to present relapses. It was not until discontinuation of natalizumab, repeated cycles of plasma exchanges and initiation of therapy with rituxan that the disease course started to stabilize. Although B cells were completely depleted, our patient experienced another severe myelitis relapse during further follow-up and an additional immunosuppressive therapy with cyclophosphamide was started. Under this regimen, no further relapses occurred over the next 24 months.This case adds further evidence to the previously discussed notion that natalizumab, while highly effective in multiple sclerosis, may not work sufficiently in neuromyelitis optica. It further advocates for repetitive testing of anti-aquaporin-4 antibodies before and after treatment initiation.
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