Publications by authors named "Susanne Knake"

133 Publications

Patients' knowledge about epilepsy-related risks, morbidity, and mortality: A multicenter cohort study from Germany.

Epilepsy Behav 2021 Oct 4;124:108343. Epub 2021 Oct 4.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Introduction: Patient education is a central component of quality care. Enhancing patient knowledge can improve patients' quality of life and facilitate successful self-management. We sought to identify patients' knowledge levels and knowledge gaps regarding epilepsy-related risks, morbidity, and mortality.

Methods: Adult patients with epilepsy presenting to the university hospitals in Frankfurt, Greifswald, and Marburg between February 2018 and May 2020 were asked to participate in this questionnaire-based study.

Results: A total of 238 patients (52% women), with a mean age of 39.2 years (range: 18-77 years), participated in this study. Spontaneously, the majority of patients (51.3%) named driving a car, and other traffic-related accidents as possible causes of morbidity and mortality, and 23.9% of patients reported various causes of premature death, such as suffocation, drowning, and respiratory or cardiac arrest due to seizures. Falls due to epilepsy (19.7%) and injuries in general (17.6%) were named as further causes of morbidity and mortality. The vast majority were aware that alcohol (87.4%), sleep deprivation (86.6%), and risky activities in daily life (80.3%) increased the risk of seizure occurrence or increased morbidity and mortality. Regarding overall mortality, 52.1% thought that people with epilepsy were at greater risk of premature death, whereas 46.2% denied this fact to be true. Only 29.4% were aware of status epilepticus, and 27.3% were aware of sudden unexpected death in epilepsy (SUDEP). Driving ability, working ability, and seizure risk were named as major or moderate concerns among patients, but the risk of premature mortality was not a major concern. One-quarter of all patients (26.9%) indicated that they were not counseled about any risk factors or causes of morbidity or mortality by their physicians.

Conclusions: A lack of knowledge concerning premature mortality, SUDEP, and status epilepticus exists among adult patients with epilepsy. A substantial number of patients indicated that these issues were not discussed adequately by their physicians.
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http://dx.doi.org/10.1016/j.yebeh.2021.108343DOI Listing
October 2021

EEG patterns and their correlations with short- and long-term mortality in patients with hypoxic encephalopathy.

Clin Neurophysiol 2021 Aug 27;132(11):2851-2860. Epub 2021 Aug 27.

Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany; Department of Neurology and Epilepsy Center Hessen, Philipps-University Marburg, Marburg (Lahn), Germany.

Objective: To analyze the association between electroencephalographic (EEG) patterns and overall, short- and long-term mortality in patients with hypoxic encephalopathy (HE).

Methods: Retrospective, mono-center analysis of 199 patients using univariate log-rank tests (LR) and multivariate cox regression (MCR).

Results: Short-term mortality, defined as death within 30-days post-discharge was 54.8%. Long-term mortality rates were 69.8%, 71.9%, and 72.9%, at 12-, 24-, and 36-months post-HE, respectively. LR revealed a significant association between EEG suppression (SUP) and short-term mortality, and identified low voltage EEG (LV), burst suppression (BSP), periodic discharges (PD) and post-hypoxic status epilepticus (PSE) as well as missing (aBA) or non-reactive background activity (nrBA) as predictors for overall, short- and long-term mortality. MCR indicated SUP, LV, BSP, PD, aBA and nrBA as significantly associated with overall and short-term mortality to varying extents. LV and BSP were significant predictors for long-term mortality in short-term survivors. Rhythmic delta activity, stimulus induced rhythmic, periodic or ictal discharges and sharp waves were not significantly associated with a higher mortality.

Conclusion: The presence of several specific EEG patterns can help to predict overall, short- and long-term mortality in HE patients.

Significance: The present findings may help to improve the challenging prognosis estimation in HE patients.
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http://dx.doi.org/10.1016/j.clinph.2021.07.026DOI Listing
August 2021

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.

CNS Drugs 2021 Oct 17;35(10):1107-1122. Epub 2021 Jul 17.

Division of Nephrology, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München - Innenstadt, München, Germany.

Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder.

Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient's perspective.

Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC.

Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m (median: 5.6 mg/m, range 2.0-15.1 mg/m) in children and adolescents and 4 ± 2.1 mg/m (median: 3.7 mg/m, range 0.8-10.1 mg/m) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items 'tiredness', 'skin problems' and 'mouth/gum problems', which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE.

Conclusions: From the patients' perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
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http://dx.doi.org/10.1007/s40263-021-00839-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478774PMC
October 2021

Perception of memory performance after first seizure in patients with and without an epilepsy diagnosis.

Epilepsy Behav 2021 09 10;122:108195. Epub 2021 Jul 10.

Epilepsy Center Hessen, Department of Neurology, Philipps-University, Marburg.

Objectives: Memory complaints in patients with epilepsy have been well-studied. Although memory complaints are commonly reported by patients with chronic epilepsy, to date, few studies exist on memory complaints at the onset of epilepsy. The present study investigated the presence of memory complaints and their relation to mood and memory performance in patients after their first seizure. Thereby, we examined differences between individuals who received a diagnosis of epilepsy immediately with the occurrence of their first seizure and those who were diagnosed as having the first epileptic seizure, without fulfilling the ILAE criteria for the diagnosis of epilepsy.

Methods: Sixty-one patients participated in the study and completed, among others, a memory task and questionnaires on memory complaints and depression after their first epileptic seizure. We investigated the level of memory complaints and their correlation and accuracy in classification with a memory measure. We compared patients who received an epilepsy diagnosis after the first seizure with those who did not.

Results: Memory complaints did not correlate with objective memory performance. Classification into impaired/unimpaired showed low concordance between memory complaints and neuropsychological memory measures. After their first epileptic seizure, patients reported few memory complaints overall (10%), and there were no differences in memory complaints between patients with and without an epilepsy diagnosis.

Conclusion: At epilepsy onset, in contrast to established epilepsies, memory complaints are rare. Although influences of anticonvulsant drugs and seizures are not present at the beginning of epilepsy, this substantial absence of memory complaints at epilepsy onset emphasizes the need for comprehensive neurological and psychological treatment early with the given diagnosis. Treatment should focus on anticonvulsant drug regimens, patients' concerns and convey realistic expectations.
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http://dx.doi.org/10.1016/j.yebeh.2021.108195DOI Listing
September 2021

Informed DEcision for cerebrospinal fluid analysis after epiLeptic seizures- the IDEAL-score: A development and validation study.

Seizure 2021 Oct 29;91:228-232. Epub 2021 Jun 29.

Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.

Background: This observational study was done to develop a score based on clinical predictors that enables a guided decision for the necessity of cerebrospinal fluid (CSF) analysis after first unprovoked epileptic seizures and to validate this score in a retrospective patient cohort.

Methods: Clinical predictors were identified by two panels of epilepsy experts and selected according to content validity ratios. Based on these predictors a score was created and applied to a cohort of patients with first epileptic seizures.

Results: The "IDEAL score" consists of 9 items (fever, prolonged disturbance of consciousness, headache, imaging results, cognitive dysfunction, status epilepticus, malignancy, autoimmune encephalitis symptoms) that are collected at two different time points (< 3 h [A-score]; > 3 h [B-score] after hospital admittance). A CSF analysis is recommended, if at least one clinical finding is present, either one of the items evaluated during the acute phase (A-score) or later in the diagnostic process (B-score). In 41 patients (13%) CSF analysis provided essential clues to the cause of the seizure. The combined IDEAL score reached a sensitivity of 98%, a specificity of 53%, a positive predictive value of 24% and a negative predictive value of 99% in this patient cohort.

Conclusions: A CSF analysis after first epileptic seizures provided decisive etiological findings in only 13% of all investigated patients. The IDEAL score offers clinicians a simple and easy-to-implement algorithm to assess the necessity of a CSF analysis, and to prevent unnecessary diagnostic procedures.
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http://dx.doi.org/10.1016/j.seizure.2021.06.019DOI Listing
October 2021

Transcutaneous auricular vagus nerve stimulation influences gastric motility: A randomized, double-blind trial in healthy individuals.

Brain Stimul 2021 Sep-Oct;14(5):1126-1132. Epub 2021 Jun 27.

Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg, Germany; Center for Mind, Brain and Behavior, CMBB, Philipps-University Marburg, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Germany. Electronic address:

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively.

Objective: To investigate the influence of taVNS on gastric motility of healthy participants using rtMRI.

Methods: We conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI.

Results: After HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003).

Conclusion: We provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.
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http://dx.doi.org/10.1016/j.brs.2021.06.006DOI Listing
June 2021

Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.

Neurol Res Pract 2021 Jun 28;3(1):35. Epub 2021 Jun 28.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.

Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC.

Methods: We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders.

Results: We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18-61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p < 0.001), active epilepsy (large effect, p < 0.001), and neuropsychiatric manifestations (medium effect, p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma.

Conclusions: Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity.

Trial Registration: DRKS, DRKS00016045 . Registered 01 March 2019.
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http://dx.doi.org/10.1186/s42466-021-00130-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237479PMC
June 2021

Satisfaction with and reliability of in-hospital video-EEG monitoring systems in epilepsy diagnosis - A German multicenter experience.

Clin Neurophysiol 2021 Sep 1;132(9):2317-2322. Epub 2021 Jun 1.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt am Main, Germany. Electronic address:

Objective: To analyze satisfaction with and reliability of video-electroencephalography-monitoring systems (VEMS) in epilepsy diagnostics.

Methods: A survey was conducted between December 2020 and January 2021 among German epilepsy centers using well-established customer satisfaction (CS) and quality assurance metrics.

Results: Among 16 participating centers, CS with VEMS was low, with only 13% of customers actively recommending their system. Only 50% of users were satisfied with the overall performance of their VEMS, and a low 18% were satisfied with the manufacturer's customer service. User interface, software stability, lack of regular updates, and missing customer-oriented improvements were reported as frequent problems jeopardizing diagnosis in approximately every 10th patient. The greatest potential for improvement was identified for software and hardware stability as well as customer service.

Conclusion: Satisfaction with VEMS and their customer service was low, and diagnostics were regularly affected by software or hardware errors. Even if this can be partly explained by the technical complexity of VEMS, there is an urgent need for improvements with regard to the reliability and durability of system components as well as signal synchrony and data management.

Significance: This analysis highlights low consumer satisfaction of users with VEMS and uncovers frequent problems and potential for improvement.
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http://dx.doi.org/10.1016/j.clinph.2021.04.020DOI Listing
September 2021

Direct and indirect costs and cost-driving factors in adults with tuberous sclerosis complex: a multicenter cohort study and a review of the literature.

Orphanet J Rare Dis 2021 06 2;16(1):250. Epub 2021 Jun 2.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.

Methods: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).

Results: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.

Conclusions: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting.

Trial Registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 .
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http://dx.doi.org/10.1186/s13023-021-01838-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170458PMC
June 2021

Wada test results contribute to the prediction of change in verbal learning and verbal memory function after temporal lobe epilepsy surgery.

Sci Rep 2021 05 26;11(1):10979. Epub 2021 May 26.

Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, University Hospital Frankfurt and Goethe University, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

In recent years, the clinical usefulness of the Wada test (WT) has been debated among researchers in the field. Therefore, we aimed to assess its contribution to the prediction of change in verbal learning and verbal memory function after epilepsy surgery. Data from 56 patients with temporal lobe epilepsy who underwent WT and subsequent surgery were analyzed retrospectively. Additionally, a standard neuropsychological assessment evaluating attentional, learning and memory, visuospatial, language, and executive function was performed both before and 12 months after surgery. Hierarchical linear regression analyses were used to determine the incremental value of WT results over socio-demographic, clinical, and neuropsychological characteristics in predicting postsurgical change in patients' verbal learning and verbal memory function. The incorporation of WT results significantly improved the prediction models of postsurgical change in verbal learning (∆R = 0.233, p = .032) and verbal memory function (∆R = 0.386, p = .005). Presurgical performance and WT scores accounted for 41.8% of the variance in postsurgical change in verbal learning function, and 51.1% of the variance in postsurgical change in verbal memory function. Our findings confirm that WT results are of significant incremental value for the prediction of postsurgical change in verbal learning and verbal memory function. Thus, the WT contributes to determining the risks of epilepsy surgery and, therefore, remains an important part of the presurgical work-up of selected patients with clear clinical indications.
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http://dx.doi.org/10.1038/s41598-021-90376-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154896PMC
May 2021

Temporal encephaloceles in epilepsy patients and asymptomatic cases: Size may indicate epileptogenicity.

Epilepsia 2021 06 3;62(6):1354-1361. Epub 2021 May 3.

Epilepsy Center Hessen, Department of Neurology, Philipps University Marburg, Marburg, Germany.

Objective: This study was undertaken to identify temporal encephaloceles (TEs) and examine their characteristics in patients with temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE), as well as in asymptomatic cases.

Methods: Four hundred fifty-eight magnetic resonance imaging scans were examined retrospectively to identify TE in 157 patients with TLE, 150 patients with ETLE, and 151 healthy controls (HCs).

Results: At least one TE was identified in 9.6% of the TLE patients (n = 15, 95% confidence interval [CI] = 5.3%-15.3%), in 3.3% of patients with ETLE (n = 5, 95% CI = 1.1%-7.6%), and in 2.0% of the HCs (n = 3, 95% CI = .4%-5.7%), indicating a significantly higher frequency in patients with TLE compared to ETLE and HC subjects (p = .027, p = .005). Examining the characteristics of TEs in both asymptomatic and epilepsy patients, we found that TEs with a diameter of less than 6.25 mm were more likely to be asymptomatic, with a sensitivity of 91.7% and a specificity of 73.3% (area under the curve = .867, 95% CI = .723-1.00, p = .001).

Significance: Temporal encephaloceles may occur without presenting any clinical symptoms. Patients with TLE show a higher frequency of TEs compared to the ETLE and HC groups. According to our study, TE size could be used to suggest potential epileptogenicity.
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http://dx.doi.org/10.1111/epi.16900DOI Listing
June 2021

Trust your gut: vagal nerve stimulation in humans improves reinforcement learning.

Brain Commun 2021 14;3(2):fcab039. Epub 2021 Mar 14.

Department of Neurology, Philipps-University Marburg, 35043 Marburg, Germany.

Whereas the effect of vagal nerve stimulation on emotional states is well established, its effect on cognitive functions is still unclear. Recent rodent studies show that vagal activation enhances reinforcement learning and neuronal dopamine release. The influence of vagal nerve stimulation on reinforcement learning in humans is still unknown. Here, we studied the effect of transcutaneous vagal nerve stimulation on reinforcement learning in eight long-standing seizure-free epilepsy patients, using a well-established forced-choice reward-based paradigm in a cross-sectional, within-subject study design. We investigated vagal nerve stimulation effects on overall accuracy using non-parametric cluster-based permutation tests. Furthermore, we modelled sub-components of the decision process using drift-diffusion modelling. We found higher accuracies in the vagal nerve stimulation condition compared to sham stimulation. Modelling suggests a stimulation-dependent increase in reward sensitivity and shift of accuracy-speed trade-offs towards maximizing rewards. Moreover, vagal nerve stimulation was associated with increased non-decision times suggesting enhanced sensory or attentional processes. No differences of starting bias were detected for both conditions. Accuracies in the extinction phase were higher in later trials of the vagal nerve stimulation condition, suggesting a perseverative effect compared to sham. Together, our results provide first evidence of causal vagal influence on human reinforcement learning and might have clinical implications for the usage of vagal stimulation in learning deficiency.
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http://dx.doi.org/10.1093/braincomms/fcab039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066886PMC
March 2021

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature.

Expert Rev Clin Pharmacol 2021 Jun 31;14(6):749-760. Epub 2021 May 31.

Department of Neuropediatrics and Social Pediatrics, St. Josef-Hospital, University Hospital of Pediatrics and Adolescent Medicine, Ruhr-University Bochum, Bochum, Germany.

Objective: Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.

Methods: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence.

Results: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.

Conclusions: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.
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http://dx.doi.org/10.1080/17512433.2021.1911643DOI Listing
June 2021

Validation of automatic MRI hippocampal subfield segmentation by histopathological evaluation in patients with temporal lobe epilepsy.

Seizure 2021 Apr 12;87:94-102. Epub 2021 Mar 12.

Epilepsy Center Hessen, Philipps-University Marburg, Department of Neurology, Baldingerstrasse, 35043, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER) Consortium, Germany.

Objective: The present study validates the results of automated hippocampal subfield segmentation with histopathology in epilepsy patients undergoing epilepsy surgery.

Methods: We performed an automated hippocampal subfield segmentation on presurgical three-dimensional, T1-weighted magnetization Prepared Rapid Acquisition of Gradient Echoes Magnetic Resonance Imaging (MRI) data of 25 patients with unilateral mesial temporal lobe epilepsy due to hippocampal sclerosis (HS), using Freesurfer Version 6.0. The resulting volumes of cornu ammonis (CA) subfields CA1, CA2/3, CA4 and the dentate gyrus (DG) were compared to the histopathological cell count.

Results: We found a significant correlation between histopathology in subregion CA2 and automated segmentation of subregion CA1 (p = 0.0062), CA2/3 (p = 0.004), CA4 (p = 0.0062) and the DG (p = 0.0054), between histopathology in CA3 and automated segmentation of CA1 (p = 0.0132), CA2/3 (p = 0.0004), CA4 (p = 0.0032) and the DG (p = 0.0037), as well as between histopathology in the DG and automated segmentation of CA1 (p = 0.0115), CA2/3 (p < 0.0001), CA4 (p < 0.0001) and the DG (p = 0.0001). The histopathological finding of HS type 1 could correctly be classified in all cases on MRI.

Significance: The present study shows significant correlations between histopathological evaluation and results of the automated segmentation of the hippocampus, thereby validating the automated segmentation method. As the differential involvement of different hippocampal subfields may be associated with clinical parameters and the outcome after epilepsy surgery, the automated segmentation is also promising for prognostic purposes.
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http://dx.doi.org/10.1016/j.seizure.2021.03.007DOI Listing
April 2021

Advantages of methohexital over amobarbital in determining hemispheric language and memory lateralization in the Wada test - A retrospective study.

Epilepsy Behav 2020 12 24;113:107551. Epub 2020 Nov 24.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Goethe University, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt am Main, Germany.

Objective: Due to supply shortage, amobarbital, the traditional anesthetic agent in Wada testing, was replaced by methohexital in many epilepsy centers. This study aimed to compare the two barbiturates to identify possible advantages or disadvantages of methohexital as compared to amobarbital with regard to the adequacy of language and memory testing during the Wada test.

Methods: Data from 75 patients with temporal lobe epilepsy who underwent bilateral Wada tests using either amobarbital (n = 53) or methohexital (n = 22) as part of presurgical work-up were analyzed retrospectively. The two subgroups were compared regarding hemispheric language and memory lateralization results and Wada testing characteristics, and the adequacy of language and memory testing was assessed.

Results: We observed shorter durations of motor-, speech-, and EEG recovery after each injection in patients receiving methohexital compared to amobarbital. In addition, significantly more items could be presented during effective hemispheric inactivation in the methohexital group. Moreover, significant correlations of Wada memory scores with standard neuropsychological memory test scores could be found in the methohexital group.

Significance: Our findings confirm that methohexital is not only equally suitable for Wada testing but has several advantages over amobarbital. Wada testing can be performed more efficiently and under more constant hemispheric inactivation using methohexital. Furthermore, the adequacy of language and memory testing during the Wada test might be affected by the anesthetic agent used.
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http://dx.doi.org/10.1016/j.yebeh.2020.107551DOI Listing
December 2020

Convergent patterns of structural brain changes in rapid eye movement sleep behavior disorder and Parkinson's disease on behalf of the German rapid eye movement sleep behavior disorder study group.

Sleep 2021 03;44(3)

Department of Neurology, RWTH Aachen University, Aachen, Germany.

Study Objectives: Rapid eye movement sleep behavior disorder (RBD) is considered a prodromal state of Parkinson's disease (PD). We aimed to characterize patterns of structural brain changes in RBD and PD patients using multimodal MRI.

Methods: A total of 30 patients with isolated RBD, 29 patients with PD, and 56 age-matched healthy controls (HC) underwent MRI at 3T, including tensor-based morphometry, diffusion tensor imaging, and assessment of cortical thickness.

Results: RBD individuals showed increased volume of the right caudate nucleus compared with HC, and higher cerebellar volume compared with both PD subjects and HC. Similar to PD subjects, RBD patients displayed increased fractional anisotropy (FA) in the corticospinal tracts, several tracts mainly related to non-motor function, and reduced FA of the corpus callosum compared with HC. Further, RBD subjects showed higher FA in the cerebellar peduncles and brainstem compared with both, PD patients and HC. PD individuals exhibited lower than normal volume in the basal ganglia, midbrain, pedunculopontine nuclei, and cerebellum. In contrast, volume in PD subjects was increased in the thalamus compared with both HC and RBD subjects.

Conclusions: We found convergent patterns of structural brain alterations in RBD and PD patients compared with HC. The changes observed suggest a co-occurrence of neurodegeneration and compensatory mechanisms that fail with emerging PD pathology. Our findings strengthen the hypothesis of RBD and PD constituting a continuous disease spectrum.
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http://dx.doi.org/10.1093/sleep/zsaa199DOI Listing
March 2021

Examination of the Flynn effect in German patients with epilepsy assessed with the Wechsler Adult Intelligence Scale (WAIS) III and IV.

Epilepsy Behav 2020 11 9;112:107337. Epub 2020 Sep 9.

The Flynn effect describes an increase in intelligence quotient (IQ) in the general population of about 3 points per decade. While this effect is well established in healthy individuals, research exploring the link to brain pathologies is scarce. We investigated the Flynn effect in a German sample of 203 patients with epilepsy with left, right, and bilateral lesions. Intelligence quotient values were obtained using the Wechsler Adult Intelligence Scales (WAIS) III and IV. Our results showed a stable Flynn effect with nearly no difference in adjusted full scale IQ (FSIQ) scores (0.02 IQ points) between the WAIS-III and WAIS-IV samples. There were no significant interactions between the side of pathology and corrected IQ values. Our sample showed a tendency towards performing worse in the WAIS-IV in three out of four subscales independently of the Flynn effect, pointing out methodological differences between the newer Wechsler editions. However, although patients with bilateral lesions performed worst across all subscales, they exhibited a similar pattern as patients with lesions in the left or right hemisphere, indicating that also more severe forms of brain pathologies can profit from the mechanisms behind the Flynn effect.
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http://dx.doi.org/10.1016/j.yebeh.2020.107337DOI Listing
November 2020

Brivaracetam substituting other antiepileptic treatments: Results of a retrospective study in German epilepsy centers.

Epilepsia Open 2020 Sep 22;5(3):451-460. Epub 2020 Jul 22.

Epilepsy Center Kleinwachau Radeberg Germany.

Objective: To evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam.

Methods: In this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation.

Results: Five hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before (3-month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs).

Significance: Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.
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http://dx.doi.org/10.1002/epi4.12415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469785PMC
September 2020

Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial.

J Neurol Neurosurg Psychiatry 2020 10 18;91(10):1067-1075. Epub 2020 Aug 18.

UCB Pharma, Monheim am Rhein, Germany.

Objective: To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE).

Methods: Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1-3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment.

Results: 242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.

Conclusions: Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.
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http://dx.doi.org/10.1136/jnnp-2020-323524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509528PMC
October 2020

Risk incidence of fractures and injuries: a multicenter video-EEG study of 626 generalized convulsive seizures.

J Neurol 2020 Dec 10;267(12):3632-3642. Epub 2020 Jul 10.

Center of Neurology and Neurosurgery, Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.

Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.

Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.

Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3-74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2-3.4%) and 3.2% per patient (95% CI 1.8-5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5-2.2%) and 1.7% per patient (95% CI 0.8-3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.

Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.
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http://dx.doi.org/10.1007/s00415-020-10065-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674387PMC
December 2020

Improved Visualization of Focal Cortical Dysplasia With Surface-Based Multiparametric Quantitative MRI.

Front Neurosci 2020 16;14:622. Epub 2020 Jun 16.

Department of Neurology, Goethe University, Frankfurt, Germany.

Purpose: In the clinical routine, detection of focal cortical dysplasia (FCD) by visual inspection is challenging. Still, information about the presence and location of FCD is highly relevant for prognostication and treatment decisions. Therefore, this study aimed to develop, describe and test a method for the calculation of synthetic anatomies using multiparametric quantitative MRI (qMRI) data and surface-based analysis, which allows for an improved visualization of FCD.

Materials And Methods: Quantitative T1-, T2- and PD-maps and conventional clinical datasets of patients with FCD and epilepsy were acquired. Tissue segmentation and delineation of the border between white matter and cortex was performed. In order to detect blurring at this border, a surface-based calculation of the standard deviation of each quantitative parameter (T1, T2, and PD) was performed across the cortex and the neighboring white matter for each cortical vertex. The resulting standard deviations combined with measures of the cortical thickness were used to enhance the signal of conventional FLAIR-datasets. The resulting synthetically enhanced FLAIR-anatomies were compared with conventional MRI-data utilizing regions of interest based analysis techniques.

Results: The synthetically enhanced FLAIR-anatomies showed higher signal levels than conventional FLAIR-data at the FCD sites ( = 0.005). In addition, the enhanced FLAIR-anatomies exhibited higher signal levels at the FCD sites than in the corresponding contralateral regions ( = 0.005). However, false positive findings occurred, so careful comparison with conventional datasets is mandatory.

Conclusion: Synthetically enhanced FLAIR-anatomies resulting from surface-based multiparametric qMRI-analyses have the potential to improve the visualization of FCD and, accordingly, the treatment of the respective patients.
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http://dx.doi.org/10.3389/fnins.2020.00622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308728PMC
June 2020

Treatment of status epilepticus with zonisamide: A multicenter cohort study of 34 patients and review of literature.

Epilepsy Behav 2020 08 14;109:107139. Epub 2020 May 14.

Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt and University Hospital Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Department of Neurology and Epilepsy Center Hessen, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Introduction: We present a summary of clinical cases of oral zonisamide (ZNS) used to treat refractory and super-refractory episodes of status epilepticus (SE).

Methods: Zonisamide administration in SE was identified in the clinical records of patients treated in Frankfurt and Marburg between 2011 and 2017.

Results: Zonisamide was administered during a total of 37 SE episodes in 34 patients with a mean age of 58.7 ± 17.8 years, 21 of them were female (61.7%). The median latency from the onset of SE to administration of ZNS was 6.3 days. Patients had already undergone unsuccessful treatment with a median of three other antiseizure drugs (ASDs). The median initial dose of ZNS was 100 mg/d, titrated to a median maintenance dose of 400 mg/d. Patients underwent ZNS treatment for a median period of 7 days. Zonisamide was the final drug administered in 9 of 37 (24.3%) episodes, with a clinical effect attributed to ZNS observed in 6 of 37 (16.2%) episodes. An effect attributed to ZNS was observed in 5 out of 30 episodes of refractory SE (RSE) and in one out of 7 episodes of super-refractory SE (SRSE). Possible negative side effects of ZNS were observed in two patients (one patient each with ataxia and skin rash). The mortality rate in hospitalized patients was 10.4% (n = 4).

Conclusion: The rate of SE resolution attributed to ZNS treatment (16.2%) can be considered relevant, particularly since ZNS treatment tends to be administered only after several other options have been tried, and has a treatment latency of over six days. Zonisamide may therefore be considered as an alternative oral treatment option in RSE and SRSE.
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http://dx.doi.org/10.1016/j.yebeh.2020.107139DOI Listing
August 2020

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring.

CNS Drugs 2020 05;34(5):545-553

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, University Hospital Frankfurt, Schleusenweg 2-16, Haus 95, 60528, Frankfurt am Main, Germany.

Background: An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus.

Objectives: This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice.

Methods: In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2 014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic-clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated.

Results: In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5-76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5-15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic-clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42-0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%).

Conclusion: We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1-2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.
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http://dx.doi.org/10.1007/s40263-020-00720-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198639PMC
May 2020

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Seizure 2020 May 5;78:31-37. Epub 2020 Mar 5.

Neurocenter Bellevue, Zurich, Switzerland.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
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http://dx.doi.org/10.1016/j.seizure.2020.02.018DOI Listing
May 2020

Prone, lateral, or supine positioning at seizure onset determines the postictal body position: A multicenter video-EEG monitoring cohort study.

Seizure 2020 Feb 21;76:173-178. Epub 2020 Feb 21.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized and Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Purpose: Most patients who die from sudden unexpected death in epilepsy (SUDEP) are found in the prone position. We evaluated whether changes in body position occur during generalized convulsive seizures (GCSs).

Method: GCSs in patients undergoing video-EEG-monitoring between 2007 and 2017 at epilepsy centers in Frankfurt and Marburg were analyzed in relation to changes in body position.

Results: A total of 494 GCSs were analyzed among 327 patients. At seizure onset, positions included supine (48.2 %), right lateral (19.0 %), left lateral (15.6 %), sitting or standing (14.0 %), and prone (3.2 %). Between seizure onset and the start of generalization, 57.5 % of participants altered body positions. During four seizures, patients adopted a prone position, while, in five seizures, patients moved from a prone position. Patients who experienced GCS onset while in a nonprone position had a 2.1 % risk of entering the prone position by the end of their seizure. In contrast, 56.2 % of those in an initial prone position remained so at the end of the GCS, with an odds ratio for maintaining that position of 60.2 (95 % confidence interval: 29.1-124.3; p < 0.001). The likelihood of ending up in the prone position post-GCS did not vary among patients with different nonprone starting positions (p = 0.147).

Conclusions: Seizures in prone position occur during sleep and the highest risk for postictal prone positioning appears to be being in the prone position at GCS onset. Epilepsy patients should therefore be advised to go to sleep in a supine or lateral position to reduce their SUDEP risk.
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http://dx.doi.org/10.1016/j.seizure.2020.02.008DOI Listing
February 2020

Predicting outcome of epilepsy surgery in clinical practice: Prediction models vs. clinical acumen.

Seizure 2020 Feb 1;76:79-83. Epub 2020 Feb 1.

Epilepsy Center Hessen, Department of Neurology, University Hospitals Giessen & Marburg, Philipps-University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany; Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Purpose: Epilepsy surgery is an evidence-based treatment for drug-refractory focal epilepsy. We aimed to evaluate how well preoperative outcome estimates of epilepsy surgery in clinical practice correlated with postoperative outcome and to compare prediction by the clinical team with available scores (m-SFS, ESN).

Method: Retrospective cohort study including patients with drug-refractory focal epilepsy who underwent resective epilepsy surgery at Epilepsy Center Hessen, Marburg, between 1998-2016. Patients were categorized into four groups based on their estimated chance of postoperative seizure freedom documented in preoperative medical records. Variables required for calculation of m-SFS and ESN were also extracted from presurgical medical records. Seizure outcome using Engel/ILAE classifications was extracted from postoperative medical records.

Results: 148 patients were included and 98 had follow-up at 5 years. 69 (70%) had Engel I and 50 (51%) ILAE 1 outcome. Observed 5-year outcome for very good candidates was 20/22 (91%) Engel I and 14/22 (64%) ILAE 1, for good candidates 29/40 (73%) Engel I and 21/40 (53%) ILAE 1, for candidates with slightly reduced chance 11/18 (61%) Engel I and 9/18 (50%) ILAE 1 and for candidates with considerably reduced chance 1/5 (20%) Engel I and 1/5 (20%) ILAE 1.There were no significant differences in discrimination or overall performance between predictions by the clinical team, ESN and m-SFS.

Conclusions: Preoperative outcome estimates corresponded well with observed outcome indicating adequate patient counseling.
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http://dx.doi.org/10.1016/j.seizure.2020.01.016DOI Listing
February 2020

Detection of cortical malformations using enhanced synthetic contrast images derived from quantitative T1 maps.

NMR Biomed 2020 02 3;33(2):e4203. Epub 2019 Dec 3.

Brain Imaging Center, Goethe University, Frankfurt am Main, Germany.

The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug-resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients. On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM-WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map. The resulting CE- and/or SM-enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces. In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM-WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.
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http://dx.doi.org/10.1002/nbm.4203DOI Listing
February 2020

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature.

Epilepsia 2019 12 11;60(12):2448-2458. Epub 2019 Nov 11.

Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University Frankfurt, Frankfurt am Main, Germany.

Objective: Novel treatments are needed to control treatment-resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE).

Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation.

Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment-emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty-four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n = 24).

Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.
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http://dx.doi.org/10.1111/epi.16382DOI Listing
December 2019

First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study.

BMJ Open 2019 11 4;9(11):e030746. Epub 2019 Nov 4.

Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.

Objectives: Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting.

Design: Retrospective, observational multicentre study.

Setting: We retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist.

Participants: Data of 615 epilepsy patients treated with BRV were included in the study.

Primary And Secondary Outcome Measures: Efficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X contingency tests and effect sizes were performed.

Results: Overall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV.

Conclusions: The present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.
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http://dx.doi.org/10.1136/bmjopen-2019-030746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858140PMC
November 2019
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