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Purpose: Neuroglial tumors are frequently associated with pharmacorefractory epilepsies. However, comprehensive knowledge about long-term outcomes after epilepsy surgery and the main prognostic factors for outcome is still limited. We sought to evaluate long-term outcomes and potential influencing factors in a large cohort of patients who underwent surgery for neuroglial tumors in a single-center setting., Methods: The study analyzed the outcomes of 107 patients who underwent epilepsy surgery for neuroglial tumors between 2001 and 2020 at the Department of Epileptology, University Hospital Bonn, in Germany. The outcomes were evaluated using Engel classification. Differences in outcome related to potential prognostic factors were examined using the Chi2-test, Fisher's exact test and sign test. Additionally, stepwise logistic regression analysis was employed to identify independent prognostic factors., Results: Complete seizure freedom (Engel Class IA) was achieved in 75% of the operated patients at 12 months, and 56% at the last follow-up visit (70.4 ± 6.2 months, median: 40 months). Completeness of resection was a crucial factor for both 12-month follow-up outcomes and the longest available outcomes, whereas lobar tumor localization, histology (ganglioglioma vs. dysembryoplastic neuroepithelial tumor), history of bilateral tonic-clonic seizures prior to surgery, invasive diagnostics, side of surgery (dominant vs. non-dominant hemisphere), age at epilepsy onset, age at surgery, and epilepsy duration did not consistently impact postsurgical outcomes. Among temporal lobe surgeries, patients who underwent lesionectomy and lesionectomy, including hippocampal resection, demonstrated similar outcomes., Conclusion: Neuroglial tumors present as excellent surgical substrates in treating structural epilepsy. To achieve an optimal postsurgical outcome, a complete lesion resection should be pursued whenever possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RS has received personal fees as speaker or for serving on advisory boards from Angelini, Arvelle, Bial, Desitin, Eisai, Jazz Pharmaceuticals Germany GmbH, Janssen-Cilag GmbH, LivaNova, LivAssured B.V., Novartis, Precisis GmbH, Rapport Therapeutics, Tabuk Pharmaceuticals, UCB Pharma, UNEEG, and Zogenix. These activities were not related to the content of this manuscript. AR has received fees as speaker from UCB Pharma, and received travel support from the Elisabeth und Helmut Uhl Stiftung. These activities were not related to the content of this manuscript. Some authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rácz, Müller, Becker, Hoffmann, Rüber, Borger, Vatter, Surges and Elger.)

Objective: Evaluation of the antiseizure efficacy, side effects and neuropsychological effects of Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT). ANT-DBS is a treatment option for patients with difficult-to-treat epilepsy. Though several works outline the cognitive and/or mood effects of ANT-DBS for the treatment of epilepsy, data on the intersection between antiseizure efficacy, cognitive and undesired effects are scarce., Methods: We retrospectively analyzed the data of our cohort of 13 patients. Post-implantation seizure frequencies were measured at 6 months, 12 months and last follow-up, as well as averaged throughout follow-up. These values were then compared with mean seizure frequencies in the 6 months before implantation. To address acute cognitive effects of DBS a baseline assessment was performed after implantation and before stimulation, and a follow-up assessment was conducted under DBS. The long-term effects of DBS on cognition were assessed by comparing the preoperative neuropsychological profile with a long-term follow-up under DBS., Results: In the entire cohort, 54.5% of patients were responders, with an average seizure reduction of 73.6%. One of these patients achieved temporary seizure freedom and near-total seizure reduction during the entire follow-up. Seizure reduction of <50% was achieved in 3 patients. Non-responders suffered an average seizure increase of 27.3%. Eight of twenty-two active electrodes (36,4%) were off-target. Two of our patients had both electrodes implanted off-target. When removing these two patients from the analysis and averaging seizure frequency during the entire follow-up period, four patients (44.4%) were responders and three experienced a seizure reduction of <50%. Intolerable side effects arose in 5 patients, mostly psychiatric. Regarding acute cognitive effects of DBS, only one patient showed a significant decline in executive functions. Long-term neuropsychological effects included significant intraindividual changes in verbal learning and memory. Figural memory, attention and executive functions, confrontative naming and mental rotation were mostly unchanged, and improved in few cases., Significance: In our cohort, more than half of patients were responders. Psychiatric side effects seem to have been more prevalent compared to other published cohorts. This may be partially explained by a relatively high occurrence of off-target electrodes., Competing Interests: KO has received speaker fees from Eisai, unrelated to this work. RS has received fees as speaker or for serving on the advisory board from Angelini, Arvelle, Bial, Desitin, Eisai, Janssen-Cilag GmbH, LivaNova, Novartis, Precisis GmbH, UCB Pharma, UnEEG, and Zogenix. These activities were not related to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Olaciregui Dague, Witt, von Wrede, Helmstaedter and Surges.)

Purpose: Limbic encephalitis is an increasingly recognized cause of medial temporal lobe epilepsy (mTLE) and associated cognitive deficits, potentially resulting in hippocampal sclerosis (HS). For several reasons, these patients usually do not undergo epilepsy surgery. Thus, histopathologic examinations in surgical specimens of clearly diagnosed limbic encephalitis are scarce. The purpose of this study was a detailed histopathologic analysis of surgical tissue alterations, including neurodegenerative markers, in patients with limbic encephalitis undergoing epilepsy surgery., Methods: We investigated the surgical specimens of six patients operated on with mTLE related to limbic encephalitis (among them four patients were with GAD65 and one with Ma1/2 antibodies), and compared the findings to a control group with six patients matched according to age at the time of surgery without limbic encephalitis and without early inciting events., Results: Histopathologic analysis in the group with limbic encephalitis revealed HS in four patients, while three of them also displayed signs of an active inflammatory reaction with lymphocytes. In one of the patients with GAD65-encephalitis who was suffering from a late-onset mTLE and a long disease course, neurodegenerative protein markers (β-amyloid and hyperphosphorylated tau) were found coexisting with inflammatory reactions and HS. Investigations in the control group did not reveal any inflammatory reaction or neurodegenerative marker., Conclusion: Our findings suggest a possible link between long-lasting immune reactions in the medial temporal lobe, HS, and further toward the development of neurodegenerative diseases. Presently, however, a causal relationship between these entities cannot yet be established. Furthermore, our results suggest that an immunological etiology should always be considered in late onset (> 18 years) mTLE, also in cases of long disease duration and the presence of HS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rácz, Hummel, Becker, Helmstaedter, Schuch, Baumgartner, von Wrede, Borger, Solymosi, Surges and Elger.)

Today's modalities for short-term monitoring of EEG are primarily meant for supporting clinical diagnosis of epilepsy or classifying seizures and interictal epileptiform discharges while long-term EEG adds the value of differential diagnosis investigation or pre-surgical evaluation. However, longitudinal epilepsy care relies on patient diaries, which is known to be unreliable for most patients and especially those with focal impaired awareness or nocturnal seizures. The subcutaneous ultra long-term EEG (ULT-EEG) systems alleviate those issue by enabling objective, continuous EEG monitoring for days, weeks, months, or years. Albeit a great advance in continuous EEG over extended periods, it comes with the caveat of limited spatial resolution of two channels. Therefore, the new subcutaneous EEG modality may be especially suited for a selected group of patients. We convened a panel of experienced epileptologists to consider the utility of a subcutaneous, two-channel ULT-EEG device with the goal of developing a consensus-based expert recommendation on selecting the optimal patient types for this investigative technique. The ideal patients to select for this type of monitoring would have focal impaired awareness seizures without predominant motor features and seizures with medium to high voltage patterns. As this technology matures and we learn more about its limitations and benefits we might find a wider array of use case scenarios as it is believed that the benefits for many patients are most likely to outweigh the risks and cost., Competing Interests: All authors received a consultancy fee from UNEEG medical for the panel discussion. JP and TK consults for UNEEG medical. AC has received support from, and/or has served as a paid consultant for NeuroPace, Sage Therapeutics, and BrainVital/Precisis. ND has served on advisory boards and has received consultancy fees from UNEEG medical, Arvelle Therapeutics, Eisai, Sanofi, and UCB Pharma. RS reports lecture and consultancy fees from Angelini, Arvelle, Bial, Desitin, Eisai, LivaNova, Novartis, UCB Pharma, and UNEEG medical. JD-H is a full-time employee at UNEEG medical., (Copyright © 2022 Pathmanathan, Kjaer, Cole, Delanty, Surges and Duun-Henriksen.)

Purpose: Focal cortical dysplasias (FCDs) are a frequent cause of drug-resistant focal epilepsies. These lesions are in many cases amenable to epilepsy surgery. We examined 12-month and long-term post-surgical outcomes and its predictors including positive family history of epilepsy. Methods: Twelve-month and long-term outcomes regarding seizure control after epilepsy surgery in patients operated on with FCD type II between 2002 and 2019 in the Epilepsy Center of Bonn were evaluated based on patient records and telephone interviews. Results: Overall, 102 patients fulfilled the inclusion criteria. Seventy-one percent of patients at 12 months of follow-up (FU) and 54% of patients at the last available FU (63 ± 5.00 months, median 46.5 months) achieved complete seizure freedom (Engel class IA), and 84 and 69% of patients, respectively, displayed Engel class I outcome. From the examined variables [histopathology: FCD IIA vs. IIB, lobar lesion location: frontal vs. non-frontal, family history for epilepsy, focal to bilateral tonic-clonic seizures (FTBTCS) in case history, completeness of resection, age at epilepsy onset, age at surgery, duration of epilepsy], outcomes at 12 months were determined by interactions of age at onset, duration of epilepsy, age at surgery, extent of resection, and lesion location. Long-term post-surgical outcome was primarily influenced by the extent of resection and history of FTBTCS. Positive family history for epilepsy had a marginal influence on long-term outcomes only. Conclusion: Resective epilepsy surgery in patients with FCD II yields very good outcomes both at 12-month and long-term follow-ups. Complete lesion resection and the absence of FTBTCS prior to surgery are associated with a better outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rácz, Becker, Quesada, Borger, Vatter, Surges and Elger.)

Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE). Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t -tests and linear regression analysis. Data are given as mean ± SD. Results: Fifty-six seizures of 14 patients (5 men, age 34.7 ± 9.8 years) were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure. Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pensel, Basili, Jordan and Surges.)

Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders. Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array. Results: We identified suitable samples from patients with AIE ( n = 13) with different antibodies and compared them to HS ( n = 13), GGE ( n = 7), and PNES ( n = 8). The NFL levels were significantly elevated in the serum ( p = 0.0009) and CSF ( p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere. Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis., Competing Interests: RN has received fees as speaker from Eisai. KA received personal compensation for oral presentation and consulting service from Biogen Idec, Merck, Sanofi, and Roche. CE has served as a paid consultant for Desitin, Pfizer, and UCB Pharma. He was an employee of the Life and Brain Institute Bonn. HR was acting on advisory boards, gave lectures, and received research grants from Abbott, Abbvie, Bayer Health Care, Bial, Boehringer/Ingelheim, Brittania, Cephalon, Desitin, GSK, Lundbeck, Medtronic, Merck-Serono, Novartis, Orion, Pfizer, TEVA, UCB Pharma, Valeant, and Zambon. TZ received personal compensation from Almirall Biogen, Bayer, Celgene, Novartis, Roche, Sanofi, and Teva for consulting services and received additional financial support for research activities from BAT, Biogen, Novartis, Roche, Teva, and Sanofi Aventis. RS has received fees as speaker or consultant from Bial, Cyberonics, Desitin, EISAI, LivaNova, Novartis, and UCB Pharma. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nass, Akgün, Dague, Elger, Reichmann, Ziemssen and Surges.)

In this narrative review, we summarize the current knowledge of neurally mediated blood pressure (BP) control and discuss how recently described epilepsy- and seizure-related BP alterations may contribute to premature mortality and sudden unexpected death in epilepsy (SUDEP). Although people with epilepsy display disturbed interictal autonomic function with a shift toward predominant sympathetic activity, prevalence of arterial hypertension is similar in people with and without epilepsy. BP is transiently increased in association with most types of epileptic seizures but may also decrease in some, illustrating that seizure activity can cause both a decrease and increase of BP, probably because of stimulation or inhibition of distinct central autonomic function by epileptic activity that propagates into different neuronal networks of the central autonomic nervous system. The principal regulatory neural loop for short-term BP control is termed baroreflex, mainly involving peripheral sensors and brain stem nuclei. The baroreflex sensitivity (BRS, expressed as change of interbeat interval per change in BP) is intact after focal seizures, whereas BRS is markedly impaired in the early postictal period following generalized convulsive seizures (GCS), possibly due to metabolically mediated muscular hyperemia in skeletal muscles, a massive release of catecholamines and compromised brain stem function. Whilst most SUDEP cases are probably caused by a cardiorespiratory failure during the early postictal period following GCS, a profoundly disturbed BRS may allow a life-threatening drop of systemic BP in the aftermath of GCS, as recently reported in a patient as a plausible cause of SUDEP in a few patients.

Background: Sudden unexpected death in epilepsy (SUDEP) is probably due to an autonomic failure in the early postictal phase after bilateral convulsive seizures (BCS) in the majority of cases. The baroreflex sensitivity (BRS) is an established and reliable biomarker of autonomic function and sudden cardiac death., Objective: To investigate whether postictal BRS depends on seizure type., Methods: Beat-to-beat systemic blood pressure and heart rate were continuously and non-invasively recorded with the ccNexfin ® device in patients with focal epilepsy undergoing video-EEG monitoring. BRS was calculated using the sequence as well as the spectral method. A random mixed linear model was applied to analyze the influence of seizure type on BRS during three different time periods of 15-min length each (interictal, preictal, and postictal). In addition, the possible effects of other factors (hypertension, hemispheric lateralization of ictal activity, epilepsy type, body position, vigilance state) were explored. Data are given as median with interquartile range., Results: A total of 26 seizures of 26 patients were analyzed. In BCS ( n  = 7), BRS significantly dropped from a preictal value of 15.0 ms/mm Hg (13.0-19.4) and an interictal value of 15.6 ms/mm Hg (12.0-20.4) to 3.1 ms/mm Hg (2.7-10.5) during the postictal period ( p  < 0.0001) according to the sequence method. This finding was replicated with the spectral method. In contrast, focal seizures ( n  = 19) did not lead to significant alterations of BRS in the postictal phase., Conclusion: Postictal BRS depends on the seizure type and is markedly impaired after BCS. The present study provides further evidence for a disturbed autonomic function following BCS. These findings might be related to cardiovascular failure in the context of SUDEP.

Background: Most antiepileptic drugs (AEDs) inhibit seizure generation by acting on voltage-dependent ion channels. Voltage-dependent sodium and calcium channels are commonly expressed in brain and heart, suggesting that AEDs may have considerable cardiodepressive effects, thereby facilitating sudden cardiac death as a potential cause of sudden unexpected death in epilepsy. Here, we investigated the effects of carbamazepine (CBZ), lamotrigine (LTG), and levetiracetam (LEV) alone and in combination on the shortening properties of isolated ventricular cardiomyocytes of wild-type mice., Methods: Properties of murine cardiomyocytes were determined by recording the sarcomere shortening with a video imaging system before, during, and after administration of AEDs in different concentrations and combinations. We assessed (i) the number of successful shortenings during continuous electrical stimulation (electromechanical coupling) and (ii) the shortening amplitude as well as other shortening-related properties upon repetitive electrical stimulation at 4 Hz. Data are given as mean ± SEM., Results: At 100 μM, CBZ (10 cells), LTG (11 cells), and LEV (11 cells) alone had no effect on the electromechanical coupling but reversibly reduced shortening amplitudes by 15 ± 4, 24 ± 3, and 11 ± 3%, respectively. Increasing the LTG concentration to 250 (21 cells) and 500 μM (4 cells) reversibly inhibited the electromechanical coupling in 62 and 100% of the experiments. Importantly, simultaneous application of CBZ, LTG, and LEV at 100 μM also impaired the electromechanical coupling in 8 of 19 cardiomyocytes (42%) and reduced the shortening amplitude by 21 ± 4%., Conclusion: Our data show that AEDs reversibly impair cardiac excitation and contraction. Importantly, the blocking effect on electromechanical coupling appears to be additive when different AEDs are simultaneously applied. The translational value of these experimental findings into clinical practice is limited. Our results, however, suggest that rationale AED therapy may be important with respect to cardiac side effects and potential facilitation of serious cardiac dysfunction especially when AEDs are used in combination or at very high doses.

Background: Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks., Methods: Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11-21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5-8 h., Results: Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures., Conclusion: In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.

Background: Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab., Case Presentation: We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR(+) CD8(+) T-lymphocytes (fCD8(+)TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8(+)TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8(+)TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described., Conclusion: The correlation of the fCD8(+)TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8(+)TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.