Patient-Centered Management of Brain Tumor-Related Epilepsy.

PURPOSE OF REVIEW: Brain tumor-related epilepsy is a heterogenous syndrome involving variability in incidence, timing, pathophysiology, and clinical risk factors for seizures across different brain tumor pathologies. Seizure risk and disability are dynamic over the course of disease and influenced by tumor-directed treatments, necessitating individualized patient-centered management strategies to optimize quality of life. RECENT FINDINGS: Recent translational findings in diffuse gliomas indicate a dynamic bidirectional relationship between glioma growth and hyperexcitability. Certain non-invasive measures of hyperexcitability are correlated with survival outcomes, however it remains uncertain how to define and measure clinically relevant hyperexcitability serially over time. The extent of resection, timing of pre-operative and/or post-operative seizures, and the likelihood of tumor progression are critical factors impacting the risk of seizure recurrence. Newer anti-seizure medications are generally well-tolerated with similar efficacy in this population, and several rapid-onset seizure rescue agents are in development and available. Seizures in patients with brain tumors are strongly influenced by the underlying tumor biology and treatment. An improved understanding of the interactions between tumor cells and the spectrum of hyperexcitability will facilitate targeted therapies. Multidisciplinary management of seizures should occur with consideration of tumor-directed therapy and prognosis, and anti-seizure medication decision-making tailored to the individual priorities and quality of life of the patient.

Characterization of anti-seizure medication reduction and discontinuation rates following epilepsy surgery.

OBJECTIVE: Many patients pursue epilepsy surgery with the hope of reducing or stopping anti-seizure medications (ASMs), in addition to reducing their seizure frequency and severity. While ASM decrease is primarily driven by surgical outcomes and patient preferences, preoperative estimates of meaningful ASM reduction or discontinuation are uncertain, especially when accounting for the various forking paths possible following intracranial EEG (iEEG), including resection, neuromodulation, or even the absence of further surgery. Here, we characterize in detail the ASM reduction in a large cohort of patients who underwent iEEG, facilitating proactive, early counseling for a complicated cohort considering surgical treatment. METHODS: We identified a multi-institutional cohort of patients who underwent iEEG between 2001 and 2022, with a minimum of two years follow-up. The total number of ASMs prescribed immediately prior to surgery, choice of investigation modality, and subsequent surgical treatment were extracted for each patient. Primary endpoints included decreases in ASM counts from preoperative baseline to various follow-up intervals. RESULTS: A total of 284 patients were followed for a median of 6.0 (range 2,22) years after iEEG surgery. Patients undergoing resection saw an average reduction of âˆ¼ 0.5 ASMs. Patients undergoing neuromodulation saw no decrease and trended towards requiring increased ASM usage during long-term follow-up. Only patients undergoing resection were likely to completely discontinue all ASMs, with an increasing probability over time approaching âˆ¼ 10 %. Up to half of resection patients saw ASM decreases, which was largely stable during long-term follow-up, whereas only a quarter of neuromodulation patients saw a reduction, though their ASM reduction decreased over time. CONCLUSIONS: With the increasing use of stereotactic EEG and non-curative neuromodulation procedures, realistic estimates of ASM reduction and discontinuation should be considered preoperatively. Almost half of patients undergoing resective surgery can expect to reduce their ASMs, though only a tenth can expect to discontinue ASMs completely. If reduction is not seen early, it likely does not occur later during long-term follow-up. Less than a third of patients undergoing neuromodulation can expect ASM reduction, and instead most may require increased usage during long-term follow-up.

Seizure onset patterns predict outcome after stereo-electroencephalography-guided laser amygdalohippocampotomy.

OBJECTIVE: Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom. METHODS: This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category. RESULTS: Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015). SIGNIFICANCE: Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Evaluation of epilepsy surgery scope and training in Latin America.

INTRODUCTION: To describe the variety of surgical epilepsy procedures offered in Latin America and characterize the training in surgical management for epilepsy and neurophysiology fellows. MATERIALS & METHODS: A 15-question survey was sent to Spanish-speaking epilepsy specialists in Latin America (members of the International Consortium in Epilepsy Surgery Education) to characterize their epilepsy surgery practices and formal training programs when present, including fellowship program characteristics, trainee involvement, and assessment of trainee performance. Epilepsy surgery procedures included resective/ablative interventions and neuromodulation therapies approved for drug-resistant epilepsy. Associations between categorical variables were evaluated using the Fisher Exact test. RESULTS: There were 42 responses from a total of 57 survey recipients (73% response rate). Most surgical programs performed either 1 to 10 procedures (36%) or 11 to 30 procedures (31%) per year. Most centers (88%) performed resective procedures, while none of the surveyed institutions performed laser ablations. Most of the centers performing intracranial EEG (88%) and advanced neuromodulation (93%) were in South America. Centers with formal fellowship training programs were more likely to perform intracranial EEG procedures compared to centers without fellows (92% vs 48%, respectively, OR = 12.2 [95% CI 1.45-583], p = 0.007). DISCUSSION: There is significant variability in surgical procedures performed across epilepsy centers in a Latin American educational consortium. Advanced surgical diagnostic procedures and interventions are performed in a fair number of surveyed institutions. Strategies to enhance access to epilepsy surgery procedures and facilitate formal training in surgical management are necessary.

Electroencephalographic Abnormalities are Common in COVID-19 and are Associated with Outcomes.

OBJECTIVE: The aim was to determine the prevalence and risk factors for electrographic seizures and other electroencephalographic (EEG) patterns in patients with Coronavirus disease 2019 (COVID-19) undergoing clinically indicated continuous electroencephalogram (cEEG) monitoring and to assess whether EEG findings are associated with outcomes. METHODS: We identified 197 patients with COVID-19 referred for cEEG at 9 participating centers. Medical records and EEG reports were reviewed retrospectively to determine the incidence of and clinical risk factors for seizures and other epileptiform patterns. Multivariate Cox proportional hazards analysis assessed the relationship between EEG patterns and clinical outcomes. RESULTS: Electrographic seizures were detected in 19 (9.6%) patients, including nonconvulsive status epilepticus (NCSE) in 11 (5.6%). Epileptiform abnormalities (either ictal or interictal) were present in 96 (48.7%). Preceding clinical seizures during hospitalization were associated with both electrographic seizures (36.4% in those with vs 8.1% in those without prior clinical seizures, odds ratio [OR] 6.51, p = 0.01) and NCSE (27.3% vs 4.3%, OR 8.34, p = 0.01). A pre-existing intracranial lesion on neuroimaging was associated with NCSE (14.3% vs 3.7%; OR 4.33, p = 0.02). In multivariate analysis of outcomes, electrographic seizures were an independent predictor of in-hospital mortality (hazard ratio [HR] 4.07 [1.44-11.51], p < 0.01). In competing risks analysis, hospital length of stay increased in the presence of NCSE (30 day proportion discharged with vs without NCSE: HR 0.21 [0.03-0.33] vs 0.43 [0.36-0.49]). INTERPRETATION: This multicenter retrospective cohort study demonstrates that seizures and other epileptiform abnormalities are common in patients with COVID-19 undergoing clinically indicated cEEG and are associated with adverse clinical outcomes. ANN NEUROL 2021;89:872-883.

Early EEG hyperexcitability is associated with decreased survival in newly diagnosed IDH-wildtype glioma.

PURPOSE: The relationship between peritumoral neuronal activity, early onset clinical seizures, and glioma survival outcomes remains poorly understood. Hyperexcitability on continuous EEG in the peri-operative period was studied as a prognostic biomarker in patients with newly diagnosed IDH-wildtype diffuse glioma. METHODS: A retrospective observational cohort study was performed including adults with newly diagnosed diffuse glioma, absence of IDH1/2 mutations, and continuous EEG monitoring prior to chemoradiation and within 1 month of initial resection. EEG hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. The primary outcome of overall survival was estimated using the Kaplan-Meier method and compared between groups using multivariate Cox proportional hazards model. RESULTS: There were 424 patients without continuous EEG and 32 with continuous EEG, of whom lateralized periodic discharges and/or electrographic seizures were seen in 17 (53%). Peri-operative EEG hyperexcitability was associated with decreased overall survival in multivariate analysis (median 12.5 [95% CI 6.2-25.6] months with hyperexcitability versus median 19.9 [95% CI 8.9-53.5] months without hyperexcitability, p = 0.043). Compared to patients without continuous EEG, overall survival was decreased in patients with hyperexcitability (p < 0.0001) and similar in patients without hyperexcitability (p = 0.193). Patients with and without hyperexcitability had similar rates of exposure to anti-seizure medication at baseline, and in long-term follow-up had no difference in number of medications required for seizure control. CONCLUSIONS: These findings indicate the potential prognostic value of a clinical EEG biomarker of glioma aggressiveness prior to the initiation of chemoradiation.

Multiscale recordings reveal the dynamic spatial structure of human seizures.

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.

Clinical features and postoperative seizure outcome in patients with drug-resistant gelastic seizures without hypothalamic hamartoma.

OBJECTIVES: The objective of this study was to describe the clinical characteristics and surgical outcome in patients with gelastic seizures without hypothalamic hamartoma. METHODS: We retrospectively reviewed all the video-EEG reports over a 5-year period (2007-2011) for the occurrence of the terms "laugh" or "giggle" in the text body. All the patients with at least one documented gelastic seizure at the epilepsy monitoring unit were studied. In patients who underwent epilepsy surgery, seizure outcomes were analyzed. RESULTS: Sixteen patients (10 females and 6 males) with a mean age of 46.3years were studied. Seven patients had invasive intracranial EEG recordings. Seizure onset zone was in a temporal lobe in four patients and the frontal lobe in one patient. Two patients did not have gelastic seizures during their intracranial EEG monitoring. Nine patients underwent resective epilepsy surgery for their seizures. Six patients (67%) were seizure-free after surgery. CONCLUSION: In adult patients, gelastic seizures can be seen in patients with focal epilepsy without hypothalamic hamartoma. Nonhypothalamic hamartoma gelastic seizures originating from the temporal lobe can be amenable to surgery.

Initiation of Antiseizure Medications by US Board-Certified Neurologists After a First Unprovoked Seizure Based on EEG Findings.

Background and Objectives: To investigate neurologists' practice variability in antiseizure medication (ASM) initiation after a first unprovoked seizure based on reported EEG interpretations. Methods: We developed a 15-question multiple-choice survey incorporating a standardized clinical case scenario of a patient with a first unprovoked seizure for whom different EEG reports were provided. The survey was distributed among board-certified neurologists practicing in the United States. Associations between categorical variables were evaluated using the Fisher Exact test. Multivariate analysis was performed using logistic regression. Results: A total of 106 neurologists responded to the survey. Most responders (75%-95%) would start ASM for definite epileptiform features on EEG, with similar rates between subgroups differing in years of practice, presence of subspecialty EEG training, and self-reported confidence in EEG interpretation. There was greater variability in practice for nonspecific EEG abnormalities, with sharply contoured activity, sharp transients, and focal delta slowing associated with the highest variability and uncertainty. Neurologists with >5 years of practice experience (21% vs 44%, OR 0.35 [95% CI 0.13-0.89], p = 0.021), subspecialty EEG training (15% vs 50%, OR = 0.17 [95% CI 0.06-0.48], p < 0.001), and greater confidence in EEG interpretation (21% vs 52%, OR 0.24 [95% CI 0.09-0.62], p = 0.001) were less likely to start ASM for ≥2 nonspecific EEG abnormalities and reported greater uncertainty. In multivariate analysis, seniority (p = 0.039) and subspecialty EEG training (p = 0.032) were associated with decreased ASM initiation for nonspecific EEG features. Discussion: There was substantial variability in ASM initiation practices between board-certified neurologists after a first unprovoked seizure with nonspecific EEG abnormalities. These findings clarify specific areas where EEG reporting may be optimized and reinforces the importance of implementing evidence-based practice guidelines.

Predictors of SOZ localization, subsequent surgical intervention, and seizure outcomes in iEEG.

OBJECTIVE: A third of the patients who undergo intracranial EEG (iEEG) for seizure-onset zone (SOZ) localization do not proceed to resective surgery for epilepsy, and over half of those who do continue to have seizures following treatment. To better identify candidates who are more likely to see benefits from undergoing iEEG, we investigated preoperative and iEEG peri-operative features associated with the localization of a putative SOZ, undergoing subsequent surgical treatment, and seizure outcomes. METHODS: We conducted a retrospective cohort study of consecutive patients who underwent iEEG from 2001 to 2022 at two institutions. Outcomes included SOZ identification, proceeding to surgical treatment (resection vs. neuromodulation), and subsequent seizure freedom. RESULTS: We identified 329 unique patients who were followed for a median of 3.9 (IQR:7) years, with a minimum of 2-year follow-up for seizure outcomes analyses. Multivariate analysis identified lateralized and lobar localization on scalp EEG (OR 3.8, p = 0.001) to be associated with SOZ localization. Patients with unilateral localization on scalp EEG (OR 3.0, p = 0.003), unilateral preimplantation hypothesis (OR 3.1, p = 0.001), and lesional preoperative MRI (OR 2.1, p = 0.033) were more likely to undergo resection than neuromodulation. Similarly, a unilateral pre-implantation hypothesis (OR 2.6, p < 0.001) favored seizure freedom, whereas prior neuromodulation (OR 0.3, p = 0.013) decreased the odds. Larger number of preoperative anti-seizure medications (ASMs) did not influence seizure freedom rates but did decrease favorable (Engel I, II) seizure outcomes (OR 0.7, p = 0.026). INTERPRETATION: Non-invasive localization data prior to iEEG are associated with subsequent resection and seizure freedom, independent of iEEG localization. Factors predictive of SOZ localization are not necessarily predictive of post-operative seizure freedom.

Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

BACKGROUND: Distinct genetic alterations determine glioma aggressiveness, however, the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of the disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability. METHODS: A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n = 1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n = 206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability. RESULTS: The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in a multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and preoperative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG. CONCLUSION: These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma.

Background: Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes. Methods: An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry. Results: HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Conclusions: A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.

Epilepsy-Related Mortality After Laser Interstitial Thermal Therapy in Patients With Drug-Resistant Epilepsy.

OBJECTIVES: The purpose of this report was to study the incidence of sudden unexpected death in epilepsy (SUDEP) after laser interstitial thermal therapy (LITT) for drug-resistant epilepsy (DRE). METHODS: A prospective observational study of consecutive patients treated with LITT between 2013 and 2021 was conducted. The primary outcome was the occurrence of SUDEP during postoperative follow-up. Surgical outcome was classified according to the Engel scale. RESULTS: There were 5 deaths, including 4 SUDEPs, among 135 patients with a median follow-up duration of 3.5 (range 0.1-9.0) years and a total of 501.3 person-years at risk. The estimated incidence of SUDEP was 8.0 (95% CI 2.2-20.4) per 1,000 person-years. Three SUDEPs occurred in patients with poor seizure outcomes, whereas 1 patient was seizure-free. Compared with pooled historical data, SUDEP occurred at a higher rate than in cohorts treated with resective surgery and at a rate similar to nonsurgical controls. DISCUSSION: SUDEP occurred early and late after mesial temporal LITT. The SUDEP rate was comparable with rates reported in epilepsy surgery candidates who did not receive intervention. These findings reinforce targeting seizure freedom to decrease SUDEP risk, including early consideration for further intervention. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that LITT is not effective in reducing SUDEP incidence in patients with DRE.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures is uncertain. In a large cohort of patients with sequenced gliomas (n=1716), we used discriminant analysis models to identify somatic mutation variants associated with electrographic hyperexcitability in a subset with continuous EEG recording (n=206). Overall tumor mutational burdens were similar between patients with and without hyperexcitability. A cross-validated model trained exclusively on somatic mutations classified the presence or absence of hyperexcitability with an overall accuracy of 70.9%, and improved estimates of hyperexcitability and anti-seizure medication failure in multivariate analysis incorporating traditional demographic factors and tumor molecular classifications. Somatic mutation variants of interest were also over-represented in patients with hyperexcitability compared to internal and external reference cohorts. These findings implicate diverse mutations in cancer genes associated with the development of hyperexcitability and response to treatment.

Association between postictal EEG suppression, postictal autonomic dysfunction, and sudden unexpected death in epilepsy: Evidence from intracranial EEG.

OBJECTIVE: The association between postictal electroencephalogram (EEG) suppression (PES), autonomic dysfunction, and Sudden Unexpected Death in Epilepsy (SUDEP) remains poorly understood. We compared PES on simultaneous intracranial and scalp-EEG and evaluated the association of PES with postictal heart rate variability (HRV) and SUDEP outcome. METHODS: Convulsive seizures were analyzed in patients with drug-resistant epilepsy at 5 centers. Intracranial PES was quantified using the Hilbert transform. HRV was quantified using root mean square of successive differences of interbeat intervals, low-frequency to high-frequency power ratio, and RR-intervals. RESULTS: There were 64 seizures from 63 patients without SUDEP and 11 seizures from 6 SUDEP patients. PES occurred in 99% and 87% of seizures on intracranial-EEG and scalp-EEG, respectively. Mean PES duration in intracranial and scalp-EEG was similar. Intracranial PES was regional (<90% of channels) in 46% of seizures; scalp PES was generalized in all seizures. Generalized PES showed greater decrease in postictal parasympathetic activity than regional PES. PES duration and extent were similar between patients with and without SUDEP. CONCLUSIONS: Regional intracranial PES can be present despite scalp-EEG demonstrating generalized or no PES. Postictal autonomic dysfunction correlates with the extent of PES. SIGNIFICANCE: Intracranial-EEG demonstrates changes in autonomic regulatory networks not seen on scalp-EEG.

Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity.

PURPOSE: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. METHODS: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. RESULTS: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03). CONCLUSIONS: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Effect of PIK3CA variants on glioma-related epilepsy and response to treatment.

Upregulation of the PI3K/AKT/mTOR pathway has been implicated in glioma-related epileptogenesis. In this retrospective analysis, epilepsy characteristics and response to treatment were evaluated in patients with gliomas harboring somatic mutation variants in PIK3CA. A cohort of 134 patients with 150 PIK3CA variants was extracted from previously validated databases. Patients with the hotspot H1047R, R88Q, E542K, and G118D variants comprised a subset (n = 41) for epilepsy phenotyping. In multivariate analysis, the presence of H1047R (n = 15) was associated with worse seizure control (p = 0.026). These results support preclinical findings and suggest that glioma PIK3CA variation may have promise as a biomarker for epilepsy severity and response to treatment.