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.

Postictal psychiatric symptoms: A neurophysiological study.

OBJECTIVE: Postictal psychiatric symptoms (PPS) are a relatively common but understudied phenomenon in epilepsy. The mechanisms by which seizures contribute to worsening in psychiatric symptoms are unclear. We aimed to identify PPS prospectively during and after admission to the epilepsy monitoring unit (EMU) in order to characterize the postictal physiologic changes leading to PPS. METHODS: We prospectively enrolled patients admitted to the EMU and administered repeat psychometric questionnaires during and after their hospital stay in order to assess for postictal exacerbations in four symptom complexes: anger/hostility, anxiety, depression, and paranoia. Electroclinical and electrographic seizures were identified from the EEG recordings, and seizure durations were measured. The severity of postictal slowing was calculated as the proportion of postictal theta/delta activity in the postictal EEG relative to the preictal EEG using the Hilbert transform. RESULTS: Among 33 participants, 8 demonstrated significant increases in at least one of the four symptoms (the PPS+ group) within three days following the first seizure. The most common PPS was anger/hostility, experienced by 7/8 participants with PPS. Among the 8 PPS+ participants, four experienced more than one PPS. As compared to those without PPS (the PPS- group), the PPS+ group demonstrated a greater degree of postictal EEG slowing at 10 min (p = 0.022) and 20 min (p = 0.05) following seizure termination. They also experienced significantly more seizures during the study period (p = 0.005). There was no difference in seizure duration between groups. SIGNIFICANCE: Postictal psychiatric symptoms including anger/hostility, anxiety, depression, and paranoia may be more common than recognized. In particular, postictal increases in anger and irritability may be particularly common. We provide physiological evidence of a biological mechanism as well as a demonstration of the use of quantitative electroencephalography toward a better understanding of postictal neurophysiology.

Modular pipeline for reconstruction and localization of implanted intracranial ECoG and sEEG electrodes.

Implantation of electrodes in the brain has been used as a clinical tool for decades to stimulate and record brain activity. As this method increasingly becomes the standard of care for several disorders and diseases, there is a growing need to quickly and accurately localize the electrodes once they are placed within the brain. We share here a protocol pipeline for localizing electrodes implanted in the brain, which we have applied to more than 260 patients, that is accessible to multiple skill levels and modular in execution. This pipeline uses multiple software packages to prioritize flexibility by permitting multiple different parallel outputs while minimizing the number of steps for each output. These outputs include co-registered imaging, electrode coordinates, 2D and 3D visualizations of the implants, automatic surface and volumetric localizations of the brain regions per electrode, and anonymization and data sharing tools. We demonstrate here some of the pipeline's visualizations and automatic localization algorithms which we have applied to determine appropriate stimulation targets, to conduct seizure dynamics analysis, and to localize neural activity from cognitive tasks in previous studies. Further, the output facilitates the extraction of information such as the probability of grey matter intersection or the nearest anatomic structure per electrode contact across all data sets that go through the pipeline. We expect that this pipeline will be a useful framework for researchers and clinicians alike to localize implanted electrodes in the human brain.

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.