A quantitative tool for seizure severity: diagnostic and therapeutic applications

Objective More than one-third of the people with focal epilepsy do not achieve seizure freedom with medication, neuromodulation, or neurosurgery therapies. Palliative care with the goal of reducing epilepsy burden is an alternative for these patients. Minimizing severe seizures is essential for reducing morbidity. Existing seizure severity scales are qualitative and rely on patient reports, limiting our ability to rigorously track and intervene to curb severe seizures. The goal of this study is to develop and validate a quantitative metric for seizure severity. Methods We retrospectively analyzed preictal and ictal intracranial-EEG (iEEG) recordings from 54 people with drug-resistant epilepsy undergoing pre-surgical evaluation. We developed a new metric that objectively combines seizure duration, spread, and semiology to quantify seizure severity. We calculated preictal iEEG network features and fit a linear mixed-effects model to quantify patient-specific associations between preictal networks and seizure severity. Results We evaluated 256 seizures from 54 patients using the quantitative seizure severity score. Seizure severity was consistent with clinical seizure type. Medication taper strategy was associated with seizure severity (p = 0.018, 97.5% confidence interval = [-1.242, -0.116]) and lower pre-surgical seizure severity was associated with better post-surgical seizure outcome (U = 465, p = 0.042). A linear mixed-effects model with preictal network features as regressors and seizure severity as response revealed a group-level positive trend. In 12 out of 14 patients with multiple types of seizures, more severe seizures were preceded by more abnormal preictal networks. Significance We present a quantitative metric for seizure severity that correlates with clinical and electrographic features. We found that the seizure severity score was associated with abnormal preictal networks. We propose this measure to holistically capture patient condition and guide incremental changes in therapy to improve patient outcome over time. ### Competing Interest Statement E.C. performs consulting work for Epiminder, an EEG device company. The remaining authors have no conflicts of interest. ### Funding Statement A.P. acknowledges funding from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) grants DP1NS122038 and R01NS125137. N.G. acknowledges funding from the NSF graduate research fellowship. A.R acknowledges funding from the NIH grant T32NS09100607. E.C. acknowledges funding from the NINDS grants R25NS065745, K23NS12140101A1, and the Burroughs Wellcome Fund. K.A.D acknowledges funding from the NINDS grants R01NS116504, R01NS125137, The Pennsylvania Tobacco Fund, and the Thornton Foundation. N.S. acknowledges funding from the American Epilepsy Society grant 953257 and NINDS grants R01NS116504 and R01NS125137. B.L. acknowledges funding from the NINDS grants DP1NS122038, R01NS125137, The Pennsylvania Tobacco Fund, Johnathan Rothberg, Neil and Barbara Smit, and the Mirowski Family Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of the Hospital of the University of Pennsylvania gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes We have made all our code available at https://github.com/penn-cnt/Pattnaik-seizure-severity. All iEEG recordings are accessible from iEEG.org.