Individuals with intractable epilepsy have a ~1% annual risk of Sudden Unexpected Death in Epilepsy (SUDEP). Pre-mortem risk factors are unknown; however, evidence suggests autonomic nervous system (ANS) failure, sustained apnea/hypoxemia, or some combination of respiratory and cardiovascular (CV) collapse underlies the fatal event. Adverse ANS signs are prominent in epilepsy, with ANS-driven cardiac arrhythmias (bradycardia, asystole, tachyarrhythmias) in ~72% of epilepsy patients, hypotension, impaired baroreflex sensitivity (potentially compromising cerebral blood flow), enhanced sympathetic outflow, expressed as increased sweating and decreased inter-ictal nocturnal heart rate variability (HRV) common. EEG characteristics, including post-ictal generalized EEG suppression (PGES) is suggestive of high SUDEP-risk, strongly correlate with increased sweating and decreased HRV, and is typically accompanied by profound hypotension. Neural mechanisms underlying these patterns need to be defined. Our findings of damage to pulvinar thalamic CO2 and O2 integration areas, and to left insular parasympathetic regulatory structures in SUDEP victims suggest that an impaired ability to integrate respiratory sensory signals, combined with exaggerated parasympathetic action, inducing hypotension, thus resulting in cerebral hypoperfusion leading to the EEG signs of PGES, contribute to a fatal scenario. Deficits in other respiratory and ANS regulatory areas may participate, but those sites must be determined. We propose to relate focal brain structural changes in persons with epilepsy to particular peri-ictal autonomic and breathing patterns recognized as indices of risk for death. We found, in other syndromes exhibiting sudden death, e.g., heart failure, significant lateralized neural injury in brainstem and forebrain ANS and respiratory areas. Such unilateral injury can induce asymmetric ANS, and especially, sympathetic drive, establishing a scenario for potentially fatal arrhythmia or hypotension. We will determine peri-ictal physiological pattern of EEG, and especially PGES, blood pressure, HRV, baroreflex sensitivity, cardiac arrhythmia, and breathing that lead to risk of SUDEP, collect high resolution T1-weighted, diffusion tensor, and kurtosis images, and relate extent and laterality of injury to the physiological patterns. The studies will provide insights into mechanisms of failure in SUDEP, and suggest pre-mortem indications of characteristics that lead to a fatal scenario that are suitable for targeted intervention.

Public Health Relevance

Sudden Unexpected Death in Epilepsy (SUDEP) affects ~5000 individuals with epilepsy in the USA annually. Death results from profound breathing and/or cardiovascular dysfunction, but mechanisms underlying failure, and risk factors identifying those most at risk are unknown. Our goal is to identify patterns of physiological dysfunction surrounding seizure periods and the underlying neural injury contributing to those patterns.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Leenders, Miriam
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Song, Xiaopeng; Roy, Bhaswati; Kang, Daniel W et al. (2018) Altered resting-state hippocampal and caudate functional networks in patients with obstructive sleep apnea. Brain Behav 8:e00994
Thom, M; Boldrini, M; Bundock, E et al. (2018) Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking. Neuropathol Appl Neurobiol 44:32-55
Trevisi, Gianluca; Eickhoff, Simon B; Chowdhury, Fahmida et al. (2018) Probabilistic electrical stimulation mapping of human medial frontal cortex. Cortex 109:336-346
Atkin, Talia A; Maher, Chani M; Gerlach, Aaron C et al. (2018) A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia 59:802-813
Murugesan, Arun; Rani, M R Sandhya; Hampson, Johnson et al. (2018) Serum serotonin levels in patients with epileptic seizures. Epilepsia 59:e91-e97
Lacuey, Nuria; Zonjy, Bilal; Hampson, Johnson P et al. (2018) The incidence and significance of periictal apnea in epileptic seizures. Epilepsia 59:573-582
Theeranaew, Wanchat; McDonald, James; Zonjy, Bilal et al. (2018) Automated Detection of Postictal Generalized EEG Suppression. IEEE Trans Biomed Eng 65:371-377
Ogren, Jennifer A; Tripathi, Raghav; Macey, Paul M et al. (2018) Regional cortical thickness changes accompanying generalized tonic-clonic seizures. Neuroimage Clin 20:205-215
Asadi-Pooya, Ali A; Shabo, Leah; Wyeth, Dale et al. (2017) Ictal coughing: Clinical features and differential diagnoses. Epilepsy Behav 73:51-53
Shi, Jianguo; Lacuey, Nuria; Lhatoo, Samden (2017) Surgical outcome of MRI-negative refractory extratemporal lobe epilepsy. Epilepsy Res 133:103-108

Showing the most recent 10 out of 25 publications