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Prevention & Risk Identification of SUDEP Mortality- The Prevention & Risk Identification of SUDEP Mortality (PRISM) Project
Samden Lhatoo, M.D. at Case Western Reserve University is the Principal Investigator, and will carry out the project in collaboration with Drs. Hans Luders, Anne Berg, Jerome Engel, Doug Nordli, and Stephan Schuele.

Abstract:  Up to 1% of patients with refractory epilepsy die suddenly every year in an unexplained phenomenon called Sudden Unexpected Death in Epilepsy (SUDEP). In 2008 a joint American Epilepsy Society and Epilepsy Foundation convened Task Force recommended hypothesis-driven, prospective, multicenter research into SUDEP with multi-modal seizure parameters including cardiovascular, respiratory, autonomic and biochemical factors. This approach is vital as SUDEP is most likely a seizure related event. In SUDEP, we hypothesize NIH research grantsexaggerated supra-pontine seizure influences produce severe autonomic dysfunction manifested as profound hypotension, fatal arrhythmia or apnea. Genetic predisposition and brainstem serotonergic dysregulation may contribute. However, critical barriers to research exist including 1) an annual SUDEP incidence of 0.5-1% making large multi-center studies necessary and 2) the collection and analysis of very large datasets of multi-modal seizure data (video, electroencephalography (EEG), electrocardiography (EKG), blood pressure, O2 & CO2 measurements, sleep data); traditional visual and statistical analyses of these multiple parameters that vary from second to second are very difficult. To overcome these barriers, a sophisticated bio-informatics system is required to acquire, standardize and analyze such data from a wide range of seizure monitoring systems in different centers. The proposed Prevention and Risk Identification of SUDEP Mortality (PRISM) Project will 1) leverage existing expertise and infrastructure at our Center to create a novel, integrated multi-modal data acquisition and management system called MEDCIS (Multi-modality Epilepsy Data Capture and Integration System). Through MEDCIS, we will aim to collect a large scale, multicenter, prospective cohort of epilepsy patients undergoing seizure monitoring. MEDCIS will prospectively create a surveillance register of SUDEP. We will 2) aim to establish capability for comprehensive comparative studies of SUDEP and near-SUDEP cases vs. cohort survivors to ascertain differences in clinical epilepsy and multi-modal physiological seizure data including EEG, EKG, autonomic, cardiovascular, respiration, sleep, endocrine and evoked potential features in order to characterize and quantify seizure induced brainstem dysfunction. 3) A SUDEP brain bank and genetics database will also be established within MEDCIS adding to an existing, substantial collection of material to investigate genetic influences and serotonergic brain dysfunction.



Predictive Genes, Mechanisms and Clinical Biomarkers of SUDEP
Jeff Noebels, M.D., Ph.D. at Baylor College of Medicine is the Principal Investigator of this group, and will collaborate with Drs. Alicia Goldman, Doug Nordli, Lisa Batemen, Jack Parent, Lori Isom, and George Richerson.   

Abstract:  Unexplained collapse of cardiac and respiratory rhythmicity is a final common mechanism for SUDEP, a major and preventable cause of death in persons with epilepsy. Recent evidence shows that dysfunctional ion channels and receptors co-expressed in brain, autonomic, heart, and respiratory pathways, along with clinical measures of functional disturbances in these pathways at times surrounding seizures represent detectable and potentially treatable risk factors for SUDEP. This proposal describes an integrated multicenter and multidisciplinary collaborative NIH Grantsproject that will combine a basic science, human neurogenetics, and clinical physiology approaches to these biological risk factors in a bench to bedside translational research program to identify, validate, and clinically evaluate predictive biomarkers and preventative treatments for SUDEP. The SUDEP Center Research Pipeline will consist of a serially interrelated work flow among 6 investigators in the center. Project 1 (Baylor) will expand the repository of DNA samples from patient at 3 centers (EMU, Dravet Syndrome Clinic, SUDEP DNA Repository) and other national networks which will be analyzed using chip microarrays for >247 prioritized ion channel and receptor genes mediating cardiac arrhythmias, respiratory depression and epilepsy. Projects 2-4 (Baylor U. Michigan, U. Iowa) analyze the biology, physiology, and pharmacology of these and related gene mutations at the cellular and in vivo level in SUDEP mouse models and induced pluripotent stem cells from Dravet Syndrome cases in order to understand and validate the SUDEP phenotypes. Project 5 (U.C. Davis/Childrens Memorial Chicago) will refine clinical respiratory and cardiac biomarkers obtained during epilepsy monitoring of individuals with Dravet Syndrome and others at high risk of sudden death (ictal hypoxemia, cardiac arrhythmia). Once validated, genes from these cases are added to an incremental diagnostic chip in development at Baylor for routine patient risk assessment in clinics in individuals with other clinical biomarkers.

 

Epi4K: Gene Discovery in 4,000 Epilepsy Genomes
The first Epilepsy Center Without Walls was awarded to David Goldstein, PhD., Principal Investigator, who will collaborate with Drs. Sam Berkovic , Dan Lowenstein, Evan Eichler, Erin Heinzen-Cox, Heather Mefford, and Kevin Shianna.

Abstract:  The primary goal of the Epi4K Center Without Walls (CWW) is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of individuals and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of individuals with epilepsy and their families, who are well-phenotyped, collected by investigators from several major research groups. The CWW will be composed of three core facilities (Administrative, Phenotyping Clinical Informatics, and Sequencing, Biostatistics & Bioinformatics) and three projects that will utilize these cores (Epileptic Encephalopathies Project, Multiplex Families & Pairs Project, and Copy Number Variant Project).

 

 

CURE For questions, please contact the CURE office, 312.255.1801, or email info@cureepilepsy.org.

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