Recurrent seizures occur in approximately 50 percent of people who undergo surgery for temporal lobe epilepsy and in 60 to 70 percent of those who have surgery for extra-temporal lobe epilepsy.
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Despite this frequency of postoperative seizure recurrence, understanding of specific molecular mechanisms underlying it is scant. To broaden that understanding, Cleveland Clinic epileptologist Lara Jehi, MD, is partnering with Cleveland Clinic’s Center for Genomics on a pilot study exploring the utility of a biospecimen bank for identifying changes in gene expression in resected brain tissue and the ultimate impact of such changes on outcomes.
A research registry has been created to collect clinical information and tissue from patients with diagnosed or suspected epilepsy. “The aim is to characterize the genetic, molecular, proteomic and/or cellular factors that may be related to the genomic mechanism of epilepsy and/or surgical treatment outcomes,” explains Dr. Jehi, Director of Research in Cleveland Clinic’s Epilepsy Center and principal investigator of the pilot study.
The registry will facilitate study of specific genes and protein targets on an ongoing basis to elucidate the role of genetic mechanisms and the downstream effects of genomic changes in medication-resistant epilepsy, as well as how these factors impact treatment outcomes in individuals with the condition. Tissue is collected from slices of brain matter resected from therapeutic epilepsy surgeries at Cleveland Clinic’s Epilepsy Center. Blood and saliva are also collected from consenting patients enrolled in the registry.
Gene expression is then compared between two surgical patient groups: those who are seizure-free after surgery and those who have recurrence of seizure symptoms following resection.
The study will also assess timing of seizure recurrence. Dr. Jehi hypothesizes that “early” postoperative seizure recurrence is due to inaccurate localization of the lesion or incomplete resection, whereas “late” recurrence is due to genetic mechanisms that drive maturation of new seizure foci. Because surgery itself, like traumatic brain injury, has the potential to cause post-interventional or post-traumatic epilepsy, Dr. Jehi’s hypothesis has significant implications for predicting postoperative and post-trauma outcomes on the basis of a patient’s genetic makeup.
“We have particular interest in IL-1β and other inflammatory cytokines and receptors, which we are now studying through further NIH-funded protocols,” she notes. Additionally, the researchers will use RNA sequencing and genotype analysis to identify particular single-nucleotide polymorphisms that may increase the risk of epilepsy.
“Gene expression signatures can provide insight into the specific molecular mechanisms for different types of recurrent seizures, which will improve understanding and targeted surgical management of these mechanisms,” says Ying Ni, PhD, a Center for Clinical Genomics project scientist collaborating with Dr. Jehi on the study.
Enrollment in the study is closed, and the investigation is now in the analytic stage. “Once data analysis is complete, we hope to have a better understanding of how we might predict which patients will have more favorable outcomes from epilepsy surgery,” Dr. Jehi observes.