Innovations In Clinical Neuroscience

Current Trends in Epilepsy 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Current Trends in Epilepsy Management [December 2015] 9 flexibility, reaction time and complex attention – between the first and second screens. Psychomotor speed did not change, however, and no distinctive patterns of change were noted in response to seizure type, medication, parent reports, or other clinical factors. PERSONALIZED MEDICINE STUDIES REVEAL GENE TARGETS FOR EPILEPSY Technological advances ranging from gene editing to next-generation sequencing offer unprecedented access to the human genome and promise to reshape the diagnosis and treatment of epilepsy. Four studies presented at the AES demonstrate how these innovative technologies are being used to identify and manipulate genes linked to epilepsy. In recent years, researchers (abstract 2.023) have turned to zebrafish (Danio rerio) to study the electrophysiological, anatomical, and behavioral effects of epilepsy. Zebrafish can be relatively easily engineered to express mutant genes, allowing researchers to explore how specific mutations alter the course of epilepsy and neurodevelopment. Mutations in one gene in particular—syntaxin-binding protein 1, STXBP1, involved in neurotransmitter release—have been linked to childhood epilepsy and other neurodevelopmental conditions. Researchers from the University of California, San Francisco (UCSF), used gene-editing technology to reveal how changes in the STXBP1 gene affect development. The authors inactivated the zebrafish stxbp1a gene, which is highly similar to human STXBP1. They report that zebrafish carrying two copies of the mutated gene exhibited profound developmental problems, including reduced movement, developmental delay, excess pigmentation and early death. Fish carrying only one copy of the gene had more limited behavioral abnormalities, including a reduced escape reflex in response to threatening stimuli. A second study (abstract 1.315|C.06) examines how spontaneous, or de novo, genetic mutations contribute to childhood epileptic encephalopathies such as Infantile Spasms or Lennox-Gastaut syndrome. Researchers from the Epi4K Consortium previously studied the genetic sequences of more than 250 children with epilepsy and their unaffected parents, uncovering de novo mutations in approximately 300 genes. To understand how these genes affect epilepsy, researchers from the University of Washington, the University of Melbourne and the University of Southern Denmark screened DNA from a larger population of patients with a range of epileptic encephalopathies for mutations in a subset of the 300 genes. The new study uncovered 16 patients with de novo mutations in seven of the genes identified earlier, including ALG13, CACNA1A, DNM1, GABRB3, GNAO1, IQSEC2, and the first report of SLC1A2 as an epilepsy gene. Nearly half of the genetic variants identified in the study were found in multiple patients, prompting the researchers to explore the relationship between these spontaneous mutations and the physical manifestations of epilepsy. A third study (abstract 3.015) hints at the possibility of using FDA-approved drugs to decrease seizure frequency by reducing faulty cell signaling between nerve cells. Researchers from Emory University discovered this possibility by exploring the roles of key proteins known as NMDA receptors (NMDAR), which contribute to the transmission of signals between nerve cells. Mutations in these proteins have been reported in patients with developmental delay and epilepsy, prompting the authors to study how mutations of a gene encoding a NMDAR subunit, GRIN2A/GluN2A, affects the receptor's function. They also evaluated the sensitivity of the mutants to FDA-approved drugs that block the NMDA receptor, known as antagonists. According to their analysis, the two mutations are more sensitive to agonists, which spark action, than the normal receptors, and are predicted to have a prolonged synapse response that may lead to overactivation of the NMDA receptors, contributing to seizures and cognitive problems. In a fourth study, (abstract 1.311) researchers from British Columbia Children's Hospital and the University of British Columbia use a technique known as whole-exome sequencing—a method for sequencing all protein-coding genes in the human genome—to diagnose and recommend treatments for patients with epilepsy. The authors began by searching for genetic mutations in 50 patients with unexplained early-onset epilepsy. Their analysis uncovered aberrations in the SCN1A, ATP1A2, ALG13, STXBP1 x 2, POLG, KCNQ2 x 3, SMC1A, ADSL, MED23, CDKL5, SLC35A2, PAFAH1B1, and TUBB2B genes, leading to a definite/likely diagnosis in 16 patients and a possible diagnosis in an additional 11 patients. Half of the definite/likely diagnoses directed clinicians toward appropriate treatments. In one case, a patient discontinued valproic acid due to the discovery of mutations in the POLG gene, as valproic acid can induce or accelerate liver disease in patients with these mutations. In another case, a patient with a SCN1A mutation, linked to Dravet syndrome, was found to have an additional mutation in SCN5A, which has been linked to epilepsy, cardiac arrhythmias and sudden death. EMERGING TECHNOLOGIES HELP TO ADVANCE THE UNDERSTANDING, DETECTION AND CONTROL OF EPILEPSY A smartphone-induced EEG waveform and an intelligent algorithm for seizure detection are among the emerging technologies to be unveiled at this year's AES. Four innovative studies presented at the meeting promise to reshape current paradigms for seizure detection and epilepsy management. In the first study, (abstract 3.277) researchers from Brighton and Sussex Medical School demonstrate that electrodermal (EDA) biofeedback—a technique that uses electrodes to detect changes in the skin's electrical activity—is an effective method for reducing seizure frequency in patients with drug-resistant epilepsy. A second study (abstract 3.114) uncovers a previously unknown waveform associated with smartphone use. Researchers from the Mayo Clinic in Highlights from the American Epilepsy Society 2015 69th Annual Meeting

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