Abstracts

Rationale: Sudden Death in Epilepsy (SUDEP) is a major cause of death in people with epilepsy. N-3 fatty acids (EPA and DHA) reduce the risk of sudden death in patients with cardiac disease, in part due to an improvement in heart rate variability (HRV). Since HRV is abnormal in many patients with epilepsy, and n-3 fatty acids improve HRV in other populations, n-3 fatty acids may be a potential therapy to prevent SUDEP. We report results from an exploratory study designed to help plan future clinical trials. To our knowledge, this is the first study to evaluate the role of n-3 fatty acids in reducing the risk of SUDEP. Methods: Pilot, randomized, crossover study of high dose n-3 fatty acids (EPA + DHA, Fish Oil) versus soybean oil in subjects with refractory epilepsy. 11 subjects were enrolled, and after a 4-week prospective baseline, were randomized to 12 weeks of Fish Oil (8 capsules/day, 9600 mg/day), or soybean oil (8 capsules/day) and then after a 6-week washout, were crossed over to the other treatment. Time dependent measures of HRV (SDANN, SDNN) were the primary surrogate markers for SUDEP risk. Other standard measures of cardiac risk, including lipid panel, c-reactive protein, blood pressure, and heart rate were also evaluated. Results: HRV improved in 4/11 subjects, of whom all four had low HRV (SDNN < 50) at baseline. Further, response to N-3 fatty acids was inversely correlated with baseline SDNN. Patients with low heart rate variability (low SDNN) tended to respond better (Spearman rank correlation -.71, p=.02). However, for the entire treatment group HRV was not significantly improved. Other markers of cardiac risk tended to show improvement with n-3 fatty acids, including triglycerides (reduced 44% versus 14% for placebo), and HDL (increased by 5.6%, similar to placebo). Conclusions: N-3 fatty acids merit further investigation for improving risk factors for SUDEP in larger populations. A subgroup with low HRV (low SDNN, higher risk of SUDEP) was identified for whom n-3 fatty acids may improve HRV. Trends toward lower triglycerides and improvements in other cardiac risk factors were also identified. As for planning future clinical trials, soybean oil may not be ideal, as it is contains 10% linolenic acid, an n-3 fatty acid, and may have positive cardiac effects. It should be replaced by another placebo, such as corn oil (linoleic acid), which has no known cardiac benefits. Also, since lower doses of n-3 fatty acids are effective in preventing sudden death in cardiac patients, a low dose group should be included in future studies. We have initiated a larger NIH/NCCAM sponsored randomized trial of low and high dose n-3 fatty acids versus corn oil to test the hypothesis that n-3 fatty acids improve risk factors associated with SUDEP. Supported by grants from James Peters, the Salter Family Foundation, the Lagermeier and Brill families, Clinical Research Center Grant M01-RR00865, and NCCAM R21AT003420.