n-3 Fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: Clues from a pilot, double-blind, exploratory study☆
Introduction
Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in epilepsy, and accounts for up to 20% of mortality [1], [2], [3], [4], [5]. SUDEP is 24 times more common than sudden death in age-matched controls, and tends to occur in young people, especially 20- to 40-year-olds [1], [2], [3], [4], [5]. In the population with medically intractable seizures, SUDEP is up to five times more common than in people with well-controlled epilepsy [1]. Key risk factors are low IQ, generalized tonic–clonic seizures, and polytherapy with antiepileptic drugs [1]. Likely causes of sudden death include seizure-induced cardiac arrhythmias caused by impaired autonomic regulation and respiratory disturbance related to asphyxia or central/obstructive apnea [4], [5], [6], [7], [8], [9], [10]. Heart rate variability (HRV), a measure of autonomic regulation, is an important marker for the risk for sudden death in people with heart disease [11], [12]. After myocardial infarction, there is a significant decrease in HRV, which is associated with increased mortality [11], [12]. This decrease in HRV causes electrical instability of the myocardium, which may provoke arrhythmias [11], [12]. Like heart disease, epilepsy is also associated with abnormally reduced HRV [7], [8], [9], [10]. Interestingly, n-3 fatty acids (eicosapentanoic acid [EPA] and docosahexanoic acid [DHA] as fish oil) improve HRV in patients with heart disease, reduce lethal arrhythmias, and reduce the risk of sudden death [11], [12], [13], [14], [15], [16]. In preparation for a larger National Institutes of Health (NIH)/National Center for Complementary and Alternative Medicine (NCCAM)-sponsored clinical trial, we explored the hypothesis that n-3 fatty acids may improve cardiac risk factors and HRV in people with intractable epilepsy.
Section snippets
Methods
Eleven subjects with intractable epilepsy were enrolled in an exploratory randomized, double-blind, two-period crossover trial of n-3 fatty acids (EPA + DHA as fish oil). Fish oil capsules and soybean oil placebo were provided by Pharmavite, Inc, Valencia, CA, USA. Subjects were randomized to eight capsules/day of high-dose fish oil for 12 weeks or eight capsules/day of soybean oil placebo. Subjects then entered a 6-week washout period during which no study drug was taken, and then they were
Results
Table 1 summarizes the results. Seizure severity, as measured by the National Hospital Seizure Severity Scale, was reduced from a median score of 8 at baseline, to 7 during the fish oil period and 7 for the soybean oil placebo period [18]. The mean seizure severity scale was reduced from 8.55 at baseline to 7.57 for fish oil and to 7.00 for soybean oil placebo, but these differences were not significant. There was no positive effect of fish oil on seizure frequency: seizure frequency was
Discussion
This pilot planning study was designed to identify trends. It was not powered to determine if those trends were statistically significant. Trends emerged that fish oil may improve triglycerides, SDNN, and SDANN in those with low HRV, important risk factors for heart disease (triglycerides) and risk of sudden death (SDNN/SDANN). In a subgroup of subjects with low HRV, who may be at higher risk for sudden death, there was a tendency for fish oil to improve SDNN and SDANN. In fact, there was a
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Supported by NIH Grant M01-RR00865, and grants from Mr. James Peters, the Salter Family Trust, and the Lagermeier, Brill, and Lester families (AMDG).