Double Blind, Crossover Study of Fish Oil [EPA and DHA] for Intractable Partial Seizures

Epilepsy is a common and disabling condition, characterized by recurrent seizures. Sudden
unexpected death (SUDEP) is a major cause of mortality in people with epilepsy. SUDEP
accounts for up to 20% of all cause mortality, and is most common in younger people,
especially in their 20's to 40's year olds. In those with drug resistant epilepsy, SUDEP is
five times more common than in well-controlled epilepsy. Likely causes of death include
cardiac arrhythmias due to impaired autonomic regulation and reduced heart rate variability.
Similarly, patients with recent myocardial infarction and congestive heart failure are at
higher risk for sudden death, and manifest markedly reduced heart rate variability. Clinical
studies of heart disease indicate that n-3 fatty acids, prevent cardiac arrhythmias, reduce
mortality after myocardial infarction, and reduce the risk of sudden cardiac death. The
mechanism by which EPA and DHA exert their anti-arrhythmia effect is due to inactivation of
high frequency sodium and L-type calcium channels in the heart. In addition, n-3 fatty acids
improve HRV in cardiac patients, and this reduction in HRV is postulated to be a marker of
the anti-arrhythmic effect of n-3 fatty acids. Preliminary data from our group indicates
that n-3 fatty acids improve HRV in people with epilepsy, especially those with low HRV
(SDNN < 50). The commonality between n-3 fatty acids and improvement in HRV in patients
with heart disease and epilepsy serves as a basis for our hypothesis that n-3 fatty acids
may reduce the risk of SUDEP in epilepsy. The purpose of this proposal is to determine if
n-3 fatty acids reduce the risk of SUDEP by improving HRV and other markers of cardiac risk
in people with epilepsy who are at risk of SUDEP.

Subjects between 18 and 50, with poorly controlled tonic-clonic or complex partial seizures,
who on initial screening have low HRV values (SDNN < 50) will be the focus of this
investigation. The central goal of this study is to determine if fish oil improves HRV in
subjects at risk. We propose a multi-center, randomized clinical trial, which explores the
following Specific Aims:

Specific Aim 1: To determine if Fish Oil improves Heart Rate Variability in subjects who are
at risk for SUDEP. At risk subjects are defined as subjects 18-65 who have had at least one
Generalized Tonic Clonic Seizure in the last year, who has had at least two GTC or complex
partial seizures in the last five years, who on screening have low heart rate variability
(operationally defined as an SDNN of less than 60 ms) We will evaluate the effect of n-3
fatty acids on both time dependent and frequency dependent measures of HRV (SDNN/SDNN, low
and high frequency power, and poincare plots).

Specific Aim 2: To determine if Fish Oil improves measures of overall cardiac health in
people with epilepsy, specifically triglycerides, HDL, High Sensitivity C-reactive protein,
and 24-hour PVC index, a measure of cardiac ectopy.

This proposal is a prospective, randomized, parallel multi-center study of Fish Oil in up to
150 at-risk subjects, collected at centers with demonstrated expertise with intractable
epilepsy, and with investigators with expertise in the area of SUDEP.

Inclusion Criteria:

- Male or female, age 18 - 70

- History of intractable localization related/partial onset seizures and generalized
tonic/clonic or tonic seizures defined according to International League Against
Epilepsy (ILAE) classification as:

- A history compatible with localization related partial epilepsy

- A history of generalized tonic clonic or tonic seizures with loss of consciousness

- Three or more simple partial, complex partial or tonic-clonic seizures per month

- An EEG and/or an MRI consistent with a localization related epilepsy

- Evidence of at least three seizures per month for at least two months prior to the
study

- Exposure to at least one antiepileptic drug at adequate dose

Exclusion Criteria:

- Significant or progressive medical, cardiac, or other illness

- Allergy to fish products or fish oil

- History of a coagulation disorder

- History of non-epileptic seizures

- Consumption of Fish Oil at any time 30 days or less prior to enrollment

- Any change in antiepileptic drugs for 30 days or less prior to enrollment

- Treatment with Warfarin for 30 days or less prior to enrollment

- Previous poor compliance with therapy

- Drug or alcohol abuse

- Uncountable seizures as a result of seizure clustering, or inadequate supervision if
the patient cannot count their own seizures.

- Pregnancy