Ketogenic diet treatment in adults with refractory epilepsy

Abstract

The ketogenic diet (KD) is an effective treatment for refractory epilepsy in children. It has been little studied in adults. We evaluated the efficacy of, safety of, and compliance with adjunctive KD treatment in adults with refractory epilepsy in a prospective open-label pilot study. Seizure frequency was evaluated for 4 baseline months, 4 months of adjunctive KD treatment with a 3:1 [fat]:[carbohydrate + protein] weight ratio and 1600 kcal/day, and subsequent elective open-ended KD treatment. A 3:1 ratio was used instead of the 4:1 ratio employed in children because of greater palatability. Average monthly seizure frequency and seizure-free months at baseline were compared with KD months 1–4 (phase 1) and all KD treatment (phase 2). Diet compliance was evaluated with daily urine ketone body and monthly serum β-hydroxybutyrate levels. Twelve subjects were treated for up to 26 months. Three stopped treatment early for psychosocial reasons (n = 2) or lack of efficacy. Seven of the 12 subjects were fully compliant, 4 were partially compliant, and 1 was noncompliant. Mean seizure frequency declined by 38.4 and 44.1% for phases 1 and 2, respectively (P = 0.04). Forty-two percent and 50% of subjects had a > 50% reduction during phases 1 and 2, respectively. Four of 12 subjects (33%) had a > 85% seizure reduction. Twenty percent of subject-months were seizure free at baseline versus 56% during both study phases (P = 0.04). Adverse effects were mild: nausea, vomiting, diarrhea, constipation, and weight loss.

Introduction

Seizures in approximately 35% of patients with epilepsy fail to respond to antiepileptic drug (AED) treatment [1], [2], [3]. The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet that is an effective treatment for refractory epilepsy in children [4], [5]. The “classic” diet consists of long-chain saturated triglycerides with a 3:1 or 4:1 [fat]:[protein + carbohydrate] ratio by weight, with 90% of calories derived from fat. In open-label review or prospective studies of the KD in children, 7–15% of children with intractable epilepsy become seizure free, 25–40% have a 90% seizure reduction, and 55% have a > 50% seizure reduction [6], [7], [8], [9], [10], [11]. In a study of 145 children randomized to immediate KD versus KD delayed for 3 months, 38% of patients in the KD group achieved > 50% and 7% > 90% seizure frequency reduction versus 6 and 0% in the control group [9]. These results compare favorably with the efficacy of new AEDs, which lead to 1–7% seizure freedom rates and 90% seizure frequency reduction in fewer than 10% patients with intractable epilepsy [12], [13].

Treatment with the KD is relatively safe. Potential side effects in children include constipation or diarrhea, nausea, vomiting, nephrolithiasis (3–7%), metabolic acidosis (2–5%), hyperuricemia (2–26%), hypocalcemia (2%), hypomagnesemia (5%), weight loss, hyperlipidemia, bruising, and osteopenia [4], [5], [14], [15], [16], [17].

Despite its success in children, the KD has been little studied in adults. Only three studies in adults and one in adolescents have been published. In a 1930 study 100 adults were treated with KD monotherapy for 1 year, of whom 12% became seizure free, 44% improved and 44% remained unchanged [18]. More recently, there have been only two small reports. In one, 11 adults with refractory epilepsy were treated for 8 months with adjunctive 4:1 ratio KD. Three had > 90%, three had 50–89%, and one had < 50% seizure reduction; four stopped the diet prematurely [19]. Adverse events (AEs) included constipation and menstrual irregularities. In another study, nine adults with refractory epilepsy were to be treated with the KD for 12 weeks. Only two subjects completed the study, both with > 50% seizure frequency reduction; the rest dropped out because of side effects (diarrhea, hunger, elevated lipids) and lack of efficacy [20].

Recently, two studies evaluated the “modified Atkins diet” in adults. This diet has a 0.9: 1 [fat]: [carbohydrate + protein] weight ratio, with 65% of calories derived from fat. In one study of 30 adults, 33% subjects achieved a > 50% seizure reduction at 6 months; one subject became seizure free [21], and 33% stopped treatment before 3 months. In another study with carbohydrate restriction of 20 g/day, three of eight patients continued with the diet for 6 months, with seizure reductions of > 50%, > 30%, and < 30% [22].

Given the apparent efficacy and safety of the KD in children and the lack of effective treatment in adults with intractable epilepsy, it is remarkable that the KD has not been evaluated more broadly in adults. The main reason appears to be an untested assumption that adults would not comply with the unpalatable diet. The goal of the present study was to obtain pilot data on compliance with and efficacy and safety of adjunctive KD treatment in adults with intractable epilepsy.