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Frank Lefevre*, and Naomi Aronson
From the * Division of General Internal Medicine, Northwestern University Medical School, and Blue Cross and Blue Shield Association Technology Evaluation Center, Chicago, Illinois.
Objectives. To systematically review and synthesize the available evidence on the efficacy of the ketogenic diet in reducing seizure frequency for children with refractory epilepsy.
Data Sources. Medline searches were performed using the keywords epilepsy/therapy, dietary therapy, and epilepsy, and the text word ketogenic diet. The Cochrane Library of clinical trials was searched using the term ketogenic diet. Bibliographies of recent review articles and relevant primary research reports, as well as Current Contents were reviewed for additional relevant citations.
Study Selection. Studies were selected for inclusion in the review that reported the reduction of seizure frequency following treatment with the ketogenic diet in children with refractory epilepsy. The outcome measures used were the percentage of patients with: 1) complete elimination of seizures, 2) >90% reduction in seizures, and 3) >50% reduction in seizures.
Results. The evidence consists entirely of uncontrolled studies. Of 11 studies identified for this review, 9 are retrospective series of patients from a single institution. Two studies are prospective, 1 of which is a multicenter trial. The results of these studies are consistent in showing that some children benefit from the ketogenic diet, demonstrated by a significant reduction in seizure frequency. Estimates of the rates of improvement by combined analysis (confidence profile method) are complete cessation of all seizures in 16% of children (95% confidence interval [CI]: 11.0-21.7); a greater than 90% reduction in seizures in 32% (95% CI: 25.3-39.8); and a greater than 50% reduction in seizures in 56% (95% CI: 41.2-69.7). It is unlikely that this degree of benefit can result from a placebo response and/or spontaneous remission.
Intractable or refractory epilepsy is defined by inadequate control of seizures despite optimal treatment with conventional medications. Of the 2.5 million patients with epilepsy in the United States, 25% to 30% can be considered to have intractable epilepsy.1,2 Poorly controlled epilepsy has been associated with higher rates of mortality, unemployment, and cognitive impairments.3
A number of new antiepileptic drugs (AEDs) have been approved for use in refractory epilepsy (eg, felbamate, lamotrigine, gabapentin, and vigabatrin)and numerous trials of these agents as add-on therapy for refractory seizures in adult patients have demonstrated a modest benefit. A recent meta-analysis included an analysis of 10 placebo-controlled trials of gabapentin and 11 placebo-controlled trials of lamotrigine.4 Response rates, defined as the percentage of patients with a greater than 50% reduction in seizures, were 20% for gabapentin versus 9.3% for placebo, and 21% for lamotrigine versus 8.9% for placebo. Although primarily labeled for adults, these agents are being used frequently by clinicians for children with refractory seizures.5
A second option for patients with refractory epilepsy is surgery. A resurgence of interest in surgical treatments for refractory seizures has occurred over the last decade. Definite indications for surgery include the presence of a epileptiform focus that is amenable to surgical resection. Approximately 10% of patients with refractory epilepsy meet these criteria.2 In such patients, the success rate of surgery in eliminating or substantially improving seizures is up to 80%,3,6 and this improvement seems to be stable for at least 4 years.7 Controversy exists in the literature concerning indications for other types of antiepileptiform surgery (temporal lobectomy, callosotomy, and hemispherectomy).7 The morbidity of neurosurgery for intractable seizures is not well-reported, with small retrospective series reporting on results from 1 type of surgery.38-10 Serious complications have been reported, such as postoperative motor deficits, recurrent central nervous system bleeding, hydrocephalus, and wound infections. Unfortunately, the rates at which these complications occur remain ill defined.
Over the last decade, the ketogenic diet has gained popularity as another treatment option for this group of patients. Dietary measures have been described for the treatment of epilepsy since ancient times. Anecdotal reports documenting the success of fasting or starvation in the treatment of seizures exist as far back as the 5th century B.C.11 Interest in this form of therapy was rekindled in the early 20th century after reports by physicians of dramatic improvements in seizure frequency after a period of fasting.
In the 1920s, pediatricians at Johns Hopkins University postulated that the antiepileptic effect of starvation resulted from ketosis, ie, the presence of ketone bodies in the circulation. These physicians demonstrated that it was possible to maintain a state of ketosis without prolonged starvation, by severely limiting the intake of carbohydrates and proteins, and thereby forcing the body to use ketone bodies as the predominant fuel source. The classic ketogenic diet, developed at Johns Hopkins, contains fats in a 4:1 ratio to carbohydrates. The amount of protein is regulated also so that ~90% of calories are derived from fat. This diet was used as a treatment for epilepsy fairly commonly in the 1920s and 1930s. In the late 1930s and 1940s, as effective antiepileptic drugs, such as phenytoin and phenobarbital, were introduced into clinical practice, the ketogenic diet was largely replaced by drug therapy.12
The mechanism of effect of ketosis on seizures is not understood. Various theories11 have postulated that: 1) there is a direct stabilizing effect of ketone bodies on the central nervous system; 2) resulting acidosis accompanying ketosis modifies the seizure threshold; 3) changes in fluid and electrolyte balance result in reduced seizures; and 4) change in lipid concentration induced by the diet has an antiseizure effect.
Despite the lack of a well-defined mechanism of action, numerous reports have appeared in the literature that have suggested benefit of this diet in reducing the frequency of seizures. The objective of this present study is to systematically review and synthesize the literature evidence reporting on the efficacy of the ketogenic diet in reducing seizure frequency in children with refractory epilepsy.
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