Ketogenic Diet is Effective for Childhood Epilepsy
Abstract & Commentary
By Padmaja Kandula, MD, Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University. Dr. Kandula reports no financial relationships relevant to this field of study.
Synopsis: The ketogenic diet was beneficial in children with medically refractory epilepsy in this randomized controlled trial.
Source: Neal EG, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008;7:500-506.
For years, the practice of medicine has relied on observational studies, case reports, and clinical experience in regard to treatment decisions. The ketogenic diet is no exception. Although the diet, in various modifications, has been used since the 1920s, no randomized controlled trials to date have been performed, despite endorsement from such groups as the International League Against Epilepsy (ILAE). Thus, this randomized controlled trial by Neal and colleagues marks an important turning point in the era of evidence-based medicine by providing confirmation of the efficacy of the ketogenic diet in medically refractory epilepsy.
Children between the ages of 2 and 16 years with medically refractory epilepsy (failure of two or more anti-epileptic agents) and seven or more clinical seizures per week were randomly assigned to one of two groups. Patients were assigned to start the diet after a four-week baseline period or after a baseline and three-month delay (control). Children also were randomly assigned to receive either the conventional or medium chain triglyceride diet. Criteria for exclusion included prior treatment with the ketogenic diet, history of hyperlipidemia, kidney stones, or organic acid-deficiency syndrome.
The classical ketogenic diet was initiated at a 2:1 ratio of fat to protein and carbohydrate and titrated to a 3:1 or 4:1 ratio over 1-2 weeks. Medium-chain triglyceride diets (MCT) were started on carbohydrate (15% of total energy), protein (10% of total energy), and long chain fat (30% of total energy). The fat content was then increased over 7-10 days to 45% of total dietary energy. Ketosis was assessed by home urine testing for ketones and blood ketone levels at follow-up appointments at 6 weeks and 3 months.
The primary outcome of this study was mean seizure reduction (efficacy). Secondary outcome included tolerability of the diet as assessed by follow-up outpatient assessment and standardized questionnaire. In the final analysis, 54 patients were assigned to the diet group and 49 to the control group.
Of the patients in the diet group, 38% of patients had a greater than 50% reduction in seizures versus a 6% reduction in the control group. Seven percent of the diet group achieved greater than 90% reduction in seizure frequency. None of the control patients had a greater than 90% reduction in seizures. There was no significant difference in improvement in seizure control in those with symptomatic generalized epilepsy (62.3%) versus those with symptomatic focal epilepsy (64.9%) in the diet treatment group. However, further extrapolation of data in regard to seizure reduction within individual epilepsy syndromes was not feasible due to the small number of patients within each group. The most commonly reported side effects at 3 months were constipation, vomiting, lack of energy, and hunger.
Commentary
It is remarkable that the ketogenic diet has stood the test of time during most of the 20th century, despite the ever-increasing number of second-generation anti-epileptic agents.
The ketogenic diet is first-line therapy for both glucose transporter protein and pyruvate dehydrogenase deficiency, allowing the body to use alternative sources of energy, and thereby improving cognitive outcome. This paper by Neal and colleagues is a first step in providing randomized controlled data to lend evidence to the utility of this alternative method of seizure control. Certainly, from the reported numbers in this study (nearly 40% of patients with greater than 50% seizure reduction, versus 6% placebo), the diet appears to be effective.
However, a potential barrier to utilizing this type of treatment has historically been the tolerability of the diet; the implementation and close follow-up necessary to monitor appropriate ketosis and nutritional requirements; and potential adverse effects both immediate and long term, including possible hyperlipidemia and decreased bone mass. Most patients who withdrew from the diet were unable to tolerate the regimen. Thus, the follow-up results comparing the MCT diet versus the classic ketogenic diet (long chain triglycerides) may be of value to determine which, if any, diet is better tolerated.
Another area of concern has been the lack of definitive data regarding the efficacy of the diet in those with localization related epilepsy versus generalized forms. Over the years, various studies have been published regarding the potential effectiveness of the diet in symptomatic or cryptogenic forms of generalized epilepsy. However, this study did not suggest a statistically significant difference between seizure reduction in those with generalized versus focal forms of symptomatic epilepsy. Thus, a larger study with greater numbers between individual syndromes, both generalized and focal, is needed to determine if certain epilepsy subsets may benefit from the diet.
Ultimately, the decision to initiate the diet has to be weighed against the risks.
Despite the above concerns, this study does present compelling evidence to support the use of the diet in refractory epilepsy.
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