Title: A randomised controlled trial of the ketogenic diet in the treatment of epilepsy in children under the age of two years
Funder: Medical Research Council

Abstract: Onset of epilepsy is most common in the first 2 years of life (56-83/100,000 children/year) and at this age is particularly associated with poor prognosis for seizure control and neurodevelopmental outcome; children resistant to medication are amongst the most burdensome to medical and care services long term. Reduction in seizure frequency and antiepileptic drug (AED) dependence will have beneficial financial implications for NHS service providers. The ketogenic diet (KD) is a high fat, low carbohydrate, resource-intensive treatment designed to induce ketosis and other biochemical changes associated with the state of starvation. Our group published the first randomised controlled trial demonstrating KD effectiveness in children age 2-16 years in 2008; no such trial has been conducted in infants despite open label data suggesting greater effectiveness in this age group. The aim of this proposed project is to determine the effectiveness of the KD compared to alternative further AED treatment in children with epilepsy aged 3 months to 2 years who have failed to respond to two or more pharmacological treatments (AED or corticosteroids). Our hypotheses are that the KD is more effective than conventional management with a further AED in the treatment of infants with drug resistant epilepsy, and that the KD is a safe and tolerable intervention to use in this group. Further, understanding that clarity is required with regard to the underlying mechanism involved in effect, we will be evaluating the role of medium chain fatty acids in the blood of participants on the KD. Recruitment will be from 9 collaborating paediatric neurology centres with existing KD services. Eligible and consented children will undergo baseline assessment, including medical and seizure history, neurological and anthropometric examination, administration of Infant Toddler Quality of Life and Vineland Adaptive Behaviour (neurodevelopmental) questionnaires, and biochemical investigations required for routine monitoring. Standardised seizure recording will be commenced. After a 2-week observation period with no change to regular AEDs, they will be randomised to receive the KD or a further AED. A second assessment (4 weeks after start of treatment) will include clinical review and questionnaire on tolerability for both groups. All assessments/investigations except neurodevelopmental questionnaire will be repeated at 8 weeks. At this appointment, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group if failed will then be offered KD outside the context of the trial. All patients will be followed and reassessed at 12 months including clinical review, Quality of Life and neurodevelopmental questionnaires, as well as blood evaluation if clinically required. To allow detection of a significant difference in mean percentage change in seizures from baseline between the two groups, at 90% power and 5% significance, accounting for 10% drop out and therapist effect inflation, a total sample size of 160 is required. If drop out is 20%, this sample size will still have 86% power. Primary outcome will be the number of seizures experienced during weeks 6-8. Secondary outcomes will include number of children seizure free, responder rate, KD tolerance as well as the relationship between medium chain fatty acids and seizure control. Data will be analysed using random effects modelling.


Research activity codes: 6.7 PHYSICAL
Health categories: NEUROLOGICAL