What are the effects of ketogenic diets on drug‐resistant epilepsy? A Cochrane Review summary with commentary

The aim of this commentary is to discuss from a rehabilitation perspective the published Cochrane Review ‘Ketogenic diets for drug-resistant epilepsy’ by Martin-McGill et al.,1 under the direct supervision of the Cochrane Epilepsy Group. This Cochrane Corner is produced in agreement with Developmental Medicine & Child Neurology by Cochrane Rehabilitation. Epilepsy is a common but serious neurological condition.2 Antiseizure medication is the mainstay of treatment, but about 35% of patients remain refractory.3, 4 Drug-resistant epilepsy (DRE) leads to an increased risk of injuries, psychosocial dysfunction, poor quality of life, and premature death, calling for the search for alternative treatments. There has been mounting interest in the ketogenic diet (KD), with high fat, adequate protein, and low carbohydrate content, and its variants.1, 5, 6 Thus it is important to provide evidence-based data and identify potential adverse effects in children and adults with DRE. An update of a Cochrane Review,1 first published in 20037 and updated in 2018,8 looked at further evidence of KD effects in individuals with DRE.1 The aim of this Cochrane Review1 was to investigate the effect of KD for DRE by reviewing the evidence from randomized controlled trials (RCTs). The population addressed in this review was children or adults with a diagnosis of DRE regardless of seizure type or epilepsy syndrome. The interventions studied were any diet-producing ketones including different types of KD (classical KD, medium-chain triglyceride [MCT] KD, modified Atkins diet [MAD], and low glycaemic index treatment). The comparators were placebo, usual, or sham diet known not to have any effect on epilepsy or any other antiseizure treatment or different types of KDs. The primary outcomes studied were seizure freedom (100% reduction in seizure frequency), seizure reduction (≥50% reduction), and adverse effects. Secondary outcomes were cognitive, behavioural, quality of life, and attrition rate. The review authors searched for studies that had been published up to 29th April 2019. The review included 13 RCTs (n=932): 10 studies of 711 children, and three of 221 adults. Only two additional studies met the inclusion criteria for the last update. The review shows that: The authors concluded that, although the overall quality of the evidence was low or very low due to risk of bias and imprecision in the limited number of studies resulting from small sample sizes, the use of KDs in epilepsy was promising, particularly in children. But there is uncertainty as to their favourable effects in adults. KD variants such as MAD may have a similar effect on seizure control as the classical KD and MAD can be assumed to have fewer adverse events. The attrition rate remained a problem in all KD variants due to the lack of observed efficacy on seizures and dietary tolerance. The authors stated that KD is a valid option in people with medically intractable epilepsy or those who are not suitable for surgical intervention. They emphasized the need for further research. According to the results of this review,1 KDs may be helpful in promoting seizure freedom and seizure reduction, especially in children. The proportions for these outcomes were the highest with 4:1 KD in children, 55% and 85% respectively, at a 3-month follow-up; however, with more adverse events in most of the studies. MAD achieved seizure freedom and reduction in up to 25% and 60% respectively. According to one study, KDs might be helpful even for children younger than 2 years, with classical KD being potentially more effective than MAD. The KDs have few side effects, mostly vomiting, constipation, and diarrhoea, not leading to significant withdrawals in children, in contrast with adults. KDs may have some positive effects such as an increase in activity or productivity levels and a decrease in anxiousness in children, which needs further investigation due to inadequacy of evidence to inform clinical practice. Nevertheless, the potentially favourable effects of KDs on daily activity is of importance given the poor adherence of individuals with epilepsy9 to physical activity guidelines for children and young people affected by epilepsy.10 In adults with DRE, the effects of KDs are understudied and less clear. However, it should be emphasized that the level of evidence suggesting the above results is of low or very low quality due to different reasons, so doubts remain as to whether KDs improve the studied outcomes (https://www.cochrane.no/sites/cochrane.no/files/public/uploads/how_to_write_a_cochrane_pls_12th_february_2019.pdf). Therefore, the current Cochrane evidence1 urges future research for more conclusive evidence on the efficacy of KDs in epilepsy. From a rehabilitation point of view, it would be more appropriate to consider the use of the International Classification of Functioning, Disability and Health categories, particularly those relevant to epilepsy,11 such as emotional functions and sensation of pain (in addition to cognitive and mobility functions), since these were not studied in any of the trials included in the review. More research is also needed to extend the results in practice, especially in adults. The author thanks Cochrane Rehabilitation and Cochrane Epilepsy Group for reviewing the contents of this Cochrane Corner. The author has stated that they had no interests that could be perceived as posing a conflict or bias.

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