Background
Epilepsy is a disorder where recurrent seizures are caused by abnormal electrical discharges from the brain. In most people, seizures can be controlled by one or more antiepileptic medicines. For people who continue to have seizures (drug-resistant epilepsy) a special diet, a ketogenic diet, may be considered. Ketogenic diets are high in fat and low in carbohydrate.
This review looked at the effects of ketogenic diets on seizure control, learning and memory, and behaviour. We also investigated the side effects of the diet and the number of people who withdrew from studies, plus the reasons why.
Study characteristics
We searched medical databases for clinical trials of adults or children with epilepsy, where a ketogenic diet was compared with other treatments. We found 13 trials, with 932 participants. The trials were between two and 16 months long.
Key results
Children given ketogenic diets may be up to three times more likely to achieve seizure freedom and up to six times more likely to experience a 50% or greater reduction in seizure frequency compared to children given their usual care. Although the rates of seizure freedom reported by most of the studies were fairly modest, in one study over half of the children given a classical ketogenic diet became seizure free. This rate reduced to only 15% of children achieving seizure freedom when they were given a less restrictive modified Atkins diet. Another study reported that 85% of children given a classical ketogenic diet had a significant reduction in their number of seizures compared to only around half of children who received a modified Atkins diet. One study, however, found similar effects on seizure control with the better tolerated modified Atkins diet as with the more restrictive ketogenic diet, highlighting that more research is required.
There were no reports of seizure freedom in adults following ketogenic diets, however, adults given ketogenic diets may be up to five times more likely to experience a 50% or greater reduction in seizure frequency.
All studies reported people dropping out due to lack of improved seizures and poor tolerance of diet. Adults following ketogenic diets may be up to five times more likely to drop out of studies compared with usual care. For children, dropout rates may be similar in ketogenic diet and usual care treatment groups.
One study reported the effects of ketogenic diets on quality of life, learning, memory, and behaviour in children. The study suggested no difference in the quality of life of children following a ketogenic diet and those receiving usual care. Children following ketogenic diets were suggested to be more active, more productive and less anxious, but more research is needed.
Certainty of the evidence
The trials only included a small number of people and their methods were unclear. We therefore judged the certainty of the evidence to be low to very low. This means that we are not confident that the results described are accurate of the true effect of ketogenic diets in people with epilepsy.
This evidence is current to April 2019.
The evidence suggests that KDs could demonstrate effectiveness in children with drug-resistant epilepsy, however, the evidence for the use of KDs in adults remains uncertain. We identified a limited number of studies which all had small sample sizes. Due to the associated risk of bias and imprecision caused by small study populations, the evidence for the use of KDs was of low to very low certainty.
More palatable but related diets, such as the MAD, may have a similar effect on seizure control as the classical KD, but could be associated with fewer adverse effects. This assumption requires more investigation. For people who have drug-resistant epilepsy or who are unsuitable for surgical intervention, KDs remain a valid option. Further research is required, particularly for adults with drug-resistant epilepsy.
Ketogenic diets (KDs) are high in fat and low in carbohydrates and have been suggested to reduce seizure frequency in people with epilepsy. Such diets may be beneficial for children with drug-resistant epilepsy.
This is an update of a review first published in 2003, and last updated in 2018.
To assess the effects of ketogenic diets for people with drug-resistant epilepsy.
For this update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 26 April 2019) on 29 April 2019. The Cochrane Register of Studies includes the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised controlled trials (RCTs) from Embase, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional relevant studies.
RCTs or quasi-RCTs of KDs for people of any age with drug-resistant epilepsy.
Two review authors independently applied predefined criteria to extract data and evaluated study quality. We assessed the outcomes: seizure freedom, seizure reduction (50% or greater reduction in seizure frequency), adverse effects, cognition and behaviour, quality of life, and attrition rate. We incorporated a meta-analysis. We utilised an intention-to-treat (ITT) population for all primary analyses. We presented the results as risk ratios (RRs) with 95% confidence intervals (CIs).
We identified 13 studies with 932 participants; 711 children (4 months to 18 years) and 221 adults (16 years and over).
We assessed all 13 studies to be at high risk of performance and detection bias, due to lack of blinding. Assessments varied from low to high risk of bias for all other domains. We rated the evidence for all outcomes as low to very low certainty.
Ketogenic diets versus usual care for children
Seizure freedom (RR 3.16, 95% CI 1.20 to 8.35; P = 0.02; 4 studies, 385 participants; very low-certainty evidence) and seizure reduction (RR 5.80, 95% CI 3.48 to 9.65; P < 0.001; 4 studies, 385 participants; low-certainty evidence) favoured KDs (including: classic KD, medium-chain triglyceride (MCT) KD combined, MCT KD only, simplified modified Atkins diet (MAD) compared to usual care for children. We are not confident that these estimated effects are accurate. The most commonly reported adverse effects were vomiting, constipation and diarrhoea for both the intervention and usual care group, but the true effect could be substantially different (low-certainty evidence).
Ketogenic diet versus usual care for adults
In adults, no participants experienced seizure freedom. Seizure reduction favoured KDs (MAD only) over usual care but, again, we are not confident that the effect estimated is accurate (RR 5.03, 95% CI 0.26 to 97.68; P = 0.29; 2 studies, 141 participants; very low-certainty evidence). Adults receiving MAD most commonly reported vomiting, constipation and diarrhoea (very low-certainty evidence). One study reported a reduction in body mass index (BMI) plus increased cholesterol in the MAD group. The other reported weight loss. The true effect could be substantially different to that reported.
Ketogenic diet versus ketogenic diet for children
Up to 55% of children achieved seizure freedom with a classical 4:1 KD after three months whilst up to 85% of children achieved seizure reduction (very low-certainty evidence). One trial reported a greater incidence of seizure reduction with gradual-onset KD, as opposed to fasting-onset KD. Up to 25% of children were seizure free with MAD and up to 60% achieved seizure reduction.
Up to 25% of children became seizure free with MAD and up to 60% experienced seizure reduction. One study used a simplified MAD (sMAD) and reported that 15% of children gained seizure freedom rates and 56% achieved seizure reduction. We judged all the evidence described as very low certainty, thus we are very unsure whether the results are accurate.
The most commonly reported adverse effects were vomiting, constipation and diarrhoea (5 studies, very low-certainty evidence). Two studies reported weight loss. One stated that weight loss and gastrointestinal disturbances were more frequent, with 4:1 versus 3:1 KD, whilst one reported no difference in weight loss with 20 mg/d versus 10 mg/d carbohydrates. In one study, there was a higher incidence of hypercalcuria amongst children receiving classic KD compared to MAD. All effects described are unlikely to be accurate.
Ketogenic diet versus ketogenic diet for adults
One study randomised 80 adults (aged 18 years and over) to either MAD plus KetoCal during the first month with MAD alone for the second month, or MAD alone for the first month followed by MAD plus KetoCal for the second month. No adults achieved seizure freedom. More adults achieved seizure reduction at one month with MAD alone (42.5%) compared to MAD plus KetoCal (32.5%), however, by three months only 10% of adults in both groups maintained seizure reduction. The evidence for both outcomes was of very low certainty; we are very uncertain whether the effects are accurate.
Constipation was more frequently reported in the MAD plus KetoCal group (17.5%) compared to the MAD only group (5%) (1 study, very low-certainty evidence). Diarrhoea and increase/change in seizure pattern/semiology were also commonly reported (17.5% to 20% of participants). The true effects of the diets could be substantially different to that reported.