In children with drug-resistant epilepsy, the modified Atkins and ketogenic diets were more effective than usual care in achieving large short-term reductions in seizures and short-term seizure freedom, a systematic review and network meta-analysis found.
Medpage Today reports that across 12 randomised trials, all three dietary interventions evaluated – ketogenic, modified Atkins, low glycaemic index therapy (LGIT) – showed a short-term benefit (three months or less) in seizure reductions of at least 50% compared with usual care, reported Dipika Bansal, DM, of the National Institute of Pharmaceutical Education and Research in Punjab, India, and colleagues.
But as they described in their study, published in JAMA Paediatrics, only the modified Atkins and ketogenic diets were effective for short-term seizure reductions of 90% or more compared with usual care (OR 5.1, 95% CI 2.2-12.0, and OR 6.5, 95% CI 2.3-18.0, respectively) and for achieving short-term freedom from seizures (OR 4.4, 95% CI 1.3-14.5, and OR 5.0, 95% CI 1.3-19.5).
These may be more meaningful outcomes for children with a very high burden of daily seizures, like those with drug-resistant epilepsy, the researchers suggested.
While direct comparisons showed no significant differences, they concluded that with its better tolerability, the modified Atkins diet “may be a sounder option than the ketogenic diet”.
Across dietary interventions, pooled results showed that 36% of children achieved short-term seizure reductions of 50% or more, 17% had reductions of 90% or more, and 10% achieved short-term seizure freedom.
Data on intermediate outcomes were more mixed and only one study examined long-term outcomes.
Modified Atkins and ketogenic diets were both associated with more adverse event-related discontinuations versus usual care (OR 6.5, 95% CI 1.4-31.2, and OR 8.6, 95% CI 1.8-40.6, respectively). Adverse events included constipation, lack of energy and vomiting.
Participants also withdrew from the diets for reasons including “inefficacy, parental unhappiness, behavioural food refusal, dissatisfaction with randomisation results, and food texture”, Bansal and co-authors noted.
“This echoes with the fact that parental food habits or feeding strategies determine their child’s eating behaviour.”
Dietary therapies have long been used to treat the nearly 30% of paediatric epilepsy patients who are resistant to anti-seizure medication, but investigations into the comparative efficacy of various interventions, along with their safety, have been lacking.
“Although epilepsy surgery is a curative treatment option for surgically amenable DRE (drug-resistant epilepsy), alternative modalities such as dietary therapies are often used on the failure of two or more appropriately chosen anti-seizure medications while awaiting epilepsy surgery, in non-surgical DRE, and specific neurometabolic disorders,” wrote Bansal and colleagues.
In addition to patient-specific factors such as primary diagnosis and child/family dietary preferences, selection of a drug-resistant epilepsy diet should take into account the interactions of different dietary therapies, including the possible adverse effects of carbonic anhydrase inhibitors and valproic acid in patients on a ketogenic diet, the group advised.
For their systematic review and network meta-analysis, the researchers identified 12 eligible randomised trials (11 open-label, one single-blinded) involving patients aged 18 years and younger with drug-resistant epilepsy, according to criteria of the International League Against Epilepsy (failure of two or more appropriately chosen anti-seizure medications).
Trials were conducted in multiple countries – India, Iran, Korea, The Netherlands, and the UK – and compared the three dietary interventions with each other or with usual care, which included ongoing use of anti-seizure medications.
Dietary interventions included the ketogenic diet (classic ketogenic diet or the medium-chain triglyceride ketogenic diet [MCT-KD]), modified Atkins, and LGIT.
Ketogenic diets “have been used for more than a century with promising results”, according to the researchers, but adherence difficulties have limited their use.
“The classic KD (ketogenic diet), with a ketogenic ratio of 4:1, derives 80% of total energy intake from fat (mostly long-chain triglycerides; medium-chain triglycerides in MCT-KD) and the rest from carbohydrate and protein combined,” the authors said. Less restrictive diets assessed included modified Atkins and LGIT, which use low-glycaemic index foods to limit daily carbohydrate intake to 10-20 g and 40-60 g, respectively, without any fixed ketogenic ratios.
Overall, 907 patients in the studies were randomised (676 to dietary interventions, 257 to care as usual). Two-thirds of the children were boys, and the average age at enrolment was 4.6 years (SD 2.4). Initiation of dietary therapies was delayed to an average age of over four years in seven studies.
Mean age at seizure onset was 1.4 years (SD 1.6) and the mean seizure frequency was 27.1 per day (SD 31.8), ranging from 4 to 59.5 per day due to different seizure types in all likelihood, according to the researchers.
As noted, short-term seizure reductions of 50% or more was achieved with all three interventions when compared with usual care:
• LGIT: OR 24.7 (95% CI 5.3-115.4)
• Modified Atkins: OR 11.3 (95% CI 5.1-25.1)
• Ketogenic: OR 8.6 (95% CI 3.7-20.0)
Limitations, the team noted, included within-study bias due to the open-label nature of most of the trials, the “clinical heterogeneity” of patients involved, and the “imprecision and unavailability of robust evidence for indirect comparison between different dietary interventions and for intermediate- and long-term outcomes”.
They added that “direct head-to-head comparison studies in the future are needed to confirm these findings further”.
Study details
Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy: A Systematic Review and Network Meta-analysis
Nagita Devi, Priyanka Madaan, Nidhun Kandoth, Dipika Bansal, Jitendra Kumar Sahu.
Published in JAMA Pediatrics on 30 January 2023
Key Points
Question How is the comparative efficacy and safety of different dietary therapies in childhood drug-resistant epilepsy?
Findings In this systematic review and network meta-analysis, all dietary interventions were found to be more efficacious than care as usual for short-term seizure reduction of 50% or higher and 90% or higher. However, adverse event–related discontinuation rates were significantly higher with ketogenic diet and modified Atkins diet; modified Atkins diet with better tolerability and higher probability for seizure reduction of 50% or higher may be a sounder option than a ketogenic diet.
Meaning Modified Atkins diet may have better tolerability and higher probability of short-term seizure reduction than ketogenic diet.
Abstract
Importance
Despite advances in the understanding of dietary therapies in children with drug-resistant epilepsy, no quantitative comparison exists between different dietary interventions.
Objective
To evaluate the comparative efficacy and safety of various dietary therapies in childhood drug-resistant epilepsy.
Study Selection
Randomised clinical trials comparing different dietary therapies (ketogenic diet, modified Atkins diet, and low glycaemic index therapy) with each other or care as usual in childhood drug-resistant epilepsy were included. Abstract, title, and full text were screened independently by 2 reviewers.
Main Outcomes and Measures
Short-term (≤3 months) 50% or higher and 90% or higher reduction in seizure frequency and treatment withdrawal due to adverse events were the primary efficacy and safety outcomes.
Results
Of 2 158 citations, 12 randomised clinical trials (907 patients) qualified for inclusion. In the short term, all dietary interventions were more efficacious than care as usual for 50% or higher seizure reduction (low glycaemic index therapy: odds ratio [OR], 24.7 [95% CI, 5.3-115.4]; modified Atkins diet: OR, 11.3 [95% CI, 5.1-25.1]; ketogenic diet: OR, 8.6 [95% CI, 3.7-20.0]), while ketogenic diet (OR, 6.5 [95% CI, 2.3-18.0]) and modified Atkins diet (OR, 5.1 [95% CI, 2.2-12.0]) were better than care as usual for seizure reduction of 90% or higher. However, adverse event–related discontinuation rates were significantly higher for ketogenic diet (OR, 8.6 [95% CI, 1.8-40.6]) and modified Atkins diet (OR, 6.5 [95% CI, 1.4-31.2]) compared with care as usual. Indirectly, there was no significant difference between dietary therapies in efficacy and safety outcomes.
Conclusions and Relevance
This study found that all dietary therapies are effective in the short term. However, modified Atkins diet had better tolerability, higher probability for 50% or higher seizure reduction, and comparable probability for 90% or higher seizure reduction and may be a sounder option than ketogenic diet. Direct head-to-head comparison studies are needed to confirm these findings.
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