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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.

Across 12 randomized trials, all three dietary interventions evaluated -- ketogenic, modified Atkins, low glycemic index therapy (LGIT) -- showed a short-term benefit (3 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 described in , 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, such as those with drug-resistant epilepsy, according to the researchers.

While direct comparisons showed no significant differences, they concluded that with its better tolerability, the modified Atkins diet "may be a sounder option than 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, behavioral food refusal, dissatisfaction with randomization results, and food texture," Bansal and co-authors noted. "This echoes with the fact that and feeding strategies determine their child's eating behavior."

Dietary therapies have long been used to treat the nearly 30% of pediatric epilepsy patients who are resistant to antiseizure 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 antiseizure medications while awaiting epilepsy surgery, in nonsurgical 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 randomized trials (11 open-label, one single-blinded) involving patients ages 18 years and younger with drug-resistant epilepsy, according to of the International League Against Epilepsy (failure of two or more appropriately chosen antiseizure medications).

Trials were conducted in multiple countries -- India, Iran, Korea, The Netherlands, and the U.K. -- and compared the three dietary interventions with each other or with usual care, which included ongoing use of antiseizure 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 over 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 explained. Less restrictive diets assessed included modified Atkins and LGIT, which use low-glycemic 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 randomized (676 to dietary interventions, 257 to care as usual). Two-thirds of the children were boys, and the average age at enrollment was 4.6 years (SD 2.4). Initiation of dietary therapies was delayed to an average age of over 4 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."

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