Efficacy of Ketogenic Diet, Modified Atkins Diet, and Low Glycemic Index Therapy Diet Among Children With Drug-Resistant Epilepsy: A Randomized Clinical Trial

Key PointsQuestionAre the modified Atkins diet and low glycemic index therapy diet noninferior to the ketogenic diet with regard to seizure reduction at 24 weeks among children aged 1 to 15 years with drug-resistant epilepsy? FindingsIn this randomized clinical trial of 158 children with drug-resistant epilepsy, the median reduction in seizure burden was similar between the ketogenic diet, modified Atkins diet, and low glycemic index therapy diet, although the noninferiority of the modified Atkins diet and low glycemic index therapy diet was not proven. The adverse events were least with the low glycemic index therapy diet, and 1 adverse event may be avoided for every 4.3 children treated with the low glycemic index therapy diet compared with a ketogenic diet. MeaningThe findings of this trial indicate that guidelines should support the use of the ketogenic, modified Atkins, and low glycemic index therapy diets for management of drug-resistant epilepsy; each dietary therapy should be discussed with caregivers in terms of the benefit in reducing seizure burden and the risk of adverse events. ImportanceThe ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet compared with the KD are scarce. ObjectiveTo determine whether the MAD and LGIT diet are noninferior to the KD among children with drug-resistant epilepsy. Design, Setting, and ParticipantsOne hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016, and August 20, 2017, at a tertiary care referral center in India. ExposuresChildren were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs. Main Outcomes and MeasuresPrimary outcome was percentage change in seizure frequency after 24 weeks of dietary therapy in the MAD cohort compared with the KD cohort and in the LGIT diet cohort compared with the KD cohort. The trial was powered to assess noninferiority of the MAD and LGIT diet compared with the KD with a predefined, noninferiority margin of -15 percentage points. Intention-to-treat analysis was used. ResultsOne hundred fifty-eight children completed the trial: KD (n=52), MAD (n=52), and LGIT diet (n=54). Intention-to-treat analysis showed that, after 24 weeks of intervention, the median (interquartile range [IQR]) change in seizure frequency (KD: -66%; IQR, -85% to -38%; MAD: -45%; IQR, -91% to -7%; and LGIT diet: -54%; IQR, -92% to -19%) was similar among the 3 arms (P=.39). The median difference, per intention-to-treat analysis, in seizure reduction between the KD and MAD arms was -21 percentage points (95% CI, -29 to -3 percentage points) and between the KD and LGIT arms was -12 percentage points (95% CI, -21 to 7 percentage points), with both breaching the noninferiority margin of -15 percentage points. Treatment-related adverse events were similar between the KD (31 of 55 [56.4%]) and MAD (33 of 58 [56.9%]) arms but were significantly less in the LGIT diet arm (19 of 57 [33.3%]). Conclusions and RelevanceNeither the MAD nor the LGIT diet met the noninferiority criteria. However, the results of this study for the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized. Trial RegistrationClinicalTrials.gov Identifier: NCT02708030 This randomized clincal trial assesses whether addition of either the modified Atkins diet or low glycemic index therapy diet to ongoing antiseizure drug therapy was noninferior to the ketogenic diet with regard to seizure reduction at 24 weeks among children aged 1 to 15 years with drug-resistant epilepsy.