Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study

Abstract

BackgroundThe ketogenic diet (KD) is increasingly used to treat drug-resistant epilepsy because of its favorable effect on seizure reduction. Patients with mitochondrial diseases tend to experience seizures. Therefore, this study aimed to test the efficacy of the KD on participants with mitochondrial diseases in a controlled trial.MethodsParticipants from fourteen clinical centers who were diagnosed with mitochondrial disease were semi-randomized to either the intervention (KD) or control group. The KD group followed a 3-month KD intervention, while the control group received a 1-month normal diet initially and then a 3-month KD intervention. The primary outcome measure was seizure reduction. Biomarker changes, cognitive impairments, and side effects were also recorded, if available.ResultA total of 33 participants were assigned to the KD (n = 22) and control groups (n = 11). In the KD group, 31.8% (7/22) of participants achieved ≥50% seizure reduction after 1 month of diet intervention, which increased to 40.9% (9/22) at 3 months. In the control group, only 18.2% (2/11) of the participants had ≥50% seizure reduction during the normal diet period. After the control group was transferred to the KD, 63.6% (7/11) of participants had >50% seizure reduction, and this rate increased to 72.7% (8/11) at 3 months. The KD also showed high efficacy in participants with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or pathogenic variants in mitochondrial DNA (mtDNA) (90% and 93.3% response rates, respectively). The most frequent side effects reported at the 3-month review were vomiting, cold, hyperlipidemia, and bloating.ConclusionThe KD is a safe and effective therapy for seizure control in mitochondrial diseases, especially MELAS and pathogenic variants of mtDNA. KD intervention can be considered in the management of these patients.

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome

“…While efforts to define the therapeutic potential of ketogenic diet in genetic mitochondrial disease are ongoing, recent studies indicate that dietary ketosis may attenuate mitochondrial epilepsies but does not benefit overall disease course in mitochondrial disease. [13][14][15] Given these data, our findings here further suggest that use of a ketogenic diet in mitochondrial disease should be carefully considered. These results may also have some bearing on the practice of fasting mitochondrial patients prior to anesthetic exposure, as a fasting induced ketogenic state may similarly impact anesthesia.…”

“…Available evidence seems to support the notion that dietary ketosis is beneficial for mitochondrial disease related epilepsies, with mitochondrial ETC CI patients appearing to show the greatest benefits. 13,14 Dietary ketosis also appears to reduce seizure incidence in the Ndufs4(−/−) mouse model of Leigh syndrome. 15 However, studies to date do not seem to support the notion that overall disease progression is altered by a ketogenic diet in either the Ndufs4(−/−) model or patients, suggesting that benefits may be limited to seizure control.…”

Dietary carbohydrates in the management of epilepsy

“…Dietary therapies can also be associated with additional benefits such as an improvement in cognition [34][35][36]. A meta-analysis found 19 studies that reported some cognitive improvement following the initiation of the ketogenic diet [35].…”

Mitochondrial Epilepsy, a Challenge for Neurologists

“…Response rates were higher in patients with MELAS or pathogenic variants in mtDNA. In conclusion, the ketogenic diet has been proven to be safe and effective for seizure control in primary mitochondrial diseases, especially MELAS and mtDNA pathogenic variants [ 76 ]. Interestingly, the ketogenic diet seems to be contraindicated for treatment of mitochondrial myopathy related to mtDNA multiple deletions.…”

“…Interestingly, the ketogenic diet seems to be contraindicated for treatment of mitochondrial myopathy related to mtDNA multiple deletions. Although data, so far, are too scarce for general guidelines, it is still recommended to consider a ketogenic diet in patients with resistant mitochondrial epilepsy, initiated by an experienced team [ 75 , 76 ].…”