The Ketogenic Diet for Epilepsy — An Old Method Returns?

Aim of the study: Ketogenic diet therapy (KDT) is an established nonpharmacologic treatment for various types of epilepsy. We aimed to evaluate the quality of systematic reviews and meta-analyses (SRMAs) of KDT for epilepsy and summarize the evidence on its effects.

Results: Overall, positive effects of KDT for epilepsy were observed in reducing seizure frequency and in cognition and behavior. In contrast, the effects of KDT on quality of life, growth, and development were more controversial. This overview indicates that KDT is safe. The most common adverse events were gastrointestinal problems, weight loss, and metabolic disorders, while the most common reasons for discontinuing treatment were a lack of observed benefit and difficulty tolerating the diet.

Aim of the study: The ketogenic diet is a non-pharmacological treatment option for children with drug-resistant epilepsy. This systematic review and meta-analysis aimed to assess the effectiveness of the ketogenic diet in reducing seizure frequency in children.

Results: Our overall meta-analysis highlighted its significant effectiveness. The KD group was 5.6 times more likely than the control group to achieve a 50% reduction in seizures after three months on the diet or earlier. QUADAS and AMSTAR assessments showed a low risk of bias and adequate accuracy. The results show that KD reduces seizure frequency in children with drug-refractory epilepsy. KD is an effective treatment option for children and adolescents with refractory epilepsy.

Aim of the study: Numerous studies have examined the effects of ketogenic diets (KD) on health-related outcomes through meta-analyses. However, the presence of biases may compromise the reliability of the conclusions.

Results: In addition, KD was associated with seizure reduction in children, which may be explained by the ketosis induced by the diet. Furthermore, KD showed a greater effect in treating refractory childhood epilepsy, based on median rates of effectiveness for seizure reduction of ≥50%, ≥90%, and seizure freedom. However, the strength of evidence supporting these associations was generally weak, which calls their reliability into question. Therefore, future studies should prioritize rigorous research protocols to determine whether KD interventions lasting longer may be a viable treatment option for various diseases.

Aim of the study: KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients have drug-resistant seizures and global developmental delays.

Results: A total of 43 studies, including 197 patients, were reviewed. For patients with EIMFS (32 studies, 135 patients), KD was beneficial in 62.5% (25/40), all types of CBD were beneficial in 50% (6/12), and QUIN was beneficial in 44.6% (25/56). For patients with (AD)SHE (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was tried in 8 patients, with no reported benefit. For patients with DEE (10 studies, 30 patients), KD was beneficial in 4/7, CBD in 1/2, and QUIN in 6/9. In all groups, conventional ASM were rarely reported as beneficial (in 5%-25% of patients).

Aim of the study: Most people with epilepsy respond to pharmacologic treatment; however, approximately 20-30% develop medically refractory epilepsy. Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, adherence, and long-term continuation of treatment.

Results: The ketogenic diet has a positive impact on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, improvements are seen in mood, sustained attention, and social interaction.

Aim of the study: Ketogenic dietary therapies, including the medium-chain triglyceride ketogenic diet (MCT KD), are established non-pharmacological treatments for drug-resistant epilepsy (DRE). MCTs may also have antiseizure effects that are partly independent of ketosis. This review evaluated the effectiveness, tolerability, safety, and adherence associated with MCT-based interventions used with or without a ketogenic diet.

Results: Twelve studies were included: three RCTs and nine observational studies. One pediatric RCT found no clear difference in seizure outcomes between MCT KD and the classical ketogenic diet (CKD), despite higher ketone levels with CKD; however, equivalence was not established. A small pediatric crossover trial suggested possible benefit from a C10-enriched KD, while a small adult RCT indicated a possible therapeutic effect of MCT supplementation. Observational studies generally reported improvement from baseline but were limited by methodological weaknesses. Gastrointestinal adverse events were common but often manageable. Certainty of the evidence was low to very low. MCT-based interventions may offer a flexible option for DRE. Low-certainty evidence suggests that MCT KD may achieve seizure outcomes similar to CKD, but equivalence remains unproven. Evidence for MCT supplementation without a strict KD is very uncertain.

Aim of the study: Miller-Dieker syndrome (MDS) is a rare genetic disorder characterized by classical lissencephaly, severe neurodevelopmental impairment, and early-onset drug-resistant epilepsy. Feeding difficulties and aspiration pneumonia significantly contribute to morbidity and mortality.

Results: We report the case of an infant with MDS and pharmacoresistant epilepsy complicated by severe feeding intolerance and recurrent aspiration pneumonia. KD was started through postpyloric enteral feeding and then administered through percutaneous endoscopic jejunostomy using a low ketogenic ratio (1.25:1). The diet was well tolerated and was associated with seizure freedom that lasted until the child’s death from an unrelated surgical complication (volvulus), improved nutritional status, and several months of clinical stability. This case highlights the feasibility of enteral KD therapy as part of a multidisciplinary, palliative-oriented approach to managing drug-resistant epilepsy in children with MDS.

Aim of the study: The ketogenic diet (KD) is an established therapy for drug-resistant epilepsy, yet its antiseizure mechanisms remain unclear. This study investigates whether KD modulates lipid metabolism-related genes to exert antiseizure effects in a mouse model of temporal lobe epilepsy.

Results: Mice fed KD had significantly lower seizure frequency and severity than CD-fed controls. Transcriptomic analysis identified 41 differentially expressed genes related to lipid metabolism in the KD group. Perilipin 1 (Plin1) emerged as a key hub gene and was markedly upregulated in the hippocampus of KD-fed mice, alongside a significant increase in neuronal lipid droplet formation. In vitro, the effects of KD were reproduced by a PPARγ agonist and blocked by an antagonist, demonstrating that PPARγ mediates this transcriptional regulation. Knocking down Plin1 in KA-treated neurons reduced lipid droplet formation and at the same time increased neuronal excitability (c-Fos expression), establishing a direct mechanistic link. The ketogenic diet exerts antiseizure effects that may be related to activation of the PPARγ pathway, which upregulates Plin1 to promote lipid droplet formation in hippocampal neurons.