In a recent review published in Nutrients, researchers investigated the mechanisms of action, efficacy, and side effects of ketogenic diet (KD) variations in epileptic patients.


Epilepsy is a neurological illness that has harmful effects on the central nervous system, hepatotoxicity, and teratogenicity. Despite adequate pharmacology, antiepileptic medications, deep brain stimulation, and surgery, a few individuals continue to be treatment-resistant.

Epilepsy reduces quality of life, causes cognitive, behavioral, and personal issues, and increases mortality risk.

Epilepsy therapy focuses on seizure management, preventing adverse effects, and increasing patient quality of life. KD is considered a last resort for drug-resistant seizures.

About the review

In the present review, researchers present ketogenic diets as a therapeutic option for epilepsy.

Ketogenic diet variants, recommendations, mechanisms, and adverse effects

KD is a high-fat, low-carbohydrate, and low to adequate protein diet that results in ketone bodies. It contains a 4:1 weight ratio of lipids to nonlipids, with fat accounting for 80% of total calories, proteins for 15%, and carbohydrates for 5.0%.

The optimal ratio for newborns and teenagers is 3:1. KD indications include uncontrolled seizures and drug-resistant epilepsy. Alternative diets to reduce side effects and enhance patient compliance include the modified Atkins diet (MAD), medium-chain triglyceride (MCT) diet, and low glycemic index therapy (LGIT).

KDs can reduce seizure frequency (SFR) by up to 70% for conditions like Angelman syndrome, Complex-1 disorders, Dravet syndrome, glucose transporter-1 (GLUT-1) deficiency, Doose syndrome, Febrile infection-associated epilepsy syndrome, Ohtahara syndrome, infantile spasms, super-refractory-type status epilepticus (SRSE), pyruvate dehydrogenase complex (PDC) deficiency, tuberous sclerosis, adenylosuccinate lyase deficiency, and cyclin-dependent kinase-like 5 (CDK). KD contraindications include errors related to lipid and pyruvate metabolisms.

KDs produce neuronal hyperpolarization by lowering glutamate levels while boosting neurotransmitters such as norepinephrine, dopamine, serotonin, galanin, neuropeptide Y, gamma-aminobutyric acid (GABA), and brain-derived neurotrophic factor.

They also restore the gut microbiota, activate adenosine triphosphate (ATP)-sensitive potassium currents, boost mitochondrial oxidative phosphorylation, improve antioxidant production, and inhibit the mammalian target of the rapamycin (mTOR) pathway. KDs also balance the brain’s excitatory and inhibitory neurotransmitter systems.

Reduced glucose levels in ketogenic patients reduce cellular pyruvate/oxaloacetate concentrations, lowering neuronal activity, guarding against seizures, and improving neuroprotection.

KD is used to manage type 2 diabetes; however, side effects such as diarrhea, constipation, nausea, vomiting, dehydration, kidney stone development, and liver damage may occur.

Alternative diets such as the medium-chain triglyceride diet (MCT), modified Atkins diet (MAD), and low-glycemic-index treatment (LGIT) are more tolerable; nonetheless, intravenous MCT diets can result in liver dysfunction, severe iron insufficiency, and temporary triglyceride and cholesterol rises.

Research on ketogenic diet efficacy in epileptic patients

Randomized clinical trials have compared the effectiveness of standard antiepileptic medication to the MAD in treating intractable seizures in children.

The MAD improved both seizure and behavioral features. The standard ketogenic diet (KD) was more beneficial as an initial nutritional therapy for children under the age of two.

MAD was more effective at four weeks than the conventional KD at 12 weeks, and it was also better tolerated. When multiple antiepileptic treatments failed to manage an infant’s seizures, the KD was more effective than the medication alone, and it reduced polypharmacy needs.

Furthermore, ketogenic formulas in the initial month of anticonvulsant therapy increased compliance and decreased seizures more effectively than MAD alone. In adult epilepsy patients, the KD terminated SRSE in most (73%) cases, with effects observed within the initial week.

Randomized controlled trials demonstrated that patients who reached seizure-free status on the ketogenic diet may remain on it even if they experienced breakthrough seizures.

Randomized, non-blinded, open-label, parallel, controlled trials evaluating the efficacy and safety of a diet with lipids and non-lipids in varied ratios to manage resistant cases of pediatric epilepsy among coronary artery disease patients found that ketogenic ratios below 4:1 also benefit seizure control.

Treatment of infantile spasms with the classic KD appeared to be as similarly effective as ACTH therapy. Aside from seizure frequency reduction, KD’s advantages included decreased seizure intensity and improved cognitive functioning, drive, mood, and life quality.


Based on the review findings, KD treats drug-resistant epilepsy and intractable epilepsy disorders in children and adolescents. It helps with generalized epilepsy but less with complex partial seizures.

The main indications include resistant and super-resistant status epilepticus, focal, multifocal, and generalized epilepsy. KD anticonvulsant mechanisms include decreasing glutamate levels while raising dopamine, norepinephrine, serotonin, GABA, neuropeptide Y, and brain-derived neurotrophic factors. KD also alters the gut flora and enhances mitochondrial activity.

Although KDs can reduce or eliminate seizure frequency and intensity, patients find KDs tedious to adhere to and unappealing due to gastrointestinal side effects and hypercholesterolemia.

Large-scale, placebo-controlled, and double-blinded, randomized clinical trials with diverse populations and longer follow-ups are required to provide high-quality evidence on the long-term outcomes of KD and confirm its cognitive and developmental effects.


Source:, Pooja Toshniwal Paharia, Lily Ramsey LLM