Ketogenic Diet in Epilepsy

The ketogenic diet is a specialised high-fat, low-carbohydrate, and moderate-protein dietary therapy used primarily in the management of epilepsy, particularly in individuals who do not respond adequately to conventional antiepileptic drugs. This therapeutic approach shifts the body’s primary energy source from glucose to fat, resulting in the production of ketone bodies a metabolic state known as ketosis. These ketone bodies serve as alternative energy substrates for the brain and are believed to possess anticonvulsant properties. The ketogenic diet has been particularly successful in managing seizures in children with drug-resistant epilepsy and has been re-evaluated in recent years as a valuable option for adults as well.

Historical Background

The concept of using diet to manage seizures has ancient origins. As early as 400 BCE, Hippocrates described fasting as a means to reduce seizure activity. However, the modern scientific exploration of dietary therapy in epilepsy began in the early twentieth century. In 1921, Dr Russell Wilder at the Mayo Clinic introduced the ketogenic diet as a dietary mimic of fasting, coining the term to describe a regimen that induces ketosis. It became a mainstream treatment for epilepsy in the 1920s and 1930s until the discovery of effective antiepileptic drugs, such as phenytoin, led to its decline.
In the late twentieth century, renewed interest emerged following public advocacy from parents whose children benefited from the diet, notably through the efforts of the Charlie Foundation, established in 1994. Since then, the ketogenic diet has regained its place as a scientifically validated and clinically important treatment for refractory epilepsy.

Biochemical Basis and Mechanism of Action

The ketogenic diet typically consists of 70–90% of total energy from fats, 6–8% from proteins, and 2–4% from carbohydrates. When carbohydrate intake is severely restricted, glucose availability decreases, forcing the body to metabolise fats into ketone bodies acetoacetate, β-hydroxybutyrate, and acetone produced in the liver. These ketones become the main energy source for the brain, replacing glucose.
The exact mechanisms by which ketosis reduces epileptic activity are not fully understood, but several interrelated pathways have been proposed:

• Neurotransmitter balance: Ketone bodies may increase levels of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) while reducing excitatory glutamate, thereby stabilising neuronal activity.
• Energy metabolism: The diet enhances mitochondrial biogenesis and improves the brain’s energy efficiency, making neurons more resistant to excitatory stress.
• Oxidative stress reduction: Ketosis appears to reduce the generation of reactive oxygen species, providing neuroprotective benefits.
• Ion channel modulation: Ketone bodies can influence potassium and calcium channels, affecting neuronal excitability.
• Adenosine signalling: Increased adenosine levels under ketosis may have anticonvulsant effects by inhibiting neuronal hyperexcitability.

Types of Ketogenic Diets

To improve patient adherence and nutritional balance, several modified forms of the ketogenic diet have been developed:

• Classic Ketogenic Diet (CKD): The traditional regimen uses a 4:1 or 3:1 ratio of fats to the combined weight of protein and carbohydrate. This strict ratio ensures a deep state of ketosis and is most commonly prescribed for children with severe epilepsy.
• Medium-Chain Triglyceride (MCT) Diet: Introduced in the 1970s, this version employs MCT oils that are more efficiently converted into ketones, allowing for higher carbohydrate and protein intake without compromising ketosis.
• Modified Atkins Diet (MAD): Designed for greater flexibility, this approach limits carbohydrate intake (usually to 10–20 grams per day) but permits unrestricted fat and moderate protein consumption. It is particularly suitable for adolescents and adults.
• Low Glycaemic Index Treatment (LGIT): Focuses on carbohydrates with a glycaemic index below 50, promoting mild ketosis while maintaining blood glucose stability. It is less restrictive and more sustainable for long-term use.

Each of these variations maintains the central therapeutic goal of achieving and sustaining ketosis, though they differ in rigidity, palatability, and tolerability.

Clinical Efficacy

Numerous clinical trials and meta-analyses have demonstrated the ketogenic diet’s efficacy in treating refractory epilepsy. Roughly 30–50% of patients experience a reduction in seizure frequency of at least 50%, and about 10–15% achieve complete seizure freedom. The response often becomes evident within two to three months of starting the diet, though full benefits may take up to six months.
Certain epilepsy syndromes are especially responsive to ketogenic dietary therapy, including:

• Glucose transporter type 1 (GLUT1) deficiency syndrome
• Pyruvate dehydrogenase deficiency
• Dravet syndrome
• Lennox–Gastaut syndrome
• Myoclonic–astatic epilepsy (Doose syndrome)

While most evidence supports its use in children, recent research has shown promising outcomes in adults with intractable epilepsy. Moreover, seizure control achieved through the ketogenic diet can sometimes permit reduction or discontinuation of antiepileptic medications.

Implementation and Monitoring

The ketogenic diet should always be implemented under medical supervision, typically by a multidisciplinary team including a neurologist, dietitian, and nursing staff. The process often begins with a hospital-based initiation phase to monitor metabolic adaptation and manage potential side effects.
Pre-diet assessment involves evaluating metabolic health, nutritional status, and laboratory parameters such as lipid profile, liver and kidney function, and blood glucose.
Monitoring throughout the diet includes:

• Ketone measurement: Regular testing of urinary or blood ketone levels to confirm adequate ketosis.
• Growth and development: Especially critical in children to ensure proper nutrition.
• Metabolic markers: Periodic checks of lipid levels, electrolytes, and organ function.
• Seizure tracking: Maintaining a seizure diary helps assess efficacy and guide dietary adjustments.

Side Effects and Complications

While generally safe under medical supervision, the ketogenic diet can cause short-term and long-term side effects.
Short-term effects may include:

• Hypoglycaemia
• Gastrointestinal disturbances such as nausea, constipation, or vomiting
• Dehydration
• Fatigue and lethargy during initial adaptation

Long-term effects may include:

• Hyperlipidaemia due to high fat intake
• Kidney stones
• Micronutrient deficiencies (calcium, selenium, zinc, and vitamins)
• Growth retardation in children if not carefully managed

These risks can be mitigated through supplementation, hydration, and regular medical monitoring.

Advantages and Limitations

Advantages:

• Effective for drug-resistant epilepsy where medications fail.
• May reduce the dosage and side effects of antiepileptic drugs.
• Can improve cognitive alertness and overall quality of life in responsive patients.
• Offers a non-invasive therapeutic option without pharmacological toxicity.

Limitations:

• Strict dietary control is difficult to maintain, especially in older children and adults.
• Potential nutritional imbalance requires meticulous planning and supervision.
• Social and lifestyle restrictions can reduce compliance.
• The mechanism remains incompletely understood, limiting predictability of response.

Recent Research and Future Directions

The ketogenic diet continues to attract research interest beyond epilepsy. It is being investigated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, metabolic disorders, autism spectrum disorders, and migraine. Recent studies have focused on ketone supplements and exogenous ketone esters, which may induce ketosis without strict dietary restriction, potentially improving patient compliance.
Emerging research in metabolomics and personalised nutrition aims to tailor ketogenic interventions to individual metabolic profiles, optimising outcomes and minimising side effects. Furthermore, understanding how ketone metabolism interacts with neuronal networks may inspire new pharmacological treatments that replicate the diet’s anticonvulsant mechanisms.