Ketogenic diet in epilepsy

Definition: A high-fat, low-carbohydrate, adequate-protein diet designed to mimic the biochemical changes of fasting (starvation), specifically the production of ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone) as the primary energy source for the brain.
Status: Established non-pharmacologic treatment for drug-resistant epilepsy.

The exact mechanism is multifactorial and not fully elucidated, but key theories include:

Direct Anticonvulsant Effect: Acetoacetate and acetone stabilize neuronal membranes.
Neurotransmitter Modulation:
- Increased synthesis of GABA (inhibitory).
- Reduced neuronal excitability via KATP channel opening (adenosine mediation).
- Inhibition of VGLUT (vesicular glutamate transporters), reducing excitatory glutamatergic transmission.
Bioenergetic Stability: Ketones provide a more efficient energy source than glucose, enhancing mitochondrial function and reducing reactive oxygen species (ROS).
mTOR Pathway: Inhibition of the mTOR pathway (similar to Rapamycin), relevant in Tuberous Sclerosis.

In these metabolic disorders, the brain cannot utilize glucose effectively; KD is disease-modifying or life-saving.

GLUT-1 Deficiency Syndrome: Glucose transporter defect; ketones bypass the transporter.
Pyruvate Dehydrogenase Deficiency (PDHD): Defect in mitochondrial glucose oxidation.

Selected syndromes where KD statistically outperforms many AEDs:

Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy).
Myoclonic Astatic Epilepsy (Doose Syndrome).
Infantile Spasms (West Syndrome) – especially if resistant to ACTH/Vigabatrin.
Tuberous Sclerosis Complex.
Rett Syndrome.

Refractory Epilepsy: Failure of 2 or more appropriate AEDs. (Likelihood of seizure freedom with a 3rd drug is <5%; KD offers ~50% chance of >50% reduction).
Status Epilepticus: Super-refractory status epilepticus (FIRES).

Before starting KD, metabolic screening is mandatory to rule out fatty acid oxidation defects. Inducing ketosis in these patients can be fatal.

Absolute Contraindications	Relative Contraindications
• Primary Carnitine Deficiency • Carnitine Palmitoyltransferase (CPT) I or II deficiency • Carnitine Translocase deficiency • Beta-oxidation defects (e.g., MCAD, LCHAD, VLCAD) • Porphyria • Pyruvate Carboxylase Deficiency	• Severe gastrointestinal reflux (GERD) • Kidney stones (Nephrolithiasis) • Failure to thrive / Severe malnutrition • Parent/Caregiver inability to maintain strict compliance • Pregnancy

The diet is tailored to the patient's age and tolerability.

Diet Type	Composition/Ratio	Pros	Cons	Target Group
Classic KD	4:1 or 3:1 Ratio (4g Fat : 1g Protein+Carb) 90% calories from Fat.	Most efficacious. Highest ketosis levels.	Strict weighing required. Low palatability. Higher side effect profile.	Infants, Tube-fed patients, Severe refractory cases.
MCT Diet	Uses Medium Chain Triglycerides (oil/emulsion). MCTs yield more ketones per kcal than LCTs.	Allows more protein/carbs. Better variety.	GI cramps, diarrhea, vomiting common. Expensive.	Children who need higher protein/carbs.
Modified Atkins (MAD)	~1:1 Ratio. Carbs restricted to 10–20g/day. High Fat, Unrestricted Protein.	No weighing of food. Socially less restrictive.	Lower ketosis than classic. Efficacy slightly lower but comparable.	Adolescents, Adults, Outpatients.
LGIT (Low Glycemic Index)	Carbs 40–60g/day but restricted to GI < 50.	Most liberal. Nutritious.	Variable ketosis. Lowest efficacy among the group.	Mild cases, families unable to manage strict KD.

History: Nutritional status, food preferences.
Labs: CBC, LFT, Lipid Profile, Renal Profile, Calcium/Vit D, Acylcarnitine Profile (to rule out fatty acid oxidation defects), Urine organic acids.
Renal USG: To rule out pre-existing calculi.

Old Method: Fasting for 24–48 hours to deplete glycogen.
Current Standard: Gradual initiation (without fasting) is preferred to reduce hypoglycemia and vomiting risk.
- Day 1: 1:1 ratio $\to$ Day 2: 2:1 ratio $\to$ Day 3: 3:1 ratio $\to$ Day 4: Full 4:1 ratio.
- Inpatient monitoring recommended for infants (risk of hypoglycemia/acidosis).

Supplements (Mandatory): The diet is nutritionally deficient.
- Calcium & Vitamin D (Bone health).
- Multivitamins (Trace elements: Selenium, Zinc).
- Oral Citrates (Polycitra) to prevent kidney stones.
- Carnitine (if levels drop).
- Note: All medications must be switched to sugar-free formulations (syrups often contain sucrose).
Routine Follow-up: Urine ketones (daily at home), Growth parameters (height/weight), Labs (Acid-base, Lipids, Carnitine) q3 months.

Timeframe	Side Effects	Management
Early (Acute)	• Hypoglycemia • Acidosis • Gastrointestinal: Vomiting, Diarrhea, Refusal to feed. • Lethargy.	• Small amount of orange juice. • Bicarbonate (rarely needed). • Adjust ratio, antiemetics.
Late (Chronic)	• Nephrolithiasis (Kidney stones, ~5%) • Dyslipidemia (High LDL/Triglycerides) • Growth Retardation (IGF-1 suppression) • Constipation (Very common) • Bone Mineral Density loss • Carnitine deficiency	• Oral Citrates, hydration. • MCT oil improves lipids; usually transient. • Monitor protein intake. • Laxatives (PEG), high fiber veg. • DEXA scans, Vit D/Ca.

Outcomes:
- ~50% of patients achieve >50% seizure reduction.
- ~10–15% achieve seizure freedom.
Duration: Typically maintained for 2 years.
Weaning: If seizure-free for 2 years, wean very slowly (over 3–6 months) to avoid rebound status epilepticus. Reduce ratio first (4:1 $\to$ 3:1), then calorie restriction.