Title: Epilepsy and the Ketogenic Diet

Key words: ketoacidosis, low carbohydrate, high fat, intractable epilepsy, ATP production, glucose transporter protein syndrome, pyruvate-dehydrogenase deficiency, gout, kidney failure, free radicals, valproate, topiramate

Date: Sept 2000

Category: Special diets

Type: Article

Author: Dr Van Rhijn

Epilepsy and the Ketogenic Diet

The ketogenic diet (KD), developed in the 1920’s, consisting of a low carbohydrate, low protein and high fat diet (90% caloric value)¹, designed to induce a relative state of ketoacidosis, has been employed successfully (>50%)^2,3,4 as a treatment for intractable, non-responsive epilepsy⁵. To use it therapeutically require careful monitoring and good compliance to avoid potential side effects, which will be further discussed.

The brain can sufficiently be maintained on glucose (in the presence of glucose transporters) and ketone bodies. A low CHO and protein (relative fasting state), but high fat diet (rich in medium chain triglycerides [MCT] or corn oil⁶) results in an increased metabolism (oxidation) of the latter into acetoacetic acid⁷, which is further converted into acetone and b -OH butyric acid⁸ (which crosses the blood-brain-barrier [BBB] freely)⁹ to become the main fuel for the brain^10,11. This is the basis for the KD, which results in an increased cerebral ATP production¹², GABA transmission (inhibitory neurotransmitter) and a higher ECV threshold, thereby reducing the risk of epileptic seizures¹³, in contrast to severe fasting where there is decreased liver ATP concentrations and ATP:phosphocreatine ratios.

The brain energy metabolism manipulation with the KD does not significantly alter regional brain glucose utilisation or cerebral concentrations of glucose, glycogen, lactate or citrate¹⁴. Indications for this diet also include defective glucose transport across the BBB (glucose transporter protein syndrome) and pyruvate-dehydrogenase deficiency.

This induced metabolic acidosis causes increased loss of electrolytes (Na, K) and vital minerals (Ca, Mg, Zn) and free Ca excretion via the kidneys with the risk of urolithiasis (Ca-oxalate)¹⁵ and gout and kidney failure, as increased serum uric acid competes with ketones for excretion. MCT may enhance absorption of fat-soluble vitamins (A/D/E), and a relative deficiency of water-soluble vitamins (B/C). Other side effects associated with the KD include a scratchy sensation in the throat, abdominal cramps, nausea, diarrhoea, dehydration, increased liver function tests, haemolytic anaemia, gall bladder stones¹⁶, hypoglycaemia, weight loss, retarded growth and weakness. The relative absence of fibre may also contribute to constipation.

MCT passes readily through cell membranes and may be stored in adipose tissues. Metabolically, there is elevation of very long chain fatty acid levels¹⁷ and a risk of hyperlipidaemia (cholesterol [HDL] and triglycerides)¹⁸, increasing the risk of hypertension, arteriosclerosis and cardiovascular disease. This is contributed to by free radical formation from incomplete lipid oxidation. There is also a potential risk of Staphylococcus aureus infections¹⁹ and women may experience menstrual irregularities.

The implementation and maintenance of this expensive diet require significant supportive collaboration between the family and Epilepsy Team²⁰. It requires intensive training and understanding regarding the restrictions, mechanisms, psychological issues, complications and responsible commitment²¹ for meticulous execution. Many factors (age, weight, height, activity levels) are considered in calculating (computer programme) a ketogenic formula, and pre-calculated charts helps to vary and fine-tune the diet to improve efficacy and compliance²².

Medium and long chain acetyl-CoA dehydrogenase deficiency are contra-indications for this diet that can be fatal in hours. Recognition is vital. Symptoms include somnolence, lethargy, coma, seizures, vomiting, hepato-splenomegaly, and viral prodrome, with a 26% mortality rate. Biochemical parameters include hypoglycaemia, hypoketonaemia, hypocarnitinaemia, hyperammonaemia and hyperuricaemia. Extra care is needed in patients requiring anaesthetics²³, or are concomitantly on antiepileptic medication such as valproate²⁴ and topiramate (carbonic anhydrase inhibitor), which may potentially worsen acidosis²⁵. The KD is riskier for individuals with medical problems such as heart disease, hypertension, kidney disease, and diabetes (which contributes to ketoacidosis). Regular blood tests are required to monitor serum lipid status, and levels of major minerals (including Fe) and electrolytes.

The KD may have serious metabolic consequences, but when properly executed with adequate medical and dietary supervision, monitoring and prevention, may become a valuable therapeutic tool²⁶ in serious intractable cases of epilepsy (well tolerated by children), with an efficacy exceeding that of numerous medications.

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