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
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 Ketogenic Diet
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 brain10,11. 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.
Potential Side Effects
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.
1. Freeman, J.M. et al. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics. 1998; 102(6): 1358 – 1363.
2. Schwartz, R.H. et al. Ketogenic diets in the treatment of epilepsy: short-term clinical effects. Dev. Med. Child Neurol. 1989; 31(2): 145 – 151.
3. Freeman, J.M. & Vining, E.P. Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Arch. Pediatr. Adolesc. Med. 1999; 153(9): 946 – 949.
4. Lefevre, F. & Aronson, N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics. 2000; 105(4): E46.
5. Batchelor, L. et al. An interdisciplinary team approach to implementing the ketogenic diet for the treatment of seizures. Pediatr. Nurs. 1997; 23(5): 465 – 471.
6. Woody, R.C. et al. Corn oil ketogenic diet for children with intractable seizures. J. Child Neurol. 1988; 3(1): 21 – 24.
7. Ross, D.L. et al. Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy. Pediatr. Neurol. 1985; 1(2): 104 – 108.
8. Schwartz, R.M. et al. Metabolic effects of three ketogenic diets in the treatment of severe epilepsy. Dev. Med. Child Neurol. 1989; 31(2): 152 – 160.
9. Janigro, D. Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res. 1999; 37(3): 223 – 232.
10. Swink, T.D. et al. The ketogenic diet: 1997. Adv. Pediatr. 1997; 44: 297 – 329.
11. Sankar, R. Et al. Metabolic and endocrine aspects of the ketogenic diet. Epilepsy Res. 1999; 37(3): 191 – 201.
12. Pan, J.W. et al. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T. Epilepsia. 1999; 40(6): 703 – 707.
13. Schwartzkroin, P.A. Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res. 1999; 37(3): 171 – 180.
14. Gibson, G.E. & Blass, J.P. Nutrition and Brain Function. In: Siegel, G.J. et al. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th Edition. Lippincott-Raven Publishers. Philadelphia. 1999; Chapter 33: 691 – 709.
15. Vining, E.P. Clinical efficacy of the ketogenic diet. Epilepsy Res. 1999; 37(3): 181 – 190.
16. Hassan, A.M. et al. Ketogenic diet in the treatment of refractory epilepsy in childhood. Pediatr. Neurol. 1999; 21(2): 548 – 552.
17. Theda, C. et al. Increased very long chain fatty acids in patients on a ketogenic diet: a cause of diagnostic confusion. J. Pediatr. 1993; 122(5) Pt 1: 724 – 726.
18. Sirven, J. et al. The ketogenic diet for intractable epilepsy in adults: preliminary results. Epilepsia. 1999; 40(12): 1721 – 1726.
19. McDonald, M.E. Use of the ketogenic diet in treating children with seizures. Pediatr. Nurs. 1997; 23(5): 461 – 644.
20. Casey, J.C. et al. The implementation and maintenance of the Ketogenic Diet in children. J. Neurosci. Nurs. 1999; 31(5): 294 – 302.
21. Withrow, CD. The ketogenic diet: mechanism of anticonvulsant action. Adv. Neurol. 1980; 27: 635 – 642.
22. Amari, A. et al. Achieving and maintaining compliance with the ketogenic diet. J. Appl. Behav. Anal. 1995; 28(3): 341 – 342.
23. McNeely, J.K. Perioperative management of a paediatric patient on the ketogenic diet. Paediatr. Anaesth. 2000; 10(1): 103 – 106.
24. Ballaban, Gil K. et al. Complications of the ketogenic diet. Epilepsia. 1998; 39(7): 744 – 748.
25. Wilner, A. et al. Topiramate and metabolic acidosis. Epilepsia. 1999; 40(6): 792 – 795.
26. Kinsman, S.L. et al. Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases. Epilepsia. 1992; 33(6): 1132 – 1136.