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Ketogenic Diet for Epilepsy

Ketogenic Diet for Epilepsy

The ketogenic diet is a high-fat, low-carbohydrate, adequate-protein diet that has been used for almost a century in the treatment of epilepsy. The Ketogenic diet is used in both children and adults and provides a practical, nonpharmaceutical alternative to anticonvulsant drugs.  The ketogenic diet for epilepsy was initially formulated to produce biochemical changes that occur during fasting, which has been known since antiquity to reduce epileptic seizure activity.


What is Epilepsy

Epilepsy is a common neurological disorder that is defined as a condition of unprovoked, recurrent seizures. Clinical manifestations vary from subtle interruptions in responsiveness to convulsions affecting the entire body.  Epilepsy affects as many as 5% of the population and may be caused by various things, such as meningitis, brain injuries, hypoxia-ischemia, to genetic, metabolic, and idiopathic etiology.

Symptoms of Epilepsy usually begin in childhood.  Although there are many antiepileptic drugs available, seizures are difficult to treat.  Luckily, nonpharmacological therapies exist.  These include electrical stimulation devices that stimulate the vagus nerve, as well as dietary interventions like the ketogenic, or “keto diet.”

The ketogenic diet intervention for epilepsy have been used for nearly 100 years and is a significant treatment that is used primarily in drug-resistant cases.  While the results of a ketogenic diet approach make it a considerable treatment approach, implementation is often difficult for patients.  However, strict compliance is necessary.


Fasting vs Ketogenic Diet For Epilepsy

The history of the Ketogenic Diet is a long one and begins with the use of fasting for epilepsy treatment.  Fasting has been used to treat epilepsy for ages and was the precursor to the ketogenic diet. For example, Hippocrates, the great scholar once reported on a man with epileptic seizures who cured himself through fasting [1].   And, fasting as a treatment for epilepsy is even mentioned in a biblical context.  In the King James Bible, Mark relates a story of Jesus curing an epileptic boy, saying that “this kind of thing can come out by nothing but prayer and fasting [2]. “

While fasting is effective, it is also a difficult, and unsustainable treatment for epilepsy.  Luckily, the ketogenic diet was uncovered in the early 20th century as a viable alternative to fasting.  The beauty of the ketogenic diet is that it enables the biochemical action of fasting to persist, but the patient would still be able to eat.  In this way, the ketogenic diet continues to be used as a treatment for epilepsy.  But it took a while before the medical community recognized the ketogenic diet as a viable alternative.


Brief History of the Ketogenic Diet

Before the understanding of the mechanisms of fasting, physicians used starvation to treat epilepsy.  Here is a short history of how food deprivation as a treatment for epilepsy unfolded into the use of the ketogenic diet for epilepsy that is used today.


Dr. Guelpa and Dr. Marie: French physicians who authored the first scientific report on the value of fasting in epilepsy in 1911.  Although their reports suggested that seizures were less severe during the fasting periods, they did not offer additional details [1].


Bernarr Macfadden:  A physical fitness guru/cultist who called the medical profession an “organized fraud.”  Macfadden believed that any disease could be cured through exercise and fasting.  He also claimed that fasting for 3 days to periods of 3 weeks would cure any disease. This included asthma, diabetes, prostate cancer, impotence, paralysis, liver and kidney disease, as well as epilepsy [ 3].


Dr. Hugh W. Conklin: An American osteopathic physician and assistant to Macfadden who adopted Macfadden’s beliefs and methods of fasting to treat epilepsy.  His impressive and positive results drew attention to other pioneers in epilepsy studies [4, 5].

H. Rawle Geyelin: An American Endocrinologist who was the first to report his use of fasting as a treatment for drug-resistant (bromides and phenobarbital) epilepsy to the American Medical Association (AMA) in 1919 [6].   Geyelin was most interested in discovering the mechanisms that made fasting such an effective treatment for epilepsy [7].


Dr. A. Goldbloom: A Canadian physician (and apparent skeptic of Dr. Conklin) who treated patients with fasting, but noticed that when the fasting period ended, the seizures returned for some. He wrote, “It would seem from this case that the starvation treatment is effective only while it is continued and while the patient remains in bed, but that it has no enduring qualities [8].  “


HTH: The boy with grand mal seizures who was treated with fasting that was initially presented to the AMA convention by Dr. Geyelin.   HTH was placed on a “Water Diet” fast for 3-4 weeks to treat his epileptic seizures. During the fasting period, his seizures disappeared.  However, his seizures returned after the conclusion of the fast as Dr. Goldbloom suggested they might.  Luckily for the boy and for the rest of the world with epilepsy, HTH was the nephew of pediatric physician Dr. John Howland, and son of a very wealthy Charles Howland [9, 10].


Dr. John Howland: Professor of pediatrics at Johns Hopkins, and director of the Harriet Lane Home for Invalid Children.  In 1915, his brother Charles Howland gave five thousand dollars to support research on the mechanisms of fasting in the treatment of epilepsy due to worries of his son HTH’s intractable seizures that were not cured with starvation by Dr. Conklin [9, 10, 11, 12 ].


Dr. Stanley Cobb and W.G. Lennox:  Dr. Stanley Cobb was a Harvard physician who was in the audience during the presentation given by Geyelin to AMA.  He was an associate professor of neuropathology at Harvard.  He and his colleague Lennox were enlisted by the parents of HTH and Dr. John Howland in 1919 to further study the mechanisms of fasting on epilepsy [9].  Cobb and Lennox conducted several studies on fasting and had reported several significant findings, noting that levels of the ketone bodies β-hydroxybutyrate, acetoacetate, and acetone are elevated in the peripheral blood and in the urine [10].


R.T. Woodyatt:  Diabetes Researcher in 1921, around the time of the studies of Cobb and Lennox, authored a review article about dietary manipulations for diabetes stating that acetone, acetic acid, and beta-hydroxybutyric acid (BHB) appears in subjects via fasting, or via a diet containing too low a proportion of carbohydrate and a high proportion of fat [13].


Dr. Wilder: Physician from the Mayo Clinic.  It was Wilder who originally coined the term “Ketogenic diet.” [17]  Based on the work by Woodyatt, Dr. Wilder proposed that the benefits of fasting could be obtained if ketone bodies had been produced by other means, such as eating a diet that was rich in fat and low in carbohydrates [14].


Wilder was the first to suggest that the ketogenic diet may be as effective as fasting, and could be maintained for an extended period to compensate for the disadvantages of prolonged fasting periods. The following day in 1921 after his proposal, a report was issued describing the success in seizure control of three patients of the Mayo Clinic using a ketogenic diet as a treatment instead of fasting.   [15, 16, 17] 


How a Ketogenic Diet works for Epilepsy

During a fasted state, the fall in blood glucose reduces plasma insulin production which stimulates lipolysis.  This process, in turn, increases the need for nonesterified fatty acids to the liver.  The liver first oxidizes these lipids to acetyl-coenzyme A (acetyl- CoA), and from this intermediate, the liver synthesizes the major ketone bodies 3- hydroxybutyrate and acetoacetate.  The liver does not utilize ketone bodies to satisfy its own metabolic needs. Instead, the liver releases the ketone bodies into the bloodstream, where they are taken up by a number of tissues, primarily skeletal muscle, kidney, and the brain [18]. 


How the ketogenic Diet works diagram


Ketogenic Diets benefit Energy Reserves

Unlike the sedative effects of most antiepileptic drugs, the biochemical changes induced by the ketogenic diet actually enhance brain function and energy reserves.  During the fasting period, the movement of ketone bodies relies on the monocarboxylic transport system, or MCT-1.  This transport system is also up-regulated during fasting and is the critical factor that limits the rate of brain utilization of ketone bodies [19, 20].  And, unlike glucose, ketone bodies can pass directly into mitochondria and may be used directly by neurons for metabolism [19]. 

But how does an increase in energy reserves help to stave off seizures?  While it is not entirely understood, some possibilities include increases in the ability to power ion pumps which lead to alterations in membrane potential, as well as increased capacity to produce inhibitory neurotransmitters.  These may also be an important mechanism involved in the resistance to seizures in ketotic brain tissue, as well as the favorable cognitive effect sometimes seen as an outcome of implementing a ketogenic diet [21].


Ketogenic Diet & Neurotransmitters

Ketone bodies acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, may influence major inhibitory and excitatory neurotransmitters.  Early in the study of the ketogenic diet, it was noted that levels of the ketone bodies β-hydroxybutyrate, acetoacetate, and acetone are elevated in the peripheral blood and in the urine by Lennox, Cobb, and Woodyatt.

Exactly how each of these metabolic changes contributes to acute seizure protection is still unclear.   However, evidence suggests that acetone displays anticonvulsant activity [22].  And, Ketone bodies have found to be protective against oxidative stress in neocortical neurons [23],  and inhibit glutamate-induced mitochondrial reactive oxygen species (ROS) generation [24]. 

Further, it was found that ketone bodies were found to increase GABA synapses. GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter, and it is believed that most anticonvulsant drugs act through the GABA system [24].   Early in the study of the ketogenic diet, a structural similarity was noted between GABA and the ketone bodies acetoacetate and β-hydroxybutyrate, and it was suggested that they might act as GABA agonists [21]. 

Despite the fact that the mechanisms have not yet been fully elucidated, it is clear that the ketogenic diet is an effective treatment for epilepsy.   However, perhaps the ketogenic diet may have other potential uses for other diseases as well, which may also be worth further clinical exploration.


ketone bodies structure acetoacetate acetone beta-hydroxybutyrate




Brief History of the Ketogenic Diet References:

1. Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia 49 (Suppl. 8), 3–5.
2. Mark 9:14-29. (New King James Version.) Guideposts, Carmel, NY, 1982.
3. Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia 49 (Suppl. 8), 3–5.
4. Lennox WG, Cobb S. Studies in epilepsy. VIII: The clinical effect of fasting. Arch Neurol Psychiatr 1928;20:771-779.
5. Conklin HW. Cause and treatment of epilepsy. JAm Osteopath 1922;22(1): 11-14.
6. Geyelin HR. Fasting as a method for treating epilepsy. Med Rec 1921;99:1037-1039.
7. Geyelin HR. The relation of chemical influences, including diet and endocrine disturbances, to epilepsy. Ann Intern Med 1929;2:678-681.
8. Goldbloom A. Some observations on the starvation treatment of epilepsy. Can Med Assoc J 1922;12:539-540.
9. Lennox WG, Cobb S. Studies in epilepsy. VIII: The clinical effect of fasting. Arch Neurol Psychiatr 1928;20:771-779.
10. Lennox WG, Lennox MA. Epilepsy and Related Disorders, Vol. 2. Little, Brown, Boston, 1960, pp. 735-739.
11. Welch HW, Goodnow FJ, Flexner S, et al. Memorial meeting for Dr. John Howland. Bull Johns Hopkins Hosp 1927;41:311-321.
12. Swink TD, Vining EPG, Freeman JM. The ketogenic diet: 1997. Adv Pediatr 1997;44:297-329.
13. Woodyatt RT. Objects and method of diet adjustment in diabetics. Arch Intern Med 1921;28: 125-141.
14. Wilder, R. M. (1924). “Optimal” Diets for Diabetic Patients. JAMA: The Journal of the American Medical Association, 83(10), 733. doi:10.1001/jama.1924.02660100007003
15. Wilder RM. (1921) The effect on ketonemia on the course of epilepsy. Mayo Clin Bull 2:307
16. Wilder RM. High fat diets in epilepsy. Mayo Clin Bulll921;2:308.
17. Wilder RM, Pollack H. Ketosis and the ketogenic diet: their application to the treatment of epilepsy and infections of the urinary tract. Int Clin 1935;1(45th Ser):1-12.

How a Ketogenic Diet works for Epilepsy References:

18. Robinson AM, Williamson OH. Physiological roles of ketone bodies as substrates and signals in mam malian tissues. Physiol Rev 1980;60: 143-187.
19. Pan JW, Telang FW, Lee JH, de Graff RA, Rothma DL, Stein DT, Hetherington HP. Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain. J Neurochem 2001;79:539-544.
20. Cremer JE, Braun LD, Oldendorf WH. Changes during development in transport processes of the blood-brain barrier. Biochim Biophys Acta 1976;448:633-637.
21. Nordli DR, De Vivo DC. The ketogenic diet revisited: back to the future. Epilepsia 1997;38:743-749.
22.  Ketogenic diet: does acetone stop seizures? Likhodii SS, Burnham WM, Med Sci Monit. 2002 Aug; 8(8):HY19-24.
23. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM
Neuroscience. 2007 Mar 2; 145(1):256-64.
24. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 2007;145:256–64.
25. Rogawski MA. Principles of antiepileptic drug action. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. 5. Philadelphia: Lippincott Williams & Wilkins; 2002. pp. 3–22.