Dietary Approaches to Epilepsy Treatment: Old and New Options on the Menu

By Carl E. Stafstrom, M.D., Ph.D.
Special to EpilepsyUSA
Posted: August 3, 2006

Dietary therapies represent a potentially valuable adjunct to other epilepsy treatments, such as anticonvulsant medications, epilepsy surgery and vagus nerve stimulation. While the ketogenic diet is the most well-established dietary therapy for epilepsy, a few other possible diets exist, such as the Atkins diet, a calorie restricted diet and a diet enriched in polyunsaturated fatty acids.

The prospect that epilepsy might be controlled – at least partially – by nutritional modification is radical but highly appealing. This review, which will be split into two parts, discusses the current clinical status of each of these dietary approaches and suggests possible mechanisms by which they might suppress neuronal hyperexcitability and seizures. This first part will focus on the ketogenic diet and the Atkins diet.

Ketogenic Diet

By now, the ketogenic diet is well known to the epilepsy community. It is a high fat, adequate protein and low carbohydrate diet that was initially devised in 1921 to mimic the anticonvulsant effects of fasting, which was known to have a seizure suppressant effect. By providing excess dietary lipids, the brain's metabolism would switch from glucose to fat as the primary energy source; however, the mechanism by which the ketogenic diet suppresses seizures remains unknown. It is assumed that the anticonvulsant mechanism is related to alteration of energy metabolism and its interaction with the regulation of neuronal excitability.

The formulation and administration of the ketogenic diet has varied little since its initial formulation in the 1920s. The ketogenic diet was used extensively until anticonvulsant drugs became available, starting in the 1930s. The use of the ketogenic diet continued through the decades, but mainly as a "last resort."

In the 1990's, the ketogenic diet use underwent a resurgence. It now holds an important place in the standard armamentarium of epilepsy treatments but is still used primarily in children (or increasingly, adults) with seizures refractory to standard anticonvulsants.

The clinical efficacy of the ketogenic diet has been verified in numerous studies, both in the United States and internationally. The success rate of the ketogenic diet in controlling refractory seizures is at least as good, and it is often better than that of the "new" antiepileptic medications.

In general, at least half of all patients treated with the ketogenic diet will exhibit a 50 percent or greater reduction of seizure frequency. Any seizure type may respond to the diet, but some generalized seizure types, such as myoclonic, atonic, generalized tonic-clonic and even infantile spasms, may be reduced preferentially.

The ketogenic diet works in all age groups, from infancy through adulthood. However, it may be maximally effective in the toddler and school-aged child.

Interestingly, the success rate of the ketogenic diet in recent years is similar to that during the early decades of its use. Perhaps most importantly, there is intriguing recent data that ketogenic diets can sometimes be discontinued without associated loss of seizure control. This observation suggests the ketogenic diet might be both anticonvulsant (stops seizures) and antiepileptogenic (delays the development of the epilepsy state).

Many clinical questions remain regarding the ketogenic diet and its use, including the necessity to start the diet with a period of fasting, the need for fluid restriction, the seizure types most benefited, the patients most amendable to it use, and its long term benefits and side effects.

Unfortunately, even after nearly a century of use, the mechanism of action of the ketogenic diet remains unclear. There were few animal studies of the ketogenic diet prior to 1996. In recent years, several laboratories have embarked on efforts to determine the biochemical and physiological basis of how the ketogenic diet works, with the ultimate goal of improving its use in patients. Any explanation of the ketogenic diet mechanism of action must take into account certain clinical observations and known biochemical alterations resulting from ingestion of the ketogenic diet.

When switching from a diet high in carbohydrates to one high in fats with stringent carbohydrate restriction, like the ketogenic diet, the body utilizes fats as the primary energy source. Fat breakdown in the liver creates ketone bodies (ß-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone), which circulate to the brain and are taken up into cerebral tissue via specific monocarboxylate transporters [22]. In neuronal mitochondria, ketones are metabolized to ATP via the tricarboxylic acid cycle and oxidative phosphorylation. The challenge has been to understand how this energy shift results in an anticonvulsant effect.

Obviously there are multiple sites in the relevant biochemical pathways at which seizure suppression could be facilitated, and the mechanism (or more likely, mechanisms) by which the ketogenic diet exerts an anticonvulsant effect likely involves the combination of the altered energy homeostasis and regulation of neuronal and synaptic excitability.

Early theories of ketogenic diet mechanisms focused on the involvement of ketone bodies. This hypothesis would make sense, since serum ketone concentration rises markedly in subjects on the ketogenic diet and urinary ketones are used clinically as the marker of ketosis.

However, several clinical and experimental studies have shown that the relationship between serum or urinary ketones and seizure control is imprecise, at best. Direct effects of ketones on neurophysiological parameters, excitatory and inhibitory neurotransmission, and ictal activity in vitro have been essentially negative, although the inclusion of glucose in the bathing medium of the brain slices in those experiments could have counteracted the influence of the ketones.

Indeed, recent experiments have shown that, in vivo, rats on the ketogenic diet or a calorie-restricted normal diet exhibited increased paired pulse inhibition in a part of the brain called the hippocampal dentate gyrus and increased resistance to a form of seizure activity called maximal dentate activation. It is possible that the unstable ketone body acetone could exert an anticonvulsant effect, and a reliable measurement system of breath acetone concentration has been developed.

At present, we may conclude that there is some "threshold level" of ketosis that is required and must be maintained for the ketogenic diet to be maximally effective. Whether seizure control correlates with ketone levels remains unclear; the concentration of ketones at the synapse is unknown but may be a critical parameter.

The alteration in cerebral energetics induced by the ketogenic diet favors an increase in "energy charge," i.e., a relative increase in the ATP/ADP ratio resulting from metabolic alterations of the enzymes involved in glycolysis and the tricarboxylic acid cycle [35, 36]. The greater availability of brain energy may reduce cellular excitability, by enhancing energy available for cellular processes such as membrane pumps and transporters, which enhance hyperpolarization [37]. The energy charge hypothesis has received some support from recent studies in fasting humans using 31P spectroscopic imaging, in which ketones are transported from the blood to the brain and are utilized by neurons [38].

Related to the action of the ketogenic diet in altering energy homeostasis is the possible role of ?-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Enhancement of GABA function by the ketogenic diet could occur through pathways of ketone body metabolism (GABA shunt), whereby glial conversion of glutamate to glutamine (a GABA precursor) is enhanced by ketosis [39]. Ketones also mimic GABA structurally, and could play a direct inhibitory role on cellular excitability by stimulating GABA receptors or enhancing their action [40, 41]. Ketogenic diet treatment (and calorie restriction) increases the expression of glutamic acid decarboxylase (GAD65 and GAD67) isoforms, providing a mechanism by which GABA synthesis might be increased on the ketogenic diet [42]. In a study utilizing a variety of seizure induction methods, the most consistent protection with the ketogenic diet was found when seizures were induced by blocking GABA receptors (i.e., picrotoxin, bicuculline, ?-butyrolactone) [43].

An alternative mechanism for ketogenic diet action would implicate the type or quantity of fat in the diet. Typically, a ketogenic diet includes mostly saturated fats, typically in the form of heavy cream or butter. Fats in the ‘classic' ketogenic diet consist of a mixture of animal and plant derived fats; fatty acids of various chain lengths are likely to be included but no attempt is made to specify fat type or chain length in the diet formulation. (An exception is the medium chain triglyceride (MCT) diet, in which oils containing certain chain lengths are the main source of fat [44].) Early clinical studies showed a correlation between plasma lipids and seizure control in children with epilepsy treated with the ketogenic diet [45]. Plasma lipid levels peaked as ketogenic diet-induced seizure control became maximal. In experimental studies, young rats fed a variety of different fat types developed seizure resistance independent of the level of ketosis [26]. The authors concluded that qualitative differences (i.e., different sources of fats) in the ketogenic diet did not markedly affect seizure control [46]. Nevertheless, quantitatively, higher fat to carbohydrate plus protein ratio can increase seizure control clinically [2] and experimentally [25]. In general, increasing the ketogenic ratio leads to improved ketogenic diet efficacy. This issue is discussed further below in the section on polyunsaturated fatty acid diets.

Numerous other possibilities are being explored in the search for the ketogenic diet mechanism. There are current experimental efforts to determine the roles of fatty acid oxidation [47], calorie restriction (see below), neurotransmitter and neuropeptide effects [48, 49], protein phosphorylation [50], and the role of glia [39, 51]. Of particular interest is whether the ketogenic diet can exert an antiepiletogenic as well as an anticonvulsant affect. As stated above, none of the currently available anticonvulsant medications prevent the progression of epilepsy. There are anecdotal clinical reports that ketogenic diet treatment results in long-term efficacy, with good seizure control even after the ketogenic diet is withdrawn [2, 52]. Experimentally, the ketogenic diet reduces the occurrence of spontaneous seizures and abnormal sprouting of dentate granule mossy fibers in the kainic acid model [53], a protective effect that was seen only if the ketogenic diet was instituted within two weeks of the initial status epilepticus [54]. Other evidence of a neuroprotective effect of the ketogenic diet was found in mice with genetic deletion of the Kv1.1 potassium channel gene; in this model, spontaneous seizures and mossy fiber sprouting were also diminished [55]. The mechanism by which seizures induce neuronal damage includes mitochondrial dysfunction with the formation of injurious reactive oxygen species (ROS). The ketogenic diet has been shown to increase the expression of mitochondrial uncoupling proteins and thereby reduce the neuronal damage induced by ROS [56]. The ketogenic diet was also neuroprotective against the damaging effects of kainic acid seizures by inhibiting caspase-3-mediated apoptosis [57].

In summary, the ketogenic diet has a long and effective history of seizure control in children refractory to standard anticonvulsants. There is a wealth of exciting ongoing research to unravel the mechanism of the ketogenic diet and thereby improve its formulation and administration. Animal studies are proceeding in parallel with clinical studies to achieve this goal.

Atkins Diet

The popularity of the Atkins Diet for weight loss is evident on a visit to any supermarket or news stand [58]. Low carbohydrate food items line grocery store shelves and testimonials to its effectiveness fill magazines and other media. Since the Atkins diet induces a state of ketosis by providing high fat and little carbohydrate, it is theoretically possible that the Atkins diet could enable seizure control by a mechanism similar to the ketogenic diet. There are two main differences between the diets (Table 2). First, the Atkins diet does not restrict calories. Second, the Atkins diet allows large amounts of protein, which is restricted on the ketogenic diet.

A small case series has appeared recently, attesting to the effectiveness of the Atkins diet on seizure control in six patients, ranging in age from 7 to 52 years, with diverse seizure types [59]. All three children and the adolescent developed ketosis as measured by large urine ketones, while neither of the two adults developed large ketones. With regard to seizure control, the results were remarkable: two children and the teenager had a greater then 90% seizure reduction. Significant seizure control was not achieved in the one child without urinary ketosis and neither adult. None of the patients had significant side effects, hypercholesterolemia, or excessive weight loss. All three of the successfully treated patients were able to taper their standard anticonvulsants.

Although this is a small, uncontrolled trial, it raises the possibility that the Atkins diet may be beneficial for children with medically refractory epilepsy. Children who withdraw from the ketogenic diet usually do so because of poor tolerability or the family's inability to maintain the rigorous dietary regimen [11]. Therefore, a dietary regime that increases palatability through less restrictive protein and calorie requirements might enhance patient compliance. The Atkins diet has seems to work better in children, as does the ketogenic diet. The Atkins diet was less encouraging in adults with epilepsy, but larger scale studies are necessary.

The observation that both diets induce ketosis and attenuate seizures may have implications in terms of mechanism, and the positive response to the Atkins diet may provide clues to the mechanism of the ketogenic diet. The relative roles of ketosis and calorie restriction need to be elucidated. No animal studies of the Atkins diet have appeared.

Ed. Note: Carl Stafstrom, M.D., Ph.D., is a professor of neurology and a professor of pediatrics of neurology at the University of Wisconsin-Madison. He is also a member of the Epilepsy Foundation 's professional advisory board.

Reprinted with permission from the American Epilepsy Society (AES), Epilepsy Currents, November/December 2004, pp.215-222. Epilepsy Currents articles are available online at http://www.aesnet.org.