The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses
The ketogenic diet initially was developed in the 1920s in response to the observation that fasting had antiseizure properties. During fasting, the body metabolizes fat stores via lipolysis and then the fatty acids undergo beta-oxidation into acetoacetate, β-hydroxybutyrate, and acetone—ketone bodies the cell can then use as precursors to generate adenosine triphosphate (ATP). The ketogenic diet, which is very high in fat and low in carbohydrates, is thought to simulate the metabolic effects of starvation by forcing the body to use primarily fat as a fuel source. The ketogenic diet fell out of favor with the development of new anticonvulsant agents, starting with phenytoin in 1938, but it has experienced a resurgence in use over the past 20 years, particularly in the treatment of refractory epilepsy.
Ketone bodies, especially β-hydroxybutyrate, can be measured easily, so much work has centered on determining how these molecules may have anticonvulsant effects. Inconsistencies in studies attempting to correlate seizure protection with levels of ketone bodies suggest that another mechanism may be involved in the diet’s beneficial effects on seizures. Several mechanisms have been proposed, including changes in ATP production making neurons more resilient in the face of metabolic demands during seizures; altered brain pH affecting neuronal excitability; direct inhibitory effects of ketone bodies or fatty acids on ion channels; and shifts in amino acid metabolism to favor the synthesis of the inhibitory neurotransmitter.
With renewed use of the ketogenic diet has come heightened interest in its potential use for other conditions (Table 1). Over the past few years, there has been an explosion in speculation about the diet’s potential applications in a variety of metabolic, oncologic, neurodegenerative, and psychiatric disorders. This review examines data supporting the potential use of the ketogenic diet in each disorder and considers potential mechanisms of action in each disorder, using these data to shed light on the diet’s disease-modifying effects. Both the human and animal studies discussed used standard ketogenic diets unless otherwise specified.
The ketogenic diet has many potential effects and is likely to have different mechanisms in different diseases. In metabolic conditions, cancer, trauma, and ischemia, the ketogenic diet may confer a protective effect by providing an additional energy substrate to tissue at risk of cell death. However, ketosis may have more complicated effects. In one model, rats fed the ketogenic diet show marked upregulation of both the ketone transporter and the glucose transporter type 1 (GLUT-1), promoting the influx of nutrients into the brain. These authors provided evidence that the ketogenic diet increases capillary density without increasing overall blood flow, providing a way that the diet may help nourish tissue at risk. This finding is particularly interesting in light of findings in animals with tumors, in which the diet is associated with an anti-angiogenic effect. These discordant results eventually will need to be reconciled; they may be due to differences in angiogenic stimuli in normal cells versus malignant cells.
It is possible to discuss two aspects of the diet: known or “direct” properties (high ketone-body levels, high fat, and restriction of calories from carbohydrate) and potential indirect effects (eg, effects on neurotransmitters, ion channels, or mitochondrial biogenesis) (Table 2). Ketone bodies provide alternative substrates for use in the tricarboxylic acid cycle and enhance mitochondrial function (evidenced by increased ATP production and decreased effects of reactive oxygen species). Fatty acids and calorie restriction may have beneficial effects by themselves. The potential indirect effects have been studied in epilepsy but have not been investigated to the same degree in other illnesses. Formal studies of the efficacy of the ketogenic diet in epilepsy should serve as a model for future clinical investigations in other diseases.
Epilepsy: expanding uses
- The ketogenic diet traditionally has been used in cases of intractable epilepsy, but it also has become established as a first-line agent in a few specific epilepsy syndromes.
- Children with epilepsy due to mutations in GLUT-1, which transports glucose across the blood-brain barrier, suffer from seizures in infancy. If not identified and treated, they develop microcephaly, mental retardation, spasticity, and ataxia as a consequence of relative brain hypoglycemia. These children respond well to the ketogenic diet, as it is believed to provide an alternative fuel source for their central nervous system.
- Similarly, children with pyruvate dehydrogenase (PDH) deficiency show improvements while on the ketogenic diet. PDH deficiency affects the cell’s ability to convert pyruvate to acetyl-CoA, thereby affecting the flow of precursors from glycolysis into the tricarboxylic acid cycle and limiting mitochondrial energy production.
- Infantile spasms respond well to the ketogenic diet.
- Another epilepsy syndrome in which the diet may be particularly useful is Dravet syndrome (also known as severe myoclonic epilepsy of infancy). This syndrome is classically described as a prolonged febrile seizure in the first 2 years of life, followed by focal-onset seizures, myoclonus, and developmental delays. Dravet syndrome is associated in many cases with mutations in the gene SCN1A, a subunit of the sodium channel.
- The ketogenic diet is also useful in myoclonic-astatic epilepsy (Doose syndrome), which is characterized by episodes of falling sometimes preceded immediately by myoclonic jerks. Other types of generalized seizures and developmental delays occur in some of these patients.
- The data for Dravet syndrome and myoclonic-astatic epilepsy are based on case series. Use of the diet early in the disease course is promising, but more formal trials would be beneficial, preferably with multicenter experience, given the small number of patients seen with each disorder at most centers.
- A number of patients previously refractory to multiple anticonvulsant medications become seizure-free or maintain a significant reduction in seizure frequency even after the ketogenic diet has been discontinued, suggesting the diet may have disease-modifying effects in some people with epilepsy. No clinical factors have been identified that predict which patients will benefit most in this regard.
- The utility of the ketogenic diet in PDH deficiency and GLUT-1 deficiency likely derives from its ability to provide 2-carbon substrates, with subsequent relief of blocks in metabolism upstream from the tricarboxylic acid cycle.
- Other genetic disorders caused by mutations limit the availability of energy substrates but do not necessarily cause seizures. One such disease is phosphofructokinase (PFK) deficiency. PFK is the rate-limiting enzyme in glycolysis for the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Patients with mutations in the muscle isoform of PFK demonstrate exercise intolerance with myalgias and stiffness. There also are rare infantile forms, such as a case reported by Swoboda et al. with myopathy and arthrogryposis. This patient displayed marked gains in muscle strength and improvement in his developmental milestones after being placed on the ketogenic diet.
- The ketogenic diet also has been used in glycogenosis type V (McArdle disease), which is caused by a defect in the muscle-specific isozyme of glycogen phosphorylase. Glycogen phosphorylase is necessary to break down glycogen into free glucose for use as an energy source in muscles. When the ketogenic diet was applied to a patient with this disorder (presumably providing an alternative means of energy production), the patient’s exercise tolerance improved and there was a trend toward decreased baseline creatine kinase levels.
- Ketogenic diets have been studied in patients with other neurologic and psychiatric disorders, even though its mechanism of action for these disorders is unclear.
- The ketogenic diet has been studied in an animal model of depression. Murphy et al. used a testing paradigm called the Porsolt test (a forced choice model) to study the ketogenic diet. Their findings suggest that the ketogenic diet can result in behavioral changes similar to those seen after antidepressants are administered.
Migraine headache, narcolepsy
- Dietary therapies similar to the ketogenic diet also may be useful in the treatment of migraine headaches and narcolepsy, and as we learn more about the mechanisms of action of the ketogenic diet, other potential applications undoubtedly will be suggested.
- In 2006, Strahlman reported the case of his own wife, whose intractable migraine headaches resolved after a medically supervised low-calorie diet. Husain and colleagues studied an Atkins diet–like plan in patients with narcolepsy and reported an 18% decrease in daytime sleepiness as measured by a standard questionnaire. The Atkins diet is less restrictive than the ketogenic diet and does not contain as much fat as “classic” ketogenic diets.
The ketogenic diet is well established as therapy for intractable epilepsy. It should be considered first-line therapy in glucose transporter type 1 and pyruvate dehydrogenase deficiency. It should be considered early in the treatment of Dravet syndrome and myoclonic-astatic epilepsy (Doose syndrome).
Initial studies indicate that the ketogenic diet appears effective in other metabolic conditions, including phosphofructokinase deficiency and glycogenosis type V (McArdle disease). It appears to function in these disorders by providing an alternative fuel source. A growing body of literature suggests the ketogenic diet may be beneficial in certain neurodegenerative diseases, including Alzheimer disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In these disorders, the ketogenic diet appears to be neuroprotective, promoting enhanced mitochondrial function and rescuing adenosine triphosphate production.
Dietary therapy is a promising intervention for cancer, given that it may target the relative inefficiency of tumors in using ketone bodies as an alternative fuel source. The ketogenic diet also may have a role in improving outcomes in trauma and hypoxic injuries.
Dr. Hartman was supported by a Neurological Sciences Academic Development Award (K12NS001696). The authors gratefully acknowledge Max Wiznitzer, MD, for helpful comments regarding some of the trials discussed here.