Most people go on a “diet” to lose weight, but research has found that certain diets confer special benefits beyond weight loss –the proper diet can go so far as to help treat diseases such as epilepsy, Alzheimer’s disease, and even brain cancer. Fasting has been used since ancient times to treat epilepsy. The ketogenic diet (KD), a low carbohydrate, high fat diet introduced in the early twentieth century, was developed as an alternative to fasting.  The KD was subsequently found to induce weight loss, paving the way for the low-carb weight loss movement, e.g. the Atkins diet.

Overall, clinical studies of epilepsy and the KD show that about half of patients with epilepsy who try the KD experience significant relief from their seizures. Epilepsy is a condition characterized by the occurrence of repeated seizures over the course of a person’s lifetime. Seizures are caused by abnormal bursts of activity in the brain that can lead to convulsions or other stereotyped mannerisms such as lip-smacking, arm waving, or even just blank stares. Close to 2 million Americans have epilepsy and about one third of cases are not alleviated by the use of antiepileptic drugs.

Despite the fact that the KD has been around for over a century, it is often recommended as a last resort for patients with epilepsy. A high fat, low carbohydrate, low protein diet is quite different than the average western diet and can cause digestive tract discomfort, making it difficult to maintain. For example, an example meal for someone on the KD would be chicken breast served with mayonnaise or a slice of turkey with gravy made from coconut flour, rather than a wheat derived flour that has many more carbohydrates. The KD allows for about 10g of carbohydrates a day, roughly a quarter cup of cooked chickpeas or a half slice of white bread. The traditional KD requires that two to four times more fat be consumed than protein and carbohydrates combined.   Recent updates on the diet have focused on creating meals with a low glycemic index, food that releases glucose slowly such as high-fiber carbohydrates, like black beans, rather than fixating so heavily on food with high fat content. This version of the diet allows much more flexibility, especially since more carbohydrates can be consumed, but still requires patients to shun high glycemic index foods like candy, white bread, pasta, and potatoes. In western cultures, avoiding high glycemic index foods takes extraordinary effort and planning as most processed food is derived from corn, wheat, and other high-carbohydrate sources.  However, when the KD is tolerated, it can be helpful for therapeutic purposes.

How does the Ketogenic Diet Work?

Usually glucose, derived from the consumption of sugars and carbohydrates like bread and cereal, is the body’s primary source of energy. The limited carbohydrate consumption characterizing KD does not provide enough glucose for the body to meet its energy requirements, so the liver switches to metabolizing fats into products called ketone bodies, leading to a process known as ketosis. In this metabolic state, the body’s cells primarily use ketone bodies, rather than glucose, for energy. In normal circumstances, when glucose is available, cells break down glucose in the cytosol (the intracellular space) to produce pyruvate. Pyruvate is then broken down by the cell’s mitochondria, which are structures in the cell that produce most of its ATP (adenosine triphosphate). ATP fuels the cell, similar to how gasoline fuels a car. When glucose is not available, but ketone bodies are, the mitochondria metabolize ketone bodies to make ATP, circumventing glucose metabolism. Interestingly, fewer free radicals (damaging agents that harm cells) are produced by metabolizing ketone bodies than during glucose metabolism.

Current research shows that the bypass of glucose metabolism by the brain and the direct action of ketone bodies on neurons are responsible for KD’s effectiveness in epilepsy.  The administration of ketone bodies to rats guards them against induced seizures, implying the protective properties of these molecules [1]. But circumventing glucose metabolism may be the dominant therapeutic pathway. A historic study from the 1970s showed that glucose infusion into patients with epilepsy on the KD leads to resumption of seizures [2], implying that bypassing glucose metabolism is central to the efficacy of the KD for treating epilepsy. A more recent laboratory experiment showed that mice with a mutation that greatly reduces glucose metabolism are much less susceptible to induced seizures than wild-type mice [3], supporting the proposed mechanism suggested by the 1970s study in humans.

Other uses of the Ketogenic Diet

Recent studies have shown that the KD and ketogenic-like diets can elicit neuroprotective effects. Interestingly, in randomized, double blind study in which patients with Alzheimer’s disease were administered a ketosis inducing supplement, their performance on cognitive tests were enhanced when compared to participants taking a placebo pill [4]. The brain areas that develop amyloid plaques, abnormal protein aggregations in brain cells and a common symptom of Alzheimer’s disease, often exhibit decreased levels of glucose metabolism in Alzheimer’s patients. It is possible that in some types of Alzheimer’s disease glucose metabolism pathways are impaired but mitochondrial metabolism is unaffected. Therefore, by making ketone bodies available in addition to glucose, neurons can take advantage of a much-needed alternative energy source.

The KD may also be useful in the treatment of brain cancer. In 1995, two children suffering from brain cancer were put on the KD after undergoing multiple courses of chemotherapy and radiation therapy. After a week on the KD, brain scans revealed a decrease in glucose consumption by the tumors [5]. One of the patients continued the diet for another year and her tumor did not grow during this time period. Multiple studies in mice with brain tumors support the efficacy of a calorie-restricted version of the KD in slowing tumor progression [6]. Interestingly, some of these studies show that calorie restriction alone has a dramatic effect on tumor growth. The results in mice are promising, but more studies must be done in humans to understand whether it can be an effective treatment for brain cancer and perhaps other types of cancer. The protective effects of the KD may be due to a decrease in free radicals as mentioned above. Additionally, if only healthy cells can properly metabolize ketone bodies, the KD may help to promote the survival of healthy cells over diseased or cancerous ones. Under this theory, the KD allows one to starve out the cancerous or diseased cells and allow only the healthy cells to survive.

The use of the KD is growing in modern society, both as a medical tool to treat neurological diseases and a means to help people lose weight. It should be used carefully and, if implemented aggressively, under a doctor’s supervision. Because of the restrictive nature of the diet, patients can suffer from malnutrition, so it is usually administered with vitamin supplements. Additionally, the focus on fat often causes digestive tract discomfort and can lead to increased cholesterol levels potentially putting those on the diet at a higher risk for heart disease when employed over an extended period of time. The medical literature describing the use of the KD to treat Parkinson’s disease, bipolar disease, and other neurological disorders and cancers, in addition to the disease mentioned above, is growing quickly. It is clear that the KD is an effective treatment for epilepsy, and more large scale studies are needed to elucidate whether the KD is useful for the treatment for a wider spectrum of disorders.

Allison Provost is a graduate student in the Program in Neuroscience at Harvard University.

Links of Interest

The Charlie Foundation: <http://www.charliefoundation.org/>

Epilepsy Foundation: <http://epilepsyfoundation.org>

Yellen Lab Website: <http://yellen.hms.harvard.edu/keto.php>

References

1.         Likhodii, S.S., et al., Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Annals of neurology, 2003. 54(2): p. 219-226.

2.         Huttenlocher, P.R., Ketonemia and Seizures: Metabolic and Anticonvulsant Effects of Two Ketogenic Diets in Childhood Epilepsy. Pediatric Research, 1976. 10(5): p. 536-540.

3.         Giménez-Cassina, A., et al., BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron, 2012. 74(4): p. 719-730.

4.         Henderson, S.T., et al., Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer&apos;s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutrition &amp; Metabolism, 2009. 6(1): p. 31.

5.         Nebeling, L.С., S.B. Shurin, and E. Lerner, Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in Pediatric Oncology Patients: Two. Journal of the American College of Nutrition, 1995. 14(2): p. 202-208.

6.         Seyfried, T.N., et al., Metabolic management of brain cancer. BBA – Bioenergetics, 2011. 1807(6): p. 577-594.

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