The ketogenic diet is a high fat, adequate protein, low carbohydrate diet, primarily used to treat difficult-to-control (refractory) epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fat rather than carbohydrate. Normally, the carbohydrates in food are converted into glucose, which is then transported around the body and is particularly important in fuelling the brain. However, if there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. When the body produces ketone bodies, a state known as ketosis, this has an anticonvulsant effect.
The diet has just enough protein for body growth and repair, and sufficient calories to maintain the correct weight for age and height. The "classic" ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate. This is achieved by eliminating foods high in carbohydrates (starchy fruits and vegetables, bread, pasta, grains and sugar) while increasing the consumption of foods high in fat (cream and butter).
Most dietary fat contains long chain triglycerides (LCT), but a form of coconut oil can be manufactured that contains only medium-chain triglycerides (MCT), which are much more ketogenic. A variant of the diet known as the MCT ketogenic diet uses MCT oil to provide between 30 and 60% of the calories. Carbohydrates and protein can be increased a little, which allows for greater freedom in planning meals.
Developed in the 1920s, the ketogenic diet's popularity waned with the introduction of effective anticonvulsant drugs. In the mid 1990s the Hollywood producer Jim Abrahams, whose son's severe epilepsy was effectively controlled by the diet, created the Charlie Foundation to promote it. Publicity included an appearance on NBC's Dateline programme and …First Do No Harm (1997), a TV movie starring Meryl Streep. The foundation sponsored a multicentre research study and the results, which were published in 1996, marked the beginning of renewed scientific interest in the diet. The potential use of the diet as a treatment for medical conditions other than epilepsy is, as of 2007, still at the research stage.
In 2008, a randomised controlled trial showed a clear benefit for treating refractory epilepsy in children. This added weight to conclusions drawn from the many earlier uncontrolled trials of the ketogenic diet's efficacy and safety, which already provided sufficient evidence to recommend clinical use. In children with refractory epilepsy, the ketogenic diet is more likely to be effective than trying an alternative anticonvulsant drug. There is some evidence that adults with epilepsy may benefit from the diet, and that a less strict regime, such as a modified Atkins, could be effective.
The ancient Greek physicians treated diseases, including epilepsy, by altering their patient's diet. However, the treatment of seizures by fasting patients was not popular. An early treatise concerning epilepsy, On the Sacred Disease, can be found in the Hippocratic Corpus and dates from around 400 BC. Its author argued against the prevailing view that epilepsy was supernatural in origin and cure, and proposed that dietary therapy had a rational and physical basis. In the same collection, the author of Epidemics describes the case of a man whose epilepsy is cured as quickly as it had appeared, through complete abstinence of food and drink. The royal physician, Erasistratus, declared, "One inclining to epilepsy should be made to fast without mercy and be put on short rations. Galen believed an "attenuating diet" might afford a cure in mild cases and be helpful in others.
The first modern study of fasting as a treatment for epilepsy was in France in 1911. Twenty patients, of all ages, were "detoxified" by consuming a low-calorie vegetarian diet, combined with periods of fasting and purging. A couple of patients benefited enormously, but most failed to maintain compliance with the imposed restrictions. The diet improved the patients' mental capabilities, in contrast to their medication, potassium bromide, which dulled the mind.
Around this time, the American exponent of physical culture, Bernarr Macfadden, popularised the use of fasting to restore health. His disciple, the osteopath physician Hugh Conklin, of Battle Creek, Michigan, began to treat his epilepsy patients by fasting them. Conklin conjectured that epileptic seizures were caused when a toxin, secreted from the Peyer's patches in the intestines, was discharged into the bloodstream. He recommended a fast lasting 18 to 25 days to allow this toxin to dissipate. Conklin probably treated hundreds of epilepsy patients with his "water diet" and boasted of a 90% cure rate in children (a rate that declined with patient age). Later analysis of Conklin's records show 20% achieved freedom from seizures and 50% had some improvement.
Conklin's fasting therapy was adopted by neurologists in mainstream practice. In 1916, a Dr. McMurray wrote to the New York Medical Journal claiming to have successfully treated epilepsy patients, since 1912, with a fast followed by a starch- and sugar-free diet. In 1921, prominent endocrinologist H. Rawle Geyelin reported his experiences to the American Medical Association convention. He had seen Conklin's success first-hand and had attempted to reproduce the results in 36 of his own patients. He got similar results, but had only studied the patients over a short period. Further studies in the 1920s indicated that seizures generally returned after the fast. Charles Howland, the parent of one of Conklin's successful patients, gave his brother John a gift of $5000 to study "the ketosis of starvation". As professor of paediatrics at Johns Hopkins Hospital, John Howland used the money to fund research undertaken by neurologist Stanley Cobb and his assistant William G. Lennox.
In 1921, Rollin Woodyatt reviewed the research on diet and diabetes. He reported that three water-soluble compounds, β-hydroxybutyrate, acetoacetate and acetone (known as ketone bodies) were produced by the liver in otherwise healthy people when they were starved or if they consumed a diet that is too low in carbohydrate and too high in fat. Russel Wilder, at the Mayo Clinic, built on this research and coined the term ketogenic diet to describe a diet that produced a high level of ketones in the blood (ketonemia) through an excess of fat and lack of carbohydrate. Wilder hoped to obtain the benefits of fasting in a dietary therapy that could be maintained indefinitely. His trial, in 1921, on a few epilepsy patients was the first use of the ketogenic diet as a treatment for epilepsy.
Wilder's colleague, paediatrician Mynie Peterman, later formulated the "classic" diet, with a ratio of one gram of protein per kg of body weight in children, 10–15 g of carbohydrate per day, and the remainder of calories from fat. Peterman's work, in the 1920s, established the techniques for induction and maintenance of the diet, and documented both positive and negative side effects. During this period, the Massachusetts General Hospital, under Fritz Talbot, established their ketogenic diet programme, which was very similar to the current one at Johns Hopkins Hospital. Talbot proposed that the ideal therapeutic ratio of fat to combined protein and carbohydrate was 4:1. He was the first to monitor the level of excess ketone production (ketosis) by measuring the amount excreted in the urine (ketonuria).
In the 1920s and 1930s, the only anticonvulsant drugs were the sedative bromides (1857) and phenobarbital (1912). The ketogenic diet was seen as an important and mainstream therapy, and widely used. This changed in 1938 when H. Houston Merritt and Tracy Putnam discovered phenytoin (Dilatin), and the focus of research shifted to discovering new drugs. With the introduction of sodium valproate in the 1970s, neurologists had drugs that were effective across a broad range of epileptic syndromes and seizure types. The use of the ketogenic diet, already restricted to difficult cases such as Lennox-Gastaut syndrome, declined further.
In the 1960s, it was discovered that medium-chain triglycerides (MCTs) are much more ketogenic than normal dietary fats (which are mostly long-chain triglycerides). This is because MCTs are absorbed rapidly and contain many calories. The classic ketogenic diet's severe carbohydrate restrictions made it difficult for parents to produce palatable meals and few could maintain it for long. In 1971, Peter Huttenlocher devised a ketogenic diet where about 60% of the calories came from the MCT oil, and this allowed more protein and up to three times as much carbohydrate as the classic ketogenic diet. The oil was mixed with at least twice its volume of skimmed milk, chilled, and sipped during the meal or incorporated into food. He tested it on a dozen children and adolescents with intractable seizures. Most children improved in both seizure control and alertness: results that were similar to the classic ketogenic diet. Gastrointestinal side effects were a problem, which led one patient to abandon the diet, but meals were easier to prepare and better accepted by the children. The MCT diet replaced the classic ketogenic diet in many hospitals, though some devised diets that were a combination of the two.
The ketogenic diet achieved national media exposure in October 1994, when NBC's Dateline television programme reported the case of Charlie Abrahams, son of Hollywood producer Jim Abrahams. The two-year-old suffered from intractable epilepsy that had remained undefeated by mainstream and alternative therapies. Abrahams discovered a reference to the ketogenic diet in an epilepsy guide for parents and brought Charlie to the Johns Hopkins Hospital, which was one of the few institutions still to offer the therapy. Under the diet, Charlie's epilepsy was rapidly controlled and his developmental progress resumed. This inspired Abrahams to create the Charlie Foundation to promote the diet and fund research. A multicentre prospective study began in 1994 and was presented to the American Epilepsy Society in 1996. There followed an explosion of scientific interest in the diet. In 1997, Abrahams produced a TV movie, …First Do No Harm, starring Meryl Streep, in which a young boy's intractable epilepsy is successfully treated by the ketogenic diet.
As of 2007, the ketogenic diet is available from around 75 centres in 45 countries. The form of classic or MCT ketogenic diet offered varies with the hospital and culturally. Less restrictive variants, such as the modified Atkins diet, have emerged as alternatives, particularly among older children and adults. The ketogenic diet is also under investigation for the treatment of a wide variety of disorders other than epilepsy.
Another difference between older and newer studies is that the type of patients treated with the ketogenic diet has changed over time. When first developed and used, the ketogenic diet was not a treatment of last resort; in contrast, the children in modern studies have already tried and failed a number of anticonvulsant drugs, so may be assumed to have more difficult-to-treat epilepsy. Modern study design prefers a prospective cohort (the patients in the study are chosen before therapy begins) and that results are presented for all patients irrespective of whether they started or completed the treatment (known as intent-to-treat analysis). This is an attempt to control for selection bias. Early and modern studies also differ because the treatment protocol has changed. In older protocols, the diet was initiated with a prolonged fast, designed to lose 5–10% body weight, this heavily restricted the calorie intake. Concerns over child health and growth led to a relaxation of the diet's restrictions.
Children with refractory epilepsy are more likely to find the ketogenic diet to be effective than trying an alternative anticonvulsant drug. For patients who benefit, half will achieve a seizure reduction within five days (if the diet starts with an initial fast of one to two days), three-quarters achieve a reduction within a fortnight and 90% achieve a reduction within 23 days. If the diet does not begin with a fast, the time for half of the patients to achieve an improvement is longer (a fortnight) but the long-term seizure reduction rates are unaffected. Since fasting increases the risk of acidosis and hypoglycaemia, its use is particularly beneficial where there is some medical urgency. If no improvement is seen within two months, it is likely that the diet has failed.
The biggest modern study with an intent-to-treat prospective design was published in 1998. As with most studies of the ketogenic diet, there was no control group (patients who were denied the treatment). A team from the Johns Hopkins Hospital studied 150 children for at least 12 months. By three months, 25 patients had dropped out, 26% had a good reduction in seizures (50–90% reduction), 31% had an excellent reduction (90–99% reduction) and 3% became seizure free. By twelve months, 67 patients had dropped out, 23% had a good reduction, 20% had an excellent reduction and 7% were seizure free. In the same year, a multicentre study of 51 children showed similar efficacy, and proved that the results could be repeated by other institutions.
It is possible to combine the results of a number of small studies to produce evidence that is stronger than available from each study alone. This statistical method is known as meta-analysis and it was performed on the ketogenic diet by the Blue Cross and Blue Shield Association in 2000. It confirmed that about half the children starting the diet will achieve at least a 50% reduction in seizure frequency. About half drop out by twelve months and these are patients who had less than 50% reduction.
In 2003, a Cochrane review of the published literature found there were no randomised controlled trials on the ketogenic diet. Such trials randomly allocate the studied patients into two groups: those that receive the treatment and those that do not. This allows the groups to be compared and is particularly important for medical conditions where patients often get better without treatment. The review concluded that there was "no reliable evidence from randomised controlled trials to support the use of ketogenic diets for people with epilepsy" and stated that the diet was merely "a possible option" in the treatment of intractable epilepsy.
Long-term blinding (where participants are unaware if they are receiving the treatment a placebo instead) is made difficult by the nature of the diet. However, a short-term blinded study is possible, by secretly introducing glucose into the diet of some patients, which spoils the effect of the diet. Children would be randomised to receive a drink that contained glucose or one containing an artificial sweetener. A long-term randomised placebo-controlled trial is not considered feasible. It may also be unethical since it would require physicians to withhold an effective treatment (meta-analysis of the many uncontrolled prospective and retrospective trials already provides sufficient evidence to recommend clinical use).
The first randomised controlled trial was published in 2008, which had an intent-to-treat prospective design, but no blinding. It studied 145 children, half of whom started the ketogenic diet immediately, and half after a three-month delay. Of the children in the diet group, 38% had at least a 50% reduction in seizure frequency, 7% had at least a 90% reduction; one child became seizure-free. Only 6% of the control group saw a greater than 50% reduction in seizure frequency and no children had a 90% reduction. The mean seizure frequency of the diet group fell by a third; the control group's mean seizure frequency actually got worse.
The ketogenic diet is indicated as an adjunctive (additional) treatment in children with drug-resistant epilepsy. The ketogenic diet is endorsed by national guidelines in Scotland, England and Wales and by US insurance companies. In the UK, the National Institute for Health and Clinical Excellence states that the diet should not be recommended for adults with epilepsy because there is insufficient evidence of efficacy.
Advocates for the diet recommend it be "seriously considered" after two medications have failed, as the chance of other drugs succeeding is only 10%. A survey in 2005 of 88 paediatric neurologists in the US found that 36% regularly prescribed the diet after three or more drugs had failed; 24% occasionally prescribed the diet as a last resort; 24% had only prescribed the diet in a few rare cases; and 16% had never prescribed the diet. There are several possible explanations for this gap between the evidence and clinical practice. One major factor may be the lack of adequately trained dietitians, who are needed to operate a ketogenic diet programme.
Because the ketogenic diet radically alters the metabolic state of the body, it is a first-line therapy in children with certain congenital metabolic diseases, but in others, it is an absolutely contraindicated. The diseases, pyruvate dehydrogenase (E1) deficiency and glucose transporter 1 deficiency syndrome prevent the body from using carbohydrate as fuel, which leads to a dependency on ketone bodies. The ketogenic diet is beneficial in treating the seizures and some other symptoms in those diseases. In contrast, the diseases pyruvate carboxylase deficiency and porphyria prevent the use of the diet. (Porphyria's acute symptoms can be brought on by fasting and are treated with a high-carbohydrate diet.) The ketogenic diet is generally contraindicated in patients with defects of fatty acid oxidation, certain mitochondrial cytopathies, and known carnitine deficiencies, which prevent the body using fat as fuel.
Most children who start the ketogenic diet have already tried six or seven anticonvulsants and are typically taking two. No single anticonvulsant drug has been found to be beneficial or harmful when used in combination with the ketogenic diet. A trial in 2007 of 30 children studied the combination of ketogenic diet and the vagus nerve stimulator (VNS). About half the children were already on the ketogenic diet and had the VNS added to their therapy; the other half had the opposite sequence. About two-thirds of the children had a greater than 50% reduction in their seizures because of combining these therapies. Those who responded well generally did so within a month. No significant side effects were noted and as with other studies, the children who did not respond well tended to be the ones who subsequently discontinued the diet.
The ketogenic diet is not a benign holistic or natural treatment for epilepsy; as with any serious medical therapy, there may be complications. These are generally less severe and less frequent than with anticonvulsant medication or surgery. Common but easily treatable side effects include constipation, lack of appropriate weight gain for age, low-grade acidosis, and hypoglycaemia if there is an initial fast. Cholesterol may increase by around 30%.
About 1 in 20 children on the ketogenic diet will develop kidney stones (compared with 1 in several thousand for the general population). A class of anticonvulsants known as carbonic anhydrase inhibitors (topiramate, zonisamide) are known to increase the risk of kidney stones, but the combination of these anticonvulsants and the ketogenic diet does not appear to elevate that risk. The stones are treatable and do not lead to discontinuation of the diet. Oral potassium citrate is preventative and has no clear disadvantages; its routine use is under investigation. Kidney stone formation (nephrolithiasis) occurs on the diet for four reasons.
The Johns Hopkins Hospital protocol for initiating the ketogenic diet has been widely adopted. It involves a consultation with the patient and their carers, and, later, a short hospital admission. Johns Hopkins begins the diet with a short fast, which occasionally poses a significant health risk in young children, so a stay in hospital is necessary to monitor for complications.
At initial consultation, patients are screened for conditions that may contraindicate the diet. Dietary history is obtained and the parameters of the diet selected: the ketogenic ratio, the calorie requirements, and the fluid intake.
The day before admission to hospital, the level of carbohydrates in the diet is decreased and the patient begins fasting after their evening meal. On admission, only fluids are allowed until dinner, which consists of "eggnog" restricted to one-third of the usual calories for a meal. The following breakfast and lunch are similar, and on the second day, the dinner is increased to "eggnog" with two-thirds of the usual calories. By the third day, dinner contains the full calorie quota and is a standard ketogenic meal (not "eggnog"). After a ketogenic breakfast on the fourth day, the patient is discharged. If possible, the patient's current medicines are exchanged for carbohydrate-free formulations.
When in the hospital, glucose levels are checked and the patient is monitored for signs of symptomatic ketosis (which can be treated with a small quantity of orange juice). Lack of energy and lethargy are common but disappear within two weeks. The parents attend classes over the first three full days, which cover nutrition, managing the diet, preparing meals, avoiding sugar and handling illness. The level of parental education and commitment required is much higher than with medication.
Variations on the Johns Hopkins protocol are common. If there is no initial fast, the time to reach ketosis is longer (but still achieved within five days), and there are fewer initial complications. The initiation can be performed using outpatient clinics rather than requiring a stay in hospital. Fluid restriction may be relaxed, leading to fewer cases of dehydration. Rather than increasing meal sizes over the three-day initiation, some institutions maintain meal size but alter the ketogenic ratio from 2:1 to 4:1.
At Johns Hopkins Hospital, outpatient clinics are held at 3, 6, 12, 18 and 24 months after initiation. A period of fine tuning is necessary to ensure consistent ketosis is maintained and better adapt the meal plans to the patient. This is typically done over the telephone with the hospital dietitian. Urinary ketone levels are checked daily to detect ketosis has been achieved, and confirm the patient is following the diet, but the level of ketones does not correlate with an anticonvulsant effect. The test strip contains nitroprusside, which turns from buff-pink to marroon in the presence of acetoacetate (one of the three ketone bodies).
A short-lived increase in seizure frequency may occur during illness or if ketone levels fluctuate. The diet may be modified if seizure frequency remains high, or the child is losing weight. Loss of seizure-control may come from unexpected sources. Even "sugar-free" food can contain carbohydrates such as maltodextrin, sorbitol, starch and fructose. The sorbitol content of suntan lotion and other skincare products may be high enough for some to be absorbed enough through the skin, and negate ketosis.
About 10% of children on the ketogenic diet achieve freedom from seizures, and many manage to reduce or discontinue anticonvulsant drugs. At around two years on the diet, or after six months of seizure freedom, the diet may be gradually discontinued over a two- to three-month period. This is done by lowering the ketogenic ratio until urinary ketosis is no longer detected, and then lifting all calorie restrictions. Children who discontinue after achieving seizure freedom have about a 20% risk of seizures returning. The length of time until recurrence is highly variable but averages two years.
This recurrence risk compares with 10% for resective surgery (where part of the brain is removed) and 30–50% for anticonvulsant therapy. Of those that have a recurrence, just over half can regain freedom from seizures either with anticonvulsants, or by returning to the ketogenic diet. Recurrence is more likely if, despite seizure freedom, an EEG shows epileptiform spikes. These spikes are an indication of epileptic activity in the brain, but are below the level that will cause a seizure. Recurrence is also likely if an MRI shows focal abnormalities (for example, children with tuberous sclerosis). Such children may remain on the diet longer than normal, and it has been suggested that children with tuberous sclerosis who achieve seizure freedom could remain on the ketogenic diet indefinitely.
The ketogenic diet is calculated by a dietitian for each child; age, weight, activity levels, culture and food preferences all affect the meal plan. First, the energy requirements are set at 80–90% of the recommended daily amounts (RDA) for the child's age (the high-fat diet requires less energy to process than a typical high-carbohydrate diet). Highly active children or those with muscle spasticity require more calories than this; immobile children require less. The ketogenic ratio of the diet compares the weight of fat to the combined weight of carbohydrate and protein. This is typically 4:1, but children who are under 18 months, who are over 12 years, or who are obese may be started on a 3:1 ratio. Fat is energy-rich, with 9 kcal/g compared to 4 kcal/g for carbohydrate or protein, so portions on the ketogenic diet are smaller than normal. The quantity of fat in the diet can be calculated from the overall energy requirements and the chosen ketogenic ratio. Next, the protein levels are set to allow for growth and body maintenance, and are around 1 g protein for each kg of body weight. Lastly, the amount of carbohydrate is set according to what allowance is left, while maintaining the chosen ratio. Any carbohydrate in medications or supplements must be subtracted from this allowance. The total daily amount of fat, protein and carbohydrate is then evenly divided across the meals.
A computer program may be used to help generate meals, which have four components: heavy whipping cream, a protein-rich food (typically meat), a fruit or vegetable, and butter, vegetable oil or mayonnaise. Only fruit and vegetables that are low in carbohydrate are allowed, which eliminates bananas, potatoes, peas and corn. Suitable fruits are divided into two groups based on the amount of carbohydrate they contain. Vegetables are similarly divided into two groups. Foods within each of these four groups may be freely substituted to allow for variation without needing to recalculate portions sizes. For example, cooked broccoli, Brussels sprouts, cauliflower and green beans are all equivalent. Fresh, canned or frozen foods are equivalent but raw and cooked vegetables differ, and processed foods are an additional complication. Parents are required to be precise when measuring food quantities on an electronic scale accurate to 1 g.
The ketogenic diet is deficient in several vitamins and minerals, so sugar-free supplements are prescribed. This child must eat the whole meal and cannot have extra portions; any snacks must be incorporated into the meal plan. A small amount of MCT oil may be used help with constipation or increase ketosis. A typical day of food for a child on a 4:1 ratio, 1500 calorie ketogenic diet comprises:
Ketogenic "eggnog" is used during induction and is a drink with the required ketogenic ratio. For example, a 4:1 ratio eggnog would contain 60 g of 36% heavy whipping cream, 25 g egg, vanilla and saccharin flavour. This contains 245 calories, 4 g protein, 2 g carbohydrate and 24 g fat (24:6 = 4:1).
Normal dietary fat contains long-chain triglycerides (LCT). Medium-chain triglycerides are more ketogenic than LCTs. Their use allows the fat content to be lowered and consequently enables greater protein and carbohydrate intake. The original MCT diet developed by Peter Huttenlocher in the 1970s derived 60% of the calories from MCT oil. It is identical in efficacy to the classic diet; abdominal bloating and diarrhoea are more common, but constipation is less of a problem. In order to improve tolerability, some hospitals have created diets using both MCT and LCT oils. One variant, studied in the 1980s by Ruby Schwartz at the John Radcliff Infirmary, derived 30% of the calories from MCT oil. In a five-year trial starting in 2001, Elizabeth Neil at the Great Ormond Street Hospital, compared children on the classical diet with children on an MCT variant that derived 45% of the calories from MCT oil.
A modified Atkins diet is effective in children and adults. The diet consists of 60% fat, 30% protein and 10% carbohydrate by weight; calories are not restricted. Carbohydrate is limited to 10 g per day for at least one month, and gradually increased to 10% if this limitation is not tolerated. Consistently strong ketosis is more difficult to achieve than on the ketogenic diet; patients with wildly fluctuating urinary ketones have unfavourable seizure outcomes. Achieving the balance of fat, protein and carbohydrate can be difficult; patients may consume the appetising protein (meat) and leave or vomit the fat. Older children and adolescents who refuse the ketogenic diet's restrictions may tolerate the modified Atkins diet.
Infants, or patients fed via a gastrostomy tube can also be given a ketogenic diet. Parents make up a prescribed powdered formula, such as KetoCal, into a liquid feed. Gastrostomy feeding avoids any issues with palatability, and bottle-fed infants readily accept the ketogenic formula. KetoCal is a nutritionally complete feed containing milk protein and supplemented with amino acids, fat, carbohydrate, vitamins, minerals and trace elements. It is used to administer the 4:1 ratio classical ketogenic diet in children over one year. Each 100 g of powder contains 73 g fat, 15 g protein and 3 g carbohydrate, and is typically diluted 1:5 with water. The formula is available unflavoured or in an artificially sweetened vanilla flavour and is suitable for tube or sip feeding.
Many hypotheses have been put forward to explain how the ketogenic diet works; it remains a mystery. Disproven hypotheses include systemic acidosis, electrolyte changes and hypoglycaemia. Changes in neurotransmitter levels occur and cerebral energy state is improved. Although many biochemical changes are known to occur in the brain of a patient on the ketogenic diet, it is not known which of these has an anticonvulsant effect. The lack of understanding in this area is similar to the situation with anticonvulsant drugs.
On the ketogenic diet, carbohydrates are severely restricted and so cannot provide for all the metabolic needs of the body. Instead, fatty acids are used as the major source of fuel. These are used through fatty-acid oxidation in the mitochondria. Humans can convert some amino acids into glucose by gluconeogenesis, but cannot do this for fatty acids. Since amino acids are needed to make proteins, these cannot be used only to produce glucose. This poses a problem for the brain since it is normally fuelled solely by glucose, and fatty acids do not cross the blood-brain barrier. To overcome this problem, the liver uses fatty acids to synthesise the three ketone bodies β-hydroxybutyrate, acetoacetate and acetone. Ketone bodies can enter the brain and substitute for glucose.
The ketone bodies are possibly anticonvlusant in themselves; acetoacetate and acetone protect against seizures in animal models. The ketogenic diet results in adaptive changes to brain energy metabolism that increases the energy reserves; ketone bodies are a more efficient fuel than glucose, and the number of mitochondria is increased. This may help the neurons to remain stable in the face of increased energy demand, and may confer a neuroprotective effect.
The ketogenic diet has been studied in at least 14 rodent animal models of seizures. It is protective in many of these models and has a different protection profile than any known anticonvulsant. This, together with studies showing its efficacy in patients who have failed to achieve seizure control on half a dozen drugs, suggests a unique mechanism of action.
Anticonvulsants suppress epileptic seizures but they neither cure nor prevent the development of the inherent seizure susceptibility. The development of epilepsy (epileptogenesis) is a process that is poorly understood. A few anticonvulsants (valproate, levetiracetam and benzodiazepines) have shown antiepileptogenic abilities in animal models of epileptogenesis. However, no anticonvulsant has ever achieved this in clinical trial in humans. The ketogenic diet has been found to have antiepileptogenic properties in rats.
A number of rare metabolic diseases may benefit directly from the ketogenic diet. Case reports on two children indicate a possible use in treating astrocytomas, which are a form of brain tumour. Autism, depression, migraine headaches, polycystic ovary syndrome, and type 2 diabetes mellitus have been shown to benefit in small case studies. There is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease, and may be protective in traumatic brain injury and stroke.
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