Sunday, September 7, 2008 by Dr. Manny
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 program and …First Do No Harm (1997), a TV movie starring Meryl Streep. The foundation sponsored a multi-centre 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 a treatment for medical conditions other than epilepsy is, as of 2007, still at the research stage.
In 2008, a randomized 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.
History
The ketogenic diet is a mainstream therapy that was developed to improve on the success and limitations of the non-mainstream use of fasting to treat epilepsy. Although popular for a while, it was discarded when anticonvulsant drugs became available. The diet has once again found a role in treating children with refractory epilepsy (epilepsy that cannot be brought under control after adequate trials of different drugs).
Fasting
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, popularized 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 pediatrics at Johns Hopkins Hospital, John Howland used the money to fund research undertaken by neurologist Stanley Cobb and his assistant William G. Lennox.
Diet
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, pediatrician 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 program, 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).
Anticonvulsants
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.
MCT diet
Medium-chain triglyceride (MCT) oil emulsion
The ketogenic diet's severe carbohydrate restrictions made it difficult for parents to produce palatable meals and few could maintain it for long. However, 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. In 1971, Peter Huttenlocher devised a diet with sufficient MCT oil to induce ketonuria and tested it on a dozen children and adolescents with intractable seizures. The oil was mixed with at least twice its volume of skimmed milk, chilled, and sipped during the meal or incorporated into food. About 60% of the diet's calories came from the MCT oil, and this allowed more protein and up to three times as much carbohydrate as the classic ketogenic diet. 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.
Revival
The ketogenic diet achieved national media exposure in October 1994, when NBC's Dateline television program 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.[5] A multi-centre 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 centers 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.
Efficacy
Early studies reported high success rates for the diet: in one study in 1925, 60% of patients became seizure free, and another 35% benefited from a halving of their seizure frequency. These studies generally examined a cohort of patients recently treated by the physician (known as retrospective studies), and selected patients who had successfully maintained the dietary restrictions. However, these studies are hard to compare to modern trials. One reason is that these older trials suffered from selection bias, as they excluded patients who were unable to start or maintain the diet and thereby selected for patients who would generate better results.
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.
Outcomes
The effect of the diet is gauged by noting any change in the frequency of seizures, rather than a laboratory measurement of ketone levels or analysis of electroencephalogram (EEG) changes. 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. There is no way to predict who will benefit from the diet, as there no relationship between outcome and age, sex, principle seizure type or initial EEG. Adults can benefit too, though adherence to the regime becomes more difficult with adolescence. Fortunately, success at reducing seizures will motivate the patient and careers to persevere with the diet's rigors.
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 hypoglycemia, 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 multi-centre 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 randomized 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 randomized 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 randomized to receive a drink that contained glucose or one containing an artificial sweetener. A long-term randomized 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 randomized 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 Medifast diet will induce a very mild state of Ketosis after a short time. This helps Medifast dieters lose weight more quickly.
