result

Epilepsy Epilepsy is one of the most common neurological disorders after stroke and affects at least 50 million people worldwide It is diagnosed in a person having recurrent unprovoked seizures These occur when cortical neurons fire excessively hypersynchronously or both leading to temporary disruption of normal brain function This might affect for example the muscles the senses consciousness or a combination A seizure can be focal confined to one part of the brain or generalised spread widely throughout the brain and leading to a loss of consciousness Epilepsy may occur for a variety of reasons some forms have been classified into epileptic syndromes most of which begin in childhood Epilepsy is considered refractory to treatment when two or three anticonvulsant drugs have failed to control it About 60 of patients will achieve control of their epilepsy with the first drug they use whereas about 30 do not achieve control with drugs When drugs fail other options include epil epsy surgery vagus nerve stimulation and the ketogenic diet History The ketogenic diet is a mainstream nonpharmacologic therapy that was developed to reproduce the success and remove the limitations of the non mainstream use of fasting to treat epilepsy Note 2 Although popular in the 1920s and 30s it was largely abandoned in favour of new anticonvulsant drugs Most individuals with epilepsy can successfully control their seizures with medication However 2030 fail to achieve such control despite trying a number of different drugs For this group and for children in particular the diet has once again found a role in epilepsy management Fasting A news report of Dr Hugh Conklin s water diet treatment from 1922 Ancient Greek physicians treated diseases including epilepsy by altering their patients diet An early treatise in the Hippocratic Corpus On the Sacred Disease mentions the disease it dates from c 400 BC Its author argued against the prevailing view that epilepsy was supernat ural in origin and cure and proposed that dietary therapy had a rational and physical basis Note 3 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 Note 4 The royal physician Erasistratus declared One inclining to epilepsy should be made to fast without mercy and be put on short rations Note 5 Galen believed an attenuating diet Note 6 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 epilepsy patients of all ages were detoxified by consuming a low calorie vegetarian diet combined with periods of fasting and purging Two 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 Bernarr Macfadden an American exponent of physical culture popularised the use of fasting to restore health His disciple the osteopathic physician Hugh Conklin of Battle Creek Michigan began to treat his epilepsy patients by recommending fasting 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 falling to 50 in adults Later analysis of Conklin s case records showed 20 of his patients 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 with a fast followed by a starch and sugar free diet sinc e 1912 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 achieved similar results despite only having studied the patients for a short time Further studies in the 1920s indicated that seizures generally returned after the fast Charles Howland the parent of one of Conklin s successful patients and a wealthy New York corporate lawyer gave his brother John a gift of 5 000 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 Diet In 1921 Rollin Woodyatt reviewed the research on diet and diabetes He reported that three water soluble compounds hydroxybutyrate acetoacetate and acetone known collectively as ketone bodies were produced by the liver i n otherwise healthy people when they were starved or if they consumed a very low carbohydrate high fat diet 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 on a few epilepsy patients in 1921 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 kilogram of body weight in children 1015 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 Peterman documented positive effects improved alertness behaviour and sleep and adverse effects nausea and vomiting due to excess ketosis The diet proved to be very successful in children Peterman reported in 1925 that 95 of 37 young patients had improved seizure control on the diet and 60 became seizure free By 1930 the diet had also been studied in 100 teenagers and adults Clifford Barborka also from the Mayo Clinic reported that 56 of those older patients improved on the diet and 12 became seizure free Although the adult results are similar to modern studies of children they did not compare as well to contemporary studies Barborka concluded that adults were least likely to benefit from the diet and the use of the ketogenic diet in adults was not studied again until 1999 Anticonvulsants and decline During the 1920s and 1930s when the only anticonvulsant drugs were the sedative bromides discovered 1857 and phenobarbital 1912 the ketogenic diet was widely used and studied This changed in 1938 when H Houston Merritt and Tracy Putnam discovered phenytoin Dilantin and the focus of research shifted to discovering new drugs With the introduction of sodium valproate in the 1970s drugs were available to neurologists that were effective across a broad range of epileptic syndromes and seizure types The use of the ketogenic diet by this time restricted to difficult cases such as Lennoxastaut syndrome declined further MCT diet Medium chain triglyceride MCT oil emulsion In the 1960s it was discovered that medium chain triglycerides MCTs produce more ketones per unit of energy than normal dietary fats which are mostly long chain triglycerides MCTs are more efficiently absorbed and are rapidly transported to the liver via the hepatic portal system rather than the lymphatic system The severe carbohydrate restrictions of the classic ketogenic diet made it difficult for parents to produce palatable meals that their children would tolerate In 1971 Peter Huttenlocher devised a ketogenic diet where about 60 of the calories came from the MCT oil and this allowed more protein an d 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 twelve 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 upset was 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 the US 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 epilepsy that had remained uncontrolled by mainstream and alternative therapies Abrahams d iscovered a reference to the ketogenic diet in an epilepsy guide for parents and brought Charlie to the Johns Hopkins Hospital which had continued 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 the results were presented to the American Epilepsy Society in 1996 and were published in 1998 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 Less restrictive variants such as the modified Atkins diet have come into use particularly among older children and adults The ketogenic diet is also under investigation for the t reatment of a wide variety of disorders other than epilepsy Efficacy The ketogenic diet reduces seizure frequency by more than 50 in half of the patients who try it and by more than 90 in a third of patients Three quarters of children who respond do so within two weeks though experts recommend a trial of at least three months before assuming it has been ineffective Children with refractory epilepsy are more likely to find the ketogenic diet to be effective than to benefit from trying another anticonvulsant drug There is some evidence that adolescents and adults may also benefit from the diet Trial design Early studies reported high success rates in one study in 1925 60 of patients became seizure free and another 35 of patients had a 50 reduction in seizure frequency These studies generally examined a cohort of patients recently treated by the physician what is known as a retrospective study and selected patients who had successfully maintained the dietary restrictions Howeve r these studies are difficult 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 from patients who would generate better results In an attempt to control for this bias modern study design prefers a prospective cohort the patients in the study are chosen before therapy begins in which the results are presented for all patients regardless of whether they started or completed the treatment known as intent to treat analysis 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 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 510 body weight and heavily restricted the calorie intake Concerns over child health and growth led to a relaxation of the diet s restrictions Fluid restriction was once a feature of the diet but this led to increased risk of constipation and kidney stones and is no longer considered beneficial Outcomes The largest modern study with an intent to treat prospective design was published in 1998 by a team from the Johns Hopkins Hospital and followed up by a report published in 2001 As with most studies of the ketogenic diet there was no control group patients who did not receive the treatment The study enrolled 150 children After three months 83 of them were still on the diet 26 had experienced a good reduction in seizures 31 had had an excellent reduction and 3 were seizure free Note 7 At twelve months 55 were still on the diet 23 had a good response 20 had an exc ellent response and 7 were seizure free Those who had discontinued the diet by this stage did so because it was ineffective too restrictive or due to illness and most of those who remained were benefiting from it The percentage of those still on the diet at two three and four years was 39 20 and 12 respectively During this period the most common reason for discontinuing the diet was because the children had become seizure free or significantly better At four years 16 of the original 150 children had a good reduction in seizure frequency 14 had an excellent reduction and 13 were seizure free though these figures include many who were no longer on the diet Those remaining on the diet after this duration were typically not seizure free but had had an excellent response It is possible to combine the results of several small studies to produce evidence that is stronger than that available from each study alone statistical method known as meta analysis One of four such analyses co nducted in 2006 looked at 19 studies on a total of 1 084 patients It concluded that half the patients achieved a 50 reduction in seizures and a third achiev