At about the same time as the study of Cobb and Lennox, in 1921, a review article about diet adjustments and diabetes by Woodyatt stated "acetone, acetic acid, and beta-hydroxybutyric acid appear ... in a normal subject by starvation, or a diet containing too low a proportion of carbohydrate and too high a proportion of fat. It [ketoacidosis] appears to be the immediate result of the oxidation of certain fatty acids in the absence of a sufficient proportion of 'oxidizing' glucose" (32).
Concurrently, Dr. Wilder at the Mayo Clinic proposed, probably based on the work summarized by Woodyatt, "that the benefits of ... fasting ... could be obtained if ketonemia was produced by other means. The ketone bodies . are formed from fat and protein whenever a disproportion exists between the amount of fatty acid and the amount of sugar actually burning in the tissues. In any case, as has long been known, it is possible to provoke ketogenesis by feeding diets which are very rich in fat and low in carbohydrate. It is proposed therefore, to try the effects of such ketogenic diets on a series of epileptics" (27). Wilder suggested that a ketogenic diet should be as effective as fasting and could be maintained for a much longer period, compensating for the obvious disadvantages of a prolonged fast.
In a report issued the following day, he described the dramatic improvement in seizure control of three patients with epilepsy who had been admitted to the Mayo Clinic for initiation of the ketogenic diet (33). He concluded, "It is impossible to draw conclusions from the results of these few patients treated with high fat diets, but we have here a method of observing the effect of ketosis on the epileptic. If this is the mechanism responsible for the beneficial effect of fasting, it may be possible to substitute for that rather brutal procedure a dietary therapy which the patient can follow with little inconvenience and continue at home as long as seems necessary" (33). It was Wilder who coined the term ketogenic diet.
Peterman and other pediatricians eagerly acted on Wilder's suggestion (34,35). Peterman first reported the calculation and effectiveness of the ketogenic diet from the Mayo Clinic in 1924 (35). Peterman's ketogenic diet, composed of one gram of protein per kilogram of body weight in children, 10-15 g of carbohydrate per day, and the remainder of the calories in fat, is identical to the ketogenic diet that is used today. Peterman documented the importance of teaching the caregivers management of the diet before discharge, individualization of the diet, close follow-up, and the potential for further adjustments at home. He also made the early observation that excess ketosis could lead to nausea and vomiting, symptoms that were quickly relieved by orange juice (34). This clinical caveat is still useful to know and is employed as needed during initiation of the ketogenic diet (36).
Peterman also noted improvements in behavior and cognitive effects that accompanied the ketogenic diet.
"The mental development has been normal in all patients, and exceptionally good in seven of the twenty who are now free from attacks. In all the children treated with the ketogenic diet there was a marked change in character, concomitant with the ketosis, a decrease in irritability, and an increased interest and alertness; the children slept better and were more easily disciplined. This action of the diet warrants further study" (34).
This last comment is as true today as it was in 1925! M. B. Pulsifer and others, 75 yr later, performed the first prospective study of the effects of the ketogenic diet on development and behavior (12). She concluded, "At follow-up, mean developmental quotient showed statistically significant improvement (p < 0.05), with significant behavioral improvements in attention and social functioning," verifying Peterman's earlier observation.
These initial reports were rapidly followed by reports from Talbot and colleagues (Harvard) (28,37-39) and from McQuarrie and Keith (Mayo Clinic) (40) in 1926 and 1927. Talbot introduced the first report as follows: "In 1921, the children's medical service of the Massachusetts General Hospital (MGH) initiated a study of the treatment of idiopathic epilepsy. The first method of attack was by the fasting method recommended by Conklin of Battle Creek" (37). This statement verifies the impact Macfad-den ultimately had, even on such prestigious institutions as MGH.
Talbot noticed some seizure freedom in all 21 children during the fast, but the seizures returned after the fast was broken. As a result, in 1924 MGH adopted the keto-genic diet as performed by the Mayo Clinic (Dr. Peterman). Talbot also noted that the diet was well tolerated, "without causing any untoward symptoms in the patients. On the contrary, they seem to be more alert and less nervous" (37). Talbot also acknowledged the critical role of the dietician and noted that "a clever dietician works out various little tricks to get in fat" (37). Talbot's 1930 textbook on the treatment of epilepsy included tables with complete discussion and instructions for the ketogenic diet (41). The current Johns Hopkins Hospital protocol (see ref. 42) for calculating and initiating the ketogenic diet after a period of fasting to hasten the production of ketosis, and gradually increasing the amount dietary fat introduced over several days, was well discussed by Talbot in 1926 (38).
By 1928, Talbot had experience with differing compositions of ketogenic diets and wrote that "the best therapeutic results in epilepsy are not obtained until the ratio has approached 4:1..." (24), which is now recognized as the most common composition for the ketogenic diet. McQuarrie and Keith, while studying the biochemistry of children on the ketogenic diet in 1927, made the initial observation that the proportion of acetone bodies in the blood runs parallel to that in the urine (40), a finding validated 62 yr later by Schwartz et al. (43). The Mayo Clinic investigators also were the first to note variations during the day in the intensity of ketosis, with a maximum in the late afternoon and the nadir in the early morning hours.
McQuarrie and Keith were aware of the recently rerecognized tendency of children to have seizures early in the morning, when ketosis is minimal, and they suggested the addition of a midnight snack to maintain early ketosis. They also recognized that the degree of ketosis to prevent seizures may vary across individuals, and as a result adjust ing the diet for the individual patient was necessary to ensure optimal ketosis. Such adjustments are routinely made in multidisciplinary epilepsy clinics today.
By 1927 Helmholz at the Mayo Clinic was aware that if the child did not have definite improvement in seizure control after 2 mo of the ketogenic diet, it was fair to say that a therapeutic failure had occurred and appropriate to abandon the diet (29). In 1927 the Section on Pediatrics and Nutrition at the Mayo Clinic prepared a pamphlet that describes in detail meal plans and recipes for a ketogenic diet (44). This was done in response to the demand for this type of practical information.
The use of the ketogenic diet was recorded in almost every comprehensive textbook on epilepsy in childhood that appeared between 1941 and 1980 (3,15,18,45-51). Most of these texts had full chapters describing the diet, telling how to initiate it and how to calculate meal plans. Extensive tables listed the nutritional composition of foods and discussed meal planning.
Throughout the 1920s and 1930s, the ketogenic diet was widely used (see next section). When Merritt and Putnam discovered diphenylhydantoin in 1938, the attention of physicians and researchers shifted focus from the mechanism of action and efficacy of the ketogenic diet to new antiepileptic drugs (AEDs) (see ref. 52). A new era of medical therapy for epilepsy had begun, and the ketogenic diet fell by the wayside. Medications were easier to administer and new chemical compounds were always on the horizon. As early as 1937, Ford, in a pediatric neurology text, found the ketogenic diet difficult, rigid, and expensive (53).
In an effort to make the classic ketogenic diet more palatable, Huttenlocher et al., in 1971, introduced a medium-chain triglyceride (MCT) oil diet that was more ketogenic per calorie, allowing less restriction of other foods (54). This 1971 report from Yale University documented a therapeutically significant anticonvulsant effect in 6 of 12 children with daily myoclonic and astatic seizures. As a result, other centers adopted the MCT diet in place of the classic ketogenic diet and reported it as the "ketogenic diet" (55-60). Almost 20 yr went by before Schwartz and colleagues conducted the only comparative trial of the MCT diet and the classic ketogenic diet (see Section 3.2.) (43,61). This report documented more side effects and less palatability of the MCT diet.
As new AEDs became available, the ketogenic diet was used less and less. After the introduction of sodium valproate, it was believed that this branched-chain fatty acid would treat children previously placed on the diet to treat the seizures of Lennox-Gas-taut syndrome and that the diet could no longer be justified (62). Pediatric neurologists and epileptologists were led to believe that better understanding of central nervous system neurotransmitters and rationally designed AEDs were the hope for the future. Fewer children were placed on the ketogenic diet, resulting in fewer dieticians who were trained in the initiation and maintenance of the diet. As Lennox stated in 1960, "Though interest in fasting (or the ketogenic diet) as a treatment has almost vanished, doubtless much scientific gold remains in 'them thar hills'" (18).
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