Variations on the Johns Hopkins protocol are common. The initiation can be performed using outpatient clinics rather than requiring a stay in hospital. Often, no initial fast is used (fasting increases the risk of acidosis, hypoglycaemia, and weight loss). 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.
The Johns Hopkins Hospital protocol for initiating the ketogenic diet has been widely adopted. It involves a consultation with the patient and their caregivers and, later, a short hospital admission. Because of the risk of complications during ketogenic diet initiation, most centres begin the diet under close medical supervision in the hospital.
There are theoretically no restrictions on where the ketogenic diet might be used, and it can cost less than modern anticonvulsants. However, fasting and dietary changes are affected by religious and cultural issues. A culture where food is often prepared by grandparents or hired help means more people must be educated about the diet. When families dine together, sharing the same meal, it can be difficult to separate the child's meal. In many countries, food labelling is not mandatory so calculating the proportions of fat, protein and carbohydrate is difficult. In some countries, it may be hard to find sugar-free forms of medicines and supplements, to purchase an accurate electronic scale, or to afford MCT oils.
Although many hypotheses have been put forward to explain how the ketogenic diet works, it remains a mystery. Disproven hypotheses include systemic acidosis (high levels of acid in the blood), electrolyte changes and hypoglycaemia (low blood glucose). 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 many anticonvulsant drugs.
In the mid-1990s, 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 made-for-television film starring Meryl Streep. The foundation sponsored a multicentre research study, the results of which—announced in 1996—marked the beginning of renewed scientific interest in the diet.
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, Jr. 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 Lennox–Gastaut syndrome, declined further.
Wilder's colleague, paediatrician Mynie Gustav Peterman, later formulated the classic diet, with a ratio of one gram of protein per kilogram 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. 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 Joseph Barborka, Sr., 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.