History

For centuries, fasting has been used to treat many diseases, including seizures; it was even used in biblical times [Bible, The King James Version, 1982; Livingston, 1972].

Contemporary accounts of fasting (Table 60-1) include a child who did not respond to the conventional treatment of the day [Hendricks, 1995; Freeman et al., 1994], which was a combination of bromides and phenobarbital [Lennox and Lennox, 1960]. This child’s seizures were managed with prayer and fasting, producing dramatic improvement in seizure control during the period of starvation. However, when the period of starvation was terminated, the seizures returned [Conklin, 1922; Freeman et al., 1994; Bridge, 1949]. The child’s uncle, a pediatrician, enlisted the aid of John Howland at Johns Hopkins Hospital to understand how starvation and fasting controlled seizures and how one could maintain the beneficial effects of fasting [Lennox and Lennox, 1960]. Concurrently, Wilder at the Mayo Clinic suggested that a diet high in fat and low in carbohydrates could maintain ketosis and its accompanying acidosis longer than fasting [Freeman et al., 1994; Schwartz et al., 1989b]. Wilder was also the first to coin the term ketogenic diet. (See Wheless [2004] for a review of the ketogenic diet history.) The beneficial effects of this diet were initially recorded by investigators from Johns Hopkins University, the Mayo Clinic, and Harvard University. Use of the ketogenic diet was included in almost every comprehensive textbook on epilepsy in childhood that appeared between 1941 and 1980 [Penfield and Erickson, 1941; Lennox, 1941; Bridge, 1949; Livingston, 1954, 1963, 1972; Lennox and Lennox, 1960; Keith, 1963; Livingston et al., 1977; Withrow, 1980; Bower, 1980].

Until 1938, the ketogenic diet was one of the few available therapies for epilepsy, but it fell into disfavor when researchers turned their attention to the development of new AEDs [Livingston and Pauli, 1975]. After the introduction of sodium valproate, it was believed that this branched-chain fatty acid would treat those children previously placed on the ketogenic diet and that the diet could no longer be justified [Aicardi, 1994]. Use of the ketogenic diet decreased greatly until it received national media attention [NBC Dateline, 1994; Hendricks, 1995; Schneider and Wagner, 1995; Charlie Foundation to Help Cure Pediatric Epilepsy, 1994a; Freeman et al., 1990, 1994, 2000]. After an almost two-decade hiatus, renewed public and scientific interest has led to a better understanding and increased worldwide use of the ketogenic diet [Kleinman, 2004; Stafstrom and Rho, 2004; Kossoff et al., 2009b; Kossoff and McGrogan, 2005a].

Efficacy

As presented in Table 60-2, initial reports began to appear in the 1920s and 1930s that documented the efficacy of the ketogenic diet [Geyelin, 1921; Wilder, 1921; Peterman, 1925; Helmholz, 1927; McQuarrie and Keith, 1927; Lennox and Cobb, 1928; Barborka, 1928a, 1929; Helmholz and Keith, 1930, 1932; Pulford, 1932; Fischer, 1935; Wilder and Pollack, 1935; Helmholz and Goldstein, 1937; Wilkins, 1937]. Over the next 60–70 years, many more clinical reports appeared (Table 60-3) [Keith, 1942; Prasad et al., 1996]. About one-third to one-half of children appeared to have had an excellent response to the diet, defined by cessation or marked reduction in seizure activity. About 10 percent of children become seizure-free after initiation of the ketogenic diet, and typically stop the diet after 2 years. Of those children who become seizure-free, a minority have recurrence after the diet is stopped [Martinez et al., 2007]. Risk factors that increase the likelihood of recurrence are epileptiform abnormalities on electroencephalograms (EEGs) obtained within 12 months of diet discontinuation, a focal abnormality on magnetic resonance imaging (MRI), lower initial seizure frequency, and tuberous sclerosis complex [Martinez et al., 2007]. When the diet has been discontinued, it has usually been due to lack of efficacy. It appears that younger children are more likely to have a more favorable response than older children [Freeman et al., 1998a].

Recent studies attest to the efficacy and safety of the ketogenic diet in infants [Nordli et al., 2001; Kossoff et al., 2002; Klepper et al., 2002; Kang et al., 2005; Eun et al., 2006]. Nordli et al. retrospectively reviewed their experience with 32 infants who had been treated with the ketogenic diet, 17 of whom had infantile spasms [Nordli et al., 2001]. Most infants (71 percent) were able to maintain robust ketosis. The overall effectiveness of the diet in infants was similar to that reported for older children; 19.4 percent became seizure-free, and an additional 35.5 percent had a greater than 50 percent reduction in seizure frequency. The diet was particularly effective for children with infantile spasms. Kossoff et al. retrospectively reviewed their experience with the ketogenic diet as a treatment for infantile spasms during a 4-year period [Kossoff et al., 2002]. Twenty-three children, aged 5 months to 2 years, 39 percent of whom had symptomatic infantile spasms and 70 percent of whom had hypsarrhythmia, were started on the ketogenic diet. The children had been previously exposed to an average of 3.3 AEDs (range 0–7), and 74 percent had previously failed or relapsed after adrenocorticotropic hormone (ACTH) or steroids. The average time on the diet was 1.6 years, with 56 percent remaining on the diet at 12 months, 46 percent of whom were over 90 percent improved (three were seizure-free), and 100 percent were over 50 percent improved. Factors that predicted greater than 90 percent improvement at 12 months were age less than 1 year (p = 0.02) and exposure to ≤3 AEDs (p = 0.03). Improvement in development was related to seizure control. The same authors retrospectively reviewed their experience with the ketogenic diet as initial monotherapy for infantile spasms [Kossoff et al., 2008e]. At the end of 1 month, 8 of 13 (62 percent) infants were seizure-free (by parental report); however, the EEG normalization did not occur for 2–5 months. Time to spasm freedom was 6.5 days, suggesting that, if the ketogenic diet is used as initial treatment, a 2-week trial period is sufficient to judge efficacy for infantile spasms. In 2010, the same authors reported their 14-year experience with 104 consecutive infants prospectively started on the ketogenic diet [Hong et al., 2010]. Thirty-seven percent became spasm-free for at least a 6-month period, within a median 2.4 months of starting the ketogenic diet. A normal EEG was eventually obtained in 18 percent, and 17 percent demonstrated resolution of hypsarrhythmia. Eun et al. reviewed their experience treating 43 children with intractable infantile spasms (mean duration 13.4 months) with the ketogenic diet. Retrospective analysis revealed that the diet resulted in 53.5 percent of the patients being seizure-free; 81 percent had a greater than 50 percent reduction in seizure frequency after a mean duration of 9 months [Eun et al., 2006]. Complete seizure control was obtained within 4 weeks in 78.3 percent of the children who obtained seizure-freedom. The improvements in seizure control correlated with improvements in EEG findings. As part of the Korean multicentered experience, Kang et al. retrospectively reviewed efficacy in 49 infants treated with the ketogenic diet [Kang et al., 2005]. Only 1 of 14 children with severe myoclonic epilepsy of infancy was seizure-free at 12 months, but 56 percent had a greater than 50 percent seizure reduction. Carraballo et al. reported similar results, with 10 percent seizure-free, and 55 percent achieving a greater than 50 percent seizure reduction at 12 months [Carraballo et al., 2005]. In a small study (n = 3) of patients with a diagnosis of early infantile epileptic encephalothopy, none achieved seizure control [Kang et al., 2005].

A few early studies evaluated use of the ketogenic diet in adults (Table 60-4). Some revealed improved seizure control [Barborka, 1928b, 1930], but subsequent reports concluded that the diet is not particularly beneficial in adolescents and adults with epilepsy [Notkin, 1934; Lennox, 1941; Bridge, 1949; Livingston, 1954, 1963, 1972; Withrow, 1980; Mosek et al., 2009]. Reasons cited for this were poor dietary compliance, types of seizures seen in these age groups, and the developmental differences in the ability of the brain to use ketone bodies. As a result, past studies suggested that the optimum age of response to the diet may be in young children before the onset of adolescence. Recent studies have challenged the belief that older patients could not maintain therapeutic ketosis or comply with the rigors of the diet, and that the ketogenic diet was less efficacious in this age group. Sirven et al. [1999] reviewed the tolerability, efficacy, and adverse events in 11 adult patients prospectively begun on the classic ketogenic diet for refractory symptomatic epilepsy. All were on stable medication, and had not achieved seizure control with two or more medications; four had prior surgery. At eight months of follow-up, 1 patient was seizure-free, 5 patients had a greater than 50 percent decrease in seizure frequency, 1 patient had a less than 50 percent seizure decrease, and 4 patients discontinued the diet. Common adverse events included gastrointestinal complaints (100 percent), menstrual irregularities in all women, and increased serum cholesterol and cholesterol high-density lipoprotein (HDL) ratios. Subjective improvements in thinking and mood, without a decrease in AEDs, were reported in 7 patients, 1 without improved seizure control. Mady et al. reviewed their experience with 45 adolescents who had been on the ketogenic diet for an average duration of 1.2 years [Mady et al., 2003]. They found no evidence to support the belief that the diet was not efficacious and was too restrictive in this age group. Adolescents with multiple seizure types did best, and those with simple and complex partial seizures had the poorest response. The retention rate for motivated adolescents on the diet was not significantly different than reports in younger children.

Recent studies have critically re-examined the benefits of the diet in selected groups of patients (see Table 60-3). Schwartz et al. [1989a, 1989b] reported on the results of metabolic profiles and seizure control in 59 epileptic children receiving a normal diet or one of three forms of the ketogenic diet:

Patients fasted for 18 hours and then were placed on one of the diets and monitored for 6 weeks. All three diets produced a significant increase in total ketone body (aceto-acetate, β-hydroxybutyrate) levels that was most marked using the classical ketogenic diet [Freeman et al., 2000]. Ketone body concentrations reached a maximum in the afternoon and were frequently lower in the morning. Urinary ketones were measured and reflected changes noted in the serum. All three diets improved seizure control and none was superior to the others during the 6 weeks of observation. The first randomized trial of the classical and medium-chain triglyceride ketogenic diets was performed about 20 years later, and confirmed comparable efficacy over a longer follow-up period (1 year) [Neal et al., 2009]. Overall, these investigators found that 81 percent of patients had greater than a 45 percent reduction in seizures. Drowsiness, which occurred in 25 percent of patients during initiation of the diet, usually resolved. The medium-chain triglyceride diet was considered less palatable and associated with more side effects, including diarrhea and vomiting.

Kinsman et al reviewed 59 patients with severe intractable epilepsy; 80 percent had multiple seizure types; and 88 percent were on multiple AEDs [Kinsman et al., 1992]. Improved seizure control occurred in 67 percent of patients; 64 percent were able to reduce the amount of AEDs they were taking; 36 percent became more alert; and 23 percent had better behavior. Comorbid neurologic conditions in this group of patients with refractory epilepsy included mental retardation (84 percent), microcephaly (15 percent), and cerebral palsy (45 percent). Seizure type did not predict success with the diet. Additionally, 75 percent of the improved patients continued the diet for at least 18 months, confirming the efficacy and palatability of the diet and willingness to continue administration of the diet on the part of patients and their families. This study confirmed the earlier work by Livingston, demonstrating that 52 percent of patients had complete control and an additional 27 percent had improved control [Livingston, 1972].

The first multicenter prospective study of the efficacy of the ketogenic diet was based on data collected at seven comprehensive epilepsy centers [Vining et al., 1998]. All children in this study had intractable epilepsy, averaging 230 seizures per month. It was found that 10 percent of treated patients were seizure-free at 1 year. A greater than 50 percent decrease in seizure frequency was observed at 3 months in 54 percent of patients. This improvement was maintained at 6 (53 percent controlled) and 12 months (49 percent controlled) after initiation of the diet. Patient age, seizure type, and EEG abnormalities were not related to outcome. Approximately 47 percent remained on the diet for at least 1 year. Reasons for discontinuation included insufficient seizure control, intolerable side effects, concurrent medical illnesses, or inability to tolerate the restrictive nature of the dietary regimen. Although the number of patients was small, the study demonstrated that the diet could be used effectively in different epilepsy centers with different support staff, and that children and their families were able to comply with the diet when it was effective.

The first large prospective evaluation of the ketogenic diet was conducted in 150 consecutive children aged 1–16 years (mean age 5.3 years) [Freeman et al., 1998a]. The children were followed for a minimum of 1 year, had previously been on an average of 6.24 medications, and were on a mean of 1.97 medications at the diet’s initiation. Seventy percent of children had an intelligence or developmental quotient of <69. The children averaged 410 seizures per month before the ketogenic diet. At 6 months, 71 percent remained on the diet and 32 percent had a greater than 90 percent decrease in seizures. At 1 year, 55 percent remained on the diet, 7 percent were seizure-free, and 27 percent had a greater than 90 percent decrease in seizure frequency. There was no statistically significant difference in seizure control based on age, sex, or seizure type, although none of the patients had only partial seizures. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive.

All of the prior reports of efficacy of the ketogenic diet described open-label trials. Only one randomized, blinded crossover study has been performed. This study evaluated the efficacy of ketogenic diet for atonic-myclonic or drop seizures associated with Lennox–Gastaut syndrome [Freeman and Vining, 1999; Freeman, 2009; Freeman et al., 2009b]. Twenty children, experiencing at least 15 atonic seizures per day, were fasted for 36 hours, and then received the ketogenic diet for 1 week, in conjunction with a solution of glucose or saccharin. They then crossed over to the other study arm for an additional week. Physicians and parents were blinded to the solution composition and level of ketosis. Fasting and the ketogenic diet resulted in a decrease in the numbers of atonic seizures, which was only partially reversed with the addition of the glucose solution. The improvement in seizure control seen even in the glucose arm may explain the effectiveness of the less restrictive diets (Atkins-like and low glycemic).

A single randomized controlled trial of the ketogenic diet has been performed in children aged 2–16 years [Neal et al., 2008a]. Children with various seizure types or epilepsy syndromes experiencing daily seizures were recruited. They were randomly assigned to receive the ketogenic diet immediately (n = 73), or after a 3-month delay, with no other changes in their treatment (n = 72, control group). Children were also randomly assigned to the classic or the MCT ketogenic diet. After 3 months, the percentage of patients with baseline numbers of seizures despite treatment was significantly lower (p <0.0001) in the diet group (62 percent) than in the controls (136.9 percent). The children in the diet group had a mean of 13.3 seizures per day at baseline, and after 3 months of treatment, 1 was seizure-free; 28 (38 percent) had a greater than 50 percent reduction in seizures and 5 (7 percent) had a greater than 90 percent reduction. Efficacy was the same for symptomatic generalized or symptomatic focal epilepsies. The most common adverse events were constipation, vomiting, lack of energy, and hunger.

The same authors reported on the 1-year follow-up of those children randomized to the classic or MCT versions of the ketogenic diet [Neal et al., 2009]. Of the 125 children who started the diets, data from 64 were available at 6 months, and from 47 at 12 months. At 12 months, there was no significant difference between groups in number achieving greater than 50 percent (17.8 vs. 22.2 percent) or 90 percent (9.6 vs. 9.7 percent) seizure reduction. There was no significant difference in tolerability of the diet, except increased reports of lack of energy after 3 months, and vomiting after 12 months, both in the classical group.

In recent years, two alternative diet regimens that are less restrictive and perhaps more palatable have emerged: the modified Atkins diet [Kossoff and Dorward, 2008a] and a low glycemic index treatment [Pfeifer et al., 2008] (Figure 60-1). No prospective, comparative trials have been performed with the three treatments to evaluate relative efficacy and side-effect profiles. The Atkins diet is less restrictive than the ketogenic diet. The modified Atkins diet is similar in fat composition to a 1:1 ketogenic ratio diet, with approximately 65 percent of the calories from fat sources; it can be started as an outpatient, with guidance from a nutritionist. Three out of 6 patients studied on this diet had a greater than 50 percent seizure reduction; 2 were seizure-free [Kossoff et al., 2003]. Subsequent studies in children, adolescents, and adults reveal that 45 percent have a 50–90 percent seizure reduction, and slightly over 25 percent have a greater than 90 percent seizure reduction (Table 60-5) [Kossoff et al., 2003, 2006, 2007, 2008b, 2008d; Kang et al., 2007b; Carrette et al., 2008; Ito et al., 2008; Weber et al., 2009; Porta et al., 2009; Kumada et al., 2010].

Fig. 60-1 Composition of diets,

CHO, carbohydrate.

The low glycemic index treatment [Pfeifer et al., 2005; Pfeifer et al., 2008] includes approximately 20–30 percent of calories from protein and 60–70 percent from fat. Total carbohydrates are gradually decreased to 40–60 g/day (about 10 percent of calories), using foods with a low glycemic index [Foster-Powell et al., 2002]. A retrospective review of the efficacy of the low glycemic treatment demonstrated 50 percent of patients (n = 20) with refractory epilepsy experiencing a greater than 90 percent in seizure reduction [Pfeifer et al., 2005]. Of these 20 patients, 9 were transitioned from the ketogenic diet and 11 were initiated on the low glycemic treatment. Those with a greater than 90 percent seizure reduction had an average blood glucose level of 72.6 mg/dL. In a second retrospective review, 76 children on the low glycemic index diet – 42, 50, 54, 64, and 66 percent, respectively – achieved a greater than 50 percent seizure reduction from baseline seizure frequency at follow-up intervals of 1, 3, 6, 9, and 12 months [Muzykewicz et al., 2009]. Efficacy did not differ between partial onset and generalized seizure types. Increased efficacy was correlated with lower serum glucose levels at the 1- and 12-month follow-up visits. Side effects were minimal, with only three patients reporting transient lethargy. Children were placed on the low glycemic treatment for several reasons:

These reports raise important questions about the level of restrictiveness of protein and calorie intake necessary for seizure control.

Mechanism of Action

While clinical reports support the efficacy of the ketogenic diet, several theories have emerged to explain the diet’s mechanism of action [Schwartzkroin, 1999]. Four major areas have been investigated: cerebral acidosis; water balance; the direct effect of ketones or lipids; and alteration in brain energy substrates. The importance of ketone body formation was recognized early in the search for the mechanism of action of the ketogenic diet [McQuarrie and Keith, 1927]. Initially, acidosis and partial dehydration were considered likely contributors to its success [Lennox, 1928; Bridge and Lob, 1931]. Even recently, the diet’s effects on water and electrolyte metabolism were thought responsible for its efficacy [Millichap et al., 1964]. Animal studies show no change in intracellular pH of the cerebral cortex on the ketogenic diet [Al-Mudallal et al., 1996; Harik et al., 1997]. Preliminary studies using MR spectroscopy have demonstrated that children on the diet do not develop alteration of brain water and electrolyte distribution [Seymour et al., 1999] or cerebral acidosis [Marks et al., 1997; Seymour et al., 1999]. This suggests that, although ketoacidosis occurs in these children, changes in brain pH may not be a critical factor. Animal models and human evidence suggest a prominent role of ketonemia [Uhlemann and Neims, 1972; Appleton and DeVivo, 1973, 1974; DeVivo et al., 1975; Al-Mudallal et al., 1995; Stafstrom, 1999a]. One study considered elevated plasma lipids a predictor of seizure control in children [Dekaban, 1966]. A subsequent analysis of blood metabolites in nine children on the ketogenic diet revealed that a rise in total serum arachidonate correlated with improved seizure control [Fraser et al., 2003]. Despite its long history of use and proven value, the exact mechanism of action of the diet remains unknown [Nordli and DeVivo, 1997].

Oxidation of Fatty Acids: Ketogenesis

Ketonemia is essential for the ketogenic diet to work. Ketonemia occurs as a result of fatty-acid oxidation during fasting or while on the ketogenic diet [Hawkins and Biebuyck, 1980; DeVivo, 1980; Cahill, 1982; Mayes, 1996a, 1996b]. Fatty-acid biosynthesis (lipogenesis) takes place in the cytosol, whereas fatty-acid oxidation occurs in mitochondria and generates adenosine triphosphate (ATP) [Roe and Coates, 1995]. The oxidizable substrate may come from dietary sources (ketogenic diet) or from mobilization of peripheral adipose stores (starvation) (Figure 60-2). The brain does not directly use fatty acids but readily oxidizes ketone bodies [Hawkins and Biebuyck, 1979, 1980]. Increased fatty-acid oxidation leading to ketone body formation by the liver is characteristic of starvation or the ketogenic diet (Figure 60-3) [Mayes, 1996a]. Glucose, present in small concentrations, is necessary to facilitate ketone body metabolism. This is referred to as the permissive effect of glucose. Acetoacetate, a ketone body constituent, continually undergoes spontaneous decarboxylation to yield acetone that is volatilized in the lungs and gives the breath its characteristic odor.

Fig. 60-2 Initial steps in ketogenesis: lipolysis.

FFA, frce fatty acids.

Fig. 60-3 Ketogenesis in the liver.

Free fatty acids (FFA) from the circulation enter the hepatocyte and then cross the mitochondrial membrane by carnitine transport (long-chain fatty acids) or diffusion (short- and medium-chain fatty acids). ATP, adenosine triphosphate.

The liver is the only organ capable of synthesizing significant quantities of ketone bodies that are released into the blood (see Figure 60-3). The liver is equipped with an active enzymatic mechanism for the production of acetoacetate. Once formed, acetoacetate cannot be significantly metabolized back to fatty acids in the liver because it lacks the enzyme 3-oxoacid-CoA transferase. This accounts for the net production of ketone bodies by the liver. Ketone bodies are then transported to and oxidized in extrahepatic tissues proportionately to their concentration in the blood. Oxidation and brain influx rates of ketone bodies are proportional to their blood concentration of approximately 12 mmol/L. At this level, the oxidative machinery and uptake mechanisms of the cell are saturated [Mayes, 1996a].

Glucose is the principal substrate for brain metabolism. Under certain conditions (e.g., fasting, ketogenic diet), the human brain uses ketone bodies for fuel [Owen et al., 1967]; the movement of ketone bodies into the brain is dependent on a monocarboxylic transport system [DeVivo, 1980]. Acetoacetate and β-hydroxybutyrate (BHB), the two constituents of ketone bodies, are metabolized primarily in the mitochondrial compartment. In the brain, the main pathway for the conversion of acetoacetate to acetoacetyl-CoA involves succinyl-CoA (Figure 60-4). Acetoacetyl-CoA is split to acetyl-CoA and oxidized in the tricarboxylic acid cycle. The enzymes that break down BHB and acetoacetate into acetyl CoA are regulated developmentally, with maximal expression early in life [Hawkins et al., 1971; Dahlquist et al., 1972; Nehlig, 1999]. This is consistent with the higher utilization of ketones by the brain in children compared to adults [Kraus et al., 1974]. Ketone bodies not only serve as a source of energy, but also contribute to the synthesis of the neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), cerebral metabolic pathways normally dependent on glucose metabolism [Cremer, 1971; Sokoloff, 1973; DeLorey and Olsen, 1994; Rodwell, 1996; Cooper et al., 1996; Yudkoff et al., 2007; Lund et al., 2009]. Furthermore, fatty-acid oxidation increases brain ATP concentration [Mayes, 1996a, 1996b]. Elevation of brain ATP concentration has been verified in an animal model of the ketogenic diet [DeVivo et al., 1978; Nakazawa et al., 1983], suggesting that the ketogenic diet improves cerebral energetics. Increased alpha-ketoglutarate on the diet may also increase activity of the GABA_A shunt [DeVivo, 1980; McGeer and McGeer, 1989; Peng et al., 1993]. Although whole-brain GABA levels are not changed in an animal model of chronic ketosis [Al-Mudallal et al., 1996; Harik et al., 1997], local changes in GABA concentration may occur [Rho et al., 1999b; Yudkoff et al., 2001a]. Two children studied with a new technology, two-dimensional double-quantum MR spectroscopy, showed low initial GABA levels that increased over time on the ketogenic diet [Wang et al., 2003]. The addition of acetoacetate or BHB to rat synaptosomes increased the rate of GABA formation by 35 and 43 percent, respectively [Erecinska et al., 1996]. The addition of β-hydroxybutyrate to cultured rat astrocytes suppresses GABA-transaminase in time- and dose-dependent manners [Suzuki et al., 2009]. This suppression of astrocytic GABA degradation may be another mechanism for increased GABA concentration. At the same time, the conversion of glutamate to aspartate, which has excitatory properties in the brain, is reduced [Erecinska et al., 1996; Yudkoff et al., 1997; Yudkoff et al., 2001b]. Thus, improved cerebral energetics, along with decreased excitatory (glutamatergic) and increased inhibitory (GABAergic) neurotransmission, may contribute to the efficacy of the ketogenic diet [Peyron et al., 1994; Greene et al., 2003].

Fig. 60-4 Ketone body use and oxidation in the brain.

1, β-hydroxybutyrate dehydrogenase; 2, 3-oxoacid coenzyme A (CoA) transferase; 3, acetoacetyl-CoA thiolase; 4, glutamic acid decarboxylase (GAD); 5, γ-aminobutyric acid (GABA). OOA, oxaloacetate; TCA, tricarboxylic acid cycle.

Selection of Candidates for the Diet

Despite the fact that several thousand patients have been treated, there currently are no consensus criteria as to which patients are candidates for the diet [Maria et al., 1997] (see Tables 60-1 to 60-4). Many seizure types appear to respond to the ketogenic diet. In general, several groups of children are potential candidates for treatment. These include the following children:

Box 60-1 Specific Conditions Treated with the Ketogenic Diet

Glucose transporter deficiency syndrome (GLUT1-DS, SLC2A1 gene, McKusick 138140)*

Pyruvate dehydrogenase complex deficiency (McKusick 312170)*

Associated with Leigh’s syndrome

Associated with lactic acidosis and cerebral dysgenesis

Succinic semialdehyde dehydrogenase (SSADH) deficiency^†

Phosphofructokinase deficiency

Mitochondrial respiratory chain complex defects

Ketotic hypoglycemia

Glycogenosis type V (McArdle’s disease)

Acquired epileptiform opercular syndrome

Acquired epileptic aphasia (Landau–Kleffner syndrome)

Rett’s syndrome

Tuberous sclerosis complex

^* The ketogenic diet is specifically indicated for these two metabolic disorders.

^† Documented improvement in mouse model [Nylen et al., 2009].

One must also consider the age of the patient. As previously discussed, successful outcomes have been experienced in children aged 1–12 years. In older children, it is often more difficult to maintain ketosis. The ketogenic diet is a strictly regulated medical diet. Its success depends on the accuracy and consistency with which the regimen is carried out within the home. Continued support, monitoring, and education by an interdisciplinary team of professionals are necessary.

Little is known about whether the ketogenic diet should be considered in patients who are being evaluated for epilepsy surgery. Forty-seven children with intractable epilepsy and surgically remediable focal malformations of cortical development were treated with the ketogenic diet [Jung et al., 2008b]. Those seizure-free at 3 months continued on the diet, while the rest underwent surgery. The seizure-free rate at 2 years was similar between the two groups, leading the authors to suggest that, in potentially surgically remediable epilepsy, a 3-month trial of the ketogenic diet may be an option. However, in those patients in whom a malignancy or vascular malformation is detected, surgery is preferable. The ketogenic diet may be the preferred initial therapy in children with seizures and specific metabolic defects or seizures associated with specific neurologic syndromes (see Box 60-1 and Figure 60-5) [DeVivo et al., 1973, 1991; Haas et al., 1986; Wijburg et al., 1992; Shafrir and Prensky, 1995; Melvin et al., 1996; Wexler et al., 1997; Bergqvist et al., 1999b; Weber et al., 2001; Klepper et al., 2002, 2004; Liebhaber et al., 2003; Busch et al., 2005; Kang et al., 2005, 2007a; Kossoff et al., 2005b; Lee et al, 2008; Brockmann, 2009, Joshi et al., 2009; Mantis et al., 2009 ? mouse model Rett?s syndrome; Nylen et al., 2009 ? mouse model SSADH; Seo et al., 2010]. These specific metabolic disorders are reviewed in other sections of this book.

Fig. 60-5 Metabolic defects and the ketogenic diet.

Glucose enters the brain by the glucose transporter, GLUT1 (A); ketones penetrate the blood-brain barrier (BBB) by the medium-chain triglyceride transporter (MCT1) (B). GLUT1 deficiency syndrome is caused by a defect in glucose transport into the brain (1). Pyruvate dehydrogenase deficiency impairs acetyl-CoA production (2). The ketogenic diet bypasses these two defects and provides acetyl-CoA for brain energy production. ATP, adenosine triphosphate.

For some patients, the ketogenic diet is contraindicated (Box 60-2). Children with acute intermittent porphyria should not be treated with the ketogenic diet because carbohydrate restriction can be harmful in this condition. The ketogenic diet may also worsen some mitochondrial diseases, pyruvate carboxylase deficiency, or organic acidurias [Demeritte et al., 1996b; Nordli, 2000; Kleinman, 2004; Kossoff et al., 2009b]. When indicated, metabolic screen, including urine amino and organic acids, serum amino acids, lactate, pyruvate, and carnitine profile, should be performed before starting the ketogenic diet [Wheless, 2001]. In addition, the combination of the use of the ketogenic diet with topiramate or zonisamide appears to be associated with an increased risk of acidosis.

Box 60-2 Specific Contraindications to the Ketogenic Diet

Pyruvate carboxylase deficiency

Organic acidurias

Selected mitochondrial disease

Porphyria

Defects in fatty acid oxidation

Short-chain acyl dehydrogenase deficiency (SCAD)

Medium-chain acyl dehydrogenase deficiency (MCAD)

Long-chain acyl dehydrogenase deficiency (LCAD)

Medium-chain 3-hydroxyacyl CoA deficiency

Long-chain 3-hydroxyacyl CoA deficiency

Carnitine deficiency (primary)

Carnitine palmitoyltransferase (CPI) I or II deficiency

Carnitine translocase deficiency

Glutaric aciduria, type II

Pyruvate dehydrogenase phosphate deficiency

Initiation and Maintenance

A comprehensive monograph on the evaluation and management of patients being considered for placement on the ketogenic diet was published [Freeman et al., 1994] and subsequently revised [Freeman et al., 2000]. In addition, a videotape, “The Ketogenic Diet for Families, Dietitians, Nurses and Physicians,” and other resource material are available from The Charlie Foundation (www.charliefoundation.org). The following is a brief overview of how the diet can be implemented.

Hospitalization

The child is typically scheduled for elective admission to the hospital for initiation of the ketogenic diet (Box 60-3). However, in recent years, both retrospective [Vaisleib et al., 2004] and prospective studies [Rizzutti et al., 2007] have documented the feasibility of initiating the diet as an outpatient. The intense educational process afforded by inpatient initiation may be preferable for some families and ketogenic diet centers. Additionally, inpatient initiation allows observation of the child to gauge the initial response to and adverse effects of the diet. Parents are told to view this treatment as a 6–8-week trial. When effective, the ketogenic diet works quickly, typically within the first 1–2 weeks [Kossoff et al., 2008c]. The time to improvement is significantly quicker (mean 5 vs. 14 days, p <0.01) in those children who are fasted at onset, but there is no effect of initial fasting on long-term outcome. If there is no seizure reduction after 6–8 weeks, the ketogenic diet can be discontinued. During this time, patients must adhere strictly to the diet, with proof of persistent ketosis. The frequency of seizures usually decreases gradually, but reversal of the effect can occur rapidly. Weeks of hard work can be undone if a child eats a cookie or a piece of candy. If the seizures are improved, this usually is sufficient motivation for the parents to have the child adhere to the diet. If the child might have an underlying metabolic disease that could be exacerbated by the initial fast, an appropriate evaluation should be performed before initiating the diet. Valproate has been demonstrated experimentally to reduce fasting ketonemia [Turnbull et al., 1986; Thurston et al., 1983]. Clinically, valproate has not impaired the ability to initiate the ketogenic diet or achieve adequate ketosis, nor has it altered the diet’s side-effect profile or efficacy [Lyczkowski et al., 2005].

Box 60-3 Initiation of the Ketogenic Diet

Hospitalization for 3 Days

Day 1

Maintenance fluids

Check urine ketones each void

Check fingerstick blood glucose every 6 hr

Initial EEG, laboratory tests

Simplify antiepileptic drug (AED) regimen; change to low carbohydrate or carbohydrate-free formulation

Dietitian consultation

Education

Day 2

4:1 ratio (3:1 in infants), with one-third of total calories using eggnog for 2–3 meals

Then two-thirds of total calories for 2–3 meals

Stop fingerstick blood glucose checks

Day 3

First regular meal on 4:1 ratio

Discharge – AED regimen

B vitamins, sugar-free multivitamin

Calcium supplements

The day before hospital admission, the parents are asked to eliminate carbohydrates from the child’s diet. The child eats foods that contain only protein or fat. After dinner, the child begins fasting, with only noncaloric, noncaffeinated beverages given. On the first hospital day, an awake-and-sleeping EEG may be performed. Laboratory studies (complete blood count, platelet count, chemistry panel, and AED levels) are obtained, either before or at the time of admission. During this time, the child receives maintenance fluids and may have one caffeine-free diet drink per day. Blood glucose levels are checked every 6 hours. The dietitian uses this time for further review of meal plans and the child’s food preferences and eating habits with the parents [Lasser and Brush, 1973]. Recent studies [Vaisleib et al., 2004; Kim et al., 2004; Bergqvist et al., 2005; Kang et al., 2005; Kossoff et al., 2008c] have suggested no improvement in seizure control with initial fasting or fluid restriction, and fewer adverse events with a nonfasting, gradual initiation. On day one, the child is started on the ketogenic diet, using a 3:1 or 4:1 ratio (fat to protein plus carbohydrate), depending on the child’s age. A ketogenic eggnog is used for the initial feedings. The child receives three meals at one-third of the total calories, is advanced as tolerated to two-thirds of the total calories for three meals (day 2), and then eats his or her first full meal. Before discharge, the parents prepare their first ketogenic meal for their child under the supervision of the dietitian. At discharge, the parents have several meal plans for their child and are instructed to monitor the urine ketones on a daily basis and record all occurrences of seizures. Individual decisions are made during the hospital stay as to whether the AED regimen will be simplified. The child is given a prescription for sugar-free multivitamin, mineral, and calcium supplementation and instructed to begin this at home. Vitamin B supplements are given to prevent optic nerve dysfunction [Hoyt and Billson, 1979]. Vitamin D supplementation and calcium prevent osteomalacia while on the ketogenic diet [Hahn et al., 1979]. Inadvertent administration of carbohydrates may occur when intercurrent illnesses are treated. Parents and pediatricians must appreciate that decongestants, antipyretics, and antibiotics are often contained in carbohydrate-containing vehicles [Feldstein, 1996; Freeman et al., 2000; Lebel et al., 2001; McGhee and Katyal, 2001]. The child is then seen regularly for follow-up (Box 60-4). Special attention should be paid to the serum albumin and total protein concentration to make sure that the diet is providing enough protein. Cholesterol and triglyceride levels typically rise when the diet is started, but the diet may be continued unless the cholesterol level rises above 1000 mg/dL and consistently stays there. It is not known whether cholesterol-reducing drugs could be safely given while the child is maintained on the diet. It is not unusual to see minor elevations in the direct bilirubin. Decisions regarding withdrawal of AEDs depend on the child’s response to the diet and the family’s wishes. Early reduction (during diet initiation or the first month afterward) of AEDs appears to be safe and well tolerated; however, it offers no definite advantage compared with a late taper [Kossoff et al., 2004]. At follow-up, the dietitian also reviews the parental concerns about implementing the diet, and makes adjustments in the meal plan, as necessary, to maintain the child in maximum ketosis. If the child is in apparent maximum ketosis (i.e., urine ketones are more than 160 mg/dL) and seizures recur, this might be the result of caloric excess, which may be manifested by excessive weight gain. Lowering the total caloric and carbohydrate intake may help reduce the number of seizure recurrences. If the child is not in maximum ketosis, this may be due to a break in the diet (e.g., “cheating” or taking medicine with sugar) or a lower than 4:1 ratio of fat to protein and carbohydrate. In children who can be successfully withdrawn from AED therapy and are seizure-free for 2 years on the ketogenic diet (about 10 percent of treated children), an EEG is repeated and the ketogenic diet is slowly withdrawn over 1 year. Many of these families elect to continue a low-carbohydrate diet, concerned that seizures may recur.

Box 60-4 Ketogenic Diet Maintenance

1 Month

Neurologist, dietitian, nurse, social worker

Adjust diet as needed

Laboratory tests – complete blood count (CBC), platelets; SMA20; antiepileptic drug (AED) level(s); serum lipid and carnitine profiles

Urine calcium, creatinine

3, 6, and 12 Months

Neurologist, dietitian, nurse

Laboratory tests – CBC, platelets, SMA20; serum lipid and carnitine profiles

AED level(s), if needed, and urine calcium, creatinine

New meals

Maintain for 2 Years (Seizure-Free)

(Shorter time interval for infantile spasms)

Wean over 1 Year

3-5:1–3 months → 3:1–3 months →

2.5:1–3 months → 2:1–3 mohths →

Off

Complications

It needs to be stressed to parents that the diet is a form of medical therapy, and as such, although it is relatively safe, it is not without side effects (Box 60-5 and Box 60-6) [Ballaban-Gil et al., 1996; Wheless, 2001; Kang et al., 2004]. However, only 6–17 percent of patients discontinue the diet for medical reasons [Thompson et al., 1998; Vining et al., 1998; Kang et al., 2004; Henderson et al., 2006]. If the child has an unrecognized metabolic defect, a catastrophic event could occur during the fasting phase (see Box 60-2). Other adverse events can occur during the initial hospital stay, and, if recognized, are usually easily treated (see Box 60-6). A number of adverse events can occur during the maintenance phase. Many can be prevented with close monitoring, vitamin supplementation, and anticipatory treatment. The most common side effect encountered is constipation, which can be reduced if a calcium supplement with magnesium is given. Many of the children who begin the diet are already prone to this problem because of limited mobility, hypotonia, or spasticity. Constipation can be treated with regular doses of polyethylene glycol, mineral oil, intermittent pediatric-dose enemas, or magnesium hydroxide. Renal stones have occurred in less than 5–10 percent of patients, and can usually be easily managed [Herzberg et al., 1990; Freeman et al., 1994, 2000; Casey et al., 1999; Chesney et al., 1999; Furth et al., 2000; Kaytal et al., 2000; Kielb et al., 2000; Maydell et al., 2001; Nordli et al., 2001; Kossoff et al., 2002; Sampath et al., 2007]. The risk of stone formation may be increased in younger patients (<3 years of age), and those with hypercalciuria and low urine volume [Furth et al., 2000; Sampath et al., 2007]. Children can be screened for hypercalciuria (urine creatinine: calcium), and fluid intake can be maximized to minimize risk of nephrolithiasis. Even children who develop renal calculi, however, may be able to remain on the ketogenic diet. Evaluation to determine the type of renal stone and the patient’s urinary calcium–creatinine ratio is necessary [Gillespie and Stapleton, 2004]. If renal stones appear to be due to hypercalciuria, then the patient can be treated with hydrochlorothiazide (2 mg/kg/day), given polycitra to alkalinize the urine, and monitored with repeated urinary studies and renal ultrasound. If the calcium–creatinine ratios normalize or dramatically improve and no additional renal stones occur, then the diet can be maintained. Oral potassium citrate as a preventative supplement results in urine alkalinization, decreasing the prevalence of kidney stones [Sampath et al., 2007]. Universal supplementation appears to be warranted.

Box 60-5 Possible Adverse Events During Initiation of the Ketogenic Diet

Adverse Event	Monitoring/Treatment Strategy
Dehydration	Encourage fluids (do not limit fluids to less than 75% of maintenance); intravenous fluids if necessary (without dextrose)
Hypoglycemia	Check blood sugars every 6 hr until diet is initiated; if symptomatic or blood sugar <30 mg/dL, give orange juice. Screen for metabolic errors in advance
Vomiting	Intravenous fluids; give orange juice

Box 60-6 Possible Adverse Events During Maintenance of the Ketogenic Diet

Adverse Event	Monitoring/Treatment Strategy
Constipation	Polyethylene glycol, mineral oil, suppositories
Exacerbation of gastroesophageal reflux disease	Medical management
Poor growth	Check albumin, total protein
	Adequate protein
	Monitor height, weight
Kidney stones	Urine dipstick for blood, renal ultrasonography
	Analyze stone (specific treatment)
	Increase fluids, alkalinize urine
Dyslipidemia, hyperlipidemia	Check liver function tests, lipid profile; if sustained elevations of cholesterol/ triglycerides, adjust diet and/or treat
Prolonged QT interval, cardiomyopathy	Electrocardiography, echocardiography, check selenium
Excessive bruising	Complete blood count, platelet count
Optic neuropathy	B vitamins
Elevated very-long-chain fatty acids	Check prior to ketogenic diet if clinically suspected
Vitamin D deficiency, osteomalacia	Vitamin D, calcium, bone mineral density/densitometry
Trace mineral deficiencies	Copper, selenium, zinc

Acetazolamide, which is sometimes used to treat certain forms of seizures, should not be used during initiation of the diet for fear of producing symptomatic metabolic acidosis [Dodson et al., 1976]. Topiramate and zonisamide are weak carbonic anhydrase inhibitors, which, when combined with the ketogenic diet, predispose to metabolic acidosis. The ketogenic diet can be cautiously initiated in children on these drugs. However, the physician should be aware that, in some children, this may cause worsening of their metabolic acidosis, especially during ketogenic diet initiation, and may require adjustments in the drug dose, adjustments in the diet, or addition of polycitra [Takeoka et al., 2002]. To date, no increased risk of nephrolithiasis has been reported in patients on topiramate or zonisamide and the ketogenic diet [Kossoff et al., 2002; Takeoka et al., 2002]. All children on one of these medicines should be treated with increased hydration and monitoring of their urine calcium–creatinine ratio; if the latter is elevated, urine alkalinization should be carried out.

Fatigue occurs in many children during initiation of the diet but is prolonged in only a small number. Children with gastroesophageal reflux, especially if they have cerebral palsy, may have increased gastroesophageal reflux while on the diet. The high fat content decreases gastric emptying, which promotes gastroesophageal reflux. This problem usually can be managed medically [Jung et al., 2008a]. Use of the ketogenic diet in infants to treat their seizure disorders or selected metabolic disorders has rarely been associated with fat malabsorption and secondary failure to thrive due to physiologic pancreatic insufficiency [Goyens et al., 2002]. This has been corrected by alteration of the diet via use of MCT and pancreatic extract. Close attention to growth measurements, laboratory data, and medical supervision is indicated in infants on the ketogenic diet. Only short-term information on growth in a limited number of patients had previously been available [Couch et al., 1999; Kossoff et al., 2002; Williams et al., 2002; Liu et al., 2003]. A prospective cohort study of 237 children, with an average length of follow-up of 308 days, analyzed height and weight measurements over time on the ketogenic diet [Vining et al., 2002]. A small decrease in height scores was observed in the first 6 months, with bigger changes by 2 years. There was a drop in weight in the first 3 months, and after this, the weight remained constant in children who started the diet below the 50th percentile for their weight, while it continued to decrease in children starting above the 50th percentile. Very young children (0–2 years) grew poorly on the diet, while older children (7–10 years) grew almost normally. A subsequent prospective study of 75 children, followed for 12 months, examined growth in children on classical and MCT ketogenic diets [Neal et al., 2009]. Both weight and height percentiles decreased, and by 12 months, there was no difference in outcome between classical and MCT protocols, despite the increased protein in the latter diet.

Twenty-two children had growth parameters monitored for 1 year prior to initiation of the ketogenic diet, and then for 1 year on the diet [Spulber et al., 2009]. Additionally, serial measurements of serum ketones and insulin-like growth factor I (IGF-I) were performed. Weight and height percentiles, body mass index, and height velocity all decreased significantly (p <0.05). Height velocity correlated negatively with serum β-hydroxybutyric acid levels, and was most affected in those with pronounced ketosis. Serum IGF-I decreased immediately at diet initiation, but then reached stable levels at around 3 months after diet initiation.

Several laboratory abnormalities have been reported in children on the ketogenic diet, although none has been found to have clinical significance. Patients on the ketogenic diet are in a chronic acidotic state, putting them at risk for osteopenia. A single longitudinal study has evaluated the effect of the ketogenic diet on bone density, serum hydroxyvitamin D, and parathyroid hormone [Bergqvist et al., 2007, 2008]. At baseline, the children with intractable epilepsy had suboptimal growth status and poor bone health. A progressive loss of bone mineral content, resulting in osteopenia and osteoporosis, occurred with ketogenic diet treatment, despite improved serum vitamin D concentrations. Supplementation of vitamin D and calcium was not sufficient to prevent bone mineral content loss. Increased supplementation and periodic surveillance with dual energy x-ray absorptiometry may be needed to prevent or treat the loss of bone mineral content in children treated with the ketogenic diet [Bergqvist et al., 2008]. This compensated metabolic acidosis puts the young child, who becomes ill, at risk of becoming markedly acidotic, ketotic, or dehydrated. This can be addressed by forewarning parents to increase fluid intake during illness. Serum cholesterol and triglycerides may increase, especially during the first 6 months; they tend to plateau by 6 months, then decline and require routine monitoring [Dekaban et al., 1966; Bergqvist et al., 1998; Chesney et al., 1999; Vining, 1999a; Kang et al., 2004]. Adjustments to the diet (e.g., increased protein and polyunsaturated fat) can be made in children with significantly high cholesterol and triglyceride concentrations. Impaired neutrophil function was described in ketotic children, but only one child had severe, recurrent infections [Woody et al., 1989]. This finding has not been replicated. Slight to significant prolongation of the bleeding time and abnormal platelet aggregation, despite normal platelet count and partial thromboplastin time (PTT), was reported in six children [Berry-Kravis et al., 2001b]. Patients on the diet and undergoing surgery should be evaluated for symptoms of bleeding tendency. Elevated very-long-chain fatty acids were found in one center in 59 percent of patients on the diet, and subsequently raised concerns about confusing this side effect with peroxisomal disorders [Theda et al., 1993]. Changes in the serum carnitine concentrations have also been described. Some believe a carnitine supplement should be given routinely [Demeritte et al., 1996b]. However, a prospective study of 11 children showed no substantial change over 1 year after initiation of the ketogenic diet [Coppola et al., 2006]. Carnitine status should be monitored, although most children do not need supplementation [Berry-Kravis et al., 1998, 2001a; Lin et al., 1998]. Carnitine supplementation may have conflicting effects; carnitine deficiency may restrict fatty-acid beta-oxidation, and carnitine may also improve glucose transport into cells. Supplementation with magnesium, zinc, calcium, vitamin D, and B vitamins is recommended to avoid deficiency-related disease states [Hahn et al., 1979; Hoyt et al., 1979]. The ketogenic diet is deficient in several trace minerals, and if children are maintained on the diet for more than 2 years, these need to be supplemented [Goodwell et al., 1998; Chee et al., 1998; Bergqvist et al., 1999, 2003].

Serious complications of the ketogenic diet are rare and typically have only been described in single reports, including those of Fanconi’s renal tubular acidosis (in co-treatment with valproate) [Ballaban-Gil et al., 1996], severe hypoproteinemia [Ballaban-Gil et al., 1998], marked increase in liver function tests (in co-treatment with valproate) [Ballaban-Gil et al., 1998], cardiomyopathy [Ballaban-Gil, 1999; Best et al., 2000; Bergqvist et al., 2003; Kang et al., 2004; Bank et al., 2008], prolonged QTc [Best et al., 2000], acute hemorrhagic pancreatitis [Stewart et al., 2001], basal ganglia injury [Erickson et al., 2002], scurvy [Willmott and Bryan, 2008], lipoid pneumonia [Kang et al., 2005], and fatal propofol infusion syndrome [Baumeister et al., 2004].

A single retrospective chart review reports maintenance of efficacy and tolerability with long-term use of the ketogenic diet (duration of 6–12 years, n = 28) [Groesbeck et al., 2006]. However, side effects of decreased growth (23 out of 28), kidney stones (7 out of 28), and fractures (6 out of 28) occurred, and careful monitoring with strategies to minimize these complications is suggested.

Advantages and Disadvantages

The Ketogenic Diet in the Twenty-First Century

More than 80 years have passed since the ketogenic diet was initially used, and many more therapies are now available for children with epilepsy. The ketogenic diet compares favorably with other new treatments that have been introduced to treat children with epilepsy [The Felbamate Study Group, 1993; George et al., 1994; The Vagus Nerve Stimulation Study Group, 1995; LeFever et al., 2000]. Studies on the newer AEDs, such as zonisamide, lamotrigine, tiagabine, gabapentin, topiramate, oxcarbazepine, lacosamide, pregabalin, and levetiracetam, typically indicate that only 3–10 percent of all intractable patients achieve complete relief of seizures. The question that remains unanswered is, “When, in the course of therapy for a child with intractable epilepsy, should the ketogenic diet be used?” Currently, it is not used until children have failed multiple medications and if they are not considered surgical candidates. However, in some epilepsy syndromes, the diet should be offered as a treatment strategy after failure of one or two drugs. If the child has an epilepsy syndrome that is often resistant to current therapy and if the seizures are not controlled on medication, the ketogenic diet should be mentioned as an alternative therapy at the time of the initial therapeutic discussions. This is especially true in children who are not good candidates for epilepsy surgery or whose parents do not wish their children to have epilepsy surgery. The renewed interest in the ketogenic diet has, once again, raised several research questions that, if answered, have the potential to improve our understanding of the neurochemistry of epilepsy and allow better treatment of all patients with epilepsy [Nordli and DeVivo, 1997; Prasad et al., 1996].

In addition to the need to gain a better understanding of the underlying neurochemical changes induced with the ketogenic diet, several other clinical questions remain. Specifically, for what seizure types or epilepsy syndromes does this diet have a higher chance of being a successful short- or long-term treatment? It would be helpful to have more long-term (i.e., 10–20 years) follow-up data on those patients who appear not to have a return of seizures after the diet is stopped [Keith, 1963].

Issues that require investigation include the risk of late seizure recurrence once the diet is terminated, presence of any long-term effects of the diet on growth and development, and whether the response to treatment is because the patient has a specific subset of known seizure type or epilepsy syndrome. Feasibility of prolonged treatment also needs to be determined. Many children who are not seizure-free or who are not able to come off all AEDs are improved on the ketogenic diet. The improvement in seizure control or behavior and cognitive abilities is such that parents wish to continue the ketogenic diet. How long can we safely maintain these children on the ketogenic diet without encountering new side effects because of micronutrient deficiency? What is the feasibility of prolonged therapy? If no other therapy works better, how do we counsel parents about patients remaining on the diet, when there is no apparent chance of withdrawing it? This same set of questions could be raised in a child who is seizure-free on the diet for 2 years but then does not tolerate withdrawal without recurrence of seizures. The effects of the ketogenic diet on family dynamics also are not known. Are there different psychosocial effects on the siblings of the child with epilepsy who is dependent on this form of therapy?

Additional questions relate to the role of the ketogenic diet in treating less affected or normal children with epilepsy. How does the risk–benefit ratio of the ketogenic diet compare with other therapies? Finally, many adults with intractable epilepsy wish to know if there is any group of adults that could benefit from the ketogenic diet. The ketogenic diet might be useful in other childhood neurologic disorders, such as alternating hemiplegia of childhood or tumors of the nervous system [Nebeling et al., 1995]. There is an expanding experimental literature suggesting that the ketogenic diet may treat several neurologic conditions [Kossoff et al., 2009c; Santra et al., 2004; Murphy et al., 2004].

The ketogenic diet is a therapy that was first used at the beginning of the 20th century and appears still to have a definitive role in the treatment of childhood epilepsy into the 21st century. The preferred sequence of treatments for children with epilepsy will continue to need reassessment and redefinition. It will likely be several years before the exact roles for all current therapies are defined. Until then, it is critical that those taking care of children with seizures be aware of all the treatment options and refer children whose seizures are not controlled to centers specializing in the care of such children [The National Association of Epilepsy Centers, 1990]. For many such children, the ketogenic diet continues to represent a therapeutic alternative.

References

The complete list of references for this chapter is available online at www.expertconsult.com.

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