Ketogenic diet in the treatment of epilepsy …

Ryan W Y Lee MD

Neurogenetic Disorders

Updated 04.17.2024
Released 07.15.1999
Expires For CME 04.17.2027

Ketogenic diet in the treatment of epilepsy

Author: Ryan W Y Lee MD

See Contributor Disclosures

Editor: Barry Wolf MD PhD

Ketogenic diet in the treatment of epilepsy

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Introduction

Key points

	• The ketogenic diet is a medical treatment for intractable epilepsy and should only be administered under direct medical supervision.
	• The ketogenic diet is an effective treatment for seizures that are refractory to antiepileptic drugs. It has been used as an earlier treatment option for infantile spasms, with some promising results.
	• The ketogenic diet serves as an effective treatment option regardless of seizure type, seizure syndrome, and age.
	• If a patient has some improvement in seizures on the ketogenic diet, but still continues to have seizures, fine-tuning the diet by adjusting the calories or the ratio may provide additional seizure control.
	• The ketogenic diet is not considered a “healthy” or “all-natural” therapy for seizures. The diet is very restrictive and does not provide adequate vitamins and nutrients for optimal growth. Thus, all patients on the ketogenic diet are required to take daily vitamin and mineral supplements in order to maintain optimal nutrition.
	• The ketogenic diet does have potential side effects, as do all treatment options for seizures. The most common side effects associated with starting the diet include nausea and vomiting. The most common side effects associated with long-term therapy on the diet include constipation and reflux. The risk of kidney stones is increased in individuals on the ketogenic diet.
	• The modified Atkins diet is a newer, more liberal version of the ketogenic diet that has shown promising results, especially for teenagers and adults interested in trying a diet therapy option. The modified Atkins diet does not restrict calories, protein, or fluids, but does encourage a high-fat diet while limiting the total daily grams of carbohydrate.
	• The low glycemic index treatment diet allows for a higher content of carbohydrates by limiting the carbohydrate sources to those that have a glycemic index of 50 and below. It also allows for higher content of protein, and encourages a high-fat content of the diet to supply energy demands. As such, the modified Atkins, as well as the low glycemic index treatment diet, can be considered as a more “natural” approach.
	• The ketogenic diet, the modified Atkins diet, and the low glycemic index treatment all require regular medical care, with frequent neurologic and dietary follow-up management.

Historical note and terminology

Many quotations from ancient texts refer to fasting as a cure for seizures. The Hippocratic text Epidemics details a case report in which complete abstinence from food and water resulted in curing the case of epilepsy (302). In modern times, as early as 1911, Guelpa and Marie mention the effect of dietary manipulation on epilepsy (103). These authors recommended a regimen of fasting, followed by a restrictive and vegetarian diet in the treatment of epilepsy. This history of fasting and the ketogenic diet in the treatment of epilepsy is extensive; it is described elsewhere (185; 196; 319; 86) and is summarized in Table 1.

Table 1. History of Fasting and Ketogenic Diet in the Treatment of Epilepsy

Circa 30 AD	The Bible states that Jesus Christ recommended fasting associated with prayer for convulsing demon possession (Mark 9:14-29).
1911	“La cure du Dr. Guelpa” was defined as fasting followed by a restrictive and vegetarian diet (103).
1921	Geyelin found that fasting suppressed seizures and that his patients remained seizure-free for many months after fasting stopped (96).
1921	Wilder published his preliminary report on the ketogenic diet in the treatment of seizures (322).
1922	Conklin published the results of the “water diet” (fasting) (42).
1925 and 1927	Peterman and Helmholz published the Mayo clinic experience with the ketogenic diet (252; 113).
1928	Lennox studied the effects of a 2-week fast in the seizure frequency of five patients (184; 185).
1954	Livingston described the methodology and some efficacy data on the ketogenic diet (195; 196).
1971	Huttenlocher described the medium-chain triglyceride diet (122).
1970s and 1980s	The diet gradually became more unpopular after the introduction of carbamazepine and valproic acid. There was a decreased need for ketogenic diet due to the perceived advances in the pharmacotherapy of epilepsy. Medical and neurology residents were taught that valproic acid is a branched-chain fatty acid that can be substituted for the diet with a lesser requirement of family training and teaching (319).
1989	Schwartz and colleagues published the first comparative study of the short-term metabolic effects and clinical efficacy of the “classical” ketogenic diet and the medium-chain triglyceride diets (276).
1992	Kinsman and colleagues reported the efficacy of the ketogenic diet for intractable seizures in 58 cases (148).
October 1994	Ketogenic diet returned to the media spotlight in an NBC Dateline report (142) on Charlie Abrahams, a toddler who was successfully treated with the ketogenic diet at Johns Hopkins Hospital by Dr. Freeman and Millicent Kelly, RD. The program increased the awareness about this form of treatment in the medical circles, and it was followed by an increase in research on the effects of the diet. That same year, The Charlie Foundation for Ketogenic Therapies was founded by Jim and Nancy Abrahams (Charlie’s parents) to provide information about diet therapies for people with epilepsy.
1995	Wheless described the overwhelming amount of lay press articles and videos for the general public following the NBC documentary (319).
1996	Freeman and colleagues extensively described the classic ketogenic diet method (86).
February 1997	Jim Abrahams produced a televised movie called “First Do No Harm”, a televised movie that again turned the public’s eye to the diet. The movie was a dramatization of the life of a patient with epilepsy, loosely resembling the case described on the October 1994 “Dateline” program. Today, there are over 200 hospitals worldwide with ketogenic diet centers.

Clinical aspects

Description

Types of ketogenic diets. There are several different types of ketogenic diets, which include the classical ketogenic diet, the medium-chain triglycerides (MCT) diet, the ketogenic diet and MCT diet, the modified Atkins diet (MAD), and the low glycemic index treatment (LGIT). The ketogenic diet is based on the premise that in the setting of limited carbohydrates, the body will preferentially turn to oxidation of fat for fuel. Unlike carbohydrates, which are mainly converted into glucose, fats are converted into free fatty acids and ketone bodies. Free fatty acids and ketone bodies fuel the skeletal muscles and ketone bodies are able to cross through the blood-brain barrier. Since the early studies by Wilder, it became clear that a fat to carbohydrate plus protein food ratio of 3 to 1 or 4 to 1 is necessary (322). The nonketogenic or antiketogenic food includes carbohydrates as well as protein, and the ketogenic food includes only lipids. Wilder did not necessarily fast all patients at the onset of the diet, but over time, fasting followed by initiation of ketogenic meals became the most popular method; now known as “the classic ketogenic diet,” or the Hopkins ketogenic diet protocol. On the other hand, the use of medium-chain triglycerides will allow a slightly higher carbohydrate and caloric intake (122). The modified Atkins diet and the low glycemic index treatment diets share the same principles of carbohydrate restriction, with fat as the predominant energy source in the diet. These diets have emerged in the last 10 years and evidence indicates a comparable success rate to that of the classic diet (165; 147; 262). These diets also are easier to administer. It is believed that all keto centers would benefit from a ketogenic teaching kitchen that supports hands-on cooking classes to enhance the learning experience for families (81).

The classic ketogenic diet. The classic ketogenic diet, or Hopkins ketogenic diet protocol, was outlined and made famous by Livingston and by Freeman and colleagues (195; 196; 86). Children being initiated on the classic ketogenic diet must be admitted to the hospital for the initial period of fasting. Patients are sometimes instructed to avoid carbohydrate-rich foods starting the day before admission, but this is not essential. On the first day of their inpatient stay, it is customary to draw “baseline labs,” which, in one institution, include serum lipid profile, triglycerides, cholesterol and fractions, glucose, and electrolytes. These children are then fasted for 24 to 72 hours until 4+ (160 mg/mL) ketonuria is obtained. Then, the patients are given one third of the full 4 to 1 diet for the first day (after 4(+) ketonuria), two thirds on the second day, and the full 4 to 1 diet on the third day. The full diet is calculated based on a composition with 4 grams of fat for each gram of carbohydrate or protein, thus, the term “4:1 ratio diet.” Because each gram of fat and carbohydrate or protein generates 9 and 4 calories respectively, the patient will actually get nine times more calories from fat than from carbohydrates or protein. These ratios were derived from studies of the tendency for ketosis induction in diabetic patients (322). Patients less than 2 years old and adolescents are often initiated on a 3 to 1 ratio after the fasting period (88).

Within the last decade, treatment protocols for initiating the classic ketogenic diet have changed, and diet initiation protocols are more variable among different institutions (166). For example, it is less common now to initiate the ketogenic diet after a fasting period of 24 to 72 hours, as was previously implemented. Additionally, the daily fluid intake is often not restricted compared to previous recommendations because of limited evidence supporting the benefits of dehydration. The rate and severity of adverse effects of the diet, such as constipation and kidney stones, are seen less frequently when patients are allowed to consume more fluids when on the ketogenic diet. Tailoring comprehensive care and awareness of possible complications of a ketogenic diet are important for the successful implementation and maintenance of ketosis (135).

The classic diet is calculated in ratios of grams of fat to grams of protein and carbohydrate combined. Typically, ratios of 3:1 and 4:1 are used in the classic diet, although ratios can be decreased to as low as 1:1. Calorie requirements are calculated at 75% to 100% of the total recommended daily allowance for the patient’s age and weight. Protein is calculated to need minimal age-based requirements, and the amount of fat and carbohydrates are calculated to yield the desired ratio. There are online calculator tools available for practitioners to calculate targeted macro nutrient amounts and to create ketogenic meals in prescribed ratios. The KetoDietCalculator tool (www.ketodietcalculator.org) is a free online program funded by The Charlie Foundation for Ketogenic Therapies, designed to calculate the ketogenic diet ratios and to help the practitioners and caregivers to calculate meals.

The traditional method of initiating the ketogenic diet includes a period of fasting and may use 3 to 5 days inpatient admission for initiating the diet. There are now retrospective data suggesting that fasting is not necessary to achieve ketosis, and using a more gradual initiation protocol can achieve the same seizure control at 3 months with fewer side effects (166). The advantage of fasting is that the child will achieve ketosis sooner, and often experience a reduction in seizures before going home.

The diet is typically initiated in the hospital. Initiation and advancement protocols vary among centers. Some centers initiate the diet at goal ratio, such as 4:1, at half the typical daily calories. Calories are then gradually increased over a 3-day admission. Other centers may start at a lower ratio, provide full calories, and advance the diet ratio during the hospital stay. During the 3-day admission, parents and caregivers can learn to weigh out the meals and how to prepare the diet at home. The 3-day admission also allows the ketogenic diet team to monitor the child and to troubleshoot for any potential side effects. Patients on the ketogenic diet should be instructed to eat the whole meal. Because every meal is calculated with the appropriate ratio, patients should not be allowed to eat only part of a meal. Eating only part of it may produce an unbalanced intake, which may break ketosis or decrease the fatty acid substrate for lipolysis, decreasing serum ketones. The meals should be prepared carefully and should follow the dietitian’s recommendations. All the food should be weighed with a gram-precision scale.

Supplementation. Due to the limited quantities of fruits, vegetables, fortified grains, and foods containing calcium, multivitamin with mineral and calcium and vitamin D supplementation is recommended (336). The diet is especially low in water-soluble vitamins (196). Clinically significant nutritional deficiencies have manifested when the ketogenic diet was used without proper vitamin supplementation. Vitamin D concentrations are often decreased in children with epilepsy because of inadequate intake, limited sunlight exposure, and interactions with antiepileptic medications and vitamin D metabolism. Multivitamin and mineral formulations without carbohydrates are recommended. There are formulations available that work well with the ketogenic diet. Oral citrates can be prescribed to reduce the risk of kidney stones, particularly in children with a family history of kidney stones or difficulties in maintaining hydration. The ketogenic diet is deficient in vitamins and calcium; therefore, it should be properly supplemented with carbohydrate-free preparations (336).

Carnitine deficiency can also be seen during the course of treatment with the ketogenic diet, but it is rarely symptomatic (192). Routine carnitine supplementation is not currently recommended. Previous use of valproic acid is a risk factor for carnitine depletion (192). It is important to monitor serum carnitine concentrations and prescribe appropriate carnitine supplementation when concentrations are low because carnitine is essential for the long-chain fatty acid entry into the mitochondria (166). Further studies are necessary to evaluate the need for routine carnitine supplementation on the ketogenic diet.

Table 2. The “Classic” Ketogenic Diet (Suggested Protocol)

• Initiation with fasting optional (not recommended in younger children)
• Initiation and advancement of feeding:
	- Day 1: Two thirds of total calculated caloric intake from ketogenic beverage divided into three servings or one full strength ketogenic solid meal + two servings ketogenic beverage.
	- Day 2: One third of total calculated caloric intake from ketogenic beverage divided between breakfast and evening snack, plus to full strength ketogenic solid meals.
	- Day 3: Advance to full strength ketogenic meals on the third day.
• Total caloric intake (full diet) is 75% to 100% of the total daily allowance for age and weight.
• Total protein intake is calculated according to age and weight.
• Initial ratio is 4 to 1 (4 gram of fat for each gram of carbohydrate and protein combined), adapted as needed according to the patient’s needs.
• Add vitamins and calcium supplements.
• Supplement carnitine if serum concentrations are low.

After initiation of the diet, urinary ketones are measured twice daily for the first month of the diet. One often relies on the urine acetoacetate testing, as it is the cheapest and easiest way to check for ketosis. Traditionally, the diet is fine-tuned to maintain the child’s urinary ketones at 3 to 4+, which registers as a dark purple color on the ketone test strip (80-160 mg/dL). Nonetheless, this type of testing has many limitations. Urinary ketones do not always reflect the concentration of ketones in the brain, as urinary ketone vary depending on hydration and do not necessarily reflect the current degree of ketosis in the body. As such, they have an indirect relation to seizure control (38). Serum beta-hydroxybutyrate is the most reliable way of confirming ketosis and should be measured any time metabolic acidosis or other potential confounding factors are suspected. Serum beta-hydroxybutyrate can be measured with meters for home use, and in some situations, blood ketone monitoring can be recommended (38).

Table 3. Strategies for Low Serum Ketone Concentrations

• Investigate sources of carbohydrates
	- Medications, over-the-counter antibiotics for intercurrent infections - “Sneaking” carbohydrate rich food - School personnel or alternative caregivers unaware of the diet - Toothpaste or dermatological product consumption
• Decrease total caloric intake (especially if there is weight gain) • Increase the ratio to 4.5 to 1 or 5 to 1 • Repeat fasting. • Consider incorporation of MCT oil into the calculated fat allotment

The ketogenic diet is typically initiated together with an existing regimen of antiepileptic medications. Medications can be eventually discontinued if the patient responds well to the diet. However, little is known about the pharmacodynamics interactions between the ketogenic diet and antiepileptic medications (166).

Monitoring parameters include anthropometric measurements (height, weight, BMI) as well as urinary and blood ketone readings, seizure frequency, and laboratory studies. The diet calculation should be adjusted to accommodate growth changes in the child and their tolerance to the diet. The diet ratio can be adjusted in cases of decreased ketosis, loss of seizure control, difficulties with compliance, and to address any lab abnormalities. Ratios higher than 4.5:1 are typically not used long-term because of the increased risk of adverse effects and difficulties with compliance.

Laboratory studies to monitor at each follow-up visit include complete blood count with platelets, electrolytes, serum liver and kidney profile, fasting lipid profile, urinary calcium, creatinine ratio, urinalysis, and a serum nasal carnitine profile. Anticonvulsant drug concentrations should be monitored, if applicable (166).

It is important to troubleshoot compliance issues ahead of time. Common problems include school personnel or other caregivers that are either unaware or unknowledgeable about the diet, and intake of medication containing sugars that are unaccounted for (over-the-counter medications or antibiotics for intercurrent infections). Some patients will literally eat toothpaste, skin creams, or lotions (196); therefore, special toothpastes with low or no carbohydrates should be used for patients on the ketogenic diet (86). Some children have highly creative ways of obtaining food, as did one patient who traded baseball cards for cookies at school. Even when the diet recommendations are followed carefully, some patients may fail to maintain ketosis. These patients will often gain weight during the first few weeks or months on the diet, which is a sign that their caloric needs were overestimated. Reduction of their total caloric intake will often fix the problem.

There are other strategies for achieving and maintaining ketosis. Changing the patients’ ratio from 4 to 1 to 4.5 to 1, or even to 5 to 1, is another strategy used to increase serum ketones. Because it can be done without altering the total daily caloric intake, this ratio change is especially useful when serum ketones are low and the patient is not gaining weight excessively. Lack of spacing liquids has been associated with poor ketosis (86). Liquid intake restriction may not be as important as previously thought, and predisposes the patient to dehydration and renal stones. Another old strategy for patients who are not responding after 1 to 2 months on the diet is to fast them for 1 day to 7 days (252). This is receiving renewed interest, and referred to as intermittent fasting. This will be discussed later in this paper.

Any time after the initiation of the fasting or introduction of the high-fat diet, these children may become nauseated. When this happens, the first step is to ensure the patient is not dehydrated, and then prescribe fluids without glucose. Also important is to look for other signs and symptoms of hypoglycemia, and to check serum glucose, urine, and serum ketones. If the patient is still fasting, starting the diet at this point can decrease the nausea. The use of ketogenic beverage or formula is a good option in these cases because it provides a balanced ratio of 3 to 1 or 4 to 1 even with the intake of small amounts. If the child is absolutely refusing all meals, the administration of small amounts of juice (10 cc at a time, up to 60 cc) can be helpful (196; 86). These patients will become less ketotic and start to eat. When nausea is a recurrent problem, a gentler ketosis induction may be beneficial.

Some patients will become briskly hyperketotic, with panting respirations associated with nausea and vomiting. In order to avoid excessive acidosis in these extreme (and uncommon) cases, one should break ketosis right away with juice or intravenous glucose if the patient appears to be poorly responsive. An oral citrate or bicarbonate can be used to counter acidosis. The diet ratio can be decreased to help with tolerance, with further adjustments for seizure control once tolerance is established (262).

Serum and urine ketone determination. Ketones can be measured in the blood and in urine. Germaine Labs AimTab™ Ketone Tablets, Ketostix, and Keto-Diastix are semiquantitative tests and are based on a nitroprusside reaction (131). The urinary acetoacetate and acetone concentrations are inferred from the color of a paper permeated with the reagent. Urinary beta-hydroxybutyrate is not measured in these tests. The ketone measurements are obviously dependent on the urinary concentration (often only specific gravity is actually measured). Urinary ketones of 4+ (160 mmol/L) are found on a dipstick when blood beta-hydroxybutyrate concentrations exceed 2 mmol/L (98). If the beta-hydroxybutyrate to acetoacetate ratio is high, the results may be abnormally low. Dehydration may produce spuriously high urinary ketone concentrations. In our practice, we recommend monitoring with a Multistix 10SG to concurrently evaluate specific gravity as well as urinary and blood protein. Parents are taught to interpret ketone and specific gravity readings in order to monitor their child closely at home.

Serum measurements are also possible. Precision Xtra meter (Abbott®) is a handheld, made-for-home use meter that tests for serum beta-hydroxybutyrate and glucose concentrations. There are a few devices that track breath-acetone concentrations as a measure of ketosis.

Table 4. An Approach to the Management of Nausea in Patients Fasting or on the Ketogenic Diet

• Maintain good hydration status (carbohydrate free fluids).
	- Initiate the diet if the patient is fasting. Use small amounts of ketogenic food, up to one third of the total daily allowance.
• Use the ketogenic shake or commercial ketogenic formula.
• “Break ketosis” with juice if the following conditions exist:
	- Nausea, refractory to the above measures
	- Clinical hyperketosis with painting respirations, nausea, and vomiting
	- Metabolic acidosis
	- Extremely high ketone concentrations (greater than 15 mm)
• Consider initiating the diet without fasting (slower ketosis induction), if the problem is recurrent.
• Soak a cotton ball in isopropyl alcohol and have the patient sniff the cotton ball.

Regular checks (every 6 to 8 hours) of the serum glucose are recommended for patients undergoing fasting.

It is important to remember that when an individual adapts to a state of ketosis, one becomes tolerant of relatively low glucose concentrations and more resistant to becoming symptomatic due to hypoglycemia (196). Glucose concentrations of 8 to 40 mg/dL have been documented in asymptomatic patients on the ketogenic diet (196). This level is probably due to the action of beta-hydroxybutyrate and acetoacetate serving as substrates for the energy metabolism in the brain after conversion into acetoacetyl-CoA and succinate. Over-treatment of asymptomatic hypoglycemia may lead to delay in the onset of seizure control and should be avoided. Patients who are hypoglycemic and symptomatic with cold sweat, tachycardia, or weak pulse should be treated with juice by mouth or with intravenous glucose if there are changes in the level of consciousness and inability to swallow. Severe hypoglycemia with low serum ketone concentrations should also be treated more aggressively. These children also should be evaluated for enzymatic deficiency of the lipolysis pathway.

Table 5. Management of Hypoglycemia in Patients Fasting or on the Ketogenic Diet

• Maintain good hydration status (carbohydrate-free fluids).
• Decrease ketosis with 1 tbl of juice or one fourth glucose tablet (equivalent to 1 gm of quick-acting carbohydrate) if the following conditions are present:
	- Symptomatic hypoglycemia (cold sweat, tachycardia, and weak pulse).
	- Severe hypoglycemia with low serum ketone concentrations (evaluate the patient for enzymatic deficiency of the lipolysis pathway).
	- Metabolic acidosis (consider using intravenous fluids if acidosis is severe).
• “Break ketosis” with intravenous fluids if there is an alteration in level of consciousness.
• Consider initiating the diet if patient is still fasting.

When patients chronically on the ketogenic diet become sick and stop eating, they do not necessarily do well; in fact, some have lower ketone concentrations and start experiencing seizures (275). Lower endogenous fat reserves may cause them to be dependent on exogenous fat for ketogenesis. The use of ketogenic shakes or commercial ketogenic formulas may help provide these patients a balanced ketogenic diet that can be consumed a little at a time.

Livingston points out that after the diet initiation, phenobarbital concentrations may go up without any changes in dosage (196). Serum anticonvulsant concentrations should be carefully followed after the diet is initiated.

At discharge, follow-up evaluation should be scheduled for 1 month following initiation of the diet. Children under 1 year of age may be seen sooner with frequent contact with the ketogenic diet team. Following the 1-month visit, the child should be seen after 3 months on the diet, and every 3 months thereafter. After 1 year on the diet, visits can be scheduled at 6-month intervals, with phone contact in the interim (166).

At least 3 to 6 months should be allowed before suspending the diet if seizure frequency is not reduced (166; 165). When patients respond positively, it is customary to keep them on the ketogenic diet for at least 2 years before gradually weaning them into a normal diet (148). The weaning period usually takes 2 to 6 months.

The ketogenic diet started without fasting (inpatient or outpatient). The initiation of the ketogenic diet without prior fasting is by no means a new idea. Wilder and Peterman started the ketogenic diet without a period of fasting (322; 251). Peterman recommended a less abrupt initiation of the diet preceded by “a few days on less rigid carbohydrate restriction,” and Wilder simply started the diet while the patients were hospitalized, but without necessarily fasting them. This method can be used in an outpatient setting and has been previously referred to as the Mayo Clinic protocol (31). A manual from that institution published in the 1990s continues to describe the nonfasting initiation as the main way to initiate the ketogenic diet (120). Currently, in most institutions the ketogenic diet is initiated in the inpatient setting without fasting. It has been noted that the achievement of ketosis is similar in patients with or without an initial fasting, but the number of acute complications were greater in the fasting group (323; 129; 16). Initiation of the ketogenic diet with fasting is associated with more complications during periods that the patient is not eating, these include greater weight loss, metabolic acidosis, and hypoglycemia as well as the need of intravenous hydration due to the latter two conditions (16).

The composition of the diet and the total caloric intake is calculated in the same fashion as the classic ketogenic diet protocol, except for the period of initiation and ketosis induction. Experimental models of the diet have shown both the presence of sustained ketosis and of seizure protection in animals that were switched from regular feeding to the ketogenic diet without fasting (04). Some institutions use a non-fasting outpatient protocol (a modification of Huse’s 1994 Mayo clinic protocol) starting at a 1:1 ratio and increasing gradually to a 4:1 ratio over a period of 1 to 3 weeks (323). The patients are not weaned from their anticonvulsant medications until an improvement in seizure control is noted. Medium-chain triglyceride oil is often added (with at least as 10% of the total fat intake) to avoid constipation and to improve ketosis. Buchhalter and colleagues achieved a 4:1 ratio in 9 days without any complications (31). Huse and Wilder reported no problems with immediate initiation of a 3:1 diet (322; 120); however, patients have been admitted and started immediately on a 3:1 ratio diet with only minimal complications (117).

The disadvantages of this approach include slower onset of ketosis and the lack of the initial “boost” of seizure control seen with fasting. Some families are also reassured by the faster onset of seizure control associated with fasting and prefer fasting, in spite of the initial inconvenience of hospitalization, fingersticks, and other problems. At times, a faster onset of seizure control is medically desirable, as in cases of infantile spasms. Even without fasting, an inpatient hospital admission is still often required for optimal safety, monitoring, and effective teaching.

There is no difference in management or efficacy of the ketogenic diet if it is initiated fasting or non-fasting (323; 16; 117).

Medium-chain triglyceride (MCT) diet. The use of medium-chain triglyceride oil in a diet, as modification of the original ketogenic diet, was described initially in 1971 by Huttenlocher and has been used ever since. Medium-chain triglycerides have a rapid intestinal absorption and delivery to the liver, where they quickly undergo degradation, and also have a strong effect as a stimulator of the production of ketone bodies (272; 276).

The medium-chain triglyceride diet has the advantage of being slightly less restrictive, with the patient’s total caloric intake initially being approximately 75 cal/kg per 24 hours. Some authors have used 100% of the recommended daily caloric intake in the medium-chain triglyceride diet (276). This higher caloric intake and carbohydrate content is more palatable for the children. Another advantage is the fact that hypercholesterolemia is less common with the medium-chain triglyceride diet (121). Usually in this diet, medium-chain triglyceride oil represents 30% to 60% of the total caloric intake, long-chain fats 11% to 41%, protein 10%, and carbohydrates 19% (275). Schwartz and colleagues called this version of the diet with lower medium-chain triglyceride content (30% of the daily caloric intake) the “modified medium-chain triglyceride diet” (275).

The use of medium-chain triglyceride oil is associated with side effects such as nausea, vomiting, and diarrhea in up to 50% of the cases (275). Diarrhea is sometimes accompanied by abdominal pain (283). In these cases, giving the medium-chain triglyceride oil with food and reducing the daily amount can minimize the diarrhea (283). Medium-chain triglyceride oil may be substituted by other sources of long-chain fatty acids such as cream. Because the medium-chain triglyceride diet is often calculated in a less restrictive way, one may also need to decrease the total caloric intake of the patient or simply consider switching the patient with significant diarrhea to the classic ketogenic diet. Alternatively, medium-chain triglyceride oil amounts may be better tolerated if increased gradually (275).

Studies comparing metabolic effects of the medium-chain triglyceride diet and the classical ketogenic diet have demonstrated that the serum ketone concentrations are either similar (121), or slightly lower in patients taking the medium-chain triglyceride diet (276). An extra dose of medium-chain triglyceride given at bedtime may improve control of nocturnal seizures.

Table 6. Effects and Benefits of Medium-Chain Triglyceride Use

• Middle-chain fatty acids cross mitochondria independently from the carnitine carrier system.
• Middle-chain fatty acids are readily oxidized by mitochondria (even in the “fed state”).
	- Quick intestinal absorption, hepatic delivery, and oxidation
	- Decreased ketone clearance
• Allows for an “extra dose” for critical periods of the day (eg, nighttime)
	- Additional ketogenic effect for cases in which ketosis is difficult to induce
	- Less hypercholesterolemia when compared with classical ketogenic diet
	- Adding medium-chain triglyceride may actually correct the constipation effect of the classical diet

In a randomized controlled trial comparing the classic ketogenic diet to the MCT diet, Neal and colleagues demonstrated that despite lower mean concentrations of beta-hydroxybutyrate and acetoacetate, the MCT diet was comparable in terms of efficacy and tolerability to the classic ketogenic diet (230). In the MCT group, 29.2% of children achieved a greater than 50% reduction in seizures, whereas in the classic ketogenic diet group, 24.7% of children achieved a greater than 50% reduction in seizures. The problem commonly encountered in the medium-chain triglyceride diet is that nausea, vomiting, and diarrhea are limiting factors when one has to increase the amount of medium-chain triglyceride. In some cases, these side effects may be overcome by slow and gradual increase in the amount of medium-chain triglyceride oil in the diet (275).

Liberal diet ratios: the modified Atkins diet and the low glycemic index treatment. Now there are more liberal variations of the ketogenic diet, such as the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT). These liberal metabolic therapies are now being considered earlier in the treatment of intractable epilepsy (123; 218).

Modified Atkins diet. The modified Atkins diet is a high-fat, low-carbohydrate diet that does not restrict calories, protein, or fluids. The modified Atkins diet provides approximately 65% of calories from fat, which is equivalent with a 1:1 ratio (fat to nonfat). Children restrict their total daily net carbohydrate intake to 10 grams per day, and adolescents and adults restrict net carbohydrates to 15 to 20 grams per day (162). Net carbohydrates are defined as the total carbohydrate grams minus the grams of dietary fiber, which allows for more carbohydrate per day. Sugar alcohols are not subtracted from the total grams of carbohydrate, which is different from the adult “Atkins Diet” used for weight loss. The advantage of a lower ratio is the higher protein and carbohydrate intake, making it more palatable and easier for adolescents and adults to adhere to. Twenty years later, after dozens of studies encompassing hundreds of patients, including several randomized controlled trials, the Modified Atkins Diet is a proven method of providing ketogenic dietary therapy for epilepsy. It is a diet therapy of choice for adolescents and adults, is being investigated for new-onset epilepsy, and is researched for neurologic conditions other than epilepsy. Adverse effects do exist, but may be less common than those that occur with the classic ketogenic diet (156).

A preliminary study showed some evidence of efficacy of the Atkins diet in patients with epilepsy (152). Kossoff and colleagues studied the short-term (6-month follow-up) efficacy of the modified Atkins diet for the treatment of medically refractory seizures in children (162). The patients were initially on a regimen of 10 gram of net carbohydrate per day. Eighteen of 20 patients were able to increase the regimen to 15 gram of net carbohydrate per day without an increase in seizures. The authors’ claim that the efficacy of the modified Atkins diet was similar to the “classic ketogenic diet” over the 6 months studied (compared to published data from the same institution). Nonetheless, the study failed to account for drop outs in its initial cohort when calculating seizure control ratio. This is significant because patients with worse seizure control tend to have a higher incidence of drop out (314).

Between 2003 and 2017, there have been at least 38 prospective and retrospective studies published about the modified Atkins diet in children, adolescents, and in adults. In summary, these studies have shown that 45% to 50% of patients have 50% to 90% reduction in seizures, and 28% have had greater than 90% reduction in seizures. The efficacy of the modified Atkins diet appears to be generally similar to that of the classic ketogenic diet (159; 165; 172; 215).

In a study of 40 individuals with intractable epilepsy, 15 were treated with the modified Atkins diet, 10 were treated on the ketogenic diet at a 4:1 ratio, and the remainder was treated with anticonvulsant medication alone (78). The individuals on the ketogenic diet had the greatest reduction in seizure frequency, followed by those treated with the modified Atkins diet. Both dietary treatment options were more effective than treating with anticonvulsant medication alone.

There is evidence that adults also are responsive to treatment with the modified Atkins diet. Smith and colleagues showed that adults with pharmacoresistant epilepsy had a moderate response to treatment with the modified Atkins diet (286). The study included 18 adult patients, ages 18 to 55 years, enrolled on the modified Atkins diet with a limit of 20 grams of carbohydrate per day; two (12%) had a greater than 50% reduction in seizures after 3 months, five (28%) after 6 months, and four (21%) after 12 months. The response at 3 months predicted the response at 12 months in 14 (79%) of the patients.

In a study of 15 adults with intractable epilepsy, the ketogenic diet or the medium-chain triglyceride diet was initiated as add-on therapy. There was a significant reduction in seizures among the five adults who continued on the diet for at least 1 year. Of these five patients, two had a reduction in seizures between 50% and 90%. There was no statistically significant impact on mood or quality of life (175).

A retrospective study examined the records of 27 children who were initiated on the modified Atkins diet, then placed on the classic ketogenic diet (154). Ten children demonstrated a modest improvement when switched to the classic ketogenic diet. Five of these children became seizure-free. Interestingly, all five of these children had myoclonic-astatic epilepsy. This strongly supports that the classic ketogenic diet is a more efficient treatment, as likened to a higher dose of medication. The modified Atkins diet can be used as a first dietary treatment because of its proven effectiveness; however, the classic ketogenic diet should be considered particularly in cases where rapid improvement is required, and in cases that may benefit from additional seizure control (07).

Initiation guidelines. The modified Atkins diet is initiated in the outpatient setting. Initial net carbohydrates are limited to 10 g per day (20 g for adults). Adolescents are initiated at 15 g per day, but adjusted up to 20 g per day if needed for ease of administration and compliance. The modified Atkins does not restrict carbohydrate-free protein foods, such as meat and chicken, although the modified ketogenic diet as outlined by The Charlie Foundation for Ketogenic Therapies will address protein intake due to its glucogenic properties. Fluids are encouraged. Urinary ketones are monitored during the first month similarly to that of the classic ketogenic diet. Carbohydrate-free multivitamin and calcium and vitamin D supplements are also given. Unless the patient has a history of kidney stones, oral citrates are not typically prescribed. Commercial ketogenic supplements can be prescribed and may be helpful for improving compliance to the diet.

In the second month, carbohydrate content is increased by 5 g per day each month, if desired. Ketones continue to be monitored, but it is not necessary to check them as frequently. It is recommended to monitor urinary ketones at least once a week.

When on the modified Atkins diet, follow-up with the neurologist and dietitian is recommended every 3 to 6 months. Laboratory monitoring should be performed every 3 to 6 months for the first year.

When discontinuing the modified Atkins, carbohydrates are increased in 10 g increments every 2 weeks until the diet reaches 60 g of carbohydrate per day. If the patient maintains seizure control, the diet can be further liberalized with additional carbohydrate containing foods (38).

The low glycemic index treatment. Jenkins and colleagues found that the ingestion of different foods with the same caloric content produced different rates of serum glucose elevation (126) and had different effects on weight gain and loss. Pfeifer and Thiele used that concept to create the low glycemic index treatment for the treatment of intractable epilepsy (254). The low glycemic index treatment focuses on limiting specific types of carbohydrates. Foods that have a high glycemic index (of 50 or greater) are eliminated from the diet. Additionally, 60% of calories are from fat, and protein intake is provided at approximately 1 g/kg/day (254). The low glycemic index diet is initiated in the outpatient setting. Food measurements are more lenient on this diet, and rely on portion sizes in household measurements as opposed to measuring foods on a digital gram scale as is required on the classic ketogenic diet. Both the modified Atkins diet and the low glycemic index treatment induce ketosis without requiring a hospital admission to initiate the diet (254; 162).

A retrospective study by Muzykewicz and colleagues reviewed 76 children who were initiated on the low glycemic index treatment between January 2002 and June 2008 (225). A greater than 50% reduction from baseline seizure frequency was observed in 50% of the population at 3 months. Interestingly, increased efficacy was correlated with lower serum glucose concentrations at some time points, but not with beta-hydroxybutyrate concentrations. Only three patients reported side effects. These results were replicated in a study published by Coppola and associates where 15 children and young adults with refractory epilepsy were treated with the low glycemic index treatment between 2005 and 2010 (44). Eight of the 16 patients were on the low glycemic index treatment as the first diet of choice, and the remaining seven were previously treated with the classic ketogenic diet and discontinued the diet for at least 2 years, then initiated on the low glycemic index treatment. Forty percent of the group had a 75% to 90% seizure reduction, whereas seizures decreased by 50% in 13.3%. Forty-six point seven percent of the patients were unchanged in seizure frequency. In addition, there were no adverse effects reported in this study. Increased efficacy was negatively correlated with lower serum glucose concentrations, as the majority of patients maintained a transient ketosis. Karimzadeh and colleagues reported on 42 children treated with the low glycemic index treatment (133). They reported a greater than 50% seizure reduction in 77.8% of their patients at the end of the second month. They did not report any significant complications related to the diet. Similarly, Kim and associates reported a greater than 50% seizure reduction in 56% patients treated with the low glycemic index treatment in a group of 36 patients (147).

Efficacy of liberal diet ratios. Current clinical evidence suggests that the modified Atkins diet and low glycemic index treatment appear to be effective in the treatment of intractable epilepsy. In determining which type of diet a patient should be started on, several other factors should be considered, including age, lifestyle, epilepsy type, and resources (218).

Studies have consistently shown that about two thirds of patients treated with the ketogenic diet have a reduction in seizures by at least 50%. Many of the studies using the modified Atkins diet show about 50% of patients experience about 50% reduction in seizures. However, currently there are some data from the literature to suggest that the classic ketogenic diet may be more efficacious than the modified Atkins diet (78; 145). Given that the modified Atkins diet is easier to administer and is better tolerated, the modified Atkins diet does offer additional benefits and utility when compared to the ketogenic diet, particularly in older children where compliance is a greater challenge (07).

Fuehrlein and colleagues have demonstrated that ketosis can be more efficiently achieved by the use of a diet rich in polyunsaturated fats (90). The latter diet is also less likely to induce elevations in LDL cholesterol. Seizure efficacy has not been tested between polyunsaturated and saturated fat rich diets. More data are necessary to show the efficacy of these versions of the diet.

The use of the ketogenic diet in surgical patients. Some of the patients on the diet may end up needing surgery such as Nissan fundoplications, gastrostomies, and spinal fusions/rod placement. In these cases, the patients can be safely managed with an intravenous solution temporally (306). During longer procedures serum glucose, pH, and electrolytes should be monitored. Bicarbonate infusions may be necessary to counteract drops in pH (306).

Liquid ketogenic diet. When patients are ill or have a labile appetite, sometimes the use of a liquid form of the ketogenic diet maybe helpful (153). The overall mixture of carbohydrate, protein, and fat in a given meal in a patient on the ketogenic diet has to be consumed in a relatively short period of time to produce ketosis. When patients eat only the carbohydrate and protein-rich part of the meal and refuse or delay for prolonged periods (more than 20 minutes) ingestion of the high part, such as the cream, lower ketosis may be the result. In these cases, the temporary use of a liquid diet can be helpful. The liquid diet is also more palatable and tastes similar for regular formulas (153). There is also less room for error, and the patient consumes a balanced ketogenic meal (153). Furthermore, the liquid diet is obviously the default method of delivering the diet by gastrostomy tubes or in infants. Usually KetoCal(TM) (SHS International) is a ready-to-use 4:1 or 3:1 product that is convenient, especially in emergencies and on trips, and that can be used in recipes for oral ketogenic diets. One of the disadvantages of KetoCal(TM) is that it contains lactose; thus, it is not ideal for patients with lactose intolerance. KetoCal 4:1(TM) powder contains aspartame whereas KetoCal 3:1(TM) powder, and KetoCal (TM) 4:1 liquid formula do not include aspartame. Alternatively, a combination of Ross Carbohydrate Free(TM), Ross Microlipid(TM), and Mead Johnson Polycose(TM) is suitable to make up the same ratios used with food (1:1 to 4:1). KetoVie™ (Cambrooke Therapeutics) is another product available for use on the ketogenic diet. KetoVie™ is formulated in a 4:1 ratio, and is flavored in vanilla and chocolate. It contains a different protein source (whey) and MCT oil comprises 25% of calories. This product also contains supplemental carnitine. Betaquik® is another MCT emulsion comprised mainly of C8-10 medium-chain fatty acids. MCT Procal is a powdered MCT powder in packets. Each packet contains 10 g of MCT oil, 3.3 g of carbohydrates, and 2 g of protein.

Duration of treatment on the ketogenic diet. A minimum of 3 to 4 months on the diet is recommended before accurately determining the efficacy of the diet (166). When patients respond positively, it is customary to keep them on the ketogenic diet for at least 2 years before gradually weaning them onto a normal diet (148). However, subsequent data show that long-term use of the ketogenic diet, beyond 2 to 3 years, has been safe and successful (166).

If the ketogenic diet has been effective in providing seizure control, the patient should be weaned from the diet gradually over the course of 2 to 12 months. However, if the ketogenic diet has not been successful in providing effective seizure control, then it can be weaned more quickly, over the course of a few weeks, after the initial 3- to 4-month trial period (166).

The goal of the ketogenic diet in patients with epilepsy is seizure control. Complete seizure freedom, although desirable, is not always attainable because this therapeutic modality is far from being 100% efficacious. Realistically, if the patient fails to respond to the diet and ketosis is achieved, other treatment options should be kept in mind (other drug trials, epilepsy surgery, or vagal nerve stimulator). These other options also can be used in combination with the ketogenic diet.

Few reports indicate when it is appropriate to stop the ketogenic diet. Historically, patients were typically weaned from the diet after being seizure-free for 2 years on the diet. There have been reports of patients continuing on the ketogenic diet for numerous years. If seizures recur when attempting to wean the diet, then long-term therapy may be more beneficial. However, the implications of long-term diet therapy remain to be determined (313). No study is available outlining the long-term consequences of a high-fat diet in childhood. Livingston found no long-term problems in patients treated with the ketogenic diet (196). Exposure to high-fat diets associated with low caloric consumption may not be as conducive to atherosclerosis as it is when associated with high caloric or high carbohydrate intake, but this remains to be proven.

Interaction between ketogenic diet and antiseizure medications. The majority of individuals on the ketogenic diet are also receiving antiseizure medications. Medication reduction is usually attempted after 1 month on ketogenic diet therapy if a child shows seizure reduction (seizure freedom is not required). “Fine tuning” the treatment combination of medications and diet may take several months. Armeno and Kossoff published a review discussing the evidence for possible negative and positive pharmacodynamic interactions between the ketogenic diet and antiseizure medications (Armeno and 156). They provide practical suggestions for weaning and adding of medications in individuals on the ketogenic diet.

Establishment of a ketogenic diet program. Much research, organization, and funding go to the assembly of a ketogenic diet program (197), and the maintenance of such programs are also highly labor intensive (35). There is a need for better interdisciplinary collaborations to increase the utilization of the ketogenic diet (295). The three main personal elements necessary for the initiation of such a program are as follows:

(1) A dietitian knowledgeable of the ketogenic diet and interested in working with the families in adapting and individualizing menus.

(2) A neurologist who is also knowledgeable of the pitfalls of maintenance of ketosis and side effects both during the initiation and throughout the course of the treatment with the diet.

(3) A nurse practitioner who can screen patients for their candidacy for the ketogenic diet, is knowledgeable about the side effects and management of side effects on the diet, and can provide detailed ketogenic diet education for families, track the patients, and follow-up with the families. The nurse practitioner can also order the necessary lab tests to monitor patients on the diet as well as order the appropriate medications and supplements that may be necessary for patients on the ketogenic diet.

In one study, the cost of the start-up of the establishment of a ketogenic diet program was 75 U.S. dollars (197). The latter cost included 55 hours of dietitian time, research, protocol development, and creation of patient and caregiver education materials.

A comprehensive ketogenic diet program requires a multidisciplinary team, which often includes a knowledgeable dietitian, neurologist, nurse practitioner, nurse, social worker, and pharmacist as well as the patient’s primary care provider (166). During initial contact, an effort should be made to educate the patient and caregivers about the ketogenic diet. They should be informed about the problems and advantages associated with use of the ketogenic diet as an anticonvulsant modality. The caregivers and physician should consider the ketogenic diet as any other antiepileptic drug, requiring monitoring and careful follow-up. After the diet initiation, further education is often necessary and can be provided by the dietitian, nurse, nurse practitioner, and physician during subsequent phone calls and clinic visits.

In 2015, the International League Against Epilepsy (ILAE) Task Force for Dietary Therapy, led by Dr. Eric Kossoff, convened to provide practical, cost-effective guidelines for new ketogenic diet centers in areas that are resource-limited (157). The recommendations require a physician, preferably a neurologist, who is familiar with the ketogenic diet, and a dietitian to monitor the classic ketogenic diet.

Patient and family education. Before the initiation of the diet, it is wise for the families or caregivers to acquire some knowledge of the basic principles of the ketosis initiation and to have maintenance explained in lay terms.

The patient and their family should have a visit with the neurologist, dietitian, and nurse practitioner before the diet initiation. At that point, the ketogenic diet team should not only educate the caregivers and patients about the steps necessary to become and remain ketotic, but also about the resources and spread of information necessary. They should be informed about the need for a gram scale. Teachers and alternative caregivers at school, home, or elsewhere should be given some teaching material about the diet. Despite the impacts that the ketogenic diet may have on caregivers' emotional and social well-being, the positive impacts of the diet are felt to outweigh any perceived risks (240).

MacCracken and Scalisi found that preadmission teaching took more than 2 hours for patients on oral feedings, and about 1 hour for children on tube feeds (197). The average dietitian time spent per patient was 7 hours outpatient time, and 9 hours during the hospitalization required for ketogenic diet initiation.

Reimbursement of the ketogenic diet treatment. Although making money is not the goal of most ketogenic diet programs, most institutions without major government funding are not able to provide long-term support of programs that are not fiscally sound.

The physician and nurse practitioner charges (in and outpatient care) and hospitalization charges are often paid on the customary rates for the insurance providers. In one study done in the state of Oregon, the average inpatient charges for a ketogenic diet admission were 78 U.S. dollars (average stay was 6.4 days), for which 43 U.S. dollars were paid, yielding a reimbursement rate of 83% (197). Some insurance companies will temporarily refuse to pay the charges of the hospital admission for the ketogenic diet initiation on the premises that the diet is an experimental treatment modality. This will often require only a letter from the treating physician explaining the literature on the subject.

In MacCracken and Scalisi’s study, the reimbursement of the outpatient dietitian services was much worse (197). One of the main reasons was the high percentage of hours (65%) needed to monitor the patient, which were represented by phone contact. In the same study, the direct patient contact hours (35% of the total time) were reimbursed on average at a lower rate of 61% (of the charge of 3 U.S. dollars, the paid amount was 5 U.S. dollars, for approximately 2.5 hours).

Indications

Seizure type and the effects of the ketogenic diet. The ketogenic diet is indicated for seizure patients who do not respond to pharmacological therapy. It has been indicated for patients whose seizures did not respond to two or more medications (88). The use of the diet as a first line therapy has not been extensively studied. Due to the intense labor involved in the implementation and maintenance of the diet, its use as a first line anticonvulsant agent is considered by practitioners to be impractical. However, families should be made aware of all the treatment options for seizures and given sufficient education to make the appropriate decision for their child. The families of patients with epileptic syndromes likely to respond to surgery, such as complex partial seizures due to unilateral mesial temporal lobe sclerosis, should be made aware of this fact. In addition, there are now more liberal variations of the ketogenic diet, such as the modified Atkins diet and the low glycemic index treatment, and dietary therapies may be considered earlier in the treatment of intractable epilepsy (123). In select situations, they may be considered as a first-line therapy for certain epilepsies, such as infantile spasms or myoclonic-astatic epilepsy, and in families who are motivated and willing to implement the diet, and for patients with access to a ketogenic diet team that is able to implement the diet in 1 to 2 days (154).

Some confusion has been generated by the earlier studies of the seizure types that respond to the ketogenic diet. A study from the Mayo Clinic mentioned that patients with symptomatic epilepsy might respond less well to the diet than patients with idiopathic epilepsy (139). Livingston, summarizing the experience from Johns Hopkins University, mentions exactly the opposite opinion, stating that patients with idiopathic epilepsy respond less well to the ketogenic diet, and the patients with myoclonic and akinetic epilepsies (which are commonly due to symptomatic epilepsy) have the best response to the diet (196). Schwartz and colleagues showed that the seizure type may not be important because, at least with short-term follow-up, no particular seizure type showed a significantly better response to the diet (275). These results were later confirmed by a prospective study of 150 patients by Freeman and colleagues (88).

The ketogenic diet continually has been effective for all seizure types as well as numerous epileptic syndromes (11; 166; 160; 296).

Several epileptic syndromes and metabolic and genetic disorders have been shown to respond favorably to the ketogenic diet, including the following:

Epileptic syndrome	Reference
Landau-Kleffner syndrome Lennox-Gastaut syndrome Dravet syndrome Myoclonic astatic epilepsy Infantile spasms/West Syndrome	(14; 15) (183) (32; 226; 310; 177) (13) (161)
Disorders	Reference
CDKL5 mutations Tuberous sclerosis Lissencephaly Hypoxic ischemic encephalopathy Rett syndrome Mitochondrial disorders Glucose transporter type 1 (GLUT-1)	(220) (164; 45) (296) (296) (106; 187; 73) (160; 260) (166; 256)

The ketogenic diet has been also used in the treatment of acquired epileptic aphasia (Landau-Kleffner Syndrome), and, in three cases, showed good response to the diet (14; 15). Speech improvement was sustained, lasting 12 months, 24 months, and 26 months, respectively (15). The range of beta-hydroxybutyrate levels, which was effective in improving the aphasia and the awake and asleep EEGs was 2.3 to 4.7 mm (15). Secondary behavioral changes and social interaction also improved during the treatment with the ketogenic diet in all three patients.

A retrospective study evaluated the treatment of new-onset infantile spasms by comparing the efficacy of the ketogenic diet to the standard treatment, ACTH (161). The side effects and relapse rates were lower among those treated with the ketogenic diet. However, ACTH normalized the EEG more rapidly compared to the ketogenic diet. The ketogenic diet stopped spasms in 8 of 13 infants; whereas, ACTH stopped spasms in 18 of 20 infants (166).

The ketogenic diet is effective in the treatment of Lennox-Gastaut syndrome, based on a retrospective review of one institution’s experience as well as from a summary of the literature (183).

Ketogenic diet in Dravet syndrome. The ketogenic diet is also an effective therapy for individuals with Dravet syndrome (formerly known as severe myoclonic epilepsy of infancy) (32; 310; 177). Additionally, the ketogenic diet has shown to be efficacious in Dravet syndrome when used in conjunction with stiripentol (226). Furthermore, Nabbout and colleagues showed that the ketogenic diet not only improved seizure control but also significantly improved behavior and hyperactivity in patients with Dravet syndrome (226).

In a study of 20 children with Dravet syndrome treated with the ketogenic diet, 13 of the children (65%) experienced a greater than 50% reduction in seizure frequency (177).

There have also been some promising data on the use of the ketogenic diet for patients with various mitochondrial disorders for which there are currently very limited effective treatment options. The ketogenic diet may be effective in the treatment of mitochondrial diseases due to complex 1 deficiencies. The rationale for this is that some of the energy generated by lipolysis enters the electron transport chain at the level of complex 2, thereby bypassing complex 1 (160; 260).

The ketogenic diet was previously considered a “last resort” treatment option for refractory epilepsy. The ketogenic diet is being considered earlier in the treatment of intractable epilepsies (229).

The ketogenic diet is recognized as a first-line treatment for individuals with glucose transporter type 1 (GLUT-1) deficiency and in pyruvate dehydrogenase deficiency (PDHD) (166). Patients with GLUT-1 deficiency benefit from early treatment with the ketogenic diet (256). Delaying treatment in patients with GLUT-1 deficiency results in worsening psychomotor development, cognition problems, and motor delays (261).

The ketogenic diet is the only first-line treatment recommended for individuals with GLUT-1 deficiency. In a study of 78 patients with GLUT-1 deficiency, the ketogenic diet was used in 82% (64/78); 67% (41/61) were seizure-free on the ketogenic diet (256). There were seven patients who became seizure-free on broad antiepileptic drugs without use of the ketogenic diet (256). Early initiation of the ketogenic diet is recommended for patients with GLUT-1 deficiency. There is insufficient evidence to recommend anything other than the ketogenic diet as the treatment of choice for these individuals (256).

Patients with myoclonic astatic epilepsy have been shown to be especially responsive to treatment with the ketogenic diet (222; 13). In a multicenter study, Stenger and colleagues reported 50 children with myoclonic astatic epilepsy who were treated with the ketogenic diet (289). Most were treated with a 3:1 or 4:1 ratio, with three patients treated with the modified Atkins diet. Within the first 20 days of diet initiation, 86% of patients had over a 70% reduction in seizure frequency, 38% had more than 90% decrease in seizures, and 26% were seizure-free. After 6 months, 54% of patients achieved seizure freedom, and 86% experienced a greater than 70% seizure reduction after 2 months on the ketogenic diet. The authors correlate this positive outcome with early initiation of the diet. This strongly suggests that the ketogenic diet should be used early in the course of myoclonic astatic epilepsy. The authors propose that the ketogenic diet should be initiated as soon as possible once the diagnosis is established. Mullen and colleagues identified that a significant proportion of patients with myoclonic astatic epilepsy have GLUT-1 deficiency, as identified by having SLC2A1 mutations (221). GLUT-1 deficiency is likely underdiagnosed in patients with myoclonic astatic epilepsy. The diagnosis of GLUT-1 deficiency would then lead to earlier treatment with the ketogenic diet among patients with intractable myoclonic astatic epilepsy. Early genetic testing for GLUT-1 deficiency is also recommended for all infants with seizures, spasms, or paroxysmal events in order to initiate earlier treatment with the ketogenic diet and to avoid unnecessary trials with antiepileptic drugs (256).

The modified Atkins diet may also be an effective treatment option for individuals with GLUT-1 deficiency. There is a case report of a 6-year-old girl with GLUT-1 deficiency who responded exceptionally well to the modified Atkins diet, with improved seizure control, alertness, cognition, and improved EEG findings (107).

Ketogenic diet in tuberous sclerosis complex. Patients with tuberous sclerosis complex appear to respond to ketogenic diet (164; 45) or low glycemic index diets (176). The idea that there was a unique mechanism in cases of tuberous sclerosis complex-related epilepsy gained some credibility when McDaniel and colleagues reported that the ketogenic diet inhibits the mammalian target rapamycin (mTOR) pathway in animal models (207). Energy and substrate deprivation seems to influence the mTOR pathway at the level of LKBeta1/AMPK, which acts on hamartia, encoded by the TSC1 gene. The ketogenic diet may also have anticonvulsant actions by inhibiting the mTOR pathway (208).

Ketogenic diet in adults. To date, there are at least 17 studies published on the use of the ketogenic diet for epilepsy in adults. Results indicate a greater than 50% seizure reduction with the range of 22% to 55% seizure reduction on the classic ketogenic diet and 12% to 67% seizure reduction rate for the modified Atkins diet (324). Barboka studied the effectiveness of the ketogenic diet in 100 adults (12). Twelve percent of the patients showed complete control of seizures (one patient took 8 months to have the complete benefit), 44% had partial control, and another 44% had no benefit. Sustained ketosis correlated well with seizure control. Patients were 16 to 51 years of age and were followed for 12 to 30 months after the study. Sirven and associates reported a group of 11 adults treated with the ketogenic diet (285). After 8 months of follow-up, the seizure reduction was 90% in three patients and between 50% and 89% in three others.

A metaanalysis of studies of adults on any type of ketogenic diet confirmed that adults have a better seizure response but have lower compliance/long-term adhesion on the classic ketogenic diet than on the modified Atkins diet (331). The most recent and largest study in adults treated with ketogenic diet provides evidence that the ketogenic diet is effective in treating seizure disorders. In addition, it shows that the diet is feasible and safe in the long-term. In this combined group of 139 participants, 41% of participants responded positively to the ketogenic diets, and of these 27% became seizure-free. Approximately 48% of the patients discontinued the diet and the predominant reason for this was the diet’s restrictiveness (37).

Ketogenic diet for status epilepticus in adults. To date, there is a prospective multicenter study describing 24 adult patients who were treated with the ketogenic diet for super refractory status epilepticus. Fourteen patients completed ketogenic diet treatment and 79% of these patients experienced resolution of super refractory status epilepticus. The authors conclude that the ketogenic diet is feasible in this condition and may be safe and effective, although additional randomized, placebo-controlled trials need to be performed to establish safety and efficacy (39).

Uses of the ketogenic diet other than for seizure control. The ketogenic diet has also been used in the treatment of glucose transport disorders. In this clinical entity, the glucose concentrations in the CNS are reduced due to a defect in the transport system (glucose transporter-1 deficiency). The use of the ketogenic diet can improve this condition significantly. Classically, the explanation for the benefits of the ketogenic diet on the treatment of glucose transporter-1 deficiency was the delivery of a glucose transporter-1-independent energy fuel to the CNS, but some have found clinical evidence that this explanation may be an oversimplification (26). The diet has been mentioned as the treatment of choice for this condition (69).

Pyruvate dehydrogenase complex deficiency has been treated successfully with the ketogenic diet (80; 321; 318). When these patients are started on a diet high enough in fat to produce ketosis, the serum pyruvate concentrations fall and frequency and severity of the episodes of neurologic deterioration decrease (80). In one study, the patients with pyruvate dehydrogenase complex deficiency, who were treated early with the ketogenic diet, had increased longevity and better mental development (318). The rationale for the use of the diet is to produce acetyl-CoA from beta-hydroxybutyrate. Acetyl-CoA then enters the Krebs cycle to produce energy without the need for the dysfunctional pyruvate dehydrogenase step.

Whether ketogenic diet can be used in the treatment of mitochondrial diseases due to complex 1 deficiencies remains speculative. The rationale for this is the fact that some of the energy generated by lipolysis enters the electron transport chain at the level of complex 2 (bypassing complex 1). We have no experience with using ketogenic diet for complex 1 deficiencies, and the literature on the subject is limited.

Phosphofructokinase deficiency, a condition that presents in the newborn period with congenital arthrogryposis and severe myopathy, may also respond to the ketogenic diet (293).

The medium-chain triglycerides diet has also been used as an adjunct treatment for astrocytomas (233). There is a feasibility study (KEATING) to evaluate ketogenic diets as an adjuvant therapy for glioblastoma (203). Animal evidence points to a potential role of the ketogenic diet in the treatment of mood disorders (223).

The ketogenic diet has received increased interest within the scientific community, particularly for the treatment of a wide variety of neurologic disorders, including age-related decline, Alzheimer disease, Parkinson disease, stroke, cancer, and autism (287). There is evidence in animal models that the ketogenic diet can be used advantageously in acute stroke and traumatic brain injury (258; 97). Currently, there are at least two clinical trials investigating the impact of the ketogenic diet in stroke rehabilitation.

EEG and the ketogenic diet. One short-term study using a mixed population of patients with refractory epilepsy failed to demonstrate any changes in EEG associated with use of the ketogenic diet (275). Another report with a 12-month follow-up found some improvement on the EEG background and on the frequency of epileptiform activity, but only a small proportion of the patients had pre- and post-diet studies (70).

On the other hand, in a study of a more homogenous patient population with atypical absences, Ross and colleagues demonstrated a statistically significant decrease in the mean number of epileptiform discharges following medium-chain triglycerides therapy (264).

Kessler and colleagues demonstrated that interictal epileptiform discharges decrease and there are improvements in EEG background slowing on treatment with the ketogenic diet (141). A reduction of interictal epileptiform discharges after 1 month on the ketogenic diet strongly predicts a patient’s response to the diet at 3 months.

Ketogenic diet for other disorders. There is a randomized, double-blinded, placebo-controlled, crossover clinical trial studying the efficacy of exogenous ketones for treatment of migraine headache (102). The ketogenic diet has also been proposed for Alzheimer disease, dementia, multiple sclerosis, cancer, weight loss, spinal cord injury, cancer, diabetes, autism, and endurance exercise (180; 270; 301; 309; 317; 330; 30; 102; 127; 150; 167; 206; 235; 241; 308; 09; 57; 111; 151; 203). Crabtree and colleagues found that a short-term, hypocaloric ketogenic diet high in saturated fat does not adversely impact liver health and is not impacted by exogenous ketones (52). They reported that a hypocaloric low-fat diet and ketogenic diet could both be used in the short term to significantly reduce liver fat in individuals with nonalcoholic, fatty liver disease.

Phillips and colleagues completed the first randomized trial to investigate the impact of a ketogenic diet in individuals with uniform diagnoses of Alzheimer disease (255). They performed a randomized, crossover trial using a modified ketogenic diet. High rates of retention, adherence, and safety were achievable in applying a 12-week modified ketogenic diet to individuals with Alzheimer disease. Compared to a usual diet supplemented with low-fat, healthy-eating guidelines, individuals on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people with dementia. A review reported the strongest evidence to date for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer disease who were negative for the apolipoprotein E4 allele (25).

Contraindications

Many disturbances in the energy metabolism are potentially aggravated by fasting or high-fat diets. This is especially true for the disorders caused by a deficiency in one of the enzymes involved in fatty acid oxidation. Many patients with these disorders may be asymptomatic until they undergo fasting, contradicting the usual presentation of inborn errors of metabolism with dramatic pictures that start early in infancy. As a matter of fact, some of these patients typically present later in childhood, such is the case in the long-chain acyl dehydrogenase deficiency (238).

A history of episodes of weakness or muscle cramps precipitated by fasting or prolonged exercise is suggestive of a disturbance in the fat oxidation metabolism (104). Other phenotypes include history of myopathy and Reye syndrome-like episodes (104). The latter are characterized by encephalopathy, elevated liver transaminases, and hyperammonemia. Many of these patients will have family histories of unexplained sudden infant death syndrome (109; 104). Middle-chain acyl dehydrogenase deficiency is the most common form of beta-oxidation enzymatic deficiency (104). Because fasting and fat-based diets (such as the ketogenic diet) could potentially worsen these patients’ clinical picture, both should be avoided in this condition. In some specific enzymatic disturbances, such as long-chain acyl dehydrogenase deficiency, a diet using middle-chain fatty acids may be tolerated, because it bypasses the faulty system. The ketogenic diet, which includes low carbohydrate and protein intake, has not been tried in these patients. Reviews of fatty acid oxidation defects are beyond the scope of this article, but such reviews are available in the literature (109; 71; 104).

To avoid starting the diet for patients with a previously undiagnosed energy metabolism enzymatic defect, urine organic acids, serum amino acids, lactate, and pyruvate must be obtained in all patients in whom an obvious cause for their seizure disorder is not evident. Special precautions are taken in patients with onset of seizures in the first year of life, or with a history of psychomotor deterioration associated with infections. Patients with a clear etiology, such as perinatal or prenatal “hypoxic-ischemic” encephalopathy (newborn encephalopathy) with neonatal seizures, followed by a static encephalopathy and epilepsy or a dysplastic lesion, could be started on the ketogenic diet and observed. Even in these cases when undue hypoglycemia without ketosis develops, one should rethink the diagnosis. Static encephalopathy and cerebral palsy tend to be used as a “waste basket” diagnosis. One should always be suspicious of the accuracy of these two nosological entities.

One should take a more cautious approach to avoid using the ketogenic diet in cases of inborn errors of metabolism, with the exception of pyruvate dehydrogenase complex, phosphofructokinase, and glucose transporter-1 deficiencies. No test is a complete safeguard. Patients with a normal urine organic acid pattern or normal serum lactate-pyruvate may have abnormal values in these tests when metabolic decompensation is induced by intercurrent illness. Radiological evidence of dysplastic lesions may be seen in glutaric aciduria type 2 (24). Careful clinical observation is necessary when starting patients on the ketogenic diet, in order not to worsen preexisting and undiagnosed conditions.

Before the initiation of the diet, issues related to etiologies of the seizures that could make the ketogenic diet an inappropriate treatment should be addressed, such as certain inborn errors of metabolism or epilepsy due to resectable tumors. In addition, social situations that make the ketogenic diet an impossibility, such as a completely unstable family structure, should be addressed before attempting the diet.

Outcomes

The efficacy of the ketogenic diet. The efficacy of the various types of ketogenic diets for improvement in seizures is discussed earlier in this article. Success rates range from 44% (283) to 79% (148). The short-term results tend to show a higher success rate for the diet with up to 80% of the patients having more than 50% seizure reduction (275). The ketogenic diet has been shown to impact individuals’ quality of life (171).

In 2008, the first randomized controlled trial on the efficacy of the ketogenic diet found the ketogenic diet group to be more effective than the control group, which was not on the ketogenic diet (231). In this study, 145 children with intractable epilepsy (having at least one seizure per day) were randomly assigned to receive the ketogenic diet immediately or to receive the ketogenic diet after a 3-month delay, with no other changes in treatment. Neither the families nor the investigators were blinded to the diet group versus the control group. At 3 months, the children in the diet group had a significant reduction in seizures compared to the control group. In the diet group, 38% had a greater than 50% reduction in seizures, compared with 6% in the control group. Seizure reduction greater than 90% was found in 7% of the diet group as compared with zero in the control group.

More objective data are shown in Table 7.

Table 7. The Efficacy of the Ketogenic Diet

Diet type	Percentage of seizure-free patients	Percentage of patients with 90% to 99% reduction	Percentage of patients with 50% to 90% reduction	Follow-up time
Classic (195)	43%	N/A	34%	N/A
Medium-chain triglyceride (264)	N/A	N/A	66%	10 weeks
Medium-chain triglyceride (283)	16%	8%	20%	N/A
Classic Medium-chain triglyceride Modified medium-chain triglyceride (275)	N/A	46% 37% 41%	46% 41% 25%	3 months 3 months 3 months
Classic (148)	29%	38%	N/A	31 months
Classic (292)	22%	22%	46%	12 months
Classic (88)	7%	20%	23%	12 months
Classic (191)	18%	14%	38%	3 months

Even though Table 7 compares patients who underwent different protocols with different times of follow-up, it appears that the differences, if any, are probably not significant.

Efficacy of the ketogenic diet was evaluated by meta-analysis using a combined sample of 1084 children from 19 different studies. In 56% of these children, seizures were reduced by over 50%. Additionally, 32% of children had a greater than 90% reduction in seizures; and 16% became seizure-free (335).

Another confounding variable is the percentage of patients remaining on the ketogenic diet over time. The patients with better results tend to remain on the diet for longer periods of time, and the nonresponders tend to drop out (292). This tends to overestimate the efficacy of the diet. One study reported that the percentages of patients remaining on the ketogenic diet were 83% at 3 months, 71% at 6 months, and 55% at 12 months (88). Another study from the same institution reported that only 37% of the patients who took the diet for 3 months were still on the diet at the end of the first year of follow-up (292). In a publication from the same institution using modern seizure quantification techniques, 27% (41 of 150) of the patients initiating the ketogenic diet have greater than 90% seizure reduction after 1 year (88). Surveys from other institutions have found similar results (70). Smaller studies have shown lower long-term (12 months) efficacy of the diet perhaps due to different methodology (47). One has to be mindful that even though long-term studies of the diet are ideal to report the outcome, the amount of effort put by the medical team to keep the patients on the treatment alters the final seizure reduction rate. Nonmedical reasons for discontinuation of the diet are as common as the traditional medical reasons such as lack of efficacy or complications (188).

During Schwartz's 3-month study, there was no difference in efficacy between the several types of diet (medium-chain triglyceride, modified medium-chain triglyceride, and classical) (275). Even though there was a trend for younger patients (2 to 5 years old) to have better results, this has never been proven to reach statistical significance (275).

Seizure type does not seem to have an impact in the response to the diet (275; 88). Both generalized and partial seizures appear to respond the same to the diet (205). Early and dramatic response can be seen in patients with myoclonic and atonic seizures and their seizure frequency will drop by more than 50% immediately after the diet initiation (87). Freeman and colleagues did not find any influence of age or seizure type on the efficacy of the diet (88). Nonetheless, a study from the same institution found that early (less than 2 weeks into the diet) seizure-freedom on the diet is more likely to occur in children who did not have complex partial seizures (297). This effect was sustained for at least 6 months.

However, the epileptic syndrome may have an impact on the response to the diet. The Johns Hopkins University group has been involved in the study of the treatment and efficacy of the ketogenic diet on infantile spasms (152; 297; 154). As a first-line therapy, the ketogenic diet seems to be effective in up to 62% of the cases, with the treatment failures responding readily to adrenocorticotropic hormone (ACTH). The response (spasm cessation/reduction) is slightly slower than that of ACTH and vigabatrin, taking 2 weeks, and the EEG normalization taking up to 2 months (154). As discussed above, side effects and relapse rates were lower among those treated with the ketogenic diet. In a study of the efficacy of the ketogenic diet on infantile spasms, 3 of 26 patients were still seizure-free after 12 months. In another study, treatment of children with Dravet syndrome, formerly known as severe myoclonic epilepsy of infancy, was evaluated (33). There was a good retention with 13 of 20 remaining, after 1 year of the diet. Two patients were seizure-free, eight had a 75% to 99% decrease in seizures, and the remaining three children had a 50% to 74% decrease in seizures. Thus, after 1 year on the diet, 10 children (50%) had achieved a greater than 75% decrease in their seizures (33).

The modified Atkins diet has also shown to be beneficial in the treatment of refractory infantile spasms (277). Among 15 children, ages 6 months to 3 years, who continued to have daily spams despite treatment with oral corticosteroids/adrenocorticotrophic hormone and/or vigabatrin as well as treatment with at least one additional anti-epileptic drug were enrolled in the study. Carbohydrate intake was restricted to 10 grams of carbohydrate per day. After 3 months, 6 of the 15 patients were spasm free (277). A study from China demonstrated that ketogenic diet therapy was effective in adjusting oral antiepileptic drugs in children with ACTH- or corticosteroid-resistant infantile spasms (334).

The authors have published an abstract about the short-term efficacy of the outpatient, nonfasting version of the ketogenic diet (64); the results appear to be similar to those seen with the “classic ketogenic diet.” Similar results have been published by Vaisleib and colleagues (305). The efficacy of the ketogenic diet has been the subject of various reviews (312; 181).

Given the variable responses to the ketogenic diet, it is possible that genetic factors influence the efficacy of the ketogenic diet. Genetic differences were studied in mice by examining the ability of the ketogenic diet to alter the seizure threshold. There was a distinct difference in response rates to the diet, suggesting that genetic factors likely influence its efficacy (75).

One of the largest groups ever treated with the ketogenic diet was the one reported by Livingston, which included 304 patients (195). In spite of the pioneer value of Dr. Livingston’s work in how to use the ketogenic diet, his use of terms such as “seizures controlled” or “major improvement in seizures” makes it hard to compare his results with modern publications (195; 196).

The full effects of the diet on seizure control are commonly delayed for 10 to 21 days after the initiation of the classical diet (72). Experimental models of the ketogenic diet confirm this slow onset of action (303; 04). In humans undergoing seizure count by means of video-EEG monitoring, the frequency of myoclonic and atonic seizures will drop by more than 50% immediately after the institution of fasting/ketogenic diet (87).

The efficacy of the ketogenesis in patients taking the diet has been traditionally measured by the means of checking urinary ketones, which is inexpensive and requires little training. Studies of patients on the ketogenic diet point out that three to four plus (80 to 160 mmol/L) urine ketones are necessary, although not always sufficient, to achieve optimal seizure control in children on the ketogenic diet (98). Seizure control of patients on the ketogenic diet correlates better with serum beta-hydroxybutyrate measurements above 4 mmol/L (98).

A transient increase in the seizure frequency was noticed in earlier studies during the first 48 hours of fasting, before an anticonvulsant effect is seen (184; 185). Another publication found that many patients stop having seizures quickly after the onset of fasting (87). A rather fast return of the seizures may be seen, both clinically and in the animal models, after the individuals on the ketogenic diet are fed a carbohydrate-rich meal. The quick block of ketogenesis by the rapid rise of insulin concentrations after carbohydrate ingestion explains this effect. Conversely, some patients who use the diet for a prolonged period of time (usually more than 2 years) will have a more prolonged protection against seizures after the diet is discontinued. This remission (commonly referred to as “cure”) of epilepsy after 2 years or more of being seizure-free, is not uncommon, even among patients who have their seizures controlled while taking anticonvulsant medication for similar periods of time. A better term for this occurrence is “remission”, rather than “cure,” because seizures may recur at any time in these individuals’ lives.

Patients who try the diet are often among the most refractory, showing resistance to multiple anticonvulsants. The use of the diet may allow the reduction of medication with minimization of their side effects. In a series by Kinsman and colleagues, 64% of the patients had their anticonvulsant medication reduced, 36% became more alert, and 23% had improved behavior (148). Objective assessment of patients both before and 1 year after initiation of the ketogenic diet found that the mean developmental quotient showed statistically significant improvement (p < 0.05), with significant behavioral improvements in attention and social functioning (259). These findings have attracted the interest of the mental health community to add the diet in their mood stabilizing armamentarium (77).

Haas and colleagues studied the effects of the medium-chain triglyceride diet in seven girls (ages 5 to 10 years old) with Rett syndrome and anticonvulsant-resistant seizures (106). Treatment with the medium-chain triglyceride diet improved seizure control in the five patients who could tolerate the diet. Slight behavioral and motor improvement has occurred in these five patients and six of seven patients gained weight.

Efficacy of the ketogenic diet is related to glucose restriction, ketosis, and the increase in polyunsaturated fatty acids. Reports indicate that efficacy of the diet is due to improved mitochondrial respiration and ATP production. Current data from Kim and Rho suggest that the ketogenic diet not only serves as an effective anticonvulsant but also contributes neuroprotective properties (144).

The ketogenic diet used for refractory status epilepticus. There have been several case reports demonstrating the efficacy of the ketogenic diet in treatment of status epilepticus. Wusthoff and colleagues demonstrated a response to the ketogenic diet for two adults with prolonged nonconvulsive status epilepticus (328). Nabbout and colleagues showed the efficacy of the ketogenic diet in treating refractory status epilepticus in school-aged patients with fever-induced refractory epileptic encephalopathy (227). The study involved nine patients treated with the ketogenic diet at a 4:1 ratio. The ketogenic diet was effective for seven patients within 2 to 4 days of the onset of ketonuria and was effective 4 to 6 days after initiating the diet. In one responder, an early disruption of the diet resulted in relapse of intractable status epilepticus and death. Cervenka and colleagues described a case of medically and surgically refractory status epilepticus in an adult in the neurocritical care unit whose seizures were controlled with the ketogenic diet (36). The patient was then maintained on the modified Atkins diet. Additional studies are underway for studying the efficacy and safety for this indication (84).

In a retrospective analysis of five children with super refractory status epilepticus, treatment was initiated with the classical ketogenic diet. After starting the ketogenic diet, there was complete resolution of clinical and electroencephalographic status epilepticus in four of the patients with good tolerance. One patient did not respond and died (304).

Since 2008, 10 retrospective publications have reported benefit from the ketogenic diet in the treatment of status epilepticus (163). Specifically, of 32 children and adults treated with the ketogenic diet in status epilepticus, 25 individuals (78%) became seizure-free. Most of these individuals responded within 7 to 10 days of initiating ketogenic diet treatment.

There is preliminary evidence that a ketogenic diet may have a positive impact on psychological state independent of seizure reduction or ketone body production and may be influenced by longer duration of diet therapy (279).

Adverse effects

Among the most common side effects of the ketogenic diet are constipation (classic diet), diarrhea (medium-chain triglyceride diet), nausea, and vomiting (196). It is not rare for some patients to react to high ketone concentrations with nausea and vomiting (196; 72). This is particularly common in the initial phase of the diet. Nausea and vomiting was an initial presentation in a relatively mild case of pancreatitis in one of the authors’ patients, and a report by Holt and colleagues gives another case of pancreatitis in a patient on the diet (116). This diagnosis can be promptly made by the serum lipase and amylase assay.

Dehydration. Dehydration is not uncommon, especially in the cases of patients who have low baseline daily fluid intake even before ketogenic diet initiation. The treating physician and dietitian should keep in mind that neurologically impaired patients might have poor regulation of thirst mechanisms, excessive losses of thirst, or both. When dehydration requires hospital treatment, the use of intravenous normal saline boluses is usually sufficient to rehydrate the patient. In more severe cases, especially those associated with diarrhea, the use of an oral rehydrating solution for a short period of time can be undertaken. The oral dehydrating solutions contain sugar and have the potential to “break ketosis” and should be avoided in cases of mild dehydration, which are often easily fixed with sugar rehydration.

Constipation. Constipation was reported in 47% of the patients followed by the Stanford group (291). The factors associated with this problem are relative dehydration and decreased bulk in the food. Adding low-carbohydrate dietary fibers may help, but often glycerin suppositories or replacement of some of the fat (eg, cream) for medium-chain triglyceride oil will be necessary to improve the problem in the more severe cases. Diarrhea is also not unusual on the medium-chain triglyceride diet.

Drowsiness. Drowsiness is seen in about 25% of the patients when first initiated on the diet, but it tends to resolve over a few days or weeks (275).

Hypoglycemia. Hypoglycemia is an uncommon but serious complication during the fasting period for patients being initiated on the classical ketogenic diet (86). To avoid this complication, periodic blood glucose checks done every 4 to 6 hours are recommended during the fasting period or initial few days of diet initiation.

Excessive ketosis. Hypoglycemia, dehydration, and high ketogenic diet ratios can lead to excess ketone production, which can cause symptoms. Excessive ketosis can also result from an illness. Families should be taught to recognize signs of excess ketosis, including vomiting, irritability, increased heart rate, facial flushing, unusual fatigue or lethargy, and rapid, shallow (Kussmaul) breathing.

Kidney stones. Nephrolithiasis is seen in 3% to 4% of the patients on the ketogenic diet (291; 65). Several factors have been postulated to contribute to the increased risk of nephrolithiasis in these patients on the ketogenic diet, including elevated plasma uric acid (any of the three diets) (276), hypercalciuria, dehydration (115), acetazolamide use (65), and hypocitraturia (65). A case control study of 112 children started on the diet found that six developed renal stones; the authors found younger age at diet initiation and hypercalciuria to be risk factors for urolithiasis (92). The universal use of potassium citrate supplementation has been recommended as an effective prophylactic treatment for the prevention of nephrolithiasis (320). Potassium citrate supplementation is not routinely recommended for patients on the modified Atkins or low glycemic index treatment diet (38).

Lipid abnormalities. Both hypercholesterolemia and hypertriglyceridemia have been reported in patients on the diet (63; 315; 08). The serum cholesterol ranged from 178 to 512 mg/dL, and the triglycerides ranged from 186 to 879 mg/dL. Sharman and colleagues found that the ketogenic diet administered in humans decreased fasting serum triglycerides and postprandial lipemia after a fat-rich meal and tended to increase HDL-cholesterol (278). Huttenlocher reported no elevation in serum cholesterol in patients given the medium-chain triglyceride diet for 3 months (121). Livingston followed some patients who were on the diet as children until they were into their 50s (196). These patients did not have evidence of vascular disease or atherosclerosis, and their blood pressure, electrocardiogram, and serum cholesterol concentrations were within normal limits. As pointed out by Kinsman and colleagues, a follow-up study is necessary to evaluate the relative increased risk of atherosclerosis and cardiovascular disease associated with the ketogenic diet (148).

Studies of carotid artery stiffness were performed in children and young adults on the ketogenic diet (46). Increased carotid artery stiffness was seen in patients on the diet compared to those not on the diet. In addition, the stiffness was seen before intima thickening can be measured (46). Another study showed similar results and found that stiffness was evident after 1 year on the diet, but was reversible and was not seen 24 months after stopping high-fat intake (130). Based on these important findings, we should inform families and patients starting on high-fat diets about the potential risks of dietary therapy and balance them with the potential value of seizure control (148; 46; 130; 155). Ozdemir and colleagues examined the impact of an olive-oil based ketogenic diet on serum lipids, carotid intima-media thickness, and the elastic properties of the carotid artery and the aorta in 52 patients on the ketogenic diet for 12 months (246). Although they found an increase in concentrations of serum lipids, they did not find any negative impact on carotid intima-media thickness and the elastic properties of the aorta and the carotid artery in these children.

Supplementing n-3 polyunsaturated fatty acids (Omega3) to a ketogenic diet used for weight loss in adults reduced the concentrations of markers for cardiovascular disease, such as total and LDL cholesterol, triglycerides, glucose, and insulin over the 12-month study period (248). All the inflammatory markers were also decreased, including cytokines (IL-1beta, IL-6, TNF-alpha) (248). These findings are important to consider in advising patients on food choices within the ketogenic diet.

Carnitine deficiency. Carnitine deficiency can also be seen during the course of treatment with the ketogenic diet, but it rarely results in symptoms (192). Concurrent use of valproic acid (Depakote®) may increase the carnitine depletion and add to the ketogenic diet effect (192; 129). Treating nutritional deficiencies and providing nutritional adequacy is an integral component of a prescribed ketogenic diet (232). Weakness and fatigue may be symptoms of carnitine depletion and should prompt the treating physician for the appropriate investigation. A cardiomyopathy may also be due to or exacerbated by carnitine deficiency (129). Carnitine status is assessed by either free carnitine or an acyl-carnitine panel. Although plasma concentrations of carnitine do not reflect what is in total body stores, the most useful measure of carnitine status in patients on the ketogenic diet is the free carnitine. Although the general consensus is to supplement with carnitine only when concentrations are low and if the child is symptomatic, many families choose to use either prescribed carnitine or over-the-counter purchased carnitine supplements with anecdotal reports of improvements in overall well-being, seizure control, and improvements and ketone levels (232).

Prurigo pigmentosa. Prurigo pigmentosa is a rare inflammatory dermatosis characterized by a pruritic eruption of erythematous papules on the trunk and neck that evolves into reticulate hyperpigmentation on resolution of the inflammatory phase of the rash. There are several triggers for the rash, including a metabolic state of ketosis through the ketogenic diet (329).

Long-term side effects.

Growth retardation. In one series of patients treated with the classical ketogenic diet, poor weight gain was present in 54%, and decreased linear growth in 66% (291). These complications are generally followed by catch-up growth and weight gain once these children are back on a regular diet (196). Conversely, Couch and colleagues found no significant change in height and weight in 21 patients followed for 6 months after the initiation of the ketogenic diet (50). In a retrospective study assessing catch-up growth in children after treatment on the ketogenic diet, data revealed a significant reduction in both height and weight gain after prolonged treatment on the classic ketogenic diet (146). A year after ketogenic diet discontinuation, there was significant catch-up growth in both height and weight (146). Among ambulatory patients, there was a more significant catch-up in growth compared to non-ambulatory patients. Starting the ketogenic diet at a younger age and having uncontrolled epilepsy both contributed a negative impact on a child's growth (146).

Data on growth trends on the ketogenic diet are conflicting. In a study comparing 14 children on the classic ketogenic diet to 11 children on the MCT diet for 4 months, Liu and colleagues demonstrated a weight decrease in the classic diet group (194). There were statistically significant increases in the height of children and both diet groups, suggesting that linear growth was not impaired by either diet. In addition, triceps skin fold, mid-arm circumference, and mid-arm muscle circumference measurements were not significantly different pre-and post-diet, although there was a trend toward lower measurements in the classic diet group. Neal and associates reported on a group of 75 children who were randomly assigned to either the classic or MCT ketogenic diet and growth data were collected for 12 months (231). Their results demonstrated significant height deceleration in both groups by 6 and 12 months. There were no significant differences in weight, height, or BMI in both diet groups. Ruiz Herrero and colleagues studied 26 children on prolonged ketogenic diet for epilepsy and found side effects common, but mild, and they deemed the ketogenic diet a safe treatment for children of all ages (268).

Groleau and colleagues studied 15 children managed on the classic ketogenic diet over 15 months (101). They observed a linear growth deceleration in these children, with stable weight, and no changes in the resting energy expenditure in the group without cerebral palsy. The authors hypothesize that the ketogenic diet may decrease insulin-like growth factor I without caloric deprivation. Another study proposed that the mechanism of decreased linear growth is due to chronic metabolic acidosis (320).

In light of this, it is important for practitioners to monitor growth trends with every visit and to address abnormalities. Ensure adequate protein and calories and adjust the diet as needed for growth. A lower ratio may be necessary in order to provide higher quantities of protein. However, this must be weighed against efficacy of the diet to provide seizure control (38).

Bone metabolism. Vitamin D and calcium supplementation is also important because osteomalacia has been reported in patients on the diet (67). Patients taking the appropriate calcium supplementation while on the ketogenic diet will show no significant change on calcium concentrations (50). A progressive decrease in bone mineral density has been shown in children with intractable epilepsy on the ketogenic diet (17). Bergqvist and colleagues found that the bone mineral density in younger nonambulatory children on the ketogenic diet, with lower body mass index scores, was associated with worse bone health compared to ambulatory children with higher body mass index scores. Practitioners may want to consider obtaining a bone mineral density scan (DEXA scan) for children on the diet for more than 2 years. Some children will be treated successfully with growth hormone, although no studies have been published on this (38).

Miscellaneous complications. Ballaban-Gil and associates found that 10% (5 of 52) of the patients treated with the ketogenic diet had serious complications (08). They suggest complications may be more common in patients on the ketogenic diet who take valproic acid, compared with those not taking the medication (08). The latter report describes two cases of liver dysfunction in patients treated with the ketogenic diet. Hypoproteinemia has been also reported in patients on the ketogenic diet (08). In a study of 21 patients followed for 6 months after the initiation of the ketogenic diet, only a small decrease in serum proteins (total protein and albumin) was seen, which did not reach statistical significance (50).

Peterman and Livingston have both stated that the ketogenic diet (referring to the classic ketogenic diet) is inadequate to supply the daily requirements of vitamins, particularly the hydrosoluble ones like B complex and C (252; 195). A symmetrical, bilateral optic neuropathy has been reported in patients being treated with ketogenic diets (119; 283). This problem commonly manifests itself with partial visual impairment or even blindness (283). These cases were probably related to thiamin deficiency because normal visual function returns after treatment with thiamin (119) or multivitamins (283), but it may take several weeks (119). Patients on the diet should undergo evaluation of optic nerve function if they have any visual symptoms.

Metabolic acidosis has been described in patients on the diet, but it is more common in individuals taking acetazolamide (72). This can be avoided by stopping the medication with the initiation of the diet. Acetazolamide is often well tolerated after metabolic adaptation takes place, but its use should be accompanied by periodic monitoring of acid-base status (72). The use of acetazolamide also increases the risk of renal stones in patients on the diet (65). Topiramate is an anticonvulsant medication that also has a carbonic anhydrase inhibitory effect. Both topiramate and the ketogenic diet have been associated with an increased risk of nephrolithiasis. One patient developed renal tubular acidosis while on the diet (08).

A significant reduction of the blood urea nitrogen was noted by an investigator 6 months after children began the diet (50). Patients on the ketogenic diet can also have spurious elevations in very long-chain fatty acid concentrations in plasma (299).

Another potential complication of the ketogenic diet is prolonged QT interval corrected for heart rate, at times accompanied by a dilated cardiomyopathy (20). Both low serum bicarbonate and high beta-hydroxybutyrate appear to have significant correlation between prolonged QT interval corrected for heart rate (20). The latter complication disappears with the discontinuation of the diet (20). Cardiomyopathy in patients on the diet may be also due to selenium deficiency (18). A case report describes a 5-year-old boy on the ketogenic diet who developed acute reversible cardiomyopathy and ventricular tachycardia associated with a selenium deficiency. He had rapid improvement with the initiation of selenium supplementation (284). This again reinforces the need for proper vitamin and mineral supplementation. Selenium deficiency was found in 20% of the ketogenic diet patients and may not be evident for several months (18).

A case report study highlights two deaths in children on the ketogenic diet allegedly due to selenium deficiency. In these reports, the selenium deficiency led to QT prolongation and impaired myocardial function. Thus, obtaining an initial echocardiogram, electrocardiography, and selenium concentration are advised prior to initiating the ketogenic diet (10).

The concentrations of some anticonvulsant medications will sometimes increase during the first few months after the initiation of the diet. This is particularly true with phenobarbital (196). Due to the lack of predictability of the ketogenic diet effects on the medication concentrations, it may be safer to check the serum concentrations more frequently during this period and to alert the parents for the signs of toxicity of the drugs.

Hematologic and infectious complications. Berry-Kravis and colleagues found an increased incidence of bruising or other minor bleeding in 16 of 51 patients (31.4%) on the diet (19). This was more common in the younger patients and was independent from the antiepileptic drugs used. Five of the 16 patients had prolonged bleeding times, and all had diminished responsiveness to platelet-aggregating agents. None the patients had significant hemorrhages. One patient had mild von Willebrand disease, which was asymptomatic prior to the diet initiation. In our experience, these problems are particularly troublesome when sending patients for surgical procedures such as gastrostomy or vagal nerve stimulator placement.

Iron-deficiency anemia was described in 1.6% of patients in a series (129). One case of hemolytic anemia has also been described in a patient taking the diet (08).

In spite of reports of impaired neutrophil function in children treated with the ketogenic diet (327), an increase in frequency of infections directly due to the diet is rarely seen in our clinical practice. Kang and colleagues reported serious infections in 9% (early onset) to 21% (late onset) of the patients (129). Nonetheless, the latter study fails to mention if this constitutes an increase in the incidence of infections in a series in which 60% of the patients had encephalopathic epilepsies. A case of clostridium difficile pseudomembranous colitis refractory to standard therapy was reported in an abstract (116). Chemical pneumonitis due to aspiration of diet fats may be seen (129). The latter is a serious complication and is more common in a patient on the diet but should raise the concern for the care of acid reflux in neurologically impaired patients who are potential candidates for the diet. In these cases, we evaluate the patient with a video-fluoroscopy swallowing study. We refer the patient for a Nissan fundoplication surgery prior to initiation of the diet when severe aspiration is present (129).

In summary, a carbohydrate-free multivitamin and calcium supplementation should be given to all patients on the ketogenic diet. Routine carnitine supplementation is not currently recommended but needs further systematic evaluation. Patients on the ketogenic diet who develop unexplained side effects, such as liver dysfunction or acute alteration in level of consciousness, should be investigated for an undiagnosed inborn error of metabolism.

Table 8. Side Effects of the Ketogenic Diet

• Hypovitaminosis and low calcium
	- Optic neuropathy - Lack of vitamin and calcium supplementation
• Metabolic acidosis
	- Intercurrent illness - Acetazolamide use (at the onset of diet)
• Renal calculi
	- Hypercalciuria - Hyperuricemia - Hypocitraturia - Dehydration
• Dehydration
• Nausea and vomiting
	- Excessive ketosis/acidosis - Pancreatitis - Liver dysfunction (?)
• Hypoglycemia
	- Fasting - Decreased food intake
• Hypercholesterolemia • Hyperlipidemia • Poor weight gain and growth • Constipation
	- Secondary to excessive dehydration - Decreased dietary fiber
• Diarrhea (medium-chain triglyceride diet) • Spurious elevations in plasma very long-chain fatty acids • Hepatic dysfunction • Mental status changes
	- Lethargy - Abnormal behavior
• Impaired neutrophil function

Special considerations

There is a lack of information regarding the safety of the ketogenic diet in pregnant women. However, with the increased usage of the ketogenic diet in women of childbearing age for treatment of epilepsy, there exists a need for information about safely managing the mother and unborn child on the diet therapy. Potential teratogenic effects of antiepileptic medications raise an additional need for nonpharmacological options for seizure control. Van der Louw and colleagues published a paper describing two pregnant women on the ketogenic diet for treatment of epilepsy (307). The first woman was treated with the ketogenic diet as a monotherapy and the second woman was on the ketogenic diet as an adjunct therapy. Both cases described successful outcomes with the ketogenic diet and both newborns were born without adverse gestational effects and normal development during the first year of life.

Clinical vignette

An 18-year-old Japanese male with intractable epilepsy was initiated on a ketogenic diet at a 2:1 fat to carbohydrate/protein ratio. Other medical diagnoses included Dandy-Walker malformation, cerebral palsy, and intellectual disability. He remained on his antiseizure medications, clobazam and lamotrigine. Seizures ceased on day 2 of the diet. On day 9, he developed a pruritic rash. Complete blood count with differential, C-reactive protein, and urinalysis were unremarkable. By day, 14 lesions were increasingly erythematous, so ketogenic diet ratio was decreased to 1:1. However, his urinary ketones remained consistent at 160 mg/dL. On day 17 the ketogenic diet ratio was decreased to 0.75:1 with the addition of apple juice. This decreased urinary ketones to 40 to 80 mg/dL, with significant improvement in pruritis and erythema by the following day. The patient continued to maintain seizure freedom throughout this time. He was returned to a 1:1 ratio to ensure seizure control and with periodic ratio decreases to 0.75:1 when the rash recurred.

Scientific basis

Understanding the ketogenic diet requires familiarity with the mechanisms by which the human metabolism switches its main source of energy from carbohydrate to fatty acids and ketones. The knowledge of these mechanisms is directly useful in the management of children on the ketogenic diet. The following is a summary of reviews of the metabolic endocrine changes associated with fasting and the ketogenic diet (269; 53):

	• Beta-oxidation is the main pathway of lipolysis for long-chain fatty acids.
	• Ketosis and lipolysis is maintained with a low insulin to glucagon ratio; therefore, the ketogenic ratio needs to be given with every meal.
	• Enteral glucose is a powerful insulin-release stimulus. Relatively high carbohydrate ingestion in a single meal may dramatically reduce or stop ketogenesis.
	• Glucose has a priming effect on insulin release. When high carbohydrate ingestion interrupts a consistent state of ketosis, subsequent amino acid and glucose ingestion will produce a sluggish insulin release, and ketosis may be slowed for several hours or days. Fasting may be needed for quick ketogenesis return.
	• High serum ketone decreases the glycolytic activity; maintaining consistency on the ketogenic diet may be helpful in maintaining the state of ketosis.
	• High serum ketone concentrations decrease low serum glucose-associated CNS dysfunction. Therefore, ketotic children may not necessitate such aggressive treatment for hypoglycemia (especially asymptomatic) as nonketotic children.
	• High serum fatty acids enhance fatty acid catabolism and ketosis by inducing transcription of the genes for key enzymes involved in lipolysis and ketogenesis.
	• Acidosis may increase the conversion of acetoacetate into beta-hydroxybutyrate. Therefore, beta-hydroxybutyrate may be a more reliable measure for children on the diet because excessive ketosis may produce acidosis.
	• Higher serum ketone concentrations may be associated with a greater chance of seizure control for some children. Ketotic rodents have a higher threshold for electroshock-induced seizure.
	• Children who are less than 12 years old have higher efficiency of extraction of ketones through the blood-brain barrier.
	• Because fasting increases the blood-brain barrier permeability to ketones, ketogenic diet initiation with fasting may be better when a quick effect is desirable.
	• Chronic ketosis increases the blood-brain barrier permeability to ketones. Consistent use of the ketogenic diet allows better results. Inconsistent ketosis tends to produce the worst seizure control, rather than fluctuation in the number of convulsions.

Fatty acid oxidation and ketone body formation. When carbohydrate intake decreases, the adipocytes start breaking down the triglycerides into glycerol and fatty acids. Subsequently, free fatty acids are released into circulation. The liver and muscles use free fatty acids as an energy source via mitochondrial beta-oxidation. The hepatocyte fatty acids can be oxidized into ketone bodies, which can be used as energy substrate by the brain and other tissues, such as muscle. At a concentration of 5 mM, plasma ketones can provide up to two thirds of the brain’s energy requirement (243).

Beta-oxidation. Beta-oxidation reduces fatty acids sequentially by the repetitive removal of two carbon fragments at the carboxy-terminal end. Each cycle of the beta-oxidation produces reduced electron-transfer flavoprotein (electron-transfer factor red), NADH (+) H(+), and acetyl-CoA. The metabolic fate of fatty acids is dependent on the chain size. The larger fatty acids are initially cleaved by their size-specific enzymatic system, and subsequently use the smaller size systems (273; 109; 104):

• Very long-chain fatty acid is 22 C to 16 C
• Long-chain fatty acid is 18 C to 12 C
• Middle-chain fatty acid is 12 C to 6 C
• Short-chain fatty acid is 6 C to 4 C

There is some overlap in the size specificity of these systems (273).

There are also differences in the rate of oxidation between fatty acids depending on their structure. Oxidation rates potentially impact ketogenic potential for different dietary fats. In humans, oxidation of saturated fatty acids decreases with increasing carbon length (laurate > palmitate > stearate), whereas oxidation rates of unsaturated fatty acids is correlated with the number of double bonds (linolenate > oleate > linoleate). Of these fatty acids, laurate (an MCT) is most highly oxidized, followed by linolenate (61). This is consistent with Likhodii and colleagues, who demonstrated the highest ketogenic effect in rats with MCT oil when compared with lard, butter, and flaxseed oil (189). Flaxseed oil also yielded a higher ketosis response compared to lard and butter in older rats.

Fatty acids greater than 12 carbons in size can only penetrate the outer mitochondrial membrane after being transformed into their acyl-CoA esters. After that, the acyl-CoA esters interact with the carnitine-palmitoyltransferase 1, which attaches carnitine and removes the CoA, producing acylcarnitine. Acylcarnitine is then carried through the inner mitochondrial membrane by the carnitine or acylcarnitine transporter into the mitochondrial matrix. The carnitine-palmitoyl transferase-2 enzyme, which is located in the internal surface of the inner mitochondrial membrane, removes the carnitine and reattaches the CoA residue, forming an acyl-CoA ester again. Carnitine-palmitoyl transferase-1 is the rate-limiting step in the beta-oxidation of fatty acids, and it is the site of action of the lipolysis inhibitor malonyl-CoA (213). Malonyl-CoA is formed from citrate derived from the Krebs cycle. Increases in free fatty acids augment the transcription of the CPT1 gene (53). Fatty acids bind and activate the peroxisome proliferator activated receptor (PPAR) alpha, which is a potent activator of the transcription of several lipolysis and ketogenesis enzymes such as CPT1, HMGCS2, and acyl-CoA synthase (53). PPAR alpha promotes transcription of these enzyme genes via the peroxisome proliferator response element (PPRE) (53).

Medium-chain fatty acids cross the inner mitochondrial membrane freely. Supplementation with MCTs alone has demonstrated a mild and safe ketogenic state. At a dose of 30 gm daily, plasma ketone concentrations are able to be increased 3-fold. Cunnane and colleagues estimated that this degree of ketonemia contributes up to 8% to 9% of brain energy metabolism (51). In fact, octanoate (a middle-chain fatty acid) infusion in fed animals promptly induces ketosis, an effect that is not seen with long-chain fatty acid infusions (210). The lipolysis requires the action of one acyl-CoA dehydrogenase, as well as three other enzymes: enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase. The entire lipolysis pathway involves several enzymes and steps, and its full description is beyond the scope of this article, but is summarized below. For more information, the reader is referred to (273; 34; 105; 125; 209; 238; 71; 104; 281).

Ketone formation. Ketones, or ketone bodies, include beta-hydroxybutyrate (3-hydroxybutyrate), acetone, and acetoacetate. Even though beta-hydroxybutyrate is not technically a ketone because its ketone group is reduced by a hydroxyl (91), it has been traditionally considered to be a ketone and will be referred to as such in this publication. Ketone formation takes place mostly in the liver, and to a lesser extent, in the kidneys, using plasma free fatty acids as substrate (209). At the cellular level, the process takes place inside the mitochondria. Most hepatic ketone body production is released into the circulation to serve as energy substrate to other tissues, such as muscle and brain. Lipolysis produces acetyl-CoA. Acetyl-CoA produced by fatty acid oxidation is primarily channeled to hepatic ketogenesis; in contrast, the acetyl-CoA derived from glucose is directed preferentially to the Krebs cycle (66; 91). Two molecules of acetyl-CoA combine to form acetoacetyl-CoA. The latter undergoes enzymatic conversion to acetoacetate. The enzyme 3-hydroxy-3-methylglutaryl-CoA synthase, which helps in this conversion, is upregulated in animals taking the ketogenic diet (54). PPAR alpha also promotes transcription of the 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) gene (53). HMGCS2 transcription is also upregulated during fasting, fat feeding, and low insulin states (53; 91). The direction of the interconversion of beta-hydroxybutyrate and acetoacetate depends on the mitochondrial redox state (201). Acetoacetate can also be decarboxylated into acetone by a slow, nonenzymatic spontaneous reaction (209).

Acetoacetate, beta-OH-butyrate, and acetone formation

(Contributed by Dr. Marcio A Sotero de Menezes.)

Peroxisomal beta-oxidation: omega and alpha oxidation. Peroxisomes contain a beta-oxidation pathway served by enzymes that are genetically distinct from the mitochondrial enzymes (178). The pathway controls the cleavage of very long-chain fatty acids (greater than 18 carbons) to hexanoyl-CoA. Under conditions of prolonged fasting, approximately 20% of fatty acids are oxidized by the peroxisomes (168).

Omega oxidation occurs in the microsomes and replaces the methyl end of the fatty acids with a carboxyl group, resulting in the formation of dicarboxylic acids (257; 104). Dicarboxylic acids are found in the urine when the capacity of the mitochondrial or peroxisomal beta-oxidation is surpassed, such as when fasting or feeding with medium-chain triglycerides, in diabetic ketoacidosis, glutaric aciduria (105), or inborn errors of beta-oxidation (109; 104).

Alpha-oxidation is a process required for cleavage of certain methylated fatty acids. The process involves the alpha-hydroxylation of long-chain fatty acids. A typical example of a fatty acid that initially cannot be cleaved by beta-oxidation is the phytanic acid (209). The same process is used to start the oxidation of shorter fatty acids. The reactions take place in the endoplasmic reticulum, as well as in the mitochondria, and require molecular oxygen, reduced nicotinamide nucleotides, and specific cytochromes.

The control of lipolysis and ketogenesis during fasting and high-fat very low carbohydrate diets. From the beginning, the ketogenic diet was administered as an attempt to replicate and prolong the metabolic effects of fasting (322; 184; 185). Most of what is known about the control of ketogenesis was learned by the study of chronic fasting in adults. The extent of the similarities between children in states of chronically enhanced lipolysis, such as the ketogenic diet and adult fasting, is not known. More experimental data are necessary to demonstrate the similarities and differences between fasting and the ketogenic diet states. The endocrine and metabolic control of lipolysis is summarized in Table 9.

Table 9. Endocrine and Metabolic Control of Lipolysis and Ketogenesis

Facilitation of lipolysis and ketogenesis
Low insulin to glucagon ratio
High glucagon concentrations (effects may be counteracted by a reactive increase of insulin).	A decrease of acetyl-carboxylase activity causes a decreased conversion of citrate to malonyl-CoA. A decrease of malonyl-CoA causes an increase in CPT-1 activity, which leads to an increase in mitochondrial entry fatty acyl esters. An increase in mitochondrial entry fatty acyl esters causes lipolysis, which leads to an increase in ketogenesis (liver).
Low insulin concentrations	An increase of hormone-sensitive lipase (adipocytes) causes an increase in serum free fatty acids, which leads to an increase in ketogenesis (liver).
High growth hormone concentrations (effects may be counteracted by reactive increase in insulin) (95; 216).	Increased serum free fatty acids and ketones (280). Increased insulin resistance and decreased insulin receptor binding (29; 263). An increase of IGF-1 leads to hypoglycemia (60). Overnight increase in ketogenesis (76). Mild ketogenic action facilitated by somatostatin (216).
High ketone concentrations	Decreased pyruvate oxidation; decreased glycolysis.
Facilitation of glycolysis and lipid storage
High insulin concentrations	A decrease in hormone-sensitive lipase (adipocytes) causes a decrease in serum free fatty acids, which leads to decreased ketogenesis (liver). An increase in glucose uptake (increased glucose transporter-4 in muscle and adipocytes). An increase of glycolysis (increased pyruvate dehydrogenase activity). An increase of glycolysis causes increased Krebs cycle activity, which leads to increased citrate. Increased citrate causes an increase of malonyl-CoA, which leads to a decrease of CPT-1 activity, and then a decrease of mitochondrial fatty acyl esters.

Five hormones are the main controllers of lipolysis and ketogenesis: glucagon, epinephrine, cortisol, growth hormone, and insulin. When there is a decrease in plasma insulin and an increase in norepinephrine or epinephrine and glucagon, an increase in the cyclic adenosine monophosphate is seen in adipocytes, which causes an enhancement of the intracellular hormone-sensitive lipase activity. The latter produces an increase in serum free fatty acids. Ketone bodies and insulin do the cyclic adenosine monophosphate feedback control loop, which causes deactivation in the lipolysis process (211; 83).

Glucose and lipid homeostasis during fasting state. Insulin is the primary regulator of the glucose uptake (128), as well as subsequent storage (23) and metabolism (200). In the CNS, two glucose transporters exist that are independent of insulin, glucose transporter-1, which transports across the blood-brain barrier, and glucose transporter-3, which is located in the neuronal membrane (82; 199).

Human studies using C(13) nuclear magnetic resonance demonstrated that gluconeogenesis and glycogenolysis each contribute about half of the body’s entire glucose production during the first several hours of fasting (265; 253). These experiments suggest a gradual initiation of lipolysis during early fasting.

Table 10. Energy Metabolism Changes Associated with Fasting

First 2 days of fasting	Hepatic glycogenolysis and gluconeogenesis occurs (265).
After 48 hours of fasting	Ketone bodies become the main sources of energy (243; 266).
Third day of fasting	Peak rates of ketone production are reached (242; 93).
Fourth to the 21st day of fasting	Serum ketone concentrations continue to increase due to decreased muscle consumption, and there is an increased availability of ketones for brain utilization (243; 244; 281).

In patients on the ketogenic diet, the chronic administration of large amounts of fat (greater than 90% of the caloric intake) in the setting of significant carbohydrate restriction allows for continued lipolysis after a period of fasting. A very low-carbohydrate and high-fat dietary intake is associated with decreased glucose utilization (68), probably due to the direct inhibitory effect of ketosis in the oxidation of pyruvate. The latter effect is associated with an enhancement of the fat catabolism caused by the increased activity of ketogenic and lipolysis enzymes. These induce an increased circulation of polyunsaturated free fatty acids that allow for a smooth switch from predominantly carbohydrates to a mixture of carbohydrate and fats to support of brain's energy demands (53).

The role of glucagon and insulin on lipolysis control. When carbohydrate ingestion is decreased during fasting, the hormone-sensitive lipase inside the adipocytes is activated to release free fatty acids into the circulation. Low serum insulin and high catecholamine concentrations mediate this effect (59). Beta adrenergic receptor stimulation-increasing cyclic AMP produces phosphorylation of the hormone-sensitive lipase (59; 91). Increased cyclic AMP also induces the dephosphorylation and displacement of perilipin (the protein that coats the triglyceride droplets) that allows the lipase action (91). Insulin is a potent inhibitor of hormone-sensitive lipase adipocytes by induction of its dephosphorylation via the phosphodiesterase 3B (59; 91). At least one other enzyme, a nonhormone sensitive lipase, has been demonstrated (91). In the hepatocyte, free fatty acids will undergo lipolysis with subsequent production of ketones. When acetyl-CoA produced by lipolysis is in excess of the Krebs cycle utilization, ketones are formed. Up to 90% of acetyl-CoA produced in the liver may be used in the formation of ketones (109). Insulin concentrations are directly proportional to the lipid storage, and inversely related to the lipolytic activity in the adipose tissue (212).

The insulin to glucagon ratio is one of the main determinants of the metabolic switch from glucose oxidation and fatty acid storage to the lipolysis and ketogenesis mode. High insulin to glucagon ratio will facilitate the former, whereas the opposite will enhance the latter.

Glucagon enhances both glycogenolysis and hepatic ketogenesis when the plasma glucose drops (211; 83). In humans, the effects of glucagon are dependent on the concomitant, and often reactive, insulin concentrations (95). When glucagon concentrations increase (within the physiologic range), but insulin concentrations remain relatively low, an increase in beta-hydroxybutyrate and free fatty acids are seen (95). When a low insulin to glucagon ratio is present in the portal circulation, acetyl-carboxylase (citrate to acetyl-CoA to malonyl-CoA) activity is decreased, and malonyl-CoA decarboxylase (cleavage of malonyl-CoA into acetyl-CoA) is enhanced (91). This produces a lowering of intracellular malonyl-CoA, which increases the carnitine-palmitoyl transferase-1 activity, promoting fatty acid oxidation and ketogenesis (213; 281). On the other hand, when both glucagon and insulin concentrations are elevated, hyperketosis is not seen (95). High insulin concentrations shut down the free fatty acid production from adipocytes, depriving the liver from its substrate for ketogenesis (211; 212).

Table 11. Stimuli for the Glucagon Secretion

	• Alanine • Arginine (also increases serum insulin secretion) • Catecholamines • Gastric inhibitory peptide • Cholecystokinin
Reproduced from (131).

The ingestion of carbohydrates produces the release of insulin, which stops the release of free fatty acids from the fat deposits, thus, depriving the liver of its substrate for the production of ketone (211). Stimuli for the insulin release are summarized in Table 12 and are reviewed by Cook and Taborsky (43) and Karam (131). The control of the insulin release by glucose is pertinent to patients taking the ketogenic diet. A high basal serum glucose concentration as a priming effect (exposure to high serum glucose followed by return to normal concentrations) can increase the magnitude of subsequent insulin release (for several hours) in response to glucose, amino acids, and other secretagogues, such as enteric hormones in vivo (43). This is a possible explanation for the prolonged loss of ketosis seen when patients on the ketogenic diet ingest a carbohydrate-rich food. When this occurs, returning to ketosis may take 24 hours or more, because the insulin response to subsequent carbohydrate or amino acid exposure with the next meals may be greater. This “break” in ketosis often offsets the seizure control for 1 day, or at times, several days. A short period (12 to 24 hours) of fasting may be necessary for a quick return to ketotic state (196).

Table 12. Factors Influencing Insulin Release

Factors causing increased insulin release
	• Carbohydrate-rich meal
		- Increased serum glucose
		- Enteric factors: GIP, glucagon-like peptide, cholecystokinin
		- Parasympathetic innervation (in response to local GI stimulation)
• Dietary amino acid
		- Branched chain (especially leucine)
		- Arginine
	• High serum ketones (4 to 6 mmol)
	• Phenobarbital (?) (174; 173; 134; 311).
	• Acetazolamide with low glucose concentrations (27)
Factors causing decreased insulin release
	• Low serum glucose
	• Epinephrine greater than norepinephrine
	• Diazoxide
	• K positive channel openers
	• Phenytoin. Clinical significance uncertain (149; 114; 179; 282; 02)
	• Somatostatin
	• Galanin
	• Acetazolamide with high glucose concentrations (27)

Acetazolamide, in association with low glucose concentrations, may increase insulin release, which may be the cause of metabolic acidosis seen during fasting (27).

In summary, lipolysis and ketogenesis are facilitated by low concentrations of insulin, which increase the availability of free fatty acids (from adipocytes to the serum), and by high glucagon concentrations, which promote lipolysis with subsequent ketogenesis at the hepatocyte.

The role of growth hormone on lipolysis control is summarized in Table 9. There is some evidence that the normal overnight increase in serum ketones is related to growth hormone concentrations, whereas quicker changes caused by diet or fasting are controlled by insulin concentrations (the lower the plasma insulin, the higher the ketones) (76).

The control of ketonemia. During fasting, and possibly during high-fat diet ingestion, peroxisome proliferator-activated receptor alpha mediates the adaptive metabolic response (140; 53). Thus, both at the level of the mitochondrial entry (CPT1 enzyme) and acetyl-CoA, conversion to acetoacetate-free fatty acids promote their own metabolism. On the other hand, excessively high concentrations of serum ketones may produce metabolic acidosis, so a feedback control also exists. When plasma ketone concentrations reach 4 to 6 mmol/L, free fatty acid mobilization from fat tissues decreases (212). This modulation is thought to be due to an effect of ketones, causing either increased insulin secretion (198), or a direct action on the free fatty acids at the level of the adipocytes (325). When some patients who have been on the ketogenic diet long term “skip” a meal, their ketone concentrations may actually drop, because they are dependent on high concentrations of exogenous lipid intake, due to the free fatty acids output being limited by the high serum ketone concentrations feedback effect.

Physiologic and pharmacological effects of ketone bodies. Ketone bodies are one of the main sources of energy during chronic starvation (greater than 48 hours) (243; 266) and during the neonatal period (219). During fasting, when acetoacetate reaches the brain, it is combined with succinyl-CoA to form acetoacetyl-CoA and succinate; it then enters the Krebs cycle to generate energy through the formation of ATP. The same is true in virtually every other tissue in the body except for the liver, as the enzyme acetoacetate-succinyl-CoA transferase is not present in the hepatocytes (209). Acetoacetyl-CoA may be also converted by beta-thiolase into acetyl-CoA, which enters the Krebs cycle for the production of energy (209). In the target tissues, such as the CNS, beta-hydroxybutyrate is converted into acetoacetate as the concentration of acetoacetate is decreased by its utilization in the energy metabolism. Expanded and more complex roles of the brain ketones have been proposed by Cullingford (53). It has become apparent that, rather than being a passive “absorber” of ketones, the brain also has a local production (53). Among the possible roles of this local ketone production, and a major one, appears to be that of astrocytes supporting the energy metabolism of adjacent neurons (53).

Humans may be more resistant to hypoglycemia when high concentrations of ketone bodies are present in the blood, as shown by the infrequent cases of symptomatic hypoglycemia during the course of the ketogenic diet (196) and fasting (74; 196). Amiel and colleagues studied volunteers in whom controlled hypoglycemia was induced by combined insulin and glucose infusions (03). When the volunteers also received a beta-hydroxybutyrate infusion, the epinephrine, growth hormone, and cortisol output in response to hypoglycemia was significantly lower. This may be partly explained by the efficient ketone oxidation in the brain during hypoglycemia (212). It is logical that ketones increase the threshold for symptomatic hypoglycemia, as acetoacetate in the brain is transformed into succinate or acetyl-CoA, which enter the citric acid cycle to produce ATP.

Children have a greater capability to extract and oxidize ketones (250; 72). This effect is even more pronounced during the state of chronic ketosis, when children seem to have an adaptive mechanism that facilitates even more ketone extraction from the blood into the brain (169; 67). An increase in the blood-brain barrier permeability to ketones during starvation has also been noticed (99). The blood-brain barrier appears to be the rate-limiting step in metabolizing ketones from the blood (112). This rate-limiting step is probably due to a saturable monocarboxylic acid carrier mechanism, which facilitates the transport of beta-hydroxybutyrate through the blood-brain barrier (239). The same author suggests that 2-carbon monocarboxylic, 3-carbon monocarboxylic, or 4-carbon monocarboxylic acids can competitively inhibit the transport of each other by this carrier. The monocarboxylate transporter (MCT1) concentrations in adult rats on a ketogenic diet for 4 weeks was 8-fold greater in the brain endothelial cells and neuropil, compared to rats on a standard diet (182). Human PET data have shown that the brain utilization of beta-hydroxybutyrate is directly proportional to the serum level (22).

An enhanced metabolism of ketones (267), or ketogenic diet feeding (68), may in fact decrease the oxidation of pyruvate in the brain, thus, lessening glucose utilization. This effect is probably mediated by inhibition of the enzymes phosphofructokinase, pyruvic dehydrogenase, and alpha-ketoglutaric dehydrogenase (68).

Ketosis tends to be more difficult to induce in patients younger than 1 year old and older than 10 years old (276). In their book, Freeman and colleagues comment on the fact that infants, at times, may not tolerate or benefit from the diet, due to the inability to maintain ketosis or normal glycemia (86). Ketosis has been successfully induced in infants by Vining (personal communication, 1998).

Other effects of ketones have been described. Acetoacetate and beta-hydroxybutyrate may serve as precursors of cerebral lipid synthesis in the neonatal period (209). Sodium butyrate at physiologic concentrations may be associated with enhanced apoptosis (programmed cell death) outside of the CNS (108).

Lactate and pyruvate versus hydroxybutyrate and acetoacetate. Reaction 1 is catalyzed by lactate dehydrogenase, and reaction 2 is catalyzed by beta-hydroxybutyrate dehydrogenase. Both reactions are in dynamic equilibrium, and an excess of NADH(+) H(+) will produce an increase in the beta-hydroxybutyrate production. Such is the case in conditions producing an increase in lactate. Decreased conversion of beta-hydroxybutyrate to acetoacetate and acetone may also occur in cases of ketosis associated with insulin deficiency (79).

Acetoacetate-beta-hydroxybutyrate and the redox potential

(Contributed by Dr. Marcio A Sotero de Menezes.)

Quantitative microtests measuring serum beta-hydroxybutyrate are available (Stat-site GDS Diagnostics). These are quick and require only 20 µL of blood. Studies of patients on the ketogenic diet point out that the urine ketones may not be a reliable indicator of the serum values and that seizure control of patients on the ketogenic diet correlates better with serum beta-hydroxybutyrate measurements (above 4 mmol/L) and with urine ketones (40; 98). In a small study the measurement of breath ketones has been found to be a reliable indicator of ketosis in adults consuming ketogenic meals (224). More extensive studies with larger numbers of patients are necessary to confirm these findings.

Fasting will produce serum beta-hydroxybutyrate concentrations of 2 to 5 mm (212), and the range of values in children on the ketogenic diet is 3 to 8 mm. The diet has a higher chance of being effective when serum beta-hydroxybutyrate concentrations are kept between 5 and 8 mm. Freeman and colleagues found that beta-hydroxybutyrate concentrations in blood correlate with seizure control in children on the ketogenic diet, and the mean level for patients with greater than 90% seizure-reduction after 3 months on the diet was 6 mm (89). The data showing a 1:1 correlation between serum ketones and seizure control have been questioned in animal models and possibly even in humans (55). Ketone concentrations greater than 16 mm are commonly associated with diabetic ketoacidosis and should probably be avoided by children on the ketogenic diet (212).

During the course of a day, patients on the ketogenic diet will have a build-up of serum ketone bodies that peaks in the afternoon (214; 276). In contrast, in a regular diet, the highest ketone concentrations are in the morning before breakfast due to the overnight fasting and the higher nocturnal concentrations of growth hormone (211; 83). Urine ketones follow the same pattern.

The effect of medications on ketosis and carbohydrate metabolism.

Antiepileptic drugs. 2-propylpentanoyl-CoA (valproyl-CoA), one of the metabolites of valproic acid, has been implicated in inhibition of the mitochondrial fatty acid oxidation (186; 274). This compound probably causes the depletion of free CoA inside the mitochondria. Another postulated mechanism is related to the reversible binding of 3-keto-2-propylpentanoyl-CoA (also a valproic acid metabolite) to 1, or several, of the beta-oxidation enzymes (274). Valproic acid may also interfere with the beta-oxidation of medium-chain fatty acids (21). This may be due to a direct action of its 2-n-propyl-4-pentenoic acid (21). Clinically, it has not been found that valproic acid significantly interferes with the ketogenesis in children on the ketogenic diet. Valproic acid may increase the risk of side effects in patients on the ketogenic diet (08).

Beta-blocking agents. Beta-blocking agents inhibit fatty acid and gluconeogenic substrate release and reduce plasma glucagon concentrations (132). Patients on both beta-blocking agents and a diet low in carbohydrates and protein, or those undergoing fasting, are potentially more susceptible to hypoglycemia with decreased capability of ketogenesis. Beta-blocking agents may also decrease the symptoms of hypoglycemia.

Animal models of the ketogenic diet. Several animal models of the ketogenic diet have been described. The highlights of the studies are summarized in Table 13.

Table 13. Animal Models of the Ketogenic Diet

(04)
	• Increased threshold for electroconvulsive seizures in rats
	• Effects peaked between 8 to 20th day on the ketogenic diet
(303)
	• Increased threshold for maximal and hydration threshold electroshock paradigms in mice
	• No effect on electroshock threshold and pentylenetetrazol-induced seizures
(118)
	• Decrease after-discharge and seizure threshold (kindling model) for the first 2 weeks of treatment
	• No effect longer than 2 weeks of treatment
	• No difference in the after-discharge and seizure duration at time
(68)
	• Increase in the cerebral energy reserve in chronically ketotic adult rats
	• Ketosis predisposes to inhibition of some glycolytic enzymes
	• Possible increase of hexose transport system
	• No difference in brain pH, water content, or electrolytes in the two groups of animals
(143)
	• Anticonvulsant effects in mice even when they are fed ketogenic diet ad lib
	• Good weight gain on ketogenic diet
	• Beta-hydroxybutyrate concentrations achieved were often less than 2 mm
(288)
	• In rats made chronically epileptic by administration of kainate, the ketogenic diet was associated with fewer spontaneous seizures and reduced CA1 excitability in vitro
(28)
	• The efficacy of the ketogenic diet is independent of the degree of ketonemia, but is markedly influenced by ketogenic ratios (more fats vs. carbohydrates and proteins) and decreasing weight (124) • Fish that evolved to be asocial remain capable of exhibiting social affinity when ketotic, possibly linking the seasonal food availability and sociality (124).

In summary, most of the animal models of the ketogenic diet do not appear to reflect the human situation. Most of them represent models of seizure challenge rather than chronic seizure models. One study found that the ketogenic diet induced long-term changes in the hippocampal network excitability in a chronic spontaneous seizures model, for instance, the kainate-induced status epilepticus (288). It is likely that the degree of ketosis achieved by these models is not sufficient to produce the same robust anticonvulsant effect seen in the ketogenic diet in humans.

Mechanisms of action and in vitro studies of the ketogenic diet. The exact mechanisms of action of the ketogenic diet remain elusive in spite of its being used for more than 70 years. Previously proposed mechanisms, such as negative sodium and potassium balances (217), have been disproved by subsequent publications (121; 276). Debakan first noticed elevations in serum lipids in patients on the diet (58). Over the past few years, elevations on polyunsaturated fatty acids have been postulated to have some effect in seizure control; this is based on a few clinical and mostly animal work (332; 316; 56; 271; 85). Special arachidonate and docosahexaenoate have been shown to have an anticonvulsant role (56). Longer-chain and unsaturated fatty acids are associated with the anticonvulsant activity (53). Polyunsaturated fatty acids acting in concert with ketones to exert their anticonvulsant role has been proposed (55). Cullingford also suggests that another possible mechanism involved is that polyunsaturated fatty acid-induced inhibition of cyclooxygenase 2 caused decreased synthesis eicosanoids, which are suspected to potentiate seizures and kainate-induced hippocampal cell death (170; 53). Other anti-inflammatory and neuroprotective actions are indirectly mediated by polyunsaturated fatty acids, including decreased action of transcription factors such as NF-kappaB and AP-1, which cause a decrease in the cyclooxygenase and inducible nitric oxide synthase activity (62).

A study demonstrated that the administration of kainic acid in rodents induces acute seizures and leads to neuronal death and cellular and molecular alterations within the limbic structures. This study found that the ketogenic diet is neuroprotective by inhibiting caspase-3-mediated apoptosis in hippocampal neurons. Thus, early implementation of the ketogenic diet can provide an antiepileptogenic effect and potentially prevent associated learning and memory deficits (234).

In animals, simple caloric restriction already produces some seizure protection. The effect may be mediated by hypoglycemia or other unknown mechanisms (100).

Lowering of pH was proposed by Lennox and Lennox to be one of the important actions of the diet (185). In spite of occasional peripheral acidosis, however, the pH measured in the brain does not appear to change during the ketogenic diet, as shown in animals (01) and in humans (237). Local changes in brain pH can be underestimated by whole brain measurements.

Other ideas that have been postulated include GABAergic effects, either indirect or indirect, and changes in the amino acid and neurotransmitter metabolism (333). About the latter, it is intriguing that, in rodent models, norepinephrine is necessary to produce the diet’s anticonvulsant effect (294). Even though the latter findings have been confirmed, the effect of the Ketogenic diet seems to depend on other factors (202).

The ketogenic diet may exert neuroprotective and anti-epileptogenic properties in addition to the known anticonvulsant effects, which improves its potential to serve as a disease-modifying intervention with implications for diverse neurologic disorders (204; 287).

The current and past ideas about the mechanisms of action of the ketogenic diet are summarized in Table 14.

McDaniel and colleagues investigated the potential for the ketogenic diet to inhibit mammalian target rapamycin (mTOR) pathway signaling in animal models (207). The ketogenic diet may have anticonvulsant actions on mTOR pathway inhibition.

Table 14. Possible Mechanisms of Action of the Ketogenic Diet

Hypothesis	Current Ideas (not necessarily proven)
Intracerebral or systemic acidosis (185)	• Unlikely to be present in animals (68; 01) or in humans (237)
Negative sodium and potassium balances (217)	• Unlikely to be a significant effect (121; 276)
Direct anticonvulsant of hyperlipidemia (58) or of increased free polyunsaturated fatty acids (55)	• Lipid concentrations are unlikely to be a significant agent of the anticonvulsant action of the diet (121; 276)
Increased “GABA shunt” activity and increased intracerebral GABA (236); caloric restriction increases brain glutamic acid Ddcarboxylase-65 and -67 expression (41)	• Not confirmed in animals (01) • Present in only three out of six humans studied by MRS (237)
Evidence for the presence of direct anticonvulsant effect of ketones	• Higher serum beta-hydroxybutyrate concentrations allow better seizure control in humans (121; 89) • Diet more efficient at an age when blood-brain barrier ketone extraction is the most efficient (250) • GABAmimetic effects of beta-hydroxybutyrate, acetoacetate (?) (236) • Acetoacetate may be anticonvulsant in rabbits (136; 137; 138); acetone directly anticonvulsant (190) • Unsustained postsynaptic field potentials in hippocampal slices (05) • Potentiation of GABAA-mediated inhibitory post-synaptic potentials in hippocampal CA1 neurons studies (94) • Local decrease of glucose transporter-1 in the epileptogenic zone • Decreased glucose transport (49) • Ketogenic diet re-establishes normal energy metabolism in the epileptogenic zone (?)
Evidence for the lack of direct anticonvulsant effect of ketones	• Medium-chain triglyceride diet-mediated high serum ketones are not protective in seizure challenge models (298) • Ketone bodies do not have a direct effect on voltage and ligand-gated channels mediating excitatory or inhibitory neurotransmission in the hippocampus (300)
Other ketogenic diet effects	Neuroprotection mediated but increasing mitochondrial uncoupling protein (290)
Chronic changes in hippocampal excitability	• Long-term changes in the hippocampal network excitability in the kainate-induced status epilepticus chronic spontaneous seizures model (288)
Alteration of CNS energy metabolism	• Local decrease of glucose transporter-1, causing decreased glucose transport in the epileptogenic region, leading to impaired energy metabolism, which is re-established to normal concentrations by the ketogenic diet (48) • Improved CNS energy metabolism on ketogenic diet shown by MRS (247).
Hypoglycemia or caloric restriction	• Animals on simple caloric restriction without major ketosis have some seizure protection (100).
Ketogenic diet anti-seizure effect is mediated in part by norepinephrine	Discovered by Szot and colleagues and later confirmed by Martillotti and colleagues (294; 202)

In summary, both clinical and experimental evidence substantiates that ketosis is required for the diet to be effective, even though high concentrations of ketone bodies may not be the direct cause of seizure control; evidence accumulated by studies of animal models of the diet speak against that (189; 298; 300; 326). The latter evidence would point to the fact that the ketogenic diet exerts its effects by some other mechanism that is coincident with the timing of the appearance of high concentrations of serum ketones. The ketogenic diet has been studied to influence the gut microbiome in epilepsy (110; 193; 228). Further studies are necessary to substantiate these findings.

The ketogenic diet and gut microbiome. Increasing evidence suggests interactions between the ketogenic diet and gut microbiome may modulate host physiology and antiseizure effects (245).

The ketogenic diet and DNA methylation. A genome-wide decrease in DNA methylation was observed after 4 and 12 weeks on a modified ketogenic diet in individuals with epilepsy (249).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ryan W Y Lee MD

Dr. Lee of the John A Burns School of Medicine at the University of Hawaii has no relevant financial relationships to disclose.
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Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
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Former Authors

Jong M Rho MD
Marcio A Sotero de Menezes MD
Jennifer L Schoenfeld ARNP
Miki Wong MACO RDN

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Ketogenic diet in the treatment of epilepsy

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Alternative therapies
Epilepsy
Nausea and vomiting
Nutrition and the brain

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NIH: Epilepsy

Ketogenic diet in the treatment of epilepsy

Introduction

Key points

Historical note and terminology

Table 1. History of Fasting and Ketogenic Diet in the Treatment of Epilepsy

Clinical aspects

Description

Table 2. The “Classic” Ketogenic Diet (Suggested Protocol)

Table 3. Strategies for Low Serum Ketone Concentrations

Table 4. An Approach to the Management of Nausea in Patients Fasting or on the Ketogenic Diet

Table 5. Management of Hypoglycemia in Patients Fasting or on the Ketogenic Diet

Table 6. Effects and Benefits of Medium-Chain Triglyceride Use

Indications

Contraindications

Outcomes

Table 7. The Efficacy of the Ketogenic Diet

Adverse effects

Table 8. Side Effects of the Ketogenic Diet

Special considerations

Clinical vignette

Scientific basis

Table 9. Endocrine and Metabolic Control of Lipolysis and Ketogenesis

Table 10. Energy Metabolism Changes Associated with Fasting

Table 11. Stimuli for the Glucagon Secretion

Table 12. Factors Influencing Insulin Release

Table 13. Animal Models of the Ketogenic Diet

Table 14. Possible Mechanisms of Action of the Ketogenic Diet

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