( Summarize) The Ketogenic Diet Treatment in Pediatric Epilepsy

( Summarize) The Ketogenic Diet Treatment in Pediatric Epilepsy

Dreamer
August 8th, 2004

Introduction:

The Ketogenic Diet is a high fat, low carbohydrate and low protein diet. As a way to treat epilepsy, it started in 1921 when Wilder designed the diet. Later on many clinical researches and animal studies have been done and still doing. It shows the Ketogenic diet is effective in epilepsy. But the mechanism is unknown. This becomes a hot study point for refractory epilepsy.

Animal studies have proved that the Ketogenic diet can increase the threshold of the seizures. The diet only uses for the refractory epilepsy as a adjuvant treatment. Before initiate the diet, fasting 36--48 hours, and then give 4:1 Ketogenic diet. Stay in it at least 6 weeks so that the body can remain ketosis. Adjust calories and water intake as individual needs to keep the patient’s weight does not change too much.

Ketogenic diet is more efficiency t in children than adults. Because the brain’s ability of using ketone body as energy source decreases with aging. And adults are difficult to remain ketosis. Also long time high fat diet can course adults serious cardiovascular and cerebrovascular diseases.

The side effects of ketogenic diet includes: constipation, abdominal distention, anorexia, hyperlipidemia, kendiny stone, vitamin deficiency, hypoproteinemia and sometimes can course dehydration, hypoglycemia and osteoporosis. Using ketogenic diet with some antiepileptic medication can make side effects more severe. So when using ketogenic with antiepileptic medication, caution needs to be taken.

Below is a summarize of the recent years publications about ketogenic diet study.

Background:

The ketogenic diet was designed in the 1920s to mimic the body's response to starvation. Starvation induces a ketotic state, shifting the body's metabolism from carbohydrate to fat utilization for fuel (1). The ketogenic diet can treat two disorders: Epilepsy and some inborn errors of metabolism (2). This article will only summarize the use of ketogenic diet in epilepsy.

Ketogenic diet can decrease seizures of patient with epilepsy. In its heyday, the diet was predominantly used to treat patients with intractable childhood epilepsy. The efficacy and tolerability of modern antiepileptic drugs (AEDs) led to decreased use of the ketogenic diet.(1)


Recently, however, there has been a rebirth of popular interest in the ketogenic diet following the television news documentary Dateline, a movie made for television First, Do No Harm, and a published report on the diet's efficacy in 58 patients. Its mechanism is not well described, but it appears to be useful when traditional AEDs have failed or there are unacceptable side effects from AED therapy.(1)

Ketosis, or the physiologic state in which there are elevated levels of ketones in the blood, usually occurs in people in the fasting state. A state similar to fasting can be induced by a very high fat diet. Hence the ketogenic diet.(3)The ketogenic diet has its origin in the observation that fasting reduces seizures. This observation is old since Hippocrates used fasting to treat seizures, and the Bible mentions fasting as a treatment for seizures (2)(4). However, the first scientific assessment using dietary manipulation was reported by Guelpa in 1911. In 1921, Geyelin confirmed that seizures ceased on absolute fasting (6). In 1921, Wilder proposed a high fat, low carbohydrate diet as a means of mimicking fasting, and attributed the anticonvulsant properties to the production of ketones (2)(6). There were not much AEDs available before 1938, the ketogenic diet was used in a group of children and adults which more representative of the current general population of people with epilepsy. (6)

After 1938, phenobarbital and phenytoin became available, interest in the diet declined (2).

However, interest has increased recently because 20-30% of epileptic children have seizures that are resistant to antiepileptic drugs (2). And the diet lack of unpleasant side-effects associated with AED's (4). In the last 10--30 years patient series reported on the diet have generally included people with multiple seizure types refractory to multiple ant epileptic drugs (AEDs) (6).

The diet has been described as difficult to tolerate, being unpalatable leading to poor compliance. However, there remains a group of children who have seizures that are difficult to control or who have significant side effects with AEDs. So the diet has been remained interested (6).

The basis of the ketogenic diet is the brain’s ability to utilize ketones as an energy source. Ketones include b-hydroxybutyrate, acetoacetate, and acetone, which are products of fat breakdown. Under normal conditions, the brain derives most of its energy from glucose. Under fasting conditions, hormonal changes cause fat cells to release fats, which are then broken down in the liver. The liver packages the energy contained in fat into ketones. The liver releases ketones into the blood, which then transports them to the brain (2).

While on the ketogenic diet, the patient will be in ketosis and will have elevated levels of ketones in his/her blood. Ketone levels can be measured in the blood, but blood levels generally are not measured daily. Instead, they are monitored using a urine dipstick since they also spillover into urine when present at high levels in the blood. Normally, urine has no ketones (2).

Descriptions of the Ketogenic Diet:

When the body is deprived of glucose, ketone bodies, acetoacetic acid (AcAc) and b-hydroxybutyrate (BHB), are formed from the breakdown of fat and cross the blood-brain barrier where they can be used by the brain for energy.(1) The ketogenic diet's aim is to simulate the body's response to starvation by inducing production of these ketone bodies.This diet is high in fat and low in carbohydrates and protein, with each component of the diet being meticulously weighed in a specific ratio and proportion. Foods in this diet are considered either "ketogenic" (fat) or "antiketogenic" (carbohydrates and protein) (1).

Accuracy and compliance with the diet are critical. It takes dedicated individuals to make the diet a successful seizure treatment. When patients are ill and either cannot ingest their diet properly or need to take additional medications (which generally contain carbohydrates), disruption of ketosis becomes more likely. It is therefore important for health care practitioners, patients, and family members to easily recognize the carbohydrate content of frequently used medications and other ingested products.
Pharmacists are the ideal source to supply this information and are essential to make the diet work with the least amount of effort (1).

The modern form of the ketogenic diet was described by Wilder in 1921. Wilder initially described a diet high in fat content (i.e., long-chain saturated fats) with a low percentage of both proteins and carbohydrates. This diet is referred to as the "classic" (4:1 or 3:1) diet comprising four or three parts fat:one part nonfat (protein or carbohydrate) kilocalories. Wilder believed this would mimic the fasting state while providing the body with enough calories to maintain proper growth and function (1).

Because the classic 4:1 diet was considered unpalatable and, hence, associated with poor compliance, Huttenlocher developed a medium-chain trigylceride (MCT) diet. The MCT diet is easier to prepare, is more ketogenic because the fats used (decanoic and octanoic acids) yield more ketones per calorie, allowing more carbohydrate and protein utility, and thus causes less elevation of serum cholesterol (1).However, recent experience suggests that the classic ketogenic diet may be better tolerated than the MCT diet (3).

In addition to the classic 4:1 and MCT diet, a third diet -- the modified MCT diet -- was developed by the John Radcliffe Hospital in Oxford that incorporates both long- and medium-chain fatty acids (1).

Efficacy:

Most epilepsy in Children can be controlled with 1 medication. Those whose seizures cannot be controlled with the first medication, properly used, have a <20% chance of their seizures being controlled with second medication. Children who have seizures that are difficult to control with two medications have only 25% to 40% chance of their seizures being controlled with other medications. It is latter population of children who have failed >3 medications that some have termed “intractable”, or that we call “difficult to control”(13).

The diet has been shown to significantly reduce the frequency of seizures in some children with difficult to control epilepsy. Not all children show an improvement in seizure control with the diet. If it is successful in controlling seizures, the doctor may decide to reduce or gradually withdraw medication (5).

Ketogenic diets have been used to treat seizures that are both idiopathic and sympto-matic. Patients with the following seizure types have been evaluated for efficacy of the diet: myoclonic, focal motor, atypical absence, generalized tonic, and tonic-clonic. All three of the diet formulations are equally efficacious. Overall efficacy ranges from 33-67%. Most of the studies that have been published use seizure frequency, intensity, and compliance as end points of the study (1).

It appears that children younger than 10 years old respond the best to the diet from a physiologic perspective. These children tend to be more prone to ketosis than older children or adults. The brain's ability to extract ketone bodies and utilize them as an energy source decreases with age. This is because the relative fractional extrac-tion of ketone bodies decreases with age.[23-25] Younger children are also more dependent on someone else preparing their diet than are older children or adults. Surprisingly, a majority of the children do not mind the taste of the high-fat diet, especially if they are involved in the selection of foods and their parents explain the importance of the special diet to them (1).

One study observed 150 children whose seizure were intractable. They averaged 410 seizures per month and has failed an average of 6 medications before the time of starting on the diet.One year after starting the ketogenic diet, 7%of these children had become seizure-free and an additional 20% children had a >90%decrease in seizures. Three to 6 years later, 27% of the 150 had a >90% decrease in their seizures, and most had discontinued the diet. Half of those(13%) were seizure-free. This 27% with marked improvement in seizure control is the same percentage as we had found after 1 year on the diet, although they are not necessarily the same children. Three to 6 years after starting the diet, a higher percentage(13%) have become free of seizures(13).


Preliminary results from a multicenter study seem to indicate that it can be useful in controlling seizures of a percentage of children who had not been controlled with anticonvulsant medications. Approximately 33% of these children gain full control, and another 33% are able to get improved control and decrease their medications. Seizure type does not predict which child may benefit from the diet(14).

There are reports on efficacy of the diet. They provided additional retrospective evidence of the efficacy of the diet in 17 children under 2 years of age. Two patients quickly withdrew; of the 15 who remained on the diet, 40% became almost seizure-free and 53% experienced more than a 50% reduction in seizure frequency. The durability of this outcome is not clear, but these investigators continue to demonstrate the lack of difficulty in using the diet in very young children(11).

In another study, they reported 4 patients with "epileptic spasms," an entity clinically similar to infantile spasms but occurring in older children. One of these patients achieved partial control (> 50% reduction) of spasms using the ketogenic diet. This would not be surprising, given the diet's recently reported efficacy in infantile spasms(11).

For treatment of seizures. Many studies report that the ketogenic diet effectively treats a variety of seizures in children and adults. The seizure types that can be helped by the diet include absence, myoclonic, generalized tonic, generalized clonic, generalized tonic-clonic, simple partial, complex partial, and partial seizures with secondary generalization. It may be most effective against myoclonic, astatic or drop seizures, and atypical absence seizures. It can be effective in children with multiple seizure types including Lennox Gastaut syndrome(2)(11). Another benefit of the ketogenic diet for some children is that it may reduce or end the need for medication and thus avoid the side effects that result from medication(12).

About 1/3 of children have a >90% reduction in seizures with 5% becoming seizure free at 6-12 months. Another 1/3 have a 50-90% reduction in seizure frequency at 6-12 months with the remainder having no significant improvement. Other potential benefits of the diet include a reduction in the number of antiepileptic drugs, increased alertness, and improved behavior even if seizure control is not improved(2)(11).

For treatment of inborn errors of metabolism. The ketogenic diet is the treatment of choice for some inborn errors of metabolism and is a treatment option for others. It is the treatment of choice for children with glucose transporter protein syndrome since they cannot get glucose to their brains. Children with diseases characterized by an inability to metabolize pyruvate such as pyruvate dehydrogenase complex deficiency are candidates for the diet. It may also be helpful in infantile phosphofructokinase deficiency(2).

A recent review of the results from numerous studies of the ketogenic diet found that over half of children with seizures that don't respond to medications who follow the ketogenic diet have a 50% or greater decrease in seizures. Some children have an even greater reduction(11)(12).

The other benefits of the ketogenic diet are mainly avoiding the side effects of
anticonvulsants such as sedation or impaired thinking, as well as the cost savings. Like
anticonvulsants, the diet is not a cure, but merely another treatment mode for hard to control seizures(14).

Mechanism:

It is not clear how the diet work and it is possible that there are two separate mechanisms. When the fats are broken down they produce ketone bodies which are passed throughout the body and then are excreted in the urine. These can be tested very simply by dipping a special stick into the urine (or on to a nappy) to ensure that the child has become ketotic. It is thought that in some children these ketone bodies are actually working like antiepileptic (anti-fit) medicines. In these children the level of ketones is crucial and must be maintained to ensure good seizure control.
In other children, who take longer to respond to the diet, they appear to receive something that is deficient from their diet. Seizure control is often not obtained for about one month but then the effects are not so dependent on the ketone levels. It is impossible to predict into which group your child will fall. Not all children respond to the diet(15).

Numerous theories have been proposed on how the ketogenic diet works in both human and animal studies. Several authors believe that the anticonvulsant effects of the ketogenic diet are related to the ketosis and production of AcAc and/or BHB. The protection against seizures by elevated blood levels of BHB and AcAc in animals also has been studied.
The mechanisms of the ketogenic diets, however, are still unknown. It does appear that BHB and AcAc are involved in the efficacy of the ketogenic diet, but elevation of these substances may not be the only mechanism of action of the diet. More animal and human research is needed to completely determine the true mechanism or mechanisms of the ketogenic diet(1).

The effectiveness of the Ketogenic Diet is a combination effect of the following processes, all of which tend to remove extra-cellular fluid. Acidosis--mild degree of compensated acidosis. Ketosis--accumulation of mildly anesthetic acetone bodies in tissue. Dehydration--slight lowering of water content of the body(4).

The ketogenic diet a "therapy in search of an explanation", Carl E. Stafstrom, M.D., Ph.D., associate professor at Tufts University School of Medicine and the New England Medical Center in Boston described research in animal models to investigate the mechanisms of action through which the ketogenic diet confers its apparent beneficial effect. Dr. Stafstrom indicated that we have learned the following from animal models:
1) the ketogenic diet appears to afford protection against acute seizures in some models, 2) the mechanism of anticonvulsant action may be related to the ketosis itself, rather than to the associated acidosis or other metabolic effects, and 3) several features of experimental responses parallel those observed clinically. For example, the diet seems to be more effective in younger animals just as it seems to be more effective in children than in adults. Also, although the onset of action is gradual, the reversal of the effect occurs rapidly. We see this clinically when it may take several days after beginning the diet for the effect to build up, but, if ketosis is interrupted by the consumption of carbohydrates, the anticonvulsant effect can reverse within hours. This is why it is so important to maintain the diet strictly, and why it is so easy to undo its effects: weeks of hard work can be undone if the child eats a couple of cookies or candies because they contain enough glucose to switch the body over to using glucose for fuel rather than the ketone bodies. (Remember that the body only uses the ketones when sugar is unavailable; as soon as the slightest amount of sugar is made available the body immediately converts it to glucose to use for fuel)(3).

Dr. Stafstrom described several experiments in which rats given ketogenic diets were compared with rats on normal diets as various parameters of cognition and behavior were tested. In general, the rats on the ketogenic diet did better in several tests, such as the "water maze", which measures the ability to learn and remember the location of food on a platform in a pool of water through which the rat has to swim to reach the food. "I am not willing to say that the ketogenic diet makes rats smarter, but at least it's clear that it doesn't make them any dumber", said Dr. Stafstrom, and this observed effect correlates with observations in children with severe epilepsy on the ketogenic diet who experience improvements in mood, behavior, and cognition. Unfortunately, this improvement carries with it an increase in activity, possibly hyperactivity, in terms of awareness and exploration of the surroundings; this may correlate with observations of increased irritability in some children on the diet(3).

Elevated levels of ketone bodies have been strongly associated with seizure control and seizure freedom, and all practicing neurologists employ them as biochemical markers of treatment. However, the ketosis produced by the ketogenic diet may not be the main factor in controlling epileptic seizures in children [Schwartzkroin 1999]. Nevertheless, the clinical goal has historically been to achieve high urine ketone levels, and the importance of this time-honored practice can only be appreciated through an understanding of intermediary metabolism(16).

When the glycolytic pathway is deprived of glucose, as during starvation or the ketogenic diet, free fatty acids are mobilized as substrates for mitochondrial oxidation. In addition, certain amino acids may be converted to ketoacids that can provide other substrates (e.g., alanine to pyruvate) for Krebs cycle activity. The hepatic microsomal system can also convert fatty acids to dicarboxylic acids (via omega oxidation). These dicarboxylic acids require carnitineesterification for urinary secretion [Sankar & Sotero de Menezes, 1999](16).

Free fatty acids are not readily available to the neuron itself. However, fatty acids can undergo aseries of conversions and translocations to produce acetate substrates for ketone body production. These ketone bodies are carried across the blood-brain barrier (by a fasting-inducible transporter called the monocarboxylic acid transporter) and into the neuron where they are available as an energy substrate for cerebral metabolism(16).

Thus, one major physiologic role for ketone bodies is to provide an alternative energy substrate for brain and muscle under conditions of fasting or a high-fat diet. In a classic study of fasting obese volunteers, for example, glucose utilization accounted for only 29% of the brain’s oxygen consumption while ketones extraction accounted for 52% [Cahill 1966]. Playing another major physiological role, ketone bodies act as the principle source of energy during early postnatal development. Furhter, they are the substrates for the carbon skeleton of lipids that comprise the cell membranes of growing brains and organs. Thus, ketones are involved in both the energy supply and lipid biosynthesis of the embryonic central nervous system (CNS)(16).

But do ketone bodies exert a direct antiepileptic effect? Can they modulate neuronal excitability? Several clinical studies have now shown that diet-induced ketosis (especially at very high concentrations) seems to correlates with the level of seizure control. (The most recent studies will be discussed later.) Also, abrupt loss of seizure control has long been known to occur within hours after ketosis is broken [Huttenlocher, 1976](16).

Thus the compelling question remains: are ketones directly responsible for anticonvulsant activity? Or are they just an epiphenomenon of some other diet-induced physiological change? These questions have been explored in varied experimental settings(16).

One recent animal study, for example, showed that ketone bodies do not directly alter the excitatory or inhibitory hippocampal synaptic transmission. [Thio 2000] Neither beta-hydroxybutyrate nor acetoacetate affected whole cell currents evoked by glutamate, kainite, or gamma aminobutyric acid (GABA) in cultured hippocampal neurons. The ketone bodies also failed to prevent spontaneous epileptiform activity in the hippocampal-enterorhinal cortex slide seizure model(16).

Results from our laboratory in cultured mouse neocortical neurons were similar, with no effects of the ketone bodies on the classic neuronal targets of anticonvulsants. Investigators should also be aware that beta-hydroxybutyrate is a stereoisomer, with the D-isomer being the biologically relevant species. The non-physiologic L-isomer possesses anticonvulsant activity both in vivo and in vitro, and is due to the presence of a contaminant, diphenylamine(16).

Similarities in the chemical structures of beta-hydroxybutyrate and GABA have led to speculation about GABAergic inhibition induced by the ketogenic diet. Results from studies are conflicting, with one showing no changes in whole brain GABA [Al-Mudallal 1996] and another demonstrating that ketonescan increase GABA in synaptosomes. [Erecinska 1996](16).

Finally, magnetic resonance spectrophotometric techniques have shown elevated levels of cerebral ketones in patients who are successfully controlled by the ketogenic diet [Pan et al., 1999](16).

Overall, the experimental evidence supporting a direct link between ketone and seizures is far from convincing. Indeed, as with the underlying causes of the seizures themselves, the ameliorating actions of the ketogenic diet may be multiple, with a host of diet-influenced metabolic changes acting in concert to decrease membrane excitability(16).

But even as research continues, the clinical connection between peripheral ketone levels and seizure control still impels clinicians to confront more practical questions. For example, what assay method should be employed to monitor diet efficacy? Urine dipsticks are commonly used for this purpose but these measure acetoacetate, the less prominent ketone body. Which ketone body actually correlates best with seizure control is unknown. If beta-hydroxybutyrate ketone is actually the preferred marker, a new reflectance meter (Keto-Site™, GDS Diagnostics) will assay the D-isomer from a small drop of blood. But then, what is the “therapeutic concentration”for either of these ketones? And what does the peripheral level predict about the brain level?(16)

Clearly, many questions remain about the physiological relevance and the practical utility of monitoring ketone bodies in the ketogenic diet(16).

Eileen P.G. Vining, MD summarized the mechanism of ketogenic diet studies on American Epilepsy Society 56th Annual Meeting (11):

Pan and colleagues[13] from Albert Einstein College of Medicine, Bronx, New York, and Yale University School of Medicine, New Haven, Connecticut, have addressed monitoring the diet from another important point of view. They have asked how the brain uses ketones, recognizing that a simple measurement of plasma ketones may not reflect the critical biological parameter. They used in vivo MR spectroscopy to evaluate how beta-hydroxybutyrate (BHB) is used in the brains of healthy adults who become ketotic. They found that the rise in plasma BHB is rapid and accompanied by a near simultaneous rise in brain BHB. Perhaps their most interesting finding is that the BHB consumption appears to be preferred by the neuronal compartment, bypassing the astrocytic compartment that had been suggested by others(11).

Five poster presentations discussed various aspects of basic science relating to the ketogenic diet. Sullivan and associates[14] from University of California at Irvine examined synaptosomal mitochondria from the cortex of mice fed either normally or with the ketogenic diet for 10 days, with BHB levels reaching twice the normal level in the ketogenic-diet-fed rats. They found increased mitochondrial uncoupling activity and reduced reactive oxygen species (ROS) production in the animals on the diet, suggesting a possible neuroprotective as well as anticonvulsant effect(11).

Bough and coworkers[15] from University of Washington, Seattle, University of California at Irvine, and University of California at Davis, reported on in vivo recordings from Kcna1-null mice with recurrent seizures, a possible model of developmental epilepsy. The ketogenic diet did not further augment the inhibition shown by Kcna1 -/- mice to paired-pulse stimulation within the dentate gyrus, resulting in an elevated threshold to electrographic seizures at 5-6 weeks of age(11).

Two other presentations dealt with seizure susceptibility using 2 different models. In a multicenter Korean study, Dong-Wook Kim and colleagues[16] examined flurothyl-induced seizure susceptibility in 3- to 12-week old rats that were treated with a ketogenic diet. Levels of ketosis were lower and seizure latencies were shorter in older animals, suggesting that the diet was more efficacious in younger animals. The efficacy of the diet is generally assumed to be better in younger patients, but substantive evidence to confirm this is not available. In a second, multicenter Korean study, Jae-Moon Kim and colleagues[17] examined the effect of the diet on continuing seizures in rats with PTZ-induced seizures. The diet was effective in reducing the length of seizures, again more so in the younger animals(11).

Finally, Eagles' group[18] at Georgetown University, Washington, DC, presented information about the effects of gamma-butyrolactone (GBL) -- which induces absence seizures -- and the ketogenic diet on the behaviors of male and female rats. Absence seizures were induced in rats, and several functions (posture, gait, and performance on a roto-rod) were scored. Ketogenic animals, particularly females, did less well behaviorally than standard-fed animals. In general, sex differences on the ketogenic diet have not been observed clinically. This preliminary finding in animals is obviously of interest as we explore the neuroendocrine effects of the diet(11).

Indication and Contraindication:

Most experts say the diet is worth trying when two or more medications have failed to control seizures, or when medications cause side effects that are having a harmful effect on a child's life. It also helps to have a child who is willing to try foods that he might otherwise not be enthusiastic about, and is tolerant and not fussy about eating. The diet seems to work for more than one kind of seizure, and for children who have a lot of seizures or few seizures. But most doctors say it shouldn't be used instead of medications if the drugs are working and the child is not having bad side effects(5)(18).

Epilepsy patients must meet certain criteria to start ketogenic diet at Johns Hopkins Hospital(17):
--They previously must have tried two anti-convulsant medications.
--They must undergo an evaluation by their own neurologist and EBMP's ketogenic team to determine their seizure type.
--They or their families must demonstrate an ability to understand the ketogenic diet and the importance of adhering to its specific requirements.
--Patients and families must be highly motivated in following the diet(17).

The ketogenic diet has two primary indications. Some children with epilepsy that standard antiepileptic drugs cannot control are candidates for the ketogenic diet. And Several specific inborn errors of metabolism can upset mitochondrial function and lead to dysfunctional glycolysis. Children with these special conditions may be strong candidates for the ketogenic diet(2)(16).

It appears that the best candidates for the ketogenic diet are those who have refractory epilepsy or unacceptable side effects to standard AEDs. In addition, patients placed on the diet must have a strong support system at home to implement the diet because of its strict guidelines. Patients and family members must be willing to work closely with a dietitian to help make meal planning more realistic(1).

John M. Freeman et el wrote the indication about the diet at the book The epilepsy diet treatment(7):
A) Children with difficult to control seizures occurring searal times each week and had failed at least two AEDs.
B) Seizure type: myoclonic, absence, and atonic (drop) seizures which are particularly
difficult to control with standard medication. The diet also helps some patients with genalized tonic-clonic seizure and even the multifocal seizures of the Lennox-Gastaut syndrom. The ketogenic diet may be tried on children with any type of seizures.
C) Age: The ketogenic diet is most often prescribed for children over one year of age. Children under the age of one year have trouble becoming ketotic and maintaining ketosis. They are also prone to hypoglycemia. The ketogenic diet may be recommended for older children provided that they and their families are highly motivated. It has been said that adults have difficulty maintaining ketosis, but to our knowledge this has not been studied in depth.(7).

There are some contraindications: Medical contraindications to the ketogenic diet include metabolic disorders with a defect in fat metabolism, ketone metabolism, or mitochondrial disorders. These include β-oxidation defects, primary and secondary carnitine deficiency, carnitine cycle defects, electron transport chain defects, ketogenic defects, ketolytic defects, pyrvuate carboxylate deficiency, and pyruvate dehydrogenase phosphatase deficiency. Though the diet can exacerbate ketotic hypoglycemia, this condition is not an absolute contraindication(2).

Most inborn errors of metabolism involving mitochondrial transport of fatty acid oxidation are absolute contraindications for the ketogenic diet. These include, for example, deficiencies in carnitine (primary or secondary), carnitine palmitoyltransferase I or II, and translocase. The most common fatty acid disorder to be vigilant for is the medium-chain acyl dehydrogenase deficiency (MCAD). Other such deficiencies include those of long-chain acyl dehydrogenase, short-chain acetyl CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA, and medium-chain 3-hydroxyacyl-CoA(16).

Clues to an inborn error of metabolism include developmental delay, hypotonia, exercise intolerance, and easy fatigability. In children with these presenting symptoms, several tests can determine if the child is suitable for the ketogenic diet. The recommended biochemical screening tests (in addition to the routine laboratory studies such as liver function tests, complete blood count, etc.) are for urine organic acids, serum amino acids, and serum lactate and pyruvate. As implied in Figure 1, findings of highly elevated dicarboxylic acids in the urine signal a problem with the normal pathway of intermediary metabolism (either mitochondrial cytopathy or a fatty acid oxidation defect) and this warrants further investigation(16).

Some antiepileptic drugs can potentially exacerbate some of the adverse effects of the ketogenic diet, and these drugs require careful use when combined with the diet. These antiepileptic drugs include acetazolamide, topiramate, and zonisamide, which all can cause acidosis and kidney stones. Another antiepileptic drug requiring careful monitoring in children on the diet is valproate.

Finally, some children and adolescents are not candidates for the diet because they can get their own food and cannot understand the restrictions of the diet. These children and adolescents will not maintain the diet without constant supervision, which usually is not practical(2).

Adverse Effects(Side effects):

Similar to other antiepileptic drugs, the ketogenic diet has a variety of side effects that range from minor to severe. Common ones include nausea, vomiting, constipation, and loss of appetite. Less common ones include poor growth, kidney stones, and abnormal heart rhythms. It may impair white blood cell and platelet function. White blood cells help our bodies to fight infections, and platelets help our blood to clot. In rare cases, it can cause death(2).During the fasting period, it may be have Nausea , Severe acidosis and Vomiting. During the diet period: One can have Vomiting , Hunger , Decreased ketosis , Constipation , Illness (4). The ketogenic diet may cause Dehydration, High cholesterol level and Behavior changes(12)(18).These may lessen with time and they can sometimes be avoided by careful monitoring. The most common side effects when starting the diet are nausea and constipation. If the diet is kept to carefully, the child will not usually become overweight or have an increased risk of heart disease(5). Possible long-term effects of high fats(cholesterol,
triglycerides), Growth retardation due to protein deficiency, Vitamin and mineral deficiencies, Impaired immune defenses (possibly related to neutrophils), Metabolic acidosis and Liver failure, etc(16).

1) Digestive system side effects: Typical early problems included GI intolerance (11). These are including nausea, vomiting, and abdominal cramping. These adverse effects are seen in approximately 50% of patients on the MCT diet because of its hyperosmolar concen-tration, and are somewhat less common with the classic diet. Excessive ketonemia also may produce GI side effects and should be ruled out. On a daily basis, urinary ketones should be monitored. Pharmacists are excellent resources for explaining how to monitor urinary ketones. A small amount of orange juice may be given for excessive nausea to lessen the degree of ketosis.[20] Medium-chain triglyceride oil is hyperosmolar, which can cause a large influx of fluid into the large intestines. When GI side effects are present with the MCT diet, they can be eliminated by decreasing the amount of MCT oil in the diet and gradually titrating it back up slowly. It may also be helpful to have the patient sip the MCT drink throughout a meal to decrease abdominal pain. A few severely retarded children treated with the classic diet have developed dehydration and severe metabolic acidosis during illnesses, requiring hospitalization. When these children required intravenous rehydration, electrolyte solutions without glucose or lactate were given(1).

2) Carnitine deficiency: Recently, carnitine deficiency has been reported in a small number of children receiving the ketogenic diet (1) (11). Although the clinical relevance of measuring free carnitine remains in question, the investigators conducted a retrospective chart review and found that 61% of 20 children on the diet developed a carnitine deficiency. However, only 1 child developed symptomatic carnitine insufficiency (acyl/free ration > 0.4) with increased seizures and lack of energy. Two of the 20 children experienced improved energy and alertness after carnitine supplementation, although free carnitine levels had improved in all of them. Children who received the diet orally appeared to have more abnormalities than those who were fed enterally, perhaps because the formula was fortified. Others who have looked at total carnitine levels find that they stabilize or return to baseline over time and that most children on the diet do not need supplementation(11). Baseline and periodic serum carnitine levels should be evaluated in patients receiving valproate, phenobarbital, phenytoin, or carbamazepine (which may also cause carnitine deficiency) who also are being treated with the ketogenic diet.[26-28] At this time, the significance of this interaction is unknown, and some clinicians contend that the only way to truly monitor carnitine stores is by muscle biopsy(1).

3) Hyperlipidemia: Hyperlipidemia with significant elevations in serum cholesterol, triglycerides, and total lipids may occur. A serum lipid panel should be obtained prior to diet initiation and periodically throughout the treatment(1). A preliminary report suggested that there realy is substantial hyperlipdemia, and if and when the it occurs, adjistment of the diet ratio will bring the lipid levels toward normal. We have not had to stop the diet whom it has been successful in controlling seizures(13).

JAMA. published the study Effect of a High-Fat Ketogenic Diet on Plasma Levels of Lipids, Lipoproteins, and Apolipoproteins in Children at 2003;290:912-920. by
Peter O. Kwiterovich, Jr, MD; Eileen P. G. Vining, MD; Paula Pyzik, BA; Richard Skolasky, Jr, MA; John M. Freeman, MD (8).

A) Their study showed after 6 months of receiving the ketogenic diet, is the marked increase in the apoB-containing lipoproteins, VLDL and LDL cholesterol. But these group was also receiving a number of medications of seizure control. It is possible that these seizure medications may have produced higher baseline VLDL cholesterol and triglyceride levels in theis population, but the mean LDL cholesterol level was similar to that found in reference healthy populations(8).

B) The ketogenic diet also had marked effect on the HDL cholesterol level in this population. At baseline, the distribution of the HDL level was similar to that expected for a pediatric population. After 6 months of ketogenic diet, only about half of the study group had an HDL level in the acceptable range(8).

C) The ratio of total to HDL cholesterol, LDL to HDL, and apoB to apoA-I have been used to assess the relative proportions of the apoB-containing and apoA-I-containing lipoprotein. Higher ratios indicate an increase in the risk of developing coronary artery disease in adults, and of parental history of myocardial infarction. Each of these ratios increased significantly after the ketogenic diet primarily because of the marked increase in the apoB-containing lipoproteins, a conclusion further supported by the significant increase in the non-HDL cholesterol, another indicator of the concentrations of the apoB-containing lipoproteins(8).

Even if the ketogenic diet in this group is inflammatory and atherogenic, this will most likely not preclude its use in intractable seizures in children. Such treatment is highly effective and its use and its anti-epileptic action may persist long after the diet is discontinued. Mosst patients have stopped the ketogenic diet after 2 years and the temporary use in childhood is unlikely to be associated with a long-term increase in risk for coronary artery disease in adulthood. Conversily, prolonged use of a hypercholesterolemic diet throughout childhood and adolescence is likely to be atherogenic(8).

In brief, a high-fat ketogenic diet produced significant increases in the atherogenic apoB-containing lipoproteins and a decrease in the antiatherogenic HDL cholesterol. Further studies are necessary to determine if such a diet adversely effects endothelial vascular function and promotes inflammation and formation of atherosclerotic lesions(8).

4) Affective of growth: Generally, growth has not been affected(1). 41% of parents who responded believed that their children did not grow as well on the diet. Most equated growth with lack of weight gain. Carefull serial measurements indicate that height, in general, increases at a low but normal rate(13). And most children who experienced growth failure showed normalization of growth when the diet was discontinued(11).
Some studies have also begun to examine bone density in children on the ketogenic diet. Using a cross-sectional (rather than longitudinal) design they showed that males on the ketogenic diet for 12-24 months experienced a significantly worse osteopenia than females. This is part of an ongoing prospective study that may clarify observations made in 1979, when Hahn and colleagues reported that children on the diet had a significant reduction in serum 25OHD as well as loss of bone mass, which can be partially reversed by vitamin D treatment. This work will be important to providing optimal care for children who are on the diet for an extended period of time(11).

5) Micronutrient deficiencies: The ketogenic diet is deficient in some micronutrients and may be deficient in carnitine. It is deficient in vitamin B, vitamin C, vitamin D, calcium, magnesium, and iron. Children on the diet receive supplements of these vitamins and minerals. Carnitine supplementation may be helpful for some children but generally is not required(2).

6) Other side effects: Including kidney stones, cardiomyopathy, Steatorrhea, Optic neuropathy, Neutrophil impairment, infections, hepatitis, lipoid pneumonia, and acute pancreatitis. Those all needs to be monitored(1)(2)(11)(13).

Food-Drug Interactions:

When ketogenic diet used with AEDs, needs to pay attention about the food-drug interactions.

A) Acetazolamide should be used with caution in patients receiving the ketogenic diet because severe metabolic acidosis may occur, especially in younger children. If the patient is to remain on acetazolamide, it should be temporarily discontinued prior to diet initiation. The drug may then be restarted cautiously after metabolic adaptation has occurred(1).
B) Phenobarbital serum levels may increase significantly in patients receiving the diet and may cause profound sedation. This is related to the acidotic state induced by the ketogenic diet and the low pKa of phenobarbital, resulting in phenobarbital accumulation in the central nervous system.[28] When the diet is initiated, phenobarbital should be tapered, or the dosage decreased with serum levels monitored(1).
C) Valproate can interfere with ketone production, causing carnitine deficiency and a Reye's-like syndrome.[33] This syndrome can cause lethargy, nausea, vomiting, hepatic failure, and encephalo-pathy. Carnitine levels should be monitored at baseline and periodically if patients are receiving concomitant antiepileptic drugs, especially valproate, or show clinical evidence of carnitine deficiency. L-Carnitine replacement may be warranted in patients with low carnitine levels, although the significance of carnitine depletion is unknown(1).
D) Topiramate (TPM) is widely used as ass-on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, co treatment with TPM and ketogenic diet may be considered, but special attention should be paid to the combines risk for metabolic acidosis and nephrolithiasis. Bicarbonate levels should be monitored carefully and bicarbonate supplements given when symptomatic(9).
E) Ketogenic diets require patients to take vitamin supplemention. Patients and their families need to know which vitamin supplements they can take safely (e.g., no carbohydrate content or the amount of carbohydrate to be calculated into their daily needs). Because this information is not easy to obtain and generally requires contact with the drug manufacturer, pharmacists are instrumental in retrieving this information(1).

Ketogenic Diet Protocol:

There are different protocol of ketogenic diet. The ratio, which refers to the grams of fat to the grams of protein plus carbohydrate, gives the strength of the diet. Thus, a 3:1 ketogenic diet means that the diet contains 3 grams of fat for every gram of protein plus carbohydrate. Since each gram of fat provides 9 calories and each gram of protein and carbohydrate provides 4 calories, 87% of the total calories in a 3:1 ketogenic diet come from fat. In comparison, fat provides 25-40% of the total calories in the typical diet consumed by American children while protein provides 10-20% and carbohydrates provide 40-60%. The ketogenic diet ratio usually ranges from 3:1 to 4.5:1. For the diet to be successful, you and your child must adhere to this ratio strictly, since any deviation may lead to your child coming out of ketosis. If your child is not consistently in ketosis, the diet will likely fail to control the seizures. Thus, the fat, protein, and carbohydrate content of everything your child eats, including medications, must be taken into account. In short, the diet will not work if you child cheats on the diet(2).

In the present time, most medical center use the classical ketogenic diet. They all follow the diet protocol shows below(2)(3)(7)(10)(11)(16):

1) GENERAL RULES FOR THE KETOGENIC DIET

A) Calorie intake should be approximately 75% of the recommended calorie level for a child's age and ideal weight. Level may be higher for an especially active child.
B) Ideal weight should be based on recognized standards.
C) Most children are on a 4:1 ketogenic ratio. Children under 15 months or obese children may be started on a 3:1 or 3.5:1 ratio of FAT:PROTEIN plus CARBOHYDRATES.
D) Liquid intake should be restricted to less than 1X maintenance (approximately 75%). As a rule of thumb, a child should not drink more cc's per day than the number of calories in the diet.
E) Diet must meet protein RDA as calculated by dietitian.
F) Diet must be supplemented daily with calcium, a sugar-free, lactose- free MVI and fluoride if indicated.

2) CALCULATING THE DIET (3)(4)(7)(10):

A) AGE AND WEIGHT AGE____________ WEIGHT_________

B) CALORIES/KG
Use chart for reference in determining the number of calories/kg:
Under 1 yr. 80 Kcal/kg
1-3 yrs. 75 Kcal/kg
4-6 yrs. 68 Kcal/kg
7-10 yrs. 60 Kcal/kg
11 and up 40-50 Kcal/kg or less

C) TOTAL CALORIES
Determine the total number of calories in the diert by multiplying the weight by the calories/kg required.
WEIGHT_________ X CALORIES/KG________ = ____________ total calories

D) DIETARY UNIT COMPOSITION
Dietary units are the building blocks of the ketogenic diet. A 4:1 diet has dietary units made up of 4 grams of fat to each 1 gram of protein plus carbohydrate. Because fat has 9 calories/gram, a dietary unit at a 4:1 ratio has 36 plus 4 = 40 calories. The caloric value and breakdown of dietary units vary with the ketogenic ratio.

Ratio Fat Calories Calories脂肪热量 Totalcarb&protein Diet. unit
2：1 2g x 9 Kcal/g =18 1g x 4 Kcal/g = 4 18 + 4 = 22
3：1 3g x 9 Kcal/g = 27 1g x 4 Kcal/g = 4 27 + 4 = 31
4：1 4g x 9 Kcal = 36 1g x 4 Kcal/g = 4 36 + 4 = 40
5：1 5g x 9 Kcal = 45 1g x 4 Kcal/g = 4 45 + 4 = 49



E) DIETARY UNIT QUANTITY
Divide the total calories allotted (from #3 above), by the number of calories in each dietary step.
total calories___________ divided by _________ calories in dietary unit =___________ dietary units/day

F) FAT ALLOWANCE
Multiply the number of dietary units X units of fat in the prescribed ketogenic ratio to determine grams of fat/day.
____________dietary units X __________ units of fat = _________fat grams/day

G) PROTEIN + CARBOHYDRATE ALLOWANCE
Dietary Units __________ X units of protein + carbohydrate (usually 1)________ = _____________ combined daily protein + carbohydrate allowance.

F) PROTEIN ALLOWANCE:
calculated by dietician; RDA requirement

I) CARBOHYDRATE ALLOWANCE
Carbohydrates are the diet's filler, and are always determined last.
Total carbohydrate + protein allowance__________ - protein allowance _______ = ____________ carbohydrate allowance in grams.

J) MEAL ORDER
Divide the daily fat, protein, and carbohydrate allotments into 3 or 4 equal meals. It is essential that the proper ratio of fat to protein + carbohydrate be maintained at each meal.

K) LIQUIDS
Calculate: standard weight X 60--70 ml = liquids allowance/day (ml)

L) DIETARY SUPPLEMENTS
Every child should take a daily dose of 600 mg of oral calcium in a sugar-free form such as Long's oyster shell calcium (500 mg) and a sugarless MVI with Fe, such as Sugar-free Bugs Bunny Complete with Iron. Sodium fluoride drops if child's water source does not contain fluoride are also necessary.

3) Ideal schedule(3)(4)(9)(10):


DAY 0 (AT HOME)
-Low carbohydrates or sweets
-Child fasts after dinner, except for water

DAY 1 (Admission to Hospital)
-Continue fast, child NEEDS fluids to prevent dehydration!
-PO liquids at 60--70 ml/kg; Water or diet, caffeine-free soda
-Family meets with dietition (order Nutrition consult)
-Baseline LABWORK: serum antiepileptic medication levels (AED), lipoprotein profile, Chem 23 (if not done within last week at clinic)
-Baseline EEG (usually done within last few weeks)
-(IF CHILD IS ON PHENOBARBITAL, THIS WILL NEED TO BE REDUCED, AS LEVELS MAY RISE DURING THE FAST) Other seizue medications are usually decreased as well
-IV start, may heparin lock
-parent to keep seizure diary
-strict Intake/Output (parents to keep diary of intake). Strict I/O EVERY DAY OF HOSPITALIZATION
-check urine for ketones q void -check blood for glucose level (glucoscan) q 4-6 hrs, as ordered
-weight (after void, in early am) and vital signs (q 4 hours); head circumference
-teach family how to check urine for ketones and blood for glucose
-NOTE: CHILD CANNOT TAKE ANY MEDICATIONS, TOOTHPASTE, MOUTHWASH WITH SUGAR OR CARBOHYDRATE IN THEM.

DAY 2
-Child begins to register elevated urine ketones (usually need 4+/large for best results)
-Dietitian calculates meal plans
-Parents begin learning how to plan and prepare diet
-Draw serum AED levels and lytes
-weight and vital signs
-if child needs IV fluids, use a saline solution, NOT a dextrose IV fluid
NURSING CONTINUES TO MONITOR CHILD'S BLOOD FOR GLUCOSE, URINE FOR KETONES

DAY 3
-Child, in ketosis, starts food with 1/3 strength meals
-parents continue with diet education
-AED levels
-weight in am and vital signs q 4 hours
NURSING CONTINUES TO MONITOR CHILD AND TEACH FAMILY HOW TO TEST URINE, BLOOD

DAY 4
-Child progresses to 2/3 strength meals
-education continues
-AED levels
-weight and vital signs
- CONTINUE MONITORING AND EDUCATION

DAY 5
-Child starts full diet, and if child is stable and parents understand diet, child is discharged from hospital
-AED levels
-weight and vital signs

At 1 month (3):

- Neurologist, nurse, dietitian Adjust diet if needed
- Blood chemistry tests, CBC, platelets
- Lipoprotein electrophoresis
- AED level(s) if needed

3, 6, 12 months(3):
- Neurologist, nurse, dietitian
- Blood chemistry tests, CBC, platelets
- Lipoprotein electrophoresis
- AED level(s) if needed

Maintain for 2 years and use abother 1 year to wean out(4):
- 4:1 Ratio--2 years
- 3:1 Ratio--6 months
- 2:1 Ratio--3 months
- Regular Diet

4) HYPOGLYCEMIA CHECKLIST(10):
-Often blood sugar falls to 40 without signs, while at other times child becomes listless or vomits
-If glucose falls to 30 or 40, and child appears well, recheck glucose in 2 hours. If child is stable, no intervention.
-If glucose drops below 30mg %, watch child very closely, give 30 cc of orange juice
-If symptoms of hypoglycemia develop: nausea, weakness, increase in sweating, dizziness, palor or very lethargic/sleepy, give 15-30 cc orange juice and a cup of ice chips. Another 15 cc of juice may be given. Too much juice will prevent ketosis.
-If child has seizures or major changes in LOC, or glucose drops below 25%, obtain order to administer 5% dextrose solution IV

Questions that need to think about:

The ketogenic diet is highly effective in some children, but efficacy rates have varied depending on the study. Results from large prospective multicenter trials using either the classic Hopkins diet or the modified medium chain triglyceride (MCT) oil-diet are listed in Table 1. In general, more recent studies have reported lower rates of seizure control, probably due to better tracking of drop-outs (i.e., intention-to-treat analysis) and longer follow-up periods. Overall, about one-third of children come close to seizure freedom on the ketogenic diet, one third have reductions in seizure frequency, and one third do not respond. In recent prospective, multicenter studies, only 10% actually become seizure-free [Vining 1998; Freeman 1998](16).


Even many studies showed the efficacy of the diet, There are many questions remaining about the practical application of the ketogenic diet.

1) When to initiate? (ie, after how many antiepileptic drug (AED) failures?) How long can it be maintained, or should it be maintained? What are the side effects, and how can we monitor and reduce them? What are the psychosocial effects of the diet on the child and on his or her siblings and family structure?(3)

2) Determining which seizure types respond best to the diet, for example, has been a subject of debate for decades. The early controversy centered on cryptogenic versus idiopathic efficacy [Keith 1963, Livingston 1972]. And more recently, despite some reports of efficacy in both partial and generalized seizures [Schwartz 1989, Freeman 1998] many patient type- for example, those with partial seizures arising from temporal lobe pathology-still appear relatively resistant to the diet’s effects. In fact, patients with partial seizures have been excluded from most studies assessing the clinical efficacy of the ketogenic diet(16).

3) Other remaining points of controversy include the benefits of the classic diet versus the modified MCT oil diet, the potential of vagal nerve stimulation as a therapeutic alternative in these drug refractory patients, the long-term developmental effects of restricted protein and calories, and the effect of age on efficacy. On this last point, note that the diet has historically been considered more effective in infants and children because ketone extraction from periphery to brain is more efficient in the developing brain. The clinical data with the ketogenic diet in the adults is sparse, with approximately half the patients responding with greater than 50 % seizure reduction [Sirven et al., 1999].

4) The potential adverse effects of the ketogenic diet are well known. In recent years, the clinical literature has focused on nephrolithiasis, growth retardation, and the potential for cardiac disease. Some of the acute toxic effects can be serious and careful monitoring is required(16).

5) Because many children with intractable epilepsy are on valproic acid, the special issue of potential exacerbation of drug side effects by the diet becomes another key issue. In particular, because carnitine deficiency is well documented with valproic acid use, supplementation is recommended in documented cases of deficiency (e.g., plasma free carnitine < 20 _mol/L after the first week of life or an esterifed to free ratio of > 0.4)(16).

6) Studies are continuing on the mechanism of the diet. Whether caloric restriction or ketosis is at the heart of the efficacy of the diet. We know that caloric restriction reduces synaptic excitability, increases fast inhibition in the dentate gyrus, and raises the electroconvulsive threshold. However, ketosis may be more important in maximal dentate afterdischarge. Participants queried whether we could possibly use blood glucose levels as a surrogate for BHB, and specifically whether lower blood glucose levels may be directly related to seizure control. One of the suggestions that also evolved from this discussion was whether a protocol should be devised that would look at calorie restriction vs nonrestriction in an otherwise classical ketogenic diet. Certainly in diabetic patients who are both ketotic and hyperglycemic, there is no protection against seizures. It might also be possible to retrospectively look at glucose levels in children who have been on the diet and establish whether there is a relationship to seizure control(11).

7) Levy R & Cooper P reviewed the Cochran Epileopsy Group trials, their conclusions are: “There is no reliable evidence from randomized trails to support the use of ketogenic diets for people with epilepsy. There are large observational studies, some prospective, suggesting an effect on seizures. These effects need validating in randomized control trails. For those with a difficult epilepsy on multiple ant epileptic drugs, we consider the ketogenic diet a possible option.”(6)

References:

(1) Jacquelyn L. Bainbridge, Pharm. D., Barry E. Gidal, Pharm. D., Melody Ryan, Pharm.D. The Ketogenic Diet Pharmacotherapy 19(6):782-786, 1999. 1999Pharmacohterapy Publications
http://www.medscape.com/viewarticle/417997?src=search

(2) Liu Lin Thio. MD. PhD Ketogenic Diet Pediatric Epilepsy Center 2002
http://www.neuro.wustl.edu/epilepsy/pediatric/articleKetogenicDiet.html

(3)Gregory Homes, MD Special Meeting: Controversies In Epilepsy The Ketogenic Diet
http://w3.ouhsc.edu/neuro/division/cope/ketogen.htm

(4) Katherine Chauncey, Ph.D., R.D. The Ketogenic Diet In The Treatment of Pediatric Epilepsy
http://www.ttuhsc.edu/SOM/FamMed/Ketogenic.html

(5)The National Society for Epilepsy
http://www.epilepsynse.org.uk/pages/info/leaflets/keto.cfm

(6) Levy R, Cooper P Ketogenic Diet For Epilepsy (Cochrane Review). The Cochrane Library, Issue 2, 2004. Chichester, UK: John Willey & Sons, Ltd.

(7) John M. Freeman, MD; Millicent T. Kelly, RD, LD.; Jennifer B. Freeman The epilepsy Diet Treatment An Introduction to The Ketogenic Diet 2en Edition, Demos Vermande publiccation

(8) Peter O. Kwiterovich, Jr., MD; Eileen P.G. Vining, MD; Paula Pyzik, BA; Richard Skolasky, Jr, MA; John M. Freeman, MD. Effect of a High-Fat Ketogenic Diet on Plasma Levels of Lipids, Lipoproteins, and Apolipoproteins In Children JAMA, August 20, 2003 ---Vol 290, No. 7 Page 912-920
http://jama.ama-assn.org/cgi/content/abstract/290/7/912?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=ketogenic+diet&searchid=1091994361646_1711&stored_search=&FIRSTINDEX=0&journalcode=jama

(9) Masanori Takeoka; James J. Riviello, Jr; Heidi Pfeifer, and Elizabeth A. Thiele Concomitant Treatment with Topiramate and Ketogenic Diet In Pediatric Epilepsy Epilepsia 43(9):1072-1075, 2002 Blackwell Publishing, Inc. International League Against Epilepsy

(10) Packard Children's Hospital Stanford University Medical Center Ketogenic Diet at Packard Children's Hospital @ Stanford
http://www.stanford.edu/group/ketodiet/download.html

（11）Eileen P.G. Vining, MD The Ketogenic Diet Medscape
http://www.medscape.com/viewarticle/450346?src=search

(12) Dana L. Rowett Ketogenic Diet for Epilepsy WebMD Health


(13) Cheryl Hemingway, MB ChB; John M. Freeman, MD; Diana J. Pillas, BA; and Paula L. Pyzik, BA Pediatrics Vol. 108 No. 4 October 2001 Page 898-905The Ketogenic Diet: A 3- to 6- year follow-up of 150 Childresn enrolled prospectively

(14) Len Leshin, MD Ketogenic Diet for Epilepsy
http://www.quackwatch.org/04ConsumerEducation/QA/keto.html

(15)R Schwartz MD The Ketogenic Diet STURGE WEBER Foundation UK
http://www.sturgeweber.org.uk/ketogenicdiet.htm

(16) Jong M. Rho, MD The Ketogenic Diet In Pediatric Epilepsy Ketogenic Diet Overciew
http://www.charliefoundation.org/noframes/diet/overview.php

(17) The Ketogenic Diet
http://www.epipro.com/k_diet.html

(18) Landover, MD Ketogenic diet The Epilepsy Foundation
http://www.epilepsyfoundation.org/answerplace/Medical/treatment/diet/index.cfm