Cyclical Ketogenic Diets Review

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Carbohydrates Bound To Lipids And To Proteins

Figure 7 Diagrammatic representation of the fluid mosaic model of the cell membrane. The basic structure of the membrane is that of a lipid bilayer in which the lipid portion (long tails) points inward and the polar portion (round head) points outward. The membrane is penetrated by transmembrane (or integral) proteins. Attached to the surface of the membrane are peripheral proteins (inner surface) and carbohydrates that bind to lipid and protein molecules (outer surface). Source Modified from Ref. 13.

Planning for Ketogenic Diet Therapy

The decision to use the ketogenic diet is based on the appropriateness of this therapy to the patient's medical condition, the willingness and ability of the patient to comply with the diet, and the availability of a ketogenic diet program. When managed successfully, the ketogenic diet can provide seizure control and even seizure freedom to individuals with difficult-to-control seizures. The ketogenic diet can also provide cost savings in the overall medical budget of the family of a child who has epilepsy (1).

Calculating The Ketogenic Diet Prescription

Calculating the ketogenic diet requires the consideration of many factors. It is important to individualize the calculations to the needs of the candidate and to use outcome data such as growth parameters, level of ketosis, seizure control, and nutritional needs to fine-tune the calculations later during therapy. The hand calculations described in the section that follow are based on the traditional long-chain triglyceride ketogenic diet. Computerized diet programs are available and can save time and ensure the accuracy of diet calculations. Ketocalculator is one example.

Incorporating Creativity into Ketogenic Diet Meals

Several ketogenic meals should be calculated for each child initially to provide variety. A protein-rich food paired with a fruit or vegetable provides the foundation of the ketogenic meal. Cream, butter, margarine, vegetable oils, and mayonnaise complete the requirement for fat. For variations of the ketogenic meals, families can incorporate combinations of protein-rich foods such as bacon and eggs or small amounts of low-carbohydrate food items such as avocado, nuts, sugar-free gelatin, and cheese.

Supplementing The Ketogenic Diet Vitamins Minerals And Essential Fatty Acids

The ketogenic diet is deficient in several vitamins and minerals owing to its high fat component and consequently low volume of carbohydrate- and protein-rich foods. The restriction of these foods limits the intake of many vitamins and minerals particularly B vitamins, vitamin D, calcium, phosphorus, potassium, iron, selenium, magnesium, and zinc (7,8). A computerized nutrient analysis of an individual's ketogenic diet selections over an extended period is helpful to identify the actual micronutrients absent from the diet. Vitamin and mineral supplementation is essential for all ketogenic diet candidates in efforts to provide optimal nutrition and to prevent micronutrient deficiencies. Supplements should be in sugar-free form. The Recommended Dietary Intakes published by the Food and Nutrition Board (2002) provide a guide for daily level of intakes of vitamins, minerals, and trace minerals based on age (5). A typical supplementation profile for a child on the oral ketogenic diet...

Initiation Of The Ketogenic Diet

During the initiation of the diet, the child is at risk for hypoglycemia, dehydration, acidosis, and antiepileptic drug toxicity. Therefore, initiation is recommended in a hospital setting under the guidance of the ketogenic diet team. Initiation of the diet has been managed in the home setting when 24-h nursing care is present. Methods of keto-genic diet initiation vary among medical centers, from fasting prior to initiating the diet to initiating the diet without any fasting period at all. Initiating the diet gradually (with or without a fast) is the usual practice among medical centers.

Initiating the Infant or Enteral Ketogenic Diet

Children with enteral feeding tubes and bottle-fed infants can be safely acclimated to the ketogenic diet with a gradual transition from the home formula to the ketogenic diet formula by combining the two formulas in a systematic fashion. Two-thirds of the home formula can be mixed with one-third of the ketogenic formula for the first day of the diet initiation, then gradually increased by thirds each day while reducing the home formula by equal volume, until the third day, when full ketogenic formula is reached. This

Ketogenic Diet Therapy Followup Program

Management of the ketogenic diet is best achieved through phone calls and regularly scheduled follow-up appointments with the ketogenic diet team. Phone calls at least weekly with the dietitian during the early weeks of this therapy are vital to the success of this therapy. A 1-mo visit after ketogenic diet initiation followed by a visit every 3 mo is commonly practiced. At each visit the child's seizures, growth, and neurological and nutritional status are evaluated. The initial laboratory studies are repeated at each visit to monitor metabolic responses. Caregivers are asked to keep a journal of seizure activity and ketone readings to facilitate objective decisions regarding therapy adjustments.

Early Studies Of Ketogenic Diet Efficacy

Wilder of the Mayo Clinic proposed manipulating the ratio of dietary fat to proteins plus carbohydrates in a variety of ratios from 2 1 to 3 1 as a method of creating ongoing ketonemia that could mimic the metabolic effects provided by lengthy starvation and dehydration (6).

Ketogenic Diet In Adults

The next systematic report regarding the KD in adults did not appear until 1999. Results were presented for 11 patients with refractory seizures treated with the KD at Thomas Jefferson University Hospital in Philadelphia (14). These individuals were placed on a 4 1 ketogenic diet (4 g of fat to 1 g of combined protein and carbohydrate) at a daily caloric intake designed for each patient's ideal body weight. Fluids were restricted to the milliliter equivalent of the caloric intake e.g., a patient on a 2000-calorie diet was allowed 2000 mL of fluids. Vitamin and mineral supplements were also prescribed. Fig. 1. Differential response of epilepsy type to ketogenic diet. The generalized epilepsies appeared to respond more favorably than the localization-related epilepsies. SZ, seizure IGE, idiopathic generalized epilepsy SGE, symptomatic generalized epilepsy. Although most patients had fewer seizures, few followed the ketogenic diet for 2 yr. The mean length of time that patients stayed on...

Is There a True Dietary Reference Intake for Carbohydrates

The amount of dietary carbohydrate needed for optimal health in humans is unknown. In the few older studies of populations that consume low-carbohydrate and high-fat and high-protein diets for their lifetime (the Masai, Greenland natives, Inuits, and indigenous people of the South American Pampas), there were no apparent effects on health or longevity (67,68). The new dietary reference intake (DRI) for carbohydrates is set at 130 g d for adults and children (69). This amount was based on the average minimum amount of glucose utilized by the brain. The average American eats two to three times this amount of carbohydrate daily. The typical KD consists of 80-90 calories from fat, protein prescribed at recommended daily allowance (RDA, if possible), and the remaining calories as carbohydrates. The total carbohydrate content per day in the KD is often under 10 g (much more restrictive than the popular Atkins diet, which tries to keep the carbohydrate content under 40 g) (70). The KD...

Ketosis And The Ketogenic Diet In Epilepsy

The approaches described thus far to study ketosis can be informative in studying the ketogenic diet. Although there are not many MR spectroscopic studies of patients on the ketogenic diet, those few reports have presented provocative data. Given the earlier animal model data suggesting enhanced bioenergetic reserve with the ketogenic diet (23), the initial ketogenic diet study from Pan et al. (24) focused on an evaluation of the brain bioenergetic status with initiation of the diet. This study used high-field (4-tesla) 31P-MR spectroscopic imaging to evaluate bioenergetic changes in a small group of patients (all younger than 13 yr), studied before initiation of the diet and after one month on the diet. Spectral data from this study are shown in Fig. 3, acquired from two children (both diagnosed with Lennox-Gastaut syndrome) who were treated with the diet. As seen in Fig. 3, there is an increase in the PCr ATP and PCr Pj ratios that is particularly notable in the patient who did well...

Carbohydrates Energy for Living Organisms

Carbohydrates are so-called because these molecules are made up of carbon atoms (carbo) bonded to groups of oxygen and hydrogen atoms, called hydroxide groups (hydrate). Carbohydrates are a major energy source for living organisms. They also have a structural role. For example, the cell walls in plants and wood are both made of a carbohydrate called cellulose. In fact, most of the weight of plants comes from a carbohydrate of one kind or another. Depending on their structure, they are grouped in families. The simplest sugars, such as glucose, are called monosaccharides. Molecules made up of two monosaccharides bonded together are called disaccharides. The word saccharide comes from the Latin saccharum, meaning sugar. Molecules made up of more than two monosaccarides are called polysaccharides. Sugars are very soluble in water, as seen when adding a spoonful to a cup of tea. Glucose, the most important monosaccharide, has the molecular formula C6H12O6 Most carbohydrates in food are...

Ketogenic Diet And Amino Acid Transport

A highly ordered array of amino acid transporters mediate the exchange of glutamate, glutamine, and related compounds between neurons, astrocytes, and capillaries (82). It is likely that the ketogenic diet, which, as we have seen, induces fundamental alterations in the metabolism of brain amino acids, and also changes the function of these tissue-specific amino acid transport systems. We cannot know a priori that these presumed adaptations will give rise to an anticonvulsant effect, although the accepted clinical efficacy of the ketogenic diet affords a rationale for future experimentation to test the hypothesis that ketosis-induced changes in the function of amino acid transporters enable the ability of the brain to contain seizures by favoring novel mechanisms for the removal of glutamic acid.

Fasting And The Ketogenic Diet

Although clinically effective, fasting is impractical for the long-term management of seizures. Consequently, the high-fat, low-carbohydrate ketogenic diet (KD) was developed to mimic the physiological effects of fasting, i.e., resulting in ketosis, without severe food restriction or starvation (16,21-23). The KD is effective in managing intractable seizures in children and may also be effective in managing seizures in adults (17,24-26). The KD is also effective in reducing epileptogenesis and seizures in animal models of epilepsy (27,28). The mechanisms by which the KD inhibits seizure susceptibility remain speculative however, alterations in brain energy metabolism are likely involved (11,29,30).

What We Know About the Anticonvulsant Mechanism of the Ketogenic Diet

From other chapters in this volume, it is apparent that our understanding of the mechanism of action of the ketogenic diet (KD) is limited. Nevertheless, we do know that the KD is an excellent antiepileptic treatment for many children who are refractory to conventional antiepileptic medications. The KD has been shown to be therapeutically effective for a large variety of epilepsies including myoclonic seizures, infantile spasms, and partial and generalized seizures (1,2).

Freeman Ketogenic Diet

The Ketogenic Diet A Treatment for Epilepsy, 3rd ed. Demos, New York, 2000. 5. Schwartz RM, Eaton J, Bower BD, Aynsley-Green A. Ketogenic diets in the treatment of epilepsy short-term clinical effects. Dev Med Child Neurol 1989 31 145-151. 15. Likhodii SS, Musa K, Cunnane SC. Breath acetone as a measure of systemic ketosis assessed in a rat model of the ketogenic diet. Clin Chem 2002 48 115-120. 16. Musa-Veloso K, Rarama E, Comeau F, Curtis R, Cunnane S. Epilepsy and the ketogenic diet assessment of ketosis in children using breath acetone. Pediatr Res 2002 52 443-448. 20. Huttenlocher, PR. Ketonemia and seizures metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr Res 1976 10 536-540. 21. Seymour KJ, Bluml S, Sutherling J, Sutherling W, Ross BD. Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet. MAGMA 1999 8 33-42. 22. Bridge EM, Iob LV. The mechanism of the...

Pre Ketogenic Diet Session

The rigors of ketogenic diet management should be discussed during the pre-keto-genic diet session. The process of food preparation and food weighing should be explained. The caregiver should be provided with the information for purchasing a scale that weighs in tenths of a gram (0.1 g). A description of the typical meals and beverages, and the requirement for the omission of carbohydrate-rich foods, should be clearly communicated. The caregiver should be informed about the appropriate foods and nutritional supplements that must accompany the diet. The follow-up appointments required to monitor the diet safely should be reviewed. The caregiver should understand the possible adverse effects of the diet, including constipation, kidney stones, and difficulty with compliance (particularly with older children). The expected length of keto-genic diet therapy should also be reviewed in this session. Eating is an activity that is highly celebrated in our society with every holiday and major...

Ketogenic Diet in the 1990s

Jim Abrahams Epilepsy

Use of the ketogenic diet decreased greatly until it received national media attention in October 1994, when NBC-TV's Dateline aired a program on the treatment (7,8,42,63-66). This television program was based on the true story of Charlie, a 2-yr-old with intractable myoclonic, generalized tonic, and tonic-clonic seizures (Fig. 4). A videotape presentation made later summarizes Charlie's condition in 1994 Thousands Fig. 4. Charlie Abrahams, age 4, with his parents Jim and Nancy, as they appeared in 1997 in a story on Charlie and the ketogenic diet published in the New York Times (Reproduced with permission from Bart Bartholomew.) Fig. 4. Charlie Abrahams, age 4, with his parents Jim and Nancy, as they appeared in 1997 in a story on Charlie and the ketogenic diet published in the New York Times (Reproduced with permission from Bart Bartholomew.) While researching treatments for epilepsy on his own, Charlie's father found a reference to the ketogenic diet and Johns Hopkins (67). Charlie...

Fasting A Precursor To The Ketogenic Diet

Hugh Conklin

It was not until the early twentieth century that medical use of the ketogenic diet emerged as a strategy to mimic the biochemical effects of fasting (or starvation) (Fig. 2). Guelpa and Marie, both French physicians, authored the first scientific report on the value of fasting in epilepsy (6). They reported that seizures were less severe during treatment, but no details were given. In the United States, contemporary accounts of fasting were also recorded early in the twentieth century (Table 1) the first was a report on a patient of an osteopathic physician, Dr. Hugh W. Conklin, of Battle Creek, Michigan, and the second concerned Bernarr Macfadden (7,8). Macfadden was a physical fitness guru cultist and publishing genius of the early part of the 20th century (9). He called the medical profession an organized fraud and said that people who followed his rules could live to age 120. At age 31 (in 1899), he established his first magazine, Phys- From Epilepsy and the Ketogenic Diet Edited...

Oxidative Damage to Carbohydrates

The endogenous Maillard reaction, that is, the formation of Maillard reaction products in vivo, commonly known as the glycation reaction, is recognized today as one of many non-enzymatic modifications of proteins that not only contribute to the aging of the body's proteins, but may also have an important regulatory role in both physiological responses and pathological processes 118 . A major outcome of the studies on glycation was the recognition that oxidative reactions, and by inference, oxidative stress and ROS, catalyze the chemical modification of proteins by Maillard reactions in vivo. Reactive carbonyl species formed upon oxidation of carbohydrates, as well as lipids and amino acids were identified as intermediates in the formation of irreversible, advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) acting on proteins (see Box 10.4). In addition to the multiplicity of AGE structures, it is now acknowledged that there are multiple pathways...

Fine Tuning the Ketogenic Diet

The goal of ketogenic diet therapy is to find and maintain a state of ketosis that serves to abate seizures. After a few weeks of ketogenic diet therapy, a defining pattern of ketosis will emerge. Ketosis is monitored at home by the caregiver with a urine ketone testing kit. Ketosis is usually lower in the morning and higher in the afternoon and evening. Urine ketone levels are a crude estimate of serum ketone levels and can be sufficient for determining level of ketosis on a daily basis. P-Hydroxybutryate is the serum ketone that is thought to impact seizure control and can be measured quantitatively by blood analysis. A P-hydroxybutryate level may be helpful when attempts to fine-tune the diet by means of urine ketone levels are inadequate. Diet manipulation can alter ketosis and effect seizure control. Several factors should be considered before deciding how to adjust the ketogenic diet. The initial goal is to ensure that 100 of the ketogenic diet is being consumed. This may take a...

The Ketogenic Diet Induction of Ketosis

The history of the ketogenic diet began with the realization that the metabolic changes induced by starvation not the alleviation of intoxication could result in seizure control (3). This innovative hypothesis led Wilder in 1921, to propose a high-fat, low-carbohydrate diet that came to be known as the ketogenic diet (3). The keto-genic diet induced metabolic changes similar to those caused by fasting, and it was equally effective at suppressing epileptic seizures (4). Ketosis, i.e., the systemic elevation of the three ketone bodies, P-hydroxybutyrate, acetoacetate, and acetone is central to the metabolic changes induced by the diet (see Fig. 1). The ketosis induced by fasting, and mimicked by the ketogenic diet, is a critical adaptative mechanism for the brain. The human brain contributes only about 2 of the body's total weight, yet its energy requirements are disproportionately high approx 20 of the body's total energy needs at rest (5). During fasting (in the absence of glucose),...

Initiating the Oral Ketogenic Diet

The process of initiating the diet gradually is usually achieved by providing one-third of the ketogenic diet (calories) on the first day, two-thirds of the ketogenic diet on the second day, and the full ketogenic diet on the third and subsequent days. The deprivation of calories incurred by this stepwise increment in calories stimulates hunger and encourages the child to consume all the diet. Ketogenic eggnog, a combination of heavy cream and pasteurized raw eggs, is often used for the first 2 d of this method because it is a ketogenically balanced liquid that is easily prepared and accepted favorably by most children. It can be sweetened with saccharine to the child's liking and flavored with vanilla extract and consumed in small portions throughout the day. For variation, the eggnog can be cooked to a custard consistency or frozen like ice cream.

Early Efficacy of the Ketogenic Diet

In the 1920s and 1930s, initial reports documented the efficacy of the ketogenic diet (Table 2) (14,29,70-78). These were all retrospective reports. Some included a small number of patients and provided few clinical details or specifications of epilepsy syndrome or seizure type. The studies clearly showed some patients had improved seizure control on the ketogenic diet. Over the next 60-70 yr, many more clinical reports appeared on the ketogenic diet (Tables 2 and 3) (79). Meta-analysis of the published data is not possible, given differences in study design and sparse clinical detail additionally, it is often not clear what is meant by good or partial response to the ketogenic diet. Despite these limitations from older studies, however, the literature supports the consensus view that the ketogenic diet improves seizure control in some children. Overall, one-third to one-half of children have an excellent response to the ketogenic diet, defined by marked cessation of seizures or...

Lipids carbohydrates

Lipids form membranes inside and around the cell. Carbohydrates form complex tree-like molecules that become attached to the surface of proteins and cellular membranes. In both cases, the three-dimensional molecular structure is not unique, but the molecular assemblies are highly flexible. Thus, analyzing the molecular structure involves the inspection of a process in time. Molecular dynamics is the only available computer-based method for doing so. Compared with protein structures there are relatively few results on lipids and carbohydrates. The book does not detail this topic.

Ketogenic Diet Steps

Enclose with the forms a brief letter on why you are interested in the ketogenic diet for you or your child along with a small picture. 3. Watch the Charlie Foundation's Introduction to the Ketogenic Diet if you have not already done so. You may get a copy of this tape by sending 10.00 to 4. You will need to purchase a book titled THE KETOGENIC DIET, third edition, by John M. Freeman, MD, Jennifer B. Freeman, Millicent T. Kelly, RD, LD. To do so call Demos Vermande at 1-800-532-8663. It is important that you thoroughly read through this book. 7. After the steps above have been completed, we would like you to speak with one of our ketogenic diet coaches. Please make a list of questions or concerns you might have before calling them. We will put you in contact with a parent or patient who is well informed about the diet and can help answer some of your questions.

Carbohydrates

Carbohydrates are the primary fuel for our muscles and the brain. Eating a high carbohydrate diet will ensure maintenance of muscle and liver glyco-gen (storage forms of carbohydrate), improve performance and delay fatigue. The word carbohydrate means 'hydrate of carbon'. Thus, carbohydrates are a group of polyhydroxy aldehydes, ketones or acids or their derivatives, together with linear and cyclic polyols. Most of these compounds are in the form CnH2nOn or Cn(H2O)n, for example glucose, C6H12O6 or C6(H2O)6. Sometimes, carbohydrates are referred to simply as sugars and their derivatives. Carbohydrates are found abundantly in nature, both in plants and animals, and are essential constituents of all living matter. Photosynthesis is the means by which plants produce sugars from CO2 and water.

The Ketogenic Diet

Throughout Charlie's epilepsy, I remember crying hardest with Nancy when we received the copy of the report that begins this afterword. It seemed so hopeless. And yes, we were fully aware of the ramifications of Charlie's diagnosis. So, as a way to prepare Charlie and the rest of us for what seemed to be many more years of seizures, drugs, and progressive retardation, I started doing some research. To my surprise, in epilepsy texts dating back to the 1920s (and in every decade from the 1920s through the present) from Hopkins, the Mayo Clinic, and many other highly regarded institutions, there was consistent anecdotal documentation regarding the ketogenic diet and its efficacy (roughly one-third of the kids who tried it became seizure free, one-third were significantly improved, and for one third it was ineffective). The documentation covered

Series Editors Introduction

Epilepsy and the Ketogenic Diet, edited by Carl E. Stafstrom and Jong M. Rho is a unique addition to the Nutrition and Health Series and fully exemplifies the potential for this Series to include clinically relevant texts that are valuable to practitioners as well as cutting-edge researchers. Moreover, this text fills a critical gap because at present, there is no work that addresses both the clinical and basic aspects of the ketogenic diet (KD) in a comprehensive, up-to-date manner. The volume includes a detailed description of the KD, which is a high-fat, low-carbohydrate, adequate-protein diet that has been used for more than 80 years for the treatment of medically intractable epilepsy. Initiation of the diet has consistently resulted in effective seizure control in a high proportion of both children and adults when patients' seizures fail to be controlled by standard anticonvulsant drugs. The diet is now an indispensable part of the armamentarium of epilepsy treatments however,...

Prediet Referral And Evaluation

Studies to Obtain Prior to Ketogenic Diet Initiation Many of our patients come from great distances, and we will communicate with their local physician about the diet, the medications that may be used, and the partnership we hope to establish. If families are coming to Hopkins for initiation of the diet, we request that they read our book, The Ketogenic Diet A Treatment for Epilepsy, and that if possible they view the video made by the Charlie Foundation (14,15). Our dietician will contact them by phone prior to admission to assess the child's usual dietary intake, food preferences, and weight and height. Because most of our patients are referred from other centers, one of our major tasks is to ensure the validity of their histories and the completeness of prior evaluations. The laboratory studies we either obtain, or ensure that they were done accurately elsewhere, are listed in Table 1. The condition of children with underlying metabolic disorders or certain mitochondrial syndromes...

Calculating the Protein

The ketogenic diet calculations should allow sufficient protein for normal growth and tissue turnover. The Dietary Reference Intakes (DRIs) provide protein goals based on age and weight as shown in Table 3. For example, A 7-yr-old child weighing 23 kg requires 22 g protein daily It is important to consider that limited energy intake may cause some of the dietary protein to be used for energy. Careful monitoring of growth and protein status (albumin and prealbumin) during ketogenic diet therapy will provide guidance in modifying the diet to preserve endogenous protein.

Tapering the Diet After Successful Therapy

Tapering of the ketogenic diet should occur after 1-2 yr of successful seizure control. Reduction in the ratio is used to gradually reduce ketosis and taper off the diet. Ketone levels should be checked after each reduction in the ketogenic diet ratio. Children usually remain on the 4 1 ratio (or the ratio that has enabled them to produce large ketones consistently) for up to 2 yr. The ratio can be gradually tapered to 3 1 for 6 mo then 2 1 for another 6 mo. Carbohydrate can be gradually added to the diet in the form of bread, pasta, rice, cereal, crackers, and dairy products to eliminate the remaining ketosis. Milk may not be tolerated initially because after a long period on the ketogenic diet, there may be no lactase stimulation in the gut.

Developing Protocols for Office and Hospital

First and foremost, we expect the family to obtain and read Dr. John Freeman's book, The Ketogenic Diet A Treatment for Epilepsy (2). We feel that it is crucial for the family to take the initiative to locate and purchase the book themselves, to demonstrate their willingness to become involved in the KD process. Because so much training and energy is devoted to KD patients, we want to ensure parental commitment. When we receive the completed packet, the child goes on our start list. It is the parents' responsibility to follow the steps and have the checklist completed before KD training begins (see Appendix 1 of this chapter).

Training of Emergency Room Staff School Personnel Physicians and Social Workers

Should be avoided unless absolutely necessary. Elixirs of common medications should be avoided because of their high carbohydrate content. Most important, emergency personnel must understand that in an emergency situation, maintaining the diet becomes secondary to the child's urgent health needs. The parents must also understand this priority.

Medications and the KD

There are no absolute contraindications to using a medication while a child is treated with the KD (see Appendix A). Children on the KD will have the normal myriad childhood diseases (otitis media, strep throat, etc.), which will require treatment with antibiotics and other medicines. However, the need for absolute control over the daily carbohydrate intake to maintain maximal ketosis makes these outside drugs the KD team's nightmare. The US Food and Drug Administration does not require the pharmaceutical industry to reveal the content of carbohydrates used as fillers in their medications. In addition, the composition of these fillers is frequently changed. The success of any KD program, therefore, depends on support from pharmacists and their ability to obtain reliable information about carbohydrate contents from pharmaceutical manufac turers. In general, suspensions are avoided because they are mixed with large amounts (grams per milliliter) of carbohydrates, but even capsules and...

Ketone Body Consumption With Glucose and Transport in Human Brain

How does the brain make use of glucose relative to available ketones Using fluo-rodeoxyglucose (FDG)-PET imaging, Redies et al. (14) demonstrated in obese subjects undergoing an extended fast (3 wk) that cerebral glucose use decreased to 54 of the unfasted baseline, seen over the entire brain. Haymond et al. (15) used deuterated glucose infusions in fasted normal children and adults, and in epileptic children on the ketogenic diet, to find an inverse relationship between estimated brain glucose consumption and plasma ketone body concentration. By correcting for brain mass differences between children and adults, the investigators were able to eliminate much of the data's variability, allowing detection of the inverse relationship. Nonetheless, the stoi-chiometry of the relationship between glucose and ketone utilization remains difficult to estimate. Using an acute hyperketonemic protocol, Hasselbalch et al. (16) reported that at 2mM plasma levels of ketones, whole-brain glucose use...

Risks For Obesity Diabetes And Cardiovascular Disease 41 Obesity

Obesity is a major public health problem in the United States, with an increasing prevalence in both adults (37,38) and children (39). Obesity increases the risk of morbidity and mortality from associated diseases such as diabetes, hypertension, coronary heart disease, and cancer (40-42). Diets have been the traditional approach to dealing with excessive weight. Robert Atkins (43) popularized the use of the ketogenic diet to deal with weight gain. This type of ketogenic diet is a low-carbohydrate but high-protein formulation and consequently is fundamentally different from diets used for seizure control. The Atkins diet is based on the premise that control of insulin is essential for weight loss and associated beneficial effects in reduction of diabetes and cardiovascular risk. By reducing carbohydrate intake to a negligible level, the diet attempts to eliminate insulin fluctuations that might occur after a typical meal. It is important to note that while this diet does not limit...

Effect Of The Kd On Brain Metabolism As Measured In Animals

Scientific studies of the KD have revealed important biochemical and metabolic observations. Appleton and De Vivo developed an animal model to permit study of the effect of the KD on cerebral metabolism (9). Adult male albino rats were placed on either a high-fat diet containing (by weight) 38 corn oil, 38 lard, 11 vitamin-free casein, 6.8 glucose, 4 US Pharmacopeia (USP) salt mixture, and 2.2 vitamin diet fortification mixture, or a high-carbohydrate diet containing (by weight) 50 glucose, 28.8 vitamin-free casein, 7.5 corn oil, 7.5 lard, 4 USP salt mixture, and 2.2 vitamin diet fortification mixture. Parallel studies were conducted to evaluate electroconvulsive shock responses and biochemical alterations. These studies revealed that the mean voltage necessary to produce a minimal convulsion remained constant for 12 d before the high-fat diet was started and for about 10 d after beginning the feedings (69.75 1.88 V). After 10-12 d on the high-fat diet, the intensity of the convulsive...

Glycolysis and Glucose Flux Are Reduced During Ketosis

As Wilder originally postulated, the effects of eating a high-fat, low-carbohydrate diet are similar to the biochemical consequences of starvation (11). In this regard, the reduction in glycolysis makes physiologic sense, since the starving organism would want to make every attempt to preserve the rather meager stores of glycogen and to provide the brain with an alternate, more substantial fuel for metabolism, i.e., ketone bodies from fats. Measurements of glucose flux in children and adults during ketosis have confirmed the reduced utilization of glucose. Haymond et al. used tagged glucose to perform sequential glucose flux studies in 11 children (5 control, 6 with epilepsy) and 10 adult volunteers (12). All subjects were studied after a fast while consuming either a normal diet or the KD. The authors found that glucose flux and ketonemia were inversely related, particularly when corrected for estimated brain mass. This was consistent with the replacement of glucose by ketone bodies...

Possible Relationship Of Metabolic Changes To Anticonvulsant Effect

Previous investigators have speculated that the ketogenic diet improves overall brain metabolism and that this might be the basis for the antiepileptic effect. Certainly the diet appears to favorably influence energy charge of the brain in selected groups of subjects (65,66). An outstanding issue is whether the improvement in overall energy metabolism is the cause or the consequence of reduced seizure frequency. It also has been postulated that the diet imposes a mild cerebral acidosis that diminishes the responsiveness of brain NMDA receptors, although efforts to document an accumulation of brain H+ have yielded a negative result (67,68). By lowering the rate of transamination of glutamate to aspartate, the ketogenic diet would attenuate the production of the latter excitatory neurotransmitter. Relatively more glutamate then would be available for conversion to GABA, thereby abetting an anticonvulsant effect, and for the production of glutamine, which is an effective GABA precursor.

Metabolic Fuel Adaptation

The sugar glucose is an essential blood fuel for all the cells in the body (1). It is derived from the breakdown of carbohydrate provided by the typical low-fat high-carbohydrate diet. Although glucose is the major cellular fuel, many cell types can also use alternative fuels such as fatty acids (derived from dietary fats and body fat stores), ketone bodies (derived from fatty acid breakdown by the liver), and amino acids (derived from dietary protein and muscle protein stores) (1). The brain can use such alternative fuels for part of its energy requirements however, unlike liver, it has an absolute requirement for a continuous supply of blood glucose fuel. The liver is the major organ responsible for the maintenance of stable blood glucose concentrations under differing dietary conditions. At the cellular level, hepatocytes can detect and flexibly respond to changes in blood fuel concentrations resulting from alterations in the quality or quantity of the diet (1). Diet quantity...

Anticonvulsant Effects of PHydroxybutyrate and Acetoacetate

The recent rebirth of clinical interest in the ketogenic diet has led to a renewed interest in its mechanism(s) of action. Recently, the effects of both P-hydroxybutyrate and acetoacetate have been studied in rat hippocampal slices. Neither compound was found to alter excitatory or inhibitory synaptic transmission (45).

Anticonvulsant Effects of Acetone

As noted earlier, Keith (1931) was the first to provide experimental evidence of acetone's anticonvulsant activity, utilizing the chemical convulsant thujone (40). In 1947 Driver showed that acetone increased the threshold for electrically induced seizures in rats (37). A subsequent series of studies showed that acetone was also effective in suppressing repeated maximal seizures produced by the powerful chemical convulsant semicarbazide (48,49,52). It was noted in these studies that acetone was more efficacious than phenytoin or pentobarbital (48). Later, acetone was shown to provide protection against the convulsions induced by isonicotinic acid and electroshock (50). In a recent series of neurotoxicity studies related to the volatile solvents, short-term inhalation of acetone vapors suppressed both audiogenic (53) and electrically induced seizures in rats (54,55). Given such reports of acetone's anticonvulsant effects, it is surprising that it has received little attention in...

Role of Ketonemia 331 PHydroxybutyrate

Regrettably, the investigators did not test seizure susceptibility. Harney et al. (43) found that blockade with mercaptoacetate, an inhibitor of fatty acid oxidation, lowered ketone-mia and shortened latency to threshold PTZ-induced seizures but reported no correlation between latency and BHB levels. Ketone bodies do not appear to have direct effects on synaptic transmission in the hippocampus, at least when applied acutely in tissue taken from rats not fed a KD (44). Cullingford et al. (45) have shown that the gene for a key ketogenic synthetic enzyme, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, is upregulated in both liver and brain in rats fed a KD. The same gene is downregulated in suckling rats weaned to a low-fat, high-carbohydrate diet (46). BHB uptake by the rat brain is proportional to the arterial blood concentration, and all BHB entering the brain is metabolized (47). Sokoloff (48) observed that when BHB completely replaced glucose in the medium used to perfuse a...

What Might the Ability of the KD to Block Seizures Tell Us

From a very broad perspective, acute studies of the KD show that excitability and synchrony, key features of seizures and epilepsy in the CNS, are markedly dependent on the quantity (ad libitum calorie restricted) and quality (chow, high fat, high carbohydrate) of the substrate that is being used to support metabolism. As Lack (93) indicated decades ago, food is one of the major factors limiting mammalian populations. Yet, humans living in developed countries and experimental animals living in regulated animal care facilities have unlimited access to food and balanced diets. Indeed, it is often necessary to justify NOT feeding laboratory animals ad libitum, despite recognition of the value of food restriction by National Institutes of Health Guidelines (see ref. 94). Caloric restriction and intermittent dependence on bodily stores of carbohydrates and fats are nearer the norm for animals in the wild and for many populations, and these were most likely the conditions our ancestors...

The Relationship Of The Kd And Caloric Restriction In Seizure Management

The KD is most effective in reducing seizure susceptibility in children when administered with fasting or under restricted caloric intake (17,77). Livingston also reported that KD efficacy was associated with body weight reductions of approx 10 and reduced blood glucose levels (78). Our findings in EL mice on the CR diet are consistent with these findings in humans. It is interesting that the anticonvulsant effects of the KD are usually lost in patients who experience a rise in blood glucose levels, i.e., in those who gain weight on the diet or consume carbohydrates (16,17,21). Based on our studies with EL mice, we suggest that the seizure-protective effects of the KD are largely dependent on the maintenance of reduced blood glucose and body weight. We suggest that the KD suppresses seizure susceptibility largely through CR.

Effects of a KD in the Kainic Acid Model

The seemingly conflicting results of the aforementioned studies may be explained in part by the timing of ketogenic diet initiation. Muller-Schwarze et al. (22) initiated the KD after spontaneous recurrent seizures had manifested, whereas Bough et al. (23) administered the KD prior to induction of acute seizures with kainic acid. In the case of KD treatment prior to kainic acid exposure in immature rats (24), there may be developmental differences as well. It could be surmised that the profound metabolic shifts induced by a KD may somehow predispose or precondition the brain to excitotoxic injury, but it is unclear how this might occur. Certainly, vulnerability to neuronal injury depends on both species and strain (25-27).

Potential Neuroprotective Mechanisms

There are two general experimental lines of evidence suggesting potential neuropro-tective effects of a ketogenic diet. The first relates to the role of polyunsaturated fatty acids (PUFAs) as potent neuroprotective agents via actions on neurotransmitter receptors and ion channels (35,36). The second involves the ketosis that accompanies the KD, or to a lesser extent, caloric restriction (37). Fasting has long been known to enhance seizure control, and indeed the KD was designed to mimic this physiological and biochemical state but the neuroprotective benefits arising from such a regimen have only recently been elucidated (38-40).

Fatty Acids and the KD

The standard KD formulation includes a preponderance of fats over protein and carbohydrates. Clinically as well as experimentally, the ketogenic potential is expressed as a ratio of grams of fat to grams of carbohydrate plus protein. A 4 1 or 3 1 ratio is usually used in clinical practice, and sometimes higher ratios are used in experimental models. Maintaining such a high ketogenic potential usually entails a diet composed of fatty foods, creams, and special oils.

Ketone Bodies and the KD

Investigators have observed that ketosis is necessary but not always sufficient for seizure control with the KD, and it is well known that seizure control gradually improves within the first few weeks of KD initiation, as serum ketone levels steadily increase. Interestingly, seizure control can be abruptly lost when ketosis is broken, usually through ingestion of carbohydrates (74). Furthermore, blood BHB levels appear to correlate directly with seizure control in children placed on a KD (75). These observations, nevertheless, have suggested a direct role for ketone bodies in limiting seizure activity.

Inborn Errors of Metabolism in Which the KD Is Contraindicated

There are definitive contraindications to the use of the KD. These include defects in fat metabolism and disorders that require high carbohydrate contents. Failure to diagnose these disorders before starting the KD could result in significant morbidity and may be fatal. These contraindications should therefore be considered in every child before the KD treatment is started. Treatment consists of avoidance of fasting, limiting the fat content in meals (often to DRI or < 25 ), and using a high percentage of complex carbohydrates in the diet (74,77). Continuous nasogastric or gastrostomy tube feedings are often used during the night. Other supplementation of the diet in these patients depends on the exact diagnosis and enzymatic defect, for example, carnitine (carnitine cycle defect), riboflavin (multiple acyl co-A dehydrogenase deficiencies), and medium-chain triglycerides (long-chain fatty acid defects). Porphyrias are a related group of diseases caused by inherited blocks in heme...

Polyunsaturated Fatty Acids PUFAs

Neuronal or glial membranes, by affecting membrane protein mobility or function, or by some metabolic mechanism. It is uncertain which, if any, lipid components are essential or modulatory on neuronal excitability in the ketotic condition. The classic KD consists of approx 80 dairy fat by weight (predominantly saturated fats, such as butter and cream) (77). Many studies, both human and animal, have demonstrated elevation of serum lipids in KD-fed individuals (78-81). However, serum lipids rise over several weeks, and a tight correlation with seizure reduction has not been established. Discontinuation of the KD quickly causes seizure recurrence, while lipids remain elevated. It may be that lipids of certain types, chain lengths, or degrees of saturation exert an important role on seizure control. In rodents, a cholesterol-rich diet protected against seizures induced by pentamethylenetetrazole and audiogenic stimuli (82), but in humans there is no consistent correlation between...

Animal Models of Ketosis

Animal models and in vitro preparations afford a number of advantages for the study of the ketogenic diet and the effects of ketosis. In animal models, blood, brain, and cerebrospinal fluid samples may be ethically obtained. Likewise, individual ketone bodies can be injected in isolation to permit the assessment of their effects on seizure threshold in the absence of the other ketone bodies. In in vitro models, voltage- or patch-clamp techniques may help to establish the molecular and cellular mechanisms associated with ketosis. Animal models, however, are useful research tools only if they parallel the effects observed in humans. For example, Fig. 3 shows proton NMR spectra obtained in our laboratory from the plasma of a rat fed the classic ketogenic diet and from a human patient undergoing treatment with the classic ketogenic diet. NMR spectroscopy can simultaneously measure the concentrations of all three ketone bodies. The second observation is that acetone plays a smaller role in...

Collecting Food Composition Data

The ketogenic diet is based on unprocessed foods such as fresh fruits and vegetables, meats, fish, and poultry, and butter and vegetable oils. Processed foods that are low in carbohydrate may be used in the diet but must be evaluated for precise food composition. Foods should be identified according to the form in which they will be consumed. For example, the nutrient values for cooked chicken breast should be used to calculate a meal, not the values for raw chicken breast.

Ketone Bodies Levels and Metabolic Roles

Ketone Body Metabolism

Both fasting and the ketogenic diet induce a number of common changes in the body. These include an elevation of ketone bodies in the blood and brain, a decrease in glucose utilization, and a shift in electrolytes and hormones. The identification of specific changes resulting in anticonvulsant effects has been challenging. Fig. 1. Both fasting and the ketogenic diet induce a number of common changes in the body. These include an elevation of ketone bodies in the blood and brain, a decrease in glucose utilization, and a shift in electrolytes and hormones. The identification of specific changes resulting in anticonvulsant effects has been challenging. Fig. 2. Biochemical pathways that generate ketone bodies and approximate concentrations of 'ketones' in blood, plasma, or serum. (In chemical terms, acetone is the only ketone among the three ketone bodies see text.) Acetoacetate is the key molecule from which both P-hydroxybutyrate and acetone are derived. P-Hydroxybutyrate,...

Plasma Ketone Analyses

Fasting breath acetone in ketogenic diet children, epilepsy controls, and healthy controls. Mean SEM n 10-13 group. Bars with different letters are significantly different (p < 0.05). At the time of the study, ketogenic diet children were consuming the classic ketogenic diet for a minimum of 1 mo. Epilepsy controls had epilepsy and were not being treated by a ketogenic diet but by anticonvulsant drugs. Healthy controls had no history of seizures and were not consuming any medications. (Reproduced with permission from ref. 16.) Fig. 1. Fasting breath acetone in ketogenic diet children, epilepsy controls, and healthy controls. Mean SEM n 10-13 group. Bars with different letters are significantly different (p < 0.05). At the time of the study, ketogenic diet children were consuming the classic ketogenic diet for a minimum of 1 mo. Epilepsy controls had epilepsy and were not being treated by a ketogenic diet but by anticonvulsant drugs. Healthy controls had no history of...

Brain Energetics and Metabolism

If deprived of glucose, either through fasting or dietary intake predominantly of fats, e.g., ketogenic diet, the brain can shift its metabolism and utilize ketones as an energy source, rather than carbohydrates. How ketones exert an antiseizure effect is unknown this question is addressed extensively in this volume. If the brain lacks an energy substrate, either through decreased supply, e.g., ischemia, or in prolonged seizures (status epilepticus), neuronal damage and even cell death can occur. The mechanisms by which epileptogenesis is enhanced in such situations are discussed in Section 5.

Calculating Energy Requirements

The calculation of the energy requirement is aimed at achieving normal growth and development while maintaining ketosis during the course of ketogenic diet therapy. A calorie level that is too high will result in rapid weight gain. A calorie level that is too low may result in poor growth and insufficient ketosis. Experience has shown that children can grow on the ketogenic diet, but often growth occurs at a decelerated rate. The calorie level may need to be adjusted several times during the course of ketogenic diet therapy to support individual growth needs. The child's ideal weight for height is the main parameter for determining caloric needs. If the child is underweight, his or her actual weight should be used as the initial caloric goal. Overweight children should be calculated at or close to their ideal weight for height. Factors affecting energy expenditure, such as immobility (low energy expenditure) or muscle spasticity (increased energy expenditure), should be taken into...

Ketosis and Seizure Control Correlational Studies

The suggestion by Wilder in 1921 that the anticonvulsant effects of fasting and the ketogenic diet were owing to the sedative effects of acetoacetate (3) reflected the belief at the time that a drug must have sedative properties to be anticonvulsant (14). It implied, however, that the ketone bodies have direct anticonvulsant effects. Not surprisingly, many studies since the time of Wilder have attempted to establish a correlation between the level of ketosis and seizure control. Fig. 3. Left 1H-NMR spectra from plasma of a rat fed control diet (bottom trace) and from plasma of a rat fed the classic ketogenic diet (top trace). Right 1H-NMR spectra from control plasma of a human volunteer (bottom trace), and from the plasma of a patient with epilepsy receiving the classic ketogenic diet (top trace). The spectra were obtained after filtering off the plasma proteins. Ketogenic diets with similar ratios of fat to protein plus carbohydrate appear to produce higher acetone concentrations in...

The Relationship Between Npy Galanin And

Because the KD is a high-fat diet, it is important to consider the effects of fat ingestion on neuropeptide expression. The relationship between NPY, galanin, and the ingestion of specific nutrients has been examined. Specifically, there appears to be a high correlation between galanin expression and fat ingestion. In animals maintained on selective macronutrient diets, the stimulatory effects of centrally administered galanin on feeding are relatively specific to fat consumption (20). Furthermore, hypothalamic galanin antagonist administration selectively inhibits fat consumption (21). Endogenous hypothalamic galanin levels, as measured by in vivo microdialysis and mRNA in situ hybridization, are positively correlated to the amount of fat ingestion in rats, whereas injection of galanin antisense oligonucleotides decreases fat ingestion (22). Importantly, galanin gene expression, peptide production, and peptide release are elevated in rats fed a high-fat diet (23), suggesting that...

Refractory Epilepsy

About 70 of epilepsy patients respond favorably to AED monotherapy. However, the remaining 30 of patients respond poorly to AEDs and comprise the group whose condition is known as refractory epilepsy. There is no uniformly accepted definition of refractory epilepsy most commonly, epilepsy is considered to be refractory to medical treatment when there is lack of seizure control after two or three AEDs, within a defined period (usually 1-2 yr in adults in children, this time frame is excessive for reasonable drug trial durations). In a study of 470 patients with newly diagnosed epilepsy, 61 were controlled on monotherapy (either the first or second drug chosen), and an additional 3 responded to therapy with two concurrent AEDs (10). However, none of the patients who were not controlled on two AEDs together achieved seizure control when a third AED was added. Therefore, the remaining 36 of the patients would be considered to be refractory. This figure coincides closely to the wider...

Conclusion

Epilepsy has many causes, both inherited and acquired. The mechanisms by which the normal brain becomes epileptic are quite diverse, ranging from the neural circuit level, to the synapse and neuronal membrane, to cascades of cellular energy production and utilization. All of these mechanisms vary over different stages of brain development. Rational treatment of epilepsy, whether with anticonvulsant medications, surgical interventions, or the ketogenic diet, requires an understanding of the age-specific physiological features that govern neuronal function.

Choosing Patients

Medications indicated that no specific epilepsy syndrome had a higher response rate to the ketogenic diet (2). In one trial, there was no difference in outcome between seizure types, although a small diminished efficacy was seen for children with multifocal spikes on electroencephalograms (EEGs) at 3 mo (p 0.04) (3). However, our impression is that children with the highest frequency of seizures, and those who are most refractory to medications, are most likely to respond. Children with the Lennox-Gastaut syndrome and atonic and tonic seizures seem to have the best clinical response. As demonstrated in our retrospective experience with 23 infants, infantile spasms may also show similar benefit from the KD (7).

Diet Initiation

Many friendships have formed during the hospital admission. One potential drawback is that some children will have very different initial responses to the ketogenic diet, and families with children having less success in the first few days may become discouraged. Throughout the 5-d hospital stay, classes are held with physicians, nurses, and dieticians to teach the family about the rationale of the ketogenic diet, calculation of meals, nutrition label reading, and management of their children during illnesses. This is just as important in achieving a favorable outcome as the actual logistics of diet initiation. Even families that do not speak English can be trained by using videotapes (which can be paused and reviewed multiple times), written handouts, and translators. We encourage both parents to be present for classes, to prepare for the likely future event of hav

Medications

A common goal of parents with children with intractable epilepsy is to reduce their medications. The side effects of sedation, irritability, and mood changes that can be seen with AEDs are much less commonly seen with the ketogenic diet. Even when the diet does not completely control the seizures, children will remain on the diet if medications can be eliminated. However, we encourage patience. In general, no changes are made in medications during the diet initiation period or for the first few weeks afterward. There is often a need to titrate each individual patient's diet before seizure reduction is achieved. Therefore, medication changes would considerably complicate the assessment of efficacy and are hence discouraged.

Candidate Selection

The typical ketogenic diet candidate has failed to achieve seizure control with antiepileptic drug treatment or has suffered unwanted effects from the antiepileptic drug(s). Children with disorders of fatty acid oxidation would not be candidates for the ketogenic diet. If these disorders exist during ketogenic diet therapy, the individual would be unable to metabolize the fatty acids that constitute the majority of the calories in the diet. In the absence of this major energy source, the body would metabolize its own protein stores, leading to severe acidosis, coma, and even death if untreated. Biochemical screening prior to admission should include profiles for urine organic and amino acids, serum amino acids, lactate, pyruvate, and carnitine (2). The ketogenic diet has been used more frequently in children than adults. A 1997 survey of 30 medical centers utilizing the diet throughout the United States reported that 80 of the individuals who had been treated with the ketogenic diet...

Calculating Fluid

Adequate fluid intake is necessary to maintain normal hydration during ketogenic diet therapy. Insufficient fluids can increase the risk for kidney stones and constipation. The ketogenic diet restricts fluids to noncaloric, caffeine-free beverages such as water, decaffeinated weak tea, and noncaloric caffeine-free soda. Fluid should be calculated for the maintenance needs of the individual. The Holiday-Segar Method is a fluid calculation that is based on weight alone (6) (Table 11). This formula does not account for abnormal fluid losses, for example, from excessive drooling or febrile illness. For example, a child weighing 23 kg needs 1000 mL (for first 10 kg) plus 500 (10 kg x 50 mL kg) plus 60 mL (3 kg x 20 mL kg) for a total of 1560 mL daily. This can be divided into six servings of 250 mL as a simple daily guide for the caregiver to manage. The child should not be allowed to drink large volumes of fluid at one time because this may upset internal fluid balance and ketosis. The...

Diet Preparation

The family can be taught to manage the fluid schedule that will be continued for home use. Ketogenic diet food weighing can be taught on the day after admission so that the parents can prepare the meals that are consumed in the hospital and for the first few meals at home. Access to a small kitchen on or near the inpatient unit is ideal for accommodating this process. Simple ketogenic meals should be taught initially to minimize food preparation and to facilitate learning. Ketogenic diet education should also include a session on appropriate vitamin and mineral supplementation and a list of carbohydrate-free health care products such as toothpastes, pain relievers, and cold remedies.

Sick Days

The caregiver must also receive counseling on management of intercurrent illnesses (sick days). If the child is vomiting or has diarrhea, ketogenic meals should be temporarily stopped and the emphasis should be on maintaining hydration with fluids. Diluted broth, noncaloric caffeine-free soda and sugar-free gelatin can be offered. If vomiting and or diarrhea persists, an oral rehydration solution may be given at half-strength. Easy-to-digest ketogenic meals such as ketogenic eggnog or chicken salad with applesauce can be restarted in half portions when the child is ready to begin eating. The signs and symptoms of hypoglycemia and excessive ketosis should be taught during the hospitalization, and the method of treatment should be outlined for home use. A visit to the pediatrician or emergency room may be necessary if symptoms persist after treatment. Caregivers should be assured that these problems are unlikely to occur once the child has begun to consume the full diet. Close contact...

The Dietitians Role

The most important member of our ketogenic diet team is the dietitian. Our dietitian is employed by our Epilepsy Center, a private clinic, rather than by the hospital, thereby assuring that she does not have conflicting responsibilities. Other centers need to utilize dietitians whose duties are shared by other clinics and by inpatient units. Based on the dietitian's workload, we have found that we can initiate and follow a maximum of one to three patients per month, also dependent on the needs of the patient and the abilities of the caregivers.

Fine Tuning the KD

Second, it is not trivial to locate all the items in a meal plan. Recently the US Food and Drug Administration ruled that carbohydrates (CHOs) need to be listed on food packaging only if they comprise 1 g or more per serving. This allows manufacturers to label many products that contain a small amount of CHO as carbohydrate free. Also, many products are labeled incorrectly. Thus when a specific product is purchased that is outside our experience, it is essential that the dietitian or caregiver call the manufacturer to get the exact product specifications.

Hyperlipidemia

This example highlights the serious nature of the ketogenic diet it is not holistic therapy or a natural homeopathic remedy, but a most powerful medical treatment for intractable epilepsy that markedly affects the body's metabolic regulation. We must monitor for potential complications closely.

Intractable Epilepsy

The ketogenic diet (KD) has historically been used in the treatment of medically refractory epilepsy. It is currently not recommended for new-onset seizures because antiepileptic drugs (AEDs) are easier to use and are effective in approx 70-80 of patients. The KD requires a significant commitment of time and effort by the patient, his or her family, the KD health-care team, and the institution that supports the KD program. Determining precisely when intractability occurs in a child with epilepsy continues to be a subject of discussion among epidemiologists (1-5). Generally, epilepsy centers will not offer the KD treatment until a patient has failed two or three standard AEDs. Most patients who start the KD have failed at least three times as many AEDs. The KD is not recommended to some patients until all other options have failed (6). Current treatments available to patients with intractable epilepsies include a plethora of conventional AEDs, the vagus nerve stimulator, epilepsy...

Pancreatitis

Stewart et al. (34) reported a case of a 9-yr-old girl who died from acute hemorrhagic pancreatitis while on the KD. There was no definitive proof that the pancreatitis was secondary to the diet, but the authors presented a potential pathophysiologic mechanism. Hyperlipidemia and hypertriglyceridemia are risk factors for the development of pancreatitis, and the ketogenic diet can be associated with hyperlipidemia. Unfortunately, these levels were not measured in this patient prior to her death.

Diabetes

Before the availability of insulin, the treatment of choice for diabetes was starvation. Limiting caloric intake reduced diabetics' acute problems, e.g., ketoacidosis, and prolonged life expectancy. The introduction of insulin for the treatment of diabetes made such extreme interventions obsolete, but diet continues to be a cornerstone of the management of diabetes. Unfortunately, current dietary recommendations for diabetes have been driven by the cardiovascular field and have thus focused on lowering dietary fat and cholesterol (56). The high-protein Atkins-type KD may be the diet of choice for control of diabetes. In a study of non-insulin-dependent diabetics given controlled formulas that contained either high complex carbohydrate or low carbohydrate and high fat, glucose control was superior in the latter group (57). Glucose, insulin, and C-pep-tide were all higher in the diabetics who were fed high complex carbohydrates (57). In general, comparative studies find that high-fat...

Perspective

The ketogenic diet (KD) is both a therapy and a tool for investigating the mechanisms of seizures and, perhaps, epilepsy. Despite our ignorance of the mechanisms by which the KD acts to alter seizures, the observation that seizure threshold can vary widely depending on what an animal eats suggests that seizure threshold is a (patho)physiological variable. The general hypothesis underlying experimental studies of the KD is that, by understanding the physiological changes consequent to a switch from a carbohydrate-based metabolism to one based on fats, we might gain insight into fundamental processes that affect ictogenesis. If a person whose seizures are controlled by a KD abandons the diet abruptly and suffers a seizure, then we might consider elevated blood glucose (or decreased ketonemia) to be ictogenic. Because central nervous system (CNS) metabolism is normally based entirely on glucose, the success of KDs in treating seizures and epilepsies presents interesting questions and...

Role of Diet Type

In general, studies of the effectiveness of KDs against acute seizures have shown that such diets are protective, irrespective of formulation. This is in contrast to a general statement by Swinyard (22) that they were ineffective in all but the hyponatremic test. The only species in which the relationship between high-fat diets and seizures has been studied are mice, rats, and humans. Experimental diets have been varied but generally are of one of two types, either the classical long-chain triglyceride (LCT) diet originally formulated by Wilder (23), implemented most often clinically as a 4 1 ratio of fats to carbohydrate + protein (24) or as the medium-chain triglyceride (MCT) diet developed by Huttenlocher et al. (25). The MCT diet was developed in an attempt to achieve Ketogenic diets fed to rodents generally conform to the classical LCT diet. Thavendiranathan et al. (26), however, fed the MCT diet to rats and found ketonemia equal to, or greater than, that found with the LCT diet,...

Energy

Carbon budgets vary with diet, and the possible relevance of such variation to seizure control is poorly understood. Kekwick and Pawan (112) found that isocaloric high-carbohydrate and high-fat diets were utilized differently by mice. The greater non-CO2 carbon loss of the high-fat diet was shown to reflect the loss of body fat and the inefficient use of fat-based carbon on such diets. Hawkins et al. (113) reported that the brains of rats starved for 2 d showed little change from glucose to ketone body utilization, unlike the large reduction (> 25 ) of brain glucose metabolism described in humans by Hasselbalch et al. (114). Brain infusion of BHB has been shown to reduce body weight without a reduction in food consumption, as happened when glucose was infused (115), but intracerebroventricular (ICV) infusion of BHB resulted in increased adiposity despite the decrease in weight (116), a phenomenon we have noted in rats fed a calorie-restricted KD (Bough and Eagles, unpublished data).

Epilogue

The story of the ketogenic diet is a fascinating one, a saga as compelling as any in clinical medicine. From both teleological and evolutionary perspectives, it makes abundant sense that dietary factors should be important in influencing brain physiology. The aphorism We are what we eat is a popular reminder that our station in life is often correlated with the perceived rarity and value of foodstuffs available for personal consumption. However, what we eat has become an even more timely consideration given the recent dramatic increase in obesity seen in both children and adults living in the United States, an ominous development that heralds an impending epidemic of diabetes, cardiovascular disease, and other long-term health consequences. Furthermore, the attainment of significant weight loss and a lean body habitus a mantra promulgated by the media has become a psychological holy grail, one that promises bountiful happiness and self-esteem, despite potential negative health effects...

The Nurses Role

It is the nurse's responsibility to work closely with the dietitian and the ketogenic diet physicians. It is the nurse who must schedule the routine labs and make sure that the results are seen by the physician. When a patient is having a difficulty that arises from the KD, the nurse will troubleshoot with the family to determine whether the problem is dietary or medical. Often the nurse will contact the patient's primary physician or dentist to coordinate care. If the patient is undergoing a surgical or dental procedure, it is the nurse's responsibility to make sure that everyone on the team is aware. If the patient is having surgery, a copy of our Ketogenic Diet Surgery Protocol is given to the surgeon so that he or she is aware of the diet and the precautions to be taken (see Appendix 3 of this chapter). Our physician is always available for questions.

The Ketogenic Ratio

Grams of fat for every 1 g of protein and carbohydrate combined. The ratio is intended to regulate the degree of ketosis, with higher ratios theoretically stimulating greater ketosis. The higher the ratio, the lower the protein and carbohydrate content of the diet. The ratio can be manipulated during the course of ketogenic diet therapy to achieve nutritional goals and to optimize seizure control. The ratio at which the ketogenic diet should be started is outlined in Table 1. It is important to keep in mind that the degree of ketosis may vary among individuals. Two different individuals of the same age and weight may experience a completely different level of ketosis on the same ratio. This difference is tentatively attributed to individual variations in energy metabolism and expenditure. The ratio is tapered at the end of ketogenic diet therapy to gradually reduce and eliminate ketosis.

Essential Fatty Acids

As far as evolutionary aspects are concerned, lipid mediators such as oxylipins confirm the hypothesis that the formation of signaling molecules may have developed as a 'by-product' of ancient metabolic pathways which were initially required for the biosynthesis and metabolism of basic biomolecules such as lipids, amino acids, peptides, nucleotides and carbohydrates.

Intervention Of Seaweed To Enhance Human Nutrition

Acquirement of a good mental and physical health through optimum nutrition is a key to wellness of humans. The nutrients in our daily diet or those synthesized in the human body using the precursor molecules play a vital role in regulating the bodily functions, essential for normal growth and development. Carbohydrates, proteins, lipids, and vitamins

Physiological Biological Principles

Active transport is an energy-consuming process whereby membrane-bound transporters bind and transport materials across membranes, even against a concentration gradient. Physiologically, these active transporters exist to promote absorption of nutrients and hence are typically related to food substances such as peptides, amino acids, carbohydrates, and vitamins. They can lead to absorption efficiency that is significantly greater than what would be predicted based on a passive diffusion mechanism. In recent years many of these transporters have been characterized with respect to structure, cellular location, and substrate specificity (Katsura and Inui, 2003 Sai, 2005). Conversely, active transport mechanisms also exist to transport materials out of cells (efflux pumps). The most well-studied efflux pumps are in the class of ATP-binding cassette (ABC) transporter proteins, including p-glycoprotein (P-gp) and the multidrug resistance protein (MRP) family (Kivisto et al., 2004 Leslie et...

Integration and Control of Nitrogen and Carbon Metabolism

Several studies indicate homeostatic co-ordination of C and N assimilation in higher plants through effects on nitrate uptake by the roots, nitrate translocation in the xylem, and nitrate reduction in the leaves (Foyer et al., 2001). Increases in CO fixation with increasing irradiance are accompanied by enhanced N uptake (Gastal and Saugier, 1989), while N assimilation is decreased at low C02 (Pace et al., 1990) or during depletion of carbohydrates in extended darkness (Rufty et al., 1989). Another important limitation over the rate of incorporation of nitrate (and ammonia) into downstream products is

Boroncontaining amino acids and related peptides

Interest in the boronated amino acids and peptides stems from the fact that p-BPA is one of only two clinically used BNCT agents. The strategy for concentrating the boronated compounds in tumor cells is that the cellular building blocks are required in greater number in rapidly dividing cells than in their normal counterparts this may lead to a greater concentration of boron-containing peptides and proteins in the tumor cell. In addition to the para-isomer of BPA, the ortho- and meta-isomers have also been evaluated (Figure 2.5).38 However, only the para-isomer has undergone extensive biological testing. Since BPA has limited water solubility, advantage has been taken of the ability of its boronic acid group to complex with carbohydrates as a means of increasing water solubility.39 There have been other attempts to increase water solubility by incorporating hydrophilic groups into BPA.40 Some structures are given in Figure 2.6.

Biosynthesis of Sugars

The synthesis of carbohydrates in plants occurs through a mechanism of carbon dioxide fixation, and was understood through the use of long-lived radioactive isotope of carbon 14C. After considerable investigations it was founded that the initial CO2 acceptor was the five-carbon compound ribulose 1,5-bis-phosphate (RuBP) which after incorporation of carbon dioxide produce a six-carbon molecule. The resulting molecule is fragmented into two molecules of 3-phosphoglycerate (PGA) that is one of the intermediates of glycolysis. This transformations takes place in the chloroplast by a large multisubunit enzyme, ribulose biphosphate carboxylase Rubisco. The following reaction sequence is cyclic and constitutes what is known as the Calvin cycle which consists after formation of PGA in reduction to glyc-eraldehydes 3-phosphate (GAP), and regeneration of RuBP. The overall process requires 6 CO2 molecules fixed, 12 molecules of GAP produced which rearrange to regenerate 6 molecules of the...

Properties Of The Gastrointestinal Tract

The surface area available for absorption is highest in the jejunum and the ileum, accounting for more than 99 of the total. In the fasted state, the pH in the stomach is 1.7. The acidified contents of the stomach are neutralized in the duodenum by the infusion of bicarbonate ions through the pancreatic duct. Past the pyloric sphincter separating the stomach and the duodenum, the pH steeply rises to 4.6. Between the proximal jejunum and the distal ileum, the pH gradually rises from 6 to 8. The pH can drop to values as low as 5 in the colon, due to the microbial digestion of certain carbohydrates, producing short-chain fatty acids (SCFAs) in concentration as high as 60-120 mM. 70 The GIT exhibits a considerable pH gradient, and the pH partition hypothesis predicts that the absorption of ionizable drugs may be location-specific.

An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

The conversion of food into a living body and into the energy that it needs depends on complex networks of biochemical reactions that must be exquisitely regulated for optimum function. Dietary carbohydrates are converted to glucose, which is used both as an energy source, through oxidation by to form CO2 and h20, and as a source of intermediates for biosynthesis (e.g., of fatty acids). Fats are converted into fatty acids, which are likewise used both as fuel and to furnish building blocks for biosynthesis. Dietary proteins are broken down to their individual amino acids, which are then used for the biosynthesis of proteins and many other substances.

Chemoenzymatic Synthesis

The reported procedure consists of the phosphorylation of dihydroxyacetone dimmer with (PhO)2POCl followed by hydrolysis of the dimmer to generate dihydroxyacetone phosphate in 61 yield.29 The chemically prepared DHAP is then used as an important material for the synthesis of natural monosaccharides and carbohydrates mimetics (Figure 1.36).

Protein and amino acids

Bioactive lectins are found in sea lettuces (Sampaio et al., 1998 Wang et al., 2004). However, lectins derived from sea lettuces are relatively recent ones compared to other seaweeds. In human body, lectins are involved in numerous biological processes such as cell-cell communication, induction of apoptosis, host-pathogen interaction, cancer metastasis and differentiation, recognizing and binding carbohydrates, increase the agglutination of blood cells (erythrocytes), detection of disease related alterations of glycan synthesis, including infectious agents such as viruses, etc. (Holdt and Kraan, 2011).

Non Receptor Mechanisms

The human relevance of these findings in the NBL rat model remains unclear at present. However, oxidative DNA damage and lipid peroxidation reflective of reactive oxygen damage have been observed in the human prostate 258 , and increased oxidative stress has been found in prostate cancer patients as compared with controls 259 . Whether these observations are related with estrogen exposure or associated with other risk factors such as a high fat diet 242 is not known, but they suggest that endogenous oxidative stress may be important in human prostate carcinogenesis, and they are consistent with the hypothesis of estrogen-generated oxidative DNA damage as an important factor.

Summary and Conclusion

There are no known exogenous hormonal or non-hormonal exposures that are associated with prostate cancer risk, with the exception of exposure to a western life style (including a high fat diet), to an African American environment, and, perhaps, to venereal disease, unknown factors related to farming, and employment in armed services and the nuclear industry. None of these associations point to specific chemicals, hormones, or other factors. In view of the high frequency of this malignancy in Western countries, this lack of known specific risk factors is remarkable and may indicate that there are many exogenous risk factors for prostate cancer which are too ubiquitous and overlapping to be detectable by epidemiologists. It is also possible that there are strong endogenous determinants of prostate cancer risk which are overwhelming most exogenous risk factors in epidemiological analyses. Androgenic hormones and androgen receptor mechanisms are prime candidates to be such important...

Product Quality Evaluations 71 Drug Substance Test Procedures

RFIX consists of both zymogen and cleavage products of the mature zymogen. The cleavage products of both rFEX and pdFIX are similar both preparations contain FIX and FIX-related species, and although the relative proportions may vary, essentially the same species are observed for both preparations and the overall amounts are approximately the same. Therefore, all of the FIX-related species described above, even though some are not active, are not considered impurities. Taken together, the mature FIX (zymogen) and the FIX-related species that are expected to be present define rFIX. Impurities are defined as all non-FIX species that are derived from the host cell or the production process, including proteins, carbohydrates, and small molecules.

Nature Of Oxidative Damage

Secondary oxidative damage results from reaction of proteins with products of oxidation of small molecules, including lipids, carbohydrates, and amino acids. The intermediates in this process are reactive carbonyl and dicar-bonyl compounds, such as malondialdehyde, a, -unsaturated and hydroxy-aldehydes, glyoxal, and methylglyoxal (MGO), which react with nucleophilic groups on protein to form lipoxidation (9) and glycoxidation (I0,l l) products (Table 1). Lipoxidation products require oxidation (peroxidation) for their formation from lipids, whereas glycoxidation products are a subclass of advanced glycation end products (AGEs), requiring autoxidation chemistry (oxidation by molecular oxygen) for their formation from reducing sugars or ascorbate. Some AGEs (e.g., pyrraline and imidazolones formed by reaction of 3-deoxy-glucosone 3DG with lysine and arginine residues in protein) do not require oxidation for their formation from reducing sugars. These AGEs are useful indicators of...

Carbonyl Stress In Diabetes

The increase in lipoxidation and glycoxidation products in diabetes is the direct result of an increase in carbonyl precursors however, not all of these intermediates are derived from oxidative reactions. 3DG, for example, is formed nonoxidatively from Amadori compounds (34) or fructose-3-phos-phate (35) and is also increased in diabetes, along with increases in both pyrra-line and 3DG-arginine imidazolone (36) adducts that are derived from 3DG by nonoxidative mechanisms. MGO adducts to protein, including CEL and MOLD, are also increased in diabetes (37,38). Like 3DG, MGO is formed by anaerobic mechanisms, either enzymatically as an intermediate in amino acid catabolism or by (3-elimination reactions of triose phosphates (39,40). However, MGO may also be produced during the oxidative chemistry of both lipids and carbohydrates, so that its precise origin in vivo is unknown. In any case, the increase in 3DG, and possibly MGO, and their adducts to proteins suggests that limitations in...

Materials and Methods

ApoE- - mice (n 12-14 group) and wild-type mice (C57BL 6J n 11-15 group) were maintained on a high-fat diet (21 fat, 0.15 cholesterol) from the age of 5 weeks. At the age of 25 weeks the animals were fasted overnight, anesthetized, and intravenously injected with 99mTc-annexin A5 or 18F-FDG (18.5 MBq mouse). Two hours after 99mTc-annexin A5 injection or 1 h after 18F-FDG injection, the aortas were collected and mounted on a glass slide after longitudinal incision.

Possible Exogenous Sources of Excitatory Ligands

Monosodium glutamate (MSG) and Glu are the most common food additive and enhancers, respectively, in commercial foods and in food condiments (Zautcke et al., 1986 Allen et al., 1987 Bertrand et al., 1992). Free Glu is a natural constituent of many foods including meat, cheeses, and vegetables providing an excellent source for exogenous Glu. However, free Glu is absorbed slowly and is dependent on the presence or absence of other nutrients, in particular carbohydrates and probably glucose. Aspartame is a dipeptide of aspar-tic acid and phenylalanine which is widely used as a sweetener of foods, beverages, and drugs. It is hydrolyzed in the gut to release Asp which is efficiently absorbed. Hydrolyzed protein (HP) is also widely used by the food industry as a flavour additive. In addition to Glu, HP can also contain Asp and various sulfur-containing amino acid. L-Cys is a common sulfur containing amino acids. Although this compound is relatively weak, in the presence of

Batches Of Virus Tested

With respect to the factor rotation methods it should be noted that owing to the complex character of pyrolysis mass spectra mathematical criteria usually cannot be found. Therefore, rotation techniques such as Varimax (ref. 138) and the method of Knorr and Futrell (139) may not perform satisfactorily. Moreover, target transformation and matching techniques (which use library criteria) are less well suited for the analysis of complex pyrolysis mass spectra, as the component sub-patterns can be influenced by the total sample matrix (see Section 4.1). For these reasons, Windig et al. (ref. 140) adapted the graphical rotation method (ref. 143), an empirical factor rotation technique, for interpreting pyrolysis mass spectra. The example in Figure 35 represents the analysis of a small set of pyrolysis mass spectra of yeast species in order to obtain a more quantitative description of the main groups of biochemical components in these microorganisms. The spectra of such yeasts (Figure 35a)...

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