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Ketogenic Diet – an overview

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The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet that has been used as a treatment for epilepsy since 1921.

From: Encyclopedia of Basic Epilepsy Research, 2009

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Roberto H. Caraballo, Eileen Vining, in Handbook of Clinical Neurology, 2012

Abstract

The ketogenic diet (KD) is an effective nonpharmacological treatment used as an alternative not only for children but also for adults in the management of refractory epilepsy. Recently, modifications of the original KD, such as the Atkins diet and a low-glycemic-index diet, have been developed. The availability of these types of diets suggests that the KD could be offered earlier in the management of refractory epilepsy. Nevertheless, these diets may not be as effective as the KD. The KD is the treatment of choice for two distinct disorders of brain energy metabolism: glucose transporter protein (GLUT-1) deficiency syndrome and pyruvate dehydrogenase deficiency (PDHD) syndrome. The KD is absolutely contraindicated in primary carnitine deficiency, carnitine palmitoyltransferase I or II deficiency, carnitine translocase deficiency, β-oxidation defects (long-chain acyl dehydrogenase deficiency, medium-chain acyl dehydrogenase deficiency, short-chain acyl dehydrogenase deficiency, long-chain 3-hydroxyacyl-coA deficiency, medium-chain 3-hydroxyacyl-coA deficiency), pyruvate carboxylase deficiency, and porphyria. The diet may also be beneficial for seizure control in specific epileptic syndromes such as epilepsy with myoclonic–astatic seizures, West syndrome, Lennox–Gastaut syndrome, and Dravet syndrome. After stopping the KD, seizures recur in a few patients with cerebral lesions and electroencephalogram abnormalities; however, long-term health implications should be investigated.

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K. Chapman, J.M. Rho, in Encyclopedia of Basic Epilepsy Research, 2009

The ketogenic diet (KD) is an effective treatment option for patients with intractable epilepsy. The recent resurgence of interest in the KD has led to an explosion of research into its clinical implementation, as well as its underlying mechanisms. The KD is often initiated in the hospital, and careful monitoring ensures a reduction in the risk of adverse events. Recent modifications to the KD have been proposed and are being studied to evaluate their effectiveness and safety. The mechanisms of action underlying the KD are not well understood, but may involve multiple, parallel and possibly synergistic mechanisms.

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Amanda G. Sandoval Karamian MD, Courtney J. Wusthoff MD, MS, in Infectious Disease and Pharmacology, 2019

Ketogenic Diet

The ketogenic diet is a dietary therapy in which the majority of caloric intake is fat to put the body in a state of chronic ketosis, in turn altering energy supply to the brain. The ketogenic diet is used in children with intractable epilepsy with good evidence, though it is used less commonly in neonates and there is less published evidence for use in this population.110,111 There may be a role for the ketogenic diet in certain cases of inborn errors of metabolism, and it is the treatment of choice in patients with pyruvate dehydrogenase complex deficiency and glucose transporter 1 (GLUT-1) deficiency.72,112 A case series of three neonates with early myoclonic epilepsy and nonketotic hyperglycinemia demonstrated good seizure response to the ketogenic diet after failure of multiple AEDs.113 More high-quality evidence is needed to determine the safety and efficacy of the ketogenic diet in neonates.

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Stacie K. Totsch, … Robert E. Sorge, in Progress in Molecular Biology and Translational Science, 2015

16 Ketogenic Diets

Ketogenic diets have been used for treatment of epilepsy in children162 and are suggested as treatments for other disorders including pain (see Ref. 163). This is a high-fat, low carbohydrate diet that encourages ketosis as a form of energy consumption and is similar to the Atkins diet. Whereas the diet has been efficacious for treating some forms of epilepsy, the results for pain reduction are mixed. Early work showed that rats fed a ketogenic diet for 10 weeks had lower tail-flick latencies,164 suggesting greater sensitivity to painful thermal stimuli. Subsequent work by Ruskin and colleagues has found that various ketogenic diet formulations resulted in less sensitivity in hot plate tests between 49 and 51 °C.165,166 These authors also noted a reduction in CFA-induced edema in the paw, though allodynia was never measured.165 However, ketogenic diets were shown to have no effect on neuropathic pain induced by sciatic nerve constriction or paclitaxel injection.167 It appears that the analgesia effect of the ketogenic diet may be very limited to a small thermal range, but there is good evidence that the diet has effects on the immune system. Rodents on ketogenic diets showed reduced IL-18 in blood168; reduced IL-1β, Il-6, and TNFα in brain169; and reduced TNFα, COX2, PGE2, and NFκB in hippocampus.170 The reduction in NFκB was thought to be due to PPARγ activation (see earlier, Section 9) in neurons in the hippocampus.170 Thus, there is good evidence that ketogenic diets have immune-cell-specific effects, but their use as analgesic treatments may be limited.

The above sections have outlined the currently available research on dietary items and their effect on immune cells and pain specifically. The following section will deal with dietary interventions for pain in animals and humans with various painful conditions. It is useful to keep in mind that many of the interventions outlined below include any number of foods from the above sections to round out a treatment strategy and that one aim of this chapter is to provide evidence that dietary interventions have the potential to reduce pain, primarily through immune system interactions.

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Antonio Paoli MD, BSc, Gerardo Bosco MD, PhD, in The Mediterranean Diet, 2015

KDs: A Summary View

KDs are characterized by a reduction of carbohydrates (usually < 50 g/day) and a relative increase in proportions of protein and fat. The knowledge regarding the metabolic aspects of classic KDs originates from the pioneering work of Cahill's group in the 1960s [10–12], but the realization of the importance of these diets from a clinical point of view can be traced back to the early 1920s, when they began to be successfully used in the treatment of epilepsy [13] are can be found in many religions’ traditions.

It seems paradoxical that such an ancient and efficient tool for treating refractory epilepsy, achieving weight control, reducing cardiovascular risk markers and inflammation as well as other pathological conditions [14] seems to be a “scotoma,” or blind spot, in nutritional research. Alongside the huge amount of data about the influence of correct nutrition on health status and disease prevention (as stated by many nutritional societies), there is also ample evidence to support the notion that a low-carbohydrate diet can lead to an improvement in some metabolic pathways in humans [14]. In light of these attractive properties, many efforts have been dedicated to finding out how very-low-carbohydrate KDs acts on human metabolism. In this chapter we explain how a KD could be considered as a tool that could be used together with the MD in certain metabolic conditions.

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T.N. Seyfried, … A.E. Greene, in Encyclopedia of Basic Epilepsy Research, 2009

The Relationship of the KD and CR in Seizure Management in Children

The KD is most effective in reducing seizure susceptibility in children when administered with fasting or under restricted caloric intake. Clinical studies have also shown that the anticonvulsant efficacy of the KD is associated with body weight and blood glucose reductions of about 10%. 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 can be lost in patients who experience a rise in blood glucose levels, as in the case of those who gain weight on the diet or who consume carbohydrates. On the basis of our studies with EL mice, we suggest that the seizure protective effects of the KD would be best when administered in reduced amounts, so that blood glucose levels and body weight are also reduced. It is also important to recognize that consumption of the KD in unrestricted amounts is unhealthy because of the high fat content of the diet. Consumption in restricted amounts provides maximum therapeutic benefit against epilepsy while reducing the adverse effects of the high fat content of the diet.

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K.J. Bough, R. Dingledine, in Encyclopedia of Basic Epilepsy Research, 2009

Introduction

The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet that has been used as a treatment for epilepsy since 1921. The KD is typically administered in a 4:1 ratio of fats to carbohydrates + proteins, whereby ∼90% of calories are derived from fat. Typically, the recommended daily caloric intake is reduced by ∼25%. During diet treatment, the liver metabolizes fats into ketone bodies, which in place of glucose then become the primary source of metabolic fuel. Somehow, this switch in metabolism confers an anticonvulsant effect. In general, the number of seizures is reduced by half or more in approximately 50% of those who adhere to the diet. This dietary regimen must be strictly maintained, however, as even small amounts of glucose (or excessive caloric intake) diminish KD efficacy.

We have focused our studies on KD mechanisms for a variety of reasons. First, anticonvulsant drugs do not adequately control seizures for many patients with epilepsy and often cause unwanted side effects. Today the diet is primarily used to treat medically refractory seizures and effectively manages a wide variety of epilepsies. There are few side effects. Perhaps most importantly, however, there are experimental hints that the diet may also limit disease progression and prevent neurodegeneration. Cross comparisons of the KD anticonvulsant profile with the spectrum of activity for other AEDs suggest that the KD acts uniquely to control seizures. Thus, elucidation of KD mechanisms will likely provide unique insights into brain metabolism from which potent new treatment strategies for epilepsy and, perhaps, other neurodegenerative disorders could emerge.

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Shyuan T. Ngo, … Karin Borges, in Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease, 2015

Ketogenic Diet

The ketogenic diet is a calorie-restricted, high-fat (3–4 g) versus low-protein, low-carbohydrate (combined 1 g) diet that is designed to mimic fasting. The ketones that are produced by the liver may act to improve mitochondrial metabolism and biogenesis (Bough et al., 2006; Hartman et al., 2007). Because mitochondrial dysfunction is thought to contribute to ALS pathogenesis (Bendotti et al., 2001; Crugnola et al., 2010; Zhou et al., 2010), it has been hypothesized that, by improving mitochondrial function, a ketogenic diet may be beneficial in ALS. When compared to ALS mice on a control diet (caloric composition: 10% fat, 70% carbohydrate, 20% protein), ALS mice supplemented with a moderate ketogenic diet (caloric composition: 60% fat, 20% carbohydrate, 20% protein caloric composition) had improved motor performance, increased body weight, and less motor neuron death. Despite these outcomes, the ketogenic diet was not able to extend survival in ALS mice (Zhao et al., 2006), and a clinical trial (NCT01016522) that aimed to test the safety and tolerability of the ketogenic diet (80% fat, 3% carbohydrate, 17% protein) in ALS was terminated with no results being published. It is important to note, however, that adults are virtually unable to adhere to the very strict and unpalatable ketogenic diets (Amari et al., 1995; Klein et al., 2010; Mosek et al., 2009).

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Samuel T. Henderson PhD, in Diet and Nutrition in Dementia and Cognitive Decline, 2015

Ketogenic Diets

KDs were developed in the 1920s to reduce the occurrence of seizures in epileptics. KDs are very low in carbohydrates and proteins and very high in fat and were developed to mimic the physiological changes seen in extended fasting [25]. KDs lead to an increase in circulating KBs (ketosis). KBs serve an essential process in adult humans to provide an alternative to glucose for the brain during periods of low glucose availability. For example, Owen et al. fasted obese volunteers for 5–6 weeks and examined changes in brain metabolism. During the 5- to 6-week fast, the concentration of the major KB β-hydroxybutyrate (BHB) was elevated to the range of 4–8 mM, 10- to 20-fold over normal 12-h fasting values. Arteriovenous differences across the brain measured significant use of KBs, and it was estimated that under these conditions, KBs supply about 60% of the brain’s energy requirements [26].

KDs have demonstrated potential in treating several neurological conditions other than epilepsy (Table 40.1). The change in macronutrient content in a KD from a standard diet induces a set of changes, such as reduced glucose, low insulin/IGF signaling, and increased levels of uncoupling proteins, each of which could contribute to neuroprotective effects. Yet KBs alone have demonstrated neuroprotective properties. KBs used in cell culture systems or infused into animal models demonstrate neuroprotection in many systems including: protection from glutamate toxicity [35], ischemia [36], and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity (Table 40.2) [45].

Table 40.1. Neuroprotection of KDs

Injury Species Outcome
ALS Mice Increased motor neuron counts [27]
Traumatic brain injury Rats Reduced contusion volume [28]
AD Mice Reduced Aβ levels [29]
KA-induced seizures Mice Increased cell survival [30]
GLUT1 haploinsufficiency Humans Decreased seizure frequency [31]
Parkinson’s disease Humans Improved motor function [32]
Ischemia Rats Protection from neurodegeneration [33]
MCI Humans Improved memory performance [34]

KDs have been shown to provide protection to neuronal cells from various insults.

Table 40.2. Neuroprotective Effects of Ketone Bodies

Intervention Injury Species Outcome
ACA Glutamate toxicity Rats, cell culturse Neuroprotection [37]
BHB/ACA Glutamate toxicity Cell cultures Increased cell survival [35]
BHB Glutamate toxicity Rats Neuroprotection and reduced lipid peroxidation [38]
BHB/ACA Glutamate toxicity Cell cultures Increased mitochondrial efficiency [39]
BHB Hypoxia Cell cultures Increased cell survival [40]
BHB Hypoxia Mice Maintained ATP and low lactate [41]
BHB Ischemia Mice Reduced cerebral infarct area [36]
BHB Traumatic brain injury Rats Restored ATP levels after CCI [42]
MCT AD Humans Improved cognitive performance [43]
BHB AD Cell cultures Increased cell survival [44]
BHB Parkinson’s disease Mice Improved neuronal survival, improved mitochondrial efficiency [45]
BHB Parkinson’s disease Cell cultures Increased cell survival [46]

Ketone bodies have been shown to provide protection to neuronal cells from various insults.

Abbreviations: ACA, acetoacetate; BHB, β-hydroxybutyrate.

KBs are a readily metabolized substrate and can lead to increased metabolic efficiency. Sato et al. treated perfused rat hearts with levels of KBs found during starvation (4 mM BHB and 1 mM ACA) and compared the rates of oxygen consumption with heart cells treated with glucose alone. KB treatment was found to increase cardiac efficiency by 13% compared to control hearts. The increase in metabolic efficiency can be attributed to increasing acetyl-CoA pools and increasing the strength of the NADH/NAD redox couple [6]. In addition, other authors have demonstrated that KB metabolism increases the mitochondrial pool of succinate, allowing bypass of complex I deficiencies [45].

Studzinski et al. examined the effects of inducing ketosis in aged beagle dogs (age 9–11 years) for 2 months. This study did not implement a KD, but instead used MCTs to induce ketosis. MCTs are triglycerides with fatty acid chains between 5 and 12 carbons. MCTs are immune to the regulation of long-chain fatty acids and are well known for their ketogenic properties independent of dietary factors [7]. The ketogenic treatment led to modest levels of ketosis, in the range of 0.1–0.3 mM. Mitochondria were isolated from parietal and frontal lobes, washed free of KBs, and found to demonstrate improved respiration rates and increased metabolic efficiency. In addition, significant reductions in markers of oxidative damage were found in the mitochondrial fraction [47]. The reader is referred to several reviews that extensively cover the metabolic efficiency of KB metabolism [48].

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Helen E. Scharfman, in Neurobiology of Brain Disorders, 2015

Ketogenic Diet

The ketogenic diet (KD) was first tested in people with epilepsy in 1921 by Russell Wilder,47 but was used less often once phenobarbital and other ASDs became available. In the 1990s, there was a resurgence of the KD after the son of a well-known movie producer was successfully treated and several programs about the KD were televised. The KD is typically used in children with drug-resistant epilepsy, and is successful in diverse types of epilepsy, such as severe myoclonic epilepsy in infancy, tuberous sclerosis, and infantile spasms.

The diet is a high-fat, low-carbohydrate, and low-protein diet, where the ratio of fat to carbohydrate and protein (in grams) is approximately 4 to 1. The response to the diet can be rapid in some patients and may take several weeks in others. The diet may be continued if seizures persist; in those patients where seizures stop, recurrence of epilepsy occurs in only 20%.

The reason for the efficacy of the KD is not entirely clear. It had been assumed that caloric restriction was an important component, because fasting can decrease seizures in patients with epilepsy47 and laboratory animals. Therefore, it had been recommended that the KD be administered with caloric restriction to 75% of the recommended dietary allowance (RDA). In addition, caloric restriction increases the production of ketones by the KD. Some studies suggest that caloric restriction is essential to the ability of the KD to stop seizures, but others have shown that it is not essential.

There are many hypotheses for the mechanism of action of the KD. The correlation of ketone levels with seizure control has led many to believe that ketones are directly responsible. In addition, the major ketone bodies, β-hydroxybutyrate, acetyl coenzyme A and acetone, all have actions that reduce seizures in laboratory animals. Another hypothesis is that the KD leads to greater production of mitochondria in neurons, and more energy. One of the reasons for increased mitochondria may be the effect of the KD to shift ATP production from glycolysis in the cytoplasm to mitochondria. Increased mitochondria could support ATPases like the Na+/K+ pump and help neurons to repolarize more quickly during seizures. As a consequence, seizures would be shortened.

A shift in cellular ATP production to mitochondria could prevent seizures in another way, based on the idea that ATP produced by glycolysis is near ATP-dependent K+ channels at the plasma membrane, but mitochondrial ATP production is not. Therefore, if glycolysis were reduced, ATP-mediated inhibition of the K+ channel would be reduced. The consequence would be K+ channel opening, causing hyperpolarization of the cell and reducing excitability.

Another explanation for the effects of the KD is based on the increased production of GABA and reduced release of glutamate-caused excess of the ketone body acetyl coenzyme A, which causes a shunt in the Krebs cycle towards production of α-ketoglutarate, which produces glutamate. One would think that an increase in glutamate levels would increase the likelihood of seizures, instead of having a protective effect, but there are two reasons why a reduction in seizures may occur instead: (1) glutamate is the precursor to GABA, so more GABA is produced; and (2) there may be a defect in the transport of glutamate into synaptic vesicles in the presence of the ketone body acetoacetate, because acetoacetate inhibits the vesicular glutamate transporter vGLUT-2. The enhanced concentration of adenosine caused by the KD has also been suggested to mediate the effects of the diet on seizures, because adenosine is an endogenous compound with anticonvulsant actions.

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