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Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington (DC): National Academies Press (US); 2011.

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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

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11Ketogenic Diet

Originally developed to mimic biochemical changes associated with starvation or periods of limited food availability, the ketogenic diet is composed of 80–90 percent fat and provides adequate protein but limited carbohydrates (Gasior et al., 2006). In normal metabolism, carbohydrates contained in food are converted into glucose, which is the body’s preferred substrate for energy production. Under some circumstances, like fasting, glucose is not available because the diet contains insufficient amounts of carbohydrates to meet metabolic needs. Consequently, fatty acid oxidation becomes favored, and the liver converts fat into fatty acids and ketone bodies that serve as an efficient alternative fuel for brain cells. The conversion leads to the synthesis of three ketone bodies in particular: β-hydroxybutyrate, acetoacetate, and acetone. Although fatty acids cannot cross the blood-brain barrier, these three ketone bodies can enter the brain and serve as an energy source.

KETOGENIC DIET AND THE BRAIN

Since their development to treat epileptic children in 1921, ketogenic diets have been most studied in the context of pediatric epilepsy syndromes (Kossoff et al., 2009), but the ketogenic diet has been further shown to be neuroprotective in animal models of several central nervous system (CNS) disorders, including Alzheimer’s disease (AD), Parkinson’s disease, hypoxia, glutamate toxicity, ischemia, and traumatic brain injury (TBI) (see Prins, 2008, for a review). Neurodegenerative disorders and other CNS injuries share some common pathophysiological events with the metabolic injury cascade that follows TBI, such as the increased production of reactive oxygen species (ROS) and mitochondrial dysfunction. Despite evidence of efficacy and a track record of clinical use and animal research on the ketogenic diet’s antiepileptic action, the mechanisms by which the ketogenic diet confers neuroprotection are still poorly understood.

The effect of the ketogenic diet on energy metabolism is believed to be a key contributor to the diet’s neuroprotective action, possibly by increasing resistance to metabolic stress and resilience to neuronal loss through the upregulation of energy metabolism genes, stimulation of mitochondrial biogenesis, and enhancement of alternative energy substrates (Bough, 2008; Bough et al., 2006; Davis et al., 2008; Gasior et al., 2006). The ketogenic diet is also hypothesized to promote neuroinhibitory actions. One aspect of this hypothesis is an associated modification of the tricarboxylic acid cycle to increase the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA), leading to neuronal hyperpolarization (Bough and Rho, 2007). GABA is the primary inhibitor of neurotransmission, making a neuron more refractory to abnormal firing due to hyperpolarization. Seizures can be decreased by effects on GABA such as increasing its synthesis or decreasing its metabolism and breakdown. For this reason, GABA effects are an important target for some anticonvulsant drugs. Polyunsaturated fatty acid (PUFA) levels are likewise increased in patients on the ketogenic diet, and consequently induce the expression of neuronal uncoupling proteins (UCPs) (Fraser et al., 2003; Freeman et al., 2006). In one experimental study, mice fed a ketogenic diet were found to have increased UCPs, thus limiting the generation of ROS (Sullivan et al., 2004). Other mechanisms that possibly contribute to neuroprotection and enhanced mitochondrial function include, but are not limited to, promoting synthesis of adenosine triphosphate (ATP), interfering with glutamate toxicity, and bypassing the inhibition of complex I in the mitochondrial respiratory chain (Gasior et al., 2006; Prins, 2008; Zhao et al., 2006). Premature electron leakage occurs at complex I; moreover, it is one of the main sites of production of harmful superoxide and resultant apoptosis. Bypassing complex I can therefore reduce production of ROS and nonlytic cell death.

There have been two studies demonstrating evidence of neuroprotection against glutamate excitotoxicity, reduced mitochondrial ROS production, chronic hypoglycemia, and oxygen-glucose deprivation with in vitro exposure to beta-hydroxybutyrate of rat brain hippocampal slice cultures that were subsequently subjected to chronic hypoglycemia, oxygen-glucose deprivation, and N-methyl-D-aspartate-induced excitotoxicity (Maalouf et al., 2009; Samoilova et al., 2010).

USES AND SAFETY

Because ketone bodies are typically developed as an alternative energy source during intervals of fasting or starvation, they are not considered an essential nutrient nor has their absence been considered a nutritional deficiency. The traditional ketogenic diet consists of four parts fat to one part protein, with the fat components derived primarily from long-chain fatty acids. Modifications to the ketogenic diet have included a change of ratio to three parts fat to one part protein, the use of medium-chain triglycerides (MCT) for the fat component, and substitution of a modified Atkins diet or low-glycemic-index diet.

The most well-known clinical application of the ketogenic diet is in pediatric epilepsy syndromes, whose patients generally tolerate the special diet well with only mild side effects. Long-term use in the pediatric population has sometimes been associated with growth retardation, kidney stones, bone fractures due to osteopenia, and hypercholesterolemia; short-term side effects include low-grade acidosis, constipation, dehydration, vomiting or nausea, and hypoglycemia (if there is an initial fasting period) (Prins, 2008).

Consideration of adverse effects should take into account complications that may arise from the associated state of starvation or fasting that may lead to formation of ketone bodies. Such starvation is typically designed to provide 80–90 percent of the estimated caloric needs, based on age and weight (Kossoff et al., 2009). When diet is the primary means of achieving ketosis, there may be a need to consider an intermittent timing schedule. There have been some studies utilizing exogenous administration of ketone body precursors such as 1,3-butanediol or MCT, but there have been reports of adverse gastrointestinal symptoms such as diarrhea from one such exogenous ketogenic agent (Henderson et al., 2009). At least one prospective study among patients with refractory epilepsy also noted that patients had difficulty adhering to the specialized diet and experienced a considerable (albeit reversible) increase of cholesterol levels, thus indicating possible impediments to long-term implementation of the ketogenic diet as a therapeutic agent (Mosek et al., 2009).

EVIDENCE INDICATING EFFECT ON RESILIENCE

There are no human clinical studies or animal studies that have specifically evaluated associations between the use of ketogenic diet and resilience prior to CNS injury.

EVIDENCE INDICATING EFFECT ON TREATMENT

A relevant selection of animal studies (years 1990 and beyond) illustrating the effectiveness of the ketogenic diet in treating TBI in the acute phase of injury is presented in Table 11-1. This table also includes supporting evidence from human studies from the same time frame that evaluate the treatment efficacy of the ketogenic diet for other CNS injuries or disorders, such as epilepsy, hypoxia, and ischemic stroke. Some evidence of the effectiveness of the ketogenic diet on neurodegenerative disorders, like amyotrophic lateral sclerosis (ALS), AD, and Parkinson’s disease, is also included in the following discussion and Table 11-1, even though this report, in general, does not review the efficacy of nutritional interventions on long-term effects of TBI. There were frequent tolerability side effects in humans, which are listed along with other side effects if mentioned by the authors.

TABLE 11-1. Relevant Data Identified for Ketogenic Diet.

TABLE 11-1

Relevant Data Identified for Ketogenic Diet.

Human Studies

There are no known human clinical trials evaluating the role of ketogenic diet in TBI; however, ketogenic diets have been shown to be effective in difficult-to-treat childhood epilepsy syndromes in many cohort studies and two recent clinical trials. The classic 4:1 ketogenic diet, as well as modified ketogenic diets like the MCT diet, demonstrated similar efficacy in symptomatic generalized epilepsy syndromes and partial epilepsy syndromes, with the majority of cohort studies indicating greater than 50 percent reduction in seizures (Beniczky et al., 2010; Coppola et al., 2010; Nathan et al., 2009; Porta et al., 2009; Sharma et al., 2009; Villeneuve et al., 2009). A combined analysis of outcome data from eleven cohort studies published since 1970 estimated that 15.8 percent of patients became free of seizures, 32 percent experienced greater than 90 percent reduction in seizure frequency, and nearly 56 percent of the patients had greater than 50 percent reduction of seizures (Cross and Neal, 2008). Similar results were found in a systematic review of 14 studies (Keene, 2006); however, the 2003 Cochrane review on the ketogenic diet for epilepsy concluded that although the diet is a treatment option for patients with difficult epilepsy (those taking multiple antiepileptic drugs), there is no reliable evidence from randomized control trials to support the diet’s general use in people with epilepsy (Levy and Cooper, 2003).

When the first multi-center, randomized control trial was reported in 2008 (Neal et al., 2008), the results at three months showed a significant effect in achieving seizure control, with a greater than one-third reduction in seizure frequency in the diet group compared to controls. This study found no significant differences in efficacy at 3, 6, and 12 months between classical ketogenic diets that contained long-chain fatty acids, and a modified ketogenic diet with MCTs (Neal et al., 2009). A clinical trial of children with intractable Lennox-Gastaut syndrome investigated the efficacy of the ketogenic diet in conjunction with a solution of either glucose or saccharin (60 g/day) to negate ketosis after a 36-hour fasting period, and found a similar significant decrease in seizures (Freeman et al., 2009).

Long-term beneficial outcomes to 24 months have been demonstrated with the ketogenic diet in certain childhood epilepsy syndromes (Kossoff and Rho, 2009). These studies have led to even more recent understandings regarding the mechanism of action, such as recent evidence that suggests the ketogenic diet mechanism is related to its increasing extracellular adenosine and the actions of adenosine at the A1 receptor, which include inhibiting glutamergic effects (Masino et al., 2009).

Studies show that the percentage of patients remaining on a ketogenic diet beyond 24 months decreases over time. Hemingway and colleagues (2001) found that 39 percent of patients remained on the diet at two years, 20 percent at three years, and 12 percent at four years. The main reason given for discontinuing the ketogenic diet beyond 24 months was the patient being seizure-free or having a significant seizure reduction. Although there are no human short- or long-term studies evaluating the ketogenic diet for TBI, these data suggest that use of the ketogenic diet should be most strongly considered during the initial rehabilitation interval associated with the greatest gains.

As mentioned earlier, several observational studies have investigated the use of ketogenic diets modified in an effort to improve tolerability. In 2009, Evangeliou and colleagues exam ined the role of branched-chain amino acids (BCAAs) as a supplemental therapeutic agent to the ketogenic diet in children with intractable epilepsy, based on evidence of antiepileptic action in animal models (for further discussion on the role of BCAAs in TBI and other CNS injuries, see Chapters 4 and 8). Although the fat-to-protein ratio was altered from the classic 4:1 to 2.5:1, there was no observed effect on ketosis. Furthermore, 47 percent (n = 17) of the patients who had already achieved a reduction of seizures on the ketogenic diet saw an even greater reduction after the BCAA supplementation, with three patients experiencing a complete cessation of seizures (Evangeliou et al., 2009). Further studies are needed to examine this particular combination; however, the results of this prospective pilot suggest a possible synergistic action between the ketogenic diet and BCAAs.

Pharmacological research on dementia has used a cognitive assessment instrument known as the Alzheimer’s disease (AD) Assessment Scale-Cognitive subscale (ADAS-Cog), which provides quantification of cognitive domains such as memory and attention in order to assess outcomes. There is some evidence that administering a form of MCTs in patients with a normal diet increased the serum level of the ketone body gamma hydroxybutyrate and increased ADAS-Cog scores in a population of patients with mild to moderate AD compared to placebo in the same population (Henderson et al., 2009; Reger et al., 2004). Given that multiple studies have shown a decreased risk of developing AD in those consuming foods high in essential fatty acids, it is also possible that the ketogenic diet may confer greater neuroprotection in people with AD than normal or high-carbohydrate diets (Gasior et al., 2006; Henderson, 2004; Morris et al., 2003a, 2003b).

Animal Studies

Studies with a rat model of TBI have suggested reduction in volume of damage and improved recovery with use of the ketogenic diet (Prins, 2008). One study demonstrated increased protection against oxidative stress and deoxyribonucleic acid damage because of increased redox status in the hippocampus (Jarrett et al., 2008). Several investigators have identified an age-dependent effect in rat TBI models, with greater levels of reduction of edema, cytochrome c release, and cellular apoptosis being observed in younger rats (Appelberg et al., 2009; Hu et al., 2009a).

Evidence of neuroprotection has been demonstrated with 24-hour fasting in rodent models of controlled cortical impact injury following moderate but not severe injury. Fasting for 48 hours demonstrated no significant benefit (Davis et al., 2008).

As mentioned earlier, animal studies have evaluated the ketogenic diet in stroke, another form of acquired brain injury, as well as in neurodegenerative disorders such as AD, Parkinson’s disease, and ALS (Gasior et al., 2006; Prins, 2008; Zhao et al., 2006). The majority of experimental studies in other models of CNS injury support the evidence suggesting beneficial effects of the ketogenic diet. It is also important to note that age-related differences in ketogenesis and cerebral utilization of ketones have been observed in animal models, and suggest the developing brain has a greater capacity to generate, transport, and utilize ketone bodies as an energy substrate (Appelberg et al., 2009; Prins, 2008; Prins et al., 2005).

Because the only TBI data available has been from rodent models, there are significant limitations (as stated in Chapter 3) in correlating the results from animal studies to humans (e.g., rodents tend to eat immediately after injury, which is not typical human behavior). An additional limitation encountered when conducting energy metabolism studies with rodents is that they have lesser energy reserves than humans and a higher metabolic rate; prolonged fasting also can be more devastating to rodents than to humans. Fasting rodents for longer than a few days will likely result in their death, while uninjured humans can fast for five to six weeks without mortality. However, feeding rats a fat-only diet has been demonstrated to prolong survival (Moldawer et al., 1981) and should be investigated as a possible model to measure the efficacy of compounds that alter energy metabolism.

CONCLUSIONS AND RECOMMENDATIONS

Based on the evidence presented, the ketogenic diet does hold some promise of effectiveness in improving the outcomes of TBI. There are indications that ketones may provide an alternative and readily usable energy source for the brain that might reduce its dependence on glucose metabolism, which may be impaired immediately following TBI. However, important knowledge gaps must be addressed before either the classic or modified ketogenic diet can be recommended as a treatment for TBI. Although it would not be feasible to prescribe ketogenic diets to improve resilience against TBI, identifying dietary compounds that are precursors of ketones, such as medium-chain triglycerides, and evaluating whether they have positive effects when administered after the injury is warranted.

There is a general need for demonstration of the benefit of ketone bodies and ketogenic diets in human TBI, including the use of exogenous agents to enhance the production and utilization of ketone bodies. Several questions relate to that broad gap in knowledge. None of the animal models previously used has incorporated blast injury as a mechanism for TBI. An appropriate animal model for following TBI recovery is also necessary to evaluate the efficacy and applicability of a ketogenic diet. This nutritional strategy utilizes an alternative metabolic pathway, and there is limited data on issues such as dosing and duration of either diet-controlled ketosis or exogenous administration of agents that enhance ketone production. As with other interventions considered in this report, there is an absence of information on which forms of TBI—mild/concussion, moderate, severe, and penetrating—might benefit from such therapy. Another consideration is the feasibility of prescribing such a strict diet when treating nonhospitalized patients. Although ensuring compliance with any nutrition intervention may present a challenge, this is especially true when the whole diet needs to be altered. Because of the diversity of nutritional needs and metabolic demands of military service, diet-induced ketosis also may not be practical for treatment of military injuries, especially in the context of polytrauma and the need to balance other nutritional recommendations following injury.

RECOMMENDATION 11-1. DoD should conduct animal studies to examine the specific effects of ketogenic diets, other modified diets (e.g., structured lipids, low-glycemic-index carbohydrates, fructose), or precursors of ketone bodies that affect energetics and have potential value against TBI. These animal studies should specifically consider dose, time, and clinical correlates with injury as variables. Results from these studies should be used to design human studies with these various diets to determine if they improve outcome against severe TBI. These studies should include time as a variable to determine whether there is an optimal initiation point and length of use.

RECOMMENDATION 11-2. If these studies show benefits, then DoD should further investigate whether the potential beneficial effect of such ketogenic or modified diets or precursors to ketone bodies applies to concussion/mild and moderate TBI. Before conducting these studies, DoD should consider the feasibility (i.e., how to ensure compliance with a modified diet) of using diets that affect the metabolic energy available, such as ketogenic diets, for the treatment of TBI.

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