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11 Ketogenic 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: b-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 com- mon 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 con- tributor 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, 140

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141 KETOGENIC DIET 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 hyperpolariza- tion (Bough and Rho, 2007). GABA is the primary inhibitor of neurotransmission, mak- ing 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 anticon- vulsant 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 ad- enosine 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 glu- tamate excitotoxicity, reduced mitochondrial ROS production, chronic hypoglycemia, and oxygen-glucose deprivation with in vitro exposure to beta-hydroxybutyrate of rat brain hip- pocampal 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 ef- fects. 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 bod- ies. 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

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142 NUTRITION AND TRAUMATIC BRAIN INJURY 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 implementa- tion 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 effec- tiveness 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 effective- ness 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 interven- tions 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. 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

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143 KETOGENIC DIET TABLE 11-1 Relevant Data Identified for Ketogenic Diet Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Freeman, Intractable Randomized, In addition There was no significant difference in 2009; Lennox-Gastaut double-blind, to a classic the number of parent-reported seizures Freeman syndrome crossover study ketogenic diet, between saccharin and glucose groups, et al., 2009 patients were and there was no difference in EEG- na=20 children, given 60 g/day identified events. The sequence of (days 1–2: all of saccharin treatment did not affect the number of patients fast; or glucose seizures identified by EEG. day 3: treatment (which began; days 6–7: At day 6, there was a reduction in both negates fasting; day 8: EEG-identified events (p=0.03) and ketosis and patients change parent-reported events (p=0.001). At day therefore treatment 12, frequency of seizures was significantly serves as groups, reduced from baseline (p=0.003). Finally, placebo) although serum b-hydroxyburate (BOH) treatment solutions; began; day 11: levels were significantly lower in glucose 24-hour EEGs treatment ends) groups when compared to saccharin were taken groups (p < 0.001), glucose group still on days 1, 6, had some levels of serum BOH (Freeman and 11 et al., 2009). Additionally, fasting appeared to effect seizure frequency regardless of treatment assignment. At day 6, EEG-identified events reduced by a median of 22.5 seizure per day (p=1.03), and parent- reported events reduced by 14.5 seizures per day (p=0.001) (Freeman, 2009). Neal et al., Intractable Randomized, Classic, There was no significant difference 2009 epilepsy double-blinded long-chain in mean seizure frequency reduction trial triglycerides between the two groups at 3, 6, or 12 ketogenic months. The type of ketogenic diet also n=94 children diet or had no significant effect on the number aged 2–16 years, of children achieving > 50% or > 90% medium-chain followed up at triglycerides seizure reduction. 3, 6, and 12 ketogenic diet months The classical ketogenic diet group had (MCT) a significantly higher mean acetoacetate level than the MCT group at 3, 6, and 12 months (p < 0.005 at all three periods) and higher BOH level at 3 and 6 months (p ≤ 0.001 for both). Seizure reduction was correlated with acetoacetate level (rb=–0.238, p < 0.036) and BOH level (r=–0.312, p < 0.01) at 3 months. There was no significant difference in tolerability to the two diet types, but the classical group reported lack of energy at 3 months and vomiting at 12 months more frequently (p < 0.05) than the MCT group. continued

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144 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Neal et al., Intractable Randomized, Diet group At 3 months, the diet group had a 38% 2008 epilepsy controlled trial (n=73) reduction in average seizure frequency, received whereas the control group had a 37% n=145 children ketogenic diet; increase; the difference between the two aged 2–16 years, groups was 76.6% (95% CIc: 44.4–108.9; control group (n=103 included p < 0.0001). The treatment had no (n=73) had in final analysis) no change to significant effect on the type of seizure their diet (generalized vs. focal) experienced by patients in either group. Levy and Epilepsy (all Meta-analysis Ketogenic diet No randomized controlled trials were Cooper, seizure types and of randomized (mainly classic found in the search of the literature; 2003 syndromes) control trials and MCT) therefore, risk of bias and treatment effect vs. placebo could not be determined. or other antiepileptic treatment Tier 2: Observational studies Beniczky Severe Retrospective Ketogenic diet After 3 months, 33 of the 50 patients had reduced seizure frequency of ≥ 50%. Of et al., 2010 pharmacoresistant study these 33 patients (responders), 18 had a > epilepsy n=50 90% reduction. Patients who had < 50% reduction had significantly greater epileptiform discharge (p=0.03) compared to responders. A multivariate analysis showed that epileptiform discharge was an independent predictor of treatment failure (ORd=5; 95% CI: 1.2–20). The difference in incidence of epileptiform discharge between responders with > 90% reduction and non-responders was significant (p=0.04).

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145 KETOGENIC DIET TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Coppola Refractory n=38 children, For 29 A seizure frequency reduction of 50% et al., 2010 epilepsy aged 3 months children, at was seen in 76% of children at 1 month, encephalopathies to 5 years, least 80% 77% at 3 months, and 100% at 6, 9, and affected by of their 12 months. Response to treatment was drug-resistant daily caloric not significantly associated with epileptic symptomatic intake came syndrome, age, sex, or etiology type. partial epilepsy from ketocal BMI also was not associated with efficacy and cryptogenic- milk during of ketogenic diet. Adverse side effects symptomatic the study; were recorded in 65.8% of the children. epileptic 9 patients encephalopathies were fed with classic ketogenic diet because of poor compliance with ketocal milk Average time on diet was 10.3±7.4 months Patel et al., Intractable Questionnaires Ketogenic diet A significantly greater (p=0.0001) number of children had a > 50% seizure reduction 2010 epilepsy n=101; median at the time of the survey (79%) than at age at the time the time of ketogenic diet discontinuation of survey was (52%). 13 years (range 2–26 years) While 96% of survey responders would recommend ketogenic diet treatment to median others, only 54% would try said diet ketogenic diet prior to anticonvulsants if given the treatment choice again. duration was 1.4 years (range The effect of ketogenic diet on growth 0.2–8 years); in children younger than 18 years was median time measured using z-scores. The mean z-score for height was –1.3 (SEMe=0.2) since treatment stopped was and for weight was –0.8 (SEM=0.2). 6 years (range BMI was used for patients older than 18; 0.8–14 years) average BMI was 22.2. A few survey responders reported adverse effects such as cardiovascular diseases, kidney stones, bone fractures, and increased illnesses. continued

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146 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Evangeliou Refractory Pilot, Ketogenic diet Adding BCAA to ketogenic diet resulted et al., 2009 epilepsy prospective supplemented in a 100% seizure reduction in 3 patients study by powdered who had previously experienced seizure mixture of reduction on ketogenic diet alone. n=17 children, branched- 4 patients who already had > 50% aged 2 to 7 chain amino years reduction on ketogenic diet alone acids (BCAA) achieved an additional 20–30% (45.5 g reduction. One patient, who had 20% leucine, 30 g reduction on ketogenic diet alone, isoleucine, and achieved 50% reduction after adding 24.5 g valine) BCAA. Fat-to-protein Addition of BCAA did not reduce seizure ratio with in patients who didn’t already experience addition seizure reduction on ketogenic diet only. of BCAA No reduction in ketosis was found with changed from the addition of BCAA. 4:1 to around 2:5:1 No side effects were observed except 3 patients with slight increase in heart rate at initiation, which returned to normal. Mosek Refractory Prospective, Classic Only 2 patients were on the diet for the et al., 2009 epilepsy pilot study ketogenic diet full 12 weeks; they had more than a 50% treatment reduction in the frequency of seizures. n=8 patients, (90% fat) for aged 18 to Compared to baseline, patients on 12 weeks 45 years ketogenic diet for 4–7 weeks experienced a 26% increase in cholesterol (p < 0.02) with at least and 32% increase in LDL (p < 0.03). two monthly focal seizures Those on ketogenic diet for 11–12 weeks documented had a 33% increase in cholesterol (p by 8-week < 0.002) and 54% increase in LDL (p follow-up < 0.0001). No significant changes in HDL or triglycerides were recorded. Improvement in quality of life was reported in only 3 patients. 72% of patients had > 50% reduction in Nathan Uncontrolled Prospective, Ketogenic diet frequency of seizures (p < 0.05) compared et al., 2009 epilepsy non-blinded consisting of study typical Indian to baseline. foods n=105 children, Of the two major types of seizure, there aged 4 months was a greater reduction in epileptic to 18 years; encephalopathies than in localization- related seizure (p < 0.05). average follow-up The average number of anti-epileptic duration was drugs (AEDs) was significantly reduced 25.7±20.3 by the end of the study (p < 0.005) from months 3.67 to 1.95. 11 patients completely stopped taking AEDs, while 70 patients took fewer drugs, and 23 patients took the same number of drugs (p < 0.005). Minor and temporary adverse effects were recorded such as gastrointestinal disturbances.

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147 KETOGENIC DIET TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results At 12 months, a slight reduction (< 85%) Nikanorova Encephalopathy n=5 children Conventional et al., 2009 with continuous between 8 antiepileptic in spike-wave index was seen in only spikes and waves and 13 years drugs and patients 1 and 2; patients 3 and 5 had an during slow sleep old (1 patient steroids increase from baseline. (CSWS) withdrew from supplemented At 24 months, patient 1 experienced an treatment at with ketogenic increase in spike-wave index, patient 2 9 months); diet remain the same, patient 3 decreased to follow-up period normal level (CSWS ceased), and patient was 2 years 5 experienced a decrease. The changes in after starting spike-wave index were correlated with ketogenic diet IQ scores—an increase in spike-wave index was associated with lowered IQ score, and a decrease was associated with improvement or maintenance of IQ score. The diet was well tolerated, and no adverse effects were mentioned. Porta et al., Intractable Retrospective Ketogenic diet After 1 month, there was no significant 2009 epilepsy study or modified difference in the number of responders (i.e., children with > 50% seizure Atkins diet n=27 children; reduction) between the two groups; 59% follow up at in ketogenic group, 50% in modified 1, 3, 6, and 12 Atkins group. months After 3 months, ketogenic group had significantly more responders than modified Atkins group (p=0.03); 64% vs. 20%. However, the significance disappeared after 6 months; 41% vs. 20%. Median frequency of status epilepticus in both diet groups was significantly lowered from 1 at baseline to 0 (p=0.005). Children’s serum fatty acid levels were tested. After 1 month, responders had higher levels of serum palmitoleic acid and lower levels of arachidonic acid (p < 0.05). And after 3 months, responders had lower levels of arachidonic acid and docosahexaenoic acid (p < 0.05). continued

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148 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Sharma Refractory Prospective, Ketogenic diet At 3 months, 24 of the 27 children were et al., 2009 epilepsy uncontrolled on the diet, but 3 discontinued the diet. study Of the 24, 66.7% of them achieved a > 50% reduction in seizure frequency, n=27 children, with 12.5% completely seizure-free. 15 aged 6 months children were on the diet at 6 months. to 5 years, Among these, 86.7% had > 50% with at least reduction. At 12 months, only 10 children 1 seizure/day were still on the diet, and all of these (or at least 7 children had > 50% reduction. seizures/week); follow-up at Biochemical analysis show that, over 1, 3, 6, and 12 the study period, the children had a months significant decrease in serum albumin (p=0.05) and a significant increase in spot urinary calcium-creatinine ratio (p=0.03) compared to baseline. Lipid profiles showed no significant change over the study period. Digestive disorder was the most common side effect, experienced by 74% of patients. 14 patients had > 50% reduction in Spulber Pharmotherapy- Prospective Ketogenic diet et al., 2009 resistant epilepsy study for 12 months seizure frequency. n=22 children Standard deviation scores (SDSs) of (median age children’s weight, height, and BMI of 5.5 years); decreased significantly after 1 year of ketogenic diet (p < 0.05); the median height, height velocity, weight, height SDS decreased 0.12 from 1 BMI, and year before to just before starting the insulin-like ketogenic diet, and it decreased 0.37 from growth factor just before to 1 year after starting the I (IGF-I) level ketogenic diet. were taken 1 In the same intervals, weight SDS year before decreased 0.17, then 0.52; and BMI SDS diet, just before decreased 0.33, then 0.5. The difference starting diet, between the SDSs of these measurements and 1 year after 1 year before and just before starting diet ketogenic diet was not significant. Height velocity, calculated at just before the start of ketogenic diet and 1 year after, was significantly lower after ketogenic diet (p < 0.05); it decreased by 3.5. IGF-I also decreased 2.21 (p < 0.05). Height velocity correlated negatively with b-hydroxybutyric acid level during ketogenic diet (r=–0.48, p < 0.05) and positively with serum IGF-I both before (r=0.52, p < 0.05) and during (r=0.41, p < 0.05) the diet. No adverse effects were mentioned.

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149 KETOGENIC DIET TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results At 1 month, 10 children had > 50% Villeneuve Pharmacoresistant Retrospective Ketogenic diet et al., 2009 focal epilepsy, study reduction in seizure frequency. Children with recent with recent worsening of seizure n=22 children, worsening of frequency before ketogenic diet were aged 5 months seizure frequency more likely to be responders than children to 18.5 years, (100% frequency who did not experience a recent increase with focal increase within in seizures (70% vs. 25%, p=0.046). 7 epilepsy; of past month) children who were responders at 1 month these, 10 had continued their response to the diet after recent worsening 6 months. of seizures 10 children experienced no side effects on the diet, but 4 patients experienced severe vomiting and 1 patient, severe anorexia. The remaining patients reported minor adverse effects. You et al., West syndrome n=98 children, Ketogenic During the study, 48 children’s West 2009 (infantile spasms) monitored for 3 diet (n=33), syndrome (49%) evolved into Lennox- years antiepileptic Gastaut syndrome, which has a worse drugs (n=31), prognosis. hormonal Bivariate logistic regression analysis therapy showed that children who were treated (n=60), with ketogenic diet, hormone therapy epileptic (prednisolone or adrenocorticotropic), surgery (n=3), or a combination of the two had a and either lower risk of West syndrome evolving to no treatment Lennox-Gastaut syndrome (p < 0.05). or herbal medication No other adverse effects were mentioned. (n=4) Hemingway Epilepsy Follow-up to Classical At the follow-up for the current study et al., 2001 prospective ketogenic diet (3–6 years after the original study), 20 study children were seizure free, 21 had 90– 99% seizure reduction, 24 had 50–90% n=150 children reduction, and 18 had < 50% reduction. with difficult-to- control seizures 83 of the 150 children were still on the diet at 12 months; of these, 11 were seizure free, 41 had > 90% reduction in seizure frequency, and 74 had > 50% reduction. 28 children were not taking any medication, and 45 were taking ≥ 1 medication at follow-up. 135 of the 150 children had discontinued the diet at follow-up. Of these, 27 discontinued because of improvement in seizure control, 49 because of ineffectiveness of the diet, 27 found the diet too restrictiveness, 28 stopped because of illness, and the remaining 4 were lost to follow-up. 4 children died and 9 children underwent cortical resection surgery. continued

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150 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Tier 3: Animal studies Appelberg TBI, controlled Male, Sprague- Postinjury, Ketogenic diet had no effect on the weight et al., 2009 cortical impact Dawley rats (35 ketogenic diet of the older rats. But younger rats on (CCI) days and 75 or standard ketogenic diet weighed less than rats of the same age on standard diet (p < 0.05). days old) diet for 7 days The older rats’ performance on beam walking test was not affected by injury or diet. However, injured 35-day-old rats on standard diet had significantly worse performance than all other groups of the same age (p < 0.05). Among older rats, footslips were more frequent in injured than uninjured rats (p < 0.05) on all days; specifically, injured rats on ketogenic diet had the most number of footslips. Among younger rats, footslips were most frequent in injured, untreated rats than all other groups (p < 0.05); injured rats on ketogenic diet had fewer footslips than sham-injured rats (p < 0.05). Injured 75-day-old rats had worse performance than sham-injured rats (p < 0.05), and ketogenic diet did not improve performance. In 35-day-old rats, injured, untreated rats performed worse than injured, treated rats and sham-injured rats (p < 0.05); performance of treated rats were not different from sham-injured rats. Swim speed was not affected by age, injury, or diet. While injury increased brain edema (p < Hu et al., TBI, Feeney’s Male, juvenile Postinjury, 2009b weight-drop Sprague-Dawley ketogenic or 0.01 vs. sham), ketogenic diet after injury reduced edema (p < 0.01 vs. injured rats model rats normal diet on normal diet). Compared to injured rats on normal diet, injured rats fed with ketogenic diet had decreased cytosolic cytochrome c level (p < 0.01) and increased cytochrome c immunoreactivity (p < 0.05). Injured rats had greater apoptosis and increased caspase-3 expression compared to uninjured rats (p < 0.01 for both), but treatment with ketogenic diet significantly reduced apoptosis and caspase-3 expression (p < 0.01 vs. injured, untreated rats).

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151 KETOGENIC DIET TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Hu et al., TBI, Feeney’s Male, juvenile Postinjury, Bax mRNA and protein levels were increased significantly by TBI (p < 0.01 2009a weight-drop Sprague-Dawley ketogenic or model rats normal diet vs. sham-injured rats) and decreased by ketogenic diet (p < 0.01 vs. rats on normal diet). Bcl-2 mRNA and protein levels were not affected by injury or diet. Apoptosis in the penumbra area was increased after TBI (p < 0.05 vs. sham-injured rats), but was decreased with ketogenic diet (p < 0.01 vs. rats on normal diet). Jarrett Epilepsy Adolescent, male Ketogenic or After 3 weeks, rats on ketogenic diet had higher serum b-hydroxybutyric levels et al., 2008 Sprague-Dawley control diet (p < 0.0001) and lower glucose levels rats (P28) for 3 weeks (p < 0.01). Assessment of hippocampal mitochondria showed significantly higher GSH levels (p < 0.01), but not GSSG levels. Rats on the ketogenic diet also had increased GSH-GSSG ratio (p < 0.05) and reduced GSH/GSSG redox potential compared to control rats (–246.6 mV vs. –230.0 mV; p < 0.05). Measurements of the two GSH biosynthetic enzymes, GCL and GS, showed 1.3 times increased activity in GCL (p < 0.05), but none in GS. Compared to control rats, subunit GCLM showed a 1.6-fold increase (p < 0.05) and GCLC showed a 1.9-fold increase (p < 0.01). To confirm the results from measurements of GSH and GSSG, a second redox couple was measured, CoASH/CoASSG. Compared to control rats, hippocampal mitochondria in rats on Ketogenic diet showed significantly increased levels of CoASH (p < 0.05), but not CoASSG, and an increased CoASH/CoASSG ratio (p < 0.05). Levels of lapoic acid were increased in the hippocampus of ketogenic diet rats, but not in the frontal cortex (p < 0.05). H2O2 production in isolated mitochondria was significantly decreased in ketogenic diet rats (p < 0.05), while no difference between the groups was observed in H2O2 production in hippocampal homogenate. When exposed to exogenous H2O2, control rats exhibited significant mtDNA damage that increased with time (p < 0.0001). continued

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152 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 11-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Prins et al., TBI, controlled Male, Sprague- Postinjury, Ketogenic diet had no effect on contusion 2005 cortical impact Dawley rats ketogenic diet volume of 17-and 65-day-old rats, but it decreased contusion volume of 35- (by aged 17, 35, 45, 58%, F=0.019, p < 0.001) and 45-day-old and 65 days (by 39%, F=0.074, p < 0.05) rats. Glucose level was increased in all age groups on ketogenic diet at 24 hours (p < 0.05) compared to rats on normal diet. Additionally, 35-day-old rats showed increased glucose at 1 hour as well as 7 days, and 45- and 65-day-old rats had increased glucose at 7 days. 17- and 35-day-old rats had decreased lactate level at 7 days (p < 0.05), while 45- and 65-day-old rats on ketogenic diet had decreased lactate level at 24 hours (p < 0.05). b-hydroxybutrate level was decreased in rats on ketogenic giet across all age groups at 24 hours and 7 days (p < 0.01 vs. rats on normal diet). a n: sample size. b r: correlation coefficient. c CI: confidence interval. d OR: odds ratio. e SEM: standard error of mean. 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 gluta- mergic 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-

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153 KETOGENIC DIET 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 clas- sic 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 experienc- ing 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, Parkin- son’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 ben- eficial 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

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154 NUTRITION AND TRAUMATIC BRAIN INJURY 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 effective- ness 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, im- portant 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 pre- scribe 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 produc- tion. 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 recom- mendations following injury. RECOMMENDATION 11-1. DoD should conduct animal studies to examine the spe- cific 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 com- pliance 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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