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