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.

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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