Effectiveness of the low glutamate diet as an adjunct treatment for pediatric epilepsy

Epilepsy is a chronic neurological disorder that results in seizures. About one third of patients are diagnosed with refractory epilepsy, meaning that they are unable to gain adequate seizure control through the use of anti-seizure medications. Alternative treatment options are critical for these patients, with one option being dietary therapy. The drawbacks of current dietary therapies include a range of side effects, in addition to being unable to supply all necessary nutrients. Hence, a novel dietary therapy with comparable efficacy to that of current dietary therapies that limits adverse events and increases nutrient intake would be advantageous. One potential option would be the low glutamate diet. Glutamate is the major excitatory neurotransmitter in the central nervous system. Animal models of epilepsy and brain microdialysis studies in humans with epilepsy have demonstrated elevated glutamate levels, which supports the excitation-inhibition imbalance theory of epileptogenesis. Increased blood brain barrier (BBB) permeability has also been observed in epilepsy, which in theory could allow dietary glutamate to enter the brain in higher amounts, thereby increasing seizure activity. Therefore, the current clinical trial investigated the effectiveness of the low glutamate diet as an adjunct treatment for refractory pediatric epilepsy. Patients ages 2-21 years old, with a minimum of 4 seizures per month, were recruited from the US and Canada. Participants underwent a baseline observation month, where seizure activity and 3 days of typical dietary intake were recorded. They were then randomized to the 1-month dietary intervention or 1-month wait-listed control group. Wait-listed controls continued onto the intervention diet following the 1-month wait-listed control period. During each month, families completed a seizure diary, 3-day food diary, food frequency questionnaire (FFQ), and online form, which included a Caregiver Global Impression of Change (CGIC) scale at the post diet timepoint. Measures were assessed within and between subjects (when applicable) after 1-month on the diet. Continuous variables from independent groups were assessed using a student’s t-test or Mann Whitney U test, depending on normality. Related samples were assessed via paired t-tests or Wilcoxon Signed Rank tests. Categorical data were analyzed via Chi-Square or Fisher’s Exact. Logistic regressions were conducted for significant bivariate analyses, with adjustments for potential confounding factors. Results indicated that there were no significant differences in percent change in seizure frequency between the diet and control groups. Pre-post diet analyses of all participants revealed that a clinical response (>50% seizure reduction) was observed in 21% of participants, 31% of caregivers reported improvement in their child’s overall health based on the CGIC, and 63% of caregivers reported ≥1 non-seizure improvements. Age was significantly associated with clinical response and overall health improvement at 1-month post diet. The likelihood of achieving a >50% seizure reduction decreased by 29% (0.71 [0.50-0.99], p=0.04) after adjusting for race, sex and change in food frequency questionnaire (FFQ) score. Similarly, the likelihood of achieving an overall improvement in health reduced by 29% (0.71 [0.54-0.92], p=0.01) with increasing age, after adjustment for sex, race, cognitive age, and change in FFQ score. This pilot study suggests that 1-month on the low glutamate diet may effectively reduce seizures in a small subset of pediatric epilepsy patients and may produce non-seizure improvements in a larger subset, even though the clinical efficacy of the diet does not equal that of current dietary therapies for epilepsy. Future research should evaluate longer-term exposure to this diet and the potential impact of improved micronutrient intake as compared to other dietary therapies.