Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in patients with drug resistant epilepsy. However, current pharmacological interventions are only partially effective since 30% of epilepsy patients do not respond to antiepileptic drugs (AEDs). Dravet Syndrome (DS) is a severe infantile-onset epileptic encephalopathy caused by mutations in SCN1A with a high incidence of SUDEP. Affected children respond poorly to available AEDs. One of the few clinically-proven dietary therapies that have successfully helped patients, especially children, with refractory epilepsy is the high-fat, low-carbohydrate Ketogenic Diet (KD). However, the mechanism underlying the anticonvulsant action of the KD remains elusive. A common theory is that the KD works through ketosis, despite the fact that circulating levels of ketone bodies correlates poorly with seizure protection. Previously, we found that DS mice are protected from postictal death by treatment with two different KDs, even when ketosis is abolished by adding glucose to their water. We hypothesize that the KD reduces the frequency and severity of seizures not through ketosis, but rather by a specific dietary component that causes changes in brain excitability. Methods: C57BL/6J mice littermates were placed either on a ketogenic diet (n=8) or a conventional diet (n=8) soon after weaning (P20) for five days. At P25, mice were sacrificed and perfused with 10-15ml cold, heparinized PBS and the forebrain was extracted. Levels of serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), L-tryptophan (Trp), dopamine (DA), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and norepinephrine (NE) were measured as pg per mg wet tissue using HPLC-ECD with isoproterenol as an internal standard. Statistical comparisons among groups were carried out with nonparametric Mann-Whitney U-tests (significance level set at p Results: 5-HT and Trp content was significantly higher (in mice on the KD compared to littermates on a control diet (p=0.0379 and p=0.02, respectively). There was a trend towards higher 5-HIAA content,but was not statistically significant (p=0.065). DOPAC, DA, HVA, and NE levels remained unchanged (p=0.956, p=0.116, p=0.351, p=0.102, respectively). Conclusions: Our findings suggest that the KD may alter 5-HT metabolism, raising the possibility that the anticonvulsant mechanism is due in part to augmentation of the 5-HT system.  Funding: NIH / NINDS U01 NS090414