Infantile spasms (IS) syndrome is a catastrophic, epileptic
encephalopathy of infancy that is often refractory to current
antiepileptic therapies. The
ketogenic diet (KD) has emerged as an alternative treatment for patients with medically
intractable epilepsy, though the prospective validity and mechanism of action for IS remains largely unexplored. We investigated the KD's efficacy as well as its mechanism of action in a rodent model of intractable IS. The
spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the KD (4:1
fats:
carbohydrate +
protein) or a control milk diet (CM; 1.7:1). 31Phosphorus magnetic resonance spectroscopy (31P MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and
sham-operated controls. The KD resulted in a peripheral
ketosis observed both in the blood and urine. The KD led to a robust reduction in the frequency of
spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the KD resulted in an intracerebral
acidosis as measured with 31P MRS. In addition, the respiratory profile of the lesioned rats on the KD was significantly altered with slower, deeper and longer breathing, resulting in decreased levels of expired CO2.
Sodium bicarbonate supplementation, acting as a pH
buffer, partially reversed the KD's protective effects on
spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the KD on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the KD produces its
anticonvulsant effects through changes in respiration leading to intracerebral
acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the KD in IS. Further research is required to determine whether the effects of the KD on breathing and intracerebral acid-base balance are seen in other paediatric models of
epilepsy.