ABSTRACT
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.
ABSTRACT
The purpose of this study was to determine time of onset of ketosis and efficacy when the classic ketogenic diet is initiated at full calories without a prior fast in children with epilepsy. A retrospective hospital and neurology clinic chart review was done of all 14 children commenced on the classic ketogenic diet at full calories without a prior fast between January 1, 1997, and May 31, 2001, to determine time to ketosis, time to good ketosis (urine ketones > or =80 mg/dL), and success of the ketogenic diet. Median age at diet initiation was 63 months (25th-75th percentile 47-149 months). There were 7 girls and 7 boys. Four had symptomatic generalized epilepsy, whereas the remainder had partial seizures +/- secondary generalization. Twelve of 14 children suffered seizures on a daily basis prior to the ketogenic diet. Six were commenced on the diet as outpatients, whereas 8 were admitted to hospital. No patients were fasted. All admitted patients were started on a 1:1 ketogenic ratio at full calories for the first 24 hours and advanced to a 3:1 or 4:1 ratio over 3 to 4 days, while outpatients were started on a 1:1 or 2:1 ratio and similarly advanced. Thirteen of 14 patients were successfully started on the diet, with 1 developing vomiting and food refusal during the initial hospitalization but after ketosis was established. One child was lost to follow-up after initial hospital discharge. Information regarding time to ketosis was determined for all inpatients. Mean time to onset of ketosis was 33 hours (range 17 to 48) and to good ketosis, 58 hours (range 40 to 84). Five of 12 children (42%) experienced success with the ketogenic diet, and all of these had their antiepileptic medications either withdrawn (n = 3) or decreased (n = 2). The ketogenic diet can be effectively initiated without a fast in children with epilepsy. Time to ketosis and diet efficacy are similar to protocols that use a fast.
