Abstracts

Rationale: Infantile Spasms (IS) is a catastrophic, developmental epileptic encephalopathy syndrome of infancy that is characterized by epileptic spasms and hypsarrhythmia on the EEG that are often associated with profound neurodevelopmental deficits. Hormonal therapies – including adrenocorticotropic hormone – and vigabatrin are the most efficacious first-line treatment options available but these treatments are often not effective. Retrospective clinical studies suggest the ketogenic diet (KD) – a high fat, low carbohydrate diet – may be an effective alternative treatment for some patients with intractable IS. No rigorous prospective studies demonstrating the effectiveness of the KD in IS has been published. In this study we evaluated the efficacy of the KD for the control of spasms in the triple-hit rodent model of IS. Methods: Spasms were induced in the neonatal rats via intracerebral injections of doxorubicin and lipopolysaccharide at postnatal day (P) 4, and a subcutaneous injection of p-chlorophenylalanine at P5. The animals were artificially reared using the “pup-in-cup” setup and fed either a normal rat’s milk diet (2:1 fats:carbohydrates/protein; ND) or the 4:1 KD. The behaviours were video recorded continuously from P4-12. We analyzed the recorded video 2 hours every 4 hours to calculate spasm frequency. Blood and urine ketone levels were measured at P4, P7 and P12. The animals underwent a battery of short-term behavioural testing – surface righting time, negative geotaxis, and open field activity – from P4 – P12 to examine the acquisition of developmental milestones. Results: The diets were well tolerated in the model but rats fed the KD were smaller at P11-12 (p<0.001). The KD increased the blood ketone levels as compared to the ND-fed rats (P7: KD= 2.75±0.0.12 vs. ND= 0.81±0.05; P12: KD= 2.81±0.29 vs. ND 1.28±0.19 mmol/L; p<0.001). Urine ketones were also significantly elevated in KD treated rats (p<0.001). The frequency of spasms was significantly lowered in the KD-fed rats with a maximum of 65% reduction in spasms frequency between P5–10 (p<0.001). The KD significantly improved survival (KD=80% vs. ND=40%; p<0.001). There were no sex specific effects of the KD on spasm frequency (p=0.352). The KD also had no short-term effects on the acquisition of the tested developmental milestones.  Conclusions: The results of this study provide preclinical evidence that the KD is an effective treatment for intractable IS. Further mechanistic studies are needed to determine how the KD produces its spasm suppressing effect in the model. Funding: Canadian Institute of Health ResearchAlberta Children's Hospital Research InstituteAlberta Innovates-Health Solutions