Exploring the Mechanism of Action of the Ketogenic Diet as a Therapeutic Intervention for medically refractory Infantile Spasms
Date
2023-12
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Abstract
Objective: Infantile Spasms (IS) are a developmental, epileptic encephalopathy syndrome of infancy. It is characterized by epileptic spasms and a severe electroencephalogram abnormality, known as hypsarrhythmia, that can result in neurodevelopmental regression. Current anti-epileptic drugs are often deemed ineffective and can carry significant toxic side effects. The ketogenic diet (KD) is an alternative treatment for patients with drug resistant epilepsy, though its prospective validity and mechanism of action for IS remains unexplored. Methods: KD’s efficacy and mechanism of action was investigated using the triple-hit model of intractable IS. The spasms were induced using the triple-hit paradigm at P4 and the rat pups were then artificially reared and put on either the KD (4:1 fats:carbohydrate + protein) or a control-milk diet (CM; 1.7:1). Their behaviours were video-EEG recorded continuously from P4-12 for epileptic spasms and EEG analysis. Blood and urine ketones were collected at P4, P7 and P12. 31-phosphorus magnetic resonance spectroscopy (31P MRS), head-out plethysmography, and mitochondrial respirometry was also conducted to examine the KD’s mechanism of action. Results: The KD resulted in a ketosis observed both in the blood and urine. The KD led to a robust reduction in the spasm frequency, with approximately a 1.5-fold increase in the rate of survival. The KD resulted in an intracerebral acidosis as measured with 31P MRS. The respiratory profile of the KD-lesioned rats 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 was no effect of the diet on mitochondrial respiratory profiles measured in the liver and brain frontal cortex. Together, our results indicate that the KD produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. Conclusion: 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 pediatric models of epilepsy.
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Keywords
Infantile Spasms, West Syndrome, Ketogenic Diet, High Fat Diet, Intracerebral Acidosis, Brain pH, Respiration
Citation
Choudhary, A. (2023). Exploring the mechanism of action of the ketogenic diet as a therapeutic intervention for medically refractory infantile spasms (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.