Non-pharmacological Interventions for Intractable Epilepsy

Abstract

In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options.

Keywords: ASDs, Antiepileptic drugs; ATP, Adenosine triphosphate; Anaplerotic diet; BBB, Blood-brain barrier; CKD, Classic ketogenic diet; CSF, Cerebrospinal fluid; EEG, Electroencephalography; EMG, Electromyography; GABA, Gamma-aminobutyric acid; Intractable epilepsy; KB, Ketone bodies; KD, Ketogenic diet; Ketogenic diet; LC, Locus coeruleus; LCFA, Long-chain fatty acids; MAD, Modified Atkin's diet; MCT, Medium-chain triglyceride; MEP, Maximal evoked potential; Music therapy; NTS, Nucleus tractus solitaries; PPAR, Peroxisome proliferator-activated receptor; PUFAs, Polyunsaturated fatty acids; RNS, Responsive neurostimulation; ROS, reactive oxygen species; SMR, Sensorimotor rhythm; TCA, Tricarboxylic acid cycle; TMS, Transcranial magnetic stimulation; Transcranial magnetic stimulation Biofeedback therapy; VNS, Vagus nerve stimulation; Vagus nerve stimulation.

Fig. 1

Metabolic fate and antiepileptic effects of ketone bodies A. Normally, glucose is used as a metabolic energy source and converted to pyruvate which is later transformed into Acetyl-CoA in the mitochondria and pass through the TCA cycle for the generation of ATP. But when the level of fatty acids is high then ketone bodies i.e., generated in the liver transformed into aceto-acetyl CoA. Then this aceto-acetyl CoA alternatively incorporated into the TCA cycle to produce ATP. These ketone bodies can pass through the blood–brain barrier employing transporters MCT and are utilized to produce ATP for meeting the energy demands of the brain. B. ketogenic-diet leads to an increase in the level of fatty acids and decreases the process of glycolysis in the brain. Alteration of these biochemical pathways result in various possible antiepileptic effects such as increase synthesis of GABA (ketone bodies are precursors for the synthesis of neurotransmitters), enhanced synthesis of ATP which increase the production of adenosine which itself have antiepileptic effects, increase mitochondrial biogenesis cause decreased production of ROS and also increase the opening of K⁺-channels.; TCA cycle = tricarboxylic acid cycle; ATP = adenosine triphosphate, MCT = monocarboxylic acid transporters, BHB = β-hydroxybutyrate, ROS = reactive oxygen species, glut1 = glucose transporters.

Fig. 2

Anaplerotic effect of Pyruvate, Triheptanoin, and Ketogenic diet. The pyruvate metabolized into acetyl-CoA by an enzyme pyruvate dehydrogenase which later condenses with the oxaloacetate to form citrate. Furthermore, pyruvate can be metabolized into the oxaloacetate directly by enzyme pyruvate carboxylase i.e., an anaplerotic reaction. On the other hand, triheptanoin metabolized into heptanoate and glycerol. Later, heptanoate converted into propionyl-CoA and acetyl-CoA. Then propionyl-CoA converted into succinyl-CoA which is an anaplerotic agent. And keto-diet metabolized into C₄-ketones which then converted into acetyl-CoA which then replenish the TCA cycle. When there is increased formation of TCA intermediates through anaplerosis then, there is an increase in neurotransmission as these TCA cycle intermediates are precursors for the formation of neurotransmitters. Triheptanoin (anaplerotic agent) by replenishing the TCA intermediates could increase the level of ATP. Hence keeping the neuronal membrane potential stable and decreases the neuronal firing rate. PC = Pyruvate carboxylase, PDH = Pyruvate dehydrogenase, BHP = β-hydroxypentanoate, BKP = β-ketopentanoate.