Current Pharmacologic Strategies for Treatment of Intractable Epilepsy in Children

Abstract

Epileptic encephalopathy (EE) is a devastating pediatric disease that features medically resistant seizures, which can contribute to global developmental delays. Despite technological advancements in genetics, the neurobiological mechanisms of EEs are not fully understood, leaving few therapeutic options for affected patients. In this review, we introduce the most common EEs in pediatrics (i.e., Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome) and their molecular mechanisms that cause excitation/inhibition imbalances. We then discuss some of the essential molecules that are frequently dysregulated in EEs. Specifically, we explore voltage-gated ion channels, synaptic transmission-related proteins, and ligand-gated ion channels in association with the pathophysiology of Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome. Finally, we review currently available antiepileptic drugs used to treat seizures in patients with EEs. Since these patients often fail to achieve seizure relief even with the combination therapy, further extensive research efforts to explore the involved molecular mechanisms will be required to develop new drugs for patients with intractable epilepsy.

Keywords: Antiepileptic drugs; Dravet syndrome; Intractable epilepsy; Lennox-Gastaut syndrome; Ohtahara syndrome.

Fig. 1.

Essential molecular targets and antiepileptic drugs in intractable pediatric epilepsies. Voltage-gated ion channels (sodium, potassium, and calcium), synaptic transmission-related proteins, and ligand-gated ion channels (glutamate receptors, γ-aminobutyric acid type A receptor) are frequently mutated in epileptic encephalopathies. Examples of mutated genes in Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome are described in black box. In addition, crucial antiepileptic drugs that are currently available for epileptic encephalopathies are illustrated in red box. Red arrow indicates potentiating effects by drugs, and red lines with blunt ends indicate inhibitory action of drugs. SCN1A, voltage-gated sodium channel α1 subunit; SCN2A, voltage-gated sodium channel α2 subunit; SCN8A, voltage-gated sodium channel α8 subunit; SCN1B, voltage-gated sodium channel β1 subunit; KCNA2, voltage‐gated potassium channel subfamily A member 2; KCNB1, voltage‐gated potassium channel subfamily B member 1; KCNQ2, voltage-gated potassium channel subfamily Q member 2; CACNA1A, voltage-gated calcium channel subunit alpha 1A; CACNA2D2, voltage-gated calcium channel auxillary subunit alpha 2 delta 2; SV2A, synaptic vesicle glycoprotein 2A; SNARE, soluble N-ethylmaleimide sensitive factor attachment protein receptor; STXBP1, syntaxin-binding protein 1; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; GABA, γ-aminobutyric acid; GRIN1, glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1; GRIN 2A, glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2A; GRIN2B, glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2B; GRIN2D, glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2D; GABRA1, γ-aminobutyric acid type A receptor α1 subunit; GABARG2, γ-aminobutyric acid type A receptor γ2 subunit; GABRB3, γ-aminobutyric acid type A receptor β3 subunit.