Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies

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The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future.

Introduction

Childhood epilepsies starting in the first few years of life frequently exhibit seizures resistant to available treatments. Intractable epilepsies and a high seizure burden during brain development are associated with severe cognitive, behavioral, and motor delay so there is a need for safe and effective therapies. In recent years several new antiepileptic drugs (AEDs) have been approved or are pursuing approval in the United States with specific indications targeting the severe epilepsies of early childhood (Table 1) (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome). Additionally, genetic research has enabled the possibility of targeted therapy using existing medicines, and improved our understanding of how to avoid serious adverse effects with some AEDs. These advances all have the potential to improve the seizure control, quality of life, and cognitive outcome for this group of children with devastating epilepsies of early childhood.

In this article we review new and emerging AEDs and their role in the treatment of the severe pediatric epilepsies.

Section snippets

Perampanel (Fycompa)

Perampanel, the first antiepileptic medication to act as an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, received Food and Drug Administration (FDA) approval for the treatment of partial seizures in patients ≥12 years of age in 2012, and for primary generalized seizures in patients ≥12 years of age in 2015.1

The AMPA receptor is an ionotropic glutamate receptor with an overall excitatory roll in the central nervous system including synchronized neuronal firing

Vigabatrin (Sabril)

Vigabatrin (VGB), originally developed in 1977 as a γ-aminobutyric acid (GABA) analogue, was approved in the United States by the FDA in 2009 for the treatment of infantile spasms in children age group ranging from 1 month to 2 years and as adjunctive therapy for rCPS in adults; subsequently this was changed to patients ≥10 years of age.

VGB exerts its antiepileptic effect by irreversibly binding to GABA-transaminase, the enzyme involved in removal of GABA from the neuronal synapse. This

Rufinamide (Banzel)

Rufinamide (RFM) is a triazole derivative approved by the FDA in 2008 for children 4 years of age and older and in 2015 for children age 1-4 years for seizures associated with Lennox-Gastaut syndrome. It has also demonstrated efficacy in adults and adolescents with partial seizures.10

The exact mechanism by which RFM suppresses seizures is not precisely known. It acts at the voltage-gated sodium channel to prolong the inactivation phase resulting in suppression of neuronal hyperexcitability.10

Clobazam (Onfi)

Since 1970, Clobazam (7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2, and 4-dione) has been available in many countries as a treatment for anxiety and epilepsy. It has been used as monotherapy in partial and generalized epilepsy, as adjunctive therapy with stiripentol in Dravet syndrome and to treat seizures in Lennox-Gastaut syndrome in combination with other AEDs. FDA approval was granted in 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Clobazam is

Stiripentol

Stiripentol (4,4-dimethyl-1-[3,4-methylene dioxyphenyl] 1-penten-3-ol) is a structurally novel AED that belongs to the group of aromatic allyl alcohols.15 It was developed 35 years ago, and has been used in France and Canada for more than 15 years. Studies in adults have been disappointing; however, pediatric trials have demonstrated efficacy for the treatment of Severe Myoclonic Epilepsy of Infancy (SMEI or Dravet syndrome) when combined with valproate and clobazam. Stiripentol was given

Fenfluramine

Fenfluramine (3-triflouromethyl-N-ethylamphetamine), a derivative of amphetamine, was approved by the FDA in the United States in 1973, as an anorectic agent. It was withdrawn from the market in 1997, because of cardiovascular side effects. There is limited data that suggest its effectiveness in Dravet syndrome and self-induced epilepsies.16 Regulatory trials are currently starting for adjunctive treatment in Dravet syndrome.

The exact antiepileptic mechanism of fenfluramine is not fully

Cannabidiol

For thousands of years the cannabis plant, Cannabis Sativa and its ~100 constituent phytocannabinoids (plant cannabinoids) have been used to treat neurologic disorders form anxiety to pain and epilepsy. The most abundant and best studied of these cannabinoids are the psychoactive component, Δ9-tetrahydrocannabinol; and the nonpsychoactive cannabidiol.

Cannabidiol treatment for epilepsy has recently received notable attention in the lay press and in social media, with reports of spectacular

Emerging Antiepileptic Drugs for Specific Diseases

Genetic research has allowed us to have a better understanding of adverse events encountered with some AEDs. Examples of this include avoiding certain sodium channel antiepileptic drugs in patients with specific human leukocyte antigen types to avoid serious skin rash; the link between DNA polymerase gamma (POLG) mutations and valproate associated hepatotoxicity, and the realization that sodium channel drugs may exacerbate seizures in patients with SCN1A mutations (eg, Dravet syndrome). Genetic

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