Topiramate for the treatment of neonatal seizures and beyond

Abstract

Acute symptomatic neonatal seizures are one of the most common neurological disorders in newborns admitted to neonatal intensive care units and require prompt treatment. Up to 50% of neonatal seizures are refractory to first-line medications such as phenobarbital (PB), and another 30% fail second-line therapy. Furthermore, antiseizure medications (ASMs) such as PB have short-term adverse effects and may exert long-term detrimental effects on neurodevelopment. Thus, the development of more effective and safer ASMs is an urgent medical need. Because of its multimodal mechanisms of action and neuroprotective activity as well as promising preclinical and clinical findings, topiramate (TPM) is currently among the most attractive ASMs for the treatment of PB-refractory neonatal seizures. However, parenteral TPM is not clinically available, which restricts its use in most newborns with acute seizures. In this review, we critically discuss the current knowledge about TPM as a treatment for neonatal seizures and associated conditions. We describe both preclinical and clinical data and highlight that the neuroprotective activity of this drug, not shared by most other ASMs, may enhance the efficacy of therapeutic hypothermia to decrease adverse neurodevelopment after neonatal brain injury. In addition, we describe two novel intravenous formulations of TPM currently being developed for clinical use. One formulation uses the highly tolerable U.S. Food and Drug Administration (FDA)-approved excipient meglumine for the preparation of an aqueous TPM solution, so is particularly suitable for neonates. We recommend prospective randomized controlled clinical trials designed to test the safety and efficacy of intravenous TPM for neonatal seizures. TPM doses in such trials should be based on the maintenance of effective plasma levels not achieved in most previous clinical studies with enteral administration of TPM suspensions. Furthermore, the potentially beneficial neuroprotective effects of TPM on adverse outcomes associated with neonatal seizures and their etiologies should be examined in such trials.

Keywords: cognition; epilepsy; hypoxic–ischemic encephalopathy; perinatal asphyxia; phenobarbital.

FIGURE 1

Relative occurrences of common etiologies of neonatal seizures in term infants. Modified from Pressler et al.

FIGURE 2

Structures of topiramate and the excipients sulfobutylether‐β‐cyclodextrin (Captisol) and the amino sugar meglumine (N‐methyl‐d‐glucamine). See text for details.

FIGURE 3

The multiple mechanisms of action of topiramate. The figure shows both an inhibitory (left‐hand side) and an excitatory nerve terminal (right‐hand side); note that, in reality, the same nerve terminal does not release both γ‐aminobutyric acid (GABA) and glutamate. AMPA, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid; GABA, γ‐aminobutyric acid; NMDA, N‐methyl‐d‐aspartate; SV2A, synaptic vesicle glycoprotein 2A. The figure was modified from Löscher and Klein. See text for details.