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  • Updated 10.13.2021
  • Released 10.13.2021
  • Expires For CME 10.13.2024

Pharmacological treatment of epilepsy in neonates

Introduction

Overview

Seizures accompanied by neurologic dysfunction are common in the neonatal period (up to 28 days of postnatal age or up to 44 weeks of gestation for preterm neonates). The highest risk of seizures during childhood is in the first year of life, and the highest risk within the first year is in the first month of life (61). The reported incidence of neonatal seizures is up to 130 per 1000 very low birth weight infants and 1.5 to 3.5 per 1000 term newborns (28; 38). Seizures in the neonate are more often related to an acute injury to the central nervous system than an initial epilepsy syndrome. The most common causes are hypoxic ischemic encephalopathy, central nervous system infections, hemorrhagic or thromboembolic brain injury, and perinatal stroke (28; 56). Neonatal-onset epilepsy constitutes a lesser proportion of these seizures. Antiepileptic drugs (or preferably antiseizure medications) are the mainstay for the management of epilepsy in the neonatal age group. There are specific forms of epilepsy that manifest in neonates, and not all forms require treatment. In contrast to epilepsy in older children and adults, early-onset epilepsy may have a significant impact on the neonates developmental, behavioral, and cognitive outcomes later in life. Seizure freedom and prognosis depend on the underlying etiology. The choice of drugs in the neonatal period is limited and often includes vitamin supplements for specific vitamin-responsive epilepsies. In contrast to older children, very few drugs have been approved to treat epilepsies in neonates. The extrapolation of drug development data from adults is not directly applicable to neonates. Drug trials in neonates are challenging due to the nonspecific clinical presentation, the need for continuous EEG monitoring, high comorbidity, and poor response to antiepileptic drugs. As the molecular basis of several epilepsies unfolds, a few targeted therapies, such as therapy for KCNQ2 mutationrelated epilepsies, pyridoxine-dependent epilepsy, and tuberous sclerosis complex, are becoming available (57). This article gives an overview of the pharmacological management of neonatal epilepsies.

Key points

Neonatal seizures are commonly due to acute symptomatic causes.

Neonatal epilepsies constitute a lesser proportion of the etiological causes.

Timely diagnosis and management of early-onset neonatal epilepsies are clinical challenges.

Very few drugs have been licensed for use in neonates due to a lack of randomized controlled trials.

Precision medicine might be possible for a limited number of syndromes.

Not all neonatal epilepsies need prolonged treatment with antiseizure medications.

The neurodevelopmental outcomes of neonatal epileptic encephalopathies are poor.

Historical note and terminology

Detailed reviews on the history of the discovery and development of antiseizure medications have been published (67; 70; 71; 15; 51). Neonatal antiseizure medication exposure in animal models altered a number of activity-dependent developmental processes, including neuronal gene expression, migration, differentiation, density, and survival (63). Drug discovery and approval in neonates is particularly challenging. When a drug is discovered to have antiseizure properties, it is typically first tested in adults with focal-onset epilepsy, the most frequent seizure type in adults. If the regulatory trial results are successful, then subsequent studies are set up for adolescents and younger children. Sometimes extrapolation of adult efficacy data is done for younger children, so only safety and pharmacokinetic studies are carried out in the younger age groups (03; 04). However, such extrapolation is problematic in neonates and in early infancy. Newer study designs, such as time to N seizures (based on previous video-EEG or video validation of specific seizure semiology), have been proposed for randomized, placebo-controlled drug trials in children aged 1 month to 4 years to reduce study duration and to facilitate earlier access to newer antiseizure medications (07).

Amongst the drugs used in neonatal seizures, phenobarbitone was the first to be widely used. The World Health Organization (WHO) recommends that phenobarbital be offered as the first-line therapy for epilepsy in adults and children due to its proven efficacy, low cost, and easy accessibility. Phenytoin was introduced in the 1930s from a list of nonsedative phenyl compounds being used for animal seizure models. It continues to be widely used as a broad-spectrum antiseizure medication. During the 1960s, benzodiazepines were synthesized and developed, and they continue to be first-line drugs for seizures and status epilepticus in neonates. Bumetanide has been in medical use as a loop diuretic since 1972 and has shown efficacy in neonatal seizures, especially in recurrent seizures when used with phenobarbital (30). The NEMO trial, which used this combination to treat acute seizures due to hypoxic ischemic encephalopathy in newborn babies, had to be prematurely terminated due to unacceptable safety issues and an association with hearing loss (55; 10).

An accelerated phase of antiseizure medication development began in 1975 with the establishment of the Anticonvulsant Drug Development Program by the National Institute of Neurological Disorders and Stroke in the United States (70; 15). In chronological order, the antiseizure medications subsequently developed were vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin, rufinamide, stiripentol, lacosamide, eslicarbazepine, perampanel, and brivaracetam (70; 51). However, most of these drugs have not been properly studied for use in neonatal epilepsies. Several newer agents and compounds are in trials as the search for a more efficacious treatment of neonatal epilepsy continues.

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