Pharmacologists at Georgetown University, Washington, DC examined functional synaptic maturation in striatal medium spiny neurons from neonatal rats exposed to antiepileptic drugs (AED) with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning. Compared to control animals that showed increased inhibitory and excitatory synaptic connectivity between postnatal day P10 and P18, rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine had impaired maturation of synaptic connectivity. Phenobarbital exposure also impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Synaptic development was not disrupted by levetiracetam. [1]

COMMENT. Protection from experimental seizures in small, laboratory animals is the backbone of development of new potentially effective and less toxic antiepileptic drugs, beginning with the introduction of phenytoin in 1937 [2]. Phenobarbital, introduced as an anticonvulsant by Hauptmann in 1912, has a troublesome sedative side effect. Phenytoin was the first AED to show anticonvulsant activity without sedation. Various laboratory methods to elicit seizures have been employed in the testing of new drugs, and major advances were made in the mid 1900s, particularly in the pharmacology department at the University of Utah, under the direction of Louis S Goodman, Ewart A Swinyard, Dixon M Woodbury and others. The current laboratory study from Georgetown University should increase concern regarding the potential hazard of continuing use of phenobarbital and phenytoin in the neonate and young infant, and should lead to the introduction of alternative therapies that control seizures without compromising synaptic maturation, cognition and behavior.

Epileptologists in a Catch-22 situation. Whereas this pharmacological study cautions the epileptologist against overuse of AEDs in the control of neonatal seizures, the following clinical study emphasizes the need for early aggressive treatment and seizure control in infants and young children.