Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

Abstract

Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ∼0.4–0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2–5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6–8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9–12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with epilepsy and children born to women who took AEDs during pregnancy.

Exposure to excess phenobarbital negatively influences the osteogenesis of chick embryos

“…It is reported that PB treatment can impair cardiovascular development, which naturally reminds us to detect the effects of PB on blood vessels since angiogenesis plays a crucial role during bone ossification and formation (Bath and Scharfman, 2013;Cheng et al, 2016). In this study, we found that PB treatment suppressed vascular invasion in the development of long bones.…”

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development

“…Clinical findings have revealed that the rate of birth defects in humans is significantly higher after prenatal exposure to valproic acid (VPA) than with any of other AED currently in use [2].…”

“…To reduce risk to the fetus, application of the lowest possible daily dose of VPA has been suggested, since a positive dose-response correlation between VPA and fetal anomalies has been observed [18]. The risk of major congenital malformations increases significantly at VPA doses of 600-700 mg/day, with the largest attributable risk observed at doses exceeding 1000 mg/day, which causes defects in 15-30% of children [1,2,18].…”

Lidocaine for Status Epilepticus in Pediatrics

“…17,19,22,29,31 Fifteen studies represented Oxford level 4 evidence for lidocaine administration in pediatric SE/ RSE. 15,16,18,20,1,[23][24][25][26]27,28,30,[32][33][34][35] Two of the 20 studies met GRADE B level of evidence, 19,29 three met GRADE C evidence, 17,22,31 whereas the remaining 15 met GRADE D level of evidence. 15,16,18,20,1,[23][24][25][26]27,28,30,[32][33][34][35] Summary of the level of evidence can be seen in Table 3.…”

“…Concerns over drug reactions and interactions in the developing child pose potential limitations to antiepileptic drug (AED) selection in the setting of SE and RSE. [1][2][3] Current management options for SE and RSE in the pediatric/ neonatal patient population include, but are not limited to: benzodiazepines, barbiturates, phenytoin, levetiracetam, carbamazepine, and lidocaine 4 -all of which have displayed varying efficacy at seizure control in SE and RSE. [4][5][6][7] Lidocaine, a class Ib antiarrhythmic agent, has known sodium channel-based AED properties in both the adult and pediatric populations stemming back to the 1950s.…”