Neonatal and Infantile Epilepsy: Acquired and Genetic Models

Abstract

The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous sclerosis, and related genetic disorders, or IS of acquired etiology. These models start to generate the first therapeutic drugs, which have been specifically developed in immature animals. However, there are challenges in translating preclinical discoveries into clinically relevant findings. The advances made so far hold promise that the new insights may potentially have curative or disease-modifying potential for many of these devastating conditions. T he neonatal and infantile periods show relatively high age-adjusted incidence of epilepsy compared with other ages of life (Hauser et al. 1993). The etiology of newly diagnosed epilepsies at these ages also is distinct, showing greater representation of epilepsies of unknown, genetic, or congenital etiologies (Hauser et al. 1993). The semiology and syndromic phenotypes of epilepsies that first appear in this early life period are also distinct and often more fulminant, appearing with evident neurodevelopmental problems or regression (e.g., epileptic encephalopathies) or characteristic seizure types (e.g., infantile spasms [IS], multifocal clonic seizures) ( Table 1). In addition, the treatments for epilepsies of these age groups can be specialized, as is the case with the use of hormonal therapies (e.g., adrenocorticotropic hormone [ACTH] in certain epileptic encephalopathies). Given the serious repercussions for the development of these neonates and infants and the importance of finding better therapies with disease-modifying potential, several efforts have been made to create animal models of these conditions to increase our understanding and ability to treat them. Here, we will review selected animal models, genetic or induced, that address epilepsies and epileptic encephalopathies characteristic of neonates and infants.

Inflammation in Epileptic Encephalopathies

“…In WS, there are numerous etiologies recorded, including at least 60 known genes affected, numerous chromosomal abnormalities or other structural and metabolic etiologies (Galanopoulou & Moshe 2015). Few of the genes linked with WS are components of neuroinflammatory pathways, including complement regulatory factors (CD46), glucocorticoid signaling, (glucocorticoid modulatory element binding protein 2 GMEB2, glucocorticoid receptor NR3C1), mTOR pathway [Tuberous sclerosis complex 1 and 2 (TSC1 and TSC2), STE20-related kinase adaptor alpha (STRADα), Phosphatase and Tensin Homolog Tumor suppressor (PTEN), Phosphoinositide 3-kinase adapter protein (PIK3AP1)], TNFα induced protein 6 (TNFAIP6)] [see Supplemental Table 1 in (Galanopoulou & Moshe 2015)].…”

“…West syndrome (WS) is an age-specific epileptic encephalopathy (EE), which typically occurs in infants and has poor epilepsy, neurodevelopmental prognosis and high risk of early mortality (Dulac 2001, Fukuyama 2001, Galanopoulou 2013, Galanopoulou & Moshe 2015). WS manifests with at least two of the following features: (a) ictal events of flexion or extension spasms, called infantile spasms (IS) that usually appear in clusters, (b) interictal chaotic high amplitude and multifocal epileptic interictal background (hypsarrhythmia), and (c) intellectual or neurodevelopmental disabilities (Galanopoulou & Moshe 2015).…”

“…WS manifests with at least two of the following features: (a) ictal events of flexion or extension spasms, called infantile spasms (IS) that usually appear in clusters, (b) interictal chaotic high amplitude and multifocal epileptic interictal background (hypsarrhythmia), and (c) intellectual or neurodevelopmental disabilities (Galanopoulou & Moshe 2015). …”

“…Epilepsy develops in 50–70% of surviving children (Koo, Hwang & Logan 1993, Riikonen 2001) and evolution to Lennox–Gastaut syndrome has been reported in 15–25% of these patients, although reports of up to 54% have been published) (Lombroso 1983, Rantala & Putkonen 1999, Rantala & Putkonen 1999, Trevathan, Murphy & Yeargin-Allsopp 1999, Hrachovy & Frost 2003, Galanopoulou 2013). Cognitive and neurodevelopmental impairments may be significant and often leading to mental retardation (70–90%) (Koo, Hwang & Logan 1993, Sidenvall & Eeg-Olofsson 1995, Trevathan, Murphy & Yeargin-Allsopp 1999, Riikonen 2001, Galanopoulou & Moshe 2015). Further evolution to autism is seen in 15% although infants with IS due to underlying structural or metabolic pathologies are at higher risk (Riikonen & Amnell 1981, Saemundsen, Ludvigsson & Rafnsson 2008, Galanopoulou 2013).…”

“…The first line treatment options for IS are hormonal therapies [adrenocorticotropic hormone (ACTH), glucocorticoid steroids] or the GABA aminotransferase inhibitor vigabatrin (Mackay, Weiss, Adams-Webber, Ashwal, Stephens, Ballaban-Gill et al 2004, Pellock, Hrachovy, Shinnar, Baram, Bettis, Dlugos et al 2010, Go, Mackay, Weiss, Stephens, Adams-Webber, Ashwal et al 2012, Riikonen 2014, Galanopoulou & Moshe 2015). Ketogenic diet has been proposed as an alternative adjunctive therapy for IS to be considered after failure of corticosteroids and/or vigabatrin and has shown some efficacy in refractory IS (Hong, Turner, Hamdy & Kossoff 2010, Pires, Ilea, Bourel, Bellavoine, Merdariu, Berquin et al 2013).…”