Infantile spasms syndrome: a clinical overview

clinical overview The early epileptic encephalopathies are a group of conditions that all manifest with three major diagnostic criteria: medically refractory seizures, diffuse encephalopathy and a poor developmental outcome. These syndromes include early infantile epileptic encephalopathy (EEIE, also known as Otahara’s syndrome), severe myoclonic epilepsy of infancy (Dravet’s syndrome), infantile spasms (IS, also known as West syndrome), Lennox-Gastaut syndrome and a few less common syndromes (for a review, see Korff and Nordli, 2006). These syndromes make up the continuum of the developmental epileptic encephalopathies and often proceed from one syndrome to another. IS syndrome, the most common developmental epileptic encephalopathy, has an estimated incidence of 1 in 20006000 live births (Hurst, 1994). Issues regarding the modeling of IS are common and applicable to any of the early epileptic encephalopathies. The characteristic features of IS are the intractable seizures, a specific electroencephalogram (EEG) finding of hypsarrythmia (Fig. 1), and a poor developmental outcome (Zupanc, 2003). The classic seizures consist of flexor or extensor truncal movements with abduction or adduction of the arms, usually in clusters, and the seizures often occur at sleep-wake transitions. Electrographically, each seizure is typically accompanied by a flattening of the EEG, termed an electrodecrement. Along with the classic spasms, IS patients often have focal, myoclonic, and/or generalized seizures. At the onset of the syndrome, normally between 3 and 12 months of age, the child can be developmentally normal or already delayed. Typically, the spasms begin subtly and can be misdiagnosed as gastroesophageal reflux, an exaggerated moro reflex, or as ‘funny baby movements’. The etiology of IS is variable. Potential etiologies for IS have characteristically been classified as cryptogenic, symptomatic and idiopathic, but a more intuitive approach is to divide the cases into two main groups: acquired and congenital/developmental. The acquired causes include, but are not limited to: sequelae from central nervous system (CNS) infections, hypoxic-ischemic damage and post-traumatic injury. The congenital/developmental conditions include: malformations of cortical development, channelopathies, metabolic disorders, known genetic disorders such as tuberous sclerosis or Rett’s syndrome, and chromosomal anomalies (trisomies 13, 18 and 21). In addition, an increasing number of single gene mutations, contiguous gene deletions and duplication syndromes are being identified as the underlying cause of these early onset developmental epilepsies. Recent work has shown that mutations in ARX, CDKL5, MUNC18-1 (also known as STXBP1), SLC25A22 and MAGI2 have each been linked to an IS or EIEE-like phenotype (Kitamura et al., 2002; Weaving et al., 2004; Molinari et al., 2005; Marshall et al., 2008; Saitsu et al., 2008). Inexplicably, each of the proteins encoded by these genes has a very different function: MUNC18 and MAGI2 are involved in synaptic development, ARX is a transcription factor, SLC25A22 is a mitochondrial glutamate/H+ symporter, and CDKL5 is a serine/threonine protein kinase with undefined phosphorylation targets. The fact that such variability in gene function leads to similar phenotypes suggests that these genes are all within a broad developmental pathway, or within a number of pathways that interact to guide the normal developmental processes. This variability in etiologies has confounded the research into the biological basis of IS. The primary goal of treatment for IS is to both stop the seizures and normalize the EEG, with the ultimate goal being to improve developmental outcome. There is