West syndrome (WS) is an epileptic encephalopathy characterized by infantile spasms and hypsarrhythmia, and often by psychomotor regression including autistic behaviors. The latter often appear later and may indicate a progression of the syndrome. In this respect, there may be evidence of progression based on a continuing interaction of underlying systems and epigenetic influences. The syndrome is a relative rare manifestation of common insults, including genetic mutations, brain dysplasias, perinatal asphyxia, and other perinatal traumatic events. It is not yet clear whether different mechanisms are responsible for hypsarrhythmia and infantile spasms (IS) and whether the psychomotor regression is a direct consequence of the hypsarrhythmic EEG pattern (Dulac, 2001a; Dulac et al., 2010). To address these questions, the presumed substrates of West syndrome need to be identified, and may encompass multiple channels of altered functions. The manifestations of West syndrome include the following: exaggerated motor phenomena that involve the pyramidal and extrapyramidal pathways as well as the assumed brainstem-originating tracts that are responsible for the expression of tonic seizures (spasms) in animal studies; intermittent dyscognitive states implicating thalamocortical or reticular formation involvement; and failure to acquire new developmental milestones and regression that may involve widespread networks organized as systems. In the recent past, two presumably competing brainstem and cortical hypotheses have been proposed to explain the pathophysiology of the spasms (Kellaway, 1959; Tucker & Solitare, 1963; Chugani et al., 1990; Panzica et al., 1999; Frost & Hrachovy, 2003). The brainstem hypothesis postulates that a brainstem generator may be responsible, whereas the cortical hypothesis emphasizes cortical malfunction. It is not clear why all infants with similar underlying insults (i.e., dysplasias and genetic mutations) will not develop WS. This heterogeneity suggests an acquired (epigenetic) influence. Contributing factors that may regulate the systems underlying the expression of the key features of WS include dysfunction of the hypothalamic-pituitary-adrenal axis (Nalin et al., 1985) and an immune-mediated disorder (Hrachovy & Frost, 1989). These factors may explain the efficacy of steroids in this condition, at least in terms of controlling the spasms and hypsarrhythmia (although not necessarily in altering the cognitive outcomes). The electrodecremental response and hypsarrhythmia each reflect diffuse or multifocal/system dysfunction. Electrodecremental seizures are hypothesized to arise from paroxysmal activity primarily in the cortex. Alternatively, electrodecremental seizures may result from increased activity in subcortical circuits projecting to cortex, leading to diffuse desynchronization and abnormal cortical electrical activation. Dysfunction in the arousal systems of the brainstem could alter cortical “tone” and result in an abnormal EEG background. Stimulation of small regions of the brainstem can produce global alterations in cortical EEG (Moruzzi & Magoun, 1949). Inactivation of the brainstem reticular activating system may produce widespread changes in cortical activity and impairment of consciousness (Plum & Posner, 1980). Paroxysmal activity in subcortical arousal systems might induce abrupt changes in cortical tone that could appear as electrodecremental responses. The arousal system of the upper pons co-localizes with reticulospinal projecting neurons projecting caudally and may mediate the “startle-like” movements associated with the spasms (Magoun, 1963; Vining, 1990). It has been proposed that hypsarrhythmia may represent ongoing seizure activity, and that infantile spasms and electrodecremental events result from activation of subcortical circuits attempting to control cortical seizure activity (see in Lado & Moshe, 2002). Recent EEG–functional magnetic resonance imaging (fMRI) studies of WS have demonstrated that epileptiform discharges in hypsarrhythmia are associated with hemodynamic and metabolic changes in the cerebral cortex, and that high-voltage slow waves correlate with blood oxygen level–dependent (BOLD) changes in cortical and subcortical structures (Siniatchkin et al., 2007). Lado and Moshe (2002) have emphasized the importance of the interaction between cortex and subcortical regions in WS, and the requirement that both regions contribute to WS. They proposed that infantile spasms originate in the abnormal interaction of cortical and subcortical circuits rather than in either region alone, and that this abnormal interaction between cortical and subcortical circuits may be further augmented by a delay in the maturation of white matter connections between cortical and subcortical regions. The data suggest that a dysfunction of a single brain structure cannot be responsible for such a complex manifestation as WS, and that the typical electroclinical picture requires the active participation of a pathologic system in which different brain areas (the cortex, thalamic nuclei, and brainstem) work (or do not work) together. When some of these stations are not involved in the pathologic epileptic process, different electroclinical phenotypes develop. WS can therefore be proposed for further investigations that might define the structures of the involved system and their interconnections. The renewed interest in developing “realistic” animal models (Scantlebury et al., 2010; Chachua et al., 2011) provide the means to test the hypothesis that WS may be a prototype of system epilepsies, with presentation of symptoms and signs depending on the properties of the system at given time, as a function of possible underlying pathology, and the developmental stage of the brain (necessary for the exquisitely narrow window in which West syndrome occurs). Taking into account the possible role of cortical and subcortical structures, as well the maturation of myelinization and immune dysfunction, Scantlebury et al. (2010) created a model of symptomatic IS that may provide insights into the system underlying the expression of hypsarrhythmia and spasms.