Epileptic encephalopathy as models of system epilepsy
The pathophysiology of epileptic encephalopathies has long been debated. Recently, some authors proposed the new concept of so-called system epilepsies. This hypothesis postulates that system epilepsies are produced by the enduring propensity to generate seizures in different cerebral areas that, alone, are unable to create a specific electroclinical phenotype. This goes beyond the classical dichotomy between focal and generalized epilepsy. Epileptic encephalopathies, in general, have the ideal profile to be considered as system epilepsies, and West syndrome and Lennox-Gastaut syndrome are two of the best examples. Apart from the conventional neurophysiologic methods for studying brain activities and the pathophysiologic mechanisms underlying epileptic syndromes, other new methods of neuroimaging support this hypothesis.
The Concept of System Epilepsy
In this hypothesis, some types of epilepsies reflect the pathologic expression of an identifiable neural system, made up of brain areas the integrated activity of which subserves normal physiologic functions (Salek-Haddadi et al., 2009; Moeller et al., 2011). We suggest, too, that system epilepsies lead to functional results that cannot be obtained by pathologic activity within the individual elements alone. This notion makes system epilepsies different from the epilepsies resulting from the spread of a discharge originating in a more or less circumscribed region (the boundaries of which do not necessarily coincide with those of a functionally defined brain area) and propagating sequentially along one or more neural pathways to other brain areas (which do not necessarily belong to a unitary brain system). The concept of epilepsies caused by the involvement of a brain system was discussed by the International League Against Epilepsy (ILAE) Task Force on Classification and Terminology (Engel, 2006), and formulated by Wolf (2006). It has been the subject of a number of ongoing discussions, many of which have been published (Bertram et al., 2008; Avanzini, 2009; Capovilla et al., 2009; Avanzini et al., 2012). The system epilepsy hypothesis postulates that the “enduring propensity to generate seizures” (Fisher et al., 2005) of some epilepsies is due to the specific susceptibility of a system as a whole, although it may be possible to identify some trigger areas within the system. The neural system responsible for system epilepsy (SE) is revealed by the clinical/electroencephalography (EEG) semiology of the seizures, but the concept refers to the persistent susceptibility of the seizure-generating system, which is assumed to exist also in the interictal period (Lopes da Silva et al., 2003). When evaluating the criteria for defining a neural system responsible for SE, it is worth considering a definition of a system in engineering, mathematics, and information technology: “A system is a construct or collection of different elements that together produce results not obtainable by the elements alone. The elements, or parts, can include people, hardware, software, facilities, policies, and documents; that is, all things required to produce system-level results. The results produced by a system can include functions, behaviors, system-level qualities, properties, characteristics, and performances. The value added by the system as a whole, beyond that contributed independently by the parts, is primarily created by the relationship among the parts: that is, how they are interconnected” (Rechtin, 2000). Although this definition is concerned mainly with human activity and seems to be aimed at concrete solutions, it contains the essence of a system: the presence of dynamic interactions among components and the overall behavior emerging from these interactions, which appears when all of the parts of a system work together.
On the basis of the preceding, many neural systems can be viewed as composed of a set of synaptically interconnected areas, the coordinated activities of which lead to functional results that cannot be obtained by the activity of the elements alone. Anatomic connections are necessary but not sufficient to define such a system, which emerges only when the different components actively participate in accomplishing system functions. Examples of activities depending on complex neural systems are the EEG rhythms generated by thalamocortical systems that are involved in the control of attention, vigilance, and sleep (Amaral & Ottino, 2004). A great deal of experimental evidence converges in supporting the primary role of the thalamic reticular nucleus, the thalamic nuclei projecting to the cortex, and the cortical areas and their interconnections in generating the 3 Hz spike and wave (SW) activity associated with absence seizures. The primary role of one or another component of the circuit has long been debated, but the evidence supports the conclusion that all parts of the system are necessary to generate SW activity, and that no one component can do so in isolation (Wolf & Goosses, 1986; Avoli et al., 2001; Avoli, 2012).
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.
As happened for West syndrome, the pathophysiology of Lennox-Gastaut syndrome (LGS) has long been debated, and two main theories have divided the scientific community between the supporters of the cortical theory opposed to the fans of the subcortical theory. Dulac (2001b), for example, suggested that many of the electroclinical signs present in LGS should be attributed to the direct involvement of the frontal cortex. On the contrary, Gastaut et al. (1963) himself gave great importance to the role of the thalamus in the pathogenesis of LGS. The seminal paper of Blume in 2001 opened a new vision in the understanding the pathophysiology of LGS. In his vision, the electroclinical phenotype would originate from the abnormal interaction of cortical and subcortical circuits rather than in a specific region alone. Blume, to explain the pathophysiologic mechanisms at the basis of LGS, hypothesized that “the occurrence of factors enhancing excitability during a vulnerable period of cortical and thalamic development may permanently imprint a bilateral, diffuse epileptogenic system upon the mammalian brain.” “Thus, enduring synaptic and non-synaptic epileptic systems would form” and could be at the basis of the mechanisms underlying LGS. EEG-fMRI combines MRI spatial resolution with EEG time resolution and has been used to study the structure and function of neural systems involved in LGS. The elegant paper of Siniatchkin et al. (2011), who studied, with fMRI, LGS patients, evidenced how both cortical and subcortical structures (thalamus, brainstem, reticular formation, and cerebellum) are activated in LGS cases, both with symptomatic and cryptogenic etiology. In contrast to children with LGS, there were no consistent positive BOLD signal changes in subcortical structures in children with multifocal partial epilepsy. Because LGS is an epileptic syndrome with variable etiology, it is easily clearly evident that multiple causes may activate a syndrome-specific neuronal network, as suggested by Blume in his 2001 original paper.
Functional neuroimaging studies have recently given great contribution to the understanding of pathophysiology of EEs. They have reinforced the hypothesis, first advanced for WS and LGS, respectively by Lado and Moshe (2002) and Blume (2001), that a complex epileptic phenotype like these two syndromes is determined by the activation of a complex pathologic system. Further studies, based in particular on functional neuroimaging, can further clarify pathophysiologic mechanisms underlying EE.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.