Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

Abstract

The mechanisms of epileptogenesis in pediatric epileptic syndromes are diverse, and may involve disturbances of neurodevelopmental trajectories, synaptic homeostasis, and cortical connectivity, which may occur during brain development, early infancy, or childhood. Although genetic or structural/metabolic factors are frequently associated with agespecific epileptic syndromes, such as infantile spasms and West syndrome, other syndromes may be determined by the effect of immunopathogenic mechanisms or energy-dependent processes in response to environmental challenges, such as infections or fever in normally-developed children during early or late childhood. Immune-mediated mechanisms have been suggested in selected pediatric epileptic syndromes in which acute and rapidly progressive encephalopathies preceded by fever and/or infections, such as febrile infection-related epilepsy syndrome, or in chronic progressive encephalopathies, such as Rasmussen encephalitis. A definite involvement of adaptive and innate immune mechanisms driven by cytotoxic CD8 +

Inflammation in Epileptic Encephalopathies

“…Malformations of brain development and focal cortical dysplasias are also common pathologies in infants with WS, which have been linked with abnormal expression of components of the mTOR signaling: TSC1 or TSC2 in Tuberous sclerosis complex (TSC), PTEN in hemimegalencephaly, STRADα in polyhydramnios, megalencephaly and symptomatic epilepsy syndrome (PMSE), and overexpression of phosphorylated S6 ribosomal protein (pS6) in focal cortical dysplasias type IIB (Baybis, Yu, Lee, Golden, Weiner, McKhann et al 2004, Chu-Shore, Major, Camposano, Muzykewicz & Thiele 2010, Orlova, Parker, Heuer, Tsai, Yoon, Baybis et al 2010, Galanopoulou, Gorter & Cepeda 2012, Epi4K. Consortium, Epilepsy Phenome/Genome Project, Allen, Berkovic, Cossette, Delanty et al 2013, Lim & Crino 2013, Pardo, Nabbout & Galanopoulou 2014). Among the acquired pathologies leading to IS, hypoxic–ischemic injury, CNS infections, perinatal strokes, metabolic disorders, or autoimmune conditions may also manifest inflammatory changes [(Mota, Rezkallah-Iwasso, Peracoli & Montelli 1984, Steele, Cheah, Veerapandiyan, Gallentine, Smith & Mikati 2012) and reviewed in (Pardo, Nabbout & Galanopoulou 2014)].…”

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

“…These observations suggest that mitochondrial disease may lead to immune dysfunction, although it is possible that the converse is also true, that immune dysfunction may be an unrecognized cause of mitochondrial disease. Of note, proven viral illness has been shown to precede initial decompensation in AlpersHuttenlocher syndrome [28] and other mitochondrial disorders [29], and immunopathogenic mechanisms coupled to energy-dependent processes have been suggested in the etiology of both febrile infectionrelated epilepsy syndrome (FIRES) and Rasmussen encephalitis [30].…”

Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats

“…As FAST rats had reactive astrogliosis in the cortex compared to SLOW rats, it is possible that reactive astrocytes or other neuroinflammatory mediators may contribute to the behavioral phenotype in FAST rats [41,42]. Furthermore, the heightened neuroinflammation may have important implications regarding the FAST rats increased sensitivity to seizures and epilepsy [43][44][45][46][47].…”