Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

Abstract

Early onset and infantile epileptic encephalopathies (EIEEs) are usually associated with medically intractable or difficult to treat epileptic seizures and prominent cognitive, neurodevelopmental and behavioral consequences. EIEEs have numerous etiologies that contribute to the inter- and intra-syndromic phenotypic variability. Etiologies include structural and metabolic or genetic etiologies although a significant percentage is of unknown cause. The need to better understand their pathogenic mechanisms and identify better therapies has driven the development of animal models of EIEEs. Several rodent models of infantile spasms have emerged that recapitulate various aspects of the disease. The acute models manifest epileptic spasms after induction and include the NMDA rat model, the NMDA model with prior prenatal betamethasone or perinatal stress exposure, and the γ-butyrolactone induced spasms in a mouse model of Down syndrome. The chronic models include the tetrodotoxin rat model, the aristaless related homeobox X-linked (Arx) mouse models and the multiple-hit rat model of infantile spasms. We will discuss the main features and findings from these models on target mechanisms and emerging therapies. Genetic models have also provided interesting data on the pathogenesis of Dravet syndrome and proposed new therapies for testing. The genetic associations of many of the EIEEs have also been tested in rodent models as to their pathogenicity. Finally, several models have tested the impact of subclinical epileptiform discharges on brain function. The impact of these advances in animal modeling for therapy development will be discussed.

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

“…The neurobiology of the very young brain is very different from that in older age groups; consequently, age‐ and sex‐specific effects, efficacy, and tolerability of tested drugs cannot be predicted by the effects in older subjects 24, 25, 26. There are also age‐ and sex‐specific mechanisms involved in ictogenesis or epileptogenesis of early life seizures and epilepsies involving different underlying pathologies, network functions, intracellular and neuronal signaling, and communication patterns that are peculiar to certain stages of the disease or developmental stages 24, 25, 27…”

“…In certain models, epilepsy progresses from predominantly nonconvulsive to predominantly convulsive 63. In others, epilepsy evolves, as in many pediatric animal models 27. Differentiating the effects of a drug on seizure types within the same model, rather than across models of different seizures, may subtract the impact of the underlying pathology and etiology and may help prioritize the effects on different seizure types.…”

“…Justification for the selection of the baseline and monitoring periods (time points, duration) would be important to report, particularly for chronic treatments in models that demonstrate progression, evolution, or seizure clustering with relatively long intercluster periods 27, 63, 64…”

Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update

“…Infantile spasms (IS) are the typical seizures observed in West syndrome, an infantile epileptic encephalopathy with multiple etiologies (structural/metabolic, genetic, or unknown), often poor prognosis in regards to developmental and epilepsy outcomes and only few available treatments [1–8]. The characteristic ictal encephalographic pattern of IS is the electrodecremental response (EDR) while hypsarrhythmia (multifocally epileptic, high amplitude disorganized and slow) is the interictal EEG signature in most, but not all, infants with West syndrome [1,9].…”

“…Therefore, the need for animal models of IS and West syndrome emerged, so as to allow for the development of syndrome-specific new treatments. The Workshop on Models of Pediatric Epilepsies (Bethesda MD, May 13–14, 2004) co-sponsored by the National Institute of Health/National Institute of Neurological Diseases and Stroke (NIH/NINDS), the American Epilepsy Society (AES), and the International League Against Epilepsy (ILAE) set the pace by defining the criteria for a model of infantile spasms and West syndrome [33], following which a growing number of models were proposed and reported [8]. In our laboratory, we have developed and optimized the multiple-hit rat model of IS, a chronic rat model induced at postnatal day 3 (PN3) by intracerebral injections of doxorubicin (DOX) and lipopolysaccharide (LPS), followed by intraperitoneal (i.p.)…”