The Epilepsy Spectrum: Targeting Future Research Challenges

Abstract

There have been tremendous recent advances in our understanding of the biological underpinnings of epilepsy and associated comorbidities that justify its representation as a spectrum disorder. Advances in genetics, electrophysiology, and neuroimaging have greatly improved our ability to differentiate, diagnose, and treat individuals with epilepsy. However, we have made little overall progress in preventing epilepsy, and the number of patients who are cured remains small. Likewise, the comorbidities of epilepsy are often underdiagnosed or not adequately treated. In this article, we suggest a few areas in which additional research will likely pay big dividends for patients and their families.T he pace of recent advances in epilepsy has been explosive, driven by our increasing understanding of the disorder's inextricable links to development, excitability, and plasticity in the central nervous system, and by the steady emergence of techniques to analyze these properties at high resolution in both human and animal models. As shown in Figure 1, there has been a near doubling in published articles dealing with epilepsy over the last 15 years. Experimental research has produced a threefold increase in peer-reviewed papers since 1970. Subareas within epilepsy research that have shown nearly exponential increases in activity include genetic models, epileptogenesis, comorbidities, and mortality.Although it is gratifying that epilepsy is now receiving the attention it deserves based on its prevalence, the new knowledge comes at a cost; the more we learn about the complex biology of epilepsy, the further away we appear to be from the therapeutic goalposts. Despite our advances in more precisely defining seizure phenotypes, isolating causative genes, and developing specific therapies, much more work needs to be done before we can hope to prevent epilepsy in vulnerable populations, reduce comorbidities associated with epilepsy, and effectively eliminate seizures without causing adverse side effects. However, clinical heterogeneity and molecular complexity are features of all human disease, and serve to position the field of epilepsy research alongside that of cancer in allowing the opportunity to make steady inroads in curing certain forms (Noebels 2015). In the future, rather than measuring our progress by the prevalence of the disorder as a whole, we will be monitoring research progress within the many

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…However, it has been suggested that most epilepsies have a polygenic basis, with multiple genetic susceptibility factors which have only partial effects, but act in concert, and interact with various environmental factors (Ferraro and Buono, 2006; Tan and Berkovic, 2010). The genes associated with epilepsy are involved in different molecular pathways, including the regulation of development and function of the nervous system (Holmes and Noebels, 2016). Although, the majority of genes associated with epilepsies are coding for different voltage and ligand-gated ion channels or regulating the action of excitatory or inhibitory neurotransmission (i.e., CHRNA4, CHRNA2, CHRNB2, GABRG2, GABRA1, KCNQ2, KCNQ3, SCN1B, SCN1A, SCN2A), the potential role of several other genes (i.e., ARX, CDKL5, LGI1, PCDH19, SLC2A1, SPTAN1, STXBP1) in the epilepsy has also been also suggested (Rees, 2010; Hildebrand et al, 2013).…”

The polymicrogyria-associatedGPR56promoter preferentially drives gene expression in developing GABAergic neurons in common marmosets

“…Mutations in its promoter region are reported to reduce SCN1A transcription, which causes SCN1A haploinsufficiency. Accordingly, the reduced sodium currents in GABAergic inhibitory neurons may cause hypoexcitability of inhibitory neurons, leading to epilepsy 36 . It is unclear how the deletion within the hGPR56 e1m non-coding region led to epilepsy.…”

Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy

“…Epilepsy-associated genes encode for ion channel and synaptic proteins, as well as cell adhesion molecules, signaling proteins and transcription factors. The mechanisms through which mutations in such different genes lead to epileptic seizures are largely unknown, although they ultimately lead to brain hyperexcitability [9].…”