Is Epilepsy a Preventable Disorder? New Evidence from Animal Models

Abstract

Epilepsy accounts for 0.5% of the global burden of disease, and primary prevention of epilepsy represents one of the three 2007 NINDS Epilepsy Research Benchmarks. In the past decade, efforts to understand and intervene in the process of epileptogenesis have yielded fruitful preventative strategies in animal models. This article reviews the current understanding of epileptogenesis, introduces the concept of a "critical period" for epileptogenesis, and examines strategies for epilepsy prevention in animal models of both acquired and genetic epilepsies. We discuss specific animal models, which may yield important insights into epilepsy prevention including kindling, poststatus epilepticus, prolonged febrile seizures, traumatic brain injury, hypoxia, the tuberous sclerosis mouse model, and the WAG/Rij rat model of primary generalized epilepsy. Hopefully, further investigation of antiepileptogenesis in animal models will soon enable human therapeutic trials to be initiated, leading to long-term epilepsy prevention and improved patient quality of life. Keywords epileptogenesis; prevention; activity dependent; animal models; acquired epilepsy; idiopathic generalized epilepsy Epilepsy is a disorder characterized by chronically recurring seizures without clear precipitants. The age-adjusted prevalence of epilepsy is in the range of 4 to 10 per 1000 people in most locations (Sander 2003; Forsgren and others 2005). The burden associated with epilepsy is great, both for the individual with epilepsy and for society at large. Epilepsy can negatively impact cognitive function, is a source of social stigma and legal marginalization, causes increased mortality, economically contributes 0.5% of the global burden of disease, and is associated with an increased risk of psychiatric disorder (de Boer and others 2008). As such, epilepsy prevention is one of the three 2007 NINDS Epilepsy Research Benchmarks (Kelley and others 2009).Work on epilepsy prevention can for the most part be parsed into prevention of epilepsy after a known inciting event (acquired epilepsy), and prevention of epilepsy in genetic © The Author(s) 2010Corresponding Author: Hal Blumenfeld, Yale University School of Medicine, Departments of Neurology, Neurobiology, and Neurosurgery, 333 Cedar Street, New Haven, CT 06520-8018, hal.blumenfeld@yale.edu. Declaration of Conflicting InterestsThe authors declared no potential conflicts of interests with respect to the authorship and/or publication of this article. NIH Public Access Author ManuscriptNeuroscientist. Author manuscript; available in PMC 2010 July 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript models where the time of epilepsy development is well characterized and may be dependent on a transient developmental milieu. Both of these approaches rest upon identification of epileptogenesis, understanding of the und erlying mechanisms of epilepsy development, and intervention targeted to these mechanisms in an appropriate time period. While prevention of epilepsy in human su...

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…Theoretically, this process might be similar to what happens during experimental electrical kindling stimulation of limbic regions where an initial subthreshold stimulus triggers over time, a larger neuronal response resulting in generalized seizures with increasing duration and intensity (Morimoto et al, 2004). Several mechanisms have been identified that may underlie this process, and it is clear that kindling causes functional plasticity in the stimulated focus while also recruiting other networks outside the stimulated area (Giblin and Blumenfeld, 2010;Morimoto et al, 2004). Accordingly, it is necessary to understand when this endogenous stimulation actually begins in WAG/Rij rats, since this will help to guide the search for the best moment for starting a treatment aimed at antiepileptogenesis.…”

“…WAG/Rij rats are currently considered a plausible model of absence epileptogenesis or more generally, a genetic animal model of epileptogenesis (Blumenfeld et al, 2008;Giblin and Blumenfeld, 2010;White and Loscher, 2014). This point is strongly supported by the recent clinical data demonstrating a potential antiepileptogenic effect of EHT in childhood absence epilepsy, similarly to its effects in this strain (Berg et al, 2014;Blumenfeld et al, 2008).…”

The rat perirhinal cortex: A review of anatomy, physiology, plasticity, and function

“…While there has been little electrophysiological work looking at synaptic plasticity in these projections, there have been a number of electrophysiological studies looking at epileptiform activity in the perirhinal cortex, especially utilising the kindling model of temporal lobe epilepsy (Goddard, 1967;Giblin and Blumenfeld, 2010). Slices of perirhinal cortex from amygdala-kindled rats showed abnormal generation and synchronisation of fEPSPs following tetanus stimulation compared to slices taken from control rats (Matsumoto et al, 1996).…”

Neuroimaging the Epileptogenic Process

“…Future preclinical and clinical studies that continue to identify and validate neuroimaging biomarkers, improve imaging methods, use multimodal imaging, and combine imaging with other validated techniques (e.g., EEG), will make further strides towards our better understanding of the epileptogenic process. There is also growing evidence from animal models that epilepsy is a preventable disorder (see [118] for a review), with the identification of promising antiepileptogenic treatments, including rapamycin and sodium selenate [118,119]. However, to maximize the translatability of these findings to human patients it is important that future preclinical anti-epileptogenic studies utilize valid and clinically applicable biomarkers, such as neuroimaging, in their assessment of these therapies [e.g., 120].…”