Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat

Abstract

Conventionally developed antiseizure drugs fail to control epileptic seizures in about 30% of patients, and no treatment prevents epilepsy. New etiologically realistic, syndrome-specific epilepsy models are expected to identify better treatments by capturing currently unknown ictogenic and epileptogenic mechanisms that operate in the corresponding patient populations. Additionally, the use of electrocorticography permits better monitoring of epileptogenesis and the full spectrum of acquired seizures, including focal nonconvulsive seizures that are typically difficult to treat in humans. Thus, the combined use of etiologically realistic models and electrocorticography may improve our understanding of the genesis and progression of epilepsy, and facilitate discovery and translation of novel treatments. However, this approach is labor intensive and must be optimized. To this end, we used an etiologically realistic rat model of posttraumatic epilepsy, in which the initiating fluid percussion injury closely replicates contusive closed-head injury in humans, and has been adapted to maximize epileptogenesis and focal non-convulsive seizures. We obtained week-long 5-electrode electrocorticography 1 month post-injury, and used a Monte-Carlo-based non-parametric bootstrap strategy to test the impact of electrode montage design, duration-based seizure definitions, group size and duration of recordings on the assessment of posttraumatic epilepsy, and on statistical power to detect antiseizure and antiepileptogenic treatment effects. We found that use of seizure definition based on clinical criteria rather than event duration, and of recording montages closely sampling the activity of epileptic foci, maximize the power to detect treatment effects. Detection of treatment effects was marginally improved by prolonged recording, and 24 h recording epochs were sufficient to provide 80% power to detect clinically interesting seizure control or prevention of seizures with small groups of animals. We conclude that appropriate electrode montage and clinically relevant seizure definition permit convenient deployment of fluid percussion injury and electrocorticography for epilepsy therapy development.

Progressive, Seizure-Like, Spike-Wave Discharges Are Common in Both Injured and Uninjured Sprague-Dawley Rats: Implications for the Fluid Percussion Injury Model of Post-Traumatic Epilepsy

“…Several independent laboratories have successfully deployed FPI, and induced various forms of convulsive and non-convulsive epileptic seizures. Our laboratory has focused on developing, characterizing and optimizing a rat model of focal neocortical non-convulsive PTE induced by rostral parasagittal FPI (rpFPI; Curia et al, 2011;D'Ambrosio et al, 2004;Eastman et al, 2015), and deploying it to test treatments (Eastman et al, 2010;D'Ambrosio et al, 2013;Curia et al, 2015).…”

The progression of electrophysiologic abnormalities during epileptogenesis after experimental traumatic brain injury

“…The extensive EEG coverage used in this study, including the frontal lobes bilaterally, should have identified frontal‐onset seizures if they occurred. Montages consisting of four electrodes versus two have been shown to more reliably detect seizures after FPI; therefore, the 16 electrodes used here should be extremely reliable for detecting seizure onset. A 10 s cutoff was used to define ictal events because of concerns voiced in the animal literature about whether shorter events are epileptic seizures, even though we are well aware that seizures in patients and animal studies can last <10 s .…”

Methodological standards and interpretation of video‐electroencephalography in adult control rodents. A TASK1‐WG1 report of theAES/ILAETranslational Task Force of the ILAE

“…Heat, trauma, and chronic compression of underlying brain tissue are the main promoters of unintended brain injury during electrode implantation. Heat can be produced during drilling and during the highly exothermic curing of the dental acrylic from which the headset is constructed . To dissipate the frictional heat generated during drilling, the skull and drill bit can be cooled continuously with sterile saline maintained at room temperature.…”

“…Heat can be produced during drilling and during the highly exothermic curing of the dental acrylic from which the headset is constructed. [23][24][25] To dissipate the frictional heat generated during drilling, the skull and drill bit can be cooled continuously with sterile saline maintained at room temperature. To dissipate the heat associated with curing, a continuous stream of cool air may be directed onto the hardening acrylic and/or alcohol can be used for evaporative cooling.…”