Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most common type of death in people with intractable epilepsies associated with cognitive impairment. These life-threatening epilepsies include epilepsy associated with focal cortical dysplasia (FCD) and Dravet syndrome (DS). FCD is a developmental disorder with early childhood onset marked by intractable seizures. Recent genetic studies have uncovered that FCD type IIa is linked with missense gain-of-function mutations in PIK3CA, a critical gene involved in development and cancer. DS is an intriguing treatment-resistant epilepsy with infantile-onset and has one of the highest rates of SUDEP. DS is often caused by heterozygous loss-of-function mutation in SCN1A, the gene encoding NaV 1.1 channels. Cardiovascular dysfunctions have been identified as the main causes of SUDEP. We conducted a dual examination of cardiac and respiratory functions during interictal, ictal, and post-ictal periods to identify and characterize signs of SUDEP susceptibility in a mouse model of FCD (carrying a gain-of-function mutation in Pik3ca) and that of DS (harboring a heterozygous knock out of Scn1a). Methods: Combined video-EEG-ECG and whole body plethysmograph were recorded from freely moving genetic mouse models of DS, FCD, and respective controls using fine silver EEG ECG and EMG electrodes. Signals were acquired on a Power Lab 8/35 using LabChart Software 8.0 (AD Instruments) during Interictal, ictal, and postictal periods. Results: In DS mice, our previous studies showed a substantial suppression of resting heart rate variability, increased frequency of AV blocks, and no change in resting heart rate (HR). In these studies, we observed suppressed respiratory responses to hypercapnia (60 8 %), hypoxia (48 5 %), and anoxia (31 6 %) in DS mice (n=6) compared to WT (n=9). In addition, these mice exhibited concurrent transient bradycardia and bradypnea during the tonic phases of thermal generalized tonic clonic seizures. Mice carrying DS-causing mutation in GABAergic interneurons alone, not excitatory neurons, revealed similar ictal and interictal dysregulations of cardiorespiratory functions. In FCD mice (n=6), resting interictal recordings also showed a decreased in HRV, but accompanied with increase in HR and absence of AV blocks. Respiratory recordings showed blunted respiratory responses to hypercapnic (80 9 %), hypoxic (60 8 %), and anoxic (30 7 %) conditions compared to controls (n=6). These defects were comparable to those of DS mice. Furthermore, PTZ-induced seizures caused similar but less severe simultaneous brief bradypnea and bradycardia, analogous to those of DS mice. Conclusions: These results suggest that regardless of the etiology of epilepsy, seizures cause similar cardiorespiratory dysfunctions leading to SUDEP. In addition, GABAergic interneurons are implicated in the mechanisms of SUDEP. Understanding the cellular and network mechanisms underlying these physiological dysfunctions may lead to better therapeutic methods for SUDEP prevention. Funding: CURE SUDEP grant Christopher Donalty and Kyle Coggins Award Ellenbogen Chair Seeds Funds