Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, estimated to account for up to 50% of all deaths in this population and up to 17% of deaths in all patients with epilepsy. There is a surprisingly common lack of awareness among patients and physicians of this increased risk of sudden death. In a recent survey, only 56% of Canadian pediatricians who treat patients with epilepsy knew their patients were at increased risk for sudden death and only 33% of these physicians knew the term SUDEP. There is controversy regarding whether cardiac failure or respiratory arrest is more important as the primary cause of death, but cardiac and respiratory data is rarely collected simultaneously from human cases of SUDEP or from mouse models. For example, in the more than 20 documented cases of SUDEP that occurred while the patient was undergoing EMU monitoring, none of these patients had measurements of ventilation or even blood oxygenation. Effective preventive strategies in high-risk epileptic patients will rely on defining the mechanisms that lead from seizures to death. Our preliminary data suggest that respiratory depression is the primary cause of death in some cases of SUDEP and that patients with Dravet syndrome have previously uncharacterized breathing abnormalities in the peri-ictal period. Furthermore, our data has indicated there is an anatomical pathway that inhibits ventilation, which extends from the amygdala and anterior temporal lobe to medullary nuclei that control breathing. However, it is unclear how this circuit is connected and the identities of the neurons involved.
In Aim 1, we will characterize peri-ictal cardiorespiratory control in human patients with Dravet syndrome as well as mouse models of this pathology.
In Aim 2, we will define the anatomical pathway from the amygdala to the brainstem that inhibits the cardiovascular and respiratory control networks during seizures. Finally, in Aim 3 we will determine the identity of brainstem neurons that receive inputs from the amygdala and inhibit breathing and consciousness during seizures. This work will identify an anatomical pathway by which cortical seizures can invade the midbrain and brainstem and cause depressed cardiorespiratory function and arousal. Our findings have the potential to characterize key components of this circuit and may identify biomarkers that can be used to develop effective screening strategies. Better understanding mechanisms that underlie SUDEP will allow future development of preventative treatments that may decrease SUDEP risk.

Public Health Relevance

SUDEP is a major cause of death in patients with epilepsy, by some estimates accounting for up to 50% of mortality in patients with chronic refractory epilepsy. Cardiac arrhythmias and respiratory depression are both proposed to be mechanisms that lead to SUDEP, however respiratory mechanisms have not been studied as extensively as cardiac causes. This proposal seeks: 1) to investigate the mechanisms underlying hypoventilation and post-ictal coma;2) to identify biomarkers;3) to aid forensic diagnosis, and;4) to discover preventive interventions to decrease SUDEP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS090414-01
Application #
8820772
Study Section
Special Emphasis Panel (ZNS1-SRB-B (40))
Program Officer
Fureman, Brandy E
Project Start
2014-09-30
Project End
2019-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$600,462
Indirect Cost
$170,462
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242