Key Points:
- CURE Epilepsy awardee Dr. Franck Kalume and colleagues at the Seattle Children’s Research Institute and New York University sought to identify simple environmental factors that may increase the risk of SUDEP.
- The team examined the effects of increased temperature and moderate exercise on several basal involuntary bodily functions of an established mouse model of Dravet syndrome (DS), a severe form of epilepsy with an increased incidence of SUDEP.
- When compared to normal mice, DS mice showed diminished regulation of core body temperature as well as cardiac and respiratory function.
- Understanding the mechanisms behind these impairments might help develop effective approaches to reduce the risk of and perhaps even prevent SUDEP.
Deep Dive:
Sudden unexpected death in epilepsy (SUDEP) is a devasting event that occurs in approximately 1 in 1,000 people with epilepsy [1,2]. It appears to be related to seizure-induced dysfunction of the autonomic nervous system (ANS) [3]. The ANS controls body functions essential for survival and is responsive to environmental changes. Some of these functions include maintenance of core body temperature as well as tight regulation of heart and breathing rates. Previous research has revealed that disruptions in ANS function related to a seizure event are marked by diminished control of these three body processes, but the precise nature and mechanisms of these weakened responses are not clear.
Dr. Franck Kalume, a recipient of CURE Epilepsy’s Sleep and Epilepsy Award, generously funded by the BAND Foundation, explored this important area of research by utilizing his mouse model of Dravet syndrome (DS). [4] DS is a treatment-resistant form of epilepsy with a high risk of SUDEP, and an increased prevalence of ANS dysfunction. This particular mouse model was developed by deleting the gene linked to most cases of DS in humans (known as SCN1A), which is also one of the many genes responsible for propagating electrical signals in the brain.
The first set of experiments involved assessing the ability of DS mice to regulate 1) core body temperature, 2) heart rate, and 3) breathing rate in response to an increase in surrounding temperature, i.e., to 86-90°F. Responses from the DS mice and control mice were subsequently compared [5].
Before elevating the external temperature, the internal body temperatures of both DS and control mice were similar. In the first 15 min after heat exposure, the core body temperature in both groups increased, although the absolute temperature and rate of this increase was much smaller in DS versus control mice. As exposure to heat was reduced, the core body temperature returned to baseline in control animals, but in DS mice, body temperature remained elevated. These observations suggest that DS mice have deficits in thermoregulation (an ability to control core body temperature).
Dr. Kalume and his team developed another set of DS mice in which the SCN1A gene had been deleted only in neurons responsible for transmitting inhibitory electrical signals in the brain [5]. The same responses were observed in this second group of DS mice, indicating that thermoregulation is most likely mediated by these inhibitory neurons.
Along with deficits in controlling core body temperature, the DS mice also had problems regulating cardiac and respiratory function in response to elevated temperature. Specifically, although the heart rate of DS mice increased to only half that of control mice, the rate of recovery was much slower after the heat source had been removed. Likewise, even though the breathing rates decreased in both DS and control mice in response to higher temperatures, it recovered partially in control mice but not at all in DS mice.
The effect of moderate exercise (running on a treadmill) on heart rate as well as heart rate variability was also assessed [5]. During this exercise challenge, the highest heart rate level reached was much lower in DS than in control mice, and it took much longer for DS mice to reach their peak values. Similar responses were observed for heart rate variability, all of which suggest impaired cardiac function in DS.
Together, these findings imply that there are clear abnormalities within the ANS of DS mice and, by extension, in people with DS and possibly other intractable epilepsies. Understanding the biological bases of these irregularities and how environmental changes may adversely affect them will likely assist in the development of novel methods to reduce seizure-related health consequences as well as the high risk of SUDEP.
This work was conducted in collaboration with Dr. Orrin Devinsky of New York University.
Read more about Dr. Kalume’s research in sleep and epilepsy here
Literature Cited
- Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
- Devinsky, O. & Sisodiya, S.M. SUDEP: Advances and challenges. Epilepsy Curr. 2020; 20(6 Suppl): 29S-31S.
- Kalume, F. Sudden unexpected death in Dravet syndrome: respiratory & other physiological dysfunctions. Respir. Physiol. Neurobiol. 2013; 189: 324-328.
- Kalume, F. et al. Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 2013; 123: 1798-1808.
- Sahai, N. et al. Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome. Neurobiol. Dis. 2021; 147: 105154.