A recent study published in the Journal of Neuroscience has revealed that impaired chemoreception due to transient inhibition of serotonergic neurons might contribute to the pathophysiology of sudden unexpected death in epilepsy (SUDEP).
The study highlighted that seizures damage CO2 chemoreception in a few epilepsy patients. Moreover, generalized convulsive impaired CO2 chemoreception and induced hypothermia are the 2 factors responsible for serotonergic neuron dysfunction.
Read more about Dravet syndrome diagnosis
SUDEP is the primary cause of premature deaths in patients with epilepsy, the study team noted. Most observed cases are often preceded by generalized convulsive seizure (GCS), and cases occurring in the epilepsy monitoring unit (EMU) indicate that the death is most often due to postictal respiratory arrest, they added.
However, the mechanisms leading seizures to fatal respiratory dysfunction remain largely unknown, the researchers noted. Prior studies have shown that patients with Dravet Syndrome (DS), an epileptic encephalopathy with a high incidence of SUDEP, might exhibit prolonged hypoventilation after a GCS, leading to increased transcutaneous CO2, the investigators noted. This evidence suggests that respiratory CO2 chemoreceptors are impaired after seizures, they added.
Serotonergic neurons in the midbrain and medulla, highly sensitive to CO2, are the potential candidates for central CO2 chemoreceptors, study team noted. Previous research has shown that a subgroup of serotonergic neurons is inhibited during seizures, demonstrating the post-ictal decrease in CO2 chemoreception, they added.
Serotonin has been involved in the pathophysiology of SUDEP; however, the mechanisms of this association remain unclear, the authors wrote. Evidence has suggested that dysfunction of the 5-hydroxytryptamine (5-HT) system has been shown to increase the mortality following seizures and the activation of serotonergic neurons that increase survival in the SUDEP model, they said.
The researchers demonstrated whether GCS causes postictal impairment of CO2 chemoreception and thermoregulation, as expected in the case of postictal inhibition of a sufficient number of serotonergic neurons. Patients, who are at least 18 years of age, with confirmed epilepsy undergoing video EEG monitoring in EMU at the University of Iowa Hospitals between March 2015 and November 2019 were included in the study.
Two mouse models of SUDEP, Scn1aR1407X/+ (Dravet Syndrome, DS) and Scn8aN1768D/+ (D/+), were employed, and hypercapnic ventilatory response (HCVR), a measure of respiratory CO2 chemoreception before and after the head induced seizures were measured.
According to study results, both focal and GCS caused a prolonged decrease in the HCVR. Moreover, convulsive seizures caused a postictal decrease in ventilation. They severely depressed the HCVR in a subset of animals, resulting in a combination of abnormal thermoregulation and blunted HCVR, known to occur with dysfunction of the serotonin system in mice.
In addition, the depletion of serotonin with parachlorophenylalanine, which mimicked seizure-induced hypoventilation, aggravated hypothermia, partially occluded the postictal decrease in HCVR, and elevated the postictal mortality in DS mice. On the other hand, pretreatment with the 5-HT agonist fenfluramine lowered postictal inhibition of HCVR and hypothermia.
“These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing post-ictal 5-HT tone,” the authors concluded.
Reference
Teran FA, Sainju RK, Bravo E, et al. Seizures cause prolonged impairment of ventilation, CO2 chemoreception and thermoregulation. Journal of Neuroscience. Published online May 9, 2023. doi:10.1523/JNEUROSCI.0450-23.2023
