Sudden unexplained death in epilepsy (SUDEP) in patients with Dravet syndrome can be caused by breathing abnormalities associated with an epileptic seizure, which may slow down the heart rate and eventually lead to death, a study shows.
Interventions aimed at re-initiating normal breathing may be more effective in preventing SUDEP in some Dravet syndrome patients than those focused only on normalizing heart function.
The study, “Severe peri-ictal respiratory dysfunction is common in Dravet syndrome,” was published in The Journal of Clinical Investigation.
Patients with epilepsy, including those with Dravet syndrome, have a high risk of SUDEP. The cause and underlying mechanism leading to this fatal event are unknown, but it is believed that most deaths occur immediately after a seizure.
Many theories have been proposed, many of which attribute the cause of death to abnormal heart rhythms, or arrhythmias.
To identify risk factors as well as develop preventive or rescuing measures, it is important to define the sequence of events that lead from a seizure to death.
A lot of useful information can be gathered by capturing these events in patients who are monitored in epilepsy monitoring units, which are inpatient units run by specialists in epilepsy. However, very few of these recordings, including video electroencephalograms (VEEG, to measure brain activity) and electrocardiograms (which measures heart activity), are available.
Recently, a small number of patients who died of SUDEP were recorded. The typical sequence of events was a generalized tonic-clonic seizure (convulsions) followed by bradycardia (slower-than-normal heart rate) and asystole (absence of heart contractions), along with decreased respiratory rate leading to terminal apnea — when breathing stops.
These observations suggested that impairments in breathing may play an important role in SUDEP. However, this type of recording, including breathing measurements, had never been performed in the context of Dravet syndrome.
To evaluate the potential role of post-seizure breathing abnormalities in SUDEP, a team led by researchers at University of Iowa reviewed the video recordings of a group of patients with Dravet syndrome admitted at the Lurie Children’s Hospital in Chicago.
Patients stayed in the epilepsy monitoring unit of the hospital for routine VEEG monitoring of treatment-resistant seizures.
Researchers compared the recordings of seven patients with Dravet syndrome versus those of seven patients with a different type of epilepsy called localization-related epilepsy. The scientists looked at chest and abdomen movements, aided by video image analysis to evaluate patients’ breathing patterns.
The analysis revealed that patients with Dravet syndrome were significantly more likely to have abnormal breathing in the peri-ictal phase, that is, before, during and after a seizure.
Four out of seven patients exhibited signs of breathing rhythm problems, which were not present in patients with localization-related epilepsy.
These perturbations were consistent with paradoxical breathing — when the primary chest muscle responsible for breathing (the diaphragm) moves opposite to the normal direction; problems in breathing; ataxic (irregular) breathing; or transient stops in breathing (apnea) for five seconds or longer.
In all of these cases, breathing abnormalities were temporary.
In one patient, a 9-year-old girl, it was possible to perform further exams to evaluate her respiratory function, including transcutaneous carbon dioxide (tcCO2) — a method based on skin sensors to estimate the levels of carbon dioxide in the blood.
This tool provides a continuous and noninvasive estimation of the arterial CO2 value and can be used for assessing how good a person’s ventilation is.
During and after three episodes of consecutive and generalized tonic-clonic seizures, the patient had apnea lasting up to 13 seconds, which was accompanied by persistent insufficient ventilation, which was not resolved through oxygen supply. This patient died three years later of SUDEP.
These data indicate that many patients with Dravet syndrome have respiratory dysfunctions accompanying a seizure that can last long after the episode is over. Such respiratory changes may become useful “biomarkers of patients at high risk,” the researchers said.
In the second part of the study, the team looked at episodes of sudden death in mouse models of Dravet syndrome. These are genetically engineered mice that “recapitulate the [disease manifestations] of [Dravet syndrome] in humans” including spontaneous seizures that can be induced by heat, according to the researchers.
Results showed that mice died due to central apnea (where breathing repeatedly stops and starts) followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced or maximal electroshock, as well as therapies known as muscarinic antagonists, as long as these therapies were able to reach the central nervous system.
“We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia,” presumably via a direct effect of low oxygen supply to the heart muscle, according to the researchers.
Therefore, in some patients with Dravet syndrome, “it can be misleading to focus attention on cardiac changes without simultaneously evaluating breathing” and changes in blood gases, since changes in oxygen, carbon dioxide, and pH can induce a variety of “cardiovascular abnormalities,” they said.
Interventions that restore breathing (e.g., stimulating arousal, ventilatory assistance with a bag valve mask, mouth-to-mouth resuscitation) may be more effective than cardiac interventions, such as a pacemaker, in patients with epilepsy who have respiratory arrests before, during, or after a seizure.
Patients with epilepsy at a high risk of apnea “would be prudent to avoid alcohol and medications that depress breathing,” the researchers cautioned.