Sudden Unexpected Death in Epilepsy: An Unrecognized Silent Killer

Epilepsy

Sudden unexpected death in epilepsy (SUDEP) is a poorly understood condition in which patients with epilepsy die with no specific cause noted upon autopsy. SUDEP accounts for 2% of deaths in populations with epilepsy and can be as high as 25% of deaths in patient populations, with the incidence of SUDEP increasing with severity of epilepsy.1 Currently, multiple institutions and private projects are investing millions of dollars into research into the causes and treatment of SUDEP. To date this has culminated in the proposition of three mechanisms as the cause of SUDEP: 1) cardiac arrhythmia, 2) neurogenic pulmonary edema and postictal suppression of the medulla (the area of the brainstem that controls breathing).2 Most research currently suggests that the most common cause of death resulting is respiratory arrest due to disruption of the medullary signaling during the seizure leading to cessation of breathing.2 This paper will investigate the causes, treatments, and preventative methods for SUDEP currently being researched, including abstracts from a private interview with Dr. George Richerson of the University of Iowa on his research into SUDEP.

Dr. Richerson, at the University of Iowa Hospitals and Clinics is investigating the prediction, treatment and prevention of SUDEP. Dr. Richerson began studying SUDEP while completing his training in neurology at Yale University in Connecticut. At the time he was studying sudden infant death syndrome (SIDS), a similar condition that affects infants less than a year old. In the course of research Dr. Richerson’s group developed the hypothesis that epileptic attacks lead to inhibition of protective responses in the brainstem that respond to homeostatic stressors such as an increase in blood CO2 levels or arrythmia of the heart. Their results pointed to abnormalities in concentrations of the neurotransmitter serotonin in the medulla as well as disruption of the hypothalamus which controls arousal of patients when asleep, preventing them from awaking and reacting to the syndrome. Recognizing the similarities between the conditions, Dr. Richerson began to investigate further into SUDEP. After leaving Yale, Dr. Richerson returned to the University of Iowa where he began by looking at the causes of SUDEP and identifying patients that were at risk for the condition.

Dr. Richerson’s research looks at the link between serotonin and the effects on the brainstem that contains the medulla as well as looking the inhibition of breathing when seizures spread to the amygdala.2,3 Dr. Richerson also looks at the effects of sodium channel mutations in the heart that further increase patients’ risk for SUDEP related death due to arrhythmic heart beats.6 Dr. Richerson hopes to find methods to identify patients that are at high risk for SUDEP. If successful, this will aid further preventive studies by facilitating the recruitment of larger number of subjects to participate in research.

Dr. Richerson’s research in animal models suggests that subjects that die from SUDEP die due to asphyxiation due to a lack of oxygen caused by seizures disrupting the medulla. This is in contrast to studies that favor disruption of cardiac activity as the major driver.4,5 If correct, this would strengthen Dr. Richerson’s previous research indicating that abnormalities in serotonergic neurons in the medulla which controls breathing is most likely the cause of SUDEP.

Current methods to prevent SUDEP are limited and primarily involve avoiding lifestyle factors that could exacerbate the patient’s initial risk for SUDEP related epilepsy. These include taking prescribed antiseizure medication and committing to a sleep schedule that enable eight hours of sleep a night.7 However, certain antiseizure mediations have been shown to increase the risk of SUDEP for certain patients. Some studies suggest that rapid fluctuations in the levels of antiseizure drugs such as carbamazepine lead to arrhythmia or alteration of normal myogenic cardiac functions.1 Doctors also recommend not sleeping alone if at risk for SUDEP as another person might be capable of rendering assistance in the event of an epileptic seizure resulting in apnea.7

Dr. Richerson’s efforts have highlighted several lines of evidence that focus on the effects of the neurotransmitter serotonin (5-HT) on the respiratory system. Mice that lacked the 5-HT displayed decreased seizure threshold and increased mortality rates when compared to control mice.4,5 Researchers concluded that proper function of 5-HT neurons raises the threshold for seizures in the control mice. Critically, it was noted that mice in the experimental group that lacked the 5-HT neuron died from lack of oxygen as opposed to cardiac arrest.4 Finally, application of selective serotonin reuptake inhibitors (SSRI’s)and mechanically assisted ventilation were also shown to decrease the risk of mortality in mice.4,5 Researchers hope that these animal models will help to determine the interplay between generalized seizures that are the primary cause of SUDEP and the 5-HT system.

Recently research into genetic-epigenetic tests for conditions ranging from heart disease to smoking cessation have made their way onto the market.12 The potential for the application of genetic-epigenetic screenings to look for early signs of epilepsy before it manifests might allow for the prediction of and early treatment of SUDEP related epilepsy. The genetic component is compounded by lifestyle or epigenetic factors such as alcohol or drugs, especially depressants such as barbiturates, opioids, and benzodiazepines such as valium, all of these will increase the like of SUDEP in the event of a seizure.7,9 Drugs like cocaine have shown to severely exasperate the risk of epileptic incidence in patients.10 Not getting enough sleep also increases the risk for SUDEP in epileptic patients.7Application of both the genetic components such as the 5-HT neuron and lifestyle factors such as substance abuse that influence a patient’s risk for epileptic episodes, the application of new genetic-epigenetic tests to predict for SUDEP related epilepsy do not seem far away.

New research into epilepsy prevention in order to prevent patient death by SUDEP has led to a serious of innovative technologies that help to prevent patients from having epileptic episodes. These include pacemakers like devices implanted in patents that stimulate the Vegas nerve to signal the brain to inhibit the seizure, or devices in your brain that detect seizure activity and provide an electrical stimulation to the area to stop the seizure. 11 A possible future method could be the use of electrodes implanted into the medulla obligate, the raspatory control center of the brain which when attached to a pacemaker could provide rhythmic stimulation to keep a patient breathing when the brain is being otherwise inhibited by a seizure. Complications to this method is the high chance of brain bleed brough in by electrode placement in this region of the brain, but research into new electrode designs that may help to alleviate this concern are in the works leaving researchers hopeful as to a solution to SUDEP inducing epilepsy.

Citations:

  1. T;, Walczak. “Do Antiepileptic Drugs Play a Role in Sudden Unexpected Death in Epilepsy?” Drug Safety, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/12862502/.
  2. Kinney HC;Richerson GB;Dymecki SM;Darnall RA;Nattie EE; “The Brainstem and Serotonin in the Sudden Infant Death Syndrome.” Annual Review of Pathology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/19400695/.
  3. Dlouhy, B. J., Gehlbach, B. K., Kreple, C. J., Kawasaki, H., Oya, H., Buzza, C., Granner, M. A., Welsh, M. J., Howard, M. A., Wemmie, J. A. & Richerson, G. B. (2015). Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 35(28), 10281-
  4. GB;, Buchanan GF;Murray NM;Hajek MA;Richerson. “Serotonin Neurones Have Anti-Convulsant Effects and Reduce Seizure-Induced Mortality.” The Journal of Physiology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/25107926/.
  5. CL;, Feng HJ;Faingold. “Abnormalities of Serotonergic Neurotransmission in Animal Models of SUDEP.” Epilepsy & Behavior : E&B, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/26272185/.
  6. “Sudden Unexpected Death in Epilepsy.” Wikipedia, Wikimedia Foundation, 31 Mar. 2021, en.wikipedia.org/wiki/Sudden_unexpected_death_in_epilepsy.
  7. Authored By: Cyndi WrightPatty Obsorne Shafer RN, and Authored Date: 08/2013. “Preventing SUDEP.” Epilepsy Foundation, www.epilepsy.com/learn/early-death-and-sudep/sudep/preventing-sudep.
  8. Schachter, Authored By: Steven C., and Authored Date: 07/2013. “What Are the Risk Factors?” Epilepsy Foundation, www.epilepsy.com/learn/about-epilepsy-basics/what-are-risk-factors.
  9. Hamerle, M., et al. “Cannabis and Other Illicit Drug Use in Epilepsy Patients.” Wiley Online Library, John Wiley & Sons, Ltd, 11 Jan. 2013, onlinelibrary.wiley.com/doi/abs/10.1111/ene.12081.
  10. Koppel, Barbara S., et al. “Relation of Cocaine Use to Seizures and Epilepsy.” Wiley Online Library, John Wiley & Sons, Ltd, 3 Aug. 2005, onlinelibrary.wiley.com/doi/abs/10.1111/j.1528-1157.1996.tb00041.x.
  11. “Seizures.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 24 Feb. 2021, www.mayoclinic.org/diseases-conditions/seizure/diagnosis-treatment/drc-20365730.
  12. 15 Philibert, Willem, et al. “The Reversion of DNA Methylation at Coronary Heart Disease Risk Loci in Response to Prevention Therapy.” MDPI, Multidisciplinary Digital Publishing Institute, 16 Apr. 2021, www.mdpi.com/2227-9717/9/4/699.

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