Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy
Corresponding Author
Ian C. Wenker PhD
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Address correspondence to Dr Wenker, Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908-0710. E-mail: [email protected]
Search for more papers by this authorFrida A. Teran
Department of Neurology, University of Iowa, Iowa City, IA
Medical Scientist Training Program, University of Iowa, Iowa City, IA
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA
Search for more papers by this authorEric R. Wengert
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Neuroscience Graduate Program, University of Virginia, Charlottesville, VA
Search for more papers by this authorPravin K. Wagley MS
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Department of Neurology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorPayal S. Panchal
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorElizabeth A. Blizzard
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorPriyanka Saraf
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorJacy L. Wagnon PhD
Department of Human Genetics, University of Michigan, Ann Arbor, MI
Search for more papers by this authorHoward P. Goodkin MD, PhD
Department of Neurology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorMiriam H. Meisler PhD
Department of Human Genetics, University of Michigan, Ann Arbor, MI
Search for more papers by this authorGeorge B. Richerson MD, PhD
Department of Neurology, University of Iowa, Iowa City, IA
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA
Veterans Affairs Medical Center, Iowa City, IA
Search for more papers by this authorManoj K. Patel PhD
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorCorresponding Author
Ian C. Wenker PhD
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Address correspondence to Dr Wenker, Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908-0710. E-mail: [email protected]
Search for more papers by this authorFrida A. Teran
Department of Neurology, University of Iowa, Iowa City, IA
Medical Scientist Training Program, University of Iowa, Iowa City, IA
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA
Search for more papers by this authorEric R. Wengert
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Neuroscience Graduate Program, University of Virginia, Charlottesville, VA
Search for more papers by this authorPravin K. Wagley MS
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Department of Neurology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorPayal S. Panchal
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorElizabeth A. Blizzard
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorPriyanka Saraf
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorJacy L. Wagnon PhD
Department of Human Genetics, University of Michigan, Ann Arbor, MI
Search for more papers by this authorHoward P. Goodkin MD, PhD
Department of Neurology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorMiriam H. Meisler PhD
Department of Human Genetics, University of Michigan, Ann Arbor, MI
Search for more papers by this authorGeorge B. Richerson MD, PhD
Department of Neurology, University of Iowa, Iowa City, IA
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA
Veterans Affairs Medical Center, Iowa City, IA
Search for more papers by this authorManoj K. Patel PhD
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorAbstract
Objective
Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures.
Methods
We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele—mutations identified from patients who died from SUDEP—and of seizure-induced death in pentylenetetrazole-treated wild-type mice.
Results
The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea.
Interpretation
We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023–1035
Potential Conflicts of Interest
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana26053-sup-0001-Movie S1.movQuickTime video, 21.8 MB | VIDEO S1. Video of a fatal tonic seizure in a W/+Emx1-Cre mouse with electroencephalographic, electrocardiographic, and breathing (pleth) signals synced to video. The mouse having the seizure is indicated by the red box. |
| ana26053-sup-0002-Movie S2.movQuickTime video, 23.9 MB | VIDEO S2. Video of nonfatal tonic seizure in a W/+Emx1-Cre mouse with electroencephalographic, electrocardiographic, and breathing (pleth) signals synced to video. The mouse having the seizure is indicated by the red box. |
| ana26053-sup-0003-Movie S3.movQuickTime video, 21.1 MB | VIDEO S3. Video of clonic seizure in a W/+Emx1-Cre mouse with electroencephalographic, electrocardiographic, and breathing (pleth) signals synced to video. The mouse having the seizure is indicated by the red box. |
| ana26053-sup-0004-Movie S4.movQuickTime video, 22.7 MB | VIDEO S4. Video of a fatal tonic seizure induced by pentylenetetrazole (90 mg/kg) in a wild-type mouse with electroencephalographic, electrocardiographic, and breathing (pleth) signals synced to video. The mouse having the seizure is indicated by the red box. |
| ana26053-sup-0005-Movie S5.movQuickTime video, 10.8 MB | VIDEO S5. Side-by-side videos of audiogenic seizures induced in 2 littermate 15-day-old W/+EIIA-Cre mice. On the left, the mouse was handled, but not ventilated, resulting in sudden death. On the right, the mouse was mechanically ventilated and survived. |
| ana26053-sup-0006-Movie S6.movQuickTime video, 30.1 MB | VIDEO S6. Video of a developmental epileptic encephalopathy patient with an L257V SCN8A mutation before, during, and after the seizure analyzed in Figure 7. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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