In gratitude of the loyal support of our members, the CNS is offering complimentary 2021 Annual Meeting registration to all members! Learn more.

  • Mechanism for sudden unexpected death in epilepsy (SUDEP): the amygdala as a pathway to seizure-induced apnea, respiratory agnosia and sudden death

    Final Number:
    190

    Authors:
    Brian J. Dlouhy MD; Brian K. Gehlbach M.D.; Collin J. Kreple B.S.; Hiroto Kawasaki MD; Hiroyuki Oya MD; Colin Buzza; Mark A. Granner M.D.; Michael J. Welsh M.D.; Matthew A. Howard MD; John A Wemmie M.D., Ph.D.; George B. Richerson M.D., Ph.D.

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Case studies suggest that the cause of SUDEP may be respiratory depression induced by seizures. Consistent with this possibility, non-fatal seizures, both focal and generalized, are often associated with apnea and oxygen desaturation. However, the mechanisms for the respiratory effects in both fatal and non-fatal seizures remain unclear.

    Methods: Because impaired breathing is thought to play a critical role in SUDEP, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We monitored breathing in a medically refractory epilepsy patient (JK) during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We used intracranial electrical stimulation to examine the function of candidate forebrain sites in three subjects.

    Results: We found that central apnea and oxygen (O2) desaturation occurred when seizures spread to the left amygdala. Localized electrical stimulation of the left amygdala reproduced the apnea and O2 desaturation. Localized electrical stimulation of the right amygdala also produced apnea and O2 desaturation. These effects of amygdala stimulation were also observed in two additional subjects (KD and SP). Surprisingly, even when patients were awake and vigilant, they were completely unaware of the apnea evoked by stimulation and expressed no dyspnea. In contrast, voluntary breath holding of similar duration caused severe dyspnea. Using an intermittent stimulation paradigm, amygdala stimulation-evoked apnea and respiratory agnosia persisted over several minutes, as would likely be the case in a seizure that could lead to SUDEP.

    Conclusions: These findings indicate a functional connection between the amygdala and medullary respiratory network in humans. Due to inhibition of breathing, respiratory agnosia and loss of dyspnea, our data suggest that seizure activity within the amygdala may lead to SUDEP. Identifying strategies to target this process might prevent SUDEP.

    Patient Care: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in chronic refractory epilepsy patients. However, the pathophysiological mechanisms underlying SUDEP are unclear. Determining the mechanisms that leads to death will allow identification of proper preventative strategies to prevent SUDEP.

    Learning Objectives: By the conclusion of this session, participants should be able to 1) Describe the importance of sudden unexpected death in epilepsy (SUDEP), 2) Discuss, in small groups, the amygdala's role in breathing, and 3) Identify an effective treatment for SUDEP.

    References: 1 Devinsky, O. Sudden, unexpected death in epilepsy. The New England journal of medicine 365, 1801-1811, doi:10.1056/NEJMra1010481 (2011). 2 Shorvon, S. & Tomson, T. Sudden unexpected death in epilepsy. Lancet 378, 2028-2038, doi:10.1016/S0140-6736(11)60176-1 (2011). 3 Nashef, L., So, E. L., Ryvlin, P. & Tomson, T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 53, 227-233, doi:10.1111/j.1528-1167.2011.03358.x (2012). 4 Sillanpaa, M. & Shinnar, S. Long-term mortality in childhood-onset epilepsy. The New England journal of medicine 363, 2522-2529, doi:10.1056/NEJMoa0911610 (2010). 5 Terrence, C. F., Jr., Wisotzkey, H. M. & Perper, J. A. Unexpected, unexplained death in epileptic patients. Neurology 25, 594-598 (1975). 6 So, E. L., Sam, M. C. & Lagerlund, T. L. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 41, 1494-1497 (2000). 7 Bateman, L. M., Spitz, M. & Seyal, M. Ictal hypoventilation contributes to cardiac arrhythmia and SUDEP: report on two deaths in video-EEG-monitored patients. Epilepsia 51, 916-920, doi:10.1111/j.1528-1167.2009.02513.x (2010). 8 Tao, J. X. et al. SUDEP, suspected positional airway obstruction, and hypoventilation in postictal coma. Epilepsia 51, 2344-2347, doi:10.1111/j.1528-1167.2010.02719.x (2010). 9 Bateman, L. M., Li, C. S. & Seyal, M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain : a journal of neurology 131, 3239-3245, doi:10.1093/brain/awn277 (2008). 10 Masaoka, Y. & Homma, I. Amygdala and emotional breathing in humans. Advances in experimental medicine and biology 551, 9-14 (2004). 11 Feinstein, J. S. et al. Fear and panic in humans with bilateral amygdala damage. Nature neuroscience 16, 270-272, doi:10.1038/nn.3323 (2013). 12 Kaada, B. R. & Jasper, H. Respiratory responses to stimulation of temporal pole, insula, and hippocampal and limbic gyri in man. A.M.A. archives of neurology and psychiatry 68, 609-619 (1952). 13 Klein, D. F. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Archives of general psychiatry 50, 306-317 (1993). 14 Hodges, M. R. et al. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 2495-2505, doi:10.1523/JNEUROSCI.4729-07.2008 (2008). 15 Richerson, G. B. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nature reviews. Neuroscience 5, 449-461, doi:10.1038/nrn1409 (2004). 16 Feldman, J. L., Mitchell, G. S. & Nattie, E. E. Breathing: rhythmicity, plasticity, chemosensitivity. Annual review of neuroscience 26, 239-266, doi:10.1146/annurev.neuro.26.041002.131103 (2003). 17 Buchanan, G. F. & Richerson, G. B. Role of chemoreceptors in mediating dyspnea. Respiratory physiology & neurobiology 167, 9-19, doi:10.1016/j.resp.2008.12.002 (2009). 18 Buchanan, G. F. & Richerson, G. B. Central serotonin neurons are required for arousal to CO2. Proceedings of the National Academy of Sciences of the United States of America 107, 16354-16359, doi:10.1073/pnas.1004587107 (2010). 19 Severson, C. A., Wang, W., Pieribone, V. A., Dohle, C. I. & Richerson, G. B. Midbrain serotonergic neurons are central pH chemoreceptors. Nature neuroscience 6, 1139-1140, doi:10.1038/nn1130 (2003). 20 Kloster, R. & Engelskjon, T. Sudden unexpected death in epilepsy (SUDEP): a clinical perspective and a search for risk factors. Journal of neurology, neurosurgery, and psychiatry 67, 439-444 (1999). 21 Fish, D. R., Gloor, P., Quesney, F. L. & Olivier, A. Clinical responses to electrical brain stimulation of the temporal and frontal lobes in patients with epilepsy. Pathophysiological implications. Brain : a journal of neurology 116 ( Pt 2), 397-414 (1993). 22 Kawasaki, H. et al. Processing of facial emotion in the human fusiform gyrus. Journal of cognitive neuroscience 24, 1358-1370, doi:10.1162/jocn_a_00175 (2012). 23 Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage 17, 825-841 (2002). 24 Oya, H., Kawasaki, H., Dahdaleh, N. S., Wemmie, J. A. & Howard, M. A., 3rd. Stereotactic atlas-based depth electrode localization in the human amygdala. Stereotactic and functional neurosurgery 87, 219-228, doi:10.1159/000225975 (2009).

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy