Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention

Key Points

  • Overwhelming evidence indicates that sudden unexpected death in epilepsy (SUDEP) is attributable to a seizure causing a primary defect in either cardiovascular or respiratory control or, less commonly, in both

  • From a research perspective, respiratory dysfunction in SUDEP has received less attention than cardiac mechanisms, despite the fact that peri-ictal hypoventilation is common and can lead to severe oxygen desaturation

  • Postictal impairment of wakefulness and arousal probably contributes to the inability of a patient to respond to an external stressor, such as lying prone in bed

  • SUDEP shares many similarities with sudden infant death syndrome, which has been linked to a defect in the 5-hydroxytryptamine (5-HT) system

  • Currently available preventive treatments for SUDEP are designed to decrease seizure frequency; potential approaches that need to be further investigated include targeting of the 5-HT and adenosine systems

  • Routine respiratory monitoring should probably be performed on every patient admitted to an epilepsy monitoring unit

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, with an estimated 35% lifetime risk in this patient population. There is a surprising lack of awareness among patients and physicians of this increased risk of sudden death: in a recent survey, only 33% of Canadian paediatricians who treated patients with epilepsy knew the term SUDEP. Controversy prevails over whether cardiac arrhythmia or respiratory arrest is more important as the primary cause of death. Effective preventive strategies in high-risk patients will rely on definition of the mechanisms that lead from seizures to death. Here, we summarize evidence for the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal period. We highlight potential cellular mechanisms underlying these abnormalities, such as a defect in the serotonergic system, ictal adenosine release, and changes in autonomic output. We discuss genetic mutations that cause Dravet and long QT syndromes, both of which are linked with increased risk of sudden death. We then highlight possible preventive interventions that are likely to decrease SUDEP incidence, including respiratory monitoring in epilepsy monitoring units and overnight supervision. Finally, we discuss treatments, such as selective serotonin reuptake inhibitors, that might be personalized to a specific genetic or pathological defect.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Distribution of SUDEP cases by age.
Figure 2: Cardiac and respiratory abnormalities following seizure activity.
Figure 3: Anatomical distribution of brainstem nuclei involved in cardiorespiratory control.
Figure 4: Hypothesized model for SUDEP.
Figure 5: Proposed sequence of events surrounding a theoretical case of 'respiratory SUDEP'.

References

  1. 1

    Schmidt, D. Drug treatment of epilepsy: options and limitations. Epilepsy Behav. 15, 56–65 (2009).

    PubMed  Article  Google Scholar 

  2. 2

    Ficker, D. M. et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 51, 1270–1274 (1998).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Nashef, L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 38 (Suppl. 11), S6–S8 (1997).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Thurman, D. J. The epidemiology of SUDEP: a public health perspective. Epilepsy Curr. 13 (Suppl. 2), 9 (2013).

    Google Scholar 

  5. 5

    Shorvon, S. & Tomson, T. Sudden unexpected death in epilepsy. Lancet 378, 2028–2038 (2011).

    PubMed  Article  Google Scholar 

  6. 6

    Hesdorffer, D. C. et al. Combined analysis of risk factors for SUDEP. Epilepsia 52, 1150–1159 (2011).

    PubMed  Article  Google Scholar 

  7. 7

    Donner, E. Talking about SUDEP: physician perspective. Epilepsy Curr. 13 (Suppl. 2), 16 (2013).

    Article  CAS  Google Scholar 

  8. 8

    Surges, R., Thijs, R. D., Tan, H. L. & Sander, J. W. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat. Rev. Neurol. 5, 492–504 (2009).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Jackson, J. H. On asphyxia in slight epileptic paroxysms. Lancet 153, 79–80 (1899).

    Article  Google Scholar 

  10. 10

    Watanabe, K. et al. Seizures with apnea in children. Pediatrics 70, 87–90 (1982).

    CAS  PubMed  Google Scholar 

  11. 11

    James, M. R., Marshall, H. & Carew-McColl, M. Pulse oximetry during apparent tonic–clonic seizures. Lancet 337, 394–395 (1991).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Nashef, L. et al. Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. J. Neurol. Neurosurg. Psychiatry 60, 297–300 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Bateman, L. M., Li, C. S. & Seyal, M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 131, 3239–3245 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Terrence, C. F., Rao, G. R. & Perper, J. A. Neurogenic pulmonary edema in unexpected, unexplained death of epileptic patients. Ann. Neurol. 9, 458–464 (1981).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Leestma, J. E., Walczak, T., Hughes, J. R., Kalelkar, M. B. & Teas, S. S. A prospective study on sudden unexpected death in epilepsy. Ann. Neurol. 26, 195–203 (1989).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 12, 966–977 (2013).

    Article  Google Scholar 

  17. 17

    Mirsky, A. F. & Vanburen, J. M. On the nature of the “absence” in centrencephalic epilepsy: a study of some behavioral, electroencephalographic and autonomic factors. Electroencephalogr. Clin. Neurophysiol. 18, 334–348 (1965).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Seyal, M., Pascual, F., Lee, C. Y., Li, C. S. & Bateman, L. M. Seizure-related cardiac repolarization abnormalities are associated with ictal hypoxemia. Epilepsia 52, 2105–2111 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Venit, E. L., Shepard, B. D. & Seyfried, T. N. Oxygenation prevents sudden death in seizure-prone mice. Epilepsia 45, 993–996 (2004).

    PubMed  Article  Google Scholar 

  20. 20

    Richerson, G. B. Response to CO2 of neurons in the rostral ventral medulla in vitro. J. Neurophysiol. 73, 933–944 (1995).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Richerson, G. B. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat. Rev. Neurosci. 5, 449–461 (2004).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Feldman, J. L., Mitchell, G. S. & Nattie, E. E. Breathing: rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. 26, 239–266 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Tecott, L. H. et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374, 542–546 (1995).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Faingold, C. L., Randall, M. & Tupal, S. DBA/1 mice exhibit chronic susceptibility to audiogenic seizures followed by sudden death associated with respiratory arrest. Epilepsy Behav. 17, 436–440 (2010).

    PubMed  Article  Google Scholar 

  25. 25

    Russell, A. E. Cessation of the pulse during the onset of epileptic fits: with remarks on the mechanism of fits. Lancet 168, 152–154 (1906).

    Article  Google Scholar 

  26. 26

    Stollberger, C. & Finsterer, J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP). Epilepsy Res. 59, 51–60 (2004).

    PubMed  Article  Google Scholar 

  27. 27

    Rowe, P. C. (Ed.) The Harriet Lane Handbook (Medical Handbook Publishers, 1987).

    Google Scholar 

  28. 28

    Moseley, B. D., Nickels, K., Britton, J. & Wirrell, E. How common is ictal hypoxemia and bradycardia in children with partial complex and generalized convulsive seizures? Epilepsia 51, 1219–1224 (2010).

    PubMed  Article  Google Scholar 

  29. 29

    Rocamora, R., Kurthen, M., Lickfett, L., Von Oertzen, J. & Elger, C. E. Cardiac asystole in epilepsy: clinical and neurophysiologic features. Epilepsia 44, 179–185 (2003).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Schuele, S. U. et al. Video-electrographic and clinical features in patients with ictal asystole. Neurology 69, 434–441 (2007).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Kiely, D. G., Cargill, R. I. & Lipworth, B. J. Effects of hypercapnia on hemodynamic, inotropic, lusitropic, and electrophysiologic indices in humans. Chest 109, 1215–1221 (1996).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Roche, F. et al. Effect of acute hypoxia on QT rate dependence and corrected QT interval in healthy subjects. Am. J. Cardiol. 91, 916–919 (2003).

    PubMed  Article  Google Scholar 

  33. 33

    Moseley, B. D. et al. Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res. 95, 237–245 (2011).

    PubMed  Article  Google Scholar 

  34. 34

    Stein, P. K. & Kleiger, R. E. Insights from the study of heart rate variability. Annu. Rev. Med. 50, 249–261 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Tomson, T., Ericson, M., Ihrman, C. & Lindblad, L. E. Heart rate variability in patients with epilepsy. Epilepsy Res. 30, 77–83 (1998).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Ronkainen, E. et al. Suppressed circadian heart rate dynamics in temporal lobe epilepsy. J. Neurol. Neurosurg. Psychiatry 76, 1382–1386 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Hilz, M. J., Devinsky, O., Doyle, W., Mauerer, A. & Dütsch, M. Decrease of sympathetic cardiovascular modulation after temporal lobe epilepsy surgery. Brain 125, 985–995 (2002).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Dütsch, M., Devinsky, O., Doyle, W., Marthol, H. & Hilz, M. J. Cerebral autoregulation improves in epilepsy patients after temporal lobe surgery. J. Neurol. 251, 1190–1197 (2004).

    PubMed  Article  Google Scholar 

  39. 39

    Persson, H., Kumlien, E., Ericson, M. & Tomson, T. Preoperative heart rate variability in relation to surgery outcome in refractory epilepsy. Neurology 65, 1021–1025 (2005).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Hartikainen, J. E., Malik, M., Staunton, A., Poloniecki, J. & Camm, A. J. Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-averaged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction. J. Am. Coll. Cardiol. 28, 296–304 (1996).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    DeGiorgio, C. M. & DeGiorgio, A. C. SUDEP and heart rate variability. Epilepsy Res. 90, 309–310 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Surges, R. et al. Do alterations in inter-ictal heart rate variability predict sudden unexpected death in epilepsy? Epilepsy Res. 87, 277–280 (2009).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Theodore, W. H. et al. The secondarily generalized tonic–clonic seizure: a videotape analysis. Neurology 44, 1403–1407 (1994).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Jobst, B. C. et al. Secondarily generalized seizures in mesial temporal epilepsy: clinical characteristics, lateralizing signs, and association with sleep–wake cycle. Epilepsia 42, 1279–1287 (2001).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Escueta, A. V., Kunze, U., Waddell, G., Boxley, J. & Nadel, A. Lapse of consciousness and automatisms in temporal lobe epilepsy: a videotape analysis. Neurology 27, 144–155 (1977).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Hoffmann, J. M., Elger, C. E. & Kleefuss-Lie, A. A. Lateralizing value of behavioral arrest in patients with temporal lobe epilepsy. Epilepsy Behav. 13, 634–636 (2008).

    PubMed  Article  Google Scholar 

  47. 47

    McPherson, A. et al. Testing for minimal consciousness in complex partial and generalized tonic–clonic seizures. Epilepsia 53, e180–e183 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Penfield, W. Centrencephalic integrating system. Brain 81, 231–234 (1958).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Jasper, H. H. Current evaluation of the concepts of centrencephalic and cortico-reticular seizures. Electroencephalogr. Clin. Neurophysiol. 78, 2–11 (1991).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Moruzzi, G. & Magoun, H. W. Brain stem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473 (1949).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Starzl, T. E., Taylor, C. W. & Magoun, H. W. Ascending conduction in reticular activating system, with special reference to the diencephalon. J. Neurophysiol. 14, 461–477 (1951).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Azmitia, E. C. & Gannon, P. J. The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. Adv. Neurol. 43, 407–468 (1986).

    CAS  PubMed  Google Scholar 

  53. 53

    Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Jones, B. E. Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog. Brain Res. 145, 157–169 (2004).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Fuller, P. M., Sherman, D., Pedersen, N. P., Saper, C. B. & Lu, J. Reassessment of the structural basis of the ascending arousal system. J. Comp. Neurol. 519, 933–956 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Blumenfeld, H. Impaired consciousness in epilepsy. Lancet Neurol. 11, 814–826 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Blumenfeld, H. et al. Positive and negative network correlations in temporal lobe epilepsy. Cereb. Cortex 14, 892–902 (2004).

    PubMed  Article  Google Scholar 

  59. 59

    Motelow, J. E. et al. Brainstem cholinergic and thalamic dysfunction during limbic seizures: possible mechanism for cortical slow oscillations and impaired consciousness [abstract 487.25]. Presented at Neuroscience 2012.

  60. 60

    Lhatoo, S. D. et al. An electroclinical case–control study of sudden unexpected death in epilepsy. Ann. Neurol. 68, 787–796 (2010).

    PubMed  Article  Google Scholar 

  61. 61

    Surges, R., Strzelczyk, A., Scott, C. A., Walker, M. C. & Sander, J. W. Postictal generalized electroencephalographic suppression is associated with generalized seizures. Epilepsy Behav. 21, 271–274 (2011).

    PubMed  Article  Google Scholar 

  62. 62

    Lamberts, R. J. et al. Postictal generalized EEG suppression is not associated with periictal cardiac autonomic instability in people with convulsive seizures. Epilepsia 54, 523–529 (2013).

    PubMed  Article  Google Scholar 

  63. 63

    Aminoff, M. J., Scheinman, M. M., Griffin, J. C. & Herre, J. M. Electrocerebral accompaniments of syncope associated with malignant ventricular arrhythmias. Ann. Intern. Med. 108, 791–796 (1988).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Dasheiff, R. M. & Dickinson, L. J. Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure. Arch. Neurol. 43, 194–196 (1986).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Purves, S. J., Wilson-Young, M. & Sweeney, V. P. Sudden death in epilepsy: single case report with video-EEG documentation. Epilepsia 33 (Suppl. 3), 123 (1992).

    Google Scholar 

  66. 66

    Bird, J. M., Dembny, A. T., Sandeman, D. & Butler, S. Sudden unexplained death in epilepsy: an intracranially monitored case. Epilepsia 38 (Suppl. 11), S52–S56 (1997).

    Article  Google Scholar 

  67. 67

    Lee, H. W., Hong, S. B., Tae, W. S., Seo, D. W. & Kim, S. E. Partial seizures manifesting as apnea only in an adult. Epilepsia 40, 1828–1831 (1999).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    McLean, B. N. & Wimalaratna, S. Sudden death in epilepsy recorded in ambulatory EEG. J. Neurol. Neurosurg. Psychiatry 78, 1395–1397 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    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 (2010).

    PubMed  Article  Google Scholar 

  70. 70

    Klassen, T. L. et al. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 55, e6–e12 (2014).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Goldenberg, I. & Moss, A. J. Long QT syndrome. J. Am. Coll. Cardiol. 51, 2291–2300 (2008).

    PubMed  Article  Google Scholar 

  72. 72

    Wang, D. W., Yazawa, K., George, A. L. Jr & Bennett, P. B. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome. Proc. Natl Acad. Sci. USA 93, 13200–13205 (1996).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Johnson, J. N. et al. Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 72, 224–231 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Anderson, J. H., Bos, J. M., Cascino, G. D. & Ackerman, M. J. Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome. Heart Rhythm 11, 53–57 (2014).

    PubMed  Article  Google Scholar 

  75. 75

    Doppelbauer, A. et al. Occurrence of epileptiform activity in the routine EEG of epileptic patients. Acta Neurol. Scand. 87, 345–352 (1993).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Casimiro, M. C. et al. Targeted point mutagenesis of mouse Kcnq1: phenotypic analysis of mice with point mutations that cause Romano–Ward syndrome in humans. Genomics 84, 555–564 (2004).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Goldman, A. M. et al. Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci. Transl. Med. 1, 2ra6 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

    Nei, M. et al. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia 45, 338–345 (2004).

    PubMed  Article  Google Scholar 

  79. 79

    Glasscock, E., Yoo, J. W., Chen, T. T., Klassen, T. L. & Noebels, J. L. Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J. Neurosci. 30, 5167–5175 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Kalume, F. Sudden unexpected death in Dravet syndrome: respiratory and other physiological dysfunctions. Respir. Physiol. Neurobiol. 189, 324–328 (2013).

    PubMed  Article  Google Scholar 

  81. 81

    Dravet, C., Bureau, M., Oguni, H., Fukuyama, Y. & Cokar, O. Severe myoclonic epilepsy in infancy: Dravet syndrome. Adv. Neurol. 95, 71–102 (2005).

    PubMed  Google Scholar 

  82. 82

    Oguni, H., Hayashi, K., Awaya, Y., Fukuyama, Y. & Osawa, M. Severe myoclonic epilepsy in infants—a review based on the Tokyo Women's Medical University series of 84 cases. Brain Dev. 23, 736–748 (2001).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Claes, L. et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327–1332 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Marini, C. et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia 48, 1678–1685 (2007).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Maier, S. K. et al. An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node. Proc. Natl Acad. Sci. USA 100, 3507–3512 (2003).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Duflocq, A., Le Bras, B., Bullier, E., Couraud, F. & Davenne, M. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Mol. Cell. Neurosci. 39, 180–192 (2008).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Catterall, W. A., Kalume, F. & Oakley, J. C. NaV1.1 channels and epilepsy. J. Physiol. 588, 1849–1859 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Kalume, F. et al. Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 123, 1798–1808 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Delogu, A. B. et al. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia 52 (Suppl. 2), 55–58 (2011).

    PubMed  Article  Google Scholar 

  90. 90

    Ptak, K. et al. Raphe neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P. J. Neurosci. 29, 3720–3737 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Depuy, S. D., Kanbar, R., Coates, M. B., Stornetta, R. L. & Guyenet, P. G. Control of breathing by raphe obscurus serotonergic neurons in mice. J. Neurosci. 31, 1981–1990 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Tupal, S. & Faingold, C. L. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 47, 21–26 (2006).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Uteshev, V. V., Tupal, S., Mhaskar, Y. & Faingold, C. L. Abnormal serotonin receptor expression in DBA/2 mice associated with susceptibility to sudden death due to respiratory arrest. Epilepsy Res. 88, 183–188 (2010).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Bateman, L. M., Li, C. S., Lin, T. C. & Seyal, M. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia 51, 2211–2214 (2010).

    PubMed  Article  Google Scholar 

  95. 95

    Hodges, M. R. et al. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J. Neurosci. 28, 2495–2505 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Corcoran, A. E. et al. Medullary serotonin neurons and central CO2 chemoreception. Respir. Physiol. Neurobiol. 168, 49–58 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Hodges, M. R., Wehner, M., Aungst, J., Smith, J. C. & Richerson, G. B. Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development. J. Neurosci. 29, 10341–10349 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Ray, R. S. et al. Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333, 637–642 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Dutschmann, M. & Dick, T. E. Pontine mechanisms of respiratory control. Compr. Physiol. 2, 2443–2469 (2012).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Dekin, M. S., Richerson, G. B. & Getting, P. A. Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarius. Science 229, 67–69 (1985).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Buchanan, G. F. & Richerson, G. B. Central serotonin neurons are required for arousal to CO2 . Proc. Natl Acad. Sci. USA 107, 16354–16359 (2010).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Richerson, G. B. & Buchanan, G. F. The serotonin axis: shared mechanisms in seizures, depression, and SUDEP. Epilepsia 52, 28–38 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Dias, R. et al. Depression in epilepsy is associated with lack of seizure control. Epilepsy Behav. 19, 445–447 (2010).

    PubMed  Article  Google Scholar 

  104. 104

    Kinney, H. C., Richerson, G. B., Dymecki, S. M., Darnall, R. A. & Nattie, E. E. The brainstem and serotonin in the sudden infant death syndrome. Annu. Rev. Pathol. 4, 517–550 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Boison, D. Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol. Sci. 27, 652–658 (2006).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    During, M. J. & Spencer, D. D. Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann. Neurol. 32, 618–624 (1992).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Barraco, R. A., Janusz, C. A., Schoener, E. P. & Simpson, L. L. Cardiorespiratory function is altered by picomole injections of 5′-N-ethylcarboxamidoadenosine into the nucleus tractus solitarius of rats. Brain Res. 507, 234–246 (1990).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Shen, H. Y., Li, T. & Boison, D. A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance. Epilepsia 51, 465–468 (2010).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Spitzer, A. R. Evidence-based methylxanthine use in the NICU. Clin. Perinatol. 39, 137–148 (2012).

    PubMed  Article  Google Scholar 

  110. 110

    Diehl, B., Diehl, R. R., Stodieck, S. R. & Ringelstein, E. B. Spontaneous oscillations in cerebral blood flow velocities in middle cerebral arteries in control subjects and patients with epilepsy. Stroke 28, 2457–2459 (1997).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Evrengul, H. et al. Time and frequency domain analyses of heart rate variability in patients with epilepsy. Epilepsy Res. 63, 131–139 (2005).

    PubMed  Article  Google Scholar 

  112. 112

    Dütsch, M., Hilz, M. J. & Devinsky, O. Impaired baroreflex function in temporal lobe epilepsy. J. Neurol. 253, 1300–1308 (2006).

    PubMed  Article  Google Scholar 

  113. 113

    Mukherjee, S. et al. Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies. Epilepsy Res. 85, 261–269 (2009).

    PubMed  Article  Google Scholar 

  114. 114

    Druschky, A. et al. Interictal cardiac autonomic dysfunction in temporal lobe epilepsy demonstrated by [123I]metaiodobenzylguanidine-SPECT. Brain 124, 2372–2382 (2001).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Kerling, F. et al. Relation between ictal asystole and cardiac sympathetic dysfunction shown by MIBG-SPECT. Acta Neurol. Scand. 120, 123–129 (2009).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Hilz, M. J. et al. Outcome of epilepsy surgery correlates with sympathetic modulation and neuroimaging of the heart. J. Neurol. Sci. 216, 153–162 (2003).

    PubMed  Article  Google Scholar 

  117. 117

    Blumhardt, L. D., Smith, P. E. & Owen, L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1, 1051–1056 (1986).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Akashi, Y. J., Goldstein, D. S., Barbaro, G. & Ueyama, T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 118, 2754–2762 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  119. 119

    Chin, P. S., Branch, K. R. & Becker, K. J. Postictal neurogenic stunned myocardium. Neurology 64, 1977–1978 (2005).

    PubMed  Article  Google Scholar 

  120. 120

    Nashef, L., Fish, D. R., Garner, S., Sander, J. W. & Shorvon, S. D. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 36, 1187–1194 (1995).

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Langan, Y., Nashef, L. & Sander, J. W. Case–control study of SUDEP. Neurology 64, 1131–1133 (2005).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Strzelczyk, A. et al. Ictal asystole in temporal lobe epilepsy before and after pacemaker implantation. Epileptic Disord. 10, 39–44 (2008).

    PubMed  Google Scholar 

  123. 123

    Morris, G. L. 3rd et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Epilepsy Curr. 13, 297–303 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  124. 124

    Morris, G. L. 3rd et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 81, 1453–1459 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125

    Bagdy, G., Kecskemeti, V., Riba, P. & Jakus, R. Serotonin and epilepsy. J. Neurochem. 100, 857–873 (2007).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Terrence, C. F. Jr, Wisotzkey, H. M. & Perper, J. A. Unexpected, unexplained death in epileptic patients. Neurology 25, 594–598 (1975).

    PubMed  Article  Google Scholar 

  127. 127

    Auerbach, D. S. et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS ONE 8, e77843 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128

    Hedley, P. L. et al. The genetic basis of Brugada syndrome: a mutation update. Hum. Mutat. 30, 1256–1266 (2009).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Martin, C. A. et al. Reduced Na+ and higher K+ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice. Open Biol. 2, 120072 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130

    Derangeon, M., Montnach, J., Baro, I. & Charpentier, F. Mouse models of SCN5A-related cardiac arrhythmias. Front. Physiol. 3, 210 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131

    Aurlien, D., Leren, T. P., Tauboll, E. & Gjerstad, L. New SCN5A mutation in a SUDEP victim with idiopathic epilepsy. Seizure 18, 158–160 (2009).

    PubMed  Article  Google Scholar 

  132. 132

    Johnson, J. N. et al. Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 72, 224–231 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Zuberi, S. M. et al. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 122, 817–825 (1999).

    PubMed  Article  Google Scholar 

  134. 134

    Tu, E., Bagnall, R. D., Duflou, J. & Semsarian, C. Post-mortem review and genetic analysis of sudden unexpected death in epilepsy (SUDEP) cases. Brain Pathol. 21, 201–208 (2011).

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Lehnart, S. E. et al. Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J. Clin. Invest. 118, 2230–2245 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Napolitano, C., Priori, S. G. & Bloise, R. Catecholaminergic polymorphic ventricular tachycardia. In GeneReviews® eds Pagon, R. A. et al. (Seattle, WA, 1993).

    Google Scholar 

  137. 137

    Sowers, L. P., Massey, C. A., Gehlbach, B. K., Granner, M. A. & Richerson, G. B. Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms. Respir. Physiol. Neurobiol. 189, 315–323 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Krous, H. F. et al. Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics 114, 234–238 (2004).

    PubMed  Article  Google Scholar 

  139. 139

    Hunt, C. E. & Brouillette, R. T. Sudden infant death syndrome: 1987 perspective. J. Pediatr. 110, 669–678 (1987).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Paterson, D. S. et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA 296, 2124–2132 (2006).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Kinney, H. C. et al. Serotonergic brainstem abnormalities in Northern Plains Indians with the sudden infant death syndrome. J. Neuropathol. Exp. Neurol. 62, 1178–1191 (2003).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Duncan, J. R. et al. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 303, 430–437 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143

    Kinney, H. C. et al. Witnessed sleep-related seizure and sudden unexpected death in infancy: a case report. Forensic Sci. Med. Pathol. 9, 418–421 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

C.A.M. and G.B.R. have received funding from the Beth L. Tross Epilepsy Research Fund. L.P.S. is funded by a T32 Multidisciplinary Lung Research Career Development Program Training Grant from the National Heart, Lung, and Blood Institute at NIH. G.B.R. has received funding from the National Institute of Neurological Disorders and Stroke (grant P20NS076916) and the National Institute of Child Health and Human Development (grants R01HD052772 and P01HD36379).

Author information

Affiliations

Authors

Contributions

C.A.M. and L.P.S. made equal contributions to the article. C.A.M., L.P.S. and G.B.R. provided substantial contributions to discussions of the content. All four authors researched data for the article, wrote the text, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to George B. Richerson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Massey, C., Sowers, L., Dlouhy, B. et al. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 10, 271–282 (2014). https://doi.org/10.1038/nrneurol.2014.64

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing