Sudden Death in Brazil: Epilepsy Should be in Horizon

Fulvio Scorza Paulo José Ferreira Tucci About the authors

Keywords
Death, Sudden / prevention & control; Death, Sudden, Cardiac; Coronary Artery Disease / mortality; Epilepsy / mortality

To date, a considerable amount of valuable information about the problem of sudden cardiac death (SCD) has been described. The incidence of SCD in the United States ranges between 180000-400000 cases per year11 Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis. 2008;51(3):213-28.. Martinelli et al demonstrated an incidence of 21270 cases of SCD per year in the Metropolitan Area of São Paulo22 Martinelli M, Siqueira SF, Zimerman LI, Neto VA, Moraes AV Jr, Fenelon G. Sudden cardiac death in Brazil: study based on physicians' perceptions of the public health care system. Pacing Clin Electrophysiol. 2012;35(11):1326-31.. Recently, Braggion-Santos et al.33 Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA, Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7. described the characteristics of SCD in Ribeirão Preto, Brazil, according to autopsy reports33 Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA, Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7.. Revising 4501 autopsies, they identified 899 cases of SCD (20%); the rate was 30/100000 residents/year33 Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA, Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7.. The vast majority of SCD cases involved coronary artery disease (64%). Based on available scientific knowledge related to SCD, it is extremely important to identify new areas of research that might improve understanding of this problem and to establish effective preventive measures to minimize or even control the occurrence of SCD.

Although studies have shown that the increase in the number of SCD caused by a combination of factors22 Martinelli M, Siqueira SF, Zimerman LI, Neto VA, Moraes AV Jr, Fenelon G. Sudden cardiac death in Brazil: study based on physicians' perceptions of the public health care system. Pacing Clin Electrophysiol. 2012;35(11):1326-31.,33 Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA, Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7., an equally important risk factor for SCD which is not reported and not explored in cardiologic research is epilepsy. Indeed, a series of data could be put forward to explain it.

Epilepsy affects approximately 65 million individuals worldwide and is one of the most common, chronic and severe neurological diseases44 Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.

5 Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy -- a review. Epilepsy Res. 2009;85(1):31-45.

6 Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe -- a systematic review. Eur J Neurol. 2005;12(4):245-53.
-77 Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16(2):165-70.. In developing and poor countries, the incidence of epilepsy is higher when compared with that of developed countries44 Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.

5 Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy -- a review. Epilepsy Res. 2009;85(1):31-45.

6 Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe -- a systematic review. Eur J Neurol. 2005;12(4):245-53.
-77 Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16(2):165-70.. The prognostic evolution has clearly shown that seizures are successfully controlled with currently available antiepileptic drugs in approximately two-thirds of individuals with epilepsy, which results in one-third with refractory epilepsy44 Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.,88 Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry. 2004;75(10):1376-81.. For these patients with uncontrolled seizures, epilepsy should be considered a malignant condition, as it carries a mortality rate that is 2‑3 times higher than that in the general population99 Gaitatzis A, Sander JW. The mortality of epilepsy revisited. Epileptic Disord. 2004;6(1):3-13.. Therefore, sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of epilepsy-related death99 Gaitatzis A, Sander JW. The mortality of epilepsy revisited. Epileptic Disord. 2004;6(1):3-13.

10 Nashef L, Ryvlin P. Sudden unexpected death in epilepsy (SUDEP): update and reflections. Neurol Clin. 2009;27(4):1063-74.

11 Nei M, Hays R. Sudden unexpected death in epilepsy. Curr Neurol Neurosci Rep. 2010;10(4):319-26.
-1212 Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Commission on Epidemiology; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150-9.. By definition, SUDEP is a sudden, unexpected, witnessed or unwitnessed, non‑traumatic and non-drowning death in individuals with epilepsy, with or without evidence of seizures, in which post-mortem examination does not reveal a toxicological or anatomical cause of death1313 Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia. 1997;38(11 Suppl):S6-8.. Epidemiological studies indicate that SUDEP is responsible for 7.5% to 17% of all deaths in epilepsy and has an incidence among adults between 1:500 and 1:1000 patient/year1414 Schuele SU, Widdess-Walsh P, Bermeo A, Lüders HO. Sudden unexplained death in epilepsy: the role of the heart. Cleve Clin J Med. 2007;74(Suppl 1):S121-7.. The main risk factors for SUDEP include the number of generalized tonic-clonic seizures, nocturnal seizures, young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic etiology of epilepsy and alcohol abuse1212 Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Commission on Epidemiology; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150-9.,1515 Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: potential role of antiepileptic drugs. CNS Drugs. 2013;27(2):113-9.. The cause or causes of SUDEP are still unknown, but one of the main proposed mechanisms is related to autonomic dysregulation, promoting cardiac abnormalities during and between seizures1616 Surges R, Taggart P, Sander JW, Walker MC. Too long or too short? New insights into abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death. Epilepsia. 2010;51(5):738-44.

17 Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr. 2005;63(4):1035-41.
-1818 Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7..

In this line of reasoning, our experimental data clarified some possibilities. Using the pilocarpine model of temporal lobe epilepsy, we evaluated heart rate in rats with epilepsy in vivo and in an isolated ex vivo preparation (Langendorff preparation)1717 Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr. 2005;63(4):1035-41.. Baseline heart rate in vivo in animals with chronic epilepsy (346 ± 7 bpm) was higher than in control rats (307 ± 9 bpm)1717 Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr. 2005;63(4):1035-41.. Incidentally, no difference was observed in the isolated ex vivo situation (control animals: 175 ± 7 bpm; chronic epilepsy: 176 ± 6 bpm), suggesting that autonomic modulation of the heart is altered in epileptic animals, explaining the maintenance of an increased basal heart rate in these animals1717 Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr. 2005;63(4):1035-41.. In addition, we also evaluated heart rate responses during stage 5 of amygdala kindling model, the phase when animals develop generalized seizures1818 Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.,1919 Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA, Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.. Animals did not show significant differences in basal heart rate; however, basal heart rate was higher during stage 5 of kindling, possibly resulting from sympathetic activation caused by the chronic epileptic condition1818 Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.,1919 Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA, Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.. As demonstrated in previous studies2020 Devinsky O. Effects of seizures on autonomic and cardiovascular function. Epilepsy Curr. 2004;4(2):43-6., intense bradycardia at the beginning of seizure was followed by rebound tachycardia1818 Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.,1919 Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA, Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.. Moreover, the intensity of tachycardia was directly related to the number of generalized seizures, suggesting that repeated generalized tonic-clonic seizures affect sympathetic outflow1818 Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.,1919 Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA, Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.. For that reason, a plausible explanation is that continuous and intermittent sympathetic activation due to uncontrolled seizures is capable of maintaining cardiac rhythm, modulating the heart in accelerated-state permanently.

Considering all these translational information, it is clear that epilepsy-related mortality, particularly SCD, is a significant public health concern. Thus, it is crucial that a concerted and collaborative approach be implemented to solve this problem. In order to do so, it is extremely necessary to attain a real convergence between cardiologists and neurologists to carefully evaluate and discuss the electroencephalographic and electrocardiographic recordings, the cardiac and cerebral imaging findings and refined histopathological studies in order to detect or prevent the occurrence of a tragic fatal event among individuals with epilepsy.

  • Sources of Funding
    This study was funded by FAPESP, CNPq, Capes e Unifesp.
  • Study Association
    This study is not associated with any thesis or dissertation work.

Acknowledgements

This study has been supported by: UNIFESP, FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico); CEPID/FAPESP; FAPESP/PRONEX and FAPESP/CNPq/MCT (Instituto Nacional de Neurociência Translacional).

References

  • 1
    Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis. 2008;51(3):213-28.
  • 2
    Martinelli M, Siqueira SF, Zimerman LI, Neto VA, Moraes AV Jr, Fenelon G. Sudden cardiac death in Brazil: study based on physicians' perceptions of the public health care system. Pacing Clin Electrophysiol. 2012;35(11):1326-31.
  • 3
    Braggion-Santos MF, Volpe GJ, Pazin-Filho A, Maciel BC, Marin-Neto JA, Schmidt A. Sudden cardiac death in Brazil: a community-based autopsy series (2006-2010). Arq Bras Cardiol. 2015;104(2):120-7.
  • 4
    Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.
  • 5
    Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy -- a review. Epilepsy Res. 2009;85(1):31-45.
  • 6
    Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe -- a systematic review. Eur J Neurol. 2005;12(4):245-53.
  • 7
    Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16(2):165-70.
  • 8
    Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry. 2004;75(10):1376-81.
  • 9
    Gaitatzis A, Sander JW. The mortality of epilepsy revisited. Epileptic Disord. 2004;6(1):3-13.
  • 10
    Nashef L, Ryvlin P. Sudden unexpected death in epilepsy (SUDEP): update and reflections. Neurol Clin. 2009;27(4):1063-74.
  • 11
    Nei M, Hays R. Sudden unexpected death in epilepsy. Curr Neurol Neurosci Rep. 2010;10(4):319-26.
  • 12
    Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Commission on Epidemiology; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150-9.
  • 13
    Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia. 1997;38(11 Suppl):S6-8.
  • 14
    Schuele SU, Widdess-Walsh P, Bermeo A, Lüders HO. Sudden unexplained death in epilepsy: the role of the heart. Cleve Clin J Med. 2007;74(Suppl 1):S121-7.
  • 15
    Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: potential role of antiepileptic drugs. CNS Drugs. 2013;27(2):113-9.
  • 16
    Surges R, Taggart P, Sander JW, Walker MC. Too long or too short? New insights into abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death. Epilepsia. 2010;51(5):738-44.
  • 17
    Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr. 2005;63(4):1035-41.
  • 18
    Pansani AP, Colugnati DB, Sonoda EY, Arida RM, Cravo SL, Schoorlemmer GH, et al. Tachycardias and sudden unexpected death in epilepsy: a gold rush by an experimental route. Epilepsy Behav. 2010;19(3):546-7.
  • 19
    Pansani AP, Colugnati DB, Schoorlemmer GH, Sonoda EY, Cavalheiro EA, Arida RM, et al. Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav. 2011;22(3):442-9.
  • 20
    Devinsky O. Effects of seizures on autonomic and cardiovascular function. Epilepsy Curr. 2004;4(2):43-6.

Publication Dates

  • Publication in this collection
    Aug 2015

History

  • Received
    05 Feb 2015
  • Reviewed
    18 Mar 2015
  • Accepted
    30 Mar 2015
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