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Tachycardias and sudden unexpected death in epilepsy: A gold rush by an experimental route

2010; Elsevier BV; Volume: 19; Issue: 3 Linguagem: Inglês

10.1016/j.yebeh.2010.08.019

1525-5069

Aline Priscila Pansani, Diego Basile Colugnati, Eliza Y.F. Sonoda, Ricardo Mário Arida, Sérgio L. Cravo, G.H.M. Schoorlemmer, Ésper A. Cavalheiro, Fúlvio A. Scorza,

EEG and Brain-Computer Interfaces

Epilepsy, which is characterized by recurrent unprovoked seizures, is considered the most common chronic neurological disorder [1Sander J.W. The epidemiology of epilepsy revisited.Curr Opin Neurol. 2003; 16: 165-170Crossref PubMed Scopus (654) Google Scholar, 2De Boer H.M. Mula M. Sander J.W. The global burden and stigma of epilepsy.Epilepsy Behav. 2008; 12: 540-546Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 3Sander J.W. Some aspects of prognosis in the epilepsies: a review.Epilepsia. 1993; 34: 1007-1016Crossref PubMed Scopus (382) Google Scholar, 4Kwan P. Sander J.W. The natural history of epilepsy: an epidemiological view.J Neurol Neurosurg Psychiatry. 2004; 75: 1376-1381Crossref PubMed Scopus (287) Google Scholar, 5Duncan J.S. Sander J.W. Sisodiya S.M. Walker M.C. Adult epilepsy.Lancet. 2006; 367: 1087-1100Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar]. About 50 million people worldwide have epilepsy, and almost 80% of these people live in developing countries [1Sander J.W. The epidemiology of epilepsy revisited.Curr Opin Neurol. 2003; 16: 165-170Crossref PubMed Scopus (654) Google Scholar, 2De Boer H.M. Mula M. Sander J.W. The global burden and stigma of epilepsy.Epilepsy Behav. 2008; 12: 540-546Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 3Sander J.W. Some aspects of prognosis in the epilepsies: a review.Epilepsia. 1993; 34: 1007-1016Crossref PubMed Scopus (382) Google Scholar, 4Kwan P. Sander J.W. The natural history of epilepsy: an epidemiological view.J Neurol Neurosurg Psychiatry. 2004; 75: 1376-1381Crossref PubMed Scopus (287) Google Scholar, 5Duncan J.S. Sander J.W. Sisodiya S.M. Walker M.C. Adult epilepsy.Lancet. 2006; 367: 1087-1100Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar]. Epilepsy occurs more frequently in young children or people over the age of 60 [1Sander J.W. The epidemiology of epilepsy revisited.Curr Opin Neurol. 2003; 16: 165-170Crossref PubMed Scopus (654) Google Scholar, 2De Boer H.M. Mula M. Sander J.W. The global burden and stigma of epilepsy.Epilepsy Behav. 2008; 12: 540-546Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 3Sander J.W. Some aspects of prognosis in the epilepsies: a review.Epilepsia. 1993; 34: 1007-1016Crossref PubMed Scopus (382) Google Scholar, 4Kwan P. Sander J.W. The natural history of epilepsy: an epidemiological view.J Neurol Neurosurg Psychiatry. 2004; 75: 1376-1381Crossref PubMed Scopus (287) Google Scholar, 5Duncan J.S. Sander J.W. Sisodiya S.M. Walker M.C. Adult epilepsy.Lancet. 2006; 367: 1087-1100Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar]. Today, the critical control points for the emergence of chronic seizures, as well as seizure frequency, persistence, severity, neurobiological mechanisms, and mortality rate, are questions that remain unresolved. With respect to mortality, individuals with epilepsy are at higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related category of death [5Duncan J.S. Sander J.W. Sisodiya S.M. Walker M.C. Adult epilepsy.Lancet. 2006; 367: 1087-1100Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 6Nashef L. Ryvlin P. Sudden unexpected death in epilepsy (SUDEP): update and reflections.Neurol Clin. 2009; 27: 1063-1074Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 7Stollberger C. Finsterer J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP).Epilepsy Res. 2004; 59: 51-60Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. SUDEP is responsible for 7.5 to 17% of all deaths in epilepsy, and has an incidence among adults of between 1:500 and 1:1000 patient-years [[8]Schuele S.U. Widdess-Walsh P. Bermeo A. Lüders H.O. Sudden unexplained death in epilepsy: the role of the heart.Cleve Clin J Med. 2007; 74: S121-S127Crossref PubMed Scopus (90) Google Scholar]. Risk factors that predispose to SUDEP include refractoriness of the epileptic condition, occurrence of generalized tonic–clonic seizures, antiepileptic medication (polytherapy with antiepileptic drugs), young age, duration of the seizure disorder, early onset of epilepsy and winter temperatures [7Stollberger C. Finsterer J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP).Epilepsy Res. 2004; 59: 51-60Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 8Schuele S.U. Widdess-Walsh P. Bermeo A. Lüders H.O. Sudden unexplained death in epilepsy: the role of the heart.Cleve Clin J Med. 2007; 74: S121-S127Crossref PubMed Scopus (90) Google Scholar, 9Surges R. Thijs R.D. Tan H.L. Sander J.W. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms.Nat Rev Neurol. 2009; 5: 492-504Crossref PubMed Scopus (338) Google Scholar, 10Scorza F.A. Colugnati D.B. Pansani A.P. Sonoda E.Y. Arida R.M. Cavalheiro E.A. Preventing tomorrow's sudden cardiac death in epilepsy today: what should physicians know about this?.Clinics. 2008; 63: 389-394Crossref PubMed Scopus (48) Google Scholar]. Although different cases may involve different mechanisms, the majority of potential mechanisms for SUDEP are autonomic, that is, mainly cardiac abnormalities during and between seizures [7Stollberger C. Finsterer J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP).Epilepsy Res. 2004; 59: 51-60Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 8Schuele S.U. Widdess-Walsh P. Bermeo A. Lüders H.O. Sudden unexplained death in epilepsy: the role of the heart.Cleve Clin J Med. 2007; 74: S121-S127Crossref PubMed Scopus (90) Google Scholar, 10Scorza F.A. Colugnati D.B. Pansani A.P. Sonoda E.Y. Arida R.M. Cavalheiro E.A. Preventing tomorrow's sudden cardiac death in epilepsy today: what should physicians know about this?.Clinics. 2008; 63: 389-394Crossref PubMed Scopus (48) Google Scholar]. Following this line of thought, tachycardia plays an important and interesting role in this scenario. As established in the literature, tachycardia and factors that increase susceptibility to tachyarrhythmias, such as pathological cardiac repolarization, are risk factors for sudden cardiac death in healthy populations as well as in individuals with epilepsy [11Surges R. Taggart P. Sander J.W. Walker M.C. 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: 738-744Crossref PubMed Scopus (112) Google Scholar, 12Morita H. Wu J. Zipes D.P. The QT syndromes: long and short.Lancet. 2008; 372: 750-763Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 13Engel G. Beckerman J.G. Froelicher V.F. et al.Electrocardiographic arrhythmia risk testing.Curr Probl Cardiol. 2004; 29: 365-432Abstract Full Text Full Text PDF PubMed Google Scholar, 14Watanabe J. Thamilarasan M. Blackstone E.H. Thomas J.D. Lauer M.S. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography.Circulation. 2001; 104: 1911-1916PubMed Google Scholar, 15Schouten E.G. Dekker J.M. Meppelink P. Kok F.J. Vandenbroucke J.P. Pool J. QT interval prolongation predicts cardiovascular mortality in an apparently healthy population.Circulation. 1991; 84: 1516-1523Crossref PubMed Scopus (562) Google Scholar, 16Di Pasquale G. Pinelli G. Andreoli A. Manini G. Grazi P. Tognetti F. Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage.Am J Cardiol. 1987; 59: 596-600Abstract Full Text PDF PubMed Scopus (121) Google Scholar]. In this sense, it is pertinent to mention that pathological cardiac repolarization may promote sudden cardiac death in individuals with epilepsy and may be a factor that contributes to SUDEP [[11]Surges R. Taggart P. Sander J.W. Walker M.C. 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: 738-744Crossref PubMed Scopus (112) Google Scholar]. Moreover, ictal tachycardia is considered one of the most frequent cardiac changes associated with seizures [17Sevcencu C. Struijk J.J. Autonomic alterations and cardiac changes in epilepsy.Epilepsia. 2010; 51: 725-737Crossref PubMed Scopus (207) Google Scholar, 18Devinsky O. Effects of seizures on autonomic and cardiovascular function.Epilepsy Curr. 2004; 4: 43-46Crossref PubMed Google Scholar]. Ictal tachycardia can precede seizure onset [17Sevcencu C. Struijk J.J. Autonomic alterations and cardiac changes in epilepsy.Epilepsia. 2010; 51: 725-737Crossref PubMed Scopus (207) Google Scholar, 19Leutmezer F. Schernthaner C. Lurger S. Potzelberger K. Baumgartner C. Electrocardiographic changes at the onset of epileptic seizures.Epilepsia. 2003; 44: 348-354Crossref PubMed Scopus (250) Google Scholar, 20Novak V. Reeves A.L. Novak P. Low P.A. Sharbrough F.W. Time frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.J Auton Nerv Syst. 1999; 77: 195-202Abstract Full Text Full Text PDF Scopus (82) Google Scholar, 21Blumhardt L.D. Smith P.E. Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures.Lancet. 1986; 1: 1051-1056Abstract PubMed Scopus (240) Google Scholar] or can occur during seizures [17Sevcencu C. Struijk J.J. Autonomic alterations and cardiac changes in epilepsy.Epilepsia. 2010; 51: 725-737Crossref PubMed Scopus (207) Google Scholar, 22Garcia M. D'Giano C. Estelles S. Leiguarda R. Rabinowicz A. Ictal tachycardia: its discriminating potential between temporal and extratemporal seizure foci.Seizure. 2001; 10: 415-419PubMed Scopus (32) Google Scholar]. During ictal tachycardia, the heart rate commonly increases to 120–150 bpm, and can reach values as high as 200 bpm [17Sevcencu C. Struijk J.J. Autonomic alterations and cardiac changes in epilepsy.Epilepsia. 2010; 51: 725-737Crossref PubMed Scopus (207) Google Scholar, 21Blumhardt L.D. Smith P.E. Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures.Lancet. 1986; 1: 1051-1056Abstract PubMed Scopus (240) Google Scholar, 23Nei M. Ho R.T. Abou-Khalil B.W. et al.EEG and ECG in sudden unexplained death in epilepsy.Epilepsia. 2004; 45: 338-345Crossref PubMed Scopus (188) Google Scholar, 24Rugg-Gunn F.J. Simister R.J. Squirrell M. Holdright D.R. Duncan J.S. Cardiac arrhythmias in focal epilepsy: a prospective long-term study.Lancet. 2004; 364: 2212-2219Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar]. As neuroscientists, these data inspired us to ask the following question: Is the use of animal models an effective strategy to examine the role of tachyarrhythmia in epilepsy? The answer is yes! Before answering this question, however, we must remember that the use of animal models has had and will continue to have a tremendous impact on our knowledge of epilepsy. Thus, we are in total agreement with the wise words of Professor Jerome Engel that chronic models are necessary for investigation of processes relevant to epileptic conditions, such as epileptogenesis, transition from interictal to ictal state, and long-term consequences of epilepsy [[25]Engel Jr., J. Critical evaluation of animal models for localization-related epilepsies.Ital J Neurol Sci. 1995; 16: 9-16Crossref PubMed Scopus (15) Google Scholar]. Furthermore, he adds that these models can be used to investigate basic mechanisms that cannot be pursued in patients, and to develop hypotheses concerning the fundamental physiological processes underlying epilepsy and epilepsy-related phenomena that subsequently can be validated in patients [[25]Engel Jr., J. Critical evaluation of animal models for localization-related epilepsies.Ital J Neurol Sci. 1995; 16: 9-16Crossref PubMed Scopus (15) Google Scholar]. On the other hand, although much has been learned from animal studies about structural, chemical, and physiological changes that contribute to seizures and epilepsy, the development of experimental preparations that closely model the human SUDEP phenomenon is essential. Returning to our original question, the experience of our research group makes us increasingly believe that some chronic models of temporal lobe epilepsy are important tools for the study of cardiovascular abnormalities in epilepsy and may even be relevant to understanding the phenomenon of SUDEP. Using the pilocarpine model, we evaluated heart rate of rats with epilepsy in vivo (ECG) and in an isolated ex vivo preparation (Langendorf preparation) [[26]Colugnati D.B. Gomes P.A. Arida R.M. et al.Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death.Arq Neuropsiquiatr. 2005; 63: 1035-1041Crossref PubMed Google Scholar]. Our results showed a significant increase in baseline heart rate in vivo in animals with epilepsy (346±7 bpm compared with 307±9 bpm in controls). In contrast, we did not find differences in the isolated ex vivo situation (control animals: 175±7 bpm; animals with epilepsy: 176±6 bpm), suggesting that autonomic modulation of the heart is changed in epileptic rats, which could explain the appearance and maintenance of an increased basal heart rate in these animals [[26]Colugnati D.B. Gomes P.A. Arida R.M. et al.Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death.Arq Neuropsiquiatr. 2005; 63: 1035-1041Crossref PubMed Google Scholar]. Very recently, our group also analyzed heart rate in rats subjected to electrical kindling of the amygdala [[27]Pansani A.P. Colugnati D.B. Cavalheiro E.A. Cravo S.L. Schoorlemmer G.H. Scorza F.A. Evidências fisiológicas da plasticidade cardíaca no modelo de epilepsia induzido por abrasamento elétrico na amígdala.J Epilepsy Clin Neurophysiol. 2010; 16: 17-18Google Scholar]. In this model, repeated administration of an initially subconvulsive electrical stimulus induces seizures that progressively become more intense. The complete process involves five stages of increasingly intense seizures: (1) facial clonus, (2) head nodding, (3) forelimb clonus, (4) rearing, and (5) rearing and falling accompanied by generalized clonic seizures [[28]Racine R.J. Modification of seizure activity by electrical stimulation: II. Motor seizure.Electroencephalogr Clin Neurophysiol. 1972; 32: 281-294Abstract Full Text PDF PubMed Scopus (5738) Google Scholar]. The main purpose of our study was to evaluate changes in baseline heart rate and heart rate responses during stage 5 of kindling, which corresponds to generalized seizures. What were the most remarkable findings so far? First, the animals did not show significant differences in basal heart rate before and after electrode implantation. On the other hand, basal heart rate was higher during stage 5 of kindling, possibly as a result of the sympathetic activation caused by the epileptic condition (Fig. 1). In agreement with previous studies [reviewed in [18]Devinsky O. Effects of seizures on autonomic and cardiovascular function.Epilepsy Curr. 2004; 4: 43-46Crossref PubMed Google Scholar], an intense bradycardia occurred at the beginning of seizure, followed by a rebound tachycardia (Fig. 2A ). Quite interestingly, our results indicated that the intensity of the tachycardia is related (r=0.29) to the number of generalized seizures (Fig. 2B). Our experimental demonstration of the relationship between seizure frequency and tachycardia shows that repeated generalized tonic–clonic seizures affect sympathetic outflow. On the whole, we are sure that seizures have a drastic effect on the autonomic nervous system and, obviously, that the mechanisms underlying SUDEP are multifaceted. Moreover, as a journey always begins with the first step, this open space encourages us to explore the map of SUDEP. In general terms, one of the reasons for these positive recent changes is the onset of translational research. The term translational research, which was recently incorporated into the Dictionary of Medical Sciences, indicates the integration of the advancements in basic science with clinical trials, taking research from bench to bedside [[29]Goldblatt E.M. Lee W.H. From bench to bedside: the growing use of translational research in cancer medicine.Am J Transl Res. 2010; 2: 1-18PubMed Google Scholar], and that is exactly what epileptologists around the world are doing in the study of SUDEP.Fig. 2(A) Changes in heart rate from baseline during stage 5 kindling seizures (n=6 seizures). Gray area represents the duration of the seizure. (B) Correlation between number of stage 5 kindling seizures and changes in heart rate from baseline in 13 rats. Pearson's correlation r=0.29.View Large Image Figure ViewerDownload (PPT)