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Sudden unexpected death in epilepsy and abnormal glucose metabolism in the rat insular cortex: A brain within the heart

Fulvio A. Scorza Antonio-Carlos G. de Almeida Carla A. Scorza Josef Finsterer About the authors

Epilepsy is one of the most common neurological diseases, affects millions of people globally, and available evidence suggests that patients with epilepsy have a higher risk of mortality compared with the general population.11 Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.,22 Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, et al. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021;116:107784. Sudden Unexpected Death in Epilepsy (SUDEP) is the most important direct epilepsy-related cause of death, accounting for 5% to 30% of deaths in individuals with epilepsy, particularly in 20- to 40-year-old patients with refractory epilepsy.11 Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.,22 Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, et al. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021;116:107784.,33 DeGiorgio CM, Curtis A, Hertling D, Moseley BD. Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention. Acta Neurol Scand 2019;139(3):220– 30.,44 Ellis Jr SP, Szabó CÁ. Sudden unexpected death in epilepsy: incidence, risk factors, and proposed mechanisms. Am J Forensic Med Pathol 2018;39(2):98–102. By far, nocturnal Generalized Tonic-Clonic Seizures (GTCS) frequency is the leading risk factor for SUDEP.11 Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.,22 Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, et al. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021;116:107784.,55 Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 2014;10(5):271–82.,66 Scorza FA, Cavalheiro EA, Costa JC. Sudden cardiac death in epilepsy disappoints, but epileptologists keep faith. Arq Neuropsiquiatr 2016;74(7):570–3. Although SUDEP likely does not have a single cause, it is already known that these fatal events are attributable to multiple mechanisms, including cardiac arrhythmias, respiratory dysfunction, and dysregulation of systemic or cerebral circulation.11 Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.,22 Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, et al. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021;116:107784.,77 So EL. Demystifying sudden unexplained death in epilepsy – are we close? Epilepsia 2006;47(Suppl 1):87–92.,88 Watkins L, Shankar R, Sander JW. Identifying and mitigating Sudden Unexpected Death in Epilepsy (SUDEP) risk factors. Expert Rev Neurother 2018;18(4):265–74.,99 Surges R, Sander JW. Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention. Curr Opin Neurol 2012;25(2):201–7. This being said, recent efforts to identify brain structural imaging biomarkers of SUDEP have revealed key structures involved in autonomic and respiratory regulation in people who died from SUDEP.1010 Allen LA, Vos SB, Kumar R, Ogren JA, Harper RK, Winston GP, et al. Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy. Epilepsia 2019;60(4):718–29.,1111 Allen LA, Harper RM, Lhatoo S, Lemieux L, Diehl B. Neuroimaging of Sudden Unexpected Death in Epilepsy (SUDEP): insights from structural and resting-state functional MRI studies. Front Neurol 2019;10:185.,1212 Wandschneider B, Koepp M, Scott C, Micallef C, Balestrini S, Sisodiya SM, et al. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138(Pt 10):2907–19. In these lines, the influence of the insula lobe in SUDEP plays an important role in the current and future scenarios.1313 Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4.,1414 Lacuey N, Garg V, Bangert B, Hampson JP, Miller J, Lhatoo S. Insular resection may lead to autonomic function changes. Epilepsy Behav 2019;97:260–4. The insula is present in all mammals as an integral part of the limbic system, both structurally and functionally.1313 Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4.,1515 Oppenheimer S, Cechetto D. The insular cortex and the regulation of cardiac function. Compr Physiol 2016;6(2):1081–133. In fact, as both cardiac and blood pressure regulatory representation show lateralization within the insula of several species, it is clearly established that derangements of insular functions by primary and secondary cerebral insults can significantly affect the cardiac structure, electrophysiology, and contractility and trigger significantly and occasionally fatal cardiac arrhythmias.1515 Oppenheimer S, Cechetto D. The insular cortex and the regulation of cardiac function. Compr Physiol 2016;6(2):1081–133. Specifically, in epilepsies, translational studies suggest a crucial role of the insula in cerebrogenic cardiovascular disturbances and SUDEP.1212 Wandschneider B, Koepp M, Scott C, Micallef C, Balestrini S, Sisodiya SM, et al. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138(Pt 10):2907–19.,1313 Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4.,1414 Lacuey N, Garg V, Bangert B, Hampson JP, Miller J, Lhatoo S. Insular resection may lead to autonomic function changes. Epilepsy Behav 2019;97:260–4.,1616 Cheung RT, Hachinski V. The insula and cerebrogenic sudden death. Arch Neurol 2000;57(12):1685–8. In brief, it has been shown that right or left lesional insular epilepsy may result in ictal bradycardia and asystole and postictal cardiac dysrhythmia.1414 Lacuey N, Garg V, Bangert B, Hampson JP, Miller J, Lhatoo S. Insular resection may lead to autonomic function changes. Epilepsy Behav 2019;97:260–4.,1717 Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12(10):966–77.,1818 Tayah T, Savard M, Desbiens R, Nguyen DK. Ictal bradycardia and asystole in an adult with a focal left insular lesion. Clin Neurol Neurosurg 2013;115(9):1885–7.,1919 Seeck M, Zaim S, Chaves-Vischer V, Blanke O, Maeder-Ingvar M, Weissert M, et al. Ictal bradycardia in a young child with focal cortical dysplasia in the right insular cortex. Eur J Paediatr Neurol 2003;7(4):177–81. Also, recent studies found abnormal autonomic function, characterized by marked differences in Heart Rate Variability (HRV) patterns, in individuals with radiological evidence of insular involvement after epilepsy surgery.1414 Lacuey N, Garg V, Bangert B, Hampson JP, Miller J, Lhatoo S. Insular resection may lead to autonomic function changes. Epilepsy Behav 2019;97:260–4. In a general context, as the anatomical substrate of epileptic activity in the CNS manifests a direct relationship with cardiovascular alterations,2020 Scorza FA, Cysneiros RM, Arida RM, Terra VC, Cavalheiro EA. Brain glucose metabolism and SUDEP: is it an important concern? Epilepsy Behav 2010;18(1-2):129–31. it is possible that patients with refractory epilepsy associated and insular lesions are at particular risk of SUDEP. Based on these important clinical findings, the present study’s research group used the pilocarpine model of epilepsy, a valuable tool to study the pathophysiology of Temporal Lobe Epilepsy (TLE) in humans,2121 Scorza FA, Arida RM, Naffah-Mazzacoratti Mda G, Scerni DA, Calderazzo L, Cavalheiro EA. The pilocarpine model of epilepsy: what have we learned? An Acad Bras Cienc 2009;81(3):345–65. to evaluate the glucose metabolism in the insula using the 2-[14C] deoxy-glucose [14C-2DG] autoradiographic technique in chronic epileptic rats. The 14C-2DG method or “metabolic encephalography”, developed by Sokoloff and colleagues in 1977, provides information concerning functional activity in specific regions of the brain.2222 Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, et al. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28(5):897–916.,2323 Sokoloff L. The radioactive deoxyglucose method: Theory, procedure, and application for the local cerebral glucose utilization in the central nervous system. Adv Neurochem 1982;4:1–82.,2424 Wree A. Principles of the 2-deoxyglucose method for the determination of the local cerebral glucose utilization. Eur J Morphol 1990;28(2-4):132–8. With this in mind, the authors observed in the present study a decrease in 14C-2DG labeling (-54%) in the insula of rats with epilepsy as compared with control animals (Fig. 1). Furthermore, cerebral glucose utilization rates measured on labeled insular cortex did not differ among nonepileptic control animals (Fig. 1).

Fig. 1
Representative 14C-2DG autoradiographs in (A) control rats and (B) rats with epilepsy. Electroencephalograph traces were obtained from control animals (C) and animals with epilepsy (D). Graphic representation of basal levels of cerebral energy metabolism in the control and experimental animals (E).

What do these results tell us? In the last decades, important advances have been achieved in understanding the brain sites involved in cardiovascular control in patients with epilepsy.1010 Allen LA, Vos SB, Kumar R, Ogren JA, Harper RK, Winston GP, et al. Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy. Epilepsia 2019;60(4):718–29.,1111 Allen LA, Harper RM, Lhatoo S, Lemieux L, Diehl B. Neuroimaging of Sudden Unexpected Death in Epilepsy (SUDEP): insights from structural and resting-state functional MRI studies. Front Neurol 2019;10:185.,1212 Wandschneider B, Koepp M, Scott C, Micallef C, Balestrini S, Sisodiya SM, et al. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138(Pt 10):2907–19.,1313 Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4.,1616 Cheung RT, Hachinski V. The insula and cerebrogenic sudden death. Arch Neurol 2000;57(12):1685–8.,2020 Scorza FA, Cysneiros RM, Arida RM, Terra VC, Cavalheiro EA. Brain glucose metabolism and SUDEP: is it an important concern? Epilepsy Behav 2010;18(1-2):129–31. In this perspective, the authors are totally in agreement that the insula lobe is probably a key cerebral region involved in SUDEP since abnormalities in this brain structure can lead to cardiac and respiratory dysfunction, central respiratory inhibition, and apnea and arrhythmias in people with refractory epilepsy.1313 Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4. In the authors’ experience, the authors are convinced that the use of experimental models of epilepsy is a valuable tool to investigate the occurrence of SUDEP.2525 Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother 2016;16(5):561–72. In this sense, current research highlights that hypoventilation, apnea, respiratory distress, pulmonary hypertension, autonomic dysregulation, and arrhythmia are common findings in epilepsy models.2525 Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother 2016;16(5):561–72. Importantly, the results of this study confirm preliminary data that SUDEP, at least in some cases, could be attributed to dysfunction or morphological alteration of specific brain structures.2626 Scorza FA, Arida RM, Cysneiros RM, Terra VC, Sonoda EY, de Albuquerque M, et al. The brain-heart connection: implications for understanding sudden unexpected death in epilepsy. Cardiol J 2009;16(5):394–9.

Overall, epilepsy is a heterogeneous, multifactorial, and systemic disease. Moreover, epilepsy is a neurological condition with cases of premature death. Finally, neuroscientists should consider that the presence of insular dysfunction in patients with epilepsy could underlie some processes that culminate in SUDEP.

Acknowledgments

The authors would like to thank Prof. Dr. Esper Abrão Cavalheiro by useful initial discussions and to Dr. Leandro Freitas Oliveira and Dr. Laís Damasceno by structuring the figure. The present studies are supported by the following grants: FAPESP (Fundac ao de Amparo à Pesquisa do Estado de São Paulo); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES).

References

  • 1
    Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.
  • 2
    Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, et al. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021;116:107784.
  • 3
    DeGiorgio CM, Curtis A, Hertling D, Moseley BD. Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention. Acta Neurol Scand 2019;139(3):220– 30.
  • 4
    Ellis Jr SP, Szabó CÁ. Sudden unexpected death in epilepsy: incidence, risk factors, and proposed mechanisms. Am J Forensic Med Pathol 2018;39(2):98–102.
  • 5
    Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 2014;10(5):271–82.
  • 6
    Scorza FA, Cavalheiro EA, Costa JC. Sudden cardiac death in epilepsy disappoints, but epileptologists keep faith. Arq Neuropsiquiatr 2016;74(7):570–3.
  • 7
    So EL. Demystifying sudden unexplained death in epilepsy – are we close? Epilepsia 2006;47(Suppl 1):87–92.
  • 8
    Watkins L, Shankar R, Sander JW. Identifying and mitigating Sudden Unexpected Death in Epilepsy (SUDEP) risk factors. Expert Rev Neurother 2018;18(4):265–74.
  • 9
    Surges R, Sander JW. Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention. Curr Opin Neurol 2012;25(2):201–7.
  • 10
    Allen LA, Vos SB, Kumar R, Ogren JA, Harper RK, Winston GP, et al. Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy. Epilepsia 2019;60(4):718–29.
  • 11
    Allen LA, Harper RM, Lhatoo S, Lemieux L, Diehl B. Neuroimaging of Sudden Unexpected Death in Epilepsy (SUDEP): insights from structural and resting-state functional MRI studies. Front Neurol 2019;10:185.
  • 12
    Wandschneider B, Koepp M, Scott C, Micallef C, Balestrini S, Sisodiya SM, et al. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138(Pt 10):2907–19.
  • 13
    Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord 2017;19(1):10–4.
  • 14
    Lacuey N, Garg V, Bangert B, Hampson JP, Miller J, Lhatoo S. Insular resection may lead to autonomic function changes. Epilepsy Behav 2019;97:260–4.
  • 15
    Oppenheimer S, Cechetto D. The insular cortex and the regulation of cardiac function. Compr Physiol 2016;6(2):1081–133.
  • 16
    Cheung RT, Hachinski V. The insula and cerebrogenic sudden death. Arch Neurol 2000;57(12):1685–8.
  • 17
    Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12(10):966–77.
  • 18
    Tayah T, Savard M, Desbiens R, Nguyen DK. Ictal bradycardia and asystole in an adult with a focal left insular lesion. Clin Neurol Neurosurg 2013;115(9):1885–7.
  • 19
    Seeck M, Zaim S, Chaves-Vischer V, Blanke O, Maeder-Ingvar M, Weissert M, et al. Ictal bradycardia in a young child with focal cortical dysplasia in the right insular cortex. Eur J Paediatr Neurol 2003;7(4):177–81.
  • 20
    Scorza FA, Cysneiros RM, Arida RM, Terra VC, Cavalheiro EA. Brain glucose metabolism and SUDEP: is it an important concern? Epilepsy Behav 2010;18(1-2):129–31.
  • 21
    Scorza FA, Arida RM, Naffah-Mazzacoratti Mda G, Scerni DA, Calderazzo L, Cavalheiro EA. The pilocarpine model of epilepsy: what have we learned? An Acad Bras Cienc 2009;81(3):345–65.
  • 22
    Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, et al. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28(5):897–916.
  • 23
    Sokoloff L. The radioactive deoxyglucose method: Theory, procedure, and application for the local cerebral glucose utilization in the central nervous system. Adv Neurochem 1982;4:1–82.
  • 24
    Wree A. Principles of the 2-deoxyglucose method for the determination of the local cerebral glucose utilization. Eur J Morphol 1990;28(2-4):132–8.
  • 25
    Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother 2016;16(5):561–72.
  • 26
    Scorza FA, Arida RM, Cysneiros RM, Terra VC, Sonoda EY, de Albuquerque M, et al. The brain-heart connection: implications for understanding sudden unexpected death in epilepsy. Cardiol J 2009;16(5):394–9.

Publication Dates

  • Publication in this collection
    09 Sept 2022
  • Date of issue
    2022

History

  • Received
    15 May 2022
  • Accepted
    26 May 2022
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