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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 108-110

Epileptic seizure-induced cardiac injury as a cause of sudden unexpected death in epilepsy: Evidence from pathological analyses

1 Department of Forensic Medicine, Hainan Medical College, Hainan, China
2 Faculty of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China
3 Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Prof. Jianbo Li
Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jfsm.jfsm_14_18

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Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of death in people with epilepsy. The detailed mechanisms of SUDEP have not been elucidated. Moreover, it is still difficult for clinicians to predict and prevent the occurrence of sudden death in patients with epilepsy. Seizure-related cardiac complications were considered to play a significant role in the physiological changes that lead to SUDEP. This report described a case of sudden death of an 11-year-old boy with epilepsy. Detailed autopsy and pathological analyses were performed to determine the cause of death. Seizure-induced myocardial fibrosis was observed and deemed to be the cause of SUDEP. This study clearly showed the importance of improving the protection of cardiac function in the reductions of sudden deaths among patients with epilepsy. In addition, further studies in the pathophysiology of patients with epilepsy may help in improving our understanding of the mechanisms of SUDEP and adding new insight into the development of seizure-induced cardiovascular and respiratory changes that may contribute to sudden death in epileptics.

Keywords: Cardiac injury, forensic science, pathological analyses, sudden unexpected death in epilepsy

How to cite this article:
Song T, Zhu S, Li J. Epileptic seizure-induced cardiac injury as a cause of sudden unexpected death in epilepsy: Evidence from pathological analyses. J Forensic Sci Med 2018;4:108-10

How to cite this URL:
Song T, Zhu S, Li J. Epileptic seizure-induced cardiac injury as a cause of sudden unexpected death in epilepsy: Evidence from pathological analyses. J Forensic Sci Med [serial online] 2018 [cited 2023 Feb 8];4:108-10. Available from: https://www.jfsmonline.com/text.asp?2018/4/2/108/235442

  Introduction Top

Sudden unexpected death in epilepsy (SUDEP) refers to a sudden and unexpected death in patients with epilepsy that is not due to trauma, drowning, status epilepticus, poisoning, or anatomic cause identified through postmortem examination but with which there is often evidence of epilepsy related.[1] SUDEP, which accounts for 7.5%–17% of all deaths in patients with epilepsy, severely reduces the life expectancy of patients.[2],[3] Epidemiological studies indicate that the incidence of SUDEP in adult is higher than in children and it increases with the duration and severity of epilepsy.[4],[5] Without or the lack of therapeutic levels of antiepileptic drugs, frequent changes in regimens, and multiple episodes of epilepsy, especially tonic–clonic seizures, are considered risk factors for SUDEP.[4],[5],[6]

While many clinical and animal experimental studies have examined the pathophysiological mechanisms underlying SUDEP, the precise mechanisms have not been elucidated, and it is still difficult for clinicians to conduct appropriate therapeutic interventions to prevent the physiological changes that complicate seizures and lead to SUDEP.[7],[8] These difficulties are in part attributed to the complexities of the mechanisms of SUDEP, the lack of an ideal animal model, and the patients' rapid progress to death without providing clinicians sufficient time to acquire complete information.[9] However, another important explanation for these difficulties is the shortage of detailed histopathological examination of patients died of SUDEP, which could provide clinicians not only a better understanding of the mechanisms of SUDEP but also a reference for evaluating the risk of sudden death and conducting accurate interventions.[9],[10]

The present study reports such a case, in which a boy patient suffered from epilepsy for years and suddenly died without presenting with any special clinical manifestations. Systematic autopsy and detailed histopathological examination were performed to determine the cause of death. This case suggests that serious seizure-induced cardiac injury can be a cause of SUDEP and preserving the cardiac function in patient with epilepsy is essential for averting potential SUDEP. Informed consent was obtained from the family of the patient, and this study was approved by the Ethical Committee of Chongqing Medical University (March 14, 2017).

  Case Report Top

An 11-year-old boy was diagnosed with epilepsy since 8 years of age. Although strictly adhered to the antiepileptic drug regimens, he had approximately ten generalized tonic–clonic seizures (GTCSs)/year on sodium valproate 1 g/d. Three months before his death, his seizures became more frequent, and he had an abnormal liver function with alanine aminotransferase (ALT) 130 U/L (normal <40 U/L), gamma-glutamyltransferase 80 (normal <40 U/L), and aspartate aminotransferase (AST) 79 U/L (normal <40 U/L). In addition, the boy had complained of left chest pain several times; however, nobody had paid much attention to his chest pain. Discontinuing the sodium valproate and starting other antiepileptic drugs were suggested to the parents of the patient, but they chose to suspend the drugs for a few weeks to observe the change of liver function. The patient had four GTCS and a further aggravation of liver impairment with ALT 271 U/L and AST 142 U/L in the following month. Then, the parents followed the physician's advice and started the boy on levetiracetam 500 mg t.i.d. Two GTCS occurred in the next 2 months, and the duration and severity of seizure decreased. However, one day morning after the boy got up, he fell to the ground with a sudden loss of consciousness. Then, the boy was brought to an urgent care center where positive measures including resuscitation efforts with cardiopulmonary resuscitation were performed, but his heart rate and blood pressure still failed to detect. The boy was confirmed dead by physicians after 1 h of rescue. The clinical diagnosis for his death was undetermined. Therefore, a medicolegal examination was ordered to investigate the cause of death.

The corpse was prompt cooling and stored at −20°C, and the medicolegal autopsy was performed 6 days later. Autopsy revealed no abnormalities aside from mild petechial hemorrhage in the conjunctiva of both sides. Histological changes, including cardiac fibrosis and formation of fiber scar [Figure 1] and pulmonary edema [Figure 2] were observed. No focal lesions were found in the brain of the patient. Poisoning and anatomic cause were completely excluded. The official cause of death was determined to be SUDEP, and the serious seizure-induced cardiac injury was believed to be the culprit of the sudden death.
Figure 1: The cardiac fibrosis and formation of fiber scar were stained with both H and E ([a] ×200) and Masson's trichrome ([b] ×200)

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Figure 2: Pulmonary edema (H and E, ×200)

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  Discussion Top

SUDEP is the most frequent cause of death in people with epilepsy. However, it is extremely difficult to predict and prevent the occurrence of SUDEP, which is due to its complex pathophysiological mechanisms and innumerous risk factors. A considerable evidence from clinical research found that most cases of SUDEP occurred after a seizure, usually a tonic–clonic seizure and the interruption of treatment with antiepileptic drugs.[4] In addition, a large number of data from animal experiment and clinical studies strongly suggest that the postictal impairment of respiration and shutdown of cerebral and brain stem function play an important role in the occurrence of sudden death.[11],[12] Hence, in this scenario, seizures, especially tonic–clonic seizures, were considered to be the main risk factors for SUDEP.

However, recent studies have shown that cardiovascular changes, especially cardiac injury, could be likely culprits in some instances of SUDEP.[4] Darbin et al. showed that after seizures induced by maximal electroshock, both sympathetic and parasympathetic activity were increased and approximate entropy was decreased.[13] The reduction of entropy is an important predictor of sudden cardiac death.[14] Read et al., using Sprague Dawley rats which were implanted with electroencephalogram/electrocardiogram electrodes, showed that the prolonged seizure activity could lead to a deterioration in cardiac structure and function.[15] Seizure-induced arrhythmias were observed in both animal models and patients.[16] Al-Najafi and Rosman who studied from a patient found that unrecognized myocardial stunning with or without malignant arrhythmias could be a risk factor for SUDEP.[17]

Seizure-related respiratory and cardiac complications have been currently considered as the two main factors of SUDEP.[4],[8],[9] A study by Nashef et al. suggested that cases that would otherwise fulfill the definition of SUDEP should be designated as “SUDEP plus” when evidence indicates that a preexisting condition, known before or after autopsy, could have contributed to the death, which otherwise is classified as SUDEP (e.g., coronary insufficiency with no evidence of myocardial infarction or long-QT syndrome with no documented primary ventricular arrhythmia leading to death).[18] In an epidemiological study of 13 cases who were identified as SUDEP, only one patient's death was clearly due to cardiac event.[4] This situation may be associated with the fact that SUDEP often occurred in the night without witness or detection of cardiac and cerebral function and the absence of detailed autopsy and pathological analyses. This not only brings clinicians tremendous difficulties to determine the exact causes of death for patients with epilepsy but also results in an inaccurate estimate of the incidence of SUDEP.[4]

Myocardial fibrosis was observed in the case presented here, which was in accordance with previous animal studies.[9] Seizure-induced activation of the sympathetic nervous system is deemed to be involved in the progress of myocardial fibrosis of patients with epilepsy.[9] Increased sympathetic dominance during seizures could increase plasma catecholamine levels, decrease myocardial blood supply, and increase cardiac oxygen consumption, which could eventually lead to myocardial ischemia, necrosis, and fibrosis.[4],[9],[11],[12] In addition, increased metabolism of catecholamine causes an overproduction of free oxygen radicals, which could increase the damage of myocardial cell and aggravate myocardial fibrosis. Furthermore, the development of myocardial necrosis and fibrosis increases the susceptibility to fatal arrhythmias in patients with epilepsy and could cause a sudden cardiac death during the ictal and interictal periods.[9]

Therefore, an effective control of seizures in the early stages is essential for blocking the process of myocardial fibrosis and reducing the probability of occurrence of sudden death in patients with epilepsy. Moreover, increasing awareness of seizure-induced life-threatening cardiac injury on the part of the patients and the medical community, especially in these cases of intractable seizures, is also an important measure of SUDEP prevention.

In conclusion, the underlying pathophysiologic mechanisms of SUDEP are still remain unelucidated. Preliminary studies have shown that SUDEP is a complexity of multistage biological process with multifactors being involved. Seizure-induced cardiac injury was observed in both animal experiment and clinical studies and may play an important role in the sudden death process of patients. This study clearly shows the serious seizure-induced cardiac injury and the importance of improving the protection of cardiac function in the reductions of sudden deaths among patients with epilepsy. In addition, detailed histopathological examination could improve our understanding of the mechanisms of SUDEP and add new insight into the development of seizure-induced cardiovascular and respiratory changes that may contribute to sudden death in epileptics. There are some limitations within this study, such as lack of animal experiments and relevant immunohistochemical staining of heart.

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  References Top

Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: A study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187-94.  Back to cited text no. 1
Nashef L, Ryvlin P. Sudden unexpected death in epilepsy (SUDEP): Update and reflections. Neurol Clin 2009;27:1063-74.  Back to cited text no. 2
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;12:966-77.  Back to cited text no. 3
Devinsky O. Sudden, unexpected death in epilepsy. N Engl J Med 2011;365:1801-11.  Back to cited text no. 4
Sillanpää M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med 2010;363:2522-9.  Back to cited text no. 5
Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology 2005;64:1131-3.  Back to cited text no. 6
Friedman D, Donner EJ, Stephens D, Wright C, Devinsky O. Sudden unexpected death in epilepsy: Knowledge and experience among U.S. and Canadian neurologists. Epilepsy Behav 2014;35:13-8.  Back to cited text no. 7
Auzmendi J, Buchholz B, Salguero J, Cañellas C, Kelly J, Men P, et al. Pilocarpine-induced status epilepticus is associated with P-glycoprotein induction in cardiomyocytes, electrocardiographic changes, and sudden death. Pharmaceuticals (Basel) 2018;11. pii: E21.  Back to cited text no. 8
Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA, et al. Furthering our understanding of SUDEP: The role of animal models. Expert Rev Neurother 2016;16:561-72.  Back to cited text no. 9
Swinghamer J, Devinsky O, Friedman D. Can post-ictal intervention prevent sudden unexpected death in epilepsy? A report of two cases. Epilepsy Behav 2012;24:377-9.  Back to cited text no. 10
Bateman LM, Spitz M, Seyal M. Ictal hypoventilation contributes to cardiac arrhythmia and SUDEP: Report on two deaths in video-EEG-monitored patients. Epilepsia 2010;51:916-20.  Back to cited text no. 11
Uteshev VV, Tupal S, Mhaskar Y, Faingold CL. Abnormal serotonin receptor expression in DBA/2 mice associated with susceptibility to sudden death due to respiratory arrest. Epilepsy Res 2010;88:183-8.  Back to cited text no. 12
Darbin O, Casebeer DJ, Naritoku DK. Cardiac dysrhythmia associated with the immediate postictal state after maximal electroshock in freely moving rat. Epilepsia 2002;43:336-41.  Back to cited text no. 13
Voss A, Kurths J, Kleiner HJ, Witt A, Wessel N, Saparin P, et al. The application of methods of non-linear dynamics for the improved and predictive recognition of patients threatened by sudden cardiac death. Cardiovasc Res 1996;31:419-33.  Back to cited text no. 14
Read MI, McCann DM, Millen RN, Harrison JC, Kerr DS, Sammut IA, et al. Progressive development of cardiomyopathy following altered autonomic activity in status epilepticus. Am J Physiol Heart Circ Physiol 2015;309:H1554-64.  Back to cited text no. 15
Schuele SU. Effects of seizures on cardiac function. J Clin Neurophysiol 2009;26:302-8.  Back to cited text no. 16
Al-Najafi S, Rosman H. Seizure-induced myocardial stunning: A possible cardiac link to sudden unexpected death in epilepsy (SUDEP). Seizure 2015;24:137-9.  Back to cited text no. 17
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 2012;53:227-33.  Back to cited text no. 18


  [Figure 1], [Figure 2]


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