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Stress and sudden death
Epilepsy & Behavior 9 (2006) 236–242 www.elsevier.com/locate/yebeh
Review
Stress and sudden death Claire M. Lathers a
a,*
q
, Paul L. Schraeder
b
Office of the Director, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855, USA b Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA Received 6 April 2006; revised 27 May 2006; accepted 5 June 2006 Available online 26 July 2006
Abstract Cardiac patients, psychiatric patients, and certain ethnic groups experiencing acute stressful circumstances are at risk for unexpected sudden death. Although stress is associated with changes in autonomic neural function, its role as a potential risk factor for sudden unexpected death in epilepsy (SUDEP) is not known. The association of epilepsy with cardiac abnormalities, such as neurogenic arrhythmias and microscopic perivascular and interstitial fibrosis, and with depression and anxiety indicates that emotional stress should be evaluated as a potential risk factor for SUDEP. The impact of adverse emotional states on the autonomic control of cardiac rhythm is a known important factor leading to cardiac dysrhythmias in humans and other species. The interaction between emotional factors and the arrythmogenic potential of epileptiform discharges and the possibility of benefit from stress management intervention need to be investigated. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Sudden death; Sudden unexpected death in epilepsy; Epilepsy; Cardiac disease; Psychiatric disorders; Stress; Depression
1. Introduction Sudden deaths associated with stress have been reported since antiquity [1]. The Acts of the Apostles 5:1–11 [2] describe how Ananias was charged by Peter to have ‘‘lied not to man but to God.’’ Ananias fell to the ground dead. His wife Sapphira met a similar fate when told that those who had buried her husband were at the door and planning to ‘‘carry thee out.’’ In 1942, Walter Cannon [3] cited examples from the anthropology literature of death from fright and entitled his article: ‘‘Voodoo Death.’’ Cannon discussed the role of the sympathico-adrenal system. Engle [4] collected 160 different accounts of sudden deaths due to emotional stress, finding that in most cases the circumstances were associated with extreme excitation, resignation, or despondency. Even if it is only in the form of a q
Opinions expressed are those of the authors and do not reflect opinions or policy of the FDA. * Corresponding author. Present address: 115 South Manning Boulevard, Albany, NY 12203, USA. Fax: +1 518 482 6732. E-mail address: [email protected] (C.M. Lathers). 1525-5050/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2006.06.001
mental image of pain, psychological stress can cause asystole [5]. Cardiac pathological changes reported in victims of stress-related deaths [6] have been designated myofibrillar degeneration or myocytolysis. This microscopic entity has been found to be identical to that identified in the hearts of patients who died of subarachnoid hemorrhage and other acute strokes. 2. Sudden death in certain ethnic populations Although Lown [7] noted that sudden cardiac death is the major challenge in cardiology, sudden death is also a recognized risk in certain ethnic populations [8]. For example, healthy Filipino men may experience Bangungut, an unexpected death during sleep. Bangungut means ‘‘to rise and moan during sleep.’’ Pokkuri is the term used to describe sudden cardiac deaths among apparently healthy Japanese soldiers during World War II [9]. In the case of the soldiers, warfare could produce major stresses including personal danger, mourning, extreme excitation, resignation, and despondency. Engle [4] described eight precipitating circumstances that precede sudden death: (1)
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illness or death of a close person, (2) acute grief, (3) threat of loss of a close person, (4) mourning or anniversary of a death, (5) loss of status or self-esteem, (6) personal danger or threat of injury, (7) relief from danger, and (8) reunion, triumph, or happy ending. The precipitating event was one that was impossible for the victim to ignore because it was abrupt, unexpected, or dramatic or because of its intensity, irreversibility, or persistence. Retrospective investigation of 51 cases of sudden unexplained death in non-East Asian subjects, including indigenous Saudis, between January 1995 and June 1997, revealed that most victims were subcontinent Indians (43%) [10]. Autopsies were done on 22 victims. Seven exhibited mild to moderate cardiac hypertrophy, with two of these seven also having mild to moderate coronary stenosis. Four other victims exhibited a similar degree of coronary narrowing, but had no evidence of myocardial hypertrophy. Severe pulmonary congestion and alveolar hemorrhage were detected in 18 of the 22 victims autopsied. A leading cause of death of young men in several East Asian populations is sudden and unexplained death in sleep [11]. A review of autopsy records from 1948 to 1982 in Manila was used to classify these types of deaths. A nested case–control study of death certificates examined birthplace as an indicator of risk of sudden, unexplained death in sleep. There were 722 sudden, unexpected deaths in sleep during this time. Characteristics of victims in each group were similar: 96% were male, mean age was 33, and modal time of death was 3:00 AM. The deaths were seasonal, peaking in December and January. The death rate for mean ages 25–44 increased from 10.8 to 26.3 per 100,000 person-years from 1948 to 1982, possibly because of more accurate classification of cause of death. Because the deaths appeared to be a regional phenomenon in Southeast Asia it was speculated that environmental factors were likely, as the deaths were seasonal, increased over the time span studied, and were more common among migrants to Manila than among people born there. Owada et al. [12] reported on autopsies of sudden death cases in Japan from May 1994 to February 1998. The medical records for 91 cases were reviewed, and interviews were conducted with the victims’ close family members. Of 271 cases, 176 patients 20 to 59 years old were classified as cases of sudden death in the working generation. Of the sudden death cases, 29 were due to coronary artery disease (31.9%), 18 to acute cardiac dysfunction (19.8%), 6 to other cardiac diseases (6.6%), 4 to acute aortic dissection (4.4%), 4 to cerebrovascular disease (4.4%), and 30 to other diseases (32.9%). Risk factors identified included long-term stress, history of heart disease, hypertension, chest symptoms, autonomic disturbance, short-term stress, and a smoking habit. Short-term stress, autonomic disturbance, and a smoking habit increased the risk of sudden death due to coronary artery disease. Long-term stress was associated with increased risk of sudden death due to acute cardiac dysfunction. Autonomic disturbance and stress were
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related to the occurrence of sudden death. The authors recommend that it would be helpful to identify subjective symptoms so one can intervene to relieve such stress and presumably reduce the risk of sudden death. Basso et al. [13] reported on 200 cases of sudden death in persons less than 35 years of age in the Veneto region in Italy. Fifteen cases (7.5%) were due to cerebral, 10 to respiratory (5%), and 163 to cardiovascular (81.5%) etiologies. Twelve deaths (6%) were unexplained. For cardiovascular sudden death, obstructive coronary atherosclerosis was found in 23% of the cases and arrhythmogenic right ventricular cardiomyopathy in 12.5%. Mitral valve prolapse occurred in 10%, conduction system abnormalities in 10%, and congenital coronary artery anomalies in 8.5%. Myocarditis was reported for 7.5%, hypertrophic cardiomyopathy for 5.5%, aortic rupture for 5.5%, and dilated cardiomyopathy for 5%. Nonatherosclerotic acquired coronary artery disease was reported in 3.5%, postoperative congenital heart disease in 13%, aortic stenosis in 2%, pulmonary embolism in 2%, and other causes in 2%. Sudden death was unexplained in 6% of the cases. Thus, even though a large spectrum of cardiovascular disorders appeared to be the most common organic substrate for most sudden deaths in this population, more than 1 in 20 cases of sudden death in this young adult population were not explained by structural risk factors. 3. Non-SIDS pediatric sudden unexplained death in the United States Sudden unexplained death claims more than 4000 persons between the ages of 1 and 22 each year in the United States. Almost half of the pediatric sudden death victims have a normal structural autopsy. Therefore, identification of children at risk for cardiac arrhythmias as a cause of seizurelike events and optimal seizure control measures in those at risk for seizure-related cardiac arrhythmias are possible approaches to risk reduction [14]. Many studies suggest that assessment of medical histories, in combination with cardiovascular and EEG evaluation of surviving family members, may help to clarify possible risks for various categories of sudden unexplained death [15–20]. The genetic basis for potentially fatal arrhythmia associated with the inherited long-QT syndrome (LQTS) may be a factor. For example, a 17-year-old sudden death victim’s mother was challenged with epinephrine and a potential defect in the phase 3 potassium current encoded by the gene KVLQT1 was identified. A 5-bp deletion was identified in the genetic material recovered from the decedent’s paraffin-embedded heart tissue [15]. Such isolated cases indicate that the ability to perform molecular autopsies on achieved necropsy material may transform the forensic evaluation of sudden death. The combination of catecholamine provocative testing in surviving family members and postmortem LQTS gene analysis may unmask families with ‘‘concealed’’ LQTS and establish the cause of previously unexplained sudden death, including, presumably, sudden
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unexpected death in epilepsy (SUDEP). Whether or not the presence of such a genetic defect in combination with epilepsy is a risk factor for SUDEP is unknown. As with adults, the mechanism of SUDEP in the pediatric age group is unclear, but quite possibly it is associated with seizure-related cardiac arrhythmia and/or respiratory insufficiency. Although children with epilepsy have an increased risk of death, SUDEP is rare: 1–2/10,000 patient-years versus 1/100–750 patient-years in adults. 4. The role of emotions as a seizure precipitant That emotions can act as a precipitant of seizures has been recognized since the time of Hughlings Jackson and Gowers [21]. Stress-laden events such as fear, worry, frustration, and anger are commonly associated with increased frequency of seizures [22]. Dominian et al. [23] reported that emotionally laden events preceded the first seizure occurrence in 20 of 51 patients studied. The definition of stressful events ranged from retirement after 45 years with the same organization to arrest by the Gestapo. Although the mechanisms involved in emotion-associated seizure activation are not known, multiple factors may explain the role of emotion, including activation of neural networks, sleep deprivation, noncompliance, alcohol use, and hyperventilation. However, even though there often is no immediate temporal relationship, in that the seizures do not occur at the moment that the patient has the negative emotional experience, the patient is at risk for one or more seizures. This risk is especially true for temporal lobe seizures occurring in close proximity to an emotional state [22]. Another circumstance that could increase the chance of seizure recurrence is the use of antidepressants and/or neuroleptics. Drugs in either of these groups may be necessary to treat the patients’ dysphoric symptoms, but also increase the chance of lowering the seizure threshold. Many clinical studies have demonstrated that poor seizure control is a major risk factor for SUDEP [24]. The interrelationship between an adverse emotional state and other related seizure-inducing circumstances warrants further investigation, especially because we know that there is an association between increased risk of SUDEP and poor seizure control [25]. Although the previous discussion emphasized the role of stress as a risk factor in various categories of sudden death, such a role may be compounded in the case of epilepsy. 5. Acute and chronic stress and sudden death Acute stress caused by emotions such as fear sometimes can cause sudden death in persons with coronary heart disease. Ackerman et al. [15] comment that chronic stress also may contribute to the development of coronary disease, in that it may promote the long-term development of coronary disease and recommended the routine use of stress management in standard cardiac rehabilitation programs. Interestingly, the distinction between Type A and Type B
personalities as risk correlates appears to be overly simplistic, in that the psychosocial factors depression, hostility, social isolation, anxiety, anger, and other stresses are related to increased cardiac death and illness in all groups with coronary heart disease [26]. All of these psychosocial risk factors may benefit from a biopsychosocial model of intervention. Death can result from acute stress related to disasters. For example, sudden deaths related to atherosclerotic coronary artery disease increased fivefold on the day of the Los Angeles earthquake in 1994 [27]. Acute mental stress induced experimentally has been associated with ST-segment deviation and wall-motion abnormalities [28]. Mental stress needs to be considered as a greater risk factor than exercise-induced ischemia in increasing the rate of fatal and nonfatal cardiac events [29], emphasizing again that psychosocial stress management treatment in a cardiac rehabilitation program reduces cardiac-related mortality and morbidity [30]. Distress within the family and/or stress at work are strong predictors of the development of stressrelated disorders, and also require intervention [31]. Whether we can extrapolate the preceding discussion of management of stress factors in coronary artery disease as being helpful in diminishing the risk of SUDEP is not known, but the fact that so many of these same factors come into play in persons with epilepsy makes it difficult to deny this possibility. 6. Are depression and stress risk factors for SUDEP? The well-established role of depression and stress as major risk factors in sudden cardiac death raises the question of whether the same risk may be extant in SUDEP. The epidemiological data on psychiatric morbidity in epilepsy are spotty at best. Nonetheless, having epilepsy is stress producing, and stress increases the frequency of seizures. The uncertainty of when a seizure can occur and the consequences of having a seizure on one’s employment status and driving privileges are common stress-producing circumstances with which the person with epilepsy must live. It is no surprise that depression and anxiety are common symptoms associated with epilepsy [32]. In addition to the common experience of ongoing depression and anxiety, depression may occur as a postictal phenomenon, and can be very severe. Whether this more profound depression is reactive or biologically linked to the seizure is unknown [33]. Although almost no studies of SUDEP address the possible role of emotional stress in the form of depression and/or anxiety as a risk factor, Earnest et al. [34] did comment on the role of acutely stressful circumstances as a possible contributor near the time of death in a case–control study of the metropolitan Denver area. Whether or not stress in the form of depression and/or acute or chronic anxiety is a common risk factor for SUDEP is not known. The known role of adverse emotional states as a risk for sudden cardiac death supports the need to investigate this factor more thoroughly in persons with epilepsy. The
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activation of stress-responsive systems during depressive episodes may contribute to metabolic risk factors and imbalance of the autonomic heart regulation [30,33,35]. 7. Autonomic dysfunction and sudden death Lathers and Schraeder [36] demonstrated that autonomic sympathetic and parasympathetic cardiac neuronal dysfunction is associated with interictal as well as ictal epileptiform discharges and with cardiac arrhythmias. Hilz et al. [37] observed influences on autonomic dysregulation, with predominant sympathetic overactivity, in association with interictal and epileptogenic discharges in persons with temporal lobe epilepsy. Surgical treatment for temporal lobe epilepsy resulted in a reduction of sympathetic cardiomodulation and decreased the baroreflex sensitivity, that is, a decrease in the influence of sympathetically mediated tachyarrhythmias and excessive bradycardic counterregulation. As these two factors are thought to contribute to the risk of SUDEP, the temporal lobe surgery itself appears to be one method to reduce and/or eliminate some risk factors associated with SUDEP [37,38]. In addition to the role of the sympathetic nervous system in cardiovascular regulation, parasympathetic nervous system activity also has ongoing action on the regulation of cardiac rhythm [39,40]. For example, drowning animals exhibit bradycardia prior to death [41]. Because atropine protected the animals and cholinergic drugs shortened the time to death, it was concluded that increased vagal discharge and tone preceded death. Stimulation of the vagus nerve or application of acetylcholine to the sinoatrial node slows or abolishes depolarization of sinus node fibers [42,43], whereas decreased depolarization and shifts of membrane threshold potentials change the sinoatrial node rate, causing sinus bradycardia. A similar mechanism occurs in the atrioventricular node [44]. Changes in the ECG and cardiac muscle necrosis result from stimulation of the efferent limb of the sympathetic nervous system and of the aortic arch and carotid baroreceptors involved in autonomic nervous system reflex activity [45–47]. Sympathetic stimulation causes a sudden release of norepinephrine from cardiac nerve endings into the heart muscle, leading to microscopic changes in the form of cardiac myocyte necrosis, cardiac dysfunction, and arrhythmias [42,43]. Stimulation of cardiac sympathetic nerves accelerates sinoatrial depolarizations and shortens the cycle length of firing of the sinus node. More recently, Natelson et al. [48] studied the hearts of persons with epilepsy who died suddenly and found pathological changes in the form of irreversible perivascular and interstitial fibrosis and myocyte vacuolization. As these lesions occurred mostly in the subendocardium, it is quite possible that they also resulted from sympathetic nerve catecholamine release with consequent cardiac arrhythmias and repolarization changes, which may predispose a patient to a form of cardiac damage known as myofibrillar degeneration or contraction band necrosis and possible sudden
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death. This lesion may be caused by four types of etiologies: stress plus or minus steroids, catecholamine infusion, nervous system stimulation, and reperfusion. Sympathetic overactivity with secondary catecholamine toxicity is the common factor among all four etiologies. Samuels [46] concludes that all forms of sudden death are based on the anatomic connection between the nervous system and the heart and lungs. 8. The central nervous system and cardiac and noncardiac sudden death syndromes When rats were exposed to stress, the initial stage of stress resulted in structural changes that were stereotypical cardiac contraction bands, irrespective of the type of stress factor, and differed only in terms of severity. At a later stage, contractures were gradually replaced by cytolytic injuries, which did not depend on the type of stress. In the case of the early predominance of myocytolysis in combination with excessive contracture injuries that led to rapid death, a genetically determined predisposition was proposed as an explanation [47]. The impact of emotional stressors on the autonomic nervous system ensures that psychogenic factors are important in leading to cardiac dysrhythmias and to coronary and noncoronary sudden death syndromes in humans and other species [49]. The cardiology literature assumes that there is a causal relationship among depression, stress, and increased cardiac mortality. Depression can be considered to be a state of prolonged negative arousal or mental stress associated with a measurably higher risk of fatal cardiac events. Stress can also result in histopathological changes in a previously normal heart, whereas genetically determined and/or acquired dysfunction of the opioidergic, GABAergic, cholinergic, adenosinergic, and other transmitter/modulator systems may interact to predispose to arrhythmias and sudden death [50]. The influence of psychological factors on autonomic, neuroendocrine, and immune systems is complex and not fully understood, yet these factors are known to have adverse effects on cardiac function. Westerhaus and Lowey [51] reported a common pattern of sympathetic representation in the medial prefrontal cortex, insular cortex, ventromedial temporal lobe, and ventral hippocampal region. The ventromedial temporal lobe regions studied included the central, basomedial posterior, and lateral amygdaloid transition areas and the posterior medial cortical amygdaloid nucleus. This latter anatomical substrate for sympathetic control is of considerable theoretical importance. The amygdala has an important role in the expression of emotional behaviors and is known to integrate the autonomic responses to emotional stimuli under certain conditions, particularly those related to fear and anxiety. The amygdala is important in cardiovascular control within the limbic system, having reciprocal connections with the insular cortex and direct projections to other autonomic control centers in the hypothalamus, pons, and medulla.
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Studies on fear and anxiety reactions demonstrate that the amygdala is involved in the integration of autonomic responses to emotional stimuli [52]. Limbic cortex activity associated with an emotionally charged stimulus can be associated with cardiac neural changes that may result in intense autonomic stimulation of both sympathetic and parasympathetic neurons, resulting in sudden stress-related death. It is assumed that the hypothalamic and brainstem structures are involved secondarily and that stress also may activate the hypothalamic–pituitary–adrenal axis. 9. Elevated prolactin levels as a marker of antemortem stress Elevated prolactin levels at necropsy were examined as a marker of antemortem stress [53]. However, postmortem prolactin values differed according to the cause of death, with higher values measured in postoperative deaths and in the chronically ill. In persons with epilepsy, an elevated prolactin level after seizures is used as an indicator that a seizure has actually occurred. The prolactin level is most consistently elevated after a generalized tonic–clonic seizure and is a less predictable marker of partial seizures [54]. This neuroendocrine response to seizures and the acute manifestations of autonomic dysfunction in association with seizures and interictal epileptogenic activity are evidence of stimulation of the hypothalamic–pituitary axis. Although we may take the liberty to suggest that the concurrence of autonomic and neuroendocrine dysfunction could be considered as a combined hypothalamic–pituitary-mediated stress response in association with epilepsy, its role in SUDEP is unknown and warrants further exploration. 10. Management of the patient with epilepsy and stress Lathers and Schraeder [55–57] have summarized data from studies [58–64] evaluating the incidence of SUDEP in various countries. SUDEP is a common cause of death in persons with epilepsy worldwide. The risk of SUDEP increases with increasing refractoriness of the seizure disorder. The risk of SUDEP is 24 times greater than that in the general population [65,66], with an overall incidence rate of 1:680 per year. However, this incidence rate varies to some degree with the severity of the seizure disorder, with a rate as high as 1:100 in populations most refractory to treatment [67]. Leestma et al. [68] reported that the risk of SUDEP was not a function of the type of antiepileptic drug used to treat the seizures. SUDEP rates appeared not to differ in patients receiving the new anticonvulsant drugs lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide versus the standard anticonvulsant drugs. Thus, the SUDEP rates reflect population rates and do not reflect a specific drug effect. As discussed by Homan [69], patients often associate increased stress with increased seizure activity. Interventions to reduce stress by using behavioral techniques such as biofeedback, relaxation and desensitization, and phar-
macological agents such as psychotherapeutic or benzodiazepine drugs have been recommended. Physical stress associated with elevated body temperatures induced by infection may also trigger seizures, and antipyretic drugs are recommended for use prophylactically. Adjunctive management of the patient with seizure and stress should increase the chance of improvement in the control of seizures and in the overall quality of life [70,71]. Education of patients about the importance of drug compliance and stress management techniques ultimately would decrease the need for high therapeutic antiepileptic drug levels and thus diminish the occurrence of dose-related side effects, leading to an improved lifestyle. Wannamaker and Booker [72] noted that patients with epilepsy have identified the common stressors of fear, worry, frustration, and anger as trigger factors, although the seizure event usually does not occur immediately in association with the stressful circumstance. The physician has an important role as counselor around the stress-related issues in the life of the patient. The physician needs to individualize recommendations for intervention that can include referral to a clinical psychologist with expertise in stress reduction. Efforts should be undertaken to diminish both internal and external stressors. Treatment with tranquilizers, antidepressants, or neuroleptics is often helpful to the patient in conjunction with counseling. The long-acting anxiolytics clorazepate and clonazepam also are relatively effective as antiepileptic drugs in selected patients. Paranoia, thought disorder, hallucinations, and extreme agitation require concurrent psychiatric consultation in addition to treatment with neuroleptics. Care must be exerted when managing the patient, as a rapid change in the levels of neuroleptics, high doses, or induction of drowsiness may worsen the occurrence of seizures. Nevertheless, the reduction in agitation, thought disorder, and hallucinations usually exerts a calming effect and contributes to lowering the stress level and to restoring the patient’s sense of well-being. In conclusion, we have provided an overview of the possible role of an adverse emotional state as a risk factor for sudden death in association with cardiac disease, psychiatric entities, and ethnic-associated disorders. We postulate that there is reason to consider the possibility that adverse emotional states and/or experiences may have a role in SUDEP. Stress and depression have been studied as risk factors for the syndromes of sudden death discussed above, but not for SUDEP. The lack of data about any association of adverse emotional factors with risk of SUDEP does not exclude the likelihood that such a correlation exists. We hope that this article will provide a stimulus for further investigation. References [1] Caplan LR, Hurst JW, Chimowitz MI. Cardiac and cardiovascular findings in patients with nervous system diseases. In: Caplan LR, Hurst JW, Chimowitz MI, editors. Clinical neurocardiology. New York: Marcel Dekker; 1999. p. 298–465.
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[54] Pritchar PB. Hormone changes in epilepsy. In: Engel J, Pedley T, editors. Epilepsy: a comprehensive textbook. Philadelphia, PA: Lippincott–Raven; 1997. p. 1997–2012. [chapter 188]. [55] Lathers CM, Schraeder PL. Clinical pharmacology: drugs as a benefit and/or risk in sudden unexpected death in epilepsy? J Clin Pharmacol 2002;42:123–36. [56] Lathers CM, Schraeder PL, editors. Epilepsy and sudden death. New York: Marcel Dekker; 1990. [57] Schraeder PL, Lathers CM. Cardiac neural discharge and epileptogenic activity in the cat: an animal model for unexplained death. Life Sci 1983;32:1371–82. [58] Timmings PL. Sudden expected death in epilepsy: a local audit. Seizure 1993;2:287–90. [59] Harvey AS, Nolan T, Carlin JB. Community-based study of mortality in children with epilepsy. Australia; 1993. [60] Coyle HP, Baker-Brian N, Brown SW. Coroners’ autopsy reporting of sudden unexplained death in epilepsy (SUDEP) in the UK. United Kingdom; 1994. [61] Nashef L, Fish DR, Garner S, Sander JWAS, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187–94. [62] Derby LE, Tennis P, Jick H. Sudden unexplained death among subjects with refractory epilepsy. Epilepsia 1996;37:931–5. [63] Bennani FK, Connolly CE. Sudden unexpected death in young adults including four cases of SADS: a 10-year review from the West of Ireland (1985–1994). Med Sci Law 1997;37:242–7.
[64] Evseeva ME. Stress-induced rearrangement of the myocardium: time course of structural changes in various types of stress. Bull Exp Biol Med 2000;130:937–9. [65] Ficker DM, So E, Sehn WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 1998;51:1270–4. [66] Ficker DM. Sudden unexplained death and injury in epilepsy. Epilepsia 2000;41(Suppl. 2):S7–S12. [67] Langan Y, Nolan N, Hutchinson M. The incidence of sudden unexpected death in epilepsy (SUDEP) in South Dublin and Wicklow. Ireland. Seizure 1998;7:355–8. [68] Leestma JE, Annegers JF, Brodie MJ, et al. Sudden unexplained death in epilepsy: observations from a large clinical trial. Epilepsia 1997;38:47–55. [69] Homan RW. Adjunctive and combination therapy. In: Engel Jr. J, Pedley TA, editors; Aicardi J, Dichter MA, Heinemann U, Moshe S, Porter RJ, Taylor DC, associate editors, Epilepsy. A comprehensive textbook, vol. 2. Philadelphia: Lippincott–Raven; 1998. p. 1265–74. [70] Fenwick P. The basis of behavioral treatment in seizure control. Epilepsia 1995;36:46–50. [71] Moffett A, Scott DF. Stress and epilepsy: the value of a benzodiazepine-lorazepam. J Neurol Neurosurg Psychiatry 1984;47:165–7. [72] Wannamaker BB, Booker HE. Treatment of provoked seizures. In: Engel Jr. J, Pedley TA, editors; Aicardi J, Dichter MA, Heinemann U, Moshe S, Porter RJ, Taylor DC, associate editors, Epilepsy. A comprehensive textbook, vol. 2. Philadelphia: Lippincott–Raven; 1998. p. 1311–16 [chapter 119].
Review
Stress and sudden death Claire M. Lathers a
a,*
q
, Paul L. Schraeder
b
Office of the Director, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855, USA b Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA Received 6 April 2006; revised 27 May 2006; accepted 5 June 2006 Available online 26 July 2006
Abstract Cardiac patients, psychiatric patients, and certain ethnic groups experiencing acute stressful circumstances are at risk for unexpected sudden death. Although stress is associated with changes in autonomic neural function, its role as a potential risk factor for sudden unexpected death in epilepsy (SUDEP) is not known. The association of epilepsy with cardiac abnormalities, such as neurogenic arrhythmias and microscopic perivascular and interstitial fibrosis, and with depression and anxiety indicates that emotional stress should be evaluated as a potential risk factor for SUDEP. The impact of adverse emotional states on the autonomic control of cardiac rhythm is a known important factor leading to cardiac dysrhythmias in humans and other species. The interaction between emotional factors and the arrythmogenic potential of epileptiform discharges and the possibility of benefit from stress management intervention need to be investigated. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Sudden death; Sudden unexpected death in epilepsy; Epilepsy; Cardiac disease; Psychiatric disorders; Stress; Depression
1. Introduction Sudden deaths associated with stress have been reported since antiquity [1]. The Acts of the Apostles 5:1–11 [2] describe how Ananias was charged by Peter to have ‘‘lied not to man but to God.’’ Ananias fell to the ground dead. His wife Sapphira met a similar fate when told that those who had buried her husband were at the door and planning to ‘‘carry thee out.’’ In 1942, Walter Cannon [3] cited examples from the anthropology literature of death from fright and entitled his article: ‘‘Voodoo Death.’’ Cannon discussed the role of the sympathico-adrenal system. Engle [4] collected 160 different accounts of sudden deaths due to emotional stress, finding that in most cases the circumstances were associated with extreme excitation, resignation, or despondency. Even if it is only in the form of a q
Opinions expressed are those of the authors and do not reflect opinions or policy of the FDA. * Corresponding author. Present address: 115 South Manning Boulevard, Albany, NY 12203, USA. Fax: +1 518 482 6732. E-mail address: [email protected] (C.M. Lathers). 1525-5050/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2006.06.001
mental image of pain, psychological stress can cause asystole [5]. Cardiac pathological changes reported in victims of stress-related deaths [6] have been designated myofibrillar degeneration or myocytolysis. This microscopic entity has been found to be identical to that identified in the hearts of patients who died of subarachnoid hemorrhage and other acute strokes. 2. Sudden death in certain ethnic populations Although Lown [7] noted that sudden cardiac death is the major challenge in cardiology, sudden death is also a recognized risk in certain ethnic populations [8]. For example, healthy Filipino men may experience Bangungut, an unexpected death during sleep. Bangungut means ‘‘to rise and moan during sleep.’’ Pokkuri is the term used to describe sudden cardiac deaths among apparently healthy Japanese soldiers during World War II [9]. In the case of the soldiers, warfare could produce major stresses including personal danger, mourning, extreme excitation, resignation, and despondency. Engle [4] described eight precipitating circumstances that precede sudden death: (1)
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illness or death of a close person, (2) acute grief, (3) threat of loss of a close person, (4) mourning or anniversary of a death, (5) loss of status or self-esteem, (6) personal danger or threat of injury, (7) relief from danger, and (8) reunion, triumph, or happy ending. The precipitating event was one that was impossible for the victim to ignore because it was abrupt, unexpected, or dramatic or because of its intensity, irreversibility, or persistence. Retrospective investigation of 51 cases of sudden unexplained death in non-East Asian subjects, including indigenous Saudis, between January 1995 and June 1997, revealed that most victims were subcontinent Indians (43%) [10]. Autopsies were done on 22 victims. Seven exhibited mild to moderate cardiac hypertrophy, with two of these seven also having mild to moderate coronary stenosis. Four other victims exhibited a similar degree of coronary narrowing, but had no evidence of myocardial hypertrophy. Severe pulmonary congestion and alveolar hemorrhage were detected in 18 of the 22 victims autopsied. A leading cause of death of young men in several East Asian populations is sudden and unexplained death in sleep [11]. A review of autopsy records from 1948 to 1982 in Manila was used to classify these types of deaths. A nested case–control study of death certificates examined birthplace as an indicator of risk of sudden, unexplained death in sleep. There were 722 sudden, unexpected deaths in sleep during this time. Characteristics of victims in each group were similar: 96% were male, mean age was 33, and modal time of death was 3:00 AM. The deaths were seasonal, peaking in December and January. The death rate for mean ages 25–44 increased from 10.8 to 26.3 per 100,000 person-years from 1948 to 1982, possibly because of more accurate classification of cause of death. Because the deaths appeared to be a regional phenomenon in Southeast Asia it was speculated that environmental factors were likely, as the deaths were seasonal, increased over the time span studied, and were more common among migrants to Manila than among people born there. Owada et al. [12] reported on autopsies of sudden death cases in Japan from May 1994 to February 1998. The medical records for 91 cases were reviewed, and interviews were conducted with the victims’ close family members. Of 271 cases, 176 patients 20 to 59 years old were classified as cases of sudden death in the working generation. Of the sudden death cases, 29 were due to coronary artery disease (31.9%), 18 to acute cardiac dysfunction (19.8%), 6 to other cardiac diseases (6.6%), 4 to acute aortic dissection (4.4%), 4 to cerebrovascular disease (4.4%), and 30 to other diseases (32.9%). Risk factors identified included long-term stress, history of heart disease, hypertension, chest symptoms, autonomic disturbance, short-term stress, and a smoking habit. Short-term stress, autonomic disturbance, and a smoking habit increased the risk of sudden death due to coronary artery disease. Long-term stress was associated with increased risk of sudden death due to acute cardiac dysfunction. Autonomic disturbance and stress were
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related to the occurrence of sudden death. The authors recommend that it would be helpful to identify subjective symptoms so one can intervene to relieve such stress and presumably reduce the risk of sudden death. Basso et al. [13] reported on 200 cases of sudden death in persons less than 35 years of age in the Veneto region in Italy. Fifteen cases (7.5%) were due to cerebral, 10 to respiratory (5%), and 163 to cardiovascular (81.5%) etiologies. Twelve deaths (6%) were unexplained. For cardiovascular sudden death, obstructive coronary atherosclerosis was found in 23% of the cases and arrhythmogenic right ventricular cardiomyopathy in 12.5%. Mitral valve prolapse occurred in 10%, conduction system abnormalities in 10%, and congenital coronary artery anomalies in 8.5%. Myocarditis was reported for 7.5%, hypertrophic cardiomyopathy for 5.5%, aortic rupture for 5.5%, and dilated cardiomyopathy for 5%. Nonatherosclerotic acquired coronary artery disease was reported in 3.5%, postoperative congenital heart disease in 13%, aortic stenosis in 2%, pulmonary embolism in 2%, and other causes in 2%. Sudden death was unexplained in 6% of the cases. Thus, even though a large spectrum of cardiovascular disorders appeared to be the most common organic substrate for most sudden deaths in this population, more than 1 in 20 cases of sudden death in this young adult population were not explained by structural risk factors. 3. Non-SIDS pediatric sudden unexplained death in the United States Sudden unexplained death claims more than 4000 persons between the ages of 1 and 22 each year in the United States. Almost half of the pediatric sudden death victims have a normal structural autopsy. Therefore, identification of children at risk for cardiac arrhythmias as a cause of seizurelike events and optimal seizure control measures in those at risk for seizure-related cardiac arrhythmias are possible approaches to risk reduction [14]. Many studies suggest that assessment of medical histories, in combination with cardiovascular and EEG evaluation of surviving family members, may help to clarify possible risks for various categories of sudden unexplained death [15–20]. The genetic basis for potentially fatal arrhythmia associated with the inherited long-QT syndrome (LQTS) may be a factor. For example, a 17-year-old sudden death victim’s mother was challenged with epinephrine and a potential defect in the phase 3 potassium current encoded by the gene KVLQT1 was identified. A 5-bp deletion was identified in the genetic material recovered from the decedent’s paraffin-embedded heart tissue [15]. Such isolated cases indicate that the ability to perform molecular autopsies on achieved necropsy material may transform the forensic evaluation of sudden death. The combination of catecholamine provocative testing in surviving family members and postmortem LQTS gene analysis may unmask families with ‘‘concealed’’ LQTS and establish the cause of previously unexplained sudden death, including, presumably, sudden
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unexpected death in epilepsy (SUDEP). Whether or not the presence of such a genetic defect in combination with epilepsy is a risk factor for SUDEP is unknown. As with adults, the mechanism of SUDEP in the pediatric age group is unclear, but quite possibly it is associated with seizure-related cardiac arrhythmia and/or respiratory insufficiency. Although children with epilepsy have an increased risk of death, SUDEP is rare: 1–2/10,000 patient-years versus 1/100–750 patient-years in adults. 4. The role of emotions as a seizure precipitant That emotions can act as a precipitant of seizures has been recognized since the time of Hughlings Jackson and Gowers [21]. Stress-laden events such as fear, worry, frustration, and anger are commonly associated with increased frequency of seizures [22]. Dominian et al. [23] reported that emotionally laden events preceded the first seizure occurrence in 20 of 51 patients studied. The definition of stressful events ranged from retirement after 45 years with the same organization to arrest by the Gestapo. Although the mechanisms involved in emotion-associated seizure activation are not known, multiple factors may explain the role of emotion, including activation of neural networks, sleep deprivation, noncompliance, alcohol use, and hyperventilation. However, even though there often is no immediate temporal relationship, in that the seizures do not occur at the moment that the patient has the negative emotional experience, the patient is at risk for one or more seizures. This risk is especially true for temporal lobe seizures occurring in close proximity to an emotional state [22]. Another circumstance that could increase the chance of seizure recurrence is the use of antidepressants and/or neuroleptics. Drugs in either of these groups may be necessary to treat the patients’ dysphoric symptoms, but also increase the chance of lowering the seizure threshold. Many clinical studies have demonstrated that poor seizure control is a major risk factor for SUDEP [24]. The interrelationship between an adverse emotional state and other related seizure-inducing circumstances warrants further investigation, especially because we know that there is an association between increased risk of SUDEP and poor seizure control [25]. Although the previous discussion emphasized the role of stress as a risk factor in various categories of sudden death, such a role may be compounded in the case of epilepsy. 5. Acute and chronic stress and sudden death Acute stress caused by emotions such as fear sometimes can cause sudden death in persons with coronary heart disease. Ackerman et al. [15] comment that chronic stress also may contribute to the development of coronary disease, in that it may promote the long-term development of coronary disease and recommended the routine use of stress management in standard cardiac rehabilitation programs. Interestingly, the distinction between Type A and Type B
personalities as risk correlates appears to be overly simplistic, in that the psychosocial factors depression, hostility, social isolation, anxiety, anger, and other stresses are related to increased cardiac death and illness in all groups with coronary heart disease [26]. All of these psychosocial risk factors may benefit from a biopsychosocial model of intervention. Death can result from acute stress related to disasters. For example, sudden deaths related to atherosclerotic coronary artery disease increased fivefold on the day of the Los Angeles earthquake in 1994 [27]. Acute mental stress induced experimentally has been associated with ST-segment deviation and wall-motion abnormalities [28]. Mental stress needs to be considered as a greater risk factor than exercise-induced ischemia in increasing the rate of fatal and nonfatal cardiac events [29], emphasizing again that psychosocial stress management treatment in a cardiac rehabilitation program reduces cardiac-related mortality and morbidity [30]. Distress within the family and/or stress at work are strong predictors of the development of stressrelated disorders, and also require intervention [31]. Whether we can extrapolate the preceding discussion of management of stress factors in coronary artery disease as being helpful in diminishing the risk of SUDEP is not known, but the fact that so many of these same factors come into play in persons with epilepsy makes it difficult to deny this possibility. 6. Are depression and stress risk factors for SUDEP? The well-established role of depression and stress as major risk factors in sudden cardiac death raises the question of whether the same risk may be extant in SUDEP. The epidemiological data on psychiatric morbidity in epilepsy are spotty at best. Nonetheless, having epilepsy is stress producing, and stress increases the frequency of seizures. The uncertainty of when a seizure can occur and the consequences of having a seizure on one’s employment status and driving privileges are common stress-producing circumstances with which the person with epilepsy must live. It is no surprise that depression and anxiety are common symptoms associated with epilepsy [32]. In addition to the common experience of ongoing depression and anxiety, depression may occur as a postictal phenomenon, and can be very severe. Whether this more profound depression is reactive or biologically linked to the seizure is unknown [33]. Although almost no studies of SUDEP address the possible role of emotional stress in the form of depression and/or anxiety as a risk factor, Earnest et al. [34] did comment on the role of acutely stressful circumstances as a possible contributor near the time of death in a case–control study of the metropolitan Denver area. Whether or not stress in the form of depression and/or acute or chronic anxiety is a common risk factor for SUDEP is not known. The known role of adverse emotional states as a risk for sudden cardiac death supports the need to investigate this factor more thoroughly in persons with epilepsy. The
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activation of stress-responsive systems during depressive episodes may contribute to metabolic risk factors and imbalance of the autonomic heart regulation [30,33,35]. 7. Autonomic dysfunction and sudden death Lathers and Schraeder [36] demonstrated that autonomic sympathetic and parasympathetic cardiac neuronal dysfunction is associated with interictal as well as ictal epileptiform discharges and with cardiac arrhythmias. Hilz et al. [37] observed influences on autonomic dysregulation, with predominant sympathetic overactivity, in association with interictal and epileptogenic discharges in persons with temporal lobe epilepsy. Surgical treatment for temporal lobe epilepsy resulted in a reduction of sympathetic cardiomodulation and decreased the baroreflex sensitivity, that is, a decrease in the influence of sympathetically mediated tachyarrhythmias and excessive bradycardic counterregulation. As these two factors are thought to contribute to the risk of SUDEP, the temporal lobe surgery itself appears to be one method to reduce and/or eliminate some risk factors associated with SUDEP [37,38]. In addition to the role of the sympathetic nervous system in cardiovascular regulation, parasympathetic nervous system activity also has ongoing action on the regulation of cardiac rhythm [39,40]. For example, drowning animals exhibit bradycardia prior to death [41]. Because atropine protected the animals and cholinergic drugs shortened the time to death, it was concluded that increased vagal discharge and tone preceded death. Stimulation of the vagus nerve or application of acetylcholine to the sinoatrial node slows or abolishes depolarization of sinus node fibers [42,43], whereas decreased depolarization and shifts of membrane threshold potentials change the sinoatrial node rate, causing sinus bradycardia. A similar mechanism occurs in the atrioventricular node [44]. Changes in the ECG and cardiac muscle necrosis result from stimulation of the efferent limb of the sympathetic nervous system and of the aortic arch and carotid baroreceptors involved in autonomic nervous system reflex activity [45–47]. Sympathetic stimulation causes a sudden release of norepinephrine from cardiac nerve endings into the heart muscle, leading to microscopic changes in the form of cardiac myocyte necrosis, cardiac dysfunction, and arrhythmias [42,43]. Stimulation of cardiac sympathetic nerves accelerates sinoatrial depolarizations and shortens the cycle length of firing of the sinus node. More recently, Natelson et al. [48] studied the hearts of persons with epilepsy who died suddenly and found pathological changes in the form of irreversible perivascular and interstitial fibrosis and myocyte vacuolization. As these lesions occurred mostly in the subendocardium, it is quite possible that they also resulted from sympathetic nerve catecholamine release with consequent cardiac arrhythmias and repolarization changes, which may predispose a patient to a form of cardiac damage known as myofibrillar degeneration or contraction band necrosis and possible sudden
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death. This lesion may be caused by four types of etiologies: stress plus or minus steroids, catecholamine infusion, nervous system stimulation, and reperfusion. Sympathetic overactivity with secondary catecholamine toxicity is the common factor among all four etiologies. Samuels [46] concludes that all forms of sudden death are based on the anatomic connection between the nervous system and the heart and lungs. 8. The central nervous system and cardiac and noncardiac sudden death syndromes When rats were exposed to stress, the initial stage of stress resulted in structural changes that were stereotypical cardiac contraction bands, irrespective of the type of stress factor, and differed only in terms of severity. At a later stage, contractures were gradually replaced by cytolytic injuries, which did not depend on the type of stress. In the case of the early predominance of myocytolysis in combination with excessive contracture injuries that led to rapid death, a genetically determined predisposition was proposed as an explanation [47]. The impact of emotional stressors on the autonomic nervous system ensures that psychogenic factors are important in leading to cardiac dysrhythmias and to coronary and noncoronary sudden death syndromes in humans and other species [49]. The cardiology literature assumes that there is a causal relationship among depression, stress, and increased cardiac mortality. Depression can be considered to be a state of prolonged negative arousal or mental stress associated with a measurably higher risk of fatal cardiac events. Stress can also result in histopathological changes in a previously normal heart, whereas genetically determined and/or acquired dysfunction of the opioidergic, GABAergic, cholinergic, adenosinergic, and other transmitter/modulator systems may interact to predispose to arrhythmias and sudden death [50]. The influence of psychological factors on autonomic, neuroendocrine, and immune systems is complex and not fully understood, yet these factors are known to have adverse effects on cardiac function. Westerhaus and Lowey [51] reported a common pattern of sympathetic representation in the medial prefrontal cortex, insular cortex, ventromedial temporal lobe, and ventral hippocampal region. The ventromedial temporal lobe regions studied included the central, basomedial posterior, and lateral amygdaloid transition areas and the posterior medial cortical amygdaloid nucleus. This latter anatomical substrate for sympathetic control is of considerable theoretical importance. The amygdala has an important role in the expression of emotional behaviors and is known to integrate the autonomic responses to emotional stimuli under certain conditions, particularly those related to fear and anxiety. The amygdala is important in cardiovascular control within the limbic system, having reciprocal connections with the insular cortex and direct projections to other autonomic control centers in the hypothalamus, pons, and medulla.
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Studies on fear and anxiety reactions demonstrate that the amygdala is involved in the integration of autonomic responses to emotional stimuli [52]. Limbic cortex activity associated with an emotionally charged stimulus can be associated with cardiac neural changes that may result in intense autonomic stimulation of both sympathetic and parasympathetic neurons, resulting in sudden stress-related death. It is assumed that the hypothalamic and brainstem structures are involved secondarily and that stress also may activate the hypothalamic–pituitary–adrenal axis. 9. Elevated prolactin levels as a marker of antemortem stress Elevated prolactin levels at necropsy were examined as a marker of antemortem stress [53]. However, postmortem prolactin values differed according to the cause of death, with higher values measured in postoperative deaths and in the chronically ill. In persons with epilepsy, an elevated prolactin level after seizures is used as an indicator that a seizure has actually occurred. The prolactin level is most consistently elevated after a generalized tonic–clonic seizure and is a less predictable marker of partial seizures [54]. This neuroendocrine response to seizures and the acute manifestations of autonomic dysfunction in association with seizures and interictal epileptogenic activity are evidence of stimulation of the hypothalamic–pituitary axis. Although we may take the liberty to suggest that the concurrence of autonomic and neuroendocrine dysfunction could be considered as a combined hypothalamic–pituitary-mediated stress response in association with epilepsy, its role in SUDEP is unknown and warrants further exploration. 10. Management of the patient with epilepsy and stress Lathers and Schraeder [55–57] have summarized data from studies [58–64] evaluating the incidence of SUDEP in various countries. SUDEP is a common cause of death in persons with epilepsy worldwide. The risk of SUDEP increases with increasing refractoriness of the seizure disorder. The risk of SUDEP is 24 times greater than that in the general population [65,66], with an overall incidence rate of 1:680 per year. However, this incidence rate varies to some degree with the severity of the seizure disorder, with a rate as high as 1:100 in populations most refractory to treatment [67]. Leestma et al. [68] reported that the risk of SUDEP was not a function of the type of antiepileptic drug used to treat the seizures. SUDEP rates appeared not to differ in patients receiving the new anticonvulsant drugs lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide versus the standard anticonvulsant drugs. Thus, the SUDEP rates reflect population rates and do not reflect a specific drug effect. As discussed by Homan [69], patients often associate increased stress with increased seizure activity. Interventions to reduce stress by using behavioral techniques such as biofeedback, relaxation and desensitization, and phar-
macological agents such as psychotherapeutic or benzodiazepine drugs have been recommended. Physical stress associated with elevated body temperatures induced by infection may also trigger seizures, and antipyretic drugs are recommended for use prophylactically. Adjunctive management of the patient with seizure and stress should increase the chance of improvement in the control of seizures and in the overall quality of life [70,71]. Education of patients about the importance of drug compliance and stress management techniques ultimately would decrease the need for high therapeutic antiepileptic drug levels and thus diminish the occurrence of dose-related side effects, leading to an improved lifestyle. Wannamaker and Booker [72] noted that patients with epilepsy have identified the common stressors of fear, worry, frustration, and anger as trigger factors, although the seizure event usually does not occur immediately in association with the stressful circumstance. The physician has an important role as counselor around the stress-related issues in the life of the patient. The physician needs to individualize recommendations for intervention that can include referral to a clinical psychologist with expertise in stress reduction. Efforts should be undertaken to diminish both internal and external stressors. Treatment with tranquilizers, antidepressants, or neuroleptics is often helpful to the patient in conjunction with counseling. The long-acting anxiolytics clorazepate and clonazepam also are relatively effective as antiepileptic drugs in selected patients. Paranoia, thought disorder, hallucinations, and extreme agitation require concurrent psychiatric consultation in addition to treatment with neuroleptics. Care must be exerted when managing the patient, as a rapid change in the levels of neuroleptics, high doses, or induction of drowsiness may worsen the occurrence of seizures. Nevertheless, the reduction in agitation, thought disorder, and hallucinations usually exerts a calming effect and contributes to lowering the stress level and to restoring the patient’s sense of well-being. In conclusion, we have provided an overview of the possible role of an adverse emotional state as a risk factor for sudden death in association with cardiac disease, psychiatric entities, and ethnic-associated disorders. We postulate that there is reason to consider the possibility that adverse emotional states and/or experiences may have a role in SUDEP. Stress and depression have been studied as risk factors for the syndromes of sudden death discussed above, but not for SUDEP. The lack of data about any association of adverse emotional factors with risk of SUDEP does not exclude the likelihood that such a correlation exists. We hope that this article will provide a stimulus for further investigation. References [1] Caplan LR, Hurst JW, Chimowitz MI. Cardiac and cardiovascular findings in patients with nervous system diseases. In: Caplan LR, Hurst JW, Chimowitz MI, editors. Clinical neurocardiology. New York: Marcel Dekker; 1999. p. 298–465.
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