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Increased prevalence of temporary cardiac pacing in people with epilepsy
Seizure 21 (2012) 518–521
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Increased prevalence of temporary cardiac pacing in people with epilepsy Umer Akbar a,*, Fred Rincon a, Melissa Carran a, Joseph Campellone a, Barry Milcarek b, Evren Burakgazi a a b
Department of Neurology, UMDNJ/Cooper University Hospital, Camden, NJ, USA Department of Biostatistics, UMDNJ/Cooper University Hospital, Camden, NJ, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 September 2011 Received in revised form 16 May 2012 Accepted 18 May 2012
Introduction: Even though ictal tachyarrhythmias are more common, ictal brady-asystole is more likely to be fatal, and yet is potentially preventable with pacemaker (PM) implantation. We sought to quantify the degree of association of PM placement in people with and without epilepsy, including neurological and cardiovascular cohorts. Methods: Retrospective cross-sectional analysis of the National Hospital Discharge database using International Classification of Diseases Clinical Modification (ICD-9-CM) codes. We identified people with and without epilepsy between 1990 and 2006. The epilepsy cohort was compared to patients without epilepsy and other cardiovascular and central nervous system (CNS) disease cohorts. Results: People with epilepsy had higher odds of temporary PM (TPM; OR 1.6) than patients without epilepsy, especially amongst males (OR 2.0), young- (OR 4.6) and middle-aged (OR 4.3) patients. The epilepsy cohort had significantly higher odds of TPM than demyelinating disease (OR 7.9) and migraine (OR 9.1) cohorts. Compared to stroke, people with epilepsy had higher odds of TPM in the male (OR 1.6) and middle-age (OR 2.4) subgroups. No significant association was seen with permanent PM (PPM). Conclusions: Our study demonstrates the high likelihood of TPM placement in epilepsy patients as compared to cohorts without epilepsy. Significant associations were seen especially in males and youngand middle-aged patients. Since demyelinating and migraine cohorts are somewhat similar to epilepsy patients in age and sex characteristics, the higher odds of TPM in epilepsy patients may be related to the disease mechanism causing brady-asystole; however this requires further study. Published by Elsevier Ltd on behalf of British Epilepsy Association.
Keywords: Asystole Bradycardia Bradyarrhythmia Complete heart block Ictal arrhythmias Cardiac pacemaker
1. Introduction Cardiac and hemodynamic abnormalities following brain injury are not uncommon,1–4 but the exact mechanisms are poorly understood.5 Some experimental and clinical observations have drawn attention to the insular cortex, which appears to be a locus of autonomic and cardiac control.4,6–9 Cingulate gyrus, amygdala and orbitofrontal cortices have also been implicated in control of autonomic function.5,10–12 Any brain injury, whether focal or diffuse, resulting from infection, trauma, mass, ischemia, hemorrhage or seizures, has been linked to cardiac dysfunction.1–3,13 Although the mechanism of a previously poorly understood phenomenon, sudden unexpected death in epilepsy (SUDEP) is thought to be multifactorial, inappropriate response of the autonomic nervous system,
* Corresponding author at: Department of Neurology, UMDNJ/Cooper University Hospital, 3 Cooper Plaza, Suite 320, Camden, NJ 08103, USA. Tel.: +1 856 342 2445; fax: +1 856 964 0504. E-mail address: [email protected] (U. Akbar).
including intra-ictal bradyrhythmias is one of the presumed culprits.6,7,14 While sinus tachycardia is the most common intra-ictal arrhythmia, bradyarrhythmias and asystole are more likely to be fatal, and yet are potentially preventable. There are no established guidelines for treating and preventing ictal bradyarrhythmias, but anecdotal reports of permanent pacemaker (PPM) placement have shown benefit in preventing sudden collapse and injury.15–17 To date, the risk of PM placement in epilepsy patients has not been studied. Thus, we sought to evaluate if epilepsy patients have increased odds of PM placement as compared to patients in other CNS and cardiovascular disease categories. 2. Methods We performed a cross-sectional analysis of the National Hospital Discharge Survey (NHDS), a database of discharges from approximately 500 nonfederal short-term hospitals throughout the 50 states. Data was reviewed from 1990 to 2006 using the International Classification of Diseases Clinical Modification (ICD-9-CM) and procedure codes to identify the number of discharges with and without epilepsy (345–345.9),
1059-1311/$ – see front matter . Published by Elsevier Ltd on behalf of British Epilepsy Association. http://dx.doi.org/10.1016/j.seizure.2012.05.007
Table 1 The odds of PM placement in epilepsy cohort vs. comparison groups. (Odds ratio (OR) >1 = higher odds of PM with epilepsy than comparison group, <1 epilepsy has lower odds, 1 = no difference). Bold highlights = epilepsy cohort has higher odds of PM placement compared to the disease listed. C = combined PM (either PM), PPM = permanent PM, TPM = temporary PM.
PM PPM TPM Male – PM
Male – TPM Female – PM Female – PPM Female – TPM <33 – PM <33 – PPM <33 – TPM 33–66 – PM 33–66 – PPM 33–66 – TPM 67–99 – PM 67–99 – PPM 67–99 – TPM
Epilepsy vs. inflammatory diseases
Epilepsy vs. hereditary/ degenerative diseases
Epilepsy vs. demyelinating diseases
Epilepsy vs. migraines
Epilepsy vs. PNS disorders
Epilepsy vs. stroke
Epilepsy vs. acute/subacute CAD
Epilepsy vs. chronic CAD
0.40 (0.39–0.42) 0.20 (0.19–0.22) 1.63 (1.55–1.70) 0.36 (0.34–0.37) 0.09 (0.08–0.10) 2.05 (1.94–2.16) 0.43 (0.41–0.45) 0.34 (0.32–0.36) 0.96 (0.88–1.06) 1.53 (1.38–1.70) 0.58 (0.47–0.70) 4.58 (4.05–5.18) 1.10 (1.04–1.15) 0.32 (0.29–0.36) 4.28 (4.03–4.53) 0.36 (0.34–0.38) 0.30 (0.28–0.32) 0.82 (0.74–0.91)
4.26 (3.75–4.85) 2.26 (1.95–2.61) 13.66 (10.13–18.43) 10.25 (7.97–13.19) 7.01 (4.42–11.14) 11.65 (8.63–15.73) 2.34 (2.01–2.72) 1.59 (1.36–1.86)
0.29 (0.28–0.30) 0.14 (0.13–0.14) 1.97 (1.86–2.08) 0.31 (0.30–0.33) 0.07 (0.06–0.08) 2.83 (2.64–3.03) 0.26 (0.250–0.28) 0.19 (0.18–0.21) 1.07 (0.97–1.18) 5.52 (4.09–7.46) 1.58 (1.12–2.22)
1.45 (1.36–1.54) 0.70 (0.65–0.76) 7.90 (6.67–9.36)
1.90 (1.79–2.01) 0.94 (0.87–1.08) 9.10 (7.93–10.43) 11.80 (9.23–15.10) 2.44 (1.87–3.17)
0.23 (0.22–0.24) 0.12 (0.11–0.13) 0.94 (0.90–0.99) 0.30 (0.29–0.32) 0.07 (0.06–0.08) 1.61 (1.51–1.70) 0.19 (0.18–0.20) 0.15 (0.14–0.16) 0.45 (0.41–0.50)
5.27 (3.91–7.10) 1.50 (1.07–2.11)
0.40 (0.39–0.42) 0.20 (0.19–0.21) 1.81 (1.70–1.94) 0.47 (0.44–0.49) 0.11 (0.10–0.12) 4.15 (3.74–4.60) 0.35 (0.33–0.37) 0.28 (0.26–0.30) 0.74 (0.67–0.83) 0.13 (0.12–0.15) 0.04 (0.03–0.05)
2.57 (2.39–2.77) 0.75 (0.66–0.84)
1.55 (1.45–1.65) 0.41 (0.37–0.46)
0.73 (0.66–0.81)
0.55 (0.52–0.59) 0.46 (0.43–0.50)
0.93 (0.88–0.98) 0.31 (0.28–0.35) 2.37 (2.21–2.56) 0.45 (0.43–0.48) 0.37 (0.35–0.39) 1.04 (0.93–1.16)
0.09 (0.08–0.10) 0.11 (0.10–0.12) 0.08 (0.07–0.09) 0.09 (0.09–0.10) 0.06 (0.05–0.07) 0.11 (0.10–0.12) 0.08 (0.07–0.09) 0.15 (0.14–0.16) 0.04 (0.03–0.05) 0.07 (0.06–0.09) 0.04 (0.03–0.05) 0.12 (0.10–0.14) 0.17 (0.16–0.18) 0.22 (0.20–0.24) 0.16 (0.15–0.17) 0.19 (0.18–0.20) 0.33 (0.31–0.35) 0.09 (0.080–0.10)
0.11 (0.10–0.12) 0.07 (0.06–0.08) 0.22 (0.21–0.23) 0.11 (0.10–0.12) 0.03 (0.02–0.04) 0.31 (0.30–0.33) 0.11 (0.10–0.12) 0.10 (0.09–0.11) 0.13 (0.12–0.14) 0.03 (0.02–0.04) 0.04 (0.03–0.05) 0.03 (0.02–0.03) 0.22 (0.21–0.23) 0.09 (0.08–0.10) 0.36 (0.34–0.38) 0.24 (0.22–0.25) 0.22 (0.20–0.23) 0.30 (0.27–0.34)
0.61 (0.57–0.64) 0.15 (0.14–0.17)
0.62 (0.58–0.65) 0.48 (0.45–0.52) 1.001 (1.001–1.001)
1.45 (1.35–1.55) 1.12 (1.04–1.22)
U. Akbar et al. / Seizure 21 (2012) 518–521
Male – PPM
Epilepsy vs. non-epilepsy
519
520
U. Akbar et al. / Seizure 21 (2012) 518–521
PPM (37.8–37.83, 0050–52) and temporary PM (TPM, 37.78), as primary or secondary diagnoses. Prevalence odds ratios (OR) and 95% confidence intervals (CI) were then calculated. The OR of PM placement in epilepsy patients were compared to other cardiac and CNS disease groups including: acute/subacute coronary artery disease (CAD; 410, 411), chronic CAD (412, 414), and stroke (430, 431, 433), inflammatory CNS disorders (320–325), hereditary/degenerative disorders (330–337), demyelinating diseases (340–341), migraines (346) and peripheral nervous system (PNS) disorders (350–359). Both hemorrhagic and ischemic strokes were included. Mantel–Haenszel test was used to analyze one subgroup variable (age, sex) at a time. Age was divided into young (<33 years), middle (34–66) and old (67–99). Data were selected from a sub-sample, in which all subjects had one or more disease of interest among the discharge orders. Analysis was not restricted to primary diagnosis. Patients who had PM placement with multiple diagnoses (i.e. epilepsy and migraines) were included under both disease categories, as the indication for PM placement could not be determined from the database. Since a de-identified, publicly available database was utilized, institutional review was waived by the board. To validate the accuracy of ICD-9 codes for epilepsy and pacemaker placement, medical records of random patients with ICD-9 codes of 345–345.9, 37.8–37.83, 0050–52 and 37.78 admitted to our hospital were selected and reviewed. The positive predictive value for these codes was 79%. 3. Results A total of 547,853,302 patient records were analyzed including 2,213,657 admitted with a diagnosis of epilepsy (Table 1). Compared to patients without epilepsy, the epilepsy cohort had higher odds of TPM (OR 1.6) especially in males (OR 2.0) and young- and middle-age patients (OR 4.6 and 4.3, respectively). Compared to inflammatory diseases, epilepsy patients had higher odds of PM, PPM and significantly higher TPM placement, especially in males. Compared to hereditary and degenerative diseases, TPM was more likely in the general epilepsy population (OR 2.0) and male patients with epilepsy in particular (OR 2.8). Compared to demyelinating diseases, the epilepsy cohort had higher odds of PM (OR 1.4), which can be expected as a result of the significantly higher odds of TPM placement (OR 7.9). A similar relationship was seen in patients with migraine disorders (OR 9.1). Compared to patients with stroke, male and middle-age patients with epilepsy had higher odds of TPM (OR 1.6 and 2.4). The epilepsy cohort did not have higher odds of either device placement in any subgroup compared to coronary artery disease cohorts. 4. Discussion As cardiac and hemodynamic derangements may result from excitation of various central autonomic centers,1,4,6,17–21 pacemaker placement may theoretically prevent bradyarrhythmiarelated sudden death in epilepsy patients. We found that compared to the general patient population, epilepsy patients had higher odds of having a TPM, males more likely than females, and young (<33) and middle (33–66) aged more likely than the elderly (67–99). This general comparison, as well as the specific comparisons made with other cohorts, reiterates that PM placement is an age-dependent risk. No significant association with PPM was seen in comparison to the general patient population, highlighting the transient and self-limited nature of peri-ictal bradyarrhythmias. If these bradyarrhythmias were persistent or recurrent, these patients would likely receive PPMs, as many may have. Additionally, epilepsy patients had higher
odds of PM placement than patients with migraine and demyelinating diseases; two categories which are somewhat comparable to epilepsy in age and sex demographics. This relationship was significantly stronger with the temporary device. Furthermore, people with epilepsy had greater odds of TPM placement than any other CNS disorder excluding stroke, indicating that the mechanism of intracranial pathology, not just the presence of such, is associated with bradyarrhythmias requiring PM placement. Concomitant CAD prevalent in stroke patients confounds the relationship of stroke and PM, since CAD patients may be more likely to be implanted with a PM. Nevertheless, males with epilepsy, as well as the 33–66 age group, had higher odds of TPM than stroke patients. Although previous studies have reported dysrhythmias associated with seizures and epilepsy,21–23 the risk of device-dependence has not been studied at a large scale. After analyzing electrocardiograms (EKGs) of 26 patients with temporal lobe epilepsy, Blumhardt et al. found that 42% of patients had ictal cardiac arrhythmias.23 Tachyarrhythmias occur more commonly than bradyarrhythmias, perhaps because of the increased adrenergic output caused by the epileptic activity, as demonstrated in animal studies.24 Occasionally, bradyarrhythmias are severe enough to cause asystole and cardiac arrest. Several cases have demonstrated ictal and peri-ictal bradycardia and asystole, some requiring PPM placement.15,16,20 A larger cohort of 1244 patients who underwent long-term video-EEG monitoring studied retrospectively showed that five patients (0.4%) had ictal asystole, with 11 asystolic events over a total of 19 seizures.21 All seizures were of focal onset. Other large studies showed ictal asystole occurred in 2 of 589 patients (0.34%)25 and 10 of 2754 (0.27%).26 With refractory focal epilepsies, 20 patients were implanted with loop recorders and studied prospectively.27 Episodes of ictal-bradycardia and asystole were recorded in 7 patients (35%) during an 18 months mean observation period. Recently, among 6326 patients with focal epilepsies studied, 16 patients (0.25%) had at least one bradyasystolic event.28 7 patients were implanted with a PPM, 2 underwent surgery and all were continued on optimal antiepileptic regimen. All patients with seizure-related falls and injuries who were treated with a PPM became fall-free, even though some continued to have seizures. Bradyarrhthymias associated with epilepsy are known to be transient, occurring in the peri-ictal period.27,28 Thus it is plausible that some hospitalized patients would require a temporary pacemaker but not a PPM. In fact, this may explain the significant differences between the epilepsy group and other cohorts studied. Furthermore, much of our understanding of the role of cardiac arrhythmias in SUDEP developed in the mid-to-late 1990s, and significant emphasis on spreading awareness had not occurred till few years later. It is conceivable that lack of such data may have resulted in implantation of temporary devices in the absence of established literature indicating recurrence of peri-ictal arrhythmias.21 Study limitations of note include reliance on the accuracy of discharge diagnosis (ICD-9-CM) codes. Although mis-coding is possible, it is unlikely to be a common occurrence among thousands of physicians in several hundred hospitals. Our validation of the code accuracy yielded an acceptable positive predictive value. The lack of clinical data about epilepsy syndrome classification, degree of seizure control and antiepileptic regimen in the epilepsy cohort precludes further analysis. These facts have shown to be related to SUDEP.14 Additionally, due to the retrospective nature of our study and the use of an administrative database which is primarily compiled for billing purposes, causality cannot be established. However, in comparison to other CNS disorders with similar epidemiology, we found significant differences, especially in younger age groups.
U. Akbar et al. / Seizure 21 (2012) 518–521
5. Conclusion Our study provides valuable information to physicians and patients in understanding the risk of bradyarrhythmias and potential need for PM placement to prevent sudden falls. Epilepsy was more likely associated with TPM placement compared to people without epilepsy and cohorts of other CNS disorders. This was especially true amongst young- and middle-aged patients. Such association was not seen with PPM, attesting to the transient nature of ictal brady-asystole. Due to lack of sufficient evidence for prophylactic PM placement to prevent recurrent falls, injuries and potentially SUDEP,14 further research is needed to identify risk factors for fatal bradyarrhythmias in epilepsy patients in whom permanent device implantation may be considered. Funding None. Conflicts of interest None of the authors has any conflict of interest to disclose. Acknowledgments None. References 1. Greenhoot JH, Reichenbach DD. Cardiac injury and subarachnoid hemorrhage. A clinical, pathological, and physiological correlation. Journal of Neurosurgery 1969;30(5):521–31. 2. Norris JW, Froggatt GM, Hachinski VC. Cardiac arrhythmias in acute stroke. Stroke 1978;9(4):392–6. 3. Oppenheimer SM, Hachinski VC. The cardiac consequences of stroke. Neurologic Clinics 1992;10(1):167–76. 4. Christensen H, Boysen G, Christensen AF, Johannesen HH. Insular lesions ECG abnormalities, and outcome in acute stroke. Journal of Neurology Neurosurgery and Psychiatry 2005;76(2):269–71. 5. Oppenheimer S. The anatomy and physiology of cortical mechanisms of cardiac control. Stroke 1993;24(12 Suppl.):I3–5. 6. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death? Brain Research 1991;550(1):115–21. 7. Cheung RT, Hachinski V. The insula and cerebrogenic sudden death. Archives of Neurology 2000;57(12):1685–8.
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8. Oppenheimer S. The insular cortex and the pathophysiology of strokeinduced cardiac changes. Canadian Journal of Neurological Sciences 1992;19(2):208–11. 9. Laowattana S, Zeger SL, Lima JA, Goodman SN, Wittstein IS, Oppenheimer SM. Left insular stroke is associated with adverse cardiac outcome. Neurology 2006;66(4):477–83. discussion 463. 10. Britton JW, Ghearing GR, Benarroch EE, Cascino GD. The ictal bradycardia syndrome: localization and lateralization. Epilepsia 2006;47(4):737–44. 11. Leung H, Kwan P, Elger CE. Finding the missing link between ictal bradyarrhythmia, ictal asystole, and sudden unexpected death in epilepsy. Epilepsy and Behavior 2006;9(1):19–30. 12. Leung H, Schindler K, Kwan P, Elger C. Asystole induced by electrical stimulation of the left cingulate gyrus. Epileptic Disorders 2007;9(1): 77–81. 13. Hersch C. Electrocardiographic changes in subarachnoid haemorrhage meningitis, and intracranial space-occupying lesions. British Heart Journal 1964;26:785–93. 14. So NK, Sperling MR. Ictal asystole and SUDEP. Neurology 2007;69(5): 423–4. 15. Mondon K, Charbonnier B, Hommet C, Corcia P, Autret A, de Toffol B. Ictal bradycardia followed by cardiac asystole: a case report. Epileptic Disorders 2002;4(4):261–4. 16. Strzelczyk A, Bauer S, Knake S, Oertel WH, Hamer HM, Rosenow F. Ictal asystole in temporal lobe epilepsy before and after pacemaker implantation. Epileptic Disorders 2008;10(1):39–44. 17. Surges R, Scott CA, Walker MC. Peri-ictal atrioventricular conduction block in a patient with a lesion in the left insula: case report and review of the literature. Epilepsy and Behavior 2009;16(2):347–9. 18. Kiok MC, Terrence CF, Fromm GH, Lavine S. Sinus arrest in epilepsy. Neurology 1986;36(1):115–6. 19. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42(9):1727–32. 20. Phizackerley PJ, Poole EW, Whitty CW. Sino-auricular heart block as an epileptic manifestation; a case report. Epilepsia 1954;3:89–91. 21. Rocamora R, Kurthen M, Lickfett L, Von Oertzen J, Elger CE. Cardiac asystole in epilepsy: clinical and neurophysiologic features. Epilepsia 2003;44(2): 179–85. 22. Baumgartner C, Lurger S, Leutmezer F. Autonomic symptoms during epileptic seizures. Epileptic Disorders 2001;3(3):103–16. 23. Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986;1(8489):1051–6. 24. Reis DJ, Oliphant MC. Bradycardia and tachycardia following electrical stimulation of the amygdaloid region in monkey. Journal of Neurophysiology 1964;27:893–912. 25. Schuele SU, Bermeo AC, Alexopoulos AV, Locatelli ER, Burgess RC, Dinner DS, et al. Video-electrographic and clinical features in patients with ictal asystole. Neurology 2007;69(5):434–41. 26. Scott CA, Fish DR. Cardiac asystole in partial seizures. Epileptic Disorders 2000;2(2):89–92. 27. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet 2004;364(9452):2212–9. 28. Strzelczyk A, Cenusa M, Bauer S, Hamer HM, Mothersill IW, Grunwald T, et al. Management and long-term outcome in patients presenting with ictal asystole or bradycardia. Epilepsia 2011;52(6):1160–7.
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Increased prevalence of temporary cardiac pacing in people with epilepsy Umer Akbar a,*, Fred Rincon a, Melissa Carran a, Joseph Campellone a, Barry Milcarek b, Evren Burakgazi a a b
Department of Neurology, UMDNJ/Cooper University Hospital, Camden, NJ, USA Department of Biostatistics, UMDNJ/Cooper University Hospital, Camden, NJ, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 September 2011 Received in revised form 16 May 2012 Accepted 18 May 2012
Introduction: Even though ictal tachyarrhythmias are more common, ictal brady-asystole is more likely to be fatal, and yet is potentially preventable with pacemaker (PM) implantation. We sought to quantify the degree of association of PM placement in people with and without epilepsy, including neurological and cardiovascular cohorts. Methods: Retrospective cross-sectional analysis of the National Hospital Discharge database using International Classification of Diseases Clinical Modification (ICD-9-CM) codes. We identified people with and without epilepsy between 1990 and 2006. The epilepsy cohort was compared to patients without epilepsy and other cardiovascular and central nervous system (CNS) disease cohorts. Results: People with epilepsy had higher odds of temporary PM (TPM; OR 1.6) than patients without epilepsy, especially amongst males (OR 2.0), young- (OR 4.6) and middle-aged (OR 4.3) patients. The epilepsy cohort had significantly higher odds of TPM than demyelinating disease (OR 7.9) and migraine (OR 9.1) cohorts. Compared to stroke, people with epilepsy had higher odds of TPM in the male (OR 1.6) and middle-age (OR 2.4) subgroups. No significant association was seen with permanent PM (PPM). Conclusions: Our study demonstrates the high likelihood of TPM placement in epilepsy patients as compared to cohorts without epilepsy. Significant associations were seen especially in males and youngand middle-aged patients. Since demyelinating and migraine cohorts are somewhat similar to epilepsy patients in age and sex characteristics, the higher odds of TPM in epilepsy patients may be related to the disease mechanism causing brady-asystole; however this requires further study. Published by Elsevier Ltd on behalf of British Epilepsy Association.
Keywords: Asystole Bradycardia Bradyarrhythmia Complete heart block Ictal arrhythmias Cardiac pacemaker
1. Introduction Cardiac and hemodynamic abnormalities following brain injury are not uncommon,1–4 but the exact mechanisms are poorly understood.5 Some experimental and clinical observations have drawn attention to the insular cortex, which appears to be a locus of autonomic and cardiac control.4,6–9 Cingulate gyrus, amygdala and orbitofrontal cortices have also been implicated in control of autonomic function.5,10–12 Any brain injury, whether focal or diffuse, resulting from infection, trauma, mass, ischemia, hemorrhage or seizures, has been linked to cardiac dysfunction.1–3,13 Although the mechanism of a previously poorly understood phenomenon, sudden unexpected death in epilepsy (SUDEP) is thought to be multifactorial, inappropriate response of the autonomic nervous system,
* Corresponding author at: Department of Neurology, UMDNJ/Cooper University Hospital, 3 Cooper Plaza, Suite 320, Camden, NJ 08103, USA. Tel.: +1 856 342 2445; fax: +1 856 964 0504. E-mail address: [email protected] (U. Akbar).
including intra-ictal bradyrhythmias is one of the presumed culprits.6,7,14 While sinus tachycardia is the most common intra-ictal arrhythmia, bradyarrhythmias and asystole are more likely to be fatal, and yet are potentially preventable. There are no established guidelines for treating and preventing ictal bradyarrhythmias, but anecdotal reports of permanent pacemaker (PPM) placement have shown benefit in preventing sudden collapse and injury.15–17 To date, the risk of PM placement in epilepsy patients has not been studied. Thus, we sought to evaluate if epilepsy patients have increased odds of PM placement as compared to patients in other CNS and cardiovascular disease categories. 2. Methods We performed a cross-sectional analysis of the National Hospital Discharge Survey (NHDS), a database of discharges from approximately 500 nonfederal short-term hospitals throughout the 50 states. Data was reviewed from 1990 to 2006 using the International Classification of Diseases Clinical Modification (ICD-9-CM) and procedure codes to identify the number of discharges with and without epilepsy (345–345.9),
1059-1311/$ – see front matter . Published by Elsevier Ltd on behalf of British Epilepsy Association. http://dx.doi.org/10.1016/j.seizure.2012.05.007
Table 1 The odds of PM placement in epilepsy cohort vs. comparison groups. (Odds ratio (OR) >1 = higher odds of PM with epilepsy than comparison group, <1 epilepsy has lower odds, 1 = no difference). Bold highlights = epilepsy cohort has higher odds of PM placement compared to the disease listed. C = combined PM (either PM), PPM = permanent PM, TPM = temporary PM.
PM PPM TPM Male – PM
Male – TPM Female – PM Female – PPM Female – TPM <33 – PM <33 – PPM <33 – TPM 33–66 – PM 33–66 – PPM 33–66 – TPM 67–99 – PM 67–99 – PPM 67–99 – TPM
Epilepsy vs. inflammatory diseases
Epilepsy vs. hereditary/ degenerative diseases
Epilepsy vs. demyelinating diseases
Epilepsy vs. migraines
Epilepsy vs. PNS disorders
Epilepsy vs. stroke
Epilepsy vs. acute/subacute CAD
Epilepsy vs. chronic CAD
0.40 (0.39–0.42) 0.20 (0.19–0.22) 1.63 (1.55–1.70) 0.36 (0.34–0.37) 0.09 (0.08–0.10) 2.05 (1.94–2.16) 0.43 (0.41–0.45) 0.34 (0.32–0.36) 0.96 (0.88–1.06) 1.53 (1.38–1.70) 0.58 (0.47–0.70) 4.58 (4.05–5.18) 1.10 (1.04–1.15) 0.32 (0.29–0.36) 4.28 (4.03–4.53) 0.36 (0.34–0.38) 0.30 (0.28–0.32) 0.82 (0.74–0.91)
4.26 (3.75–4.85) 2.26 (1.95–2.61) 13.66 (10.13–18.43) 10.25 (7.97–13.19) 7.01 (4.42–11.14) 11.65 (8.63–15.73) 2.34 (2.01–2.72) 1.59 (1.36–1.86)
0.29 (0.28–0.30) 0.14 (0.13–0.14) 1.97 (1.86–2.08) 0.31 (0.30–0.33) 0.07 (0.06–0.08) 2.83 (2.64–3.03) 0.26 (0.250–0.28) 0.19 (0.18–0.21) 1.07 (0.97–1.18) 5.52 (4.09–7.46) 1.58 (1.12–2.22)
1.45 (1.36–1.54) 0.70 (0.65–0.76) 7.90 (6.67–9.36)
1.90 (1.79–2.01) 0.94 (0.87–1.08) 9.10 (7.93–10.43) 11.80 (9.23–15.10) 2.44 (1.87–3.17)
0.23 (0.22–0.24) 0.12 (0.11–0.13) 0.94 (0.90–0.99) 0.30 (0.29–0.32) 0.07 (0.06–0.08) 1.61 (1.51–1.70) 0.19 (0.18–0.20) 0.15 (0.14–0.16) 0.45 (0.41–0.50)
5.27 (3.91–7.10) 1.50 (1.07–2.11)
0.40 (0.39–0.42) 0.20 (0.19–0.21) 1.81 (1.70–1.94) 0.47 (0.44–0.49) 0.11 (0.10–0.12) 4.15 (3.74–4.60) 0.35 (0.33–0.37) 0.28 (0.26–0.30) 0.74 (0.67–0.83) 0.13 (0.12–0.15) 0.04 (0.03–0.05)
2.57 (2.39–2.77) 0.75 (0.66–0.84)
1.55 (1.45–1.65) 0.41 (0.37–0.46)
0.73 (0.66–0.81)
0.55 (0.52–0.59) 0.46 (0.43–0.50)
0.93 (0.88–0.98) 0.31 (0.28–0.35) 2.37 (2.21–2.56) 0.45 (0.43–0.48) 0.37 (0.35–0.39) 1.04 (0.93–1.16)
0.09 (0.08–0.10) 0.11 (0.10–0.12) 0.08 (0.07–0.09) 0.09 (0.09–0.10) 0.06 (0.05–0.07) 0.11 (0.10–0.12) 0.08 (0.07–0.09) 0.15 (0.14–0.16) 0.04 (0.03–0.05) 0.07 (0.06–0.09) 0.04 (0.03–0.05) 0.12 (0.10–0.14) 0.17 (0.16–0.18) 0.22 (0.20–0.24) 0.16 (0.15–0.17) 0.19 (0.18–0.20) 0.33 (0.31–0.35) 0.09 (0.080–0.10)
0.11 (0.10–0.12) 0.07 (0.06–0.08) 0.22 (0.21–0.23) 0.11 (0.10–0.12) 0.03 (0.02–0.04) 0.31 (0.30–0.33) 0.11 (0.10–0.12) 0.10 (0.09–0.11) 0.13 (0.12–0.14) 0.03 (0.02–0.04) 0.04 (0.03–0.05) 0.03 (0.02–0.03) 0.22 (0.21–0.23) 0.09 (0.08–0.10) 0.36 (0.34–0.38) 0.24 (0.22–0.25) 0.22 (0.20–0.23) 0.30 (0.27–0.34)
0.61 (0.57–0.64) 0.15 (0.14–0.17)
0.62 (0.58–0.65) 0.48 (0.45–0.52) 1.001 (1.001–1.001)
1.45 (1.35–1.55) 1.12 (1.04–1.22)
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Male – PPM
Epilepsy vs. non-epilepsy
519
520
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PPM (37.8–37.83, 0050–52) and temporary PM (TPM, 37.78), as primary or secondary diagnoses. Prevalence odds ratios (OR) and 95% confidence intervals (CI) were then calculated. The OR of PM placement in epilepsy patients were compared to other cardiac and CNS disease groups including: acute/subacute coronary artery disease (CAD; 410, 411), chronic CAD (412, 414), and stroke (430, 431, 433), inflammatory CNS disorders (320–325), hereditary/degenerative disorders (330–337), demyelinating diseases (340–341), migraines (346) and peripheral nervous system (PNS) disorders (350–359). Both hemorrhagic and ischemic strokes were included. Mantel–Haenszel test was used to analyze one subgroup variable (age, sex) at a time. Age was divided into young (<33 years), middle (34–66) and old (67–99). Data were selected from a sub-sample, in which all subjects had one or more disease of interest among the discharge orders. Analysis was not restricted to primary diagnosis. Patients who had PM placement with multiple diagnoses (i.e. epilepsy and migraines) were included under both disease categories, as the indication for PM placement could not be determined from the database. Since a de-identified, publicly available database was utilized, institutional review was waived by the board. To validate the accuracy of ICD-9 codes for epilepsy and pacemaker placement, medical records of random patients with ICD-9 codes of 345–345.9, 37.8–37.83, 0050–52 and 37.78 admitted to our hospital were selected and reviewed. The positive predictive value for these codes was 79%. 3. Results A total of 547,853,302 patient records were analyzed including 2,213,657 admitted with a diagnosis of epilepsy (Table 1). Compared to patients without epilepsy, the epilepsy cohort had higher odds of TPM (OR 1.6) especially in males (OR 2.0) and young- and middle-age patients (OR 4.6 and 4.3, respectively). Compared to inflammatory diseases, epilepsy patients had higher odds of PM, PPM and significantly higher TPM placement, especially in males. Compared to hereditary and degenerative diseases, TPM was more likely in the general epilepsy population (OR 2.0) and male patients with epilepsy in particular (OR 2.8). Compared to demyelinating diseases, the epilepsy cohort had higher odds of PM (OR 1.4), which can be expected as a result of the significantly higher odds of TPM placement (OR 7.9). A similar relationship was seen in patients with migraine disorders (OR 9.1). Compared to patients with stroke, male and middle-age patients with epilepsy had higher odds of TPM (OR 1.6 and 2.4). The epilepsy cohort did not have higher odds of either device placement in any subgroup compared to coronary artery disease cohorts. 4. Discussion As cardiac and hemodynamic derangements may result from excitation of various central autonomic centers,1,4,6,17–21 pacemaker placement may theoretically prevent bradyarrhythmiarelated sudden death in epilepsy patients. We found that compared to the general patient population, epilepsy patients had higher odds of having a TPM, males more likely than females, and young (<33) and middle (33–66) aged more likely than the elderly (67–99). This general comparison, as well as the specific comparisons made with other cohorts, reiterates that PM placement is an age-dependent risk. No significant association with PPM was seen in comparison to the general patient population, highlighting the transient and self-limited nature of peri-ictal bradyarrhythmias. If these bradyarrhythmias were persistent or recurrent, these patients would likely receive PPMs, as many may have. Additionally, epilepsy patients had higher
odds of PM placement than patients with migraine and demyelinating diseases; two categories which are somewhat comparable to epilepsy in age and sex demographics. This relationship was significantly stronger with the temporary device. Furthermore, people with epilepsy had greater odds of TPM placement than any other CNS disorder excluding stroke, indicating that the mechanism of intracranial pathology, not just the presence of such, is associated with bradyarrhythmias requiring PM placement. Concomitant CAD prevalent in stroke patients confounds the relationship of stroke and PM, since CAD patients may be more likely to be implanted with a PM. Nevertheless, males with epilepsy, as well as the 33–66 age group, had higher odds of TPM than stroke patients. Although previous studies have reported dysrhythmias associated with seizures and epilepsy,21–23 the risk of device-dependence has not been studied at a large scale. After analyzing electrocardiograms (EKGs) of 26 patients with temporal lobe epilepsy, Blumhardt et al. found that 42% of patients had ictal cardiac arrhythmias.23 Tachyarrhythmias occur more commonly than bradyarrhythmias, perhaps because of the increased adrenergic output caused by the epileptic activity, as demonstrated in animal studies.24 Occasionally, bradyarrhythmias are severe enough to cause asystole and cardiac arrest. Several cases have demonstrated ictal and peri-ictal bradycardia and asystole, some requiring PPM placement.15,16,20 A larger cohort of 1244 patients who underwent long-term video-EEG monitoring studied retrospectively showed that five patients (0.4%) had ictal asystole, with 11 asystolic events over a total of 19 seizures.21 All seizures were of focal onset. Other large studies showed ictal asystole occurred in 2 of 589 patients (0.34%)25 and 10 of 2754 (0.27%).26 With refractory focal epilepsies, 20 patients were implanted with loop recorders and studied prospectively.27 Episodes of ictal-bradycardia and asystole were recorded in 7 patients (35%) during an 18 months mean observation period. Recently, among 6326 patients with focal epilepsies studied, 16 patients (0.25%) had at least one bradyasystolic event.28 7 patients were implanted with a PPM, 2 underwent surgery and all were continued on optimal antiepileptic regimen. All patients with seizure-related falls and injuries who were treated with a PPM became fall-free, even though some continued to have seizures. Bradyarrhthymias associated with epilepsy are known to be transient, occurring in the peri-ictal period.27,28 Thus it is plausible that some hospitalized patients would require a temporary pacemaker but not a PPM. In fact, this may explain the significant differences between the epilepsy group and other cohorts studied. Furthermore, much of our understanding of the role of cardiac arrhythmias in SUDEP developed in the mid-to-late 1990s, and significant emphasis on spreading awareness had not occurred till few years later. It is conceivable that lack of such data may have resulted in implantation of temporary devices in the absence of established literature indicating recurrence of peri-ictal arrhythmias.21 Study limitations of note include reliance on the accuracy of discharge diagnosis (ICD-9-CM) codes. Although mis-coding is possible, it is unlikely to be a common occurrence among thousands of physicians in several hundred hospitals. Our validation of the code accuracy yielded an acceptable positive predictive value. The lack of clinical data about epilepsy syndrome classification, degree of seizure control and antiepileptic regimen in the epilepsy cohort precludes further analysis. These facts have shown to be related to SUDEP.14 Additionally, due to the retrospective nature of our study and the use of an administrative database which is primarily compiled for billing purposes, causality cannot be established. However, in comparison to other CNS disorders with similar epidemiology, we found significant differences, especially in younger age groups.
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5. Conclusion Our study provides valuable information to physicians and patients in understanding the risk of bradyarrhythmias and potential need for PM placement to prevent sudden falls. Epilepsy was more likely associated with TPM placement compared to people without epilepsy and cohorts of other CNS disorders. This was especially true amongst young- and middle-aged patients. Such association was not seen with PPM, attesting to the transient nature of ictal brady-asystole. Due to lack of sufficient evidence for prophylactic PM placement to prevent recurrent falls, injuries and potentially SUDEP,14 further research is needed to identify risk factors for fatal bradyarrhythmias in epilepsy patients in whom permanent device implantation may be considered. Funding None. Conflicts of interest None of the authors has any conflict of interest to disclose. Acknowledgments None. References 1. Greenhoot JH, Reichenbach DD. Cardiac injury and subarachnoid hemorrhage. A clinical, pathological, and physiological correlation. Journal of Neurosurgery 1969;30(5):521–31. 2. Norris JW, Froggatt GM, Hachinski VC. Cardiac arrhythmias in acute stroke. Stroke 1978;9(4):392–6. 3. Oppenheimer SM, Hachinski VC. The cardiac consequences of stroke. Neurologic Clinics 1992;10(1):167–76. 4. Christensen H, Boysen G, Christensen AF, Johannesen HH. Insular lesions ECG abnormalities, and outcome in acute stroke. Journal of Neurology Neurosurgery and Psychiatry 2005;76(2):269–71. 5. Oppenheimer S. The anatomy and physiology of cortical mechanisms of cardiac control. Stroke 1993;24(12 Suppl.):I3–5. 6. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death? Brain Research 1991;550(1):115–21. 7. Cheung RT, Hachinski V. The insula and cerebrogenic sudden death. Archives of Neurology 2000;57(12):1685–8.
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