ORIGINAL ARTICLE
QTc Prolongation in Acute Pediatric Migraine Lindsay J. May, MD,* Kelly Millar, MD, MSc,† Karen M. Barlow, MB, ChB, MRCPCH (UK),‡§ and Frank Dicke, MD|| Objectives: Migraine headache is common in pediatrics and is frequently assessed in emergency departments. Altered cardiac conduction, including prolongation of the QTc interval on electrocardiogram, has been observed in adults during migraine headache and resolves interictally. Prolonged QTc is associated with life-threatening arrhythmia, and many acute and prophylactic therapies for migraine can further prolong the QTc interval. It is the objective of this prospective cohort study to examine whether the QTc interval prolongs significantly during periods of acute migraine headache in children. Methods: Patients ages 6 to 17 years presenting to the emergency department with acute migraine headache were recruited prospectively. Exclusion criteria included the use of QTc-prolonging medications and medical illnesses, including cardiovascular abnormalities, infection, or head injury. Paired, one-tailed Student t tests compared QTc intervals with and without headache and evaluated for QTc prolongation of 30 ms or longer during headache. Results: Thirteen patients with migraine (mean age, 11.6 ± 2.6 years) were evaluated. Mean QTc interval during headache was significantly longer than the QTc interval in the absence of headache (437.9 ± 27.7 ms compared with 419.3 ± 29.9 ms; p = 0.04). Three patients (23%) had unequivocal prolongation of the QTc (>460 ms) during the migraine, two of which normalized with headache resolution. The mean increase in QTc during headache did not reach or exceed 30 ms (p = 0.86) Conclusions: This study is the first to illustrate a connection between QTc prolongation and acute migraine headache in children. If confirmed in future studies, children should be monitored for QTc prolongation during the acute treatment of migraine in the emergency department when using medications that can lengthen the QTc interval. Key Words: migraine, QTc interval, arrhythmia (Pediatr Emer Care 2015;31: 409–411)
M
igraine is the most common cause of acute, recurrent headache in the pediatric population and can significantly impact a child's quality of life.1 Approximately 25% of migraine sufferers have symptoms in their first decade.2 It is suspected that autonomic dysregulation is involved in the pathophysiology of migraine, as well as a constellation of associated features, such as pallor, nausea, vomiting, vasodilation, pilo-erection, and diaphoresis.2–4 It has been proposed that these symptoms may result from a relative disparity of specific neurotransmitters in the sympathetic system.5 This imbalance between the sympathetic and parasympathetic systems can alter atrial and ventricular repolarization, thereby generating changes on electrocardiogram (ECG) during periods of From the *Division of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; †Department of Pediatrics; ‡Division of Pediatric Neurology, Department of Pediatrics, Alberta's Children Hospital; §Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada; and ||Division of Pediatric Cardiology, Department of Pediatrics, Alberta's Children Hospital, Calgary, Alberta, Canada. Disclosure: The authors declare no conflict of interest. Reprints: Lindsay J. May, MD, Division of Pediatric Cardiology, 750 Welch Road, Suite 325, Palo Alto, CA 94304 (e‐mail: [email protected]). Funding was provided internally by the Divisions of Pediatric Cardiology and Pediatric Neurology at the Alberta Children's Hospital. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161
headache.6 In one of the first studies to explore this concept, Pogacnik et al7 reported an increased frequency of arrhythmias using a single-lead ECG. A subsequent study comparing ECGs during acute migraine to those obtained when the patients were pain-free, illustrated sinus bradycardia, prszemature ventricular beats, right bundle branch block, and nonspecific ST segment and T wave abnormalities during headaches.8 Aygun et al. 9 reported that 30% of migraineurs developed arrhythmia in association with migraine attacks and significant prolongation of PR and QTc intervals. Similarly, Duru et al10 reported increased QTc intervals, QTc dispersion, and P-wave dispersion during acute migraine. Prolonged QTc interval is of particular interest because of the potential for ventricular arrhythmias in this context. This may be relevant for migraine sufferers because certain medications for the acute treatment or prophylaxis of migraine headache may also lengthen the QTc interval. Examples of agents associated with prolongation of the QTc interval include triptans, tricyclic antidepressants (including amitriptyline and nortriptyline), trazodone which is a triazolopyridine antidepressant, selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, and citalopram), and calcium channel blockers (e.g., flunarizine, nifedipine).11–14 Several of the triptan drug class (sumatriptan, naratriptan, and zolmitriptan ) used for acute migraine therapy have been associated with increased risk of torsades de pointes.15 The QTc prolongation observed in adults with migraine is concerning. The potential for arrhythmia in the setting of long QTc is notable, and exacerbation by migraine therapies adds magnitude to this field of research. In theory, prolongation of QTc because of autonomic dysregulation during migraine, in combination with QTc-lengthening medications, could put these patients at risk of significant arrhythmia. There is a paucity of data regarding cardiac conduction, specifically QTc interval, changes during migraine headache in pediatric patients. This prospective cohort study tested the hypothesis that in children, the QTc interval is significantly lengthened during acute migraine headache, compared with the QTc interval when the patient is pain-free.
METHODS Patients were recruited prospectively from the Alberta Children’s Hospital Emergency Department (ED) between April 2010 and May 2012. The study protocol was approved by the Conjoint Health Research Ethics Board for the University of Calgary (E-22189). Written informed consent and assent were obtained. Patients at least 6 years to 18 years, with a chief complaint of acute (less than 24 hours in duration) headache were eligible for inclusion. They were later screened for migraine headache using the International Classification of Headache Disorders-II as described below. Funding was provided internally by the Divisions of Pediatric Cardiology and Pediatric Neurology at the Alberta Children's Hospital. Patients with fever or suspected infection, head injury, thyroid or parathyroid disorders, systemic lupus erythematosus, known cardiac abnormalities (including congenital heart disease, cardiomyopathy, arrhythmia), or neurological abnormalities (i.e., intracranial shunts, masses, epilepsy) were excluded. Patients who had used
Pediatric Emergency Care • Volume 31, Number 6, June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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409
Pediatric Emergency Care • Volume 31, Number 6, June 2015
May et al
amitriptyline, nortriptyline, any triptan medication, selective serotonin reuptake inhibitors, macrolides, or antiarrhythmic medications within 1 month before presentation were also excluded.
of 30 ms or longer during headache. A P value less than 0.05 was considered to be significant. Adjustments were not made for multiple comparisons.
Data Collection
RESULTS
A12-lead ECG was obtained in the ED at the time of acute headache and prior to treatment with migraine-specific medication. A clinical interview was performed in the ED and if necessary, supplemental history was obtained by phone after discharge. Headaches were classified using the International Classification of Headache Disorders-II diagnostic criteria for migraine with or without aura, or probable migraine (lacking one diagnostic criterion) modified for children.16,17 Follow-up ECGs were conducted only for the patients who met criteria for probable or definite migraine headache. These ECGs were performed within 6 months on an outpatient basis, while headache-free. If the ED ECG was interpreted as normal by the computer software (Muse Editor Cardiology Information System; GE Healthcare, Michigan), the ECGs were over-read by a pediatric cardiologist within 1 week, per the standard of care. Should the software interpretation be abnormal or QTc longer than 460 ms, an ED physician immediately evaluated the ECG. All ECGs were later analyzed for study purposes by 1 of 2 blinded pediatric cardiologists (using PC software). All reported QTc intervals were measured (and adjusted for heart rate using Bazett's formula) by 1 of 2 blinded cardiologists. The ECG abnormalities that warranted cardiology or other follow-up were flagged, and families were contacted accordingly.
There were 34 patients initially recruited but 13 were subsequently excluded for the following reasons: insufficient criteria for migraine headache (n =7), use of medications which could prolong the QTc interval (n = 4), diagnosis of an intracranial mass (n =1), and lack of an initial 12-lead ECG in the ED (n = 1). Of the remaining 21 patients, 8 were lost to follow-up. Patient characteristics and ECG findings for the 13 study subjects are shown in Table 1. There were 8 female patients (61%), and the mean age was 11.6 ± 2.6 years. Two participants had migraine without aura (15%) and 8 had probable migraine without aura (62%). With the exception of prolonged or borderline prolonged QTc intervals, there were no other significant abnormalities on ECG, either with or without headache. One 8-year old patient had sinus tachycardia and met voltage criteria for right ventricular hypertrophy (subject b). In total, four patients had prolonged QTc intervals (>450 ms) during migraine headache. Only one of these participants had prolonged QTc during headache and while pain-free (subject g). Two participants demonstrated a prolongation of the QTc interval above 470 ms during acute migraine (subjects b and i), and another had a QTc of 469 ms (subject h). The mean QTc interval during headache was significantly longer than the QTc interval in the absence of headache (437.9 ms ± 27.7 compared with 419.3 ms ± 29.9; P = 0.04). The mean increase in QTc during headache did not reach or exceed 30 ms (P = 0.86).
Sample Size Calculation and Statistical Methods Sample size was calculated using a one-tailed, paired Student t test, assuming that the data would be normally distributed. The variability of the change in QTc interval for children experiencing migraine is unknown, but based on adult data, the standard deviation of the change in QTc (during and after migraine) is 25.5 ms.10 Thus, the effect size was set at 30 ms. For the purposes of this study, prolonged QTc was defined as greater than 450 ms. Power for the study was set at 80%. The target sample size for this study was 12 patients. We estimated that half of patients consented and enrolled would be either lost to follow-up or fail to meet migraine criteria. As such, target enrolment was 30 patients. A 1-tailed, paired Student t test was used to compare mean QTc interval during migraine and pain-free periods, and to evaluate for QTc prolongation
DISCUSSION This prospective cohort study is the first to illustrate an association between migraine headache and prolongation of the QTc interval in children. The QTc during acute migraine headache was unequivocally prolonged (>460 ms)18 in 3 children, 23% of this small sample. This is similar to the study by Aygun et al where 34% of adult migraineurs demonstrated a significantly prolonged QTc. No other rhythm disturbances were recorded in our study. This is in contrast with the literature in adults, which illustrates a variety of other conduction and rhythm issues during migraine headache, such as sinus bradycardia, premature ventricular beats, right bundle branch block, nonspecific ST-T wave abnormalities,8 and prolongation of the PR interval.9 This could be related to the
TABLE 1. Patient Demographics and QTc Intervals With and Without Migraine Headache (N = 13)
a b c d e f g h i j k l m
Age, y
Sex
Headache Classification
QTc With Headache
QTc Without Headache
Change in QTc
7 8 9 10 10 11 12 13 13 13 14 15 16
Female Male Male Male Male Female Female Female Female Female Male Female Female
probable migraine without aura probable migraine without aura probable migraine without aura migraine without aura migraine without aura probable migraine without aura probable migraine without aura complicated migraine migraine with aura probable migraine without aura probable migraine without aura probable migraine without aura migraine with aura
404 481 436 424 400 447 454 469 485 418 400 441 434
424 442 404 382 378 431 465 428 376 447 382 451 441
−20 39 32 42 22 16 −11 41 109 −29 18 −10 −7
The International Classification of Headache Disorders- Version II16 was used for headache diagnostics.
410
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Pediatric Emergency Care • Volume 31, Number 6, June 2015
prevalence of ischemic heart disease and other cardiac comorbidities in the adult population. This study has several limitations. The sample size is small and because many potentially eligible patients were not enrolled, this cohort may not be representative. The lack of QTc prolongation greater than 30 ms during migraine may be related to this small sample size. Of note, a clinically significant increase in QTc may be shorter than 30 ms, depending on the patients' baseline QTc. In future large-scale studies, it would also be informative to compare the QTc interval of children during acute migraine headache to those with acute nonmigraine headache. This would help clarify whether our findings are truly unique to migraineurs. In addition, prolonged ECG monitoring was not performed in the ED and transient arrhythmias cannot be excluded. Another potential limitation is the diagnostic challenge of pediatric migraine headache in the emergency room. Migraine cannot be diagnosed in a child presenting with their first severe headache; this classification requires recurrent headaches. Further, the report or behavior of photophobia or phonophobia may not be apparent (especially in younger children) before this event.16,17 This is reflected in the frequency of “probable” migraine in our study population. Some patients with true migraine may not have been included because of these challenges. Longitudinal follow-up would be helpful for those who partially met criteria to clarify whether they continued to have similar headaches, thus meeting a clear diagnosis of migraine and expanding our study population.
CONCLUSIONS This study is the first to illustrate a connection between migraine headache and prolonged QTc interval in the pediatric population. If confirmed in future larger studies, QTc prolongation could profoundly impact the management of acute migraine in the ED. In this scenario, medication selection would be crucial with the goal of avoiding QTc-prolonging therapies. To clarify the implications of these data, rigorous evaluation in a full-scale prospective study is warranted. REFERENCES 1. Behrman RE, Kliegman RM. Nelson Essentials of Pediatrics. 4th ed. Philadelphia, PA: W.B. Saunders Company; 2002:791–793.
QTc Prolongation in Migraine
2. Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 6th ed. United States: McGraw-Hill Companies Inc; 2005:Chapter 2. 3. Havanka-Kannianen H, Tolonen U, Myllyla VV. Autonomic dysfunction in migraine: a survey of 188 patients. Headache. 1988;28:465–70. 4. Appel S, Kuritzky A, Zahavi I. Evidence for instability of the autonomic nervous system in patients with migraine headache. Headache. 1992;32:10–17. 5. Peroutka S. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44:53–64. 6. Melek IM, Seyfeli E, Duru M, et al. Autonomic dysfunction and cardiac repolarization abnormalities in patients with migraine attacks. Med Sci Monit. 2007;13:RA47–49. 7. Pogacnik T, Sega S, Pecnik B, et al. Autonomic function testing in patients with migraine. Headache. 1993;33:545–50. 8. Jhee SS, Salazar DE, Ford NF, et al. Monitoring of acute migraine attacks: placebo response and safety data. Headache. 1998;38:35–38. 9. Aygun D, Altintop L, Doganay Z, et al. Electrocardiographic changes during migraine attacks. Headache. 2003;43:861–866. 10. Duru M, Melek ES, Duman T, et al. QTc dispersion and P-wave dispersion during migraine attacks. Chephalagia. 2006;26:672–677. 11. Arizona Center for Education and Research on Therapeutics, The Critical Path Institute website. Available at: http://www.torsades.org/ medical-pros/drug-lists/pubMed-drug-list.cfm. Accessed August 25, 2013. 12. Dattilo PB, Nordin C. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry. 2007;68:1309–10. 13. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram induced torsade de pointes, a rare life threatening side effect. Int J Cardiol. 14. Yap YG, Camm AJ. Drug-induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–1372. 15. Cubeddu LX. QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther. 2003;10:452–457. 16. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders:2nd ed. Cephalagia. 2004;24(suppl 1):9–160. 17. Hershey AD, Winner P, Kabbouche MA, et al. Use of the ICHD-II criteria in the diagnosis of pediatric migraine. Headache. 2005;45:1288–97. 18. Moss AJ, Robinson JL. The long QT syndrome: genetic considerations. Trends Cardiovasc Med. 1992;2:81–83.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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411
QTc Prolongation in Acute Pediatric Migraine Lindsay J. May, MD,* Kelly Millar, MD, MSc,† Karen M. Barlow, MB, ChB, MRCPCH (UK),‡§ and Frank Dicke, MD|| Objectives: Migraine headache is common in pediatrics and is frequently assessed in emergency departments. Altered cardiac conduction, including prolongation of the QTc interval on electrocardiogram, has been observed in adults during migraine headache and resolves interictally. Prolonged QTc is associated with life-threatening arrhythmia, and many acute and prophylactic therapies for migraine can further prolong the QTc interval. It is the objective of this prospective cohort study to examine whether the QTc interval prolongs significantly during periods of acute migraine headache in children. Methods: Patients ages 6 to 17 years presenting to the emergency department with acute migraine headache were recruited prospectively. Exclusion criteria included the use of QTc-prolonging medications and medical illnesses, including cardiovascular abnormalities, infection, or head injury. Paired, one-tailed Student t tests compared QTc intervals with and without headache and evaluated for QTc prolongation of 30 ms or longer during headache. Results: Thirteen patients with migraine (mean age, 11.6 ± 2.6 years) were evaluated. Mean QTc interval during headache was significantly longer than the QTc interval in the absence of headache (437.9 ± 27.7 ms compared with 419.3 ± 29.9 ms; p = 0.04). Three patients (23%) had unequivocal prolongation of the QTc (>460 ms) during the migraine, two of which normalized with headache resolution. The mean increase in QTc during headache did not reach or exceed 30 ms (p = 0.86) Conclusions: This study is the first to illustrate a connection between QTc prolongation and acute migraine headache in children. If confirmed in future studies, children should be monitored for QTc prolongation during the acute treatment of migraine in the emergency department when using medications that can lengthen the QTc interval. Key Words: migraine, QTc interval, arrhythmia (Pediatr Emer Care 2015;31: 409–411)
M
igraine is the most common cause of acute, recurrent headache in the pediatric population and can significantly impact a child's quality of life.1 Approximately 25% of migraine sufferers have symptoms in their first decade.2 It is suspected that autonomic dysregulation is involved in the pathophysiology of migraine, as well as a constellation of associated features, such as pallor, nausea, vomiting, vasodilation, pilo-erection, and diaphoresis.2–4 It has been proposed that these symptoms may result from a relative disparity of specific neurotransmitters in the sympathetic system.5 This imbalance between the sympathetic and parasympathetic systems can alter atrial and ventricular repolarization, thereby generating changes on electrocardiogram (ECG) during periods of From the *Division of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; †Department of Pediatrics; ‡Division of Pediatric Neurology, Department of Pediatrics, Alberta's Children Hospital; §Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada; and ||Division of Pediatric Cardiology, Department of Pediatrics, Alberta's Children Hospital, Calgary, Alberta, Canada. Disclosure: The authors declare no conflict of interest. Reprints: Lindsay J. May, MD, Division of Pediatric Cardiology, 750 Welch Road, Suite 325, Palo Alto, CA 94304 (e‐mail: [email protected]). Funding was provided internally by the Divisions of Pediatric Cardiology and Pediatric Neurology at the Alberta Children's Hospital. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161
headache.6 In one of the first studies to explore this concept, Pogacnik et al7 reported an increased frequency of arrhythmias using a single-lead ECG. A subsequent study comparing ECGs during acute migraine to those obtained when the patients were pain-free, illustrated sinus bradycardia, prszemature ventricular beats, right bundle branch block, and nonspecific ST segment and T wave abnormalities during headaches.8 Aygun et al. 9 reported that 30% of migraineurs developed arrhythmia in association with migraine attacks and significant prolongation of PR and QTc intervals. Similarly, Duru et al10 reported increased QTc intervals, QTc dispersion, and P-wave dispersion during acute migraine. Prolonged QTc interval is of particular interest because of the potential for ventricular arrhythmias in this context. This may be relevant for migraine sufferers because certain medications for the acute treatment or prophylaxis of migraine headache may also lengthen the QTc interval. Examples of agents associated with prolongation of the QTc interval include triptans, tricyclic antidepressants (including amitriptyline and nortriptyline), trazodone which is a triazolopyridine antidepressant, selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, and citalopram), and calcium channel blockers (e.g., flunarizine, nifedipine).11–14 Several of the triptan drug class (sumatriptan, naratriptan, and zolmitriptan ) used for acute migraine therapy have been associated with increased risk of torsades de pointes.15 The QTc prolongation observed in adults with migraine is concerning. The potential for arrhythmia in the setting of long QTc is notable, and exacerbation by migraine therapies adds magnitude to this field of research. In theory, prolongation of QTc because of autonomic dysregulation during migraine, in combination with QTc-lengthening medications, could put these patients at risk of significant arrhythmia. There is a paucity of data regarding cardiac conduction, specifically QTc interval, changes during migraine headache in pediatric patients. This prospective cohort study tested the hypothesis that in children, the QTc interval is significantly lengthened during acute migraine headache, compared with the QTc interval when the patient is pain-free.
METHODS Patients were recruited prospectively from the Alberta Children’s Hospital Emergency Department (ED) between April 2010 and May 2012. The study protocol was approved by the Conjoint Health Research Ethics Board for the University of Calgary (E-22189). Written informed consent and assent were obtained. Patients at least 6 years to 18 years, with a chief complaint of acute (less than 24 hours in duration) headache were eligible for inclusion. They were later screened for migraine headache using the International Classification of Headache Disorders-II as described below. Funding was provided internally by the Divisions of Pediatric Cardiology and Pediatric Neurology at the Alberta Children's Hospital. Patients with fever or suspected infection, head injury, thyroid or parathyroid disorders, systemic lupus erythematosus, known cardiac abnormalities (including congenital heart disease, cardiomyopathy, arrhythmia), or neurological abnormalities (i.e., intracranial shunts, masses, epilepsy) were excluded. Patients who had used
Pediatric Emergency Care • Volume 31, Number 6, June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.pec-online.com
409
Pediatric Emergency Care • Volume 31, Number 6, June 2015
May et al
amitriptyline, nortriptyline, any triptan medication, selective serotonin reuptake inhibitors, macrolides, or antiarrhythmic medications within 1 month before presentation were also excluded.
of 30 ms or longer during headache. A P value less than 0.05 was considered to be significant. Adjustments were not made for multiple comparisons.
Data Collection
RESULTS
A12-lead ECG was obtained in the ED at the time of acute headache and prior to treatment with migraine-specific medication. A clinical interview was performed in the ED and if necessary, supplemental history was obtained by phone after discharge. Headaches were classified using the International Classification of Headache Disorders-II diagnostic criteria for migraine with or without aura, or probable migraine (lacking one diagnostic criterion) modified for children.16,17 Follow-up ECGs were conducted only for the patients who met criteria for probable or definite migraine headache. These ECGs were performed within 6 months on an outpatient basis, while headache-free. If the ED ECG was interpreted as normal by the computer software (Muse Editor Cardiology Information System; GE Healthcare, Michigan), the ECGs were over-read by a pediatric cardiologist within 1 week, per the standard of care. Should the software interpretation be abnormal or QTc longer than 460 ms, an ED physician immediately evaluated the ECG. All ECGs were later analyzed for study purposes by 1 of 2 blinded pediatric cardiologists (using PC software). All reported QTc intervals were measured (and adjusted for heart rate using Bazett's formula) by 1 of 2 blinded cardiologists. The ECG abnormalities that warranted cardiology or other follow-up were flagged, and families were contacted accordingly.
There were 34 patients initially recruited but 13 were subsequently excluded for the following reasons: insufficient criteria for migraine headache (n =7), use of medications which could prolong the QTc interval (n = 4), diagnosis of an intracranial mass (n =1), and lack of an initial 12-lead ECG in the ED (n = 1). Of the remaining 21 patients, 8 were lost to follow-up. Patient characteristics and ECG findings for the 13 study subjects are shown in Table 1. There were 8 female patients (61%), and the mean age was 11.6 ± 2.6 years. Two participants had migraine without aura (15%) and 8 had probable migraine without aura (62%). With the exception of prolonged or borderline prolonged QTc intervals, there were no other significant abnormalities on ECG, either with or without headache. One 8-year old patient had sinus tachycardia and met voltage criteria for right ventricular hypertrophy (subject b). In total, four patients had prolonged QTc intervals (>450 ms) during migraine headache. Only one of these participants had prolonged QTc during headache and while pain-free (subject g). Two participants demonstrated a prolongation of the QTc interval above 470 ms during acute migraine (subjects b and i), and another had a QTc of 469 ms (subject h). The mean QTc interval during headache was significantly longer than the QTc interval in the absence of headache (437.9 ms ± 27.7 compared with 419.3 ms ± 29.9; P = 0.04). The mean increase in QTc during headache did not reach or exceed 30 ms (P = 0.86).
Sample Size Calculation and Statistical Methods Sample size was calculated using a one-tailed, paired Student t test, assuming that the data would be normally distributed. The variability of the change in QTc interval for children experiencing migraine is unknown, but based on adult data, the standard deviation of the change in QTc (during and after migraine) is 25.5 ms.10 Thus, the effect size was set at 30 ms. For the purposes of this study, prolonged QTc was defined as greater than 450 ms. Power for the study was set at 80%. The target sample size for this study was 12 patients. We estimated that half of patients consented and enrolled would be either lost to follow-up or fail to meet migraine criteria. As such, target enrolment was 30 patients. A 1-tailed, paired Student t test was used to compare mean QTc interval during migraine and pain-free periods, and to evaluate for QTc prolongation
DISCUSSION This prospective cohort study is the first to illustrate an association between migraine headache and prolongation of the QTc interval in children. The QTc during acute migraine headache was unequivocally prolonged (>460 ms)18 in 3 children, 23% of this small sample. This is similar to the study by Aygun et al where 34% of adult migraineurs demonstrated a significantly prolonged QTc. No other rhythm disturbances were recorded in our study. This is in contrast with the literature in adults, which illustrates a variety of other conduction and rhythm issues during migraine headache, such as sinus bradycardia, premature ventricular beats, right bundle branch block, nonspecific ST-T wave abnormalities,8 and prolongation of the PR interval.9 This could be related to the
TABLE 1. Patient Demographics and QTc Intervals With and Without Migraine Headache (N = 13)
a b c d e f g h i j k l m
Age, y
Sex
Headache Classification
QTc With Headache
QTc Without Headache
Change in QTc
7 8 9 10 10 11 12 13 13 13 14 15 16
Female Male Male Male Male Female Female Female Female Female Male Female Female
probable migraine without aura probable migraine without aura probable migraine without aura migraine without aura migraine without aura probable migraine without aura probable migraine without aura complicated migraine migraine with aura probable migraine without aura probable migraine without aura probable migraine without aura migraine with aura
404 481 436 424 400 447 454 469 485 418 400 441 434
424 442 404 382 378 431 465 428 376 447 382 451 441
−20 39 32 42 22 16 −11 41 109 −29 18 −10 −7
The International Classification of Headache Disorders- Version II16 was used for headache diagnostics.
410
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Pediatric Emergency Care • Volume 31, Number 6, June 2015
prevalence of ischemic heart disease and other cardiac comorbidities in the adult population. This study has several limitations. The sample size is small and because many potentially eligible patients were not enrolled, this cohort may not be representative. The lack of QTc prolongation greater than 30 ms during migraine may be related to this small sample size. Of note, a clinically significant increase in QTc may be shorter than 30 ms, depending on the patients' baseline QTc. In future large-scale studies, it would also be informative to compare the QTc interval of children during acute migraine headache to those with acute nonmigraine headache. This would help clarify whether our findings are truly unique to migraineurs. In addition, prolonged ECG monitoring was not performed in the ED and transient arrhythmias cannot be excluded. Another potential limitation is the diagnostic challenge of pediatric migraine headache in the emergency room. Migraine cannot be diagnosed in a child presenting with their first severe headache; this classification requires recurrent headaches. Further, the report or behavior of photophobia or phonophobia may not be apparent (especially in younger children) before this event.16,17 This is reflected in the frequency of “probable” migraine in our study population. Some patients with true migraine may not have been included because of these challenges. Longitudinal follow-up would be helpful for those who partially met criteria to clarify whether they continued to have similar headaches, thus meeting a clear diagnosis of migraine and expanding our study population.
CONCLUSIONS This study is the first to illustrate a connection between migraine headache and prolonged QTc interval in the pediatric population. If confirmed in future larger studies, QTc prolongation could profoundly impact the management of acute migraine in the ED. In this scenario, medication selection would be crucial with the goal of avoiding QTc-prolonging therapies. To clarify the implications of these data, rigorous evaluation in a full-scale prospective study is warranted. REFERENCES 1. Behrman RE, Kliegman RM. Nelson Essentials of Pediatrics. 4th ed. Philadelphia, PA: W.B. Saunders Company; 2002:791–793.
QTc Prolongation in Migraine
2. Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 6th ed. United States: McGraw-Hill Companies Inc; 2005:Chapter 2. 3. Havanka-Kannianen H, Tolonen U, Myllyla VV. Autonomic dysfunction in migraine: a survey of 188 patients. Headache. 1988;28:465–70. 4. Appel S, Kuritzky A, Zahavi I. Evidence for instability of the autonomic nervous system in patients with migraine headache. Headache. 1992;32:10–17. 5. Peroutka S. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44:53–64. 6. Melek IM, Seyfeli E, Duru M, et al. Autonomic dysfunction and cardiac repolarization abnormalities in patients with migraine attacks. Med Sci Monit. 2007;13:RA47–49. 7. Pogacnik T, Sega S, Pecnik B, et al. Autonomic function testing in patients with migraine. Headache. 1993;33:545–50. 8. Jhee SS, Salazar DE, Ford NF, et al. Monitoring of acute migraine attacks: placebo response and safety data. Headache. 1998;38:35–38. 9. Aygun D, Altintop L, Doganay Z, et al. Electrocardiographic changes during migraine attacks. Headache. 2003;43:861–866. 10. Duru M, Melek ES, Duman T, et al. QTc dispersion and P-wave dispersion during migraine attacks. Chephalagia. 2006;26:672–677. 11. Arizona Center for Education and Research on Therapeutics, The Critical Path Institute website. Available at: http://www.torsades.org/ medical-pros/drug-lists/pubMed-drug-list.cfm. Accessed August 25, 2013. 12. Dattilo PB, Nordin C. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry. 2007;68:1309–10. 13. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram induced torsade de pointes, a rare life threatening side effect. Int J Cardiol. 14. Yap YG, Camm AJ. Drug-induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–1372. 15. Cubeddu LX. QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther. 2003;10:452–457. 16. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders:2nd ed. Cephalagia. 2004;24(suppl 1):9–160. 17. Hershey AD, Winner P, Kabbouche MA, et al. Use of the ICHD-II criteria in the diagnosis of pediatric migraine. Headache. 2005;45:1288–97. 18. Moss AJ, Robinson JL. The long QT syndrome: genetic considerations. Trends Cardiovasc Med. 1992;2:81–83.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.pec-online.com
411
