- Email: [email protected]
Transient Prolonged Corrected QT interval in Lyme Disease
TRANSIENT PROLONGED CORRECTED QT INTERVAL IN LYME DISEASE STEPHEN P. SESLAR, MD, PHD, CHARLES I BERUL, MD, THOMAS R. BURKLOW, MD, FRANK CECCHIN, MD, MARK E ALEXANDER, MD
AND
Lyme disease, caused by the spirochete Borrelia burgdorferi, has known cardiovascular effects typically manifesting in varying degrees of atrioventricular block. Three patients presented with QT interval prolongation associated with Lyme disease, a previously unreported manifestation of Lyme carditis. Implications and a proposed clinical management approach are discussed. (J Pediatr 2006;148:692-7)
yme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. Cardiac manifestations have been well studied and occur in ⬃8%. Typically, these manifestations include heart block of varying degrees and less commonly, pericarditis, myocarditis, pericardial effusions, tachyarrhythmias, and congestive heart failure.1 We describe here a previously unreported cardiac manifestation of Lyme disease: prolongation of the QT interval. The QT interval is an electrocardiographic measurement of ventricular repolarization, and prolongation of this interval is associated with an increased risk of polymorphic ventricular tachycardia (known as torsades de pointes) and cardiac syncope.
L
CASE REPORTS Patient I A previously healthy 13 year-old Caucasian male resident of southern Massachusetts complained of headache, stiff neck, fever, and intermittent dizziness 2 weeks before admission. When symptoms persisted, he presented in August for further evaluation. There was no obvious tick exposure or history of rash or joint pain. On presentation, he was alert and cooperative. He had a mildly elevated temperature at 37.7° C. His resting heart rate was normal at 62 beats/min, and other vital signs were similarly normal. Neither rash nor arthritis was evident. He did demonstrate meningism, but there were no focal neurologic findings, and the cardiovascular examination result was normal. Lumbar puncture revealed 112 white blood cells/mm3, with 79% lymphocytes, 17% monocytes, and 2% neutrophils in the cerebrospinal fluid (CSF). CSF protein and glucose were normal. The diagnosis of Lyme disease was confirmed by serum serologic studies and Western blot. His ECG demonstrated first-degree atrioventricular (AV) block. The patient was admitted and started on intravenous ceftriaxone for Lyme meningitis. Overnight, the first-degree heart block progressed to Wenckebach-type secondFrom the Arrhythmia Service, Department of Cardiology, Children’s Hospital and the degree heart block. He remained hemodynamically stable with a heart rate of 40 to 50 Department of Pediatrics, Harvard Medical beats/min. That morning, because of concerns over progressing heart block, he was School, Boston, Mass, Department of Peditransported to a university hospital cardiac intensive care unit setting for closer monitoratrics, Walter Reed Army Medical Center, Washington, DC, and Uniformed Services, ing. On arrival, he was additionally noted to have a markedly prolonged corrected QT University of Health Sciences, Bethesda interval (QTc) of 560 ms (normal ⱕ440 ms). The result of electrocardiography (ECG) Md. was otherwise notable for mild left-axis deviation and a narrow QRS (Figure 1, a). The The opinions expressed in this manuscript represent those of the authors and do not Table shows a detailed record of the electrocardiographic intervals for each of the 3 represent the official views of the United patients over time. States Army or United States Government. There were no identifiable secondary causes of prolonged QT (eg, drug-effect or Submitted for publication Jun 21, 2005; last revision received Sep 29, 2005; accepted electrolyte disturbance) by history or laboratory investigation. Family members including Nov 11, 2005. both parents and 2 siblings were tested and found to have normal ECG results without Reprint requests: Mark Alexander, MD, ArQT prolongation, making congenital long QT syndrome less likely. Before discharge, the rhythmia Service, Department of Cardiology, Children’s Hospital-Boston, 300 Longpatient exercised for 13 minutes with a Bruce treadmill protocol, with below average AV CNS CSF
692
Atrioventricular Central nervous system Cerebrospinal fluid
ECG ELISA QTc
Electrocardiography Enzyme-linked immunosorbent assay Corrected QT interval
wood Ave, Boston, MA 02115. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.11.031
Figure 1. Twelve-lead ECGs from patient 1 early in illness (A) and after recovery (B). ECGs are performed with standard settings: paper speed 25 mm/ sec and amplitude 10 mm/mV. B has precordial leads at 5 mm/mV.
exercise tolerance (25th percentile). The corrected QT interval was prolonged at baseline and increased early in the protocol, in contrast to the shortening of the QT interval Transient Prolonged Corrected QT Interval in Lyme Disease
typically observed during exercise. Other markers of repolarization abnormalities, such as ventricular ectopia, torsades de pointes, ST-T wave changes, or microvolt T-wave alternans, 693
Table. Electrocardiographic parameters for each patient at the peak of QT prolongation and recovery Patient
1 1 2 2 3
Illness Day#
18 109 3 41 9
Lead II Measurements
QTc/JTc Max
SCL
PR
QRS
QT
QTc
JT
JTc
Lead
1000 949 840 820 760
246 149 200 160 200
103 103 98 97 100
560 377 485 360 520
560 387 520 390 596
457 274 380 270 420
457 281 410 290 482
V2 V5 V6 2 V3
QTc/JTc Min
QTc JTc max max 670 436 540 390 545
541 329 430 270 446
QT/JT Dispersion
Lead
QTc min
JTc min
QTd
JTd
AVL II II I III
480 387 410 350 510
388 281 300 250 413
175 17 130 40 100
140 23 130 20 85
JTc, Rate corrected JT; interval; JTd, JT dispersion; Max, maximal value; Min, minimal value; PR, PR interval; QRS, QRS duration; QTc, rate corrected QT interval; QTd, QT dispersion; SCL, sinus cycle length. Pertinent formulae in text.
were not observed. The result of echocardiography was normal. His AV node conduction abnormalities progressively resolved, and he remained symptom free. The patient was discharged home on post-onset of illness day 18 with instructions to avoid high-intensity athletic activity until his QT interval normalized. A 4-week course of ceftriaxone was completed, and he experienced gradual but complete normalization of his QT interval over 6 to 7 weeks (Table). The mild left axis deviation persisted. Repeat exercise testing showed improved exercise tolerance (⬎90th percentile) and no electrocardiographic abnormalities during the study. A subsequent 24-hour Holter monitor showed a wandering atrial pacemaker with normal heart rate variability, rare isolated atrial and ventricular premature beats, and normal intervals including the PR and QT. At latest follow-up, now 24 months after the illness, the patient remains symptom free and has returned to full athletic participation.
Patient II A 14 year-old male resident of eastern Massachusetts with B-thalassemia minor, presented in August with a 5-day history of headache and fatigue, as well as a 3-day history of neck pain. He had a 2-day history of Bell’s palsy. There was no known tick exposure, but he lived in a heavily wooded area and spent much of his time outdoors. There was no history of joint pain or swelling, nor had there been a history of rash. There was no recent travel and no known ill contacts. His primary care provider referred him to a university hospital where the above-noted physical examination findings were corroborated. Vital signs were within normal limits except for mild bradycardia (heart rate 54 beats/min). There was no rash evident, and he had a normal musculoskeletal examination. No meningism was reported. Apart from the findings of Bell’s palsy, his neurologic examination was unremarkable. The cardiovascular examination result was normal except for the bradycardia. A lumbar puncture revealed 45 white blood cells/mm3, with 56% lymphocytes, 40% monocytes, 3% atypical lymphocytes and 1% neutrophils in the CSF. CSF glucose was mildly decreased at 51 mg/dL. CSF protein was normal 43 mg/dL. 694
Seslar et al
The diagnosis of Lyme disease was again confirmed by serum serologic studies. The enzyme-linked immunosorbent assay (ELISA) for Lyme immunoglobulin G/immunoglobulin M antibodies was positive. Western blot analysis for immunoglobulin M was positive. The patient was admitted for intravenous ceftriaxone therapy and cardiac monitoring. The ECG result on the day of admission was notable for mild first-degree AV block (PR ⫽ 200 ms), T-wave inversion in leads II, III, and AVF, and a QTc of 520 ms (Table). Shortly after admission, on post onset of illness day 9, he exercised using a Bruce treadmill protocol for 15 minutes, with above-average exercise tolerance. ECG done during exercise demonstrated a baseline QTc interval in lead II of 560 ms at rest (Figure 2). During activity the QTc shortened to 500 ms, during recovery, it shortened further to 460 to 520 ms, although it did not normalize during the study. Occasional single ventricular premature beats were seen during stage 4 to 5. Similar to patient 1, there were no additional markers of repolarization instability such as ST-T wave changes, torsades de pointes, or microvolt T-wave alternans. Again historic and laboratory investigation did not reveal any obvious congenital or secondary causes of QT prolongation. Echocardiography demonstrated hyperdynamic left ventricular function with otherwise normal findings. The patient was discharged home to complete a 4-week course of intravenous ceftriaxone. A 24-hour Holter monitor performed soon after going home showed unremarkable sinus rhythm, although there continued to be an unusual T-wave morphology with prolonged corrected QT intervals. Follow-up exercise testing and ECG, done on post-illness onset day 41, showed average exercise tolerance for age and complete normalization of his QTc and PR intervals (Table). He has remained symptom free and has resumed full athletic participation.
Patient III A previously healthy 13-year-old male presented in early September with a history of a small circular rash on the flexor surface of his left forearm. Concomitant with the rash, he reported having had a mild headache and mild arthralgia of both knees and elbows. One week before admission, he began The Journal of Pediatrics • May 2006
Figure 2. Twelve-lead ECGs from patient 2 early in illness. ECG is performed with standard 25 mm/sec and 10 mm/mV amplitude.
to experience left-sided facial numbness and paralysis, with increased arthralgia of both knees and elbows. He resided in the mid-Atlantic states, although his recent travels included New York, Georgia, Alabama, and Connecticut. He was diagnosed with Lyme disease by ELISA in a local emergency department, placed on oral doxycycline, and discharged home. One week later, he returned for follow-up at his primary care provider’s office where ECG demonstrated mild first-degree AV block (PR 200 ms). Because of the Bell’s palsy and atrioventricular block, he was admitted to the hospital for parenteral antibiotic therapy. At the time of admission, review of systems demonstrated continued left-sided facial weakness, mild headache, and mild arthralgia of the knees and elbows. He also noted mild dyspnea on exertion with climbing stairs. Physical examination revealed Bell’s palsy. There was no meningism. Neurologic examination was otherwise unremarkable. His resting heart rate was normal at 65 beats/min, and he demonstrated a normal cardiovascular examination result. No rashes were noted. He was tender to palpation and range of motion testing in both knees. ECG demonstrated a mildly prolonged PR interval, as described above, and a QTc of 500 ms (Figure 3). Assessment for secondary causes of the prolonged QT interval, as with the previous patients, was negative. Doxycycline was discontinued and he was begun on intravenous ceftriaxone. Serial ECG was performed. Over the following 2 days the QTc ranged from 500 to 520 ms (Table; Figure 3). An echocardiography result was normal. After an unremarkable inpatient course, he was Transient Prolonged Corrected QT Interval in Lyme Disease
discharged after 3 days to complete 3 weeks of ceftriaxone at home. Subsequently, he was lost to follow-up, and repeat evaluation of his QT interval has not yet been obtained.
DISCUSSION We report 3 patients with Lyme carditis who manifested prolongation of the QT interval, in addition to the varying degrees of AV nodal block more characteristic of this disease. The differential diagnosis of QT interval prolongation has traditionally been divided into primary (ie, congenital LQTS) or secondary (acquired) causes. In 2 of the 3 cases, primary LQTS was deemed unlikely given the normal screening ECGs done on family members, the unremarkable nature of the family histories, and perhaps most importantly, the complete normalization of the patient’s QT interval observed during follow-up. In each case, common causes of acquired long QT syndrome were excluded, including electrolyte abnormalities and drug effect. Less commonly, significant central nervous system (CNS) injury has been associated with prolongation of the QT interval.2,3 While each patient in this series had some form of Lyme-related CNS involvement, the clinical impact of this involvement was mild, and symptomatic neurologic improvement significantly preceded normalization of the QT interval. Hence, it seems unlikely that the derangement of the QT interval was secondary to the CNS effects of Lyme disease in these patients. Bundle branch blocks have been reported in association with Lyme carditis4 and could result in a longer QT interval because of longer QRS duration.5 However, each of these patients had normal 695
Figure 3. Twelve-lead ECG from patient 3 early in illness. E ECG is performed with standard 25 mm/sec and 10 mm/mV amplitude.
QRS duration and the corrected JT intervals (QT intervalQRS duration) were prolonged as well (Table). These cases therefore suggest the possibility that acquired long QT syndrome can result specifically from Lyme-induced carditis. The mechanism by which Lyme carditis could result in QT prolongation is unknown. Although not previously reported in association with Lyme carditis, prolongation of the QT interval has been reported in several other paradigms. For example, exposure to anthracyclines, used in the treatment of variety of adult and pediatric malignancies, has been associated with QTc prolongation.6,7 As with Lyme carditis–mediated QT prolongation, the mechanism of this association is unclear but may reflect a non-specific effect of myocyte injury. In other cases, QT prolongation may result from an autoantibody mediated myocardial injury, as in the case of infants born with a prolonged QT interval in the setting of antiLa/Ro antibodies.8 In both congenital heart block and anthracycline toxicity of those patients also have quite significant myocardial dilation, which may contribute to their findings. Perhaps the best-characterized paradigm of is that of drug induced QT prolongation, in which cardiac ion-channel gene polymorphisms have recently been shown to render afflicted individuals exceptionally sensitive to the QT prolonging effect of certain drugs.9-11 On the basis of histopathologic data, the more common cardiac manifestations of Lyme disease are thought to be due to direct invasion of the cardiac tissue by the spirochete or by the inflammatory response induced by the organism’s presence.12 It 696
Seslar et al
is not clear why the organism predominantly affects the conduction system and more specifically the atrioventricular nodal tissue. Intracardiac electrophysiological studies in patients with Lyme carditis with complete heart block have demonstrated supra-Hisian block with little or no ventricular escape rhythm. No abnormalities in repolarization were noted.13,14 How recovery of AV conduction temporally relates to elimination of the organism and dissolution of the inflammatory response has not been systematically studied in human beings. In a mouse model of Lyme carditis, researchers have shown that the resolution of the inflammatory response closely parallels the correction of all electrophysiological abnormalities in these mice.15 Given the parallels between recovery of AV node function and QT normalization in these patients, we presume that the same pathologic process causes both electrophysiological abnormalities, although the nature of this process and whether these patients have some intrinsic (eg, genetic) vulnerability remains a matter of speculation. At the time of these cases there was not commercially available gene testing for LQTS. This test demonstrates a 30% “false-negative” rate in patients with clear clinical diagnoses of genetic long QT. Hence, the diagnosis of long QT remains a clinical/phenotype diagnosis. The T-wave patterns between patients 1 and 2 were biphasic in multiple leads reminiscent of the HERG defects in long QT 2, whereas patient 3 had a broader T wave without the biphasic character seen in the first 2.16 These patients were previously healthy and had no indication for an ECG before their illness. Hence, we are unable to comment on preexisting ECG abnormalities. This The Journal of Pediatrics • May 2006
is particularly relevant in patient 3 who did not get effective follow-up or demonstrate resolution of the ECG findings. As with any isolated case series, this experience cannot assess the incidence or implications of prolonged QTc in the setting of Lyme carditis. Systemic review of ECGs in patients with clinical Lyme disease will be required to understand the epidemiologic condition of this association. Given its apparent rarity, identification of an individual with a prolonged QT interval in the setting of Lyme disease should prompt a thorough evaluation for other more common causes of QT prolongation. In addition, it would be reasonable to obtain screening ECG’s on first-degree relatives. It is notable that none of the patients discussed here had documented ventricular arrhythmia or symptoms attributable to QT prolongation, despite potentially provocative exercise testing. Even though the absolute daily risks are quite low in congenital long QT, any patient with significant prolongation of the QT interval is at increased risk of torsades de pointes and cardiac syncope. As such, patients with Lyme carditis that manifest QTc prolongation should be counseled to avoid medications that may further prolong the QT/JT intervals. In addition, these patients should probably be counseled to avoid vigorous exercise until conduction returns to normal and repolarization has normalized.17 If our experience is representative, serial ECG performed over a 2- to 3-month period of time should demonstrate normalization of the corrected QT interval. We suggest that close cardiology follow-up is warranted, at least until the QT interval has normalized and any coexisting cardiovascular manifestations of Lyme disease have resolved, and the transient nature of the finding confirmed.
REFERENCES 1. Pinto DS. Cardiac manifestations of Lyme disease. Med Clin North Am 2002;86:285-96. 2. Eckardt M, Gerlach L, Welter FL. Prolongation of the frequencycorrected QT dispersion following cerebral strokes with involvement of the insula of Reil. Eur Neurol 1999;42:190-3. 3. Lindgren A, Wohlfart B, Pahlm O, Johansson BB. Electrocardio-
Transient Prolonged Corrected QT Interval in Lyme Disease
graphic changes in stroke patients without primary heart disease. Clin Physiol 1994;14:223-31. 4. van der Linde MR. Lyme carditis: clinical characteristics of 105 cases. Scand J Infect Dis Suppl 1991;77:81-4. 5. Berul CI, Sweeten TL, Dubin AM, Shah MJ, Vetter VL. Use of the rate-corrected JT interval for prediction of repolarization abnormalities in children. Am J Cardiol 1994;74:1254-7. 6. Bender KS, Shematek JP, Leventhal BG, Kan JS. QT interval prolongation associated with anthracycline cardiotoxicity. J Pediatr 1984;105:442-4. 7. Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993;11:1906-10. 8. Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43:1049-53. 9. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175-87. 10. Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H, et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002;106:1269-74. 11. Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691-6. 12. de Koning J, Hoogkamp-Korstanje JA, van der Linde MR, Crijns HJ. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease. J Infect Dis 1989;160:150-3. 13. van der Linde MR, Crijns HJ, Lie KI. Transient complete AV block in Lyme disease. Electrophysiological observations. Chest 1989;96:219-21. 14. van der Linde MR, Crijns HJ, de Koning J, Hoogkamp-Korstanje JA, de Graaf JJ, Piers DA, et al. Range of atrioventricular conduction disturbances in Lyme borreliosis: a report of four cases and review of other published reports. Br Heart J 1990;63:162-8. 15. Saba S, VanderBrink BA, Perides G, Glickstein LJ, Link MS, Homoud MK, et al. Cardiac conduction abnormalities in a mouse model of Lyme borreliosis. J Interv Card Electrophysiol 2001;5:137-43. 16. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929-34. 17. Maron BJ, Zipes DP. Introduction: eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol 2005;45:1318-21.
697
AND
Lyme disease, caused by the spirochete Borrelia burgdorferi, has known cardiovascular effects typically manifesting in varying degrees of atrioventricular block. Three patients presented with QT interval prolongation associated with Lyme disease, a previously unreported manifestation of Lyme carditis. Implications and a proposed clinical management approach are discussed. (J Pediatr 2006;148:692-7)
yme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. Cardiac manifestations have been well studied and occur in ⬃8%. Typically, these manifestations include heart block of varying degrees and less commonly, pericarditis, myocarditis, pericardial effusions, tachyarrhythmias, and congestive heart failure.1 We describe here a previously unreported cardiac manifestation of Lyme disease: prolongation of the QT interval. The QT interval is an electrocardiographic measurement of ventricular repolarization, and prolongation of this interval is associated with an increased risk of polymorphic ventricular tachycardia (known as torsades de pointes) and cardiac syncope.
L
CASE REPORTS Patient I A previously healthy 13 year-old Caucasian male resident of southern Massachusetts complained of headache, stiff neck, fever, and intermittent dizziness 2 weeks before admission. When symptoms persisted, he presented in August for further evaluation. There was no obvious tick exposure or history of rash or joint pain. On presentation, he was alert and cooperative. He had a mildly elevated temperature at 37.7° C. His resting heart rate was normal at 62 beats/min, and other vital signs were similarly normal. Neither rash nor arthritis was evident. He did demonstrate meningism, but there were no focal neurologic findings, and the cardiovascular examination result was normal. Lumbar puncture revealed 112 white blood cells/mm3, with 79% lymphocytes, 17% monocytes, and 2% neutrophils in the cerebrospinal fluid (CSF). CSF protein and glucose were normal. The diagnosis of Lyme disease was confirmed by serum serologic studies and Western blot. His ECG demonstrated first-degree atrioventricular (AV) block. The patient was admitted and started on intravenous ceftriaxone for Lyme meningitis. Overnight, the first-degree heart block progressed to Wenckebach-type secondFrom the Arrhythmia Service, Department of Cardiology, Children’s Hospital and the degree heart block. He remained hemodynamically stable with a heart rate of 40 to 50 Department of Pediatrics, Harvard Medical beats/min. That morning, because of concerns over progressing heart block, he was School, Boston, Mass, Department of Peditransported to a university hospital cardiac intensive care unit setting for closer monitoratrics, Walter Reed Army Medical Center, Washington, DC, and Uniformed Services, ing. On arrival, he was additionally noted to have a markedly prolonged corrected QT University of Health Sciences, Bethesda interval (QTc) of 560 ms (normal ⱕ440 ms). The result of electrocardiography (ECG) Md. was otherwise notable for mild left-axis deviation and a narrow QRS (Figure 1, a). The The opinions expressed in this manuscript represent those of the authors and do not Table shows a detailed record of the electrocardiographic intervals for each of the 3 represent the official views of the United patients over time. States Army or United States Government. There were no identifiable secondary causes of prolonged QT (eg, drug-effect or Submitted for publication Jun 21, 2005; last revision received Sep 29, 2005; accepted electrolyte disturbance) by history or laboratory investigation. Family members including Nov 11, 2005. both parents and 2 siblings were tested and found to have normal ECG results without Reprint requests: Mark Alexander, MD, ArQT prolongation, making congenital long QT syndrome less likely. Before discharge, the rhythmia Service, Department of Cardiology, Children’s Hospital-Boston, 300 Longpatient exercised for 13 minutes with a Bruce treadmill protocol, with below average AV CNS CSF
692
Atrioventricular Central nervous system Cerebrospinal fluid
ECG ELISA QTc
Electrocardiography Enzyme-linked immunosorbent assay Corrected QT interval
wood Ave, Boston, MA 02115. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.11.031
Figure 1. Twelve-lead ECGs from patient 1 early in illness (A) and after recovery (B). ECGs are performed with standard settings: paper speed 25 mm/ sec and amplitude 10 mm/mV. B has precordial leads at 5 mm/mV.
exercise tolerance (25th percentile). The corrected QT interval was prolonged at baseline and increased early in the protocol, in contrast to the shortening of the QT interval Transient Prolonged Corrected QT Interval in Lyme Disease
typically observed during exercise. Other markers of repolarization abnormalities, such as ventricular ectopia, torsades de pointes, ST-T wave changes, or microvolt T-wave alternans, 693
Table. Electrocardiographic parameters for each patient at the peak of QT prolongation and recovery Patient
1 1 2 2 3
Illness Day#
18 109 3 41 9
Lead II Measurements
QTc/JTc Max
SCL
PR
QRS
QT
QTc
JT
JTc
Lead
1000 949 840 820 760
246 149 200 160 200
103 103 98 97 100
560 377 485 360 520
560 387 520 390 596
457 274 380 270 420
457 281 410 290 482
V2 V5 V6 2 V3
QTc/JTc Min
QTc JTc max max 670 436 540 390 545
541 329 430 270 446
QT/JT Dispersion
Lead
QTc min
JTc min
QTd
JTd
AVL II II I III
480 387 410 350 510
388 281 300 250 413
175 17 130 40 100
140 23 130 20 85
JTc, Rate corrected JT; interval; JTd, JT dispersion; Max, maximal value; Min, minimal value; PR, PR interval; QRS, QRS duration; QTc, rate corrected QT interval; QTd, QT dispersion; SCL, sinus cycle length. Pertinent formulae in text.
were not observed. The result of echocardiography was normal. His AV node conduction abnormalities progressively resolved, and he remained symptom free. The patient was discharged home on post-onset of illness day 18 with instructions to avoid high-intensity athletic activity until his QT interval normalized. A 4-week course of ceftriaxone was completed, and he experienced gradual but complete normalization of his QT interval over 6 to 7 weeks (Table). The mild left axis deviation persisted. Repeat exercise testing showed improved exercise tolerance (⬎90th percentile) and no electrocardiographic abnormalities during the study. A subsequent 24-hour Holter monitor showed a wandering atrial pacemaker with normal heart rate variability, rare isolated atrial and ventricular premature beats, and normal intervals including the PR and QT. At latest follow-up, now 24 months after the illness, the patient remains symptom free and has returned to full athletic participation.
Patient II A 14 year-old male resident of eastern Massachusetts with B-thalassemia minor, presented in August with a 5-day history of headache and fatigue, as well as a 3-day history of neck pain. He had a 2-day history of Bell’s palsy. There was no known tick exposure, but he lived in a heavily wooded area and spent much of his time outdoors. There was no history of joint pain or swelling, nor had there been a history of rash. There was no recent travel and no known ill contacts. His primary care provider referred him to a university hospital where the above-noted physical examination findings were corroborated. Vital signs were within normal limits except for mild bradycardia (heart rate 54 beats/min). There was no rash evident, and he had a normal musculoskeletal examination. No meningism was reported. Apart from the findings of Bell’s palsy, his neurologic examination was unremarkable. The cardiovascular examination result was normal except for the bradycardia. A lumbar puncture revealed 45 white blood cells/mm3, with 56% lymphocytes, 40% monocytes, 3% atypical lymphocytes and 1% neutrophils in the CSF. CSF glucose was mildly decreased at 51 mg/dL. CSF protein was normal 43 mg/dL. 694
Seslar et al
The diagnosis of Lyme disease was again confirmed by serum serologic studies. The enzyme-linked immunosorbent assay (ELISA) for Lyme immunoglobulin G/immunoglobulin M antibodies was positive. Western blot analysis for immunoglobulin M was positive. The patient was admitted for intravenous ceftriaxone therapy and cardiac monitoring. The ECG result on the day of admission was notable for mild first-degree AV block (PR ⫽ 200 ms), T-wave inversion in leads II, III, and AVF, and a QTc of 520 ms (Table). Shortly after admission, on post onset of illness day 9, he exercised using a Bruce treadmill protocol for 15 minutes, with above-average exercise tolerance. ECG done during exercise demonstrated a baseline QTc interval in lead II of 560 ms at rest (Figure 2). During activity the QTc shortened to 500 ms, during recovery, it shortened further to 460 to 520 ms, although it did not normalize during the study. Occasional single ventricular premature beats were seen during stage 4 to 5. Similar to patient 1, there were no additional markers of repolarization instability such as ST-T wave changes, torsades de pointes, or microvolt T-wave alternans. Again historic and laboratory investigation did not reveal any obvious congenital or secondary causes of QT prolongation. Echocardiography demonstrated hyperdynamic left ventricular function with otherwise normal findings. The patient was discharged home to complete a 4-week course of intravenous ceftriaxone. A 24-hour Holter monitor performed soon after going home showed unremarkable sinus rhythm, although there continued to be an unusual T-wave morphology with prolonged corrected QT intervals. Follow-up exercise testing and ECG, done on post-illness onset day 41, showed average exercise tolerance for age and complete normalization of his QTc and PR intervals (Table). He has remained symptom free and has resumed full athletic participation.
Patient III A previously healthy 13-year-old male presented in early September with a history of a small circular rash on the flexor surface of his left forearm. Concomitant with the rash, he reported having had a mild headache and mild arthralgia of both knees and elbows. One week before admission, he began The Journal of Pediatrics • May 2006
Figure 2. Twelve-lead ECGs from patient 2 early in illness. ECG is performed with standard 25 mm/sec and 10 mm/mV amplitude.
to experience left-sided facial numbness and paralysis, with increased arthralgia of both knees and elbows. He resided in the mid-Atlantic states, although his recent travels included New York, Georgia, Alabama, and Connecticut. He was diagnosed with Lyme disease by ELISA in a local emergency department, placed on oral doxycycline, and discharged home. One week later, he returned for follow-up at his primary care provider’s office where ECG demonstrated mild first-degree AV block (PR 200 ms). Because of the Bell’s palsy and atrioventricular block, he was admitted to the hospital for parenteral antibiotic therapy. At the time of admission, review of systems demonstrated continued left-sided facial weakness, mild headache, and mild arthralgia of the knees and elbows. He also noted mild dyspnea on exertion with climbing stairs. Physical examination revealed Bell’s palsy. There was no meningism. Neurologic examination was otherwise unremarkable. His resting heart rate was normal at 65 beats/min, and he demonstrated a normal cardiovascular examination result. No rashes were noted. He was tender to palpation and range of motion testing in both knees. ECG demonstrated a mildly prolonged PR interval, as described above, and a QTc of 500 ms (Figure 3). Assessment for secondary causes of the prolonged QT interval, as with the previous patients, was negative. Doxycycline was discontinued and he was begun on intravenous ceftriaxone. Serial ECG was performed. Over the following 2 days the QTc ranged from 500 to 520 ms (Table; Figure 3). An echocardiography result was normal. After an unremarkable inpatient course, he was Transient Prolonged Corrected QT Interval in Lyme Disease
discharged after 3 days to complete 3 weeks of ceftriaxone at home. Subsequently, he was lost to follow-up, and repeat evaluation of his QT interval has not yet been obtained.
DISCUSSION We report 3 patients with Lyme carditis who manifested prolongation of the QT interval, in addition to the varying degrees of AV nodal block more characteristic of this disease. The differential diagnosis of QT interval prolongation has traditionally been divided into primary (ie, congenital LQTS) or secondary (acquired) causes. In 2 of the 3 cases, primary LQTS was deemed unlikely given the normal screening ECGs done on family members, the unremarkable nature of the family histories, and perhaps most importantly, the complete normalization of the patient’s QT interval observed during follow-up. In each case, common causes of acquired long QT syndrome were excluded, including electrolyte abnormalities and drug effect. Less commonly, significant central nervous system (CNS) injury has been associated with prolongation of the QT interval.2,3 While each patient in this series had some form of Lyme-related CNS involvement, the clinical impact of this involvement was mild, and symptomatic neurologic improvement significantly preceded normalization of the QT interval. Hence, it seems unlikely that the derangement of the QT interval was secondary to the CNS effects of Lyme disease in these patients. Bundle branch blocks have been reported in association with Lyme carditis4 and could result in a longer QT interval because of longer QRS duration.5 However, each of these patients had normal 695
Figure 3. Twelve-lead ECG from patient 3 early in illness. E ECG is performed with standard 25 mm/sec and 10 mm/mV amplitude.
QRS duration and the corrected JT intervals (QT intervalQRS duration) were prolonged as well (Table). These cases therefore suggest the possibility that acquired long QT syndrome can result specifically from Lyme-induced carditis. The mechanism by which Lyme carditis could result in QT prolongation is unknown. Although not previously reported in association with Lyme carditis, prolongation of the QT interval has been reported in several other paradigms. For example, exposure to anthracyclines, used in the treatment of variety of adult and pediatric malignancies, has been associated with QTc prolongation.6,7 As with Lyme carditis–mediated QT prolongation, the mechanism of this association is unclear but may reflect a non-specific effect of myocyte injury. In other cases, QT prolongation may result from an autoantibody mediated myocardial injury, as in the case of infants born with a prolonged QT interval in the setting of antiLa/Ro antibodies.8 In both congenital heart block and anthracycline toxicity of those patients also have quite significant myocardial dilation, which may contribute to their findings. Perhaps the best-characterized paradigm of is that of drug induced QT prolongation, in which cardiac ion-channel gene polymorphisms have recently been shown to render afflicted individuals exceptionally sensitive to the QT prolonging effect of certain drugs.9-11 On the basis of histopathologic data, the more common cardiac manifestations of Lyme disease are thought to be due to direct invasion of the cardiac tissue by the spirochete or by the inflammatory response induced by the organism’s presence.12 It 696
Seslar et al
is not clear why the organism predominantly affects the conduction system and more specifically the atrioventricular nodal tissue. Intracardiac electrophysiological studies in patients with Lyme carditis with complete heart block have demonstrated supra-Hisian block with little or no ventricular escape rhythm. No abnormalities in repolarization were noted.13,14 How recovery of AV conduction temporally relates to elimination of the organism and dissolution of the inflammatory response has not been systematically studied in human beings. In a mouse model of Lyme carditis, researchers have shown that the resolution of the inflammatory response closely parallels the correction of all electrophysiological abnormalities in these mice.15 Given the parallels between recovery of AV node function and QT normalization in these patients, we presume that the same pathologic process causes both electrophysiological abnormalities, although the nature of this process and whether these patients have some intrinsic (eg, genetic) vulnerability remains a matter of speculation. At the time of these cases there was not commercially available gene testing for LQTS. This test demonstrates a 30% “false-negative” rate in patients with clear clinical diagnoses of genetic long QT. Hence, the diagnosis of long QT remains a clinical/phenotype diagnosis. The T-wave patterns between patients 1 and 2 were biphasic in multiple leads reminiscent of the HERG defects in long QT 2, whereas patient 3 had a broader T wave without the biphasic character seen in the first 2.16 These patients were previously healthy and had no indication for an ECG before their illness. Hence, we are unable to comment on preexisting ECG abnormalities. This The Journal of Pediatrics • May 2006
is particularly relevant in patient 3 who did not get effective follow-up or demonstrate resolution of the ECG findings. As with any isolated case series, this experience cannot assess the incidence or implications of prolonged QTc in the setting of Lyme carditis. Systemic review of ECGs in patients with clinical Lyme disease will be required to understand the epidemiologic condition of this association. Given its apparent rarity, identification of an individual with a prolonged QT interval in the setting of Lyme disease should prompt a thorough evaluation for other more common causes of QT prolongation. In addition, it would be reasonable to obtain screening ECG’s on first-degree relatives. It is notable that none of the patients discussed here had documented ventricular arrhythmia or symptoms attributable to QT prolongation, despite potentially provocative exercise testing. Even though the absolute daily risks are quite low in congenital long QT, any patient with significant prolongation of the QT interval is at increased risk of torsades de pointes and cardiac syncope. As such, patients with Lyme carditis that manifest QTc prolongation should be counseled to avoid medications that may further prolong the QT/JT intervals. In addition, these patients should probably be counseled to avoid vigorous exercise until conduction returns to normal and repolarization has normalized.17 If our experience is representative, serial ECG performed over a 2- to 3-month period of time should demonstrate normalization of the corrected QT interval. We suggest that close cardiology follow-up is warranted, at least until the QT interval has normalized and any coexisting cardiovascular manifestations of Lyme disease have resolved, and the transient nature of the finding confirmed.
REFERENCES 1. Pinto DS. Cardiac manifestations of Lyme disease. Med Clin North Am 2002;86:285-96. 2. Eckardt M, Gerlach L, Welter FL. Prolongation of the frequencycorrected QT dispersion following cerebral strokes with involvement of the insula of Reil. Eur Neurol 1999;42:190-3. 3. Lindgren A, Wohlfart B, Pahlm O, Johansson BB. Electrocardio-
Transient Prolonged Corrected QT Interval in Lyme Disease
graphic changes in stroke patients without primary heart disease. Clin Physiol 1994;14:223-31. 4. van der Linde MR. Lyme carditis: clinical characteristics of 105 cases. Scand J Infect Dis Suppl 1991;77:81-4. 5. Berul CI, Sweeten TL, Dubin AM, Shah MJ, Vetter VL. Use of the rate-corrected JT interval for prediction of repolarization abnormalities in children. Am J Cardiol 1994;74:1254-7. 6. Bender KS, Shematek JP, Leventhal BG, Kan JS. QT interval prolongation associated with anthracycline cardiotoxicity. J Pediatr 1984;105:442-4. 7. Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993;11:1906-10. 8. Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43:1049-53. 9. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175-87. 10. Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H, et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002;106:1269-74. 11. Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691-6. 12. de Koning J, Hoogkamp-Korstanje JA, van der Linde MR, Crijns HJ. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease. J Infect Dis 1989;160:150-3. 13. van der Linde MR, Crijns HJ, Lie KI. Transient complete AV block in Lyme disease. Electrophysiological observations. Chest 1989;96:219-21. 14. van der Linde MR, Crijns HJ, de Koning J, Hoogkamp-Korstanje JA, de Graaf JJ, Piers DA, et al. Range of atrioventricular conduction disturbances in Lyme borreliosis: a report of four cases and review of other published reports. Br Heart J 1990;63:162-8. 15. Saba S, VanderBrink BA, Perides G, Glickstein LJ, Link MS, Homoud MK, et al. Cardiac conduction abnormalities in a mouse model of Lyme borreliosis. J Interv Card Electrophysiol 2001;5:137-43. 16. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929-34. 17. Maron BJ, Zipes DP. Introduction: eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol 2005;45:1318-21.
697