354
Breath Holding Spells in Children with Long QT Syndrome Jeffrey A. Robinson, MD,* J. Martijn Bos, MD, PhD,*§ Susan P. Etheridge, MD,† and Michael J. Ackerman, MD, PhD*‡§ *Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, ‡Department of Medicine, Division of Cardiovascular Diseases and §Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minn; †Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA ABSTRACT
Background. Long QT syndrome (LQTS) is a genetic heart rhythm disorder that may present with syncope, seizures, or sudden cardiac death. Breath holding spells (BHS) occur in 5% of all children and have been noted in children with LQTS anecdotally. The purpose of this study was to determine the frequency of BHS in children diagnosed with LQTS at ≤5 years of age. Design. A retrospective review was performed to identify children diagnosed with LQTS who were ≤5 years old at initial presentation to our LQTS clinic from August 1999 to November 2013. The mean length of follow-up was 6.4 ± 2.8 years. The electronic medical records were reviewed for clinical presentation of BHS, as well as LQTSassociated symptoms, diagnostic tests, and treatment. Results. The study cohort consisted of 115 children with LQTS (58% male; median age at diagnosis, 11 months [range, birth to 5 years]; mean corrected QT interval (QTc), 478 ± 60 milliseconds). At presentation, 80% of patients were asymptomatic. Genetic testing revealed type 1 LQTS (LQT1) in 48%. Overall, 5 of 115 patients (4.3%) had BHS (2 of 5 [40%] male, mean QTc: 492 ± 14 milliseconds, 4 [80%] with family history of LQTS). BHS were the presenting symptom in 1 of 23 symptomatic patients (4.3%). All BHS occurred in patients with LQT1 (P = .02). Conclusions. Although BHS among children with LQTS are relatively rare and occur at similar frequency as the general population, they can be the presenting symptom for a heart rhythm disorder. Careful attention to BHS is important to distinguish an innocent BHS from a potential LQTS-triggered cardiac event so that proper treatment is initiated. Key Words. Long QT Syndrome; Breath Holding Spells; Spells; Children; Torsades de Pointes
Introduction
Q
T prolongation is an electrocardiographic abnormality that may present in childhood with syncope, seizures, or sudden cardiac death (SCD). QT prolongation can occur transiently in the general population, for example, consequent to medications, electrolyte abnormalities, or endocrine disease. However, in approximately 1 in 2500 people, QT prolongation is congenital, commonly caused by mutations of cardiac ion channels (congenital long QT syndrome [LQTS]).1 Patients with LQTS are at an increased risk for developing life-threatening arrhythmias stemming from the
Congenit Heart Dis. 2015;10:354–361
trademark LQTS-triggered arrhythmia, known as torsades de pointes (TdP). Treatment is therefore targeted at reducing this torsadogenic potential. While the mainstay treatment is pharmacological (predominantly beta-blockers), left cardiac sympathetic denervation (LCSD) and implantable cardioverter defibrillator (ICD) placement are also utilized to decrease mortality. In contrast, breath holding spells (BHS) are a relatively common occurrence in the general pediatric population, found in approximately 5% of all children, with typical age of onset between 6 and 18 months.2 Classically, BHS are precipitated by a strong emotional stimulus, immediately after © 2015 Wiley Periodicals, Inc.
Breath Holding Spells and Long QT Syndrome
355
which there is a vigorous cry followed by cessation of normal respiration. Breathing is held, generally in expiration, for at least 20 seconds. Both cyanotic and pallid episodes have been described. Although the majority of BHS resolve spontaneously without apparent soliloquy, others may lead to temporary loss of consciousness, limpness, posturing, clonic jerking, or urine incontinence.3 Moreover, self-limited asystole (a sinus pause of up to 25 seconds) has been recorded during typical BHS in children under 2 years of age.4 Although BHS by themselves are generally benign, various underlying conditions may also be present. While BHS have been reported anecdotally as the presenting symptom in children with LQTS,5 the true incidence of BHS among children with LQTS is unknown. Therefore, the purpose of this study was to determine the frequency and clinical phenotype of BHS in children diagnosed with LQTS at ≤5 years of age.
seizures, or cardiac arrest), past medical history, family history of LQTS and SCD, and all LQTSassociated diagnostic tests and treatments. For electrocardiograms (ECGs), all corrected QT intervals (QTc) obtained were first estimated by computer and then verified by manual measurement and calculation at the time of consultation. BHS were defined as a period of apnea (>20second pause in respiration), preceded by a strong emotional precipitant and followed by either gross color changes (cyanosis or pallor) or loss of consciousness with spontaneous recovery. Statistical analyses were performed using JMP Software (version 9.0.1, SAS Institute, Inc., Cary, NC, USA) utilizing Fisher’s exact test. A P value < .05 was considered statistically significant.
Methods
This study complies with the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board. A retrospective review of the electronic medical record (EMR) was performed to identify all children ≤5 years of age at initial presentation to Mayo Clinic’s Long QT Syndrome Clinic from August 1999 through November 2013. All documentation reviewed was authored by a single physician (MJA); however, management for BHS or LQTS may have been initiated prior to the patient’s first visit to this referral clinic. Charts were reviewed for all details surrounding the evaluation and diagnosis of LQTS, including associated symptoms (syncope, Table 1.
Results
Overall, 115 patients ≤5 years of age (67 male [58%]; median age at presentation, 11 months [range, 0 to 5 years]) were included in the study cohort. Baseline patient characteristics are outlined in Table 1. All patients were diagnosed clinically and/or genetically with LQTS. Among these 115 patients, the mean QTc was 478 ± 60 milliseconds. The contribution of each LQTS genotype in the study cohort is represented in Figure 1, with type 1 LQTS (LQT1) comprising the majority (48%) of genotype-positive LQTS. The mean follow-up for these patients in our Long QT Syndrome Clinic was 6.4 ± 2.8 years. The majority of the children (92/115; 80%) were asymptomatic at presentation, having been diagnosed with LQTS from an incidental ECG finding or from cascade screening consequent to established familial LQTS. As such, 23 (20%) of
Demographics of Study Cohort, BHS Chort and Remaining LQTS Patients
n Gender, M/F (% male) Mean age at diagnosis, mo (range) Mean QTc, ms Symptomatic at presentation, n (%) First symptom, n (%) None Syncope or seizure Fetal arrhythmia Cardiac arrest BHS Family history of LQTS, n (%) Family history of SCD, n (%)
Study Cohort
BHS
Remaining LQTS Patients
115 67/48 (58) 11 mo (0 to 5 y) 478 ± 60 23 (20)
5 65/45 (60) 12 mo (0 to 2.6 y) 481 ± 27 1 (20)
110 2/3 (40) 22 mo (0 to 6.1 y) 477 ± 61 22 (20)
92 (80%) 8 (7%) 8 (7%) 6 (5%) 1 (1%) 92 (80%) 46 (40%)
4 (80) 0 (0) 0 (0) 0 (0) 1 (20) 2 (40) 1 (20)
88 (80) 9 (8) 8 (7) 5 (5) 0 (0) 79 (72) 43 (39)
Demographics or the study cohort, BHS cohort, and remaining patients are shown in the table above. Although limited by the small number of patients, there were no significant clinical differences between the patients with BHS and the remaining LQTS patients. BHS, breath holding spells; F, female; LQTS, long QT syndrome; M, male; QTc, corrected QT interval; SCD, sudden cardiac death.
Congenit Heart Dis. 2015;10:354–361
356
Robinson et al.
Figure 1. Breakdown of study cohort (n = 115) by long QT syndrome (LQTS) genotype. Pie chart showing the breakdown by LQTS genotype for the study cohort with majority of patients classified as type 1 LQTS (LQT1).
Figure 2. Frequency of breath holding spells (BHS) (%) by long QT syndrome (LQTS) genotypes. Bar diagram showing the frequency of BHS in general population, LQTS cohort, and by LQTS subtype. 1Frequency of BHS in the general population as defined by Lombroso and Lerman.
the total 115 patients were symptomatic at the time of initial presentation, with first symptoms including syncope or seizure, fetal arrhythmia, cardiac arrest, or BHS. At diagnosis, the most common presenting symptoms were syncope or seizure (n = 8, 35%) and fetal arrhythmia (n = 8, 35%), while a BHS was the presenting symptom in 1 (4%) of these 23 symptomatic patients. Overall, 5 of 115 patients with LQTS (4.3%) had BHS on systems review. The 5 cases are sumCongenit Heart Dis. 2015;10:354–361
marized in Table 2. Of these, 2 of 5 (40%) were male, 4 of 5 (80%) had a known family history of LQTS, and 2 patients (Cases Nos. 2 and 3) were siblings. The mean QTc for these five patients was 492 ± 14 milliseconds. All 5 patients with BHS had LQT1 (Figure 2). Two patients had more than one LQTS-associated mutation, with one patient (Case No. 5) having a maternal LQT1-causative mutation (Arg591His-KCNQ1) and a paternally derived type 5 LQTS (LQT5)-associated
Pacemaker placed at 30 mo of age ∼30 BHS noted in total
F
F
4
5
LQT1/LQT5
R591H-KCNQ1 and S28L-KCNE1
482
None
Propranolol; videoscopic LCSD
14 mo
None Twice weekly 18 mo Propranolol None 508 G568R-KCNQ1
F 3
LQT1
None Weekly 12 mo Propranolol None 477 I235N-KCNQ1
M 2
LQT1
None Twice daily 6 mo Propranolol None 505 I235N-KCNQ1
M 1
LQT1
Sex No.
BHS, breath holding spells; F, female; LCSD, left cardiac sympathetic denervation; LQTS, congenital long QT syndrome; LQT1, type 1 LQTS; LQT5, type 5 LQTS; M, male; QTc, corrected QT interval.
Ongoing at last visit (55 mo)
61 mo
Ongoing at last visit (14 mo) 40 mo
34 mo
Spells were diagnosed as BHS and as seizures, prior to discovery of LQTS Known family history of LQT1; BHS resolved spontaneously Sister of Case 2; BHS resolved spontaneously Known family history of LQT1; no initial symptoms except BHS Holter recording showed prolonged asystole during an episode None Weekly, starting at 18 mo of age 31 mo Propranolol; videoscopic LCSD BHS spells 486
Other Mutation
V215M-KCNQ1 and W392X-KCNQ1
Intervention for BHS Frequency of BHS Age at Diagnosis of BHS Treatment for LQTS Symptoms at LQTS Diagnosis QTc (ms) LQTS Genotype
Characteristics of Children with LQTS and Concomitant BHS Table 2.
LQT1
Age at Resolution of BHS
Breath Holding Spells and Long QT Syndrome
357 mutation (Ser28Leu-KCNE1). BHS occurred in 9% of all LQT1 patients, but in none of the other LQTS genetic subtypes (P = .02), with the exception of the LQT1/LQT5 compound genotype as described in Case No. 5. All 5 patients with BHS were described as very active, healthy, and vibrant; they had met age-appropriate developmental milestones. Aside from the LQTS, there were no additional or ongoing medical concerns documented for these five patients. Case No. 1 presented to our clinic at 3 years of age. At 18 months of age, he experienced the first of many, seizure-like episodes, described as prolonged periods of altered consciousness. Given suspicion for generalized seizure, he underwent a comprehensive neurological evaluation, but no clear evidence for seizure disorder was found, and he was diagnosed with BHS. Regardless, he was started on phenytoin (Dilantin) because of the frequent recurrence of his spells. Between 25 and 30 similar, self-resolving episodes occurred over a 13-month span, all precipitated by ageappropriate physical activity (running or playing) or temper tantrums. Then, at 31 months of age, the patient collapsed during play. Whereas previous instances had ended in brief loss of consciousness, this episode resulted in cardiac arrest requiring cardiopulmonary resuscitation (CPR). Normal sinus rhythm spontaneously returned, without application of an external defibrillator. Upon review by a neurologist, a concomitant diagnosis of LQTS was suspected and subsequent ECG showed a QTc of 486 milliseconds with abnormal T-waves. The patient was diagnosed with LQTS and started on betablocker therapy. While taking the beta-blocker over the next 3 months, 3 breakthrough spells occurred (similar to those described before, with only brief loss of consciousness). This prompted implantation of a loop recorder at 34 months of age. During a particularly intense temper tantrum, the device captured a significant breakthrough episode of recurrent self-terminating TdP/polymorphic ventricular tachycardia (5 distinct instances over a span of 5 minutes, none requiring defibrillation; Figure 3). At that time, genetic analysis demonstrated two discrete LQT1 mutations residing on separate KCNQ1 alleles: Val215Met-KCNQ1 and Trp392Ter-KCNQ1. The loop recorder demonstrated QTc measurements of 550–600 milliseconds immediately preceding TdP (Figure 3) despite beta-blocker therapy. The patient was deemed at significant risk for further Congenit Heart Dis. 2015;10:354–361
358
Robinson et al.
Figure 3. (A) Prolonged corrected QT interval (QTc) 550–600 milliseconds. Tracing from a loop recording device starting at the zero-second time interval (as noted along the x-axis), immediately preceding an episode of self-terminating torsades/ polymorphic ventricular tachycardia. (B) Self-limited torsades/polymorphic ventricular tachycardia. An implanted loop recorder device demonstrated episodic, self-limited torsades/polymorphic ventricular tachycardia in a 34-month-old boy during an intense temper tantrum. This tracing starts at the 72-second mark, following the tracing in (A).
breakthrough ventricular arrhythmia and for this reason, LCSD surgery was performed. Despite all interventions, the patient had a single out-ofhospital cardiac arrest with external defibrillator rescue at 42 months of age, which prompted ICD placement as secondary prevention of sudden death. In retrospect, it is unclear which of the Congenit Heart Dis. 2015;10:354–361
many previous spells were BHS and which were potentially LQTS-triggered episodes of TdP. Case No. 2 was born with a known family history of genetically proven LQT1 (Ile235AsnKCNQ1). On his first day of life, the QTc was 505 milliseconds and prophylactic propranolol was initiated. At 6 months of age, classic BHS were first
Breath Holding Spells and Long QT Syndrome
359
noted, ranging in frequency from twice daily spells to no spells for up to 4 weeks. All were associated with either tiredness or emotional upset. Most BHS were accompanied with brief loss of consciousness and spontaneous recovery always occurred. While a 24-hour Holder monitor recorded a single 3.5-second sinus pause during rest, no such pauses were noted during typical BHS. Patient was asymptomatic from an LQT1 standpoint. Case No. 3 (the sister of Case No. 2) was diagnosed similarly based on family history mutationspecific cascade genetic testing. Although initial ECG showed QTc of 444 milliseconds, prophylactic propranolol was started. Around 12 months of age, stereotypical BHS were noted. Breath holding lasted approximately 30 to 60 seconds, usually following an intense cry. After turning blue and becoming limp, spontaneous recovery occurred within 3 seconds. These BHS continued, with once-weekly occurrence representing the most intense frequency at approximately age 2 years, and subsequently resolved by 3 years of age. As of most recent follow-up (at 5 years of age), the patient had otherwise remained completely asymptomatic for LQT1-associated symptoms. For Case No. 4, stereotypical BHS had started at about 18 months of age and persisted at a frequency of approximately one event per week— some resulting in physical collapse—with complete and spontaneous recovery after 30 to 60 seconds. Holter monitoring recorded up to a 7-second sinus pause during one such event. BHS persisted until 5 years of age, without further recurrence. The patient’s family history of genetically proven LQT1 (Gly568Arg-KCNQ1) was discovered when the patient was 24 months old, after which propranolol was started. QTc at that time was 460 milliseconds. As of most recent follow-up (6.5 years of age), QTc was 478 milliseconds and the patient was asymptomatic with respect to the LQT1. Case No. 5 had a known maternal family history of LQT1 at birth with a QTc of 540 milliseconds; propranolol was started at that time. At age of 10 months, the patient was playing quietly when she collapsed and lost consciousness. Though spontaneous recovery occurred, the incident (which occurred while the patient was on propranolol) stimulated further investigation. Comprehensive genetic testing was initiated after this event, revealing a compound LQT1/LQT5 genotype. The patient harbored the maternal
LQT1 mutation (Arg591His-KCNQ1), as well as a paternal LQT5 mutation (Ser28LeuKCNE1). Seemingly typical BHS started at 14 months of age, with each episode generally involving a protracted loss of consciousness and occasionally involving seizure-like activity. During one such episode (at 2.5 years of age), a Holter recorded prolonged asystole, prompting an implantation of a pacemaker for severe BHS. By age 4.5 years, approximately 30 classic BHS episodes had occurred. Given concern for the previously recorded LQT1/LQT5-triggered syncopal episodes while on beta-blocker therapy, videoscopic LCSD was performed at this age and there have been no LQT1/LQT5-related recurrences thus far. In addition, BHS resolved by 5 years of age. On review, it was believed that the patient had exhibited both BHS and LQT1/LQT5-related episodes. Discussion
BHS in young children are common and benign events that usually resolve by 6 years of age without further known complications or soliloquy. To our knowledge, this is the first study describing the prevalence of BHS among a referral cohort of children with LQTS, with an estimated prevalence of 4.3% among our cohort of patients. This frequency did not differ from that described in the general population, reported as early as 1967 to be 4.7% in a prospective survey of children aged 2 to 6 years at an academic medical center in the United States.2 Similarly, a cross-sectional survey published in 2013 from Turkey found a prevalence of BHS of 3.6% among the general population of children up to 6 years of age.6 While the exact cause of BHS is unknown, the similar frequencies in our LQTS cohort compared with the general population suggest there is no causal relationship/ interaction between the two. An underlying genetic etiology or predisposition for BHS has not been discovered. On review of the current literature, there are no associations identified between specific genetic mutations and BHS. Various mechanisms have been proposed regarding the cause of BHS, including neurologic, autonomic, metabolic, and cardiac. Currently, no studies have linked QTc changes or LQTS to BHS. Some have suggested an association between BHS and autonomic dysfunction.7 Moreover, markers of autonomic nervous system function have been correlated with the phenotypic variabilCongenit Heart Dis. 2015;10:354–361
360 ity in patients with KCNQ1-mediated LQTS (i.e., LQT1).8,9 However, a link between the two could not be established based on our current study and further studies would be needed to determine whether the concomitant occurrence of BHS and autonomic dysfunction can be attributed to effects of the same autonomic pathways. Among the patients in our cohort, no heritable pattern for BHS was apparent as per medical history; none of the parents mentioned having BHS themselves as a child. It must be acknowledged from the cohort herein that all 5 cases of BHS in LQTS were found to occur in patients with KCNQ1-encoded LQT1-causative mutations. Despite a uniform LQT1 genotype in these cases, the causative LQT1 mutations were all at different loci and no common variant was identified. Based on these observations and the fact that the prevalence of BHS in our LQTS cohort was similar to the normal population, it seems most likely that LQTS and BHS were unrelated findings without—at this moment—a common pathogenetic link. Nevertheless, it must be recognized that for some children with LQTS, episodes mimicking a BHS could be the presenting symptom of a potentially life-threatening disease. Therefore, distinguishing the “benign” BHS from an LQTStriggered torsadogenic episode is of the utmost importance. BHS are much more common than LQTS, occurring in approximately 1 in 20 children vs. 1 in 2000, respectively. As such, BHS are encountered frequently in a pediatric practice. Clinicians must be careful not to overtreat or overinterpret the root cause when confronted with a classicsounding BHS—even when that spell occurred in a child who has concomitant LQTS. This case series demonstrates that the interpretation of spells in young children can be challenging to decode clinically. At present, to our knowledge, there is no guideline or evidencebased algorithm for the diagnosis and management of a child suspected of having BHS. Certainly, not all children presenting to general practice or pediatric cardiology clinics with a questionable BHS require ECG screening for LQTS. In addition, not every spell occurring in a child with known LQTS is necessarily a torsadogenic one. Admittedly, the scope of this study precludes comprehensive recommendations for detecting LQTS in patients presenting with spells. In any case, history should be the hallmark in determinCongenit Heart Dis. 2015;10:354–361
Robinson et al. ing what further testing is required. While an episode may be comprised of a BHS and spontaneous recovery, it always remains a possibility that an LQTS-triggered event could be at play. Likewise, a fainting episode could result directly because of LQTS, in the absence of a breath hold. Overall, the following points should prompt further investigation with ECG for LQTS in patients presenting with spells: • Loss of consciousness • Spells that persist and occur beyond 6 years of age • Family history of spells, LQTS, arrhythmia, or sudden death Lastly, it is certainly possible that the frequency of BHS in LQTS could have been underestimated in the present study. As is the nature of retrospective research, inquiry for BHS may not have been completed during every clinical encounter or may not have been fully detailed in the EMR. Though both cyanotic and pallid types of BHS have been described, these sometimes were not distinguished in the clinical notes. Conclusions
In our study of this pediatric LQTS cohort, approximately 1 in 25 children with LQTS experiences BHS, a frequency similar to the general population. Although BHS are usually benign and resolve by 6 years of age, distinguishing a nonarrhythmic BHS from an LQTS-triggered cardiac event is important to avoid misdiagnosis and inappropriate treatment. Authors’ Contributions JAR: Data collection, data analysis/interpretation, statistics, and drafting the article. JMB: Data analysis/interpretation, statistics, and critical revision of the article. SPE: Concept/design and critical revision of the article. MJA: Concept/design and critical revision of the article.
Corresponding Author: Michael J. Ackerman, MD, PhD, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-2840101; Fax: 507-284-3757; E-mail: ackerman.michael@ mayo.edu Conflict of interest: Dr. Ackerman is a consultant for Boston Scientific, Gilead Sciences, Medtronic, St. Jude
Breath Holding Spells and Long QT Syndrome
361
Medical, and Transgenomic. Mayo Clinic and MJA receive royalties from Transgenomic with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests. The other authors have no conflicts of interest to disclose. None of the disclosures pertain to this study and none of the companies provided financial support for this study.
5 Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–1767. 6 Carman KB, Ekici A, Yimenicioglu S, Arslantas D, Yakut A. Breath holding spells: point prevalence and associated factors among Turkish children. Pediatr Int. 2013;55:328–331. 7 Kolkiran A, Tutar E, Atalay S, Deda G, Cin S. Autonomic nervous system functions in children with breath-holding spells and effects of iron deficiency. Acta Paediatr. 2005;94:1227–1231. 8 Schwartz PJ, Vanoli E, Crotti L, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol. 2008;51:920–929. 9 Crotti L, Spazzolini C, Porretta AP, et al. Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. J Am Coll Cardiol. 2012;60:2515–2524.
Accepted in final form: March 23, 2015. References
1 Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics. 1967;39:563–581. 2 Rathore G, Larsen P, Fernandez C, Parakh M. Diverse presentation of breath holding spells: two case reports with literature review. Case Rep Neurol Med. 2013;2013:603190. 3 Kanter RJ. Pediatric electrophysiology. Curr Opin Cardiol. 1993;8:119–127. 4 Franklin WH, Hickey RW. Images in clinical medicine. Long QT syndrome. N Eng J Med. 1995;333:355.
Congenit Heart Dis. 2015;10:354–361
Breath Holding Spells in Children with Long QT Syndrome Jeffrey A. Robinson, MD,* J. Martijn Bos, MD, PhD,*§ Susan P. Etheridge, MD,† and Michael J. Ackerman, MD, PhD*‡§ *Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, ‡Department of Medicine, Division of Cardiovascular Diseases and §Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minn; †Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA ABSTRACT
Background. Long QT syndrome (LQTS) is a genetic heart rhythm disorder that may present with syncope, seizures, or sudden cardiac death. Breath holding spells (BHS) occur in 5% of all children and have been noted in children with LQTS anecdotally. The purpose of this study was to determine the frequency of BHS in children diagnosed with LQTS at ≤5 years of age. Design. A retrospective review was performed to identify children diagnosed with LQTS who were ≤5 years old at initial presentation to our LQTS clinic from August 1999 to November 2013. The mean length of follow-up was 6.4 ± 2.8 years. The electronic medical records were reviewed for clinical presentation of BHS, as well as LQTSassociated symptoms, diagnostic tests, and treatment. Results. The study cohort consisted of 115 children with LQTS (58% male; median age at diagnosis, 11 months [range, birth to 5 years]; mean corrected QT interval (QTc), 478 ± 60 milliseconds). At presentation, 80% of patients were asymptomatic. Genetic testing revealed type 1 LQTS (LQT1) in 48%. Overall, 5 of 115 patients (4.3%) had BHS (2 of 5 [40%] male, mean QTc: 492 ± 14 milliseconds, 4 [80%] with family history of LQTS). BHS were the presenting symptom in 1 of 23 symptomatic patients (4.3%). All BHS occurred in patients with LQT1 (P = .02). Conclusions. Although BHS among children with LQTS are relatively rare and occur at similar frequency as the general population, they can be the presenting symptom for a heart rhythm disorder. Careful attention to BHS is important to distinguish an innocent BHS from a potential LQTS-triggered cardiac event so that proper treatment is initiated. Key Words. Long QT Syndrome; Breath Holding Spells; Spells; Children; Torsades de Pointes
Introduction
Q
T prolongation is an electrocardiographic abnormality that may present in childhood with syncope, seizures, or sudden cardiac death (SCD). QT prolongation can occur transiently in the general population, for example, consequent to medications, electrolyte abnormalities, or endocrine disease. However, in approximately 1 in 2500 people, QT prolongation is congenital, commonly caused by mutations of cardiac ion channels (congenital long QT syndrome [LQTS]).1 Patients with LQTS are at an increased risk for developing life-threatening arrhythmias stemming from the
Congenit Heart Dis. 2015;10:354–361
trademark LQTS-triggered arrhythmia, known as torsades de pointes (TdP). Treatment is therefore targeted at reducing this torsadogenic potential. While the mainstay treatment is pharmacological (predominantly beta-blockers), left cardiac sympathetic denervation (LCSD) and implantable cardioverter defibrillator (ICD) placement are also utilized to decrease mortality. In contrast, breath holding spells (BHS) are a relatively common occurrence in the general pediatric population, found in approximately 5% of all children, with typical age of onset between 6 and 18 months.2 Classically, BHS are precipitated by a strong emotional stimulus, immediately after © 2015 Wiley Periodicals, Inc.
Breath Holding Spells and Long QT Syndrome
355
which there is a vigorous cry followed by cessation of normal respiration. Breathing is held, generally in expiration, for at least 20 seconds. Both cyanotic and pallid episodes have been described. Although the majority of BHS resolve spontaneously without apparent soliloquy, others may lead to temporary loss of consciousness, limpness, posturing, clonic jerking, or urine incontinence.3 Moreover, self-limited asystole (a sinus pause of up to 25 seconds) has been recorded during typical BHS in children under 2 years of age.4 Although BHS by themselves are generally benign, various underlying conditions may also be present. While BHS have been reported anecdotally as the presenting symptom in children with LQTS,5 the true incidence of BHS among children with LQTS is unknown. Therefore, the purpose of this study was to determine the frequency and clinical phenotype of BHS in children diagnosed with LQTS at ≤5 years of age.
seizures, or cardiac arrest), past medical history, family history of LQTS and SCD, and all LQTSassociated diagnostic tests and treatments. For electrocardiograms (ECGs), all corrected QT intervals (QTc) obtained were first estimated by computer and then verified by manual measurement and calculation at the time of consultation. BHS were defined as a period of apnea (>20second pause in respiration), preceded by a strong emotional precipitant and followed by either gross color changes (cyanosis or pallor) or loss of consciousness with spontaneous recovery. Statistical analyses were performed using JMP Software (version 9.0.1, SAS Institute, Inc., Cary, NC, USA) utilizing Fisher’s exact test. A P value < .05 was considered statistically significant.
Methods
This study complies with the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board. A retrospective review of the electronic medical record (EMR) was performed to identify all children ≤5 years of age at initial presentation to Mayo Clinic’s Long QT Syndrome Clinic from August 1999 through November 2013. All documentation reviewed was authored by a single physician (MJA); however, management for BHS or LQTS may have been initiated prior to the patient’s first visit to this referral clinic. Charts were reviewed for all details surrounding the evaluation and diagnosis of LQTS, including associated symptoms (syncope, Table 1.
Results
Overall, 115 patients ≤5 years of age (67 male [58%]; median age at presentation, 11 months [range, 0 to 5 years]) were included in the study cohort. Baseline patient characteristics are outlined in Table 1. All patients were diagnosed clinically and/or genetically with LQTS. Among these 115 patients, the mean QTc was 478 ± 60 milliseconds. The contribution of each LQTS genotype in the study cohort is represented in Figure 1, with type 1 LQTS (LQT1) comprising the majority (48%) of genotype-positive LQTS. The mean follow-up for these patients in our Long QT Syndrome Clinic was 6.4 ± 2.8 years. The majority of the children (92/115; 80%) were asymptomatic at presentation, having been diagnosed with LQTS from an incidental ECG finding or from cascade screening consequent to established familial LQTS. As such, 23 (20%) of
Demographics of Study Cohort, BHS Chort and Remaining LQTS Patients
n Gender, M/F (% male) Mean age at diagnosis, mo (range) Mean QTc, ms Symptomatic at presentation, n (%) First symptom, n (%) None Syncope or seizure Fetal arrhythmia Cardiac arrest BHS Family history of LQTS, n (%) Family history of SCD, n (%)
Study Cohort
BHS
Remaining LQTS Patients
115 67/48 (58) 11 mo (0 to 5 y) 478 ± 60 23 (20)
5 65/45 (60) 12 mo (0 to 2.6 y) 481 ± 27 1 (20)
110 2/3 (40) 22 mo (0 to 6.1 y) 477 ± 61 22 (20)
92 (80%) 8 (7%) 8 (7%) 6 (5%) 1 (1%) 92 (80%) 46 (40%)
4 (80) 0 (0) 0 (0) 0 (0) 1 (20) 2 (40) 1 (20)
88 (80) 9 (8) 8 (7) 5 (5) 0 (0) 79 (72) 43 (39)
Demographics or the study cohort, BHS cohort, and remaining patients are shown in the table above. Although limited by the small number of patients, there were no significant clinical differences between the patients with BHS and the remaining LQTS patients. BHS, breath holding spells; F, female; LQTS, long QT syndrome; M, male; QTc, corrected QT interval; SCD, sudden cardiac death.
Congenit Heart Dis. 2015;10:354–361
356
Robinson et al.
Figure 1. Breakdown of study cohort (n = 115) by long QT syndrome (LQTS) genotype. Pie chart showing the breakdown by LQTS genotype for the study cohort with majority of patients classified as type 1 LQTS (LQT1).
Figure 2. Frequency of breath holding spells (BHS) (%) by long QT syndrome (LQTS) genotypes. Bar diagram showing the frequency of BHS in general population, LQTS cohort, and by LQTS subtype. 1Frequency of BHS in the general population as defined by Lombroso and Lerman.
the total 115 patients were symptomatic at the time of initial presentation, with first symptoms including syncope or seizure, fetal arrhythmia, cardiac arrest, or BHS. At diagnosis, the most common presenting symptoms were syncope or seizure (n = 8, 35%) and fetal arrhythmia (n = 8, 35%), while a BHS was the presenting symptom in 1 (4%) of these 23 symptomatic patients. Overall, 5 of 115 patients with LQTS (4.3%) had BHS on systems review. The 5 cases are sumCongenit Heart Dis. 2015;10:354–361
marized in Table 2. Of these, 2 of 5 (40%) were male, 4 of 5 (80%) had a known family history of LQTS, and 2 patients (Cases Nos. 2 and 3) were siblings. The mean QTc for these five patients was 492 ± 14 milliseconds. All 5 patients with BHS had LQT1 (Figure 2). Two patients had more than one LQTS-associated mutation, with one patient (Case No. 5) having a maternal LQT1-causative mutation (Arg591His-KCNQ1) and a paternally derived type 5 LQTS (LQT5)-associated
Pacemaker placed at 30 mo of age ∼30 BHS noted in total
F
F
4
5
LQT1/LQT5
R591H-KCNQ1 and S28L-KCNE1
482
None
Propranolol; videoscopic LCSD
14 mo
None Twice weekly 18 mo Propranolol None 508 G568R-KCNQ1
F 3
LQT1
None Weekly 12 mo Propranolol None 477 I235N-KCNQ1
M 2
LQT1
None Twice daily 6 mo Propranolol None 505 I235N-KCNQ1
M 1
LQT1
Sex No.
BHS, breath holding spells; F, female; LCSD, left cardiac sympathetic denervation; LQTS, congenital long QT syndrome; LQT1, type 1 LQTS; LQT5, type 5 LQTS; M, male; QTc, corrected QT interval.
Ongoing at last visit (55 mo)
61 mo
Ongoing at last visit (14 mo) 40 mo
34 mo
Spells were diagnosed as BHS and as seizures, prior to discovery of LQTS Known family history of LQT1; BHS resolved spontaneously Sister of Case 2; BHS resolved spontaneously Known family history of LQT1; no initial symptoms except BHS Holter recording showed prolonged asystole during an episode None Weekly, starting at 18 mo of age 31 mo Propranolol; videoscopic LCSD BHS spells 486
Other Mutation
V215M-KCNQ1 and W392X-KCNQ1
Intervention for BHS Frequency of BHS Age at Diagnosis of BHS Treatment for LQTS Symptoms at LQTS Diagnosis QTc (ms) LQTS Genotype
Characteristics of Children with LQTS and Concomitant BHS Table 2.
LQT1
Age at Resolution of BHS
Breath Holding Spells and Long QT Syndrome
357 mutation (Ser28Leu-KCNE1). BHS occurred in 9% of all LQT1 patients, but in none of the other LQTS genetic subtypes (P = .02), with the exception of the LQT1/LQT5 compound genotype as described in Case No. 5. All 5 patients with BHS were described as very active, healthy, and vibrant; they had met age-appropriate developmental milestones. Aside from the LQTS, there were no additional or ongoing medical concerns documented for these five patients. Case No. 1 presented to our clinic at 3 years of age. At 18 months of age, he experienced the first of many, seizure-like episodes, described as prolonged periods of altered consciousness. Given suspicion for generalized seizure, he underwent a comprehensive neurological evaluation, but no clear evidence for seizure disorder was found, and he was diagnosed with BHS. Regardless, he was started on phenytoin (Dilantin) because of the frequent recurrence of his spells. Between 25 and 30 similar, self-resolving episodes occurred over a 13-month span, all precipitated by ageappropriate physical activity (running or playing) or temper tantrums. Then, at 31 months of age, the patient collapsed during play. Whereas previous instances had ended in brief loss of consciousness, this episode resulted in cardiac arrest requiring cardiopulmonary resuscitation (CPR). Normal sinus rhythm spontaneously returned, without application of an external defibrillator. Upon review by a neurologist, a concomitant diagnosis of LQTS was suspected and subsequent ECG showed a QTc of 486 milliseconds with abnormal T-waves. The patient was diagnosed with LQTS and started on betablocker therapy. While taking the beta-blocker over the next 3 months, 3 breakthrough spells occurred (similar to those described before, with only brief loss of consciousness). This prompted implantation of a loop recorder at 34 months of age. During a particularly intense temper tantrum, the device captured a significant breakthrough episode of recurrent self-terminating TdP/polymorphic ventricular tachycardia (5 distinct instances over a span of 5 minutes, none requiring defibrillation; Figure 3). At that time, genetic analysis demonstrated two discrete LQT1 mutations residing on separate KCNQ1 alleles: Val215Met-KCNQ1 and Trp392Ter-KCNQ1. The loop recorder demonstrated QTc measurements of 550–600 milliseconds immediately preceding TdP (Figure 3) despite beta-blocker therapy. The patient was deemed at significant risk for further Congenit Heart Dis. 2015;10:354–361
358
Robinson et al.
Figure 3. (A) Prolonged corrected QT interval (QTc) 550–600 milliseconds. Tracing from a loop recording device starting at the zero-second time interval (as noted along the x-axis), immediately preceding an episode of self-terminating torsades/ polymorphic ventricular tachycardia. (B) Self-limited torsades/polymorphic ventricular tachycardia. An implanted loop recorder device demonstrated episodic, self-limited torsades/polymorphic ventricular tachycardia in a 34-month-old boy during an intense temper tantrum. This tracing starts at the 72-second mark, following the tracing in (A).
breakthrough ventricular arrhythmia and for this reason, LCSD surgery was performed. Despite all interventions, the patient had a single out-ofhospital cardiac arrest with external defibrillator rescue at 42 months of age, which prompted ICD placement as secondary prevention of sudden death. In retrospect, it is unclear which of the Congenit Heart Dis. 2015;10:354–361
many previous spells were BHS and which were potentially LQTS-triggered episodes of TdP. Case No. 2 was born with a known family history of genetically proven LQT1 (Ile235AsnKCNQ1). On his first day of life, the QTc was 505 milliseconds and prophylactic propranolol was initiated. At 6 months of age, classic BHS were first
Breath Holding Spells and Long QT Syndrome
359
noted, ranging in frequency from twice daily spells to no spells for up to 4 weeks. All were associated with either tiredness or emotional upset. Most BHS were accompanied with brief loss of consciousness and spontaneous recovery always occurred. While a 24-hour Holder monitor recorded a single 3.5-second sinus pause during rest, no such pauses were noted during typical BHS. Patient was asymptomatic from an LQT1 standpoint. Case No. 3 (the sister of Case No. 2) was diagnosed similarly based on family history mutationspecific cascade genetic testing. Although initial ECG showed QTc of 444 milliseconds, prophylactic propranolol was started. Around 12 months of age, stereotypical BHS were noted. Breath holding lasted approximately 30 to 60 seconds, usually following an intense cry. After turning blue and becoming limp, spontaneous recovery occurred within 3 seconds. These BHS continued, with once-weekly occurrence representing the most intense frequency at approximately age 2 years, and subsequently resolved by 3 years of age. As of most recent follow-up (at 5 years of age), the patient had otherwise remained completely asymptomatic for LQT1-associated symptoms. For Case No. 4, stereotypical BHS had started at about 18 months of age and persisted at a frequency of approximately one event per week— some resulting in physical collapse—with complete and spontaneous recovery after 30 to 60 seconds. Holter monitoring recorded up to a 7-second sinus pause during one such event. BHS persisted until 5 years of age, without further recurrence. The patient’s family history of genetically proven LQT1 (Gly568Arg-KCNQ1) was discovered when the patient was 24 months old, after which propranolol was started. QTc at that time was 460 milliseconds. As of most recent follow-up (6.5 years of age), QTc was 478 milliseconds and the patient was asymptomatic with respect to the LQT1. Case No. 5 had a known maternal family history of LQT1 at birth with a QTc of 540 milliseconds; propranolol was started at that time. At age of 10 months, the patient was playing quietly when she collapsed and lost consciousness. Though spontaneous recovery occurred, the incident (which occurred while the patient was on propranolol) stimulated further investigation. Comprehensive genetic testing was initiated after this event, revealing a compound LQT1/LQT5 genotype. The patient harbored the maternal
LQT1 mutation (Arg591His-KCNQ1), as well as a paternal LQT5 mutation (Ser28LeuKCNE1). Seemingly typical BHS started at 14 months of age, with each episode generally involving a protracted loss of consciousness and occasionally involving seizure-like activity. During one such episode (at 2.5 years of age), a Holter recorded prolonged asystole, prompting an implantation of a pacemaker for severe BHS. By age 4.5 years, approximately 30 classic BHS episodes had occurred. Given concern for the previously recorded LQT1/LQT5-triggered syncopal episodes while on beta-blocker therapy, videoscopic LCSD was performed at this age and there have been no LQT1/LQT5-related recurrences thus far. In addition, BHS resolved by 5 years of age. On review, it was believed that the patient had exhibited both BHS and LQT1/LQT5-related episodes. Discussion
BHS in young children are common and benign events that usually resolve by 6 years of age without further known complications or soliloquy. To our knowledge, this is the first study describing the prevalence of BHS among a referral cohort of children with LQTS, with an estimated prevalence of 4.3% among our cohort of patients. This frequency did not differ from that described in the general population, reported as early as 1967 to be 4.7% in a prospective survey of children aged 2 to 6 years at an academic medical center in the United States.2 Similarly, a cross-sectional survey published in 2013 from Turkey found a prevalence of BHS of 3.6% among the general population of children up to 6 years of age.6 While the exact cause of BHS is unknown, the similar frequencies in our LQTS cohort compared with the general population suggest there is no causal relationship/ interaction between the two. An underlying genetic etiology or predisposition for BHS has not been discovered. On review of the current literature, there are no associations identified between specific genetic mutations and BHS. Various mechanisms have been proposed regarding the cause of BHS, including neurologic, autonomic, metabolic, and cardiac. Currently, no studies have linked QTc changes or LQTS to BHS. Some have suggested an association between BHS and autonomic dysfunction.7 Moreover, markers of autonomic nervous system function have been correlated with the phenotypic variabilCongenit Heart Dis. 2015;10:354–361
360 ity in patients with KCNQ1-mediated LQTS (i.e., LQT1).8,9 However, a link between the two could not be established based on our current study and further studies would be needed to determine whether the concomitant occurrence of BHS and autonomic dysfunction can be attributed to effects of the same autonomic pathways. Among the patients in our cohort, no heritable pattern for BHS was apparent as per medical history; none of the parents mentioned having BHS themselves as a child. It must be acknowledged from the cohort herein that all 5 cases of BHS in LQTS were found to occur in patients with KCNQ1-encoded LQT1-causative mutations. Despite a uniform LQT1 genotype in these cases, the causative LQT1 mutations were all at different loci and no common variant was identified. Based on these observations and the fact that the prevalence of BHS in our LQTS cohort was similar to the normal population, it seems most likely that LQTS and BHS were unrelated findings without—at this moment—a common pathogenetic link. Nevertheless, it must be recognized that for some children with LQTS, episodes mimicking a BHS could be the presenting symptom of a potentially life-threatening disease. Therefore, distinguishing the “benign” BHS from an LQTStriggered torsadogenic episode is of the utmost importance. BHS are much more common than LQTS, occurring in approximately 1 in 20 children vs. 1 in 2000, respectively. As such, BHS are encountered frequently in a pediatric practice. Clinicians must be careful not to overtreat or overinterpret the root cause when confronted with a classicsounding BHS—even when that spell occurred in a child who has concomitant LQTS. This case series demonstrates that the interpretation of spells in young children can be challenging to decode clinically. At present, to our knowledge, there is no guideline or evidencebased algorithm for the diagnosis and management of a child suspected of having BHS. Certainly, not all children presenting to general practice or pediatric cardiology clinics with a questionable BHS require ECG screening for LQTS. In addition, not every spell occurring in a child with known LQTS is necessarily a torsadogenic one. Admittedly, the scope of this study precludes comprehensive recommendations for detecting LQTS in patients presenting with spells. In any case, history should be the hallmark in determinCongenit Heart Dis. 2015;10:354–361
Robinson et al. ing what further testing is required. While an episode may be comprised of a BHS and spontaneous recovery, it always remains a possibility that an LQTS-triggered event could be at play. Likewise, a fainting episode could result directly because of LQTS, in the absence of a breath hold. Overall, the following points should prompt further investigation with ECG for LQTS in patients presenting with spells: • Loss of consciousness • Spells that persist and occur beyond 6 years of age • Family history of spells, LQTS, arrhythmia, or sudden death Lastly, it is certainly possible that the frequency of BHS in LQTS could have been underestimated in the present study. As is the nature of retrospective research, inquiry for BHS may not have been completed during every clinical encounter or may not have been fully detailed in the EMR. Though both cyanotic and pallid types of BHS have been described, these sometimes were not distinguished in the clinical notes. Conclusions
In our study of this pediatric LQTS cohort, approximately 1 in 25 children with LQTS experiences BHS, a frequency similar to the general population. Although BHS are usually benign and resolve by 6 years of age, distinguishing a nonarrhythmic BHS from an LQTS-triggered cardiac event is important to avoid misdiagnosis and inappropriate treatment. Authors’ Contributions JAR: Data collection, data analysis/interpretation, statistics, and drafting the article. JMB: Data analysis/interpretation, statistics, and critical revision of the article. SPE: Concept/design and critical revision of the article. MJA: Concept/design and critical revision of the article.
Corresponding Author: Michael J. Ackerman, MD, PhD, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-2840101; Fax: 507-284-3757; E-mail: ackerman.michael@ mayo.edu Conflict of interest: Dr. Ackerman is a consultant for Boston Scientific, Gilead Sciences, Medtronic, St. Jude
Breath Holding Spells and Long QT Syndrome
361
Medical, and Transgenomic. Mayo Clinic and MJA receive royalties from Transgenomic with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests. The other authors have no conflicts of interest to disclose. None of the disclosures pertain to this study and none of the companies provided financial support for this study.
5 Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–1767. 6 Carman KB, Ekici A, Yimenicioglu S, Arslantas D, Yakut A. Breath holding spells: point prevalence and associated factors among Turkish children. Pediatr Int. 2013;55:328–331. 7 Kolkiran A, Tutar E, Atalay S, Deda G, Cin S. Autonomic nervous system functions in children with breath-holding spells and effects of iron deficiency. Acta Paediatr. 2005;94:1227–1231. 8 Schwartz PJ, Vanoli E, Crotti L, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol. 2008;51:920–929. 9 Crotti L, Spazzolini C, Porretta AP, et al. Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. J Am Coll Cardiol. 2012;60:2515–2524.
Accepted in final form: March 23, 2015. References
1 Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics. 1967;39:563–581. 2 Rathore G, Larsen P, Fernandez C, Parakh M. Diverse presentation of breath holding spells: two case reports with literature review. Case Rep Neurol Med. 2013;2013:603190. 3 Kanter RJ. Pediatric electrophysiology. Curr Opin Cardiol. 1993;8:119–127. 4 Franklin WH, Hickey RW. Images in clinical medicine. Long QT syndrome. N Eng J Med. 1995;333:355.
Congenit Heart Dis. 2015;10:354–361
