ORIGINAL ARTICLE
Sudden Arrhythmic Death Syndrome: Diagnostic Yield of Comprehensive Clinical Evaluation of Pediatric First-Degree Relatives VALENTINA GIUDICI, M.D.,*,† ADRIANI SPANAKI, PH.D.,* JENNIFER HENDRY, B.SC.,* SARAH MEAD-REGAN, R.C.N.,* ELLA FIELD, R.C.N.,* GIAN VINCENZO ZUCCOTTI, PH.D.,† DOMINIC ABRAMS, M.D.,‡ MARTIN LOWE, PH.D.,* and JUAN PABLO KASKI, M.D.*,§ From the *Inherited Cardiovascular Diseases Unit, Department of Cardiology, Great Ormond Street Hospital, London, United Kingdom; †Department of Paediatrics, Ospedale Luigi Sacco, University of Milan, Italy; ‡Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; and §Institute of Cardiovascular Science, University College London, United Kingdom
Aims: Sudden arrhythmic death syndrome (SADS) is most often caused by heritable cardiac diseases. Studies in adults have identified evidence of inherited cardiovascular diseases in up to 53% of families, but data on the prevalence of familial disease in children are scarce. The aim of this study was to evaluate the yield of clinical screening in pediatric first-degree relatives of victims of SADS using a systematic and comprehensive protocol. Methods: Patients referred for family screening after sudden cardiac death (SCD) of a family member were, retrospectively, enrolled into the study. Systematic evaluation of the children included clinical examination, family history, electrocardiogram (ECG), echocardiogram, 24-hour tape, and signal-averaged ECG. Older patients also underwent exercise testing, cardiac magnetic resonance imaging, and ajmaline provocation testing. Results: A total of 90 children from 52 consecutive families were included in the study. An inherited cardiac disease was identified in seven first-degree children from seven (13.5%) families (five children were diagnosed with Brugada syndrome, one with long QT syndrome, and one with catecholaminergic polymorphic ventricular tachycardia). Two further children had late potentials on signal-averaged ECGs with no other abnormalities. Conclusions: These data show a high prevalence of inherited heart disease in pediatric first-degree relatives of SADS victims. The results highlight the importance of a systematic, comprehensive approach and ongoing screening of pediatric family members. (PACE 2014; 00:1–5) pediatric, sudden death, arrhythmia, screening, long QT syndrome, Brugada syndrome
Introduction Sudden arrhythmic death syndrome (SADS) is the sudden and unexpected death of a previously healthy individual, where no specific cause is identified despite detailed postmortem histological and toxicological examination.1 A substantial proportion of SADS cases are caused by potentially heritable cardiac disease (primarily ion channel disease and, less frequently, Disclosures: None. Address for reprints: Juan Pablo Kaski, M.D., Inherited Cardiovascular Diseases Unit, Department of Cardiology, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom. Fax: 44 20 7829 8673; e-mail: [email protected] Received March 5, 2014; revised May 21, 2014; accepted June 17, 2014. doi: 10.1111/pace.12479
cardiomyopathy), and the recognition and subsequent screening of the proband’s relatives is extremely important, allowing early identification of surviving relatives at risk of sudden cardiac death (SCD).2 Previous studies have demonstrated evidence of familial cardiac disease in up to 53% of predominantly adult relatives of SADS cases on clinical cardiological assessment.2–4 Although small numbers of pediatric relatives are included in these studies, there has only been one series specifically evaluating pediatric relatives of individuals with SADS or resuscitated outof-hospital cardiac arrest.5 Cardiac disease was identified in three of 16 families (19%), but this study included families with a known inherited cardiac disease as well as non-firstdegree relatives of the index patients. In addition, only a limited clinical evaluation was
©2014 Wiley Periodicals, Inc. PACE, Vol. 00
2014
1
GIUDICI, ET AL.
Figure 1. Systematic clinical cardiological evaluation algorithm for pediatric first-degree relatives of SADS victims. ECG = electrocardiogram; ICC = inherited cardiac condition; ILR = implantable loop recorder; MRI = magnetic resonance imaging; SADS = sudden arrhythmic death syndrome; SAECG = signal-averaged ECG.
performed routinely in all patients (12-lead and 24-hour electrocardiogram [ECG] and echocardiography), with additional investigations at the cardiologists’ discretion.5 The aim of this study, therefore, was to evaluate pediatric first-degree relatives of individuals with a history of SADS using a comprehensive and systematic clinical investigation protocol.
Clinical Evaluation Systematic evaluation of the referred children included a detailed medical and family history, physical examination, 12-lead and ambulatory ECG, signal-averaged ECG, and two-dimensional echocardiogram (Fig. 1). Patients old enough to use the equipment also underwent treadmill or ergometer exercise testing (n = 42 [47%]). In addition, patients older than 5 years of age routinely underwent ajmaline provocation testing (n = 26 [29%]) with no complications, unless a parent had already had a negative ajmaline test previously. In addition, one child aged 22 months underwent ajmaline provocation testing under general anesthesia at the time of implantation of a loop recorder, following the SCD of a 3-year-old sibling. Additional investigations, including cardiac magnetic resonance imaging, event recorder, and insertion of implantable loop recorders were performed, where indicated clinically. Standard criteria for the diagnosis of LQTS,1 BrS,1 arrhythmogenic right ventricular cardiomyopathy (ARVC,7 and CPVT1 were employed.
Methods Patients All consecutive patients attending the Inherited Arrhythmia Clinic at Great Ormond Street Hospital, London, UK, for family screening after a SCD of a family member between August 2003 and June 2013, were included in the study. Inclusion criteria for the proband were: sudden unexpected death aged 1–50 years, no known family history of inherited cardiac disease, and absence of evident cardiac pathology at post mortem. Probands were also included if there were nonpathognomonic histopathological autopsy findings, such as ventricular hypertrophy and myocardial fibrosis.6 Only first-degree relatives were included in the analyses, although second-degree relatives are reported as a separate subgroup. Children referred to the service, but in whom concurrent screening of their adult relatives (in adult specialist centers) revealed an inherited cardiac disease, were excluded from this study (nine families with Brugada syndrome [BrS; n = 4]; long QT syndrome [LQTS; n = 3]; catecholaminergic polymorphic ventricular tachycardia [CPVT; n = 1], and hypertrophic cardiomyopathy [HCM; n = 1]).
2
Statistical Analysis Data are presented as mean values (± standard deviation) if normally distributed, or median values (interquartile range [IQR]) if not normally distributed. Categorical data are presented as proportions. Pearson’s χ 2 test was used to compare proportions. Student’s t-test was used to compare continuous, normally distributed variables; nonnormally distributed data were assessed using the Kruskal-Wallis or Mann-Whitney U tests. SPSS for Mac (v22.0; IBM Corp., Armonk, NY, USA)
2014
PACE, Vol. 00
SADS—PEDIATRIC EVALUATION
Table I. Characteristics of Pediatric First-Degree Relatives Screened Patients Families Male : female Age at screening (range) Median age at screening (years) Relationship to Proband Offspring Siblings
90 52 50 (56%): 40 (44%) 3 months to 17 years
7 (IQR 3–10)
35 (66%) 18 (34%)
Values are n (%). IQR = interquartile range.
was used for all analyses. A P value of
Sudden Arrhythmic Death Syndrome: Diagnostic Yield of Comprehensive Clinical Evaluation of Pediatric First-Degree Relatives VALENTINA GIUDICI, M.D.,*,† ADRIANI SPANAKI, PH.D.,* JENNIFER HENDRY, B.SC.,* SARAH MEAD-REGAN, R.C.N.,* ELLA FIELD, R.C.N.,* GIAN VINCENZO ZUCCOTTI, PH.D.,† DOMINIC ABRAMS, M.D.,‡ MARTIN LOWE, PH.D.,* and JUAN PABLO KASKI, M.D.*,§ From the *Inherited Cardiovascular Diseases Unit, Department of Cardiology, Great Ormond Street Hospital, London, United Kingdom; †Department of Paediatrics, Ospedale Luigi Sacco, University of Milan, Italy; ‡Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; and §Institute of Cardiovascular Science, University College London, United Kingdom
Aims: Sudden arrhythmic death syndrome (SADS) is most often caused by heritable cardiac diseases. Studies in adults have identified evidence of inherited cardiovascular diseases in up to 53% of families, but data on the prevalence of familial disease in children are scarce. The aim of this study was to evaluate the yield of clinical screening in pediatric first-degree relatives of victims of SADS using a systematic and comprehensive protocol. Methods: Patients referred for family screening after sudden cardiac death (SCD) of a family member were, retrospectively, enrolled into the study. Systematic evaluation of the children included clinical examination, family history, electrocardiogram (ECG), echocardiogram, 24-hour tape, and signal-averaged ECG. Older patients also underwent exercise testing, cardiac magnetic resonance imaging, and ajmaline provocation testing. Results: A total of 90 children from 52 consecutive families were included in the study. An inherited cardiac disease was identified in seven first-degree children from seven (13.5%) families (five children were diagnosed with Brugada syndrome, one with long QT syndrome, and one with catecholaminergic polymorphic ventricular tachycardia). Two further children had late potentials on signal-averaged ECGs with no other abnormalities. Conclusions: These data show a high prevalence of inherited heart disease in pediatric first-degree relatives of SADS victims. The results highlight the importance of a systematic, comprehensive approach and ongoing screening of pediatric family members. (PACE 2014; 00:1–5) pediatric, sudden death, arrhythmia, screening, long QT syndrome, Brugada syndrome
Introduction Sudden arrhythmic death syndrome (SADS) is the sudden and unexpected death of a previously healthy individual, where no specific cause is identified despite detailed postmortem histological and toxicological examination.1 A substantial proportion of SADS cases are caused by potentially heritable cardiac disease (primarily ion channel disease and, less frequently, Disclosures: None. Address for reprints: Juan Pablo Kaski, M.D., Inherited Cardiovascular Diseases Unit, Department of Cardiology, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom. Fax: 44 20 7829 8673; e-mail: [email protected] Received March 5, 2014; revised May 21, 2014; accepted June 17, 2014. doi: 10.1111/pace.12479
cardiomyopathy), and the recognition and subsequent screening of the proband’s relatives is extremely important, allowing early identification of surviving relatives at risk of sudden cardiac death (SCD).2 Previous studies have demonstrated evidence of familial cardiac disease in up to 53% of predominantly adult relatives of SADS cases on clinical cardiological assessment.2–4 Although small numbers of pediatric relatives are included in these studies, there has only been one series specifically evaluating pediatric relatives of individuals with SADS or resuscitated outof-hospital cardiac arrest.5 Cardiac disease was identified in three of 16 families (19%), but this study included families with a known inherited cardiac disease as well as non-firstdegree relatives of the index patients. In addition, only a limited clinical evaluation was
©2014 Wiley Periodicals, Inc. PACE, Vol. 00
2014
1
GIUDICI, ET AL.
Figure 1. Systematic clinical cardiological evaluation algorithm for pediatric first-degree relatives of SADS victims. ECG = electrocardiogram; ICC = inherited cardiac condition; ILR = implantable loop recorder; MRI = magnetic resonance imaging; SADS = sudden arrhythmic death syndrome; SAECG = signal-averaged ECG.
performed routinely in all patients (12-lead and 24-hour electrocardiogram [ECG] and echocardiography), with additional investigations at the cardiologists’ discretion.5 The aim of this study, therefore, was to evaluate pediatric first-degree relatives of individuals with a history of SADS using a comprehensive and systematic clinical investigation protocol.
Clinical Evaluation Systematic evaluation of the referred children included a detailed medical and family history, physical examination, 12-lead and ambulatory ECG, signal-averaged ECG, and two-dimensional echocardiogram (Fig. 1). Patients old enough to use the equipment also underwent treadmill or ergometer exercise testing (n = 42 [47%]). In addition, patients older than 5 years of age routinely underwent ajmaline provocation testing (n = 26 [29%]) with no complications, unless a parent had already had a negative ajmaline test previously. In addition, one child aged 22 months underwent ajmaline provocation testing under general anesthesia at the time of implantation of a loop recorder, following the SCD of a 3-year-old sibling. Additional investigations, including cardiac magnetic resonance imaging, event recorder, and insertion of implantable loop recorders were performed, where indicated clinically. Standard criteria for the diagnosis of LQTS,1 BrS,1 arrhythmogenic right ventricular cardiomyopathy (ARVC,7 and CPVT1 were employed.
Methods Patients All consecutive patients attending the Inherited Arrhythmia Clinic at Great Ormond Street Hospital, London, UK, for family screening after a SCD of a family member between August 2003 and June 2013, were included in the study. Inclusion criteria for the proband were: sudden unexpected death aged 1–50 years, no known family history of inherited cardiac disease, and absence of evident cardiac pathology at post mortem. Probands were also included if there were nonpathognomonic histopathological autopsy findings, such as ventricular hypertrophy and myocardial fibrosis.6 Only first-degree relatives were included in the analyses, although second-degree relatives are reported as a separate subgroup. Children referred to the service, but in whom concurrent screening of their adult relatives (in adult specialist centers) revealed an inherited cardiac disease, were excluded from this study (nine families with Brugada syndrome [BrS; n = 4]; long QT syndrome [LQTS; n = 3]; catecholaminergic polymorphic ventricular tachycardia [CPVT; n = 1], and hypertrophic cardiomyopathy [HCM; n = 1]).
2
Statistical Analysis Data are presented as mean values (± standard deviation) if normally distributed, or median values (interquartile range [IQR]) if not normally distributed. Categorical data are presented as proportions. Pearson’s χ 2 test was used to compare proportions. Student’s t-test was used to compare continuous, normally distributed variables; nonnormally distributed data were assessed using the Kruskal-Wallis or Mann-Whitney U tests. SPSS for Mac (v22.0; IBM Corp., Armonk, NY, USA)
2014
PACE, Vol. 00
SADS—PEDIATRIC EVALUATION
Table I. Characteristics of Pediatric First-Degree Relatives Screened Patients Families Male : female Age at screening (range) Median age at screening (years) Relationship to Proband Offspring Siblings
90 52 50 (56%): 40 (44%) 3 months to 17 years
7 (IQR 3–10)
35 (66%) 18 (34%)
Values are n (%). IQR = interquartile range.
was used for all analyses. A P value of
