Suspicion and Persistence: A Case of Pediatric Brugada Syndrome Brynn E. Dechert, MSN, CPNP,a Martin J. LaPage, MD, MS,a Mitchell I. Cohen, MDb

This is the case of a 9-year-old girl who initially presents with episodes of abstract and potentially concerning family history. An extensive evaluation is unrevealing, and she appears to have simple benign autonomic dysfunction. Eventually, a rare and life-threatening disease is uncovered, and she receives appropriate treatment. The case report highlights the persistence and suspicion of the managing providers that ultimately allowed the diagnosis to be revealed as well as some of the key features of the underlying disease.

Suspicion is the feeling or thought that consults and EEG and head computed something is possible. Persistence is tomography, was unremarkable. the continuance in a course of action Her father had been evaluated 7 years despite difficulty or opposition. aDepartment of Pediatrics, University of Michigan, Ann before for reported Brugada pattern on Arbor, Michigan; and bInova Fairfax Children’s Hospital, Falls Frequently, the art of medicine requires electrocardiogram during . He had Church, Virginia the provider to make conclusions with also had several syncopal episodes incomplete information; investigation Ms Dechert and Dr LaPage cared directly for the diagnosed as vasovagal. Evaluation at presented patient, drafted the initial case report, ’ into the patient s ailment must be that time led to a reported and reviewed and revised the manuscript; Dr Cohen based on experience and suspicion. A recommendation for an implantable cared directly for this presented patient and critically reviewed and revised the article for diagnosis is not always immediately cardioverter defibrillator (ICD), but he intellectual content; and all authors approved the clear even with comprehensive testing ’ declined. The father s final manuscript as submitted and agree to be and only reveals itself with persistence electrocardiogram result, at the time of accountable for all aspects of the work. ’ and time. In the case to follow, the the subject patient s presentation, was DOI: https://doi.org/10.1542/peds.2018-3296 patient’s ongoing normal. He was referred to adult Accepted for publication Jan 11, 2019 continued to stack evidence against any , which did not suspect Address correspondence to Brynn E. Dechert, MSN, serious underlying disease, and it was a diagnosis of Brugada syndrome. The CPNP, Division of Pediatric Cardiology, Department of ’ only the persistence and suspicion of patient s 4 siblings were asymptomatic Pediatrics, University of Michigan, 1540 E Hospital Dr, the managing providers that ultimately with normal electrocardiogram results. Ann Arbor, MI 48109. E-mail: [email protected] allowed the diagnosis to be revealed. The patient’s cardiac evaluation PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). included normal echocardiogram and results. Her Copyright © 2019 by the American Academy of Pediatrics CASE REPORT electrocardiogram result was normal, FINANCIAL DISCLOSURE: including placement of V1 and V2 at The authors have indicated The patient presented at age 9 to they have no financial relationships relevant to this a pediatric electrophysiologist (M.I.C.) a high intercostal space. article to disclose. challenge caused some mild changes in after experiencing 4 episodes of FUNDING: No external funding. the V1 and V2 ST segments but was not syncope, occurring during various POTENTIAL CONFLICT OF INTEREST: diagnostic for Brugada. An implantable The authors have daily activities but not during exercise indicated they have no potential conflicts of interest or with fever. Occasionally, these were loop recorder (ILR) was implanted to to disclose. clarify any future syncope episodes. associated with palpitations or tonic- clonic–type movements and an ashen Three months later, the family To cite: Dechert BE, LaPage MJ, Cohen MI. appearance. Her initial hospital relocated, and she established care with Suspicion and Persistence: A Case of Pediatric evaluation, including neurology, another pediatric electrophysiologist Brugada Syndrome. Pediatrics. 2019;144(1): e20183296 gastroenterology, and infectious disease (M.J.L.). Aside from electrocardiogram,

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 144, number 1, July 2019:e20183296 CASE REPORT FIGURE 1 Wide complex tachycardia recorded by ILR on the day of fever. ECG, electrocardiogram; TS, tachycardia sensed; VS, ventricular sensed beat.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 2 DECHERT et al FIGURE 2 Baseline, afebrile electrocardiogram showing normal sinus rhythm at 71 beats per minute. A normal appearance of the V1 and V2 precordial leads with upright T waves in V2 is shown. no testing was repeated at that time. challenge was repeated, resulting in treated with antipyretics and Over the following year, she T-wave inversion in V1 and V2 but instructed to present to the clinic to continued to have frequent, weekly insufficient ST elevation to qualify as attempt to obtain an symptoms, including episodes of a positive test result. A ventricular electrocardiogram during fever. The dizziness, chest pain, and near stimulation study without result from afebrile syncope; hundreds of ILR recordings isoproterenol using single and double electrocardiogram on arrival was showed sinus rhythm. At the annual premature ventricular extrastimuli normal (Fig 2). Six hours later, she follow-up, the family inquired about from the apex resulted in occasional remanifested a temperature of 39.3ºC removing the ILR. The provider couplets and triplets of ventricular while in the clinic. Electrocardiogram recommended leaving the ILR in ectopy. A more aggressive approach then performed with high V1-V2 lead place because of the low risk and using S4 premature ventricular placement was diagnostic of the potential benefit of ongoing extrastimuli induced monomorphic Brugada sign (Fig 3). She was monitoring. , which promptly treated with ibuprofen and progressed abruptly to polymorphic admitted for observation. Serendipitously, 5 months later ventricular tachycardia and (20 months after ILR implant), ventricular fibrillation necessitating She underwent successful a sustained wide complex defibrillation. These findings, in light implantation of a S-ICD 2 days later. was documented by her ILR (Fig 1) of the previous history, were Her genetic test eventually returned during a febrile illness. At the time of discussed with the family as well as with a positive result for a pathologic arrhythmia, she was transiently several colleagues who varied widely in SCN5A (c.384011G.A) lightheaded but not syncopal. Full in their opinions on whether to as well as a variant of unknown evaluation was repeated, including implant an ICD. It was decided to significance identified in PKP2 echocardiogram and exercise tests, implant a subcutaneous implantable (c.974C.T) also potentially affiliated which had normal results. cardioverter defibrillator (S-ICD). with Brugada syndrome. The genetic Electrocardiogram obtained after the testing facility reported the SCN5A fever resolved did not show Just 2 days before her scheduled mutation to be likely pathogenic, a diagnostic Brugada pattern. Genetic S-ICD implantation, the patient having been previously reported testing was sent. Procainamide became febrile. She was immediately multiple times in association with

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 144, number 1, July 2019 3 FIGURE 3 Febrile electrocardiogram with high V1 and V2 placement in the second intercostal space. There is ST elevation $2 mm in V2 with a rectilinear downslope to baseline followed by an inverted T-wave consistent with the Brugada sign.

Brugada syndrome and absent in with antipyretic therapy. This case eventually became positive after large population cohorts. Familial report highlights the impact of fever puberty, indicating that Brugada can cascade screening revealed only inducing both ventricular become unmasked with age.8 The 1 genotype-positive sibling who and the Brugada sign, difficulty in diagnosis is important to harbored both . The SCN5A identifies differing management overcome because Brugada is thought mutation was inherited from the approaches among pediatric to be the cause of sudden cardiac father, and the variation of uncertain electrophysiologists, and illustrates death in 4% to 12% of children and significance in PKP2 was inherited the role of suspicion and persistence, young athletes.9 from the mother. which may be critical to accurate The patient’s frequent symptoms diagnosis. were repeatedly correlated with DISCUSSION benign rhythms, and the suspected The majority of presenting and early diagnosis appeared more unlikely Brugada syndrome is a rare, evidence in this case did not support with each passing month. Although autosomal-dominant, inherited the ultimate diagnosis. Brugada there had been initial suspicion of her that predisposes syndrome typically presents in adult father having a Brugada pattern patients to ventricular arrhythmias men, is more often seen in those of during a fever, the diagnosis of and sudden cardiac death.1,2 The Asian descent, and rarely manifests in Brugada pattern had never been hallmark of the disease is a specific children. The diagnosis can be confirmed, and subsequent pattern of ST segment elevation in the difficult because of the inconsistent evaluations had been unremarkable. precordial leads (V1–V3). The presence of the Brugada sign on – Brugada pattern may be baseline electrocardiogram.3 7 The Brugada syndrome in a 10-year-old intermittently present and only procainamide challenge may not be with documented ventricular revealed during fever, which also reliable in pediatric patients, as arrhythmias would be a class 1 increases the likelihood of lethal shown by a large study on indication for an ICD implantation. In arrhythmias.3–6 It is therefore asymptomatic children evaluated this case, however, a definitive recommended that patients with because of family history in which diagnosis of Brugada syndrome had known or suspected Brugada 23% of patients had a negative drug not yet been established, and syndrome aggressively treat fever challenge result before puberty that mildly symptomatic, well-tolerated,

Downloaded from www.aappublications.org/news by guest on September 23, 2021 4 DECHERT et al self-terminating ventricular CONCLUSIONS document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, tachycardia would not be an The diagnosis of Brugada syndrome, PACES, and AEPC in June 2013. appropriate indication for an or any rare disease, in children may Rhythm. 2013;10(12):1932–1963 ICD. Repeat testing, including be difficult. Pediatric diseases can procainamide challenge, was again evolve over time. Suspicion and 3. Bayés de Luna A, Brugada J, Baranchuk unrevealing in clarifying a diagnosis, persistence are important qualities A, et al. Current electrocardiographic and induced polymorphic ventricular for a provider to apply judiciously criteria for diagnosis of Brugada tachycardia at electrophysiology and may even be critically important pattern: a consensus report [published fi study was not speci cally in life-threatening diseases, such as correction appears in J Electrocardiol. diagnostic. Additionally, there are Brugada syndrome. The early 2013;46(1):76]. J Electrocardiol. 2012; fi 45(5):433–442 signi cant complication risks of markers of Brugada syndrome in ICDs in children, including the high pediatric patients and the best 4. Dumaine R, Towbin JA, Brugada P, et al. rate of inappropriate shocks. treatments are yet to be discovered, Ionic mechanisms responsible for the Before a clear diagnosis of Brugada and future effort should be directed electrocardiographic phenotype of the being established by at developing pediatric Brugada syndrome are temperature electrocardiogram findings or genetic electrocardiogram standards as well dependent. Circ Res. 1999;85(9): testing, the provider (M.J.L.) had as management recommendations for 803–809 decided to implant an ICD in this pediatric patients. 5. Porres JM, Brugada J, Urbistondo V, patient. This decision came to be García F, Reviejo K, Marco P. Fever after extensive discussion with the unmasking the Brugada syndrome. patient and her family as well as ABBREVIATIONS Pacing Clin Electrophysiol. 2002;25(11): with multiple colleagues. The case 1646–1648 ICD: implantable cardioverter was discussed with 4 additional defibrillator 6. Kum LC, Fung JW, Sanderson JE. pediatric electrophysiologists, 2 of ILR: implantable loop recorder Brugada syndrome unmasked by whom stated they would implant an S-ICD: subcutaneous implantable febrile illness. Pacing Clin ICD and 2 whom stated they would cardioverter defibrillator Electrophysiol. 2002;25(11):1660–1661 not in this case. These opinions were openly shared with the family, 7. Probst V, Denjoy I, Meregalli PG, et al. who ultimately agreed with S-ICD Clinical aspects and prognosis of Brugada syndrome in children. implantation, which is REFERENCES Circulation. 2007;115(15):2042–2048 recommended to mitigate the long- 1. Brugada P, Brugada J. Right bundle term complications of 8. Conte G, de Asmundis C, Ciconte G, et al. branch block, persistent ST segment Follow-up from childhood to adulthood a transvenous system. The diagnosis elevation and sudden cardiac death: fi of individuals with family history of was ultimately con rmed by the a distinct clinical and Brugada syndrome and normal febrile electrocardiogram findings electrocardiographic syndrome. A and shortly thereafter by the multicenter report. J Am Coll Cardiol. electrocardiograms. JAMA. 2014; – results. The case is 1992;20(6):1391–1396 312(19):2039 2041 illustrative of the wide variation in 2. Priori SG, Wilde AA, Horie M, et al. HRS/ 9. Sarquella-Brugada G, Campuzano O, treatment strategies for nonspecific EHRA/APHRS expert consensus Iglesias A, et al. Genetics of sudden diagnostic findings even a life- statement on the diagnosis and cardiac death in children and young threatening disease is potentially management of patients with inherited athletes. Cardiol Young. 2013;23(2): present. primary arrhythmia syndromes: 159–173

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 144, number 1, July 2019 5 Suspicion and Persistence: A Case of Pediatric Brugada Syndrome Brynn E. Dechert, Martin J. LaPage and Mitchell I. Cohen Pediatrics originally published online June 12, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2019/06/10/peds.2 018-3296 References This article cites 9 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2019/06/10/peds.2 018-3296#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Cardiology http://www.aappublications.org/cgi/collection/cardiology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 23, 2021 Suspicion and Persistence: A Case of Pediatric Brugada Syndrome Brynn E. Dechert, Martin J. LaPage and Mitchell I. Cohen Pediatrics originally published online June 12, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2019/06/10/peds.2018-3296

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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