CASE REPORT

A 14-year-old boy with hypertension, obesity, anxiety, obstructive sleep apnea, and self-reported irritable bowel syndrome presented to an outside hospital with symptoms of nausea, vomiting, diaphoresis, dizziness, and weakness. He also admitted to a long-standing history of loperamide abuse (≤40 mg nightly) to treat his gastrointestinal symptoms and reported missing his nightly dose the previous evening. On the morning of admission, he took 20 mg of loperamide to treat developing gastrointestinal symptoms; this was followed by 1 episode of emesis.

His home medications included Carafate, cetirizine, fluticasone, lisinopril, and omeprazole. His family history was negative for cardiac channelopathies, cardiomyopathies, or other significant cardiovascular pathologies. Informed consent was obtained from the family of the patient.

At the outside hospital emergency department, he was hemodynamically stable, with an unremarkable

electrolyte screen including a magnesium level of 2.1 mg/dL. His electrocardiogram (ECG) noted a qR pattern and ST segment elevations in leads V1 and V2, which is concerning for Brugada pattern.

After consultation, the patient was transferred to our PICU. He received intravenous normal saline, magnesium sulfate, 1 mg of lorazepam, and 4 mg of ondansetron. His presenting vitals included a blood pressure of 152 over 90 mm Hg and heart rate of 74 beats per minute. His ECG is shown in Fig 1, revealing anterior precordial ST segment elevation in leads V1–V3 with a “coved” appearance consistent with a type 1 Brugada pattern. His QRS duration was 160 milliseconds, and his QTc interval was 568 milliseconds. On cardiac monitor, he demonstrated he was able to isolate monomorphic premature ventricular beats.

His physical examination was significant only for diffuse flushing. An echocardiogram was normal. A complete urine and blood toxicology screen was negative, although this did not include a loperamide level.

Brugada Syndrome Associated With Adolescent Loperamide AbuseBryan Stefek, MD, L. Timothy Wolfe, MD, Mark Cohen, MD

We present the case of a 14-year-old boy with obesity, hypertension, and chronic loperamide abuse who presented to our facility with symptoms of opioid withdrawal and type 1 Brugada pattern on an electrocardiogram. He was treated for anxiety and withdrawal. There were no documented dysrhythmias. His Brugada pattern resolved by hospital day 5 and remained resolved 12 days postadmission. Genetic testing revealed a heterozygous missense mutation in the SCN5A gene (c. 5038G>A, p. Ala1680Thr), which has been reported in association with Brugada syndrome. To date, there are no published reports of pediatric loperamide use associated with a Brugada pattern on an electrocardiogram. We propose that chronic loperamide use unmasked the electrocardiographic phenotype associated with his gene mutation.

abstract

To cite: Stefek B, Wolfe LT, Cohen M. Brugada Syndrome Associated With Adolescent Loperamide Abuse. Pediatrics. 2018;142(4):e20181423

Department of Pediatrics, Penn State Children’s Hospital, Hershey, Pennsylvania

Dr Stefek was involved in clinical care of the patient, conceptualized the case report, collected the relevant information, obtained consent, and drafted the initial manuscript; Drs Wolfe and Cohen were involved in clinical care of the patient and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 1423

Accepted for publication Jul 5, 2018

Address correspondence to Bryan Stefek, MD, Penn State Children’s Hospital, 500 University Dr, Mail Code HS83, Hershey, PA 17033. E-mail: bstefek@pennstatehealth.psu.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

PEDIATRICS Volume 142, number 4, October 2018:e20181423 CASE REPORT by guest on October 7, 2020www.aappublications.org/newsDownloaded from

His inflammatory markers were not elevated, and he was euthyroid.

The patient was admitted for 6 days during which time he remained hemodynamically stable with no dysrhythmias. He was treated for anxiety, possible opioid withdrawal, hypertension, and gastrointestinal discomfort. Medications included a sodium bicarbonate infusion, pantoprazole, lorazepam, morphine, and acetaminophen. He was continued on his home lisinopril and started on clonidine for anxiety. The anterior precordial ST segment elevations in leads V1–V3 declined throughout admission, returning to near-normal by the first cardiology follow-up (Figs 2, 3, and 4).

At a 2-month pediatric cardiology visit, an ECG revealed the resolution of his ST pattern in the anterior precordial leads with persistence of deep Q waves (Fig 5). His QRS duration was 98 milliseconds and QTc was 409 milliseconds.

Genetic testing (Invitae Brugada Syndrome Panel) was productive for

a heterozygous missense mutation of uncertain significance in the SCN5A gene (c. 5038G>A, p. Ala1680Thr). Taken together, a diagnosis of Brugada syndrome (BrS) was made. Apart from routine follow-up, no therapies were initiated. The family was advised to treat fevers aggressively and present to an emergency department immediately for an ECG evaluation if fevers occurred.

DISCUSSION

Loperamide is an opioid receptor agonist that binds to microreceptors within the myenteric plexus of the large intestine, thus decreasing forward peristalsis and prolonging transit time. Loperamide is also used to augment anal sphincter tone.1 The combined use with P-glycoprotein inhibitors (proton pump inhibitors and antiarrhythmics such as quinidine and ritonavir) has been associated with a significant increase in the plasma concentrations of loperamide.2, 3 For children and

adolescents, the maximum dosage per day ranges from 4 to 8 mg; for adults, 16 mg.1, 4

Initially classified as a narcotic, loperamide was classified as a controlled substance from 1976 to 1982.5 Abuse potential still exists, however, with authors of multiple recent reports detailing dependency and abuse of what some have called “the methadone of the poor.” 6 – 8

Loperamide has been associated with a wide variety of changes to the heart’s electrophysiology, including a prolonged QT interval, prolonged QRS duration, and polymorphic ventricular tachycardia. The proposed mechanisms include an inhibition of the following cardiac channels: sodium channels (shown in vitro), delayed-rectifier potassium channel (shown in vitro), and L-type Ca2+ channels.9, 10 The relationship between Brugada pattern and loperamide use is less well described. Sun et al11 describe the case of a 49-year-old man with loperamide abuse of 200 to 400 mg

STEFEK et al2

FIGURE 1ECG: hospital day 1, time: 2330. PR interval 192 milliseconds, QRS duration 160 milliseconds, and QTc 568 milliseconds.

by guest on October 7, 2020www.aappublications.org/newsDownloaded from

daily to alleviate opioid withdrawal symptoms. He was noted to have a QRS duration of 170 milliseconds,

QTc interval of 644 milliseconds, and type 1 Brugada pattern on a routine ECG during a psychiatric admission.

His serum loperamide concentration was 56 ng/mL (normal being <2–3.1 ng/mL). He abstained from

PEDIATRICS Volume 142, number 4, October 2018 3

FIGURE 2ECG, note precordial leads V1–V3. Hospital day 4, time: 1038.

FIGURE 3ECG, note precordial leads V1–V3. Hospital day 6, time: 0520.

by guest on October 7, 2020www.aappublications.org/newsDownloaded from

loperamide use during admission, and his Brugada pattern was resolving by discharge.11 Leung

et al12 also report a 48-year-old woman with loperamide abuse of up to 16 mg daily who presented

with unstable bradycardia and polymorphic ventricular tachycardia. Her ECG showed an exposed type 1

STEFEK et al4

FIGURE 4ECG, note precordial leads V1–V3. 6 days postdischarge.

FIGURE 5ECG, 172 days postdischarge. PR interval 148 milliseconds, QRS duration 98 milliseconds, and QTc 409 milliseconds.

by guest on October 7, 2020www.aappublications.org/newsDownloaded from

Brugada pattern, which resolved by day 3 of hospitalization.12 The association has also been referenced and presented in poster form.8, 13 The official Food and Drug Administration packaging insert for loperamide also describes a link.1 Postema et al14 do not list loperamide as a medicine to avoid with BrS.

BrS is a heritable cardiac channelopathy characterized by specific ST segment changes within the right precordial leads of a 12-lead ECG. It carries an increased risk for sudden cardiac death. Three distinct ST segment changes are described, with type 1 pattern being described as a coved-type and types 2 to 3 as saddleback-type.

Approximately 0.05% to 0.6% of the general population displays 1 of 3 patterns without provocation, 15 with type 2 being the most common. The Heart Rhythm Society, European Heart Rhythm Association, and Asia Pacific Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes published in 2013 asserts that BrS is diagnosed when a type 1 pattern is found, with or without infusion of a sodium channel blocker.16

BrS is inherited in an autosomal dominant fashion. To date, ∼17 genes have been identified in the pathogenesis of this syndrome. SCN5A abnormalities are found in <30% of those clinically found to have BrS, specifically, loss of function mutations. Within this genetic subset (BrS1), up to 300 specific mutations have been recognized.15

Our patient was found to have a missense mutation in the SCN5A gene (c. 5038G>A, p. Ala1680Thr) of uncertain significance. The genetic report explains that the mutation’s effect on the ultimate protein is unclear. This aberrancy has been described in 8 other cases: 1 patient with BrS, 17 3 who died suddenly,

2 referred for Brugada evaluation, and 2 referred for long QT syndrome evaluation.18 –21

Taken together, we feel that our patient has BrS1 and is at an increased risk for sudden cardiac death. His case reveals that loperamide has the potential to unmask phenotypic ECG changes in a patient with genotypic BrS1. It is unclear whether concomitant medications (ie, omeprazole) contributed to the overall toxicity of this drug. We recognize that the absence of a quantified loperamide level is a limitation of our report. His presentation also suggests that this medication should be added to the avoidance list for patients with Brugada. Considering the current climate of opioid abuse, we hope that our case contributes to the overall discussion surrounding these medications and their potential cardiovascular toxicity.

ABBREVIATIONS

BrS:  Brugada syndromeECG:  electrocardiogram

REFERENCES

1. US Food and Drug Administration. Imodium capsules Rx. 2018. Available at: https:// www. accessdata. fda. gov/ drugsatfda_ docs/ label/ 2016/ 017694s052lbl. pdf. Accessed April 1, 2018

2. Srivalli KMR, Lakshmi PK. Overview of P-glycoprotein inhibitors: a rational outlook.Braz J Pharm Sci. 2012;48(3):353–367

3. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther. 2000;68(3):231–237

4. Johnson & Johnson Consumer, Inc. Imodium. Products: Imodium Oral Solution Treatment (Liquid). 2018. Available at: https:// www. imodium. com. Accessed August 6, 2018

5. US Department of Justice. Lists of: scheduling actions, controlled substances, regulated chemicals. 2018. Available at: https:// www. deadiversion. usdoj. gov/ schedules/ orangebook/ orangebook. pdf. Accessed April 1, 2018

6. Lasoff DR, Koh CH, Corbett B, Minns AB, Cantrell FL. Loperamide trends in abuse and misuse over 13 years: 2002-2015. Pharmacotherapy. 2017;37(2):249–253

7. Zarghami M, Rezapour M. Loperamide dependency: a case report. Addict Health. 2017;9(1):59–63

8. Smith NA, Sehring M, Chambers J. Loperamide abuse and cardiotoxicity. J Community Hosp Intern Med Perspect. 2017;7(4):275

9. Eggleston W, Marraffa JM, Stork CM, et al. Notes from the field: cardiac dysrhythmias after loperamide abuse - New York, 2008-2016. MMWR Morb Mortal Wkly Rep. 2016;65(45):1276–1277

10. Enakpene EO, Riaz IB, Shirazi FM, Raz Y, Indik JH. The long QT teaser: loperamide abuse. Am J Med. 2015;128(10):1083–1086

11. Sun C, Brice JA, Clark RF. Brugada-type pattern on electrocardiogram associated with high-dose loperamide abuse. J Emerg Med. 2018;54(4):484–486

12. Leung G, Altshuler D, Goldenberg R, Fridman D, Yuriditsky E. Conduction disturbances and ventricular arrhythmias associated with high-dose loperamide. J Clin Toxicol. 2016;6:309

13. Sobrietyland. Loperamide abuse/misuse/addiction and cardiac conduction disturbances — article clearinghouse. 2014. Available at: https:// madmargaret. wordpress. com/ 2014/ 07/ 23/ loperamide- abusemisuseaddict ion- and- cardiac- conduction- disorders/ . Accessed April 1, 2018

14. Postema PG, Wolpert C, Amin AS, et al. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www. brugadadrugs. org). Heart Rhythm. 2009;6(9):1335–1341

15. Allen HD, Shaddy RE, Penny DJ, Feltes TF, Cetta F. Moss and Adams’ Heart Disease in Infants, Children, and

PEDIATRICS Volume 142, number 4, October 2018 5 by guest on October 7, 2020www.aappublications.org/newsDownloaded from

Adolescents: Including the Fetus and the Young Adult. 9th ed. Philadelphia, PA: Wolters Kluwer; 2016: 572–573

16. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932–1963

17. Lambiase PD, Ahmed AK, Ciaccio EJ, et al. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis.

Circulation. 2009;120(2):106–117, 1–4

18. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29(13):1670–1680

19. Hofman-Bang J, Behr ER, Hedley P, et al. High-efficiency multiplex capillary electrophoresis single strand conformation polymorphism (multi-CE-SSCP) mutation screening of SCN5A: a rapid genetic approach to cardiac arrhythmia. Clin Genet. 2006;69(6):504–511

20. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010;7(1):33–46

21. Papadakis M, Raju H, Behr ER, et al. Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous interpretation [published correction appears in Circ Arrhythm Electrophysiol. 2013;6(4):e67]. Circ Arrhythm Electrophysiol. 2013;6(3):588–596

STEFEK et al6 by guest on October 7, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2018-1423 originally published online September 25, 2018; 2018;142;Pediatrics 

Bryan Stefek, L. Timothy Wolfe and Mark CohenBrugada Syndrome Associated With Adolescent Loperamide Abuse

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/142/4/e20181423including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/142/4/e20181423#BIBLThis article cites 16 articles, 2 of which you can access for free at:

Subspecialty Collections

http://www.aappublications.org/cgi/collection/cardiology_subCardiologyicine_subhttp://www.aappublications.org/cgi/collection/adolescent_health:medAdolescent Health/Medicinefollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on October 7, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2018-1423 originally published online September 25, 2018; 2018;142;Pediatrics 

Bryan Stefek, L. Timothy Wolfe and Mark CohenBrugada Syndrome Associated With Adolescent Loperamide Abuse

http://pediatrics.aappublications.org/content/142/4/e20181423located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on October 7, 2020www.aappublications.org/newsDownloaded from