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CMJ Case Report June 2016, Volume: 38, Number: 2 Cumhuriyet Medical Journal 147-152 http://dx.doi.org/10.7197/cmj.v38i2.5000137562 Acute myocarditis induced by dosage increment of in an adolescent patient Genç erişkin hastada metilfenidat doz artışına bağlı gelişen akut miyokardit

Osman Beton1, Recep Kurt1, Hakan Güneş2, Hakkı Kaya1, Mehmet Birhan Yılmaz1

1Cumhuriyet University, Faculty of Medicine, Department of Cardiology, Sivas, Turkey 2Sivas Numune Hospital, Cardiology Clinic, Sivas, Turkey Corresponding author: Osman Beton, Cumhuriyet Universitesi, Tıp Fakültesi, Kardiyoloji Anabilim Dalı, TR-58140, Sivas, Turkey E-mail: [email protected] Received/Accepted: August 12, 2015 / April 07, 2016 Conflict of interest: There is not a conflict of interest.

SUMMARY Attention deficit-hyperactivity disorder (ADHD) is one of the most common psychiatric disorders seen in children and adolescents. ADHD is increasingly diagnosed and treated nowadays. Methylphenidate is a potent psychostimulant that exerts its effects by increasing and levels in synapses. It is a widely used medication for treatment of ADHD in children and adolescents. Although not well-established, a causal relationship between treatment of ADHD and development of cardiomyopathy has been suggested. However, this suggestion was supported by the normalization or improvement in cardiac function and functional class after cessation of anti-ADHD medications in patients suffering from cardiomyopathy related to anti- ADHD medications. In this case report, we describe a case of 14-year-old male patient who developed acute myocarditis due to the dose increment of methylphenidate. The patient completely recovered after discontinuation of methylphenidate. Cardiovascular monitoring of patients on methylphenidate treatment should be an important task for psychiatrists, general practitioners and cardiologists. Keywords: Attention deficit-hyperactivity disorder, methylphenidate, acute myocarditis

ÖZET Dikkat eksikliği-hiperaktivite bozukluğu (DEHB), çocuk ve gençlerde en çok karşılaşılan psikiyatrik hastalıklardan biridir. DEHB tanısı ve tedavisi bu günlerde giderek artmaktadır. Metilfenidat, sinapslardaki dopamin ve norepinefrin düzeylerini arttırarak etkisini gösteren, güçlü bir psikostimulan ajandır. Çocuk ve gençlerde DEHB tedavisinde yaygın olarak kullanılan bir ilaçtır. İyice anlaşılmamış olmasına rağmen, DEHB tedavisi ve kardiyomiyopati gelişimi arasında nedensel bir ilişki öne sürülmüştür. Fakat bu nedensel ilişki, anti-DEHB ilaçlarına bağlı kardiyomyopati gelişen hastalarda, anti-DEHB ilaçların kesildikten sonra kalp fonksiyonu ve fonksiyonel sınıfın düzelmesi veya normale dönmesi ile desteklenmektedir. Bu olgu sunumunda, metilfenidat doz artışına bağlı akut miyokardit gelişen 14 yaşında bir erkek hastayı betimledik. Hasta, medilfenidat kesilmesinden sonra tamamen düzeldi. Metilfenidat tedavisi alan hastaların kardiyovasküler yönden izlenmesi, psikiyatristler, pratisyen hekimler ve kardiyologlar için önemli bir görev olmalıdır. Anahtar sözcükler: Dikkat eksikliği - hiperaktivite bozukluğu, metilfenidat, akut miyokardit

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INTRODUCTION this drug, so the dose of methylphenidate Attention deficit-hyperactivity disorder was increased to 36mg daily six days prior. (ADHD), the most common He denied tobacco, alcohol or illicit drug neurobehavioral disorder of childhood, is use and family history was unremarkable. characterized by developmentally He denied any upper respiratory tract inappropriate levels of hyperactivity, infections in the preceding weeks. On inattention, and impulsivity1. The vast admission, his temperature was 37.6º C, increase in the diagnosis of ADHD and the was 120/80 mmHg, with a frequency of treatment for the condition in pulse of 90 bpm, a respiratory rate of 18 children and adolescents is not specific to per minute, and an oxygen saturation of develped countries, but is also true for 98% on room air. Cardiac examination developing countries. Medications revealed an irregular rhythm in the absence commonly used in treatment of ADHD of murmurs. All other system examinations may be associated with cardiovascular risk, were within normal limits. Upon arrival to but the degree of risk and the types of emergency department, an cardiac events are insufficiently electrocardiogram (ECG) revealed investigated. Several cases of ventricular bigeminy with an underlying methylphenidate-induced cardiomyopathy, sinus rhythm (Figure 1). Chest X-ray was including patients of 17-20 years of age, 2- normal with no consolidations or 5 two cases of methylphenidate induced cardiomegaly. Arterial blood gas analyses acute myocarditis in patients of 17 and 18 and D-Dimer test were normal. White years of age 5, 6 and several cases of acute blood cell counts and hemoglobin level possibly due to were in normal range. Urine test was methylphenidate7-9, have been reported. A normal. His initial creatinine kinase (CK), 2006 Food and Drug creatinine kinase MB fraction (CK-MB) Administration report ordered a black box and troponin I levels were 950 U/L, 80 warning placed on drugs used in treatment U/L and 6.29 ng/ml, respectively. Initial of ADHD due to various cardiovascular levels were peak values for cardiac side effects, including cardiomyopathy10. markers. C-reactive protein level was 24.2 However, two recent, large scale trials mg/l with sedimentation rate of 14 mm/h. found no evidence of a direct link between He was given aspirin and transferred to ADHD medications and cardiovascular CCU. 11, 12 risk in children and young adults . Echocardiography revealed global mild Herein, we report the case of a male hypokinesis with a left ventricular ejection adolescent who developed acute fraction (EF) of 50% (without segmental or myocarditis after increasing the dose of his regional wall motion abnormality). No methylphenidate. pericardial effusion was detected. CASE REPORT However, his EF was found to be 65% in a prior echocardiographic evaluation. A previously healthy 14-year-old male Thyroid function tests, immunological with a past medical history of ADHD markers (ANA, ANCA, RF), and presented to emergency department with electrolytes were normal. Bacterial the complaints of crushing , cultures and hepatitis serologies were dyspnea and sweating, which had been negative. Methylphenidate was present for four days. He reported that his discontinued following hospitalization. chest pain and dyspnea were initially mild, Coronary angiography showed normal but increased gradually, and became severe coronary arteries and the patient did not and intolerable which made him apply to develop decompensated . Eight our emergency department. His ADHD days after hospitalization, CK, CK-MB, was diagnosed three months ago. troponin I and CRP levels returned to Psychotherapy, education and training normal values and the patient had complete therapy were initiated, but because of recovery. Control echocardiography unsatisfactory response, he was started on performed before discharge showed methylphenidate (Concerta®) 18 mg daily normal left ventricular systolic function a month prior. He had a partial response to

CMJ Cumhuriyet Medical Journal 149 with EF of 60%. He was diagnosed with cardiology follow-up and repeat acute myocarditis and discharged on echocardiography in one month. metoprolol and ramipril with plans for

Figure 1: Admission ECG which demonstrated ventricular bigeminy.

causes cardiac side effects is still unclear, DISCUSSION but scientific data indicated that We described a patient with myocarditis stimulation of catecholaminergic system in secondary to drug treatment with frontal lobes caused a reflex increase in methylphenidate soon after dose cardiac diastolic pressure15, 16. These two increment. The evidence supporting the theories might be potential mechanisms in etiologic relationship with this setting. Moreover, norepinephrine methylphenidate included significant sensitivity exhibits variations between improvement after cessation of drug, individuals, thus one cannot expect quick absence of other etiological factors of and uniform reactions in all patients17. The myocarditis, and the temporal relationship differential sensitivity to these drugs can between dose increment and the also in part be explained by different complaints. Although little is known about genetic backgrounds of individuals18, 19. the cardiac effects of methylphenidate, the Methylphenidate can also act as a trigger explanation may lie in the direct effects of for acute inflammatory response. on cardiac myocytes, acute Similarly, patients who use have inflammatory response and endothelial five times increased risk of myocarditis, injury13, 14. which is caused by the microvascular analoges and several other injury13. Cocaine can directly affect psychotropic drugs cause norepinephrine myocardial muscle by causing acute release and increase its levels at the nerve deteriorations in systolic and diastolic terminal, an effect which was thought to be function, as well as alterations in calcium only central in nature15. Chronic transport in myocytes13. The mechanisms sympathetic activation causes impaired underlying these effects are unknown, but beta adrenoreceptor mediated inotropic may involve -mediated response of the heart, leading to myocyte increases in lymphocyte and natural killer apoptosis and impaired systolic functions cell activity13. This inflammatory response of left ventricle16. The mechanism by may exert cytotoxic effect on the which central nervous system activation myocardium. Methylphenidate may have a

CMJ Cumhuriyet Medical Journal 150 similar mechanism of action leading findings bring up the questions regarding myocarditis. In our case, elevated CRP the risks of these drugs. have level may be explained by the sympathomimetic effects, increase blood inflammatory response. Sympathomimetic pressure and heart rate, and may drugs, including and theoretically increase cardiovascular cocaine can cause AMP-induced cardiac risk.10 FDA approved these medications, injury which includes coronary spasm, but included a "black box" warning 10 due prothrombotic state, and accelerated to potential risks for coronary artery atherosclerosis due to endothelial injury14. disease, heart failure and fatal . Methylphenidate-induced myocarditis may However, large scale studies suggested that also be caused by endothelial impairment ADHD medications did not actually and disturbance of microcirculation in increase the risk of several types of addition to direct injury to cardiac cardiovascular events. Cooper, et al. myocytes. Methylphenidate effect on studied patients between 2-24 years of age, endothelial function should be further with 2.5 million person years of follow up, investigated in order to understand the of which nearly 400 000 people used anti- underlying mechanisms. ADHD medications, and there was no increased risk of sudden cardiac death, Stimulants are usually titrated until there is heart attack or stroke13, 14. Habel, et al. 13, 14 optimal symptom reduction or significant reported that among adults with 800,000 -related side effects appear. Mild person years of follow up, of which over side effects are commonly reported in 100 000 people used anti-ADHD children who take stimulant medications, medications, there was no increased risk and changes in timing and dosage often for adverse cardiac events and .A result in improvement20. A question arises small study suggested that the risk of whether dose increment could explain the sudden cardiac death or may be clinical progression observed in our case. increased but the causal relationship was It was shown that methylphenidate had still not fully clarified13, 14. dose-related effect on dopaminergic system to increase heart rhythm and Case reports should be taken as important cardiac contraction, which can potentially warnings2-9. Although they cannot explain degenerative ultrastructural influence the indications and changes in mitochondrial path when given contraindications per se, they point to the at high doses to rats21. However, only heart importance of careful monitoring. The rate and blood pressure effects were screening and monitoring which has been demonstrated in clinical trials at high proposed is reasonable. The possible doses20, 22. causal relationship attributable to adrenergic effects can in part be monitored The prevalence of ADHD has increased easily by blood pressure and heart rate substantially which may in part be due to recordings. In line with the increased use establishment of better diagnostic criteria of anti-ADHD medications, this and increased awareness. Current monitoring is of particular importance for estimated prevalence among children of 2- psychiatrists, primary care and consultant 18 years of age varies greatly, depending cardiologists. on the diagnostic criteria used and the population studied13. It was long thought In conclusion; acute myocarditis, that ADHD occurred only in children, but myocardial infraction and dilated 30 to 70 percent of children with ADHD cardiomyopathy are adverse cardiac events had residual symptoms as adults, and the observed in some patients with prevalence of ADHD or ADHD symptoms methylphenidate. Causative link between in adults was 1-7%14. Stimulants (mainly methylphenidate use and the development amphetamines and methylphenidate) have of myocardial pathology is still not known. been shown in studies to improve Additionally, determining the patients at symptoms among children and adults, risk for myocardial pathology while on especially in short term, an affect more methylphenidate should be a future task to predominant in children13, 14. These further utilize individual treatment options.

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