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ARTICLE IN PRESSG ModelCCASE-480; No. of Pages 3

Journal of Cardiology Cases xxx (2014) xxx–xxx

Contents lists available at www.sciencedirect.com

Journal of Cardiology Cases

journa l h om epage: www.elsev ier .com/ locate / j ccase

ase Report

rare complication of a common stress test

arichart Junpaparp (MD)a,∗, Harish Raj Seetha Rammohan (MD, MRCP)b,aranya Buppajarntham (MD)a, Vincent M. Figueredo (MD)b

Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, USADepartment of Cardiology, Albert Einstein Medical Center, Philadelphia, PA, USA

r t i c l e i n f o

rticle history:eceived 28 January 2014eceived in revised form 1 March 2014ccepted 4 March 2014

eywords:egadenosoneizureelective adenosine receptor agonistyocardial perfusion imaging

a b s t r a c t

In 2008, regadenoson, a selective adenosine2A (A2A) receptor agonist, was approved by the US Fed-eral and Drug Administration for use as a pharmacologic stress agent in myocardial perfusion studies.By stimulating A2A receptors in coronary smooth muscle, it can increase coronary blood flow by 2.5-fold or greater. Previous data showed non-inferiority of regadenoson in detecting reversible myocardialischemia, compared to adenosine. Given less serious adverse effects, being better tolerated and easilyadministered, regadenoson has been widely used for myocardial perfusion imaging. As adenosine recep-tors have many sub-types and are located in multi-organ systems, regadenoson can cause various adverseeffects, including bronchospasm, atrioventricular block, or hypotension. However, adverse effects on thecentral nervous system are rarely reported. As adenosine receptors (A1 and A2A receptors) play a majorrole in neuron–glial cells interaction, regadenoson can provoke seizure through A2A receptor activation.We hereby report a case of regadenoson associated-seizure and review seizure mechanism. This may raise

more concern for a rare serious adverse effect of regadenoson which should be taken into considerationwhen selecting cardiac stress modalities.<Learning objective: Regadenoson can provoke seizure through central A2A receptor activation. Thisshould be taken into consideration when selecting cardiac stress test modalities, particularly in patientswith known seizure disorder or history of organic brain disease.>

4 Jap

© 201

ntroduction

In 2008, regadenoson, selective adenosine2A (A2A) receptorgonist, was approved by the US Food and Drug Administra-ion (FDA) for use as a pharmacologic stress agent in myocardialerfusion studies. Given less serious adverse effects, being bet-er tolerated and easily administered, regadenoson has beenidely used for myocardial perfusion imaging. Common adverse

eactions of regadenoson are dyspnea, headache, flushing, chestiscomfort, dizziness, nausea, and abdominal discomfort. However,egadenoson-related seizure has only been reported once.

ase report

Please cite this article in press as: Junpaparp P, et al. A rare cohttp://dx.doi.org/10.1016/j.jccase.2014.03.007

A 63-year-old male with a history of hypertension, sick sinusyndrome with pacemaker placed in 2012, and ischemic stroke

∗ Corresponding author at: Albert Einstein Medical Center, 5501 Old York Road,hiladelphia, PA 19141, USA. Tel.: +1 310 382 6703; fax: +1 215 456 7926.

E-mail addresses: junpapap@einstein.edu, toon mu@hotmail.comP. Junpaparp).

ttp://dx.doi.org/10.1016/j.jccase.2014.03.007878-5409/© 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights re

anese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

with residual right hemiparesis and expressive aphasia, presentedfor a stress test following multiple episodes of intermittent exer-tional chest pain associated with diaphoresis. Given multipleatherosclerotic risk factors, the pre-test probability was consid-ered as moderate risk and he was arranged for regadenoson stresstest. In the stress laboratory, the patient was injected intravenouslywith regadenoson 0.4 mg over 15 s per protocol. An estimation of5 min later, the patient developed generalized tonic–clonic seizurewhich lasted for 2 min. The patient remained confused for 15 minafter seizure stopped. At the time, the patient was afebrile withblood pressure of 115/70 mmHg and heart rate of 80/min. Therewas no bowel or bladder incontinence or new focal neurolog-ical deficit observed. The patient denied any history of seizuredisorder or recent head injury. He also denied any fever, chills,or recent illness. His home medications were aspirin, metopro-lol, and simvastatin. Upon admission, the patient was alert withnormal orientation. Neurological examinations revealed expres-sive aphasia, with motor power grade 2/5 and 3/5 at right upper

mplication of a common stress test. J Cardiol Cases (2014),

and lower extremities which were unchanged from baseline. Therest of the physical examination was unremarkable. The restingelectrocardiography (ECG) showed electronic atrial pacing with nosignificant ST–T wave abnormality (Fig. 1). Blood chemistry showed

served.

ARTICLE IN PRESSG ModelJCCASE-480; No. of Pages 3

2 P. Junpaparp et al. / Journal of Cardiology Cases xxx (2014) xxx–xxx

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Fig. 1. The resting electrocardiogram showed electron

erum sodium of 142 mmol/L, potassium of 4 mmol/L, calciumf 9.6 mg/L, and glucose of 116 mg/dL. Emergent computerizedomography of brain showed cystic encephalomalacia, compatibleith chronic left middle cerebral artery territory infarct (Fig. 2).o acute intracranial abnormality was observed. Subsequent elec-

roencephalography (EEG) study did not reveal any epileptiformctivity. The patient was admitted to the observation unit for theext 24 h, during which he remained seizure free. He was subse-uently discharged home. It was concluded that the seizure wasrovoked by regadenoson.

iscussion

Myocardial perfusion imaging (MPI) is a well-validated, non-

Please cite this article in press as: Junpaparp P, et al. A rare cohttp://dx.doi.org/10.1016/j.jccase.2014.03.007

nvasive test for determining the diagnosis, severity, and prognosisf coronary artery disease. With an inability of the stenotic vessel toilate, the discrepancy between normal and diseased myocardiuman be visualized with the myocardial perfusion scan. In general,

ig. 2. Chronic evolution of the left middle cerebral artery infarct territory involvinghe left lentiform nucleus and posterior limb of the internal capsule has occurredith associated ex vacuo dilatation of the left lateral ventricle. No acute intracranial

bnormality is observed.

ial pacing with no significant ST–T wave abnormality.

physical exercise is a preferred method of inducing stress. How-ever, it is not suitable for all patients (e.g. musculoskeletal diseases,neurological diseases, morbid obesity, or debilitated patients).Therefore, pharmacological stress tests play a role among thesegroups. In the past, adenosine and dipyridamole (inhibiting the cel-lular uptake of adenosine) were widely used, as they both increaseinterstitial adenosine concentration, causing coronary vasodila-tion through adenosine A2A receptor. However, neither of them isspecific to A2A receptor on coronary smooth muscles. With the con-comitant blocking of A1, A2B, and A3, they can cause various sideeffects, such as flushing, chest pain, bronchospasm (A2B, A3), atrio-ventricular block (A1), and peripheral vasodilation (A2B) [1]. Thus,the selective A2A receptor agonist, regadenoson, came into interestafter being approved by the FDA in 2008. According to ADVANCEMPI 1 and 2 trials, regadenoson was non-inferior to adenosinein detecting reversible myocardial perfusion defects, while beingbetter tolerated and causing less serious side effects [2,3]. More-over, regadenoson is more practical and cost-effective, as it doesnot require dose adjustment for renal function or body weightand can be given by a single injection of 0.4 mg intravenously. Itcan be safely used in chronic obstructive pulmonary disease andasthma patients, as studies showed no significant difference in pul-monary function parameters or clinical symptoms after being givenregadenoson compared to placebo [4,5]. Regadenoson remains con-traindicated in second- or third-degree atrioventricular block andsinus node dysfunction (with an absence of pacemaker) given alow affinity toward A1 receptor. The report on safety and tolera-bility of regadenoson from a cross-sectional study in 753 subjectsshowed that regadenoson was well tolerated with only one casereported of bronchospasm and heart failure exacerbation. The com-mon adverse symptoms were dyspnea (30%), chest discomfort(27%), and headache (15%) [6]. In addition, there were no seriousadverse events observed among patients with stage 3–4 chronickidney disease, as well as, end-stage renal disease [7,8]. However,regadenoson provoked seizure in one report [9].

In 1972, Burnstock et al. were the first to discover purinergicneurotransmission, involving release of adenosine tri-phosphate(ATP) as an efferent neurotransmitter [10]. Later, multiple studiesconfirmed that adenosine plays a key role in seizure regulation bycontrolling neuron–glial cell interactions, which made adenosine

mplication of a common stress test. J Cardiol Cases (2014),

augmentation a new target of antiepileptic therapy [11]. Adeno-sine exerts central neuromodulation mainly through A1 and A2Areceptors, given significantly lower affinity of A2B and A3 recep-tors. A1 receptor activation can decrease neuronal transmission

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ARTICLECCASE-480; No. of Pages 3

P. Junpaparp et al. / Journal of C

hrough inhibition of pre-synaptic neurotransmitter release andtabilization of post-synaptic membrane potential, which leadso seizure termination. In contrast, A2A receptor activation hasoth proconvulsant and anticonvulsant activities, depending on therain location. In animal models, A2A receptor activation at cere-ral cortex can enhance glutamatergic excitatory, and inhibit theeuroprotective activity of the A1 receptor thereby causing cor-ex and limbic seizures, whereas activation at brainstem inhibitseizure. Based on this mechanism, the use of a selective adeno-ine A2A receptor agonist can potentially cause seizure [12,13]. Inontrast, adenosine and dipyridamole have never been reportedo cause seizure as they also activate A1 receptor which is neu-oprotective. By excluding other potential causes of seizure, suchs metabolic causes and acute intracerebral pathology, we believehat regadenoson caused seizure in our patient. In 2012, Paget al. reported a case series of regadenoson-associated seizure,n which most of the patients had known epilepsy. The seizurevolved from partial to secondary generalized seizure. Althoughminophylline is used to treat other reactions, its role in treatingeizure remains inconclusive as it was found to prolong seizure inne case [9]. We therefore suggest having access to seizure ter-ination medications (e.g. benzodiazepines) in the area of stress

aboratories.In conclusion, we hereby report a rare complication of a common

ardiac stress test, which may raise more concern on stress testelection, particularly in patients with known seizure disorder oristory of organic brain disease.

Please cite this article in press as: Junpaparp P, et al. A rare cohttp://dx.doi.org/10.1016/j.jccase.2014.03.007

onflict of interest

The authors declare no conflict of interest.

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PRESSlogy Cases xxx (2014) xxx–xxx 3

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