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Clozapine-induced myocarditis
SCHRES-06802; No of Pages 4 Schizophrenia Research xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Clozapine-induced myocarditis Laurens E. Swart a,⁎, Kenneth Koster b, Marieke Torn c, Ricardo P.J. Budde a, Ruben Uijlings c a b c
Department of Radiology, Erasmus Medical Centre, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands Department of Radiology, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands Department of Cardiology, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands
a r t i c l e
i n f o
Article history: Received 2 February 2016 Received in revised form 6 April 2016 Accepted 11 April 2016 Available online xxxx Keywords: Clozapine Myocarditis Magnetic resonance imaging Schizophrenia Drug hypersensitivity reaction
et al., 2015a) with increasing incidences over the past two decades of up to 1.2% among patients on clozapine (Haas et al., 2007). Although this increase could partially be attributable to rising awareness, the true incidence (which is expected to be around 3% (Ronaldson et al., 2015a)) probably remains underestimated, as many of the nonspecific symptoms associated with myocarditis such as hypotension, tachycardia and fatigue are still considered to be benign side effects of clozapine dose up-titration (Munshi et al., 2014). Through the following case and subsequent overview of literature, we've attempted to emphasize the importance and difficulty of the timely diagnosis of clozapine-induced myocarditis, and demonstrate that cardiac magnetic resonance imaging (CMR) can herein be of additional value. 1. Case presentation
Dear Editors, Clozapine is considered to be the reference standard in treatment of refractory schizophrenia because of its greater efficacy and lesser tendency to induce extrapyramidal side effects when compared to conventional neuroleptics such as haloperidol (Toren et al., 1998). However, due to several other adverse effects including severe gastrointestinal obstruction, diabetic ketoacidosis and most notably potentially fatal agranulocytosis, its applicability has been limited to last-line therapy (Miller, 2000). Over the past two decades, mandatory registration and closer monitoring of patients started on clozapine have greatly reduced the incidence of these serious complications (Kilian et al., 1999) and allowed for wider clinical use to be advocated (Warnez and AlessiSeverini, 2014). Other complications arose however, with an increasing number of reports on possible cardiac side effects appearing in literature, such as arrhythmia, (peri-)myocarditis and even dilated cardiomyopathy after prolonged use (Kilian et al., 1999). Among these, myocarditis has been of particular recent interest because of its dose-independent, acute onset that often shortly follows clozapine initiation. Since the first case of clozapine-induced myocarditis was documented in 1994 (Jensen and Gøtzsche, 1994), over 250 cases have been described (Ronaldson
⁎ Corresponding author at: Department of Radiology, Erasmus MC, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E-mail addresses: [email protected], [email protected] (L.E. Swart), [email protected] (K. Koster), [email protected] (M. Torn), [email protected] (R.P.J. Budde), [email protected] (R. Uijlings).
A 22-year-old Caucasian male without prior somatic medical history was referred to the coronary care unit (CCU) because of acute-onset pleuritic chest pain. He had been started on clozapine 11 days prior to admission and had experienced a fever (spiking up to 40 °C), hypotension and mild but progressive tachycardia over the past five days. For over a year now, he had intermittently been admitted to our psychiatric unit because of a psychotic disorder not-otherwise-specified (possibly schizophrenia) combined with an autism spectrum disorder. He had previously been treated with high doses of haloperidol, olanzapine and quetiapine consecutively, all of which had to be discontinued due to intolerable adverse effects and little to no improvement in his mental wellbeing. At clozapine initiation, baseline investigations including vital signs, ECG and laboratory tests had been within normal limits. During the following week, the dose of clozapine had been gradually increased from 25 mg once daily up to 100 mg twice daily, with the last increase having taken place 5 days prior to referral, before the fever arose. Three days prior to admission, the clozapine had already shortly been discontinued because of worsening symptoms, which had resulted in resolution of the fever and alleviation of physical complaints. The next day however, the clozapine had to be reinitiated due to psychiatric deterioration, after which the fever reappeared. At admission in the CCU, the patient's main complaint was a nagging, sharp, non-radiating pain on the left side of his chest, which was accompanied by malaise, a moderate fever and a tickly cough. Besides slightly lowered blood pressure and tachycardia, the additional history and physical examination were unremarkable; there were no risk factors
http://dx.doi.org/10.1016/j.schres.2016.04.016 0920-9964/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
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L.E. Swart et al. / Schizophrenia Research xxx (2016) xxx–xxx
for cardiovascular disease. His concurrent medications included temazepam, lorazepam, biperiden, glycopyrrolate and a low dose of haloperidol. Furthermore, amoxicillin/clavulanate had been added at the first occurrence of fever for suspected upper respiratory tract infection. The ECG showed a sinus tachycardia of 127 bpm without any repolarization disturbances, and laboratory testing revealed an elevated white blood cell (WBC) count (14.2 × 109/L; normal range 4.5– 11 × 109) and elevated blood levels of CRP (54 mg/L; normal range ≤ 10 mg/L) and hsTnT (112 ng/L; normal range ≤ 14 ng/L). CK was within normal limits (59 U/L; normal range 55–170 U/L). Cultures of blood, feces and urine, as well as autoantibody screening and viral serologies were all negative, and extensive examinations including abdominal ultrasound and chest and sinus X-rays revealed no infectious focus. Transthoracic echocardiography (TTE) in the CCU demonstrated slight global hypokinesia of the left ventricle and 1 cm of circumferential pericardial effusion. Afterwards, using a 1.5 T scanner (Signa HDxt, GE Healthcare, Waukesha, WI) and an 8-channel cardiac coil, CMR was performed, which included cine images, triple-inversion recovery (fat-saturated) T2-weighted images and delayed enhancement sequences obtained 15 min after gadolinium injection (Fig. 1, panels A–C). The cine images likewise showed a slightly decreased left ventricular function (ejection fraction 43%) and an ample amount of pericardial effusion, while the T2-weighted images demonstrated a clearly delineated area of myocardial edema in the basal anteroseptal wall (panel B, arrow). Although the delayed enhancement images were of poor quality, they gave the impression of a thin rim of gadolinium retention in the same area, but this was not clearly distinguishable from the blood pool in the right ventricle (panel C).
The patient was concluded to have clozapine-induced perimyocarditis and the clozapine was ceased, after which his symptoms quickly resolved and the WBC count and CRP and hsTnT levels normalized within 3 days. Repeat TTE showed a slight decrease in pericardial effusion and normalization of left ventricular function, whereupon the patient was returned to the psychiatric facility for assessment of alternative antipsychotic medications. Six months later, repeat CMR revealed a normalized global left ventricular function (ejection fraction 53%), near complete resorption of the pericardial effusion and full resolution of the myocardial edema. Furthermore, mild local hypokinesia and now more clearly delineated delayed enhancement were found in the basal anteroseptal wall (panels D–F). 2. Background While the exact mechanism underlying clozapine-related myocarditis remains unknown, it is hypothesized that clozapine, a tricyclic dibenzodiazepine derivative, induces an IgE-mediated hypersensitivity reaction that is characterized by myocardial eosinophilic infiltrates, as seen in a biopsy (Kilian et al., 1999). This hypothesis is supported by evidence that the reaction is often accompanied by hypereosinophilia, generally occurs within 2–3 weeks after initiation of clozapine (Ronaldson et al., 2010) and is considered to be dose-independent (Haas et al., 2007). Other (as yet unsupported) theories attribute the cause of myocarditis to toxic clozapine accumulation due to a cytochrome P450 1A2/1A3 deficiency or increased plasma levels of norepinephrine and inflammatory cytokines. Although a few cases of late clozapine-induced myocarditis have been reported (Lang et al., 2008; Tan et al., 2015), the vast majority manifest in the initial two months of treatment (while the dose is still
Fig. 1. First (A–C) and second (D–F) CMR scan, acquired clinically during acute myocarditis and in an out-patient setting after 6 months of follow-up respectively. On the first scan, the short-axis cine (A) and triple-inversion recovery T2-weighted (B) CMR images showed circumferential pericardial effusion (asterisk) and myocardial edema in the basal anteroseptal wall (arrow), while the delayed enhancement sequence gave the impression of a thin line of gadolinium retention in the same area (C), that could however not easily be distinguished from the blood pool in the right ventricle. After 6 months, the short-axis cine (D) and double-inversion recovery T2-weighted (E) CMR images showed almost no more pericardial effusion and complete resolution of the myocardial edema, while an area of mid- to epicardial delayed enhancement (F) was now clearly delineated in the same region (arrowhead).
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
L.E. Swart et al. / Schizophrenia Research xxx (2016) xxx–xxx
gradually being increased), with 75% occurring in the first four weeks (Hägg et al., 2001). The clinical presentation of clozapine-induced myocarditis can vary widely from subclinical or mild atypical symptoms to acute heart failure or presumably even sudden cardiac death. The most common symptoms are similar to that of (peri-) myocarditis of other etiologies (e.g. viral), including chest discomfort and hypotension with persistent tachycardia, which are often preceded or accompanied by flu-like symptoms such as a fever, fatigue, a dry cough and dyspnea (Magnani and Dec, 2006). Occurrence of any of these non-specific symptoms within the first 2 months after initiation of clozapine should prompt additional investigations which are discussed below, as early recognition of clozapine-induced myocarditis may improve clinical outcomes (Annamraju et al., 2007; Razminia et al., 2006). Despite the aforementioned association with hypereosinophilia, the eosinophil count does not rule out myocarditis when it is within normal range, and is useless for its early detection since an elevation has been found to be delayed for as long as 7 days after the peak in troponin levels (Ronaldson et al., 2010). This rise in troponin levels however, which usually occurs approximately 3 days after a fever arises and CRP levels surpass 50 mg/L (Ronaldson et al., 2015b), has proven to be sensitive (86%) and particularly specific (100%) in a case–control study of 38 cases and 47 controls that employed a fairly easily-met definition of clozapine-induced myocarditis (Ronaldson et al., 2010). Creatine kinase is inferior to troponins due to its lower predictive value (Magnani and Dec, 2006) and can therefore, just like N-terminal Brain-type Natriuretic Peptide Prohormone (NT-proBNP), not be used diagnostically. Both however conceivably indicate life-threatening illness and predict unfavorable outcomes such as cardiac death in patients with suspected myocarditis when they are greatly elevated (Ronaldson et al., 2011a; Ukena et al., 2014). While echocardiography can adequately assess the consequences of myocarditis on regional left ventricular function and should readily be performed repeatedly in any patient with a suspicion of clozapineinduced myocarditis, these effects can often be subtle and cannot be distinguished from pre-existing dysfunction without a baseline assessment. Routine echocardiography prior to clozapine commencement has therefore been proposed to be added to clozapine-related side effect monitoring guidelines (Ronaldson et al., 2011b, 2012c). Furthermore, when clozapine-induced myocarditis has been diagnosed, echocardiography should be used as the primary monitoring tool during follow-up, as improvement of left ventricular function after clozapine discontinuation is closely related to favorable clinical outcomes. When blood tests or echocardiography remain inconclusive, several case studies have demonstrated that CMR, which is known to have very high diagnostic accuracy for acute myocarditis in general (Abdel-Aty et al., 2005), can be of additional value in patients with suspected clozapine-induced myocarditis (Belloni et al., 2007). The diagnostic CMR criteria for myocarditis require either increased early (hyperemia) or late (fibrosis) gadolinium enhancement on T1-weighted images, and/or increased signal intensity on T2-weighted images for the diagnosis to be made (Friedrich et al., 2009). As demonstrated by our case, the latter, which indicates myocardial edema, is particularly useful in the acute clinical setting, while late gadolinium enhancement is a sign of myocardial fibrosis that indicates irreversible damage that persists, but is less likely to be seen in milder cases of myocarditis (De Cobelli et al., 2006). In fact, based on a report of 3 very mild cases of possible myocarditis related to clozapine in which CMR did not find any signs of myocardial edema or fibrosis, it has been suggested that CMR may not show any abnormalities when the ECG and echocardiogram are unremarkable and creatinine kinase levels are within normal range (Ariyarajah et al., 2010), something which is known to also apply to mild myocarditis of other etiologies (Friedrich and Marcotte, 2013). Interestingly enough, the role of positron emission tomography (PET), which is increasingly being used for the detection of cardiac inflammatory disease including sarcoidosis and endocarditis, has barely been explored yet, although preliminary evidence suggests it could
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provide additional information on disease activity and thereby guide treatment strategies (Piriou et al., 2015). A myocardial biopsy on the other hand, which used to be considered the reference standard, has generally been disregarded because of its considerable procedural risk and limited diagnostic yield due to the patchy and transient nature of the eosinophilic infiltrates that are to be detected. When clozapine-induced myocarditis is suspected, cessation of clozapine and supportive care are the mainstays of treatment and can also help to confirm the diagnosis when symptoms alleviate shortly thereafter, since the physiological half-life of clozapine approximates 12–18 h. With timely diagnosis and cessation of clozapine, the prognosis of mild cases that do not require supportive therapy is excellent, with complete recovery of global left ventricular function, as in our patient, occurring in the majority of cases. However, as in our case, discontinuation of clozapine may sometimes initially prove to be problematic due to rapid psychiatric deterioration. In some mild cases of suspected clozapine-induced myocarditis (as identified by troponin levels within 2–4× the normal limit), continuation of clozapine under close laboratory and cardiac monitoring could therefore be considered when the risks of cessation and continuation have been carefully weighed (Ronaldson et al., 2011b, 2012a). Some risk factors for the development of clozapine-induced myocarditis have been suggested, such as increasing age and the concomitant use of sodium valproate (Ronaldson et al., 2012d). In particular, rapid dose up-titration should be avoided in light of a possibly increased risk associated with faster dose escalation and a higher success rate reported among patients who were rechallenged with clozapine in an even more gradually increasing manner (Ronaldson et al., 2012b). While this rechallenge itself remains controversial, it may be considered when the risk of psychiatric deterioration or even suicide outweighs the risk of cardiac complications in patients for whom no other treatments have been adequately effective, but warrants even more precautions (Manu et al., 2012; Ronaldson et al., 2012b). To conclude, clozapine-induced myocarditis is an underemphasized complication of an otherwise very potent drug of last resort for refractory schizophrenia, which usually occurs during the first four weeks of treatment and comprises a wide spectrum of clinical presentations ranging from very mild complaints to fulminant heart failure or presumably even sudden cardiac death. Clinical vigilance and awareness of this potentially fatal adverse effect are warranted when starting patients on clozapine, as manifestation of any of the often atypical symptoms must prompt additional investigations, of which CMR should readily be considered because of its excellent diagnostic accuracy for myocarditis in general. Although it has been shown that clozapine can safely be continued under strict monitoring in very mild cases, suspicion of clozapine-related myocarditis usually warrants immediate discontinuation. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Abbreviations CMR Cardiac Magnetic Resonance imaging CCU Coronary Care Unit WBC White Blood Cell count TTE Transthoracic Echocardiography NT-proBNP N-terminal Brain-type Natriuretic Peptide Prohormone PET Positron Emission Tomography Role of the funding source Not applicable.
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
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L.E. Swart et al. / Schizophrenia Research xxx (2016) xxx–xxx
Authors' contributions LS, RU and MT were involved in primary care for the patient described in this case report, and documented all relevant data. KK acquired and reviewed the cardiac magnetic resonance images and provided image reconstructions specifically tailored for this study. LS, RU and MT were involved in critical review of all available literature on the topic at hand, while KK and RB were consulted to review the available literature on the imaging part of this study. The preliminary manuscript was drafted by LS. RU and RB critically reviewed the case and revised the manuscript several times for important intellectual content. All authors revised the final manuscript, gave approval for this version to be published and agreed to be accountable for all aspects of the work regarding its accuracy and integrity. Competing interests All authors have declared that they have no relationships relevant to the contents of this paper to disclose. Acknowledgements No additional acknowledgements.
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Lang, U.E., Willbring, M., von Golitschek, R., Schmeisser, A., Matschke, K., Malte Tugtekin, S., 2008. Clozapine-induced myocarditis after long-term treatment: case presentation and clinical perspectives. J. Psychopharmacol. 22, 576–580. Magnani, J.W., Dec, G.W., 2006. Myocarditis: current trends in diagnosis and treatment. Circulation 113, 876–890. Manu, P., Sarpal, D., Muir, O., Kane, J.M., Correll, C.U., 2012. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr. Res. 134, 180–186. Miller, D., 2000. Review and management of clozapine side effects. J. Clin. Psychiatry 61 (Suppl. 8), 14–19. Munshi, T.A., Volochniouk, D., Hassan, T., Mazhar, N., 2014. Clozapine-induced myocarditis: is mandatory monitoring warranted for its early recognition? Case Rep. Psychiatry 2014, 513108. Piriou, N., Sassier, J., Pallardy, A., Serfaty, J.-M., Trochu, J.-N., 2015. Utility of cardiac FDGPET imaging coupled to magnetic resonance for the management of an acute myocarditis with non-informative endomyocardial biopsy. Eur. Heart J. Cardiovasc. Imaging http://dx.doi.org/10.1093/ehjci/jeu319 (Epub ahead of print). Razminia, M., Salem, Y., Devaki, S., Shah, N., Khosla, S., 2006. Clozapine induced Myopericarditis early recognition improves clinical outcome. Am. J. Ther. 13, 274–276. Ronaldson, K.J., Taylor, A.J., Fitzgerald, P.B., Topliss, D.J., Elsik, M., McNeil, J.J., 2010. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. J. Clin. Psychiatry 71, 976–981. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., Topliss, D.J., McNeil, J.J., 2011a. Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophr. Res. 128, 161–165. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., Topliss, D.J., McNeil, J.J., 2011b. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust. N. Z. J. Psychiatry 45, 458–465. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., McNeil, J.J., 2012a. Continuation of clozapine following mild myocarditis. Aust. N. Z. J. Psychiatry 46, 910–911. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., McNeil, J.J., 2012b. Observations from 8 cases of clozapine rechallenge after development of myocarditis. J. Clin. Psychiatry 73, 252–254. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., Topliss, D.J., McNeil, J.J., 2012c. Clozapineinduced myocarditis and baseline echocardiography. Aust. N. Z. J. Psychiatry 46, 1006–1007. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., Topliss, D.J., Wolfe, R., McNeil, J.J., 2012d. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case–control study. Schizophr. Res. 141, 173–178. Ronaldson, K.J., Fitzgerald, P.B., McNeil, J.J., 2015a. Clozapine-induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr. Scand. http://dx.doi.org/10.1111/acps. 12416 (Epub ahead of print). Ronaldson, K.J., Fitzgerald, P.B., McNeil, J.J., 2015b. Evolution of troponin, C-reactive protein and eosinophil count with the onset of clozapine-induced myocarditis. Aust. N. Z. J. Psychiatry http://dx.doi.org/10.1177/0004867414566871 (Epub ahead of print). Tan, L.H., Suetani, S., Clark, S., Wilson, D., 2015. Late onset myocarditis with clozapine use. Aust. N. Z. J. Psychiatry 49, 295. Toren, P., Laor, N., Weizman, A., 1998. Use of atypical neuroleptics in child and adolescent psychiatry. J. Clin. Psychiatry 59, 644–656. Ukena, C., Kindermann, M., Mahfoud, F., Geisel, J., Lepper, P.M., Kandolf, R., Böhm, M., Kindermann, I., 2014. Diagnostic and prognostic validity of different biomarkers in patients with suspected myocarditis. Clin. Res. Cardiol. 103, 743–751. Warnez, S., Alessi-Severini, S., 2014. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry 14, 102.
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Clozapine-induced myocarditis Laurens E. Swart a,⁎, Kenneth Koster b, Marieke Torn c, Ricardo P.J. Budde a, Ruben Uijlings c a b c
Department of Radiology, Erasmus Medical Centre, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands Department of Radiology, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands Department of Cardiology, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands
a r t i c l e
i n f o
Article history: Received 2 February 2016 Received in revised form 6 April 2016 Accepted 11 April 2016 Available online xxxx Keywords: Clozapine Myocarditis Magnetic resonance imaging Schizophrenia Drug hypersensitivity reaction
et al., 2015a) with increasing incidences over the past two decades of up to 1.2% among patients on clozapine (Haas et al., 2007). Although this increase could partially be attributable to rising awareness, the true incidence (which is expected to be around 3% (Ronaldson et al., 2015a)) probably remains underestimated, as many of the nonspecific symptoms associated with myocarditis such as hypotension, tachycardia and fatigue are still considered to be benign side effects of clozapine dose up-titration (Munshi et al., 2014). Through the following case and subsequent overview of literature, we've attempted to emphasize the importance and difficulty of the timely diagnosis of clozapine-induced myocarditis, and demonstrate that cardiac magnetic resonance imaging (CMR) can herein be of additional value. 1. Case presentation
Dear Editors, Clozapine is considered to be the reference standard in treatment of refractory schizophrenia because of its greater efficacy and lesser tendency to induce extrapyramidal side effects when compared to conventional neuroleptics such as haloperidol (Toren et al., 1998). However, due to several other adverse effects including severe gastrointestinal obstruction, diabetic ketoacidosis and most notably potentially fatal agranulocytosis, its applicability has been limited to last-line therapy (Miller, 2000). Over the past two decades, mandatory registration and closer monitoring of patients started on clozapine have greatly reduced the incidence of these serious complications (Kilian et al., 1999) and allowed for wider clinical use to be advocated (Warnez and AlessiSeverini, 2014). Other complications arose however, with an increasing number of reports on possible cardiac side effects appearing in literature, such as arrhythmia, (peri-)myocarditis and even dilated cardiomyopathy after prolonged use (Kilian et al., 1999). Among these, myocarditis has been of particular recent interest because of its dose-independent, acute onset that often shortly follows clozapine initiation. Since the first case of clozapine-induced myocarditis was documented in 1994 (Jensen and Gøtzsche, 1994), over 250 cases have been described (Ronaldson
⁎ Corresponding author at: Department of Radiology, Erasmus MC, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E-mail addresses: [email protected], [email protected] (L.E. Swart), [email protected] (K. Koster), [email protected] (M. Torn), [email protected] (R.P.J. Budde), [email protected] (R. Uijlings).
A 22-year-old Caucasian male without prior somatic medical history was referred to the coronary care unit (CCU) because of acute-onset pleuritic chest pain. He had been started on clozapine 11 days prior to admission and had experienced a fever (spiking up to 40 °C), hypotension and mild but progressive tachycardia over the past five days. For over a year now, he had intermittently been admitted to our psychiatric unit because of a psychotic disorder not-otherwise-specified (possibly schizophrenia) combined with an autism spectrum disorder. He had previously been treated with high doses of haloperidol, olanzapine and quetiapine consecutively, all of which had to be discontinued due to intolerable adverse effects and little to no improvement in his mental wellbeing. At clozapine initiation, baseline investigations including vital signs, ECG and laboratory tests had been within normal limits. During the following week, the dose of clozapine had been gradually increased from 25 mg once daily up to 100 mg twice daily, with the last increase having taken place 5 days prior to referral, before the fever arose. Three days prior to admission, the clozapine had already shortly been discontinued because of worsening symptoms, which had resulted in resolution of the fever and alleviation of physical complaints. The next day however, the clozapine had to be reinitiated due to psychiatric deterioration, after which the fever reappeared. At admission in the CCU, the patient's main complaint was a nagging, sharp, non-radiating pain on the left side of his chest, which was accompanied by malaise, a moderate fever and a tickly cough. Besides slightly lowered blood pressure and tachycardia, the additional history and physical examination were unremarkable; there were no risk factors
http://dx.doi.org/10.1016/j.schres.2016.04.016 0920-9964/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
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for cardiovascular disease. His concurrent medications included temazepam, lorazepam, biperiden, glycopyrrolate and a low dose of haloperidol. Furthermore, amoxicillin/clavulanate had been added at the first occurrence of fever for suspected upper respiratory tract infection. The ECG showed a sinus tachycardia of 127 bpm without any repolarization disturbances, and laboratory testing revealed an elevated white blood cell (WBC) count (14.2 × 109/L; normal range 4.5– 11 × 109) and elevated blood levels of CRP (54 mg/L; normal range ≤ 10 mg/L) and hsTnT (112 ng/L; normal range ≤ 14 ng/L). CK was within normal limits (59 U/L; normal range 55–170 U/L). Cultures of blood, feces and urine, as well as autoantibody screening and viral serologies were all negative, and extensive examinations including abdominal ultrasound and chest and sinus X-rays revealed no infectious focus. Transthoracic echocardiography (TTE) in the CCU demonstrated slight global hypokinesia of the left ventricle and 1 cm of circumferential pericardial effusion. Afterwards, using a 1.5 T scanner (Signa HDxt, GE Healthcare, Waukesha, WI) and an 8-channel cardiac coil, CMR was performed, which included cine images, triple-inversion recovery (fat-saturated) T2-weighted images and delayed enhancement sequences obtained 15 min after gadolinium injection (Fig. 1, panels A–C). The cine images likewise showed a slightly decreased left ventricular function (ejection fraction 43%) and an ample amount of pericardial effusion, while the T2-weighted images demonstrated a clearly delineated area of myocardial edema in the basal anteroseptal wall (panel B, arrow). Although the delayed enhancement images were of poor quality, they gave the impression of a thin rim of gadolinium retention in the same area, but this was not clearly distinguishable from the blood pool in the right ventricle (panel C).
The patient was concluded to have clozapine-induced perimyocarditis and the clozapine was ceased, after which his symptoms quickly resolved and the WBC count and CRP and hsTnT levels normalized within 3 days. Repeat TTE showed a slight decrease in pericardial effusion and normalization of left ventricular function, whereupon the patient was returned to the psychiatric facility for assessment of alternative antipsychotic medications. Six months later, repeat CMR revealed a normalized global left ventricular function (ejection fraction 53%), near complete resorption of the pericardial effusion and full resolution of the myocardial edema. Furthermore, mild local hypokinesia and now more clearly delineated delayed enhancement were found in the basal anteroseptal wall (panels D–F). 2. Background While the exact mechanism underlying clozapine-related myocarditis remains unknown, it is hypothesized that clozapine, a tricyclic dibenzodiazepine derivative, induces an IgE-mediated hypersensitivity reaction that is characterized by myocardial eosinophilic infiltrates, as seen in a biopsy (Kilian et al., 1999). This hypothesis is supported by evidence that the reaction is often accompanied by hypereosinophilia, generally occurs within 2–3 weeks after initiation of clozapine (Ronaldson et al., 2010) and is considered to be dose-independent (Haas et al., 2007). Other (as yet unsupported) theories attribute the cause of myocarditis to toxic clozapine accumulation due to a cytochrome P450 1A2/1A3 deficiency or increased plasma levels of norepinephrine and inflammatory cytokines. Although a few cases of late clozapine-induced myocarditis have been reported (Lang et al., 2008; Tan et al., 2015), the vast majority manifest in the initial two months of treatment (while the dose is still
Fig. 1. First (A–C) and second (D–F) CMR scan, acquired clinically during acute myocarditis and in an out-patient setting after 6 months of follow-up respectively. On the first scan, the short-axis cine (A) and triple-inversion recovery T2-weighted (B) CMR images showed circumferential pericardial effusion (asterisk) and myocardial edema in the basal anteroseptal wall (arrow), while the delayed enhancement sequence gave the impression of a thin line of gadolinium retention in the same area (C), that could however not easily be distinguished from the blood pool in the right ventricle. After 6 months, the short-axis cine (D) and double-inversion recovery T2-weighted (E) CMR images showed almost no more pericardial effusion and complete resolution of the myocardial edema, while an area of mid- to epicardial delayed enhancement (F) was now clearly delineated in the same region (arrowhead).
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
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gradually being increased), with 75% occurring in the first four weeks (Hägg et al., 2001). The clinical presentation of clozapine-induced myocarditis can vary widely from subclinical or mild atypical symptoms to acute heart failure or presumably even sudden cardiac death. The most common symptoms are similar to that of (peri-) myocarditis of other etiologies (e.g. viral), including chest discomfort and hypotension with persistent tachycardia, which are often preceded or accompanied by flu-like symptoms such as a fever, fatigue, a dry cough and dyspnea (Magnani and Dec, 2006). Occurrence of any of these non-specific symptoms within the first 2 months after initiation of clozapine should prompt additional investigations which are discussed below, as early recognition of clozapine-induced myocarditis may improve clinical outcomes (Annamraju et al., 2007; Razminia et al., 2006). Despite the aforementioned association with hypereosinophilia, the eosinophil count does not rule out myocarditis when it is within normal range, and is useless for its early detection since an elevation has been found to be delayed for as long as 7 days after the peak in troponin levels (Ronaldson et al., 2010). This rise in troponin levels however, which usually occurs approximately 3 days after a fever arises and CRP levels surpass 50 mg/L (Ronaldson et al., 2015b), has proven to be sensitive (86%) and particularly specific (100%) in a case–control study of 38 cases and 47 controls that employed a fairly easily-met definition of clozapine-induced myocarditis (Ronaldson et al., 2010). Creatine kinase is inferior to troponins due to its lower predictive value (Magnani and Dec, 2006) and can therefore, just like N-terminal Brain-type Natriuretic Peptide Prohormone (NT-proBNP), not be used diagnostically. Both however conceivably indicate life-threatening illness and predict unfavorable outcomes such as cardiac death in patients with suspected myocarditis when they are greatly elevated (Ronaldson et al., 2011a; Ukena et al., 2014). While echocardiography can adequately assess the consequences of myocarditis on regional left ventricular function and should readily be performed repeatedly in any patient with a suspicion of clozapineinduced myocarditis, these effects can often be subtle and cannot be distinguished from pre-existing dysfunction without a baseline assessment. Routine echocardiography prior to clozapine commencement has therefore been proposed to be added to clozapine-related side effect monitoring guidelines (Ronaldson et al., 2011b, 2012c). Furthermore, when clozapine-induced myocarditis has been diagnosed, echocardiography should be used as the primary monitoring tool during follow-up, as improvement of left ventricular function after clozapine discontinuation is closely related to favorable clinical outcomes. When blood tests or echocardiography remain inconclusive, several case studies have demonstrated that CMR, which is known to have very high diagnostic accuracy for acute myocarditis in general (Abdel-Aty et al., 2005), can be of additional value in patients with suspected clozapine-induced myocarditis (Belloni et al., 2007). The diagnostic CMR criteria for myocarditis require either increased early (hyperemia) or late (fibrosis) gadolinium enhancement on T1-weighted images, and/or increased signal intensity on T2-weighted images for the diagnosis to be made (Friedrich et al., 2009). As demonstrated by our case, the latter, which indicates myocardial edema, is particularly useful in the acute clinical setting, while late gadolinium enhancement is a sign of myocardial fibrosis that indicates irreversible damage that persists, but is less likely to be seen in milder cases of myocarditis (De Cobelli et al., 2006). In fact, based on a report of 3 very mild cases of possible myocarditis related to clozapine in which CMR did not find any signs of myocardial edema or fibrosis, it has been suggested that CMR may not show any abnormalities when the ECG and echocardiogram are unremarkable and creatinine kinase levels are within normal range (Ariyarajah et al., 2010), something which is known to also apply to mild myocarditis of other etiologies (Friedrich and Marcotte, 2013). Interestingly enough, the role of positron emission tomography (PET), which is increasingly being used for the detection of cardiac inflammatory disease including sarcoidosis and endocarditis, has barely been explored yet, although preliminary evidence suggests it could
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provide additional information on disease activity and thereby guide treatment strategies (Piriou et al., 2015). A myocardial biopsy on the other hand, which used to be considered the reference standard, has generally been disregarded because of its considerable procedural risk and limited diagnostic yield due to the patchy and transient nature of the eosinophilic infiltrates that are to be detected. When clozapine-induced myocarditis is suspected, cessation of clozapine and supportive care are the mainstays of treatment and can also help to confirm the diagnosis when symptoms alleviate shortly thereafter, since the physiological half-life of clozapine approximates 12–18 h. With timely diagnosis and cessation of clozapine, the prognosis of mild cases that do not require supportive therapy is excellent, with complete recovery of global left ventricular function, as in our patient, occurring in the majority of cases. However, as in our case, discontinuation of clozapine may sometimes initially prove to be problematic due to rapid psychiatric deterioration. In some mild cases of suspected clozapine-induced myocarditis (as identified by troponin levels within 2–4× the normal limit), continuation of clozapine under close laboratory and cardiac monitoring could therefore be considered when the risks of cessation and continuation have been carefully weighed (Ronaldson et al., 2011b, 2012a). Some risk factors for the development of clozapine-induced myocarditis have been suggested, such as increasing age and the concomitant use of sodium valproate (Ronaldson et al., 2012d). In particular, rapid dose up-titration should be avoided in light of a possibly increased risk associated with faster dose escalation and a higher success rate reported among patients who were rechallenged with clozapine in an even more gradually increasing manner (Ronaldson et al., 2012b). While this rechallenge itself remains controversial, it may be considered when the risk of psychiatric deterioration or even suicide outweighs the risk of cardiac complications in patients for whom no other treatments have been adequately effective, but warrants even more precautions (Manu et al., 2012; Ronaldson et al., 2012b). To conclude, clozapine-induced myocarditis is an underemphasized complication of an otherwise very potent drug of last resort for refractory schizophrenia, which usually occurs during the first four weeks of treatment and comprises a wide spectrum of clinical presentations ranging from very mild complaints to fulminant heart failure or presumably even sudden cardiac death. Clinical vigilance and awareness of this potentially fatal adverse effect are warranted when starting patients on clozapine, as manifestation of any of the often atypical symptoms must prompt additional investigations, of which CMR should readily be considered because of its excellent diagnostic accuracy for myocarditis in general. Although it has been shown that clozapine can safely be continued under strict monitoring in very mild cases, suspicion of clozapine-related myocarditis usually warrants immediate discontinuation. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Abbreviations CMR Cardiac Magnetic Resonance imaging CCU Coronary Care Unit WBC White Blood Cell count TTE Transthoracic Echocardiography NT-proBNP N-terminal Brain-type Natriuretic Peptide Prohormone PET Positron Emission Tomography Role of the funding source Not applicable.
Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016
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Authors' contributions LS, RU and MT were involved in primary care for the patient described in this case report, and documented all relevant data. KK acquired and reviewed the cardiac magnetic resonance images and provided image reconstructions specifically tailored for this study. LS, RU and MT were involved in critical review of all available literature on the topic at hand, while KK and RB were consulted to review the available literature on the imaging part of this study. The preliminary manuscript was drafted by LS. RU and RB critically reviewed the case and revised the manuscript several times for important intellectual content. All authors revised the final manuscript, gave approval for this version to be published and agreed to be accountable for all aspects of the work regarding its accuracy and integrity. Competing interests All authors have declared that they have no relationships relevant to the contents of this paper to disclose. Acknowledgements No additional acknowledgements.
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Please cite this article as: Swart, L.E., et al., Clozapine-induced myocarditis, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.04.016