Abstract
To The Editor:
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The diagnosis of clozapine-induced myocarditis is challenging, and relies on the combination of clinical, electrocardiographic, echocardiographic, or biochemical changes indicative of myocardial damage and inflammation. In reported cases, myocardial biopsy was rarely performed to confirm the diagnosis of myocarditis. Recently, cardiovascular magnetic resonance imaging (CMRI) has become the primary tool for noninvasive assessment of myocardial inflammation in patients with suspected myocarditis (Friedrich et al. 2009).
We describe the first adolescent case of CMRI-confirmed clozapine-induced myocarditis and subsequent successful clozapine rechallenge without recurrence of myocarditis, as evidenced by serial monitoring over 12 months with biochemistry and imaging modalities. The role of gradual dose escalation in permitting successful rechallenge is discussed.
Case Report
We describe a 15-year-old adolescent who was first diagnosed with schizophrenia in March 2011 after having exhibited increasingly disabling psychotic symptoms over a 3 year period prior to his formal diagnosis. From March 2011 to July 2011, he was trialed on multiple atypical antipsychotic medications with limited effect. He was commenced on clozapine in July 2011, according to a standardized protocol, and soon after starting clozapine, there was a significant improvement in his mental state.
Fourteen days after the commencement of clozapine, he developed sinus tachycardia and experienced an episode of chest discomfort at rest, associated with nausea and vomiting. He was afebrile with heart rate of 110 beats per minute, and his electrocardiogram (ECG) revealed sinus rhythm with new T wave inversion in leads V4-V6. Troponin I 3.99 was elevated to nearly 40 times the upper limit of normal (reference range <0.10) compared with normal Troponin I <0.10 prior to commencement of clozapine treatment.
An urgent CMRI was performed, and revealed a focus of late gadolinium enhancement within the basal lateral wall of the left ventricle (LV) in the outer epicardial portion of the myocardium. This enhancement pattern is consistent with myocarditis. LV function remained normal with LV ejection fraction (LVEF) measured at 54% (Fig. 1A). A diagnosis of clozapine-induced myocarditis was made. Clozapine was ceased and Troponin I returned to normal within 48 hours. No further episodes of chest discomfort were noted. Viral serology and eosinophil counts were normal.
Following the cessation of clozapine and recommencement of previously prescribed antipsychotics, the patient's mental state rapidly deteriorated. He was subsequently transferred to our tertiary center in November 2011 for ongoing management of treatment- refractory schizophrenia. Following a case conference with the patient and his family, a decision was made in February 2012 to rechallenge him with clozapine, as the quality of life improvement was deemed to outweigh the risk of rechallenge with clozapine. A repeat CMRI (7 months after the initial CMRI) was scheduled prior to rechallenge. This showed a persistent unchanged focus of late gadolinium enhancement in the lateral wall, consistent with myocardial scarring (Fig. 1B). There were no new areas of abnormal enhancement. LV function remained normal on both CMRI and transthoracic echocardiography, as assessed by Simpson's ejection fraction (EF) (Lang et al. 2005). Repeat blood tests prior to rechallenge, including high-sensitivity Troponin T (HsTropT) and high-sensitivity C-reactive protein (HsCRP), were normal.
Our patient was rechallenged with clozapine in March 2012. Clozapine was recommenced at a low dose of 6.25 mg and slowly titrated up by 6.25 mg every 2 days. The patient underwent routine weekly blood tests (full blood count [FBC], HsCRP) and ECG, and had daily observations recorded (heart rate, temperature, and blood pressure). In view of his prior history of clozapine-induced myocarditis, additional weekly follow-up was scheduled at the cardiology clinic for the first 8 weeks following clozapine rechallenge. Ongoing monthly cardiology follow-up was then scheduled for the next 4 months. At 6 months after clozapine rechallenge, our patient was reviewed every 3 months at the cardiology clinic. At each cardiology review, echocardiography, ECG, and biochemical markers including HsTropT, N-terminal pro brain natriuretic peptide (Nt-proBNP), HsCRP, and FBC including eosinophil count were performed to screen for recurrence of myocarditis and cardiomyopathy.
Following the recommencement of clozapine, the patient's mental state gradually improved with reduction in both positive and negative psychotic symptoms. His clozapine dose was successfully up-titrated to a maintenance dose of 325 mg twice daily without recurrence of myocarditis, based on clinical, biochemical, and echocardiographic assessment at 9 months. In particular, there was no increase in serial serum inflammatory markers (HsCRP, neutrophil, eosinophil counts) and myocardial damage (HsTropT, Nt-proBNP) or changes in LV contractility on echocardiography via Simpson's EF (Fig. 1C).
A repeat CMRI performed 6 months following recommencement of clozapine showed unchanged chronic scarring from the patient's initial episode of myocarditis, with no new areas of myocardial inflammation and preserved LV contractility (Fig. 1D). The patient was discharged from our center at 9 months to ongoing follow-up by his local psychiatrist. He was reviewed in the cardiology clinic 12 months following recommencing clozapine, and remained well with normal ECG, normal HsTropT, and preserved LV function on a maintenance dose of clozapine 325 mg twice daily.
Discussion
Clozapine-induced myocarditis is an uncommon complication, with a reported incidence of fatal and nonfatal myocarditis of 0.2%, and a median time of onset of symptoms of 15 days (Kilian et al. 1999). However, it can be potentially life threatening, with a mortality rate of 10–51% among patients (Merrill et al. 2005; Haas et al. 2007). The etiology of clozapine myocarditis is unknown, but has been postulated to be associated with a direct myotoxic effect of clozapine (Scelsa et al. 1996) and/or an immunoglobulin E (IgE)-mediated hypersensitivity reaction (Kilian et al. 1999).
Clozapine rechallenge following myocarditis has met with varying success in adults (Jayathilake and Singh 2009; Bray and Reid 2011; Reid 2001; Ronaldson et al. 2012), but to date, there are no reported cases of rechallenge in child or adolescent patients. The diagnosis of myocarditis is difficult, and in the majority of reported cases, it was based on clinical and biochemical suspicions only in the absence of direct myocardial tissue assessment with endomyocardial biopsy and/or CMRI. This raises the possibility that some cases of apparent myocarditis may result from causes other than clozapine (Rosenfeld et al. 2010).
In a systematic review of 138 patients to assess the outcome of clozapine rechallenge after potentially life-threatening adverse effects including neutropenia and myocarditis, Manu et al. (2012) reported a successful rechallenge rate of 75% among four patients who developed myocarditis, with no deaths reported at mean follow-up of 27 weeks. In each of the four patients, the diagnosis of clozapine-induced myocarditis was considered probable based on clinical presentation, laboratory values, and temporal relationship to introduction and discontinuation of clozapine, but without direct myocardial tissue assessment. Although this seemed encouraging, the authors concluded that more case reports were needed before specific recommendations could be made regarding clozapine rechallenge.
Whereas endomyocardial biopsy remains the widely accepted standard for diagnosis of myocarditis, it is an invasive procedure associated with severe complications, such as cardiac perforation and tamponade. When compared with autopsy findings, it has a sensitivity and specificity of 60% and 80%, respectively, because of sampling error and poor inter-observer agreement (Hauck et al. 1989). In contrast, CMRI is a safe, noninvasive imaging modality that assesses not only functional and morphological abnormalities, but also myocardial tissue pathology in myocarditis including: 1) intracellular and interstitial edema, 2) hyperemia and capillary leakage via myocardial early gadolinium enhancement, and 3) subsequent necrosis and fibrosis via late gadolinium enhancement. In the presence of two or more of the three tissue-based criteria, CMRI has a similar pooled sensitivity and specificity of 67% and 91%, respectively, to endomyocardial biopsy in the diagnosis of myocarditis (Hauck et al. 1989).
To date, there are no specific protocols to minimize the recurrence of clozapine-induced myocarditis following rechallenge. From the largest retrospective case series published to date of eight patients who were rechallenged with clozapine following case definition of myocarditis, Ronaldson et al. (2012) identified the severity of the original acute myocarditis, the time between the myocarditis event and rechallenge, and the rate of clozapine dose titration during rechallenge, as important factors that may influence the success of clozapine rechallenge following myocarditis. These factors were all important for our patient. He was rechallenged with clozapine >6 months after the initial episode of myocarditis, and a slow escalation in the dose of clozapine, starting with 6.25 mg every two days, was employed during rechallenge. We postulate that his myocarditis was likely caused by direct myotoxic dose-dependent effects of clozapine rather than an IgE-mediated hypersensitivity reaction, as slow uptitration of clozapine did not result in recurrence of myocarditis, and no eosinophilia was observed throughout the rechallenge period.
Conclusions
In conclusion, we have demonstrated successful rechallenge of clozapine in an adolescent following clozapine-induced myocarditis. Delayed rechallenge with gradual uptitration of clozapine dose, appear to reduce the risk of cardiomyotoxicity.
Footnotes
Disclosures
No competing financial interests exist.