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Clozapine-induced myocarditis: Separating the wheat from the chaff Karl Winckel1, Dan Siskind2,3, Samantha Hollingworth4 and Amanda Wheeler5,6

ANZJP Correspondence may be due to two factors: insufficient data to support a diagnosis of myocarditis; or where there is sufficient data to support the diagnosis but there is an alternative primary cause such as a viral respiratory tract infection. We recently reviewed 20 cases with a recorded diagnosis of clozapine-induced myocarditis at a large tertiary referral hospital in Brisbane (reported between 2005 and 2013). We reviewed clinical information in the patient’s chart against the comprehensive set of diagnostic criteria for clozapine-induced myocarditis developed by Ronaldson et al. (2010). We found that 13/20 (65%) cases did not meet the Ronaldson criteria for a diagnosis of clozapine-induced myocarditis. Whilst an elevated troponin was present in 17/20 (85%) cases, other parameters were either not assessed or not indicative of myocarditis. Electrocardiogram abnormalities were only present in 12/20 (60%) cases, fever in 12/20 (60%) and a heart rate >100bpm in 11/20 (55%) cases. Additionally, 5/20 (25%) cases had documented upper respiratory tract infections, which was an alternate possible cause of the myocarditis. No cardiac MRI or cardiac biopsies were performed in any of these cases. These findings suggest that the veracity of the diagnoses of clozapineinduced myocarditis may be suboptimal. Appropriate clinical investigations to clarify and confirm the diagnosis were not done, or not recorded in clinical notes. There are substantial short and long term ramifications of clozapine

cessation in people with treatment resistant schizophrenia including acute relapse of psychotic symptoms, deterioration in function and loss of access to the gold standard treatment. Close communication between psychiatrists and cardiologists is essential to reduce the risk of inappropriate myocarditis diagnosis. People with treatment resistant schizophrenia who have ceased clozapine following a presumptive diagnosis of clozapine-induced myocarditis may benefit from revisiting this diagnosis. If the diagnosis of clozapine-induced myocarditis is in question, they may be eligible for a closely monitored clozapine rechallenge.

Neuropsychiatric presentation following acute hypoxic-ischaemic encephalopathy Brad Hayhow1,2, Dennis Velakoulis1,2, Rebecca Dewhurst2 and Frank Gaillard3,4

3Department

1Melbourne

DOI: 10.1177/0004867414555418

disorder was referred for neuropsychiatric assessment with a recent history of apathy, memory impairment, and becoming lost on public transport. His family related the onset of these symptoms to a heroin overdose 3 months previously, at which time he required emergency treatment for respiratory arrest at another institution. KN’s past medical history included osteomyelitis, heroin addiction and hepatitis C, but his only regular medications were olanzapine 10 mg daily and escitalopram 20 mg daily.

1Princess

Alexandra Hospital, Brisbane, Australia 2School of Medicine, University of Queensland, Brisbane, Australia 3Metro South Addiction and Mental Health Service, Brisbane, Australia 4School of Pharmacy, University of Queensland, Brisbane, Australia 5Griffith Health Institute, Griffith University, Brisbane, Australia 6Faculty of Medical and Health Sciences, University of Auckland, New Zealand Corresponding author: Karl Winckel, Pharmacy Department, Princess Alexandra Hospital, Cnr Ipswich Rd and Cornwall St, Brisbane, Qld 4102, Australia. Email: [email protected] DOI: 10.1177/0004867414554269

To the Editor, There has been increased awareness of clozapine-induced myocarditis since the publication of the review of fifteen clozapine-induced myocarditis cases reported to the Australian Adverse Drug Reaction Committee (Kilian et  al., 1999). Rates of clozapineinduced myocarditis appear to be higher in Australia than in other countries (Lambert, 2010: 24). Whilst recognition of this problematic adverse effect is encouraged, concern has been raised about possible over diagnosis (Ronaldson et al., 2010). Misdiagnosis

Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Parkville, Australia 2Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, Australia

of Radiology, Royal Melbourne Hospital, Parkville, Australia 4Department of Radiology, University of Melbourne, Parkville, Australia Corresponding author: Brad Hayhow, Neuropsychiatry Unit, Royal Melbourne Hospital, Level 2, John Cade Building, Parkville, VIC 3050, Australia. Email: [email protected]

A 33-year-old Vietnamese man (KN) with a 10-year history of schizoaffective

Funding This research received no specific grant from any funding agency in the public, commercial, or not for profit sectors.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Kilian JG, Kerr K, Lawrence C and Celermajer DS (1999) Myocarditis and cardiomyopathy associated with clozapine. Lancet 354: 1841–1845. Lambert T (2010) Targeting treatment-refractory schizophrenia: A multidimensional outcomes approach to the diagnosis and management of incomplete recovery. Australian Consensus Panel for Treatment-Refractory Schizophrenia. Available at: www.trsconsensus.com.au (accessed 24 July 2014). Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al (2010) A new monitoring protocol for clozapineinduced myocarditis identified by an analysis of 75 cases and 94 controls. Journal of Clinical Psychiatry 71: 976–981.

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ANZJP Correspondence

Figure 1.  (A) Scan performed on admission demonstrates bilaterally small and high T2 signal hippocampi (black arrows). (B–D) The MRI scan obtained 3 months earlier demonstrates the hippocampi (white arrows) to be symmetrically abnormal. (B) Coronal T2-weighted fast spin echo: high T2 signal involves particularly CA1 and CA2, with mild swelling and blurring of the internal architecture in the affected parts. (C) Axial fluid-attenuated inversion recovery (FLAIR) of the right hippocampal head/ body (open arrow) and tail (open arrowhead): high T2 signal extends throughout the hippocampus. (D) Diffusion-weighted imaging (DWI): restricted diffusion (confirmed by apparent diffusion coefficient – not shown) is seen in the areas of high T2 signal, consistent with acute ischaemia.

been recognised to be particularly vulnerable to hypoxic-ischaemic injury (Smith et al., 1984), with the concept of differential sensitivity of specific neuronal populations originally ascribed to Vogt and Vogt (1937). While unilateral injury of the hippocampus may have negligible clinical consequences, bilateral injury can cause severe anterograde amnesia and focal impairment of spatial and navigational memory (Moser et  al., 2008). While each of these symptoms was exemplified by our patient, his diagnosis was initially delayed by their attribution to his premorbid psychiatric conditions. Besides warning against diagnostic overshadowing, this case demonstrates the important contribution of MRI in elucidating the pathophysiology and facilitating the definitive diagnosis of a complex neuropsychiatric presentation – neither would have occurred in the absence of early imaging, or if a computed tomography (CT) scan had been selected as the preferred modality. The case also highlights the value of retrospectively reviewing all available imaging, as findings crucial to establishing a diagnosis are occasionally overlooked or underappreciated. A close working relationship between psychiatrists and radiologists is essential to this task. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

On admission, KN’s basic blood tests and physical examination were essentially normal, but cognitive testing revealed substantial short-term memory deficits with relatively preserved remote and autobiographical memory, attention, visual construction, language, and executive function. KN also demonstrated a striking inability to navigate around the hospital, although this elicited neither his interest nor concern. During his admission a magnetic resonance imaging (MRI) scan was performed demonstrating subtle atrophy and increased T2 signal of both hippocampi (Figure 1A). The finding was

felt to be important in the context of KN’s clinical presentation, and prompted a review of the MRI obtained at the time of his respiratory arrest 3 months earlier. When this scan was received, additional abnormalities were identified: both hippocampal heads were swollen with blurred laminar architecture (Figure 1B); there was high T2 signal throughout the head, body and tail of the hippocampi (Figure 1C); and diffusion was restricted (Figure 1D). The findings were consistent with acute hypoxic-ischaemic encephalopathy. The pyramidal neurons of the CA1 sub-field of the hippocampus have long

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Moser EI, Kropff E and Moser MB (2008) Place cells, grid cells, and the brain’s spatial representation system. Annual Review of Neuroscience 31: 69–89. Smith ML, Auer RN and Siesjo BK (1984) The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathologica 64: 319–332. Vogt C and Vogt O (1937) Sitz und Wesen der Krankheiten im Lichte der topistischen Hirnforschung und des Variierens der Tiere, Teil I. Journal für Psychologie und Neurologie 47.

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Neuropsychiatric presentation following acute hypoxic-ischaemic encephalopathy.

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