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European Journal of Heart Failure 2003 5(4):575-578; doi:10.1016/S1388-9842(03)00036-9
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© 2003 European Society of Cardiology

Acute cardiac failure in neuroleptic malignant syndrome*

Patrick Sparrowa,*, Dermot Murnaghanb, Peter Kearneya, John Hoganc and Mary N. Sheppardd

a Department of Cardiology Cork University Hospital, Cork, Ireland
b Department of Medicine Cork University Hospital, Cork, Ireland
c Department of Pathology Cork University Hospital, Cork, Ireland
d Department of Pathology Royal Brompton Hospital, London, UK

* Corresponding author. Present address: BHF Cardiac MRI Unit, B Floor Clarendon Wing, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. Tel.: +44-113-392-5617; fax: +44-113-392-3775 E-mail address: patsparrow{at}doctors.net.uk


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Case report
 3. Discussion
 References
 
We present a case of rapid onset acute cardiac failure developing as part of Neuroleptic malignant syndrome in a 35-year-old woman following treatment with Thioridazine and Lithium. Post mortem histology of cardiac and skeletal muscle showed similar changes of focal cellular necrosis and vacuolation suggesting a common disease process.

Key Words: Acute cardiac failure • Neuroleptic malignant syndrome • Myocyte necrosis • Vacuolation

Received October 4, 2002; Revised December 12, 2002; Accepted January 23, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Case report
 3. Discussion
 References
 
Neuroleptic Malignant Syndrome is a clinical condition characterised by fever, rigidity and increased tonicity, altered levels of consciousness and varying degrees of autonomic disturbance. It occurs on exposure to anti-psychotic agents including drugs of both the phenothiazine and butyrophenone group, but also has been described following use of lithium and tricyclic anti-depressants. There is a quoted mortality rate of 10–20% [1]. Treatment consists of recognition of the syndrome with subsequent immediate withdrawal of the causative agents, adequate hydration and, depending on the severity, use of benzodiazepines, dantrolene, centrally acting dopaminergic agonists such as bromocriptine and neuromuscular paralysis and ventilation. In this report we describe the case of a patient who developed acute cardiac failure as part of her illness and subsequently died. Post mortem showed similar histological changes in both skeletal and cardiac muscle cells suggesting a common disease process.


   2. Case report
Top
 Notes
 Abstract
 1. Introduction
 2. Case report
3. Discussion
 References
 
A 35-year-old female with a 14-year history of bipolar affective disorder was admitted with confusion and agitation. She had been recommenced on thioridazine and lithium treatment 4 days previously following a recent deliberate self-overdose of approximately fifty 25-mg thioridazine tablets 2 weeks earlier. Examination revealed a core temperature of 37.4 °C, agitation and lead pipe hypertonicity of her lower limbs. Biochemical investigation showed a raised creatine kinase of 6315 units/l (NR 40–180). A diagnosis of Neuroleptic Malignant Syndrome was made and the thioridazine and lithium were withdrawn. She was treated with oral and intravenous rehydration, dantrolene and lorazepam. Her clinical condition initially improved with a reduction in serum creatine kinase to 450 units/l, but over the following 4 weeks she redeveloped intermittent pyrexia with persistent clinical signs of agitation and hypertonicity. An ongoing sepsis screen yielded a positive catheter specimen of urine of greater than 100,000 coliforms/ml, which was treated with intravenous co-amoxyclav. On day 33, her temperature climbed to 40–41.2 °C and she developed dyspnoea. Examination showed her to be tachypnoeic, with a sinus tachycardia of 140 bpm, a systolic bp of 104 mmHg, and clinical signs of biventricular failure. ECG showed new T wave inversion across the precordial leads. Creatine kinase rose dramatically to 5305 units/l with a CK-MB fraction of 2.9%. Aspartate transaminase and lactate dehydrogenase were also raised at levels of 174 units/l (NR 6–42) and 1368 units/l (NR 150–540) respectively. An echocardiogram showed global left ventricular systolic dysfunction. Cardiac catheterisation performed on the same day demonstrated normal coronary arteries with severe left ventricular hypokinesia. Left ventricular systolic pressure was 80 mmHg with an end diastolic pressure of 15 mmHg. Pulmonary capillary wedge pressure was 20 mmHg and cardiac output was 4.8 l/min. She was transferred to the Intensive Care Unit and mechanically ventilated but became progressively hypotensive. Repeat full blood count showed an acute 4 g/dl fall in haemoglobin. Blood transfusion and fluid resuscitation, as well as inotropic and vasopressor therapies were instigated, but despite this she died soon after. Post mortem showed an acute upper GI bleed secondary to gastric erosions. The heart was dilated and flabby with normal coronary arteries and no macroscopic evidence of necrosis. Histology showed extensive interstitial oedema and diffuse patchy areas of myocytolysis with degenerate dead myocytes surrounded by macrophages and lymphocytes (Fig. 1). This was confirmed by immunostaining for macrophages (CD68 antibody) and complement 9 (C9) which is positive in dead myocytes (Fig. 2). There was in addition marked myofibrillar vacuolation in the subendocardial myocytes throughout the left ventricle (Fig. 3). Histological sections of skeletal muscle from the psoas showed diffuse patchy areas of myocytolysis with degenerate myocytes surrounded by macrophages and lymphocytes with interstitial oedema (Fig. 4). There was, in addition, marked myofibrillar vacuolation (Fig. 5).


Figure 1
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  		Fig. 1 Haematoxylin and eosin stain, magnification x200: Section of myocardium showing myocytolysis with individual cell surrounded by macrophages (arrow).

 


Figure 2
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  		Fig. 2 Avidin biotin method, magnification x200. Stained with marker for macrophages (CD68): Section of myocardium showing myocytolysis with individual cell surrounded by macrophages (arrow).

 


Figure 3
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  		Fig. 3 Haematoxylin and eosin stain, magnification x350: Section of myocardium showing vacuolation.

 


Figure 4
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  		Fig. 4 Haematoxylin and eosin stain, magnification x200: Section of skeletal muscle showing myocytolysis with individual cell surrounded by macrophages (arrow).

 


Figure 5
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  		Fig. 5 Haematoxylin and eosin stain, magnification x350: Section of skeletal muscle showing myocyte vacuolation (arrow). All the specimens had been fixed by immersion in 10% formaldehyde solution. The slices of skeletal muscle and myocardium were processed routinely for histology and sectioned at 7 µm. The sections were stained to show macrophages using monoclonal antibody directed against CD68 (Dako Laboratories, UK) utilising an automated immunohistochemistry processor with avidin biotin method of labelling.

 

   3. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Case report
 3. Discussion
References
 
Neuroleptic Malignant Syndrome is a relatively uncommon side effect of treatment, occurring in approximately 0.4–0.9% of patients treated. Clinical onset of the syndrome is anything from hours to weeks from time of introduction of the agent [2]. Its aetiology is felt to be secondary to severe and rapid shutdown of the dopaminergic neurotransmission pathways in the basal ganglia. This leads to uninhibited activation of alpha and gamma motor neurones in the anterior horn cells, which ultimately leads to prolonged contraction and rigidity in skeletal muscles and subsequent myocytolysis [3]. Inhibition of dopaminergic receptors in the lateral hypothalamus may contribute to the pyrexia, while autonomic disruption may be secondary to noradrenergic overactivity [4]. Importantly neuroleptics have also been shown to inhibit mitochondrial enzymes directly [5]. The main causes of death are respiratory failure secondary to decreased chest wall compliance, sepsis and pulmonary thrombo-embolism and renal failure secondary to massive rhabdomyolysis and subsequent myoglobinuria [1].

There have been two previously reported cases of acute cardiac pump failure associated with this condition, as well as one case of acute myocardial infarction [6–8]. In one such case in which the patient survived with no apparent long-term sequelae, biventricular failure was also evident clinically with normal coronary arteries and global LV dysfunction on angiography [6]. Endomyocardial biopsy demonstrated increased cell size with areas of vacuolation felt to be lipid droplets within subendocardial myocytes. Our patient had similar subendocardial myofibrillar vacuolation, but in addition had extensive myocytolysis, which may have been responsible for the poor outcome.

The typical changes seen in skeletal muscle with Neuroleptic Malignant Syndrome are of patchy cell involvement with areas of sparing, cellular oedema and focal areas of necrosis with vacuolation being a particularly prominent feature [9]. It has been hypothesised that the changes in muscle result as a consequence of glycogenolysis with free fatty acid mobilisation; when these are expended through constant contraction there is a consequent increase in cell membrane permeability, which leads to cellular oedema. There is also inadequate substrate available for energy dependent calcium reuptake in the sarcoplasmic reticulum and mitochondria; in the latter this will lead to protease activation and subsequent fibre necrosis [10]. Usually the cellular changes in cardiac muscle associated with periods of hypotension are those of subendocardial infarction and not patchy focal necrosis as here. There are no reports in the literature of any of the drugs used in this patient's treatment causing direct myocyte toxicity; indeed the recent revision of the license for thioridazine in the UK was based on propensity for prolongation of Q–T interval with associated risk of ventricular arrhythmias [11]. Excessive catecholamines have been documented as causing myocarditis resulting in cardiac failure with histological evidence of focal myocyte necrosis and cellular oedema but not vacuolation which is a prominent feature in this case [12–14]. The evidence for increased sympathetic-adrenal activity in neuroleptic malignant syndrome is contradictory and somewhat anecdotal but elevated intra-cellular calcium may be a feature common to both conditions [4,15]. Our case is unique in that we have demonstrated changes in cardiac myocytes typically seen in skeletal muscle. Given this histopathological similarity, we feel the cardiac toxicity and consequent pump failure experienced must be considered part of the Neuroleptic Malignant Syndrome and that clinicians should be aware of the possible development of rapid and severe cardiac failure as part of the clinical spectrum. Disordered cell membrane and mitochondrial function is of probable pathophysiological significance.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Case report
 3. Discussion
 References
 
* No support grants were received in the writing of this paper. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Case report
 3. Discussion
 References
 

  1. Shalev A., Harmesh H., Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry (1989) 50:18–25.[Web of Science][Medline]
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  3. Parada M.A., de Parada M.P., Rada P., Hernandez L. An animal model for neuroleptic malignant syndrome. Brain Res (1995) 674(1):117–121.[CrossRef][Web of Science][Medline]
  4. Fiebel J.H., Schiffer R.B. Sympathoadrenomedullary hyperactivity in the neuroleptic malignant syndrome. Am J Psych (1981) 138:1115–1116.[Abstract/Free Full Text]
  5. Purkhardt C., Kelly J.P., Lim J.H. Neuroleptics inhibit complex 1 of the electron complex chain. Amt Neurol (1993) 33:512–517.[CrossRef]
  6. Watanabe K., Izumi T., Inomata T., Miyakita Y., Masani F., Shibata A. Clustered droplets in the endomyocardial biopsies from a patient with neuroleptic malignant syndrome. Clin Cardiol (1994) 17:623–626.[CrossRef][Web of Science][Medline]
  7. Bennaissa M.L., Bekka R., Baud F.J. Acute cardiac failure in a case of rapidly lethal NMS. Int Care Med (1998) 24:86–92.[CrossRef][Web of Science][Medline]
  8. Becker D., Birger M., Samuel E., Floru S. Myocardial Infarction: an unusual complication of neuroleptic malignant syndrome. J Nerv Ment Dis (1988) 176:377–378.[Web of Science][Medline]
  9. Behan W.M., Madigan M., Clark B.J., Goldberg J., Mc Lellan D.R. Muscle changes in the neuroleptic malignant syndrome. J Clin Pathol (Mar 2000) 53(3):223–227.[Abstract/Free Full Text]
  10. Bertorini T.E. Myoglobinaemia, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clinic (1997) 15:649–671.[CrossRef]
  11. Reilly J.G., Ayis S.A., Ferrier I.N., Jones S.J., Thomas S.H.L. QTc interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet (2000) 355:1048–1052.[CrossRef][Web of Science][Medline]
  12. Kline I.K. Myocardial alterations associated with phaeochromocytomas. Am J Path (1961) 38:539–551.[Web of Science][Medline]
  13. Van Vliet P., Burchell H.B., Titus J.L. Focal myocarditis associated with phaeochromocytoma. N Engl J Med (1966) 274:1102–1108.[Web of Science][Medline]
  14. Sardesai S., Mourant A.J., Sivathandon Y., Farrow R., Gibbons D.O. Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure. Br Heart J (1990) 63:234–237.[Abstract/Free Full Text]
  15. Scarlet J.D., Zimmerman R., Berkovic S.F. Neuroleptic malignant syndrome. Aust NZ J Med (1983) 13:70–73.[Web of Science][Medline]

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