Introduction
Neuroleptic malignant syndrome (NMS) is a life-threatening condition associated with the use of neuroleptic agents and is characterized by a clinical syndrome of mental status change, muscle rigidity, fever, and autonomic instability.1 We present a case of NMS in a patient on neuroleptic therapy who had the atypical presentation of not having muscle rigidity, in spite of an extremely elevated CK level, which was initially misdiagnosed as a case of acute liver failure secondary to acetaminophen toxicity. Atypical presentations such as these pose a challenge to the early diagnosis and treatment of NMS, and we highlight the importance of having a high index of suspicion for this condition.
Case Summary
A 36-year-old woman with a history of bipolar affective disorder presented to the emergency department with headache, fever, nausea, vomiting, and diarrhea. Her medications included lithium, sertraline, venlafaxine, bupropion, lamotrigine, loxapine, and trazodone for her psychiatric condition. On further review of her medication history, we noted that she was recently prescribed loxapine by her psychiatrist, and her primary care provider started her on ciprofloxacin, ondansetron, and acetaminophen for a presumed urinary tract infection around the same time. The patient had a heart rate of 120 beats/min, blood pressure of 90/60 mm Hg, temperature of 38.6°C, and a normal systemic examination. Initial laboratory investigations were notable for a serum acetaminophen level of 32 U/L, international normalized ratio of 1.5, and aspartate transaminase/alanine transaminase (AST/ALT) of 723/179 U/L.
Despite full doses of N-acetylcysteine for suspected acetaminophen toxicity and improvement of international normalized ratio with vitamin K replacement, she continued to have high grade fevers and deterioration in her mental status. As there was a disproportionate elevation of AST compared to ALT, an extrahepatic source of elevation of transaminases was considered. Serum creatine kinase (CK) was checked to look for a possible muscle source for elevated liver enzymes, and the CK level was found to be 93,283 U/L. We considered the diagnosis of NMS versus serotonin syndrome superimposed on possible acetaminophen induced liver toxicity, based on the elevated body temperature, alteration of mental status, autonomic instability, and highly elevated CK levels, in the background of the recent administration of the antipsychotic loxapine and concomitant use of ondansetron with serotonergic agents. However, as there was no clinical improvement, in spite of discontinuation of all serotonergic agents and trial of benzodiazepines, the diagnosis of was NMS was strongly considered, in contrast to serotonin syndrome. The patient was started on bromocriptine, and the dose was gradually increased to a maximum dose of 40 mg per day, in addition to aggressive intravenous hydration for prevention of myoglobinuric renal failure, with gradual improvement of her symptoms. The patient's AST, ALT, and CK were as high as 3318 U/L, 426 U/L, and 354,160 U/L, respectively (Figs. 1 and 2). Serum transaminases and CK levels were normal at a 4 week follow-up clinic visit. The interesting aspect about this atypical case of NMS was the absence of rigidity on clinical examination, despite an extremely elevated CK level of 354,160 U/L.
Trend of hepatic transaminases during hospital course. AST = aspartate transaminase. ALT= alanine transaminase.
Trend of serum creatine phosphokinase during hospital course.
Discussion
NMS is primarily a diagnosis of exclusion, and there is no consensus about the precise definition of this condition. There exist at least 5 different sets of criteria for the diagnosis of NMS.2 The criteria put forth in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) is widely used in both clinical and research settings. It requires the presence of 2 core features of severe muscle rigidity and elevated temperature after recent initiation or change in dosage of an antipsychotic, along with 2 or more of the following symptoms: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and elevated CK levels. These features should not be better accounted for by a substance-induced, neurological, or general medical condition. Neither duration nor dose of the drug has been shown to have any association with the risk of developing NMS.3 The frequency of NMS among patients receiving antipsychotic medication ranges from 0.07% to 2.2%, and mortality rates from this condition range from 10% to 30%.4
Abrupt and profound dopamine D2 receptor blockade by antipsychotic drugs has been proposed to be the cause of the signs and symptoms of NMS. Muscle rigidity is thought to be caused by dopamine blockade in the nigrostriatal region, and extreme muscle rigidity can produce hyperthermia. In addition, hypothalamic dopamine blockade may result in impaired temperature regulation and precipitate the autonomic changes associated with NMS. Disequilibrium in neurotransmitter systems involving epinephrine, norepinephrine, and serotonin, caused by antipsychotics, are also thought to play a role in the pathophysiology of NMS.2
Though not specific for NMS, CK levels are important to detect and monitor this condition, especially in cases with an atypical presentation.5 The cause of increased CK levels in NMS is unclear. It has commonly been ascribed to rhabdomyolysis, physical muscle injury, agitation, hyperactivity, and medication.6 Some studies have shown that elevated CK levels may be due to endogenous or physiologic causes.6 This may explain the findings in our case. The increased level of CK to the extent seen in our patient is rare, and is hence noteworthy, especially in the absence of severe muscle rigidity.
Atypical cases of NMS without muscle rigidity and/or hyperthermia have been reported. While not yet proven, it has been hypothesized that such atypical cases are a prodrome of the disease and represent impending NMS with typical presentation.2 The differential diagnoses of NMS include an infectious process, encephalitis, central nervous system (CNS) tumor, CNS trauma, malignant hyperthermia, lethal catatonia, pheochromocytoma, amphetamine or cocaine intoxication, thyrotoxicosis, acute porphyria, tetany, akinetic mutism, serotonin syndrome, heat stroke, severe extrapyramidal symptoms, and anticholinergic delirium.7–9
Cessation of the neuroleptic trigger is the first step in the management of NMS. Supportive therapy, such as fever reduction, hydration, and nutrition, is important until the blood levels of the neuroleptic drug decrease. The role of intravenous dantrolene sodium therapy, used widely in malignant hyperthermia, is unclear, but it is administered in the acute stage to reduce body temperature and to relax peripheral muscles by inhibiting the release of calcium from the sarcoplasmic reticulum of muscle. The recommended dose is 2 mg/kg intravenously, repeated every 10 min if necessary, to a maximum of 10 mg/kg daily, beyond which hepatotoxic effects may occur. Bromocriptine, a dopamine agonist, has also been used in doses of 2.5–10 mg up to 4 times daily. It improves muscle rigidity within a few hours, followed by a reduction in temperature and an improvement in blood pressure. Hypotension is the most common adverse effect of bromocriptine therapy.4 Electroconvulsive therapy has also been shown to be an effective treatment in cases of NMS when drug therapy has failed.10
Teaching Points
NMS is a potentially life-threatening condition that has variable clinical presentation. It is important to have a high index of suspicion for NMS, even in the absence of typical symptoms, while managing patients on neuroleptic therapy, because an early diagnosis is crucial to successful patient outcome. Patients with adverse effects from neuroleptic therapy might have elevated levels of serum acetaminophen secondary to excessive intake of acetaminophen for control of fever and malaise. The diagnostic workup for acute elevation of liver enzymes in such cases should not end with establishment of a diagnosis of acetaminophen induced liver toxicity, when signs and symptoms of autonomic instability are present. The absence of muscle rigidity should not exclude a diagnosis of NMS when the rest of the clinical picture might point to this diagnosis.
Footnotes
- Correspondence: Savio John MBBS, Division of Gastroenterology and Hepatology, Department of Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210.
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The authors have disclosed no conflicts of interest.
- © 2012 by Daedalus Enterprises Inc.
