Background

Neuroleptic malignant syndrome (NMS) is a severe disorder caused by an adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (thorazine).¹ Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a “syndrome malin des neuroleptiques.”² Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics³; however, as physicians have become increasingly aware of the syndrome and as newer neuroleptic agents have become available, the incidence has declined more recently to around 0.01% to 0.02%.⁴ Although NMS occurs only rarely, it remains an unpredictable and potentially life-threatening neurologic condition that hospitalists must be able to recognize, as early identification and proper medical management are essential to ensure improved patient outcomes. Neuroleptic Malignant Syndrome Essay.

Clinical Presentation

The diagnosis of NMS is based on history and the presence of certain physical examination and laboratory findings.^5,6 Patients typically develop NMS within hours or days after exposure to a causative drug, with most exhibiting symptoms within 2 weeks and nearly all within 30 days.⁷ Although NMS has classically been characterized by the presence of the triad of fever, muscle rigidity, and altered mental status, its presentation can be quite heterogeneous, as reflected in the current Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition [DSM-IV] criteria (see Table 1 ).⁸ The clinical course typically begins with muscle rigidity followed by a fever within several hours of onset and mental status changes that can range from mild drowsiness, agitation, or confusion to a severe delirium or coma.

Signs of autonomic nervous system instability that frequently accompany NMS include labile blood pressure, tachypnea, tachycardia, sialorrhea, diaphoresis, flushing, skin pallor, and incontinence. Neuroleptic Malignant Syndrome Essay. Once symptoms appear, progression can be rapid and can reach peak intensity in as little as 3 days. Although muscle rigidity is the most frequently described motor sign, a large number of additional extrapyramidal motor findings have been reported including tremor, chorea, akinesia, and dystonic movements including opisthotonos, trismus, blepharospasm, and oculogyric crisis.^3,9,10 Other symptoms that have been associated with NMS include dysphagia, dyspnea, abnormal reflexes, mutism, and seizures.^3,11–13

Characteristic laboratory findings seen in NMS include elevated creatinine phosphokinase (CPK) due to rhabdomyolysis and leukocytosis, but these are neither specific for the syndrome nor present in all cases.¹⁴ When rhabdomyolysis is present, it can be severe enough to cause renal failure, requiring hemodialysis.¹³ Additional common laboratory abnormalities include a metabolic acidosis and iron deficiency.¹⁵The cerebrospinal fluid (CSF) and imaging studies are usually normal, but an electroencephalogram (EEG) may show nongeneralized slowing.⁷

Causative Agents

The primary trigger of NMS is dopamine receptor blockade and the standard causative agent is an antipsychotic. Potent typical neuroleptics such as haloperidol, fluphenazine, chlorpromazine, trifluoperazine, and prochlorperazine have been most frequently associated with NMS and thought to confer the greatest risk. Although atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics,¹⁰ a significant number of cases have been reported with most atypical neuroleptics including risperidone,¹⁶ clozapine,¹⁷ quetiapine,¹⁸ olanzapine,¹⁹ariprazole,²⁰ and ziprasidone.²¹ Neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as metoclopramide,²² promethazine,¹⁰ tetrabenzine,²³ droperidol,²⁴ diatrizoate,²⁵ and amoxapine.^{26  Neuroleptic Malignant Syndrome Essay.}

The abrupt cessation or reduction in dose of dopaminergic medications such as levodopa in Parkinson disease may also precipitate NMS.²⁷ The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS,²⁸ and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine²⁹ and tolcapone.³⁰ Neuroleptic malignant syndrome has also been rarely associated with a number of other medications not known to have any central antidopaminergic activity such as lithium,³¹ desipramine, trimipramine, dosulpin,³² and phenelzine (Table 2 ).^33a    Neuroleptic Malignant Syndrome Essay.