Special Feature: Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome
By William J. Brady, MD, FACEP, FAAEM, Professor of Emergency Medicine and Internal Medicine, Vice Chair, Emergency Medicine, University of Virginia, Charlottesville. Dr. Brady is on the Editorial Board of Emergency Medicine Alert.
Introduction
Neuroleptic malignant syndrome (NMS) is a disease process usually occurring in patients who use neuroleptic agents; classically, it is characterized by altered mental status, muscular rigidity, fever, and autonomic instability. The incidence of NMS ranges from 0.5% to 1% of all patients exposed to neuroleptic agents.1,2 Men are affected twice as often as women; mean age is 40 years at syndrome onset; however, NMS can affect people of any age. NMS generally is associated with exposure to dopamine antagonist agents in the management of psychiatric illness, most commonly antipsychotic medications (e.g., butyrophenones, phenothiazines, and thioxanthenes);1,2,3 however, these agents may be used in different clinical settings for other indications, such as the management of emesis and vascular headache. Additionally, patients with idiopathic parkinsonism who undergo either a rapid reduction in, or cessation of, dopaminergic therapy may develop NMS.1,4
Etiology
While the exact pathogenesis of NMS remains unclear, reduced dopaminergic activity in the central nervous system likely plays a major role as suggested by the development of NMS with withdrawal of dopamine agonist therapy and successful treatment of NMS with L-dopa replacement therapy.1,3 Dopamine is involved in the control of body temperature centrally in the CNS as well as peripherally at the muscular level. Neuroleptic agents block dopaminergic receptors in the hypothalamus; such receptor antagonism may produce elevations in body temperature and, if unchecked, result in systemic hyperthermia. Acute dopamine depletion also may lead to development of extrapyramidal symptoms, including muscular rigidity, which can contribute to increased heat production and further heat stress.
Neither the dosage of neuroleptic medication used nor the duration of therapy appears to be important.
Particular agents, however, do have a higher associated risk. For example, high-potency neuroleptic drugs more often are encountered in the NMS patient and, therefore, are believed to have a higher risk of inducing the illness. Additionally, depot forms of these drugs seem to impart a higher risk of developing NMS than the oral or shorter-duration parenteral forms. Other risk issues for NMS include dehydration, malnutrition, physical exhaustion, intense psychomotor agitation, lithium co-therapy, and organic brain disease.5
Clinical Presentation
NMS typically develops rapidly over 24 to 72 hours.2,4 The progression of symptoms most commonly starts with mental status changes followed sequentially by muscular rigidity, hyperthermia, and autonomic dysfunction.6 The mental status almost always is impaired, ranging from agitation and rage to stupor and coma.
Muscular rigidity is described as lead-pipe rigidity, similar to that seen in the patient with severe Parkinsons disease. Other motor abnormalities include akinesia, cogwheeling, fluctuating tremors, and involuntary movements.7 Fever as high as 41°C generally follows.
Autonomic changes are manifested by alterations in blood pressure and heart rate. Dehydration, most likely secondary to the patient’s increased metabolic demand coupled with a reduction in oral intake, often is present and clinically significant.
Although most laboratory studies are either normal or nonspecific, several investigations may assist in establishing the diagnosis. Serum levels of muscle enzymes, especially creatine phosphokinase (CPK), often are elevated and most likely result from myonecrosis developing due to sustained muscle contractions.2 However, at least one study has suggested that CPK elevation in in febrile, neuroleptic-treated patients is a nonspecific finding; its presence in this setting as a diagnostic criterion could lead to an overdiagnosis of NMS.8 Elevation of liver transaminases, alkaline phosphatase, and lactate dehydrogenase levels also are found often. Electrolyte abnormalities generally will reflect underlying complications of the syndrome, including rhabdomyolysis, dehydration, and acute renal failure. Analyses of the cerebrospinal fluid as well as the results of computed tomography of the head and electroencephalography studies are often normal or nonspecifically abnormal; these studies serve to rule out life-threatening syndromes such as meningitis, encephalitis, intracranial hemorrhage, and status epilepticus.
Several different sets of diagnostic criteria for NMS have been proposed. Levenson published the diagnostic criteria that are best known and employed most widely, including major and minor descriptors. Major criteria include fever, muscular rigidity, and elevated CPK levels. Minor criteria include tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, and leukocytosis. The diagnosis strongly is suggested by the presence of all three major criteria; alternatively, two major criteria and four minor criteria also support the diagnosis.9
Management
Treatment of NMS centers primarily on supportive care, coupled with removal of the inciting agent and exclusion of other diseases (e.g., meningitis and intracranial hemorrhage). Rhabdomyolysis is treated with the usual measures. Dantrolene, which has been used very successfully in treating malignant hyperthermia, has been effective in shortening the duration of illness.10 Dosages range from 0.8-3.0 mg/kg intravenously (IV) every 6 hours—to 10 mg/kg/day; certain authorities recommend initial bolus doses of 2 mg/kg IV, repeated once as needed. It is important to note that dantrolene is hepatotoxic at levels above 10 mg/kg/day — patients should be started at lower drug dosages, and then gradually advanced as needed. Dantrolene appears to offer the most benefit in patients with pronounced muscular rigidity. The second most widely used agent, bromocriptine mesylate, is a dopamine agonist that also has been administered alone, or in combination with dantrolene, to treat NMS. Dosage ranges from 2.5 to 7.5 mg orally (or via nasogastric tube) every eight hours. Other dopamine agonists also have been used to treat patients with NMS, including amantadine, levodopa, and carbidopa-levodopa.
References
1. Granner MA, et al. Neuroleptic malignant syndrome or parkinsonism hyperpyrexia syndrome. Semin Neurol 1991;11:228-235.
2. Guze BH, et al. Current concepts. Neuroleptic malignant syndrome. N Engl J Med 1985;313:163-166.
3. Schneider SM. Neuroleptic malignant syndrome: Controversies in treatment. Am J Emerg Med 1991;9: 360-362.
4. Lavie CJ, et al. Neuroleptic malignant syndrome: An underdiagnosed reaction to neuroleptic agents? Postgrad Med 1986;80:171-178.
5. Naganuma H, et al. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatr Scand 1994;90:424-426.
6. Velamoor VR, et al. Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis 1994; 182:168-173.
7. Sewell DD, et al. Distinguishing neuroleptic malignant syndrome from NMS-like acute medical illnesses: A study of 34 cases. J Neuropsychiatry Clin Neurosci 1992;4:265-269.
8. O’Dwyer AM, et al. The role of creatinine kinase in the diagnosis of neuroleptic malignant syndrome. Psychol Med 1993;23:323-326.
9. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985;142:1137-1145.
10. Rosenberg MR, et al. Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989;149:1927-1931.
Neuroleptic malignant syndrome is a disease process usually occurring in patients who use neuroleptic agents; classically, it is characterized by altered mental status, muscular rigidity, fever, and autonomic instability.
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