By Glenn C. Freas, MD, JD

Neuroleptic malignant syndrome (nms) is a relatively rare disease that is difficult to diagnose, and one where treatment options are poorly studied and limited. It was first described in the medical literature in the 1960s. The disease is clearly linked to use of neuroleptic medications and is classically described as the clinical tetrad of hyperpyrexia, muscular rigidity, alterations in mental status, and autonomic instability. Diagnosis is difficult for a number of reasons, including uncertain diagnostic criteria and overlap with other diseases. Treatment options are unclear because prospective trials on pharmacologic agents are difficult to conduct. Nonetheless, it is important for emergency physicians to know both the consensus issues and the controversies surrounding diagnosis and emergency management of this potentially lethal disease.

Epidemiology

The incidence of NMS in people taking neuroleptics has decreased in the last 15 years to a range of 0.05-0.2%1and is probably closer to the latter.2Estimates can vary because of differences in diagnostic criteria, the retrospective nature of most studies, varying survey techniques, and differing patient populations. Mortality rates have also decreased and have recently been estimated to be between 4%1and 10%.2It is difficult to definitively list risk factors. Age, gender, environmental conditions, and type of neuropsychiatric disorder do not appear to be independent risk factors for developing the disease; however, previous episodes of NMS do appear to put the patient at significantly higher risk if they are re-exposed to neuroleptics.2The rate of administration and the magnitude of dosing increment may predispose patients to the development of NMS. Patients with exhaustion, particularly as a result of psychomotor agitation, and patients with dehydration or organic brain syndrome may be more predisposed to develop NMS.3

All classes of D2 dopamine receptor antagonists have been associated with NMS. Haloperidol is more commonly implicated because it is more commonly used. While many patients with NMS are also on other psychotropic medications, none has definitively been shown to increase the risk of developing the disease, although some say that concomitant lithium administration is linked to an increased propensity to develop NMS.4 There are well-documented cases in the literature of patients who are not on neuroleptics, but who have been taken off anti-Parkinson medications (dopamine agonists) and have developed NMS.2

Pathophysiology

The most accepted theory of pathogenesis of NMS is that of central dopamine depletion, which adequately explains the classic tetrad of signs and symptoms. Muscle contraction and rigidity generate heat and can occur when dopamine is blocked in the corpus striatum; hyperthermia occurs with impaired heat dissipation when dopamine receptors are blocked in the anterior hypothalamus; mental status changes result from dopamine receptor blockade in the nigrostrial and mesocortical systems; and dopamine blockade at the spinal cord may cause autonomic dysfunction.3

The theory of central dopamine depletion is not universally accepted as the only pathophysiologic mechanism implicated in the development of NMS. Yet, to-be-defined predisposing factors may play an important role. Some postulate that the balance between dopamine and serotonin (or other neurotransmitters) may more completely describe both NMS and closely related diseases like serotonin syndrome and lethal catatonia.5

Clinical Features and Diagnosis

The most consistent features of NMS are: 1) recent use of neuroleptic medications or recent decrease or withdrawal of dopaminergic medications; 2) rapid increase in temperature; 3) muscular rigidity; 4) alteration in level of consciousness; and 5) autonomic dysfunction. Despite two simultaneous case reports of NMS without hyperthermia,3,4an elevated temperature with profuse diaphoresis occurs in 98% of cases, with the temperature exceeding 38°C in 87% of cases and 40°C in 40%.2Generalized muscle rigidity ("lead pipe" rigidity) occurs in 97% of NMS cases,2which can lead to rhabdomyolysis and myoglobinuria. The classic description of the change in mental status is alert yet dazed and mute, but stupor, coma, delirium, and catatonia have been described. Alterations in the level of consciousness occur in 97% of cases.2Autonomic dysfunction can manifest as tachycardia, fluctuations in blood pressure, and diaphoresis. Some evidence of autonomic dysfunction is present in 95% of cases.2

Laboratory findings are nonspecific but do figure into some diagnostic schemes. Elevations in serum creatine phosphokinase (CPK), due to muscle rigidity, occur in roughly 95% of cases of NMS.2 The magnitude of CPK elevation is frequently cited as a marker for the severity of the muscular rigidity and the likelihood of renal failure. One study documented an average CPK elevation of 3700 U/L.6 White blood cell counts are frequently elevated with a left shift.

Complications, which may present with NMS or develop during the course of the disease, include respiratory failure from aspiration or cardiac dysfunction, cardiovascular instability from arrhythmias or heart failure, renal failure secondary to volume depletion and/or myoglobinuria, thromboembolic events, and disseminated intravascular coagulation.

Diagnostic criteria have not been widely agreed upon. One suggested scheme is:71) increased temperature; 2) muscular rigidity; and 3) two or more of the following: diaphoresis, tremor, dysphagia, altered state of consciousness, tachycardia, incontinence, blood pressure changes, leukocytosis, and elevated serum CPK.

Another set of diagnostic criteria were recently put forth as:2 1) treatment with neuroleptics within seven days of onset (2-4 weeks for depot neuroleptics); 2) hyperthermia (> 38°C); 3) muscle rigidity; and 4) five of the following: change in mental status; tachycardia; hypertension or hypotension; tachypnea or hypoxia; diaphoresis or sialorrhea; tremor; incontinence; CPK elevation or myoglobinuria; or metabolic acidosis; and 5) exclusion of other drug-induced, systemic, or neuropsychiatric illness.

The differential diagnosis of NMS includes: malignant hyperthermia, CNS infection, rabies, serotonin syndrome, lethal catatonia, environmental heat disorders, extrapyramidal symptoms with fever, thyroid storm, and other toxins and drugs. Diagnosis can be particularly difficult in cases where the patient is on neuroleptics and has features of these other diseases.

Treatment

Cessation of neuroleptics and intensive supportive care are the only widely accepted treatments for NMS once the diagnosis is established or strongly suspected. Fluid replacement, reduction of temperature with aggressive cooling measures, and maintenance of cardiac, renal, and pulmonary function are the mainstays of supportive care. Psychosis and agitation can be treated with benzodiazepines.

Controversy surrounds the use of other pharmacologic agents for NMS. The two most frequently mentioned drugs are bromocriptine and dantrolene. The former is a dopamine agonist that acts centrally, and the latter is a skeletal muscle relaxant that acts peripherally. Some recommend one or the other drug, and others recommend both.

Recommendations for using one of the drugs find a modicum of support in a few retrospective series, although methodological flaws are the rule in these studies. Recommendations for using both drugs have essentially no support in the literature.

Because there are no good prospective studies on these medications, it is difficult to articulate when they should be used, which one should be used, and for how long. The threshold issues appear to be making the diagnosis and evaluating the severity of the disease. When the diagnosis is clear and the patient is severely ill, using one of the drugs may shorten the duration of the disease, decrease mortality, or both.6 When the diagnosis is uncertain, using either of the drugs appears to be unwarranted.

Bromocriptine must be administered orally or via nasogastric tube in divided doses, with recommended doses ranging from 7.5-60 mg/d. Side effects include nausea, hypotension, delirium, and exacerbation of the underlying psychotic illness. Recurrence of NMS symptoms may occur when the drug is stopped. Dantrolene is available in oral and parenteral form. Initial intravenous doses of 1-2 mg/kg may be effective. The maximum dose is 10 mg/kg/d. Once skeletal muscle relaxation is achieved, changing over to the oral form seems prudent. The major complication of dantrolene is hepatotoxicity, which is thought to be more likely to occur in cases of high doses or prolonged use.

Summary

NMS is a rare complication of neuroleptic therapy, characterized by hyperthermia, muscular rigidity, alterations in level of consciousness, and autonomic instability. Renal failure, cardiac complications, and respiratory failure are possible in severe cases. Diagnosis is complicated by a lack of consensus on diagnostic criteria. Treatment is mainly supportive. There is some evidence that treating patients with NMS with either bromocriptine or dantrolene may decrease morbidity and mortality.

References

1. Bertorini TE. Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome.Neurologic Clin1997;15:649-671.

2. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin N Amer 1993;77:185-202.

3. Lev R, Clark RF. Neuroleptic malignant syndrome presenting without fever: A review of the literature. J Emerg Med 1993;12:49-55.

4. Totten VY, et al. Neuroleptic malignant syndrome presenting without initial fever: A case report. J Emerg Med 1993;12:43-47.

5. Martin TG. Serotonin syndrome. Ann Emerg Med 1996;28:520-526.

6. Rosenberg MR, Green M. Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989;149:1927-1931.

7. Diagnostic and Statistical Manual for Mental Disorders. 4th ed. Washington: American Psychiatric Press; 1994:739.

The use of CT scan in the patient with lower abdominal pain and the "rule-out" appendicitis case is characterized by the following except:

a. It can be rapidly performed.

b. It may provide an alternative diagnosis in patients without acute appendicitis.

c. It is highly dependent upon operator expertise as is ultrasound.

d. It demonstrates impressive sensitivity, diagnostic accuracy, and positive/negative predictive values.

Which of the following statements is true?

a. Compression ultrasonography demonstrates poor sensitivity and specificity for the diagnosis of proximal DVT.

b. A high percentage of patients with initially normal ultrasounds will develop ultrasonographic evidence of DVT on one-week and three-month follow-up.

c. In the DVT-naive patient, an initial negative ultrasound allows the physician to safely discharge the patient without anticoagulation.

d. Serial testing for extension of clot from calf veins to the proximal leg has no bearing on the clinical management of the patient.

In the study on noninvasive cerebral cooling during an animal cardiac arrest, the authors were able to show:

a. significant neurologic improvement in the swine who had cerebral cooling compared to the group that were not cooled.

b. that their technique for noninvasive cooling achieved temperatures that have been previously shown to be beneficial regarding neurologic recovery after cardiac arrest.

c. that cooling the animals after resuscitation was over, and when reperfusion was established, was the most effective technique when measuring full neurologic recovery.

d. that human brains cool much quicker than swine brains with the noninvasive technique.

According to the study by Zink, et al, ethanol:

a. improves cardiovascular function.

b. lowers hemoglobin acutely.

c. is associated with higher cerebral venous lactate levels post-trauma.

d. serves a protective effect in blunt trauma.

Neuroleptic malignant syndrome:

a. is most commonly caused by chlorpromazine.

b. is more commonly seen in elderly females.

c. may respond to lithium if treatment is begun early in the course of the disease.

d. may occur in patients not on neuroleptics, but who have recently stopped taking dopamine agonists.