it is a drug-induced disorder characterized by 4 clinical features: increased body temperature, As the name implies, NMS is caused by neuroleptic agents (an alternate term for antipsychotic medications). A list of offending drugs and drug regimens in NMS is shown in Table 38.2. Note that drugs other than neuroleptic agents can trigger NMS, so the name of this syndrome is misleading.

Pathogenesis
The one property shared by all the drugs in Table 38.2 is the ability to influence dopamine-mediated synaptic transmission in the central nervous system. A decrease in dopaminergic neurotransmission in the basal ganglia and hypothalamic-pituitary axis may be responsible for many of the clinical manifestations of NMS (12). As indicated in Table 38.2, there
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are two clinical situations that predispose to NMS: (1) therapy with drugs that inhibit dopaminergic transmission, or (2) discontinuing therapy with drugs that facilitate dopaminergic transmission. Most cases of NMS are triggered by drugs that inhibit dopaminergic neurotransmission, and the ones reported most frequently are haloperidol and fluphenazine (12). The incidence of NMS during therapy with neuroleptic agents is reported at 0.2% to 1.9% (13).
TABLE 38.2 Drugs Implicated in the Neuroleptic Malignant Syndrome
I. Ongoing Drug Intake
Antipsychotic agents: Butyrophenones (eg, haloperidol), phenothiazines, clozapine, olanzapine, respiradone
Antiemetic agents: Metoclopramide, droperidol, prochlorperazine
CNS stimulants: Amphetamines, cocaine
Other: Lithium, overdose with tricyclic antidepressants
II. Discontinued Drug Intake
Dopaminergic drugs: Amantidine, bromocriptine, levodopa
There is no relationship between the intensity or duration of drug therapy and the risk of NMS (12), so NMS is an idiosyncratic drug reaction and not a manifestation of drug toxicity. There is some evidence of a familial tendency, but a genetic pattern of transmission has not been identified (14).
Clinical Features
Most cases of NMS begin to appear 24 to 72 hours after the onset of drug therapy, and almost all cases are apparent in the first 2 weeks of drug therapy. The onset is usually gradual, and can take days to fully develop. In 80% of cases, the initial manifestation is muscle rigidity or altered mental status (12). The muscle rigidity has been described as lead-pipe rigidity to distinguish it from the rigidity associated with tremulousness (cogwheel rigidity). The change in mental status can range from confusion and agitation to obtundation and coma. Hyperthermia (body temperature can exceed 41°C) is required for the diagnosis of NMS (12), but the increase in body temperature can be delayed for 8 to 10 hours after the appearance of muscle rigidity or change in mental status (15). Autonomic instability can produce cardiac arrhythmias, labile blood pressure, or persistent hypotension.
Laboratory Studies
It may be difficult to distinguish the extrapyramidal side effects of neuroleptic agents from the motor effects of NMS. The serum CK level can help in this regard because, although it can rise slightly in dystonic reactions, it should be higher than 1000 Units/L in NMS (13). The leukocyte count in blood can increase to 40,000/μL with a leftward shift in NMS (12), so the clinical presentation of NMS (fever, leukocytosis, altered mental status, hypotension) can be confused with sepsis. The serum CK level will distinguish NMS from sepsis.
Management
The single most important measure in the management of NMS is immediate removal of the offending drug. If NMS is caused by discontinuation of dopaminergic therapy, it should be restarted immediately with plans for a gradual reduction in dosage at a later time. General measures, including volume resuscitation and evaluation for multiorgan involvement (e.g., rhabdomyolysis), are the same as described for malignant hyperthermia.
Dantrolene sodium (the same muscle relaxant used in the treatment of MH) can be given intravenously for severe cases of muscle rigidity.
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The optimal dose is not clearly defined, but one suggestion is to start with a single dose of 2–3 mg/kg/day (12,16), and increase this every few hours if necessary to a total dose of 10 mg/kg/day. Oral dantrolene has also been used successfully in NMS in doses of 50 to 200 mg daily (usually given in divided doses every 6 to 8 hours) (16). In cases of severe muscle rigidity (when the CPK is markedly elevated), the intravenous route seems a better choice, at least in the first few days of treatment. The risk of liver injury should be considered when using dantrolene in NMS because there are alternative treatments.
Bromocriptine mesylate is a dopamine agonist that has been successful in treating NMS when given orally in a dose of 2.5 to 10 mg three times daily (16). Some improvement in muscle rigidity can be seen within hours after the start of therapy, but the full response often takes days to develop. Hypotension is a troublesome side effect. There is no advantage with bromocriptine over dantrolene, except in patients with advanced liver disease (where dantrolene is not advised). Treatment of NMS should continue for about 10 days after clinical resolution because of delayed clearance of many neuroleptics (when depot preparations are implicated, therapy should continue for 2 to 3 weeks after clinical resolution) (12). There is a heightened risk of venous thromboembolism during NMS (12), so heparin prophylaxis is recommended (see Chapter 5). The mortality rate from NMS is about 20% (13), and (surprisingly) it is unclear if specific treatment with dantrolene or bromocriptine has a favorable effect on mortality (12,13).

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