Diagnostic criteria. Clinical signs of NMS as a fullblown hypermetabolic syndrome are distinctive and well described (Table 1).5,6,11,12 Elevated temperature is accompanied by profuse sweating. Extreme temperatures (>104° F), especially if prolonged or associated with hypoxia or hypotension, pose a high risk for brain damage, rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure, and death.
Muscle rigidity is a characteristic finding and may be accompanied by tremors, cogwheeling, myoclonus, or rhabdomyolysis. Changes in vital signs—such as tachycardia and tachypnea—are typical.
Mental status examination usually reveals catatonic signs of mutism and stupor, but delirium and coma also have been described. No laboratory findings are specific for NMS, but elevated white blood cell counts, low serum iron, metabolic acidosis, hypoxia, and elevated serum CPK and catecholamines have been reported.
Table 1
Common clinical features of NMS
| Signs and symptoms | Altered level of consciousness, catatonia, dysarthria, dysphagia, elevated temperature, labile blood pressure, muscle rigidity, mutism, myoclonus, tachycardia, tachypnea, tremor |
| Laboratory findings | Elevated catecholamines and serum creatine phosphokinase, hypoxia, leukocytosis, low serum iron, metabolic acidosis |
Resolution. If recognized promptly, NMS resolves within 1 to 2 weeks in two-thirds of patients after antipsychotics are discontinued. The average recovery time of 7 to 10 days may be prolonged in patients who were taking long-acting depot antipsychotics or in those with persistent residual catatonic symptoms.13
Risk of death. NMS remains potentially fatal, especially if high temperatures develop or episodes are prolonged. Causes of death include cardiorespiratory arrest, renal failure, pulmonary emboli, pneumonia, sepsis, disseminated intravascular coagulation, and multisystem organ failure.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of NMS encompasses disorders that present with fever and encephalopathy.5,6,12 Primary brain disorders that resemble NMS include:9,14-16
- infections
- acute psychotic disorders that progress to malignant catatonia or delirious mania
- midbrain structural lesions
- seizures.
Also exclude hormonal and autoimmune disorders and environmental heatstroke (Table 2).17,18 Similar hyperthermic syndromes have been reported with other toxins and drugs, including malignant hyperthermia of anesthesia, serotonin syndrome, and dopamine agonist withdrawal in patients with Parkinson’s disease (Table 3).5,6,19
Table 2
7 disease states most often confused with NMS
| Infections |
| Malignant catatonia secondary to psychotic disorders |
| Benign extrapyramidal side effects |
| Agitated delirium from diverse causes |
| Environmental heatstroke |
| Serotonin syndrome |
| Withdrawal from dopamine agonists, other drugs, or alcohol |
| Source: Neuroleptic Malignant Syndrome Information Service hotline |
Table 3
Drugs that can cause NMS-like hyperthermic syndromes
| Anticholinergics Dopamine antagonists Hallucinogens Inhalational anesthetics Monoamine oxidase inhibitors Psychostimulants Salicylates | Serotonergic drugs Succinylcholine Withdrawal from: • Dopamine agonists • Alcohol • Sedative/hypnotics • Baclofen |
MANAGING NMS
The standard approach to managing patients with NMS includes four steps:
- recognize the diagnosis early
- exclude alternate causes of symptoms
- discontinue suspected triggering drugs
- provide supportive care to reduce temperatures, ensure fluid balance, and detect complications.5,6,20
Beyond supportive care, several specific therapies have been proposed based on theoretical mechanisms of NMS and meta-analyses of offlabel use in anecdotal clinical reports (Table 4). If benzodiazepines, dopamine agonists, or dantrolene are effective, taper slowly after recovery to prevent rebound symptoms.
Benzodiazepines. Given the concept of NMS as a form of catatonia, benzodiazepines have been used effectively in some cases.20,21 A trial of lorazepam, 1 to 2 mg parenterally, is a reasonable first step. Higher doses may be required, with adequate monitoring of respiratory status. Oral lorazepam can maintain the therapeutic effect.
Dopamine agonists. To reverse the parkinsonism and dopamine antagonist properties of antipsychotics, dopamine agonists such as bromocriptine or amantadine have been tried and have reduced NMS duration and mortality.20,22,23 Newer drugs such as ropinorole and pramipexole may also be useful. Dopaminergic drugs, however, can worsen psychosis and cause hypotension and emesis.
Dantrolene may reduce hyperthermia related to skeletal muscle hypermetabolism of any cause and has been effective in rapidly reducing extreme temperatures in some NMS cases.20,22-26 Dantrolene is given IV, 1 to 2.5 mg/kg every 6 hours. An oral form can be substituted if a response is obtained. Dantrolene can impair respiratory and hepatic function and should not be combined with calcium channel blockers.
ECT is increasingly recognized as an effective NMS treatment and should not be overlooked for patients:
Standard ECT is given, although nondepolarizing muscle relaxants instead of succinylcholine are used in patients with serious rhabdomyolysis to avoid the risk of hyperkalemia.20
Recommendation. Although these modalities offer a spectrum of therapeutic options, it is premature to recommend any single remedy over others or over supportive care alone because:
- randomized, controlled trials have not been conducted
- NMS episodes are heterogeneous in presentation and outcome
- the syndrome is often self-limited after antipsychotics are discontinued.