Approach Considerations
Treatment of neuroleptic malignant syndrome (NMS) is mainly supportive; it is directed toward controlling the rigidity and hyperthermia and preventing complications (eg, respiratory failure, renal failure). Monitoring and management in an intensive care unit (ICU) is recommended.
The most important intervention is to discontinue all antipsychotics. Signs and symptoms should improve after the antipsychotic is stopped. No new focal neurologic deficits should develop, although cases of neurologic sequelae have been reported rarely. In most cases, symptoms will resolve in 1-2 weeks. Episodes precipitated by long-acting depot injections of antipsychotics can last as long as a month.
Patients should receive circulatory and ventilatory support as needed. Antipyretics, evaporative cooling, ice packs, and cooled intravenous (IV) fluids can be used to reduce hyperthermia. Consider prophylactic intubation for patients with excessive salivation, swallowing dysfunction, coma, hypoxemia, acidosis, and severe rigidity with hyperthermia. Aggressive fluid resuscitation and alkalization of urine can help prevent acute renal failure and enhance excretion of muscle breakdown products. [34]
Other interventions have been advocated (eg, dantrolene, bromocriptine, amantadine, lorazepam, electroconvulsive therapy), but their value is controversial. [3, 45]
Prehospital Care
Any patient being evaluated by prehospital personnel requires assessment of the airway, breathing, and circulation (ABCs). Prehospital personnel should consider administration of thiamine, dextrose (or rapid glucose determination), and/or naloxone, in case of alcohol withdrawal, hypoglycemia, and opioid overdose, respectively.
Prehospital personnel should assess the patient's safety and, if necessary, restrain the patient. Restraint use in agitated, hyperthermic patients can increase the risk of significant morbidity and mortality in neuroleptic malignant syndrome and other disease states (eg, cocaine intoxication, amphetamine abuse). Chemical restraints (eg, benzodiazepines), if available, may be preferable in such situations.
To identify possible precipitants of neuroleptic malignant syndrome, prehospital personnel should try to obtain an accurate medication list. If that is impossible, they should bring all the medication bottles found with the patient.
Emergency Department Care
Treatment of patients with neuroleptic malignant syndrome may include the following:
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Benzodiazepines for restraint may be useful
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Stop all neuroleptics
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Correct volume depletion and hypotension with intravenous fluids
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Reduce hyperthermia
Methods to reduce the temperature include the following:
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Cooling blankets
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Antipyretics
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Cooled intravenous fluids
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Ice packs
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Evaporative cooling
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Pharmacologic therapies to reduce rigidity (see below)
When rhabdomyolysis occurs, maintain vigorous hydration and alkalinize the urine with intravenous sodium bicarbonate to prevent acute kidney injury.
Additional evaluation and treatment should be in an inpatient setting, preferably an ICU.
Electroconvulsive Therapy
In patients with neuroleptic malignant syndrome, electroconvulsive therapy (ECT) can help with the alteration of temperature, level of consciousness, and diaphoresis. It may also be useful in treating the underlying psychiatric disease in patients who are unable to take neuroleptics. [46, 47] A retrospective case series of 15 patients with refractory NMS who were treated with ECT over a 17-year period reported a remission rate of 73.3%. Although early response occurred after a mean of 4.2 treatments, an average of 17.7 treatments were needed to keep catatonic signs from recurring. [48]
ECT with anesthesia has generally been safe, with no increased incidence of malignant hyperthermia from succinylcholine administration. [49, 50] However, serious treatment-related complications have occurred. Specifically, patients with neuroleptic malignant syndrome have developed ventricular fibrillation and cardiac arrest after ECT.
Pharmacologic Therapy
A variety of medications have been used to provide symptomatic treatment of neuroleptic malignant syndrome. Dantrolene sodium directly relaxes muscles by inhibiting calcium release from the sarcoplasmic reticulum. Most patients respond to 400 mg/day or less.
Dantrolene therapy alone appears to shorten the duration of illness, but use is controversial. Reduction of fever and rigidity is not immediate but occurs over a mean of 1.7 days. A review of case reports concluded that combining dantrolene with other drugs prolongs the recovery period, and that using dantrolene as monotherapy seemed to be associated with increased mortality. The only benefit from dantrolene was in patients who had been on neuroleptic monotherapy. [51]
Bromocriptine is a dopamine agonist that overcomes neuroleptic-induced dopaminergic blockade. It has also been used in combination with dantrolene, but studies have questioned the benefit of this approach. [52, 51]
Other agents that have been tried include amantadine, which enhances presynaptic release of dopamine, and levodopa/carbidopa, which increase presynaptic dopamine stores. Dopaminergic medications can be especially useful if the NMS was caused by withdrawal of anti-Parkinson medication. [52, 53, 45]
Use of nondepolarizing neuromuscular blocking agents (eg, pancuronium, other newer agents) may be considered. These may achieve rapid, predictable, and effective control of rigidity and hyperthermia. However, such medications can be used only in patients who have been intubated and sedated and are receiving mechanical ventilation.
Antimuscarinic agents are not recommended. They are not only ineffective but also may worsen hyperthermia.
Deterrence/Prevention
Clinicians should take a careful history before starting a new neuroleptic medication, to uncover any previous instances of neuroleptic malignant syndrome, as those patients are at risk for recurrence. Because neuroleptic malignant syndrome usually develops while the dose is being increased, the clinician, patient, and family members must be alert to this possibility until a steady dose is achieved.
Patient education should be provided regarding avoidance of factors that may increase the risk for development of neuroleptic malignant syndrome. These include dehydration, agitation, exhaustion, and malnutrition (see Patient Education).
Consultations
Consultation with a neurologist may be needed if the diagnosis is in question. Consultation with a nephrologist is needed if the patient develops rhabdomyolysis and renal failure.
Consultation with a psychiatrist can be helpful to manage the underlying psychiatric disease once the neuroleptics have been withdrawn. On the other hand, if neuroleptic malignant syndrome is diagnosed in a psychiatric facility, the patient should be transferred to an acute care medical facility where intensive monitoring and treatment is available.
Long-Term Monitoring
Neuroleptic malignant syndrome may be prolonged. If the patient is discharged, close follow-up care should be given to monitor residual symptoms. The patient's psychiatric disease must be evaluated and treated during withdrawal of the neuroleptic medication.
If neuroleptics are to be reinstituted, they should be administered at relatively low initial doses. Challenge with an atypical antipsychotic may be appropriate, since these drugs have a lower incidence of neuroleptic malignant syndrome.
