Neuroleptic malignant syndrome: Still a risk,
but which patients may be in danger?
...page 2

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

Table 3
Drugs that can cause NMS-like hyperthermic syndromes

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 off-label 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:
• who fail to respond to drug therapy or supportive care
• with residual catatonic symptoms.13,20,27,28

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.

I recommend that you choose therapies empirically, based on the character, severity, and duration of symptoms in a given case.5,6,20

Table 4
How to treat neuroleptic malignant syndrome

REDUCING RISK OF RECURRENCE
Patients vary in susceptibility to recurrence after they recover from NMS, but the risk approaches 30% with future exposure to antipsychotics.5,6 You may be able to minimize recurrence risk by:

• reducing risk factors, such as dehydration
• considering alternatives to antipsychotics, such as treating bipolar disorder with lithium or ECT
• using atypical instead of conventional antipsychotics, starting with low dosages and titrating slowly.

Before you reintroduce antipsychotics, carefully document informed consent and your rationale for treatment decisions in the patient’s chart.

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