Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to neuroleptic medications that is characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction. The syndrome was first described by Delay and colleagues in 1960, in patients treated with high-potency antipsychotics. ^[5]

Neuroleptic drugs are primarily used to treat schizophrenia and other psychotic states. Traditional agents (eg, chlorpromazine, haloperidol) act through inhibition of dopaminergic receptors, whereas the second-generation (atypical) agents work by causing blockade of serotonin receptors. These agents also have dopamine-blocking properties, though not as potent as those of the traditional agents, and while they are not classified accurately as neuroleptics, almost all of them can cause NMS. ^[6] Atypical antipsychotic drugs that may cause NMS include the following:

• Olanzapine
• Risperidone
• Paliperidone
• Aripiprazole
• Ziprasidone
• Amisulpride
• Quetiapine

The second-generation antipsychotic agent clozapine may also be associated with the development of NMS. However, it appears to be less likely to produce extrapyramidal features, including rigidity and tremor, and more likely to produce diaphoresis. ^[7]

In general, over the past several decades, NMS has been associated with a variety of drugs that lead to decreased dopamine receptor activation. ^[8] Cases have been reported in association with antiemetics (eg, metoclopramide, promethazine, levosulpiride), tricyclic antidepressants, and lithium. ^{[8, 9]} A drug's potential for inducing NMS seems to parallel its antidopaminergic activity.

NMS frequently occurs shortly after the initiation of neuroleptic treatment. The mean onset is 10 days after starting the new medication. Onset of NMS may also follow dose increases of an established medication. No clear relationship has been established between neuroleptic dosage and risk of developing neuroleptic malignant syndrome, however. Of note, NMS has also been precipitated by the abrupt withdrawal of anti-Parkinson medication, which effectively decreases the domaminergic activity of the brain.

While some clear risk factors for NMS have been identified, the low incidence of this syndrome and the consequent difficulty in studying it in a controlled, prospective manner make clinical features, predisposing conditions, treatment, and prognosis difficult to define. Successful treatment requires prompt recognition, withdrawal of neuroleptic agent, exclusion of other medical conditions, aggressive supportive care, and administration of certain pharmacotherapies (see Treatment and Medication).

See Neuroleptic Agent Toxicity for discussion of the range of adverse effects seen with therapeutic doses and overdoses of these drugs.

The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways.

Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms (eg, cutaneous vasodilation, sweating), while nigrostriatal blockade results in muscular rigidity. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. ^{[10, 11]} The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While that has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome. ^[12]

A genetic mechanism underlying this process has been suggested. Carriage of the A1 allele of the dopamine D2 receptor (DRD2) gene has been associated with low density of dopamine D2 receptors in the brain, mostly on the corpus striatum on the caudate region. Carriers of the A1 allele have a 10.5 times higher risk of developing NMS than noncarriers. ^[13]

Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome.

All classes of antipsychotics have been associated with neuroleptic malignant syndrome, including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical) antipsychotics. Neuroleptic malignant syndrome has been reported most frequently in patients taking haloperidol and chlorpromazine. Lithium at toxic levels may also reportedly cause neuroleptic malignant syndrome. ^[14]

The clearest risk factors for neuroleptic malignant syndrome relate to the time course of therapy. Strongly associated factors are as follows ^[15] :

• High-potency neuroleptic use
• High-dose neuroleptic use
• Rapid increase in neuroleptic dose
• Depot injectable (long-acting) neuroleptic use (ie, fluphenazine decanoate, fluphenazine enanthate, haloperidol decanoate, risperdal consta)
• Prior episodes of neuroleptic malignant syndrome
• Recent episode of catatonia ^[16]

A number of demographic features have been implicated, including male sex (2:1 ratio) and age 20-25 years. However, those features may simply indicate the higher usage of potent neuroleptics in this population.

Other potential risk factors include the following:

• Dehydration ^[17]
• Agitation ^[17]
• Exhaustion
• Malnutrition
• Organic brain syndromes
• Nonschizophrenic mental illness
• Lithium use
• Past history of electroconvulsive therapy
• Warm and humid environments
• Inconsistent use of neuroleptics
• Postpartum period ^[18]

Genetic factors also might play a role. Case reports have been published on neuroleptic malignant syndrome occurring in identical twins as well as in a mother and two of her daughters. ^[19]

In patients who have experienced an episode of neuroleptic malignant syndrome, the risk of recurrence is strongly related to the elapsed time between the episode and restarting antipsychotics. ^[20] Delaying reintroduction of antipsychotic medication until at least 2 weeks after the resolution of symptoms is typically recommended for patients who had been taking an oral antipsychotic and at least 6 weeks for those on a depot form. ^[21]

The majority of patients who develop neuroleptic malignant syndrome will be able to tolerate an antipsychotic at some point in the future. ^{[20, 22]} Given the potentially life-threatening nature of neuroleptic malignant syndrome, reintroduction of antipsychotic treatment must be approached cautiously. The risk of recurrence may be reduced by switching to a different antipsychotic class and, if possible, using an atypical antipsychotic rather than a traditional agent.

In the United States, neuroleptic malignant syndrome has been variably reported as occurring in 0.07-2.2% of patients taking neuroleptics. ^[23] Data largely come from case control studies rather than prospective randomized trials. Because of increased awareness of this syndrome and efforts at prevention, the incidence is probably lower now than in the past. ^[24]

The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial variation. The one large randomized trial conducted in China showed an incidence of 0.12% in patients taking neuroleptics. ^[25] A retrospective study conducted in India showed an incidence of 0.14%. ^[26]

Onset of neuroleptic malignant syndrome ranges from 1-44 days after initiation of neuroleptic drug therapy; mean onset is 10 days. Lazarus et al reported neuroleptic malignant syndrome occurring in 67% of patients within 1 week and 96% of patients within 30 days following administration of neuroleptics. ^{[27, 28]}

Sex- and age-related variations in incidence

Neuroleptic malignant syndrome has been reported to be more common in males, although that most likely reflects greater neuroleptic usage rather than greater susceptibility. ^[29] The male-to-female ratio is 2:1.

The reported mean age of patients experiencing neuroleptic malignant syndrome is 40 years, but the syndrome may occur in patients of any age who are receiving neuroleptics or other precipitating medications. ^[28] Differential incidence simply might reflect a population that has a high rate of antipsychotic usage. Some small case series suggest that onset in elderly patients might occur after a longer duration of antipsychotic use.

Although NMS is rare in children, studies suggest that clinicians should maintain a high level of suspicion in children. Symptoms of NMS in children are consistent with those described in adults. ^[30]

The prognosis in patients with neuroleptic malignant syndrome depends on how promptly treatment is instituted and on the presence of associated complications. In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and with good supportive care, the prognosis for recovery is good.

In patients who develop neuroleptic malignant syndrome after taking an oral agent, the syndrome may last 7-10 days after discontinuation of the drug. In those who have received depot neuroleptics (eg, fluphenazine), the syndrome may last up to a month.

The mortality rate in patients with neuroleptic malignant syndrome, once reported at 20-30%, is now estimated at 5-11.6%. The mortality rate rises to about 50% if neuroleptic malignant syndrome is complicated by renal failure.

Patients who have previously experienced episodes of neuroleptic malignant syndrome are at risk for recurrences, especially if antipsychotics are restarted shortly afterward. However, the majority of these patients will be able to tolerate another antipsychotic, which is very important because most patients taking neuroleptics require them to maintain a reasonable functional status.

Complications

Complications of neuroleptic malignant syndrome include dehydration from poor oral intake, acute renal failure from rhabdomyolysis, and deep venous thrombosis and pulmonary embolism from rigidity and immobilization.

Avoiding antipsychotics can cause complications related to uncontrolled psychosis. Most patients taking antipsychotic medicines are being treated for a severe and persistent psychiatric disorder; a high likelihood exists that a patient will relapse while off antipsychotics.

A summary of the potential complications of neuroleptic malignant syndrome includes the following:

• Rhabdomyolysis
• Acute kidney injury
• Cardiovascular arrhythmias and collapse
• Aspiration pneumonia
• Respiratory failure
• Seizure
• Pulmonary embolism and deep venous thrombosis (DVT)
• Liver failure
• Disseminated intravascular coagulation (DIC)
• Decompensation of psychiatric disease following the withdrawal of neuroleptics

Mortality/morbidity

Mortality from neuroleptic malignant syndrome is very difficult to quantify, because the literature on this subject consists largely of case reports and because the diagnostic parameters used have been inconsistent. In some series, mortality rates as high as 76% have been reported. Most series suggest, however, that the mortality rate is 10-20%. When reporting bias is factored in, the true rate of mortality from neuroleptic malignant syndrome might be much lower.

Studies have also found that the mortality rate has been decreasing over the past 2 decades. In a US population–based study of cases from the years 2002-2011, the unadjusted mortality rate was 5.6%. ^[31]

Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism, DIC). ^[32] Renal failure is associated with a 50% mortality rate.

No consistent long-term physical, neurological, cognitive, or laboratory sequelae have been attributed to neuroleptic malignant syndrome alone, although sequelae may result from such secondary complications as prolonged hypoxia or ischemic encephalopathy. Researchers have noted sporadic cases of prolonged rigidity and long-term neuropsychological deficits.

When prescribing neuroleptic medications, clinicians should explain and educate the patient and caretakers about possible adverse effects of the medications. After an episode of neuroleptic malignant syndrome, educational approaches can help patients and their relatives to understand what has happened to the patient, why the neuroleptic malignant syndrome has developed in the past, and the possibility of recurrence if antipsychotic therapy is restarted.

This education may help patients and their relatives to decide about giving consent to restart antipsychotics. If they give consent, they have to be aware of the early signs of neuroleptic malignant syndrome (eg, rigidity, hyperthermia, and changes of consciousness) and the importance of immediately seeking medical care if these arise.

For patient education information, see Neuroleptic Malignant Syndrome. Helpful Web sites for patients include the following:

• Neuroleptic Malignant Syndrome Information Service

• NINDS Neuroleptic Malignant Syndrome Information Page (National Institute of Neurological Disorders and Stroke)