Neuroleptic Malignant Syndrome 

Updated: Dec 07, 2020
Author: Theodore I Benzer, MD, PhD; Chief Editor: Gil Z Shlamovitz, MD, FACEP 

Overview

Practice Essentials

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. NMS often occurs shortly after the initiation of neuroleptic treatment, or after dose increases.[1]

Signs and symptoms

The key to diagnosis is that NMS occurs only after exposure to an neuroleptic drug. On average, onset is 4-14 days after the start of therapy; 90% of cases occur within 10 days. However, NMS can occur years into therapy. Once the syndrome starts, it usually evolves over 24-72 hours.

Cardinal features are as follows:

  • Severe muscular rigidity
  • Hyperthermia (temperature >38°C)
  • Autonomic instability
  • Changes in the level of consciousness

A summary of the clinical features of neuroleptic malignant syndrome includes the following:

  • Muscular rigidity (typically, “lead pipe” rigidity)
  • Hyperthermia (temperature >38°C)
  • Diaphoresis
  • Pallor
  • Dysphagia
  • Dyspnea
  • Tremor
  • Incontinence
  • Shuffling gait
  • Psychomotor agitation
  • Delirium progressing to lethargy, stupor, coma

Other general examination findings indicative of autonomic dysregulation include the following:

  • Diaphoresis
  • Sialorrhea
  • Tachycardia
  • Tachypnea, respiratory distress (31% of cases)
  • Increased or labile blood pressure
  • Hypoxemia (low pulse oximeter reading)

See Presentation for more detail.

Diagnosis

No laboratory test result is diagnostic for NMS. Laboratory studies are used to assess severity and complications or rule out other diagnostic possibilities. A summary of the laboratory abnormalities that may be found in neuroleptic malignant syndrome includes the following:

  • Increased LDH
  • Increased creatine kinase (50-100% of cases)
  • Increased AST and ALT
  • Increased alkaline phosphatase
  • Hyperuricemia
  • Hyperphosphatemia
  • Hyperkalemia
  • Myoglobinemia
  • Leukocytosis (70-98% of cases)
  • Thrombocytosis
  • Proteinuria
  • Decreased serum iron [2]
  • Increased CSF protein
  • Hypocalcemia
  • Myoglobinuria
  • Metabolic acidosis

See Workup for more detail.

Management

Treatment of NMS is mainly supportive; it is directed toward controlling the rigidity and hyperthermia and preventing complications (eg, respiratory failure, rhabdomyolysis, renal failure). Limited evidence supports the use of dantrolene and bromocriptine to hasten clinical response; other interventions that have been used include amantadine, lorazepam, and electroconvulsive therapy.[3, 4] Monitoring and management in an ICU is recommended.

The most important intervention is to discontinue all neuroleptic agents. In most cases, symptoms will resolve in 1-2 weeks. Episodes precipitated by long-acting depot injections of neuroleptics can last as long as a month.

See Treatment and Medication for more detail.

Background

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 30 years, NMS has been associated with a variety of drugs that lead to decreased dopamine receptor activation.[8] 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.

Pathophysiology

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.[9, 10] 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.[11]

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.[12]

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

 

Etiology

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.[13]

The clearest risk factors for neuroleptic malignant syndrome relate to the time course of therapy. Strongly associated factors are as follows[14] :

  • 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 [15]

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 [16]
  • Agitation [16]
  • 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 [17]

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.[18]

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.[19] 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.[20]

The majority of patients who develop neuroleptic malignant syndrome will be able to tolerate an antipsychotic at some point in the future.[19, 21] 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.

Epidemiology

In the United States, neuroleptic malignant syndrome has been variably reported as occurring in 0.07-2.2% of patients taking neuroleptics.[22] 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.[23]

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.[24] A retrospective study conducted in India showed an incidence of 0.14%.[25]

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.[26, 27]

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. 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.[27] 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.[28]

Prognosis

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%.[29]

Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism, DIC).[30] 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.

Patient Education

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)

 

Presentation

History

The diagnosis of neuroleptic malignant syndrome is based on clinical features. Cardinal features are as follows:

  • Severe muscular rigidity

  • Hyperthermia

  • Autonomic instability

  • Changes in the level of consciousness

The syndrome occurs only after exposure to a neuroleptic drug. Most cases develop shortly after initiation of therapy or increasing the dose. The onset can be within hours, but on average is 4-14 days, after the start of therapy; 90% of cases occur within 10 days. However, neuroleptic malignant syndrome can occur at any time during neuroleptic use, even years into therapy. Once the syndrome starts, it usually evolves over 24-72 hours.

A summary of the clinical features of neuroleptic malignant syndrome includes the following:

  • Rigidity

  • Hyperthermia

  • Diaphoresis

  • Pallor

  • Dysphagia

  • Dyspnea

  • Tremor

  • Incontinence

  • Tachycardia

  • Shuffling gait

  • Psychomotor agitation

  • Delirium progressing to lethargy, stupor, coma

Patients with atypical presentations of neuroleptic malignant syndrome may not exhibit muscle rigidity or hyperthermia initially; those features may develop over time or not at all.[31, 32] Clozapine-induced neuroleptic malignant syndrome may be more likely to manifest without extrapyramidal features, including rigidity and tremor, but cases involving other atypical antipsychotic drugs generally present in a typical manner.[3]

Physical Examination

Neuroleptic malignant syndrome tends to start with muscular rigidity and progress to hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared with adults, children and adolescents with neuroleptic malignant syndrome tend to present with more dystonia and less tremor.

General examination findings indicative of autonomic dysregulation include the following:

  • Hyperthermia (temperature >38°C)

  • Diaphoresis

  • Sialorrhea

  • Tachycardia

  • Tachypnea, respiratory distress (31% of cases)

  • Increased or labile blood pressure

  • Hypoxemia (low pulse oximeter reading)

  • Incontinence

Patients may exhibit signs of dehydration secondary to hyperpyrexia and inadequate oral intake. Pallor or rash may be present. In rare cases, a reversible cardiomyopathy mimicking cardiac infarction may develop.[33]

Signs and symptoms of decreased dopaminergic activity include the following:

  • Muscular rigidity (typically, “lead pipe” rigidity)

  • Dysphagia

  • Short, shuffling gait

  • Resting tremor

  • Dystonia

  • Dyskinesia

Excessive or purposeless motor activity and tremor can reflect psychomotor agitation. Mental status may be altered, ranging from agitation to drowsiness, confusion, and coma. Delirium is characterized by the following:

  • Loss of awareness of both the internal and external worlds

  • Loss of orientation in time and space

  • Reduced ability to direct and sustain attention

  • Speech that is often mumbled and incoherent

  • Delusions and hallucinations, especially visual

  • Fluctuating level of consciousness, from lethargy to stupor and coma

 

DDx

Diagnostic Considerations

Neuroleptic malignant syndrome (NMS) is a heterogeneous condition that spans a broad severity continuum. The diagnosis is made on clinical grounds and is based on the presence of certain historical, physical, and laboratory findings. The diagnosis is confirmed by the presence of recent treatment with neuroleptics (within the past 1-4 weeks), hyperthermia (temperature above 38°C), and muscular rigidity, along with at least five of the following features:

  • Change in mental status

  • Tachycardia

  • Hypertension or hypotension

  • Diaphoresis or sialorrhea

  • Tremor

  • Incontinence

  • Increased creatine phosphokinase (CPK) or urinary myoglobin level

  • Leukocytosis

  • Metabolic acidosis

  • Autonomic instability

In addition, diagnosis of neuroleptic malignant syndrome requires exclusion of other drug-induced, systemic, or neuropsychiatric illness. The clinician must rule out another medication reaction that might be a more likely cause of the patient’s symptoms than use of a neuroleptic. Exposure to other psychotropic drugs can result in disorders very similar to neuroleptic malignant syndrome. Medical conditions must also be considered.

Diagnostic criteria created by a consensus of an international multispecialty expert panel, including psychiatrists, neurologists, anesthesiologists, and emergency physicians, were released in 2011. In addition to hyperthermia and rigidity, at least two other clinical features of neuroleptic malignant syndrome, including leukocytosis and laboratory evidence of muscle injury, should be present. Although the criteria require validation before being used in clinical settings, they can provide guidance for clinicians.[9]

Neuroleptic syndrome also has been associated with the rapid removal of medications with dopaminergic properties.[34] Medications in these classes often are used to treat Parkinson disease and include levodopa, bromocriptine, and amantadine. In such cases, dopaminergic drugs should be started as soon as possible to prevent rhabdomyolysis and renal failure.[35] Evaluation and treatment is otherwise the same as in neuroleptic syndrome involving other drugs.

Other neuroleptic-induced reactions

Antipsychotics can cause a variety of reactions that can be confused with neuroleptic malignant syndrome. These neuroleptic-induced reactions often occur with increasing medication dosages and include the following:

  • Acute dystonia - Abnormal contraction or spasm of a group of skeletal muscles, often involving the head or neck

  • Acute akathisia - Motor restlessness, particularly involving the legs

  • Tardive dyskinesia - Involuntary, rhythmic movements starting with mouth movements

  • Parkinsonism, or pseudoparkinsonism - Classically presents as the triad of tremor, muscular rigidity, and akinesia

Despite the term neuroleptic-induced, these conditions also can be caused, although less frequently, by many of the newer, nontraditional antipsychotic medications, which also have some dopamine-blocking activity. For more information, see Medication-Induced Dystonic Reactions and Neuroleptic Agent Toxicity .

Lethal catatonia

Lethal catatonia (LC) is a similar condition that might be confused with neuroleptic malignant syndrome. Lethal catatonia occurs in people with schizophrenia or during manic episodes. Neuroleptics might either improve or worsen the symptoms of lethal catatonia.

Distinguishing lethal catatonia from neuroleptic malignant syndrome can be difficult, although a detailed history might reveal episodes of catatonia while a patient is not taking neuroleptics. Lethal catatonia also tends to have a prodrome of excitement and agitation prior to the onset of rigidity, while neuroleptic malignant syndrome tends to begin with rigidity.[36]

Serotonin syndrome

The serotonin syndrome is similar to neuroleptic malignant syndrome. It is characterized by the triad of altered mental status, autonomic dysfunction, and movement disorder (tremor and abnormal involuntary movement) following exposure to serotonergic agents.[37]

Diagnosis may be especially challenging in patients taking both serotonergic and neuroleptic agents, who may meet criteria for both syndromes.[38] However, laboratory findings characteristic of neuroleptic malignant syndrome (eg, elevated creatine kinase level, liver function test results, and white blood cell count, coupled with a low serum iron level) do not occur in serotonin syndrome.[39]

The proposed mechanism of serotonin syndrome is excessive 5-hydroxytryptamine (5-HT or serotonin) stimulation. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used medications in this class. Given the increasing use of SSRIs, the serotonin syndrome might become increasingly prevalent.

The serotonin syndrome can be distinguished from neuroleptic malignant syndrome in most cases by a detailed history of medication use, with particular attention to recent dosage changes and the presence of tremor and abnormal movements but the absence of severe rigidity. Treatment of this condition includes removal of the offending drug and supportive management, though 5-HT1A antagonists might have a role.[37, 40]

Malignant hyperthermia

Malignant hyperthermia (MH) occurs after administration of halogenated inhalational anesthetics (eg, halothane) or depolarizing muscle relaxants (eg, succinylcholine) to genetically susceptible individuals.[41] An underlying defect is an autosomal dominant mutation in the ryanodine receptor, which leads to excessive calcium release from the sarcoplasmic reticulum in skeletal muscle when one of the above agents is administered. A multifactorial pattern of inheritance also has been postulated.

Malignant hyperthermia can be distinguished readily by history. Treatment is based on supportive care, use of dantrolene to decrease calcium release, and subsequent avoidance of precipitating medications. No evidence shows that neuroleptic malignant syndrome occurs more frequently in patients susceptible to malignant hyperthermia.

Medical mimics

General medical conditions that might mimic neuroleptic malignant syndrome include the following:

  • Central nervous system infections

  • Status epilepticus

  • Stroke

  • Brain trauma

  • Neoplasms

  • Acute intermittent porphyria

  • Tetanus

  • Thyroid Storm

  • Heat stroke

  • Sepsis

Differential Diagnoses

 

Workup

Approach Considerations

No laboratory test result is diagnostic for neuroleptic malignant syndrome (NMS). However, the following laboratory studies may be indicated, to assess severity and complications or rule out other diagnostic possibilities:

  • Complete blood count (CBC)

  • Blood cultures

  • Liver function tests (LFTs)

  • Blood urea nitrogen (BUN) and creatinine levels

  • Calcium and phosphate levels

  • Creatine kinase (CK) level

  • Serum iron level

  • Urine myoglobin level

  • Arterial blood gas (ABG) levels

  • Coagulation studies

  • Serum and urine toxicologic screening (eg, salicylates, cocaine, amphetamines)

General laboratory features in neuroleptic malignant syndrome include leukocytosis, thrombocytosis, and evidence of dehydration. The serum iron concentration might be decreased. The cerebrospinal fluid (CSF) protein concentration might be elevated.[42]

The rigidity and hyperthermia in neuroleptic malignant syndrome contribute to muscle damage and necrosis, which is reflected in elevated blood levels of the following:

  • CK

  • LFTs (aspartate aminotransferase [AST], alanine aminotransferase [ALT])

  • Lactate dehydrogenase (LDH)

Muscle damage and necrosis can progress quickly to rhabdomyolysis with hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. Elevated levels of myoglobin can be observed in blood and urine, and may ultimately lead to renal failure.

Assessment of the serum CK level is especially frequently used in psychiatric practice for diagnostic evaluation of rhabdomyolysis in patients with possible neuroleptic malignant syndrome. Other causes of CK elevation may include prescription drugs, alcohol, acute coronary syndrome, and other medical conditions.

Other causes of fever should be investigated, depending on the clinical scenario. This may include urinary tract, respiratory, and central nervous system (CNS) infections. Cultures from various sites may be indicated.

A summary of the laboratory abnormalities that may be found in neuroleptic malignant syndrome includes the following:

  • Increased LDH

  • Increased CK (50-100% of cases)

  • Increased AST and ALT

  • Increased alkaline phosphatase

  • Hyperuricemia

  • Hyperphosphatemia

  • Hyperkalemia

  • Myoglobinemia

  • Leukocytosis (70-98% of cases)

  • Thrombocytosis

  • Proteinuria

  • Decreased serum iron[2]

  • Increased CSF protein

  • Hypocalcemia

  • Myoglobinuria

  • Metabolic acidosis

If thromboembolic phenomenon or disseminated intravascular coagulation (DIC) is suspected, the following coagulation studies may be performed:

  • Platelet count

  • Prothrombin time (PT) and international normalized ratio (INR)

  • Activated partial thromboplastin time (aPTT)

Imaging studies do not yield any diagnostic information for neuroleptic malignant syndrome per se. However, computed tomography (CT) or magnetic resonance imaging of the brain may be performed to rule out other conditions, such as intracranial hemorrhage (ICH), trauma, or structural lesions. Chest radiography is indicated for suspected aspiration pneumonia.

A lumbar puncture (LP) is indicated to rule out meningitis as a cause of fever and altered mental status. No universal agreement exists on the absolute need for a head CT scan before performing an LP in patients without clinical evidence of a structural lesion of the brain; the decision is left to the individual practitioner.

 

Treatment

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.[32]

Other interventions have been advocated (eg, dantrolene, bromocriptine, amantadine, lorazepam, electroconvulsive therapy), but their value is controversial.[3, 43]

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:

  • Benzodiazepines for restraint may be useful
  • Stop all neuroleptics
  • Correct volume depletion and hypotension with intravenous fluids
  • Reduce hyperthermia

Methods to reduce the temperature include the following:

  • Cooling blankets
  • Antipyretics
  • Cooled intravenous fluids
  • Ice packs
  • Evaporative cooling
  • 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.[44, 45] 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.[46]

ECT with anesthesia has generally been safe, with no increased incidence of malignant hyperthermia from succinylcholine administration.[47, 48] 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.[49]

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.[50, 49]

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.[50, 51, 43]

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.

 

Medication

Medication Summary

Specific drug therapies, such as dantrolene, amantadine, and bromocriptine, have an uncertain role in the treatment of neuroleptic malignant syndrome. Recommendations for the use of these drugs are from noncontrolled prospective and retrospective studies and case reports; no controlled studies exist. While the drugs generally are felt to be helpful, they have been found to have deleterious effects in some studies.

Skeletal Muscle Relaxants

Class Summary

These agents stimulate muscle relaxation by modulating skeletal muscle contractions at sites beyond the myoneural junction and by acting directly on muscle itself. Benzodiazepines are used in a small number of patients with neuroleptic malignant syndrome unresponsive to other measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.

Dantrolene (Dantrium, Revonto)

Dantrolene interferes with the release of calcium from sarcoplasmic reticulum, thus directly inhibiting muscle contraction. It also prevents or reduces the increase in myoplasmic calcium ion concentration that activates acute catabolic process associated with malignant hyperthermia. It is used to treat muscular rigidity and hyperthermia associated with neuroleptic malignant syndrome.

Dantrolene is available as a sodium salt in 25-mg, 50-mg, and 100-mg capsules and in 20-mg vial for intravenous (IV) administration. The IV form is much more expensive and should be reserved for patients unable to take oral medications.

Benzodiazepine-Antispasmodic Agents

Class Summary

By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and the action of other inhibitory transmitters.

Diazepam

Diazepam modulates postsynaptic effects of gamma amino-butyric acid A (GABA-A) transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, as well as on the thalamus and hypothalamus, to induce a calming effect. Individualize dosage and increase cautiously to avoid adverse effects.

Lorazepam (Ativan)

Lorazepam is a benzodiazepine with short onset of effects and intermediate-long half-life.

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it might depress all levels of CNS, including the limbic and reticular formation.

Dopamine Agonists

Class Summary

A dopamine agonist must stimulate D2 receptors if it is to offer clinical benefit in neuroleptic malignant syndrome. D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents (eg, phenothiazines).

Bromocriptine (Parlodel)

Bromocriptine is a semisynthetic, ergot alkaloid derivative that is a strong dopamine D2-receptor agonist and a partial dopamine, D1-receptor agonist. It stimulates dopamine receptors in the corpus striatum. Bromocriptine may relieve akinesia, rigidity, and tremor associated with Parkinson disease. Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess dosage titration every 2 weeks. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.

Amantadine

Amantadine has been used to treat Parkinson disease and has been tried in neuroleptic malignant syndrome because it increases synaptic dopamine activity. Its antiparkinsonian activity results from blocking reuptake of dopamine into presynaptic neurons and causing direct stimulation of postsynaptic receptors.

 

Questions & Answers

Overview

What is neuroleptic malignant syndrome (NMS)?

What are the signs and symptoms of neuroleptic malignant syndrome (NMS)?

What are the clinical features of neuroleptic malignant syndrome (NMS)?

Which physical findings indicate autonomic dysregulation in neuroleptic malignant syndrome (NMS)?

Which lab abnormalities suggest neuroleptic malignant syndrome (NMS)?

What are the treatment options for neuroleptic malignant syndrome (NMS)?

What is neuroleptic malignant syndrome (NMS)?

What is the role of atypical antipsychotic drugs in the etiology of neuroleptic malignant syndrome (NMS)?

What precipitates the onset of neuroleptic malignant syndrome (NMS)?

What is the pathophysiology of neuroleptic malignant syndrome (NMS)?

Which medications causes neuroleptic malignant syndrome (NMS)?

What are the risk factors for neuroleptic malignant syndrome (NMS)?

Which factors increase the risk of recurrence for neuroleptic malignant syndrome (NMS)?

What is the prevalence of neuroleptic malignant syndrome (NMS) in the US?

What is the global prevalence of neuroleptic malignant syndrome (NMS)?

Which patient groups are at higher risk for developing neuroleptic malignant syndrome (NMS)?

What is the prognosis of neuroleptic malignant syndrome (NMS)?

What are the complications of neuroleptic malignant syndrome (NMS)?

What is the mortality rate for neuroleptic malignant syndrome (NMS)?

What are the sequelae of neuroleptic malignant syndrome (NMS)?

What is included in patient education about neuroleptic malignant syndrome (NMS)?

Presentation

What are the cardinal clinical features of neuroleptic malignant syndrome (NMS)?

When does neuroleptic malignant syndrome (NMS) occur?

What are the signs and symptoms of neuroleptic malignant syndrome (NMS)?

What is the role of antipsychotic drugs in the development of neuroleptic malignant syndrome (NMS)?

What is the progression of neuroleptic malignant syndrome (NMS)?

What are the physical findings characteristic of neuroleptic malignant syndrome (NMS)?

How is delirium characterized in neuroleptic malignant syndrome (NMS)?

DDX

How is neuroleptic malignant syndrome (NMS) diagnosed?

How is neuroleptic malignant syndrome (NMS) caused by dopamine agonists treated?

Which neurologic conditions should be included in the differential diagnoses of neuroleptic malignant syndrome (NMS)?

How is lethal catatonia (LC) differentiated from neuroleptic malignant syndrome (NMS)?

How is serotonin syndrome differentiated from neuroleptic malignant syndrome (NMS)?

How is malignant hyperthermia differentiated from neuroleptic malignant syndrome (NMS)?

Which general medical conditions should be included in the differential diagnoses of neuroleptic malignant syndrome (NMS)?

What are the differential diagnoses for Neuroleptic Malignant Syndrome?

Workup

Which lab studies are performed in the evaluation of neuroleptic malignant syndrome (NMS)?

Which lab findings suggest neuroleptic malignant syndrome (NMS)?

How are the rigidity and hyperthermia of neuroleptic malignant syndrome (NMS) reflected in lab findings?

How do muscle damage and necrosis in neuroleptic malignant syndrome (NMS) progress?

What lab abnormalities are characteristic of neuroleptic malignant syndrome (NMS)?

When are coagulation studies indicated in the workup of neuroleptic malignant syndrome (NMS)?

What is the role of imaging studies in the diagnosis of neuroleptic malignant syndrome (NMS)?

Treatment

What are the treatment options for neuroleptic malignant syndrome (NMS)?

What is the prehospital care for neuroleptic malignant syndrome (NMS)?

What is included in the treatment of neuroleptic malignant syndrome (NMS)?

How is temperature reduced in the treatment of neuroleptic malignant syndrome (NMS)?

What is the role of electroconvulsive therapy (ECT) in the treatment of neuroleptic malignant syndrome (NMS)?

What is the role of pharmacologic therapy in the treatment of neuroleptic malignant syndrome (NMS)?

How is neuroleptic malignant syndrome (NMS) prevented?

Which specialist consultations are beneficial in the treatment of neuroleptic malignant syndrome (NMS)?

What is included in the long-term monitoring of patients with neuroleptic malignant syndrome (NMS)?

Medications

What is the role of medications in the treatment of neuroleptic malignant syndrome (NMS)?

Which medications in the drug class Dopamine Agonists are used in the treatment of Neuroleptic Malignant Syndrome?

Which medications in the drug class Benzodiazepine-Antispasmodic Agents are used in the treatment of Neuroleptic Malignant Syndrome?

Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Neuroleptic Malignant Syndrome?