Neuroleptic malignant syndrome

INTRODUCTION — 

Neuroleptic malignant syndrome (NMS) is a neurologic emergency associated with the use of antipsychotic (neuroleptic) agents and characterized by a distinctive clinical syndrome of mental status change, rigidity, fever, and dysautonomia [1].

EPIDEMIOLOGY — 

Incidence rates for NMS range from 0.02 to 3 percent among patients taking antipsychotic agents [2,3]. This wide range probably reflects differences in the populations sampled (for example, inpatient versus outpatient psychiatric populations), as well as differences in the surveillance methods and definitions of disease used. Requiring a high clinical suspicion for diagnosis and treatment, NMS is appropriately a syndrome more often considered than truly diagnosed. Studies relying on unconfirmed diagnostic codes may overestimate the frequency of the disease.

While most patients with NMS are young adults, the syndrome has been described in all ages [2,4]. Age is not a risk factor for the occurrence of NMS [5]. A trend towards male predominance has been documented in most series [4-6], but there is no evidence that sex contributes to the risk of the disease. It is believed that age and sex distributions correspond to the distribution of the exposure to antipsychotic agents [4,5].

CAUSES AND RISK FACTORS

Antipsychotic and antiemetic agents — NMS is most often seen with high-potency first-generation antipsychotic agents, formerly called neuroleptic agents (eg, haloperidol, fluphenazine) (table 1) [7,8]. However, every class of antipsychotic drug has been implicated, including the low-potency first-generation drugs (chlorpromazine, thioridazine) and second-generation antipsychotic drugs (eg, clozapine, risperidone, olanzapine, aripiprazole) (table 2), as well as the antiemetic drugs whose mechanism of action involves dopamine blockade (eg, metoclopramide, promethazine, domperidone, droperidol, prochlorperazine, and levosulpiride) [4,9-12].

While symptoms usually develop during the first week after initiation or increase of antipsychotic therapy, the association of the syndrome with drug use is idiosyncratic. NMS can occur after a single dose or, rarely, after treatment with the same agent at the same dose for many years [13-15]. It is not a dose-dependent phenomenon, but higher doses are a risk factor [4]. Case-control studies implicate recent or rapid dose escalation, a switch from one agent to another, and parenteral administration as risk factors [5,16-18].

Antiparkinson medication withdrawal — Although less common in this setting, NMS is also seen in patients treated for parkinsonism in the setting of withdrawal of levodopa or dopamine agonist therapy, as well as with dose reductions and a switch from one agent to another [3,16,19-22]. Infection, dehydration, and surgery are possible precipitants as well [21,23].

This may be considered a distinct disorder from NMS and is sometimes called neuroleptic malignant-like syndrome or parkinsonism hyperpyrexia syndrome, as well as acute akinesia or the malignant syndrome in Parkinson disease [23,24]. While some report that the clinical syndrome and laboratory findings are milder and the prognosis is better in this disorder [25], more severe cases and even fatalities have been reported [22,23,26,27]. In one series of 93 patients, 31 percent did not recover to their prior baseline [21].

Risk factors — Some risk factors, such as concomitant use of lithium or other psychotropic drugs, higher-potency agents, depot formulations, comorbid substance use or neurologic disease, and acute medical illness (including trauma, surgery, and infection), have been suggested but not universally substantiated in case-control studies [2,4,11,28-32]. It is also unclear whether dehydration, present in 92 percent of patients, is a risk factor for, as well as an early complication of, NMS [4,33].

PATHOGENESIS — 

The cause of NMS is unknown. Current theories are limited in their ability to explain all clinical manifestations and in supporting data. An animal model for NMS has been developed, but it does not fully correspond with the human syndrome [34].

Because of the class of agents with which NMS is associated, dopamine receptor blockade is central to most theories of its pathogenesis. Central dopamine receptor blockade in the hypothalamus may cause hyperthermia and other signs of dysautonomia [35,36]. Interference with nigrostriatal dopamine pathways may lead to parkinsonian-type symptoms such as rigidity and tremor [28,36]. Other neurotransmitter systems (gamma-aminobutyric acid, epinephrine, serotonin, and acetylcholine) also appear to be involved, either directly or indirectly [34,37].

A primary role has also been proposed for a disrupted modulation of the sympathetic nervous system, manifesting in increased muscle tone and metabolism and unregulated sudomotor and vasomotor activity; these in turn lead to ineffective heat dissipation, as well as labile blood pressure and heart rate [38]. In this model, dopamine antagonists precipitate symptoms by destabilizing normal dopamine regulation of efferent sympathetic activity.

Familial clusters of NMS suggest a genetic predisposition to the disorder [39]. One study reported that a specific allele of the dopamine D2 receptor gene that is associated with reduced density and function of dopamine receptors as well as decreased dopaminergic activity and metabolism was overrepresented in NMS patients [40]. No genetic polymorphisms affecting the metabolism of antidopaminergic medications have been consistently found to be more common in patients with NMS [41].

CLINICAL MANIFESTATIONS — 

NMS is defined by its association with a class of medications that block dopamine transmission and a tetrad of distinctive clinical features: fever, rigidity, mental status changes, and autonomic instability (table 3) [1,3].

Typical symptoms — The tetrad of NMS symptoms typically evolves over one to three days. Each feature eventually manifests in nearly all cases:

●Mental status change is the initial symptom in most patients [42]. This often takes the form of an agitated delirium with confusion rather than psychosis. Catatonic signs and mutism can be prominent. Evolution to profound encephalopathy with stupor and eventual coma occurs in the most severe cases [43].

●Muscular rigidity is generalized and often extreme. The increased tone can be demonstrated by moving the extremities and is usually characterized by "lead-pipe rigidity" (ie, stable resistance through all ranges of movement) [2,4]. Some patients exhibit cogwheel rigidity and tremor.

●Hyperthermia is a defining symptom according to many diagnostic criteria. Temperatures of more than 38°C are typical (close to 90 percent of cases), but even temperatures greater than 40°C are common (40 percent of cases) [4]. Fever may be a less consistent symptom in patients with NMS associated with second-generation antipsychotic agents [44,45].

●Autonomic instability typically takes the form of tachycardia (in 88 percent), labile or high blood pressure (in 61 to 77 percent), and tachypnea (in 73 percent) [2,33]. Dysrhythmias may occur. Diaphoresis is often profuse.

Less common manifestations can include dystonia, opisthotonus, trismus, chorea, and other dyskinesias. Patients can also have prominent sialorrhea, dysarthria, and dysphagia.

In an analysis of 340 cases, 70 percent of patients followed a typical course of mental status changes appearing first, followed by rigidity, then hyperthermia, and autonomic dysfunction [42]. Some case reports document delay in the appearance of fever of more than 24 hours, leading to initial diagnostic confusion [2]. There is substantial variability in the presentation of NMS; atypical antipsychotics are probably associated with milder presentations [44-46].

Less typical presentations — There is debate in the literature about milder or atypical cases of NMS. A "forme fruste" of the syndrome has been suggested to occur in milder cases, those associated with lower-potency agents, or those diagnosed early on.

In particular, rigidity may be milder and perhaps even absent in these situations [46]. While many consider fever to be an essential feature of the diagnosis, cases are reported where it is absent [4]. Complicating this issue is the fact that the isolated appearance of dysautonomia, hyperthermia, parkinsonian rigidity, and serum creatine kinase (CK) elevations all occur with antipsychotic therapy. Individually, they do not necessarily appear to be a harbinger of NMS [28,47].

From a practical clinical point of view, it seems reasonable to consider the diagnosis when any two of the tetrad of symptoms are present in the setting of an offending agent.

Laboratory abnormalities

Elevated serum CK — In NMS, CK is typically more than 1000 international units/L and can be as high as 100,000 international units/L [2,3,28,33,48,49].

The degree of elevation often reflects the clinical manifestations, with more severe rigidity leading to more profound CK elevation. Normal CK can be seen if rigidity is not clearly well developed, particularly early in the onset of the syndrome.

Elevated CK, particularly in the mild to moderate range, is not specific for NMS and is often seen in patients with acute and chronic psychosis due to intramuscular (IM) injections and physical restraints, and sometimes without specific explanation [38,48].

CK levels greater than 1000 international units/L, however, are probably more specific for NMS, and the degree of CK elevation correlates with disease severity and prognosis [2]. A case-control study demonstrated that patients with NMS were more likely to have had elevated CK levels during previous non-NMS admissions than did controls (76 versus 30 percent) [49].

CK levels usually normalize after an NMS episode.

Other findings — Other laboratory abnormalities are common but nonspecific.

●A consistent laboratory finding is leukocytosis, with a white blood cell count typically 10,000 to 40,000/mm³ [2,4,33]. A left shift may be present.

●Mild elevations of lactate dehydrogenase, alkaline phosphatase, and liver transaminases are common.

●Electrolyte abnormalities: hypocalcemia, hypomagnesemia, hypo- and hypernatremia, hyperkalemia, and metabolic acidosis are frequently observed.

●Myoglobinuric acute kidney injury can result from rhabdomyolysis [2,50,51]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

●A low serum iron concentration (mean 5.71 micromol/L; normal 11 to 32 micromol/L) is commonly seen in NMS patients and is a sensitive (92 to 100 percent) but not specific marker for NMS among acutely ill psychiatric patients [33,52].

EVALUATION AND DIAGNOSIS

Evaluation — Although there is no diagnostic test for NMS, some testing (table 3) is useful to rule out alternative diagnoses and early complications, such as sepsis. As examples, we often obtain laboratory studies to exclude toxic-metabolic encephalopathy and systemic infection. Brain imaging, lumbar puncture, and electroencephalography are obtained more selectively (for example, when central nervous system infection or seizures are suspected).

In patients with NMS, brain imaging studies are typically normal [3,53]. Cerebrospinal fluid is also usually normal, but a nonspecific elevation in protein has been reported in 37 percent of cases [33]. Electroencephalography may show generalized slow-wave activity [3,33].

Diagnosis — The diagnosis of NMS is made in a patient who develops the typical clinical syndrome while taking an associated medication. (See 'Causes and risk factors' above.)

Published criteria differ in requiring all or just some of the cardinal clinical and laboratory features [45]. The best known are the diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) [54].

An international multispecialty consensus group published diagnostic criteria for NMS in 2011 (table 4) [55]. These are based on positive clinical and laboratory findings as well as the exclusion of alternative causes, and each item is given a priority score for its relative importance in contributing to the diagnosis. However, no threshold score has been defined, the criteria have not been independently validated, and they have not been extensively used either in research or in clinical practice.

DIFFERENTIAL DIAGNOSIS — 

NMS is one of a group of diagnoses characterized by rigidity, hyperpyrexia, and dysautonomia [1,4,56]. These entities are usually distinguishable, if only by the implicated drugs.

●Serotonin syndrome – Serotonin syndrome is caused by exposure to one or multiple serotonin-enhancing medications [57].

Typical features observed in patients with serotonin syndrome that are not often seen in NMS patients are shivering, hyperreflexia, myoclonus, and clonus [57,58]. Nausea, vomiting, and diarrhea are also a common part of the prodrome in serotonin syndrome and are rarely described in NMS. Rigidity and hyperthermia, when present, are usually less severe than in patients with NMS. While the symptoms of serotonin syndrome classically evolve more quickly than NMS does, the speed of onset of both syndromes is variable and overlapping [58]. Some case reports have described concurrent NMS and serotonin syndrome [59,60]. (See "Serotonin syndrome (serotonin toxicity)".)

●Malignant hyperthermia – A rare genetic disorder, malignant hyperthermia (MH) is usually distinguished from NMS by its clinical setting: occurring with use of potent halogenated inhalational anesthetic agents and succinylcholine. However, MH has also been reported in susceptible patients who are exposed to heat stress or vigorous exercise.

Its clinical appearance with hyperthermia, muscle rigidity, and dysautonomia is quite similar to NMS, although often more fulminant. Studies using muscle contracture testing to evaluate MH susceptibility among NMS patients have yielded conflicting results, with some finding a high and others a low prevalence of susceptibility. The test may be unreliable in the setting of acute or recent NMS [28,38,61]. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

●Catatonia – Most problematic in the differential diagnosis of NMS, malignant catatonia shares the clinical features of hyperthermia and rigidity with NMS. However, in this syndrome, there is usually a behavioral prodrome of some weeks that is characterized by psychosis, agitation, and catatonic excitement [62]. The motor symptoms are also characterized by more positive phenomena (dystonic posturing, waxy flexibility, and stereotyped repetitive movements) than are described in NMS [63,64]. Laboratory values are more typically normal. Both NMS and malignant catatonia can be precipitated by antipsychotic administration [65].

The two disorders can be difficult to distinguish clinically, and historic details, particularly in the typical patient population, can be hard to elicit and interpret. The two syndromes may occasionally overlap [3,64]. (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis", section on 'Malignant catatonia'.)

●Withdrawal of intrathecal baclofen – Withdrawal of intrathecal baclofen therapy has been associated with an NMS-like syndrome [66]. In these instances, the increased muscle tone is often described as rebound spasticity rather than rigidity. Otherwise, the spectrum of symptoms appears similar to NMS, with dysautonomia, altered sensorium, fever, and elevated creatine kinase (CK) levels. Reduced gamma-aminobutyric acid activity is believed to be the pathophysiologic cause. The symptoms reverse with reinstitution of therapy, and benzodiazepines may be helpful.

●Anticholinergic syndrome – A central anticholinergic syndrome most often associated with intended or inadvertent drug overdose is better known. Patients present with encephalopathy and elevated body temperatures that are usually not as severe as those in NMS. Other features seen in NMS (diaphoresis, rigidity, and elevated CK levels) are absent, while atypical features of NMS (flushing, mydriasis, bladder distension) are common. (See "Anticholinergic poisoning", section on 'Clinical features of overdose'.)

●Recreational drug intoxication – Acute intoxication with certain recreational drugs such as cocaine, ecstasy (3,4-methylenedioxymethamphetamine [MDMA]), phencyclidine, and amphetamines can be confused with NMS.

These potent neurostimulants can manifest with psychomotor agitation, delirium, and even psychosis. Hyperthermia and rhabdomyolysis can develop, usually in association with increased physical exertion and ambient temperature. Rigidity is not common in these cases. These syndromes are discussed in detail separately. (See "MDMA (ecstasy) intoxication" and "Cocaine: Acute intoxication" and "Methamphetamine: Acute intoxication".)

MDMA use can also cause a serotonin syndrome. (See "MDMA (ecstasy) intoxication", section on 'Serotonin syndrome findings'.)

●Other disorders – Alternative neurologic and medical disorders should be considered in the patient with NMS. Clinical symptoms of these disorders can overlap with NMS, particularly in patients who have extrapyramidal side effects of concomitant antipsychotic use. These diagnoses have serious prognostic and treatment implications and should not be overlooked [7]:

•Central nervous system infection (meningitis, encephalitis)

•Sepsis from systemic infections

•Seizures

•Paroxysmal sympathetic hyperactivity after severe head trauma (see "Paroxysmal sympathetic hyperactivity")

•Heat stroke (antipsychotics predispose to heat stroke by impairing thermoregulation) (see "Nonexertional (classic) heat stroke in adults")

•Acute dystonia (see "Etiology, clinical features, and diagnostic evaluation of dystonia")

•Tetanus (see "Tetanus")

•Acute alcohol withdrawal (see "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis")

•Thyrotoxicosis (see "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Encephalopathy')

•Pheochromocytoma (see "Clinical presentation and diagnosis of pheochromocytoma")

•Autoimmune encephalitis (particularly anti-N-methyl-D-aspartate [anti-NMDA] encephalitis) [67] (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis")

•Acute porphyria (see "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis")

MANAGEMENT — 

The management of patients with NMS should be based upon a hierarchy of clinical severity and diagnostic certainty [1,3]. When manifestations are severe, intensive care unit monitoring and treatment are required (table 3).

Stop causative agent — Removal of the causative agent is the single most important treatment in NMS. Other potential contributing psychotropic agents (lithium, anticholinergic therapy, serotonergic agents) should also be stopped if possible. When the precipitant is discontinuation of dopaminergic therapy, it should be reinstituted.

Supportive care — The intensive nature of the required monitoring and supportive treatment often requires admission to the intensive care unit. The following supportive treatment should be provided:

●Maintain cardiorespiratory stability. Provide mechanical ventilation and antiarrhythmic agents as needed. When intubation is indicated, it is safer to use nondepolarizing neuromuscular blocking agents to avoid the potential risk of hyperkalemia and cardiac arrhythmias that can occur with succinylcholine in patients with rhabdomyolysis.

●Maintain euvolemic state using intravenous (IV) fluids. Insensible fluid loss from fever and from diaphoresis should also be considered [1].

If serum creatine kinase (CK) is very elevated, administer high-volume IV isotonic saline to help prevent or mitigate kidney failure from rhabdomyolysis. There is limited evidence that urine alkalinization with sodium bicarbonate may be beneficial in cases of severe rhabdomyolysis; it should not be used in the presence of hypocalcemia. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

●Lower fever using cooling blankets. More aggressive physical measures may be required: ice water gastric lavage and ice packs in the axilla. The use of acetaminophen or aspirin may have a role in reducing temperature in NMS, but it is not established. (See "Nonexertional (classic) heat stroke in adults".)

●Lower blood pressure if markedly elevated. The use of any specific agent over another is not supported by clinical data. Clonidine is effective in this setting [68]. (See "Drugs used for the treatment of hypertensive emergencies".)

●Prescribe heparin or low molecular weight heparin for prevention of deep venous thrombosis. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Monitor for and manage complications — Patients should be monitored for complications, which are common; they may be severe, even fatal. These include:

●Dehydration

●Electrolyte imbalance (eg, hyperkalemia, hypocalcemia)

●Acute kidney injury associated with rhabdomyolysis (see "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)")

●Cardiac arrhythmias, including torsades de pointes and cardiac arrest

●Myocardial infarction from demand ischemia

●Stress-induced cardiomyopathy (see "Management and prognosis of stress (takotsubo) cardiomyopathy")

●Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary embolism

●Venous thromboembolism

●Sepsis

Medical therapies — Medications are often used in patients with moderate or severe clinical manifestations of NMS. Recommendations for specific medical treatments in NMS are based upon case reports and clinical experience, not upon data from clinical trials. Commonly used agents are dantrolene, bromocriptine, and amantadine [1,69-71]. Their efficacy is unclear and disputed [72]. We are more likely to use these agents in more severe cases and escalate treatment if there is no effect or the patient worsens.

●Lorazepam, a benzodiazepine, is used 1 to 2 mg intramuscular (IM) or IV every four to six hours.

Diazepam is dosed as 10 mg IV every eight hours.

In addition to mitigating agitation, benzodiazepines, particularly diazepam, may also have a muscle relaxant effect [28,53,73,74].

As an alternative, dexmedetomidine can be useful to ameliorate tachycardia, hypertension, and agitation [1,56,75].

●Dantrolene is a direct-acting skeletal muscle relaxant. Doses of 1 to 2.5 mg/kg IV are typically used in adults and can be repeated to a maximum dose of 10 mg/kg/day [76]. Benefits include reduction of heat production as well as rigidity; effects are reported within minutes of administration [77]. There is an associated risk of hepatotoxicity, and dantrolene should probably be avoided if liver function tests are very abnormal. While some recommend discontinuing it after a few days, others suggest continuing for 10 to 14 days followed by a slow taper to minimize risk of relapse [78].

●Bromocriptine, a dopamine agonist, is prescribed to restore dopaminergic transmission [70]. It is well tolerated in patients with psychosis. Doses of 2.5 mg (through nasogastric tube) every six to eight hours are titrated up to a maximum dose of 40 mg/day. It is suggested that this be continued for 7 to 14 days after NMS is controlled and then tapered slowly.

●Amantadine has dopaminergic and anticholinergic effects and is used as an alternative to bromocriptine [31,79-82]. An initial dose is 100 mg orally or via gastric tube and is titrated upward as needed to a maximum dose of 200 mg every 12 hours.

●Other medications used with anecdotal success include levodopa (particularly in patients with NMS related to antiparkinson medication withdrawal) [21,36,83] and apomorphine [84].

Electroconvulsive therapy — Electroconvulsive therapy (ECT) is generally reserved for patients not responding to other treatments or in whom nonpharmacologic psychotropic treatment is needed. (See "Overview of electroconvulsive therapy (ECT) for adults".)

The rationale for the use of ECT in NMS includes its efficacy in treating malignant catatonia and reports of parkinsonism improving with ECT. A further impetus for ECT comes from the frequent need for psychotropic therapy in a setting in which antipsychotics cannot be used.

Case series and case reports support the usefulness of ECT in select cases of NMS [85,86]. However, there are no prospective, randomized, controlled data supporting its efficacy. Interpretation of published experience is confounded by the variable timing of ECT in relation to both symptom onset and resolution. While these results are interpreted as supporting ECT use in NMS, methodologic issues, including publication bias and lack of randomization, preclude conclusions about the efficacy of ECT in NMS.

There are safety concerns for ECT in NMS. In one series, cardiovascular complications occurred in 4 of 55 patients, including 2 patients with ventricular fibrillation and cardiac arrest with permanent anoxic brain injury [85]. Seizures, status epilepticus, and aspiration pneumonia are also concerns.

PROGNOSIS

●Recovery – Most episodes resolve within two weeks. The reported mean recovery time is 7 to 11 days and varies depending on the half-life of the implicated medication [4,33]. Risk factors for a prolonged course are depot antipsychotic exposure and concomitant structural brain disease [87].

Most patients recover without neurologic sequelae, except where there is severe hypoxia or very elevated temperatures for a long duration.

●Mortality – Mortality may result directly from dysautonomic manifestations of the disease but most often occurs because of systemic complications. (See 'Monitor for and manage complications' above.)

Disease severity and the occurrence of medical complications are the strongest predictors of mortality. Factors associated with increased risk of mortality include respiratory failure, acute kidney injury, cardiac failure, and sepsis [6]. Lower mortalities have been reported with atypical compared with typical antipsychotic drugs [88].

Mortality has declined from the earliest reports in the 1960s of 76 percent and is more recently estimated between 5 and 10 percent [6,16,70,73,82,88,89]. This decline over time probably reflects greater awareness of the disease, earlier diagnosis, and more aggressive intervention.

RESTARTING ANTIPSYCHOTICS — 

Patients restarted on antipsychotic agents may or may not have a recurrent NMS episode. It is difficult to quantify this risk from the available data. Different case series with variable duration of follow-up and various use of precautionary measures report relapse rates between 10 and 90 percent [4,13,16,90]. Early resumption of antipsychotic therapy, use of high-potency parenteral antipsychotics, and concomitant use of lithium appear to be risk factors for recurrence [4,90]. Recurrent NMS is also idiosyncratic, with reports of patients with no sequelae after early resumption of a high-potency antipsychotic, and relapses of NMS occurring on low-potency agents up to two years later [13,90].

If antipsychotic medication is required, the following guidelines may minimize the risk of NMS recurrence [3,33,90,91]:

●Wait at least two weeks before resuming therapy, or longer if any clinical residua exist.

●Use lower- rather than higher-potency agents.

●Start with low doses and titrate upward slowly.

●Avoid concomitant lithium.

●Avoid dehydration.

However, none of these guarantee either success or failure. Therefore, clinicians should always carefully monitor for the re-emergence of symptoms of NMS whenever antipsychotics are reinstated.

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Neuroleptic malignant syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Causes – Neuroleptic malignant syndrome (NMS) is a neurologic emergency associated with the use of dopamine antagonists, and less commonly with dopamine agonist withdrawal. (See 'Causes and risk factors' above.)

First-generation antipsychotic agents are most commonly implicated, but NMS can occur with any antipsychotic agent and also with dopamine-blocking antiemetic drugs. (See 'Antipsychotic and antiemetic agents' above.)

●Clinical manifestations – Cardinal clinical and laboratory features include (table 3) (see 'Clinical manifestations' above):

•Mental status change, which may take the form of an agitated or hypoactive delirium

•Muscular rigidity, typically manifested as generalized "lead-pipe" rigidity

•Hyperthermia, temperatures above 38°C, sometimes higher than 40°C

•Dysautonomia, manifesting as tachycardia, labile blood pressure, tachypnea; arrhythmias may occur

•Elevated creatine kinase (CK), the severity of which mirrors muscular rigidity, typically more than 1000 international units/L

●Differential diagnosis – Important considerations in the differential diagnosis include serotonin syndrome, malignant hyperthermia (MH), catatonia, acute intoxication with potent psychostimulants, meningitis, encephalitis, systemic infections, and heat stroke, among others. (See 'Differential diagnosis' above.)

●Evaluation and diagnosis – NMS is a clinical diagnosis; no laboratory test confirms the diagnosis. Testing is performed to rule out other conditions (table 3).

Diagnostic criteria have been proposed (table 4). (See 'Evaluation and diagnosis' above.)

●Acute management – The management of patients with NMS is based upon a hierarchy of clinical severity and diagnostic certainty (table 3):

•Withhold antipsychotic agents if there is suspicion for NMS. Patients should have close inpatient monitoring of clinical signs and laboratory values. (See 'Supportive care' above.)

•Admit patients with significant hyperthermia and rigidity to an intensive care unit setting and initiate aggressive supportive care as outlined above, as well as monitoring for potential dysautonomia and other complications. (See 'Supportive care' above.)

•For patients with CK elevations or hyperthermia on presentation and those who do not respond to withdrawal of medication and supportive care within the first day or two, we suggest medical therapy (Grade 2C).

-Benzodiazepines are typically initiated first to mitigate agitation and/or muscle rigidity.

-Dantrolene and/or bromocriptine may be added depending on symptom severity. (See 'Monitor for and manage complications' above.)

•Electroconvulsive therapy (ECT) is an option in patients not responding to medical therapy in the first week, those in whom residual catatonia persists after other symptoms have resolved, and those in whom lethal catatonia is suspected as an alternative or concomitant disorder. (See 'Electroconvulsive therapy' above.)

●Resuming antipsychotic therapy – The magnitude of the risk of recurrent NMS following resumption of antipsychotic agents is uncertain.

If antipsychotic medication is required, we monitor closely for symptoms of NMS and attempt to minimize risk with the following measures (see 'Restarting antipsychotics' above):

•Wait at least two weeks before resuming therapy.

•Use lower- rather than higher-potency agents.

•Start with low doses and titrate upward slowly.

•Avoid concomitant lithium.

•Avoid dehydration.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Eelco FM Wijdicks, MD, who contributed to earlier versions of this topic review.