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Neuroleptic malignant syndrome

Author: Eelco FM Wijdicks, MD
Section Editor: Michael J Aminoff, MD, DSc
Deputy Editor: Janet L Wilterdink, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2022. | This topic last updated: May 31, 2019.

INTRODUCTION

Neuroleptic malignant syndrome (NMS) is a life-threatening 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.

Mortality results directly from the dysautonomic manifestations of the disease and
from systemic complications. Mortality has declined from the earliest reports in the
1960s of 76 percent and is more recently estimated between 10 and 20 percent
[1,2]. This probably reflects greater awareness of the disease, earlier diagnosis, and
more aggressive intervention. Requiring a high clinical suspicion for diagnosis and
treatment, NMS is appropriately a syndrome more often considered than truly
diagnosed.

EPIDEMIOLOGY

Incidence rates for NMS range from 0.02 to 3 percent among patients taking
antipsychotic agents [3,4]. 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.

While most patients with NMS are young adults, the syndrome has been described
in all age groups from 0.9 to 78 years [3,5-7]. Age is not a risk factor [8]. In most
studies, men outnumber women twofold. Both age and gender distributions
correspond with the distribution of the exposure to antipsychotic agents [5,8].

ASSOCIATED MEDICATIONS

Antipsychotic and antiemetic agents — NMS is most often seen with high-
potency first-generation antipsychotic agents, formerly called neuroleptic agents
(eg, haloperidol, fluphenazine) [9-11]. However, every class of antipsychotic drug has
been implicated, including the low-potency (eg, chlorpromazine) and second-
generation antipsychotic drugs (eg, clozapine, risperidone, olanzapine) as well as
antiemetic drugs (eg, metoclopramide, promethazine, and levosulpiride) [5,12,13].
Associated medications are listed in the table ( table 1).

While symptoms usually develop during the first two weeks of antipsychotic therapy,
the association of the syndrome with drug use is idiosyncratic. NMS can occur after
a single dose or after treatment with the same agent at the same dose for many
years [14]. It is not a dose-dependent phenomenon, but higher doses are a risk
factor [5]. Case-control studies implicate recent or rapid dose escalation, a switch
from one agent to another, and parenteral administration as risk factors [1,8,15,16].

Associated risk factors — Case series and case-control studies also suggest that
certain psychiatric conditions, acute catatonia, and extreme agitation are over-
represented in patients who develop NMS [4,15-17]. It is possible that these
represent conditions of higher risk simply because of the increased use of higher
doses, rapid escalation, and parenteral therapy.

Other commonly listed risk factors, such as concomitant use of lithium or other
psychotropic drugs, higher-potency agents, depot formulations, comorbid
substance abuse or neurologic disease, and acute medical illness (including trauma,
surgery, and infection), have not been substantiated in case-control studies
[3,5,9,18-20]. 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 [5,21].
 Antiparkinson medication withdrawal — NMS is also seen in patients treated for
parkinsonism in the setting of withdrawal of L-Dopa or dopamine agonist therapy,
as well as with dose reductions and a switch from one agent to another [1,4,22,23].
Infection and surgery are possible precipitants as well [24]. 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 [24,25]. While some report that the
clinical syndrome and laboratory findings are milder and the prognosis is better in
this disorder [26], more severe cases and even fatalities have been reported
[24,27,28].

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 [29,30].

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 [31,32]. Interference with nigrostriatal dopamine pathways may lead
to parkinsonian-type symptoms such as rigidity and tremor [18,32]. Other
neurotransmitter systems (gamma aminobutyric acid, epinephrine, serotonin, and
acetylcholine) also appear to be involved, either directly or indirectly [29,33].

An alternative theory is that rigidity and muscle damage represent a primary effect
on the peripheral muscle system, perhaps from direct changes in muscle
mitochondrial function [18,34]. This in itself may represent a primary skeletal muscle
defect or a direct toxic effect by these drugs on skeletal muscle.

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, and labile blood pressure and heart rate [34]. In this model,
dopamine antagonists precipitate symptoms by destabilizing normal dopamine
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 regulation of efferent sympathetic activity.

Familial clusters of NMS suggest a genetic predisposition to the disorder [35].

Genetic studies have shown that the presence of a specific allele of the dopamine
D2 receptor gene is over-represented in NMS patients [36]. This allele is associated
with reduced density and function of dopamine receptors as well as decreased
dopaminergic activity and metabolism.

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 [4,37].

Typical symptoms — The tetrad of NMS symptoms typically evolves over one to
three days. Each feature is present in 97 to 100 percent of patients:

● Mental status change is the initial symptom in 82 percent of patients [38]. It is

not surprising, given the usual psychiatric comorbidity of the typical patient,
that its significance is often underappreciated. 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 is typical [17].

● Muscular rigidity is generalized and is often extreme. The increased tone can
be demonstrated by moving the extremities and is characterized by "lead-pipe
rigidity" or stable resistance through all ranges of movement. Superimposed
tremor may lead to a ratcheting quality or a cogwheel phenomenon. Other
motor abnormalities include tremor (seen in 45 to 92 percent), and less
commonly, dystonia, opisthotonus, trismus, chorea, and other dyskinesias
[3,5]. Patients can also have prominent sialorrhea, dysarthria, and dysphagia.

● Hyperthermia is a defining symptom according to many diagnostic criteria.

Temperatures of more than 38°C are typical (87 percent), but even higher
temperatures, greater than 40°C, are common (40 percent) [5]. Fever may be a
less consistent symptom in patients with NMS associated with second-
:
 generation antipsychotic agents [39,40].

● 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) [3,21]. Dysrhythmias may occur. Diaphoresis is often profuse.

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 [38]. Some case reports document delay in the appearance
of fever of more than 24 hours, leading to initial diagnostic confusion [3]. There is
substantial variability in the presentation of NMS, and other reports do not
necessarily substantiate a typical course.

Laboratory abnormalities

Elevated serum CK — Laboratory findings often reflect the clinical manifestations

of NMS, with more severe rigidity leading to more profound creatine kinase (CK)
elevation. In NMS, CK is typically more than 1000 international units/L and can be as
high as 100,000 international units/L [3,4,18,21,41,42]. 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
injections and physical restraints, and sometimes without specific explanation
[34,41]. 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 [3]. 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) [42]. CK levels do usually
normalize after an NMS episode.

Other — 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 [3,5,21]. 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 renal failure can result from rhabdomyolysis [3,43]. (See
"Clinical manifestations and diagnosis of rhabdomyolysis".)

● 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
[21,44].

Atypical cases — 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 [45].
While many consider fever to be an essential feature of the diagnosis, cases are
reported where it is absent [5]. Complicating this issue is the fact that the isolated
appearance of dysautonomia, hyperthermia, parkinsonian rigidity, and CK
elevations all occur with antipsychotic therapy. Individually they do not necessarily
appear to be a harbinger of NMS [18,46]. 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.

EVALUATION AND DIAGNOSIS

The diagnosis of NMS is made in a patient who is taking an associated medication (

table 1) and who develops a typical clinical syndrome. An international
multispecialty consensus group published diagnostic criteria for NMS in 2011 (
table 2) [47]. 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 and validated for making a diagnosis of NMS. These criteria
require independent validation before their use can be recommended in clinical
practice. Other published criteria differ in requiring all or just some of the cardinal
clinical and laboratory features [40].
:
 Although there is no diagnostic test for NMS, testing has a crucial role in the
evaluation of patients with potential NMS. Typical laboratory abnormalities help to
confirm the clinical diagnosis, some tests rule out other conditions, and others are
used to monitor patients for complications of NMS.

In patients with possible NMS, brain imaging studies and lumbar puncture are
required to exclude structural brain disease and infection [45]. Magnetic resonance
imaging (MRI) and computed tomography (CT) are typically normal. In isolated cases
diffuse cerebral edema has been reported in the setting of severe metabolic
derangements [48], as well as signal abnormalities in the cerebellum and basal
ganglia that are similar to those seen in malignant hyperthermia (MH) [49].
Cerebrospinal fluid is usually normal, but a nonspecific elevation in protein is
reported in 37 percent of cases [21].

Electroencephalography may be done to rule out nonconvulsive status epilepticus.

In NMS patients, generalized slow wave activity is seen [4,21].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of NMS can be broadly defined in two categories: those
conditions that are related to NMS and those unrelated to NMS but commonly
considered in the differential diagnosis.

NMS is one of a group of acute dysautonomias that share common features: rigidity,
hyperpyrexia, and dysautonomia [5,7,45,50]. These entities are usually
distinguishable, if only by the implicated drugs.

Serotonin syndrome — The most commonly diagnosed related disorder is

serotonin syndrome [45,51,52]. This is usually caused by use of selective serotonin
reuptake inhibitors and has a similar presentation that is difficult to distinguish from
NMS [19]. Typical features in these patients that are not often seen in NMS patients
are shivering, hyperreflexia, myoclonus, and ataxia [53,54]. 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 less severe
than in patients with NMS. While the symptoms of serotonin syndrome classically
evolve more quickly than NMS, the speed of onset of both syndromes is variable and
:
 overlapping [55]. (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 patients with MH susceptibility 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
[18,34,50]. (See "Malignant hyperthermia: Diagnosis and management of acute
crisis".)

Malignant catatonia — Most problematic in the differential diagnosis of NMS,

malignant catatonia shares 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. The motor
symptoms are also characterized by more positive phenomena (dystonic posturing,
waxy flexibility, and stereotyped repetitive movements) than are described in NMS
[56,57]. Laboratory values are more typically normal. 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 overlap;
many case descriptions exist of NMS arising in patients with malignant catatonia
[4,17]. One reviewer found it impossible to distinguish between the two disorders in
22 percent of cases [30]. (See "Catatonia in adults: Epidemiology, clinical features,
assessment, and diagnosis", section on 'Malignant catatonia'.)

Other drug-related syndromes — Withdrawal of intrathecal baclofen therapy has

been associated with an NMS-like syndrome in several case reports [58]. 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.
:
 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 NMS. Other
features seen in NMS (diaphoresis, rigidity, and elevated CK levels) are absent here,
while atypical features of NMS (flushing, mydriasis, bladder distension) are
common. (See "Anticholinergic poisoning", section on 'Clinical features of overdose'.)

Acute intoxication with certain recreational drugs, especially cocaine and ecstasy
(3,4-methylenedioxymethamphetamine [MDMA]), can be confused with NMS. Both
potent stimulants of the central nervous system, these agents are attractive to
abusers because they produce heightened vigilance, energy, and euphoria;
however, these same effects can also manifest as 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. MDMA use can also cause a serotonin syndrome. These
syndromes are discussed in detail separately. (See "MDMA (ecstasy) intoxication"
and "Cocaine: Acute intoxication" and "Methamphetamine: Acute intoxication".)

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 [10,45]:

● Central nervous system infection (eg, meningitis, encephalitis)

● Systemic infections (eg, pneumonia, sepsis)
● Seizures
● Acute hydrocephalus
● Acute spinal cord injury
● Heat stroke (antipsychotics predispose to heat stroke by impairing
thermoregulation)
● Acute dystonia
● Tetanus
● Central nervous system vasculitis
● Thyrotoxicosis
● Pheochromocytoma
:
 ● Drug intoxication, toxicity (eg, phencyclidine, ecstasy, cocaine, amphetamines,
lithium)
● Withdrawal states
● Autoimmune or paraneoplastic encephalitis
● Acute porphyria

TREATMENT

The management of patients with NMS should be based upon a hierarchy of clinical
severity and diagnostic certainty [4,30]. When manifestations are severe, intensive
care unit monitoring and treatment are required.

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 need for aggressive and supportive care in NMS is essential
and uncontroversial [59]. Complications are common and severe, even fatal. These
include:

● Dehydration
● Electrolyte imbalance
● Acute renal failure associated with rhabdomyolysis
● Cardiac arrhythmias, including torsades de pointes and cardiac arrest
● Myocardial infarction
● Cardiomyopathy
● Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary
embolism
● Deep venous thrombophlebitis
● Thrombocytopenia
● Disseminated intravascular coagulation
● Deep venous thrombosis
● Seizures from hyperthermia and metabolic derangements
:
 ● Hepatic failure
● Sepsis

The intensive nature of the required monitoring and supportive treatment is such
that admission to the intensive care unit is required. The following supportive
treatment should be provided:

● Discontinue any antipsychotic agent or precipitating drug.

● Maintain cardiorespiratory stability. Mechanic ventilation, antiarrhythmic

agents, or pacemakers may be required [60].

● Maintain euvolemic state using intravenous fluids. Insensible fluid loss from
fever and from diaphoresis should also be considered [61]. If creatine kinase
(CK) is very elevated, high-volume intravenous fluids with urine alkalinization
may help prevent or mitigate renal failure from rhabdomyolysis [62]. (See
"Clinical manifestations and diagnosis of rhabdomyolysis".)

● 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 "Severe nonexertional hyperthermia (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
[63]. Nitroprusside may have advantages by also facilitating cooling through
cutaneous vasodilation [64]. (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".)

● Use benzodiazepines (eg, lorazepam 0.5 to 1 mg) to control agitation, if

necessary [30].

Specific treatments
:
 Medical therapy — Recommendations for specific medical treatments in NMS are
based upon case reports and clinical experience, not upon data from clinical trials.
Their efficacy is unclear and disputed [65]. Commonly used agents are dantrolene,
bromocriptine, and amantadine. We are more likely to use these agents in more
severe cases and escalate treatment if there is no effect or the patient worsens. A
reasonable approach is to start with benzodiazepines (lorazepam or diazepam)
along with dantrolene in moderate or severe cases, followed by the addition of
bromocriptine or amantadine [66].

● Lorazepam, a benzodiazepine, is used 1 to 2 mg IM or IV every four to six

hours. Diazepam is dosed as 10 mg IV every eight hours.

● Dantrolene is a direct-acting skeletal muscle relaxant and is effective in

treating malignant hyperthermia (MH). 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
[67,68]. Efficacy includes reduction of heat production as well as rigidity, and
effects are reported within minutes of administration. There is 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 days followed by a slow taper to
minimize relapse [69].

● Bromocriptine, a dopamine agonist, is prescribed to restore lost dopaminergic

tone. It is well tolerated in psychotic patients. 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 recommended that this be continued for 10 days after NMS
is controlled and then tapered slowly.

● Amantadine has dopaminergic and anticholinergic effects and is used as an

alternative to bromocriptine. 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 [32],

apomorphine [70], carbamazepine [71], bupropion [72], and benzodiazepines
(lorazepam or clonazepam) [18,45,73].
:
 The use of any of these medications is controversial and largely unsupported. In an
animal model of NMS, dantrolene reduced body temperature, CK levels, and an
electromyography (EMG) activation measure of rigidity compared with control [29].
A retrospective analysis of published cases indicates that the use of bromocriptine
and/or dantrolene appeared to hasten clinical response [74]. Time to complete
recovery was reduced from a mean of 15 days (with supportive care alone) to 9 days
(with dantrolene) and 10 days (with bromocriptine). Another analysis found reduced
mortality: 8.6 percent in patients treated with dantrolene, 7.8 percent in patients
treated with bromocriptine, and 5.9 percent in patients treated with amantadine
compared with 21 percent in those receiving supportive care alone [75].

These and similar analyses are of questionable validity because of publication and
other biases [1,75]. By contrast, a small prospective study in 20 patients showed that
dantrolene and/or bromocriptine use was associated with a more prolonged course
(9.9 versus 6.8 days) and a higher incidence of sequelae compared with those
receiving supportive care alone [76]. However, the findings in this nonrandomized
study could be explained by the fact that patients in the treated group were sicker
than those not treated.

While evidence supporting the use of these agents is limited, they are frequently
used because of anecdotal evidence of efficacy, lack of other proven treatments, and
high morbidity and mortality of the disorder.

Electroconvulsive therapy — The rationale for the use of electroconvulsive

therapy (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.

ECT is a reasonable treatment option in NMS; however, there are no prospective,

randomized, controlled data supporting its efficacy. A review of published cases
found a lower mortality rate in ECT-treated patients compared with those receiving
supportive care alone (10.3 versus 21 percent) [77]. In other literature reviews and
case series, clinical response is described after an average of four treatments
[78,79]. However, interpretation of these reports is complicated 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. Cardiovascular complications occurred in
4 of 55 patients, including 2 patients with ventricular fibrillation and cardiac arrest
with permanent anoxic brain injury [78]. Another patient had status epilepticus.
Other authors also report uncontrolled spontaneous seizures and aspiration
pneumonia complicating ECT treatment for NMS [77,78,80].

The use of ECT in this setting is further challenged by the requirement for
anesthesia. Because of concerns for associated MH, some authors suggest the use
of nondepolarizing agents. However, in over 16 reported cases of NMS patients
treated with succinylcholine, there was no MH [18,78]. Succinylcholine may also
cause hyperkalemia and cardiac arrhythmias in patients with rhabdomyolysis and
autonomic dysfunction [30].

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".)

PROGNOSIS

Most episodes resolve within two weeks. Reported mean recovery times are 7 to 11
days [5,21]. Cases persisting for six months with residual catatonia and motor signs
are reported [6]. Risk factors for a prolonged course are depot antipsychotic use and
concomitant structural brain disease [80]. Most patients recover without neurologic
sequelae except where there is severe hypoxia or grossly elevated temperatures for
a long duration.

Reported mortality rates for NMS vary between 5 to 20 percent [1,6,73,81]. Disease
severity and the occurrence of medical complications are the strongest predictors of
mortality [45]. A systematic review of published cases before 1989 revealed
increased mortality in patients with myoglobinuria and renal failure compared with
controls (50 versus 18.8 percent) [1]. Patients with neurologic disease including
alcohol and drug addiction had a mortality of 38.5 percent. Others have
:
 documented lower mortalities associated with higher-potency versus lower-potency
agents [6] and with atypical compared with typical antipsychotic drugs [81].

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 [1,5,14,82]. Early
resumption of antipsychotic therapy; use of high-potency, parenteral antipsychotics;
and concomitant use of lithium appear to be risk factors for recurrence [5,82].
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 [14,82].

If antipsychotic medication is required, the following guidelines may minimize risk

of NMS recurrence [4,21,82]; none of these guarantee either success or failure.

● 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.
● Carefully monitor for symptoms of NMS.

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
5th to 6th 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 10th to 12th 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

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency

associated with the use of antipsychotic agents and characterized by a distinctive
clinical syndrome.

● The diagnosis should be suspected when any two of the four cardinal clinical
features (mental status change, rigidity, fever, or dysautonomia) appear in the
setting of antipsychotic use or dopamine withdrawal. (See 'Clinical
manifestations' above.)

● Important considerations in the differential diagnosis include meningitis,

encephalitis, systemic infections, heat stroke, and other drug-induced
dysautonomias. (See 'Differential diagnosis' above.)

● Diagnostic testing includes tests to rule out these conditions and laboratory
evaluation of common metabolic sequelae of NMS, especially elevated creatine
kinase (CK). (See 'Evaluation and diagnosis' above.)

● The management of patients with NMS should be based upon a hierarchy of

clinical severity and diagnostic certainty:

• When there is any suspicion of NMS, antipsychotic agents should be

withheld. Patients should have close inpatient monitoring of clinical signs
and laboratory values. (See 'Supportive care' above.)
:
 • Patients with significant hyperthermia and rigidity should be admitted to an
intensive care unit setting and undergo aggressive supportive care as
outlined above, as well as monitoring for potential dysautonomia and other
complications. (See 'Supportive care' above.)

• In patients with CK elevations or hyperthermia on presentation, or who do

not respond to withdrawal of medication and supportive care within the
first day or two, the use of benzodiazepines, dantrolene, bromocriptine,
and/or amantadine should be considered in a stepwise approach
depending on severity and response to treatment. (See 'Specific treatments'
above.)

• Electroconvulsive therapy (ECT) should be considered 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.)

• Patients restarted on antipsychotic agents may or may not have a recurrent

NMS episode. If antipsychotic medication is required, risk may be
minimized by following some general guidelines. (See 'Restarting
antipsychotics' above.)

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Topic 4829 Version 12.0
:
 GRAPHICS

Drugs that can cause neuroleptic malignant syndrome

Antipsychotic agents* Antiemetic agents

Aripiprazole Domperidone

Chlorpromazine Droperidol

Clozapine Metoclopramide

Fluphenazine Prochlorperazine

Haloperidol Promethazine

Olanzapine

Paliperidone

Perphenazine

Quetiapine

Risperidone

Thioridazine

Ziprasidone

Amisulpride

Zotepine

* This list is not complete. Virtually every antipsychotic agent has been associated with
neuroleptic malignant syndrome.

Graphic 75621 Version 4.0

:
 Neuroleptic malignant syndrome diagnostic criteria: Expert panel
consensus

Priority
Diagnostic criterion
score*
Exposure to dopamine antagonist, or dopamine agonist withdrawal, within 20
past 72 hours

Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally) 18

Rigidity 17

Mental status alteration (reduced or fluctuating level of consciousness) 13

Creatine kinase elevation (at least 4 times the upper limit of normal) 10

Sympathetic nervous system lability, defined as at least 2 of the following: 10

Blood pressure elevation (systolic or diastolic ≥25 percent above
baseline)
Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25
mmHg systolic change within 24 hours)
Diaphoresis
Urinary incontinence

Hypermetabolism, defined as heart-rate increase (≥25 percent above 5

baseline) AND respiratory-rate increase (≥50 percent above baseline)

Negative work-up for infectious, toxic, metabolic, or neurologic causes 7

Total:
100

No threshold score has been defined and validated for us in making a diagnosis of
NMS.

* The mean priority score indexes each criterion according to its relative importance in
making a diagnosis of neuroleptic malignant syndrome (NMS) according to an expert
panel.

Gurrera RJ, Caroff SN, Cohen A, et al. An International Consensus Study of Neuroleptic Malignant Syndrome
Diagnostic Criteria Using the Delphi Method. The Journal of Clinical Psychiatry, Volume 72, Pages 1222-8,
2011. Copyright © 2011, Physicians Postgraduate Press. Reprinted with permission.

Graphic 85984 Version 5.0

:
 Contributor Disclosures
Eelco FM Wijdicks, MD No relevant financial relationship(s) with ineligible companies to
disclose. Michael J Aminoff, MD, DSc Consultant/Advisory Boards: Brain Neurotherapy Bio
[Parkinson disease]. All of the relevant financial relationships listed have been mitigated. Janet L
Wilterdink, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements
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