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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

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Mar 2019. | This topic last updated: Nov 27, 2017.

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

emergency associated with the use of 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
neuroleptic 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 neuroleptic agents [5,8].

ASSOCIATED MEDICATIONS

Neuroleptic agents — NMS is most often seen with high-potency first-generation neuroleptic
agents (eg, haloperidol, fluphenazine) [9-11]. However, every class of neuroleptic 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) [5,12]. Associated medications are listed in the table (table
1).
While symptoms usually develop during the first two weeks of neuroleptic 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 [13]. 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
[1,8,14,15].

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 [4,14-16]. 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 [3,5,9,17-19]. 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 [5,20].

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 [1,4,21,22]. Infection and surgery are possible
precipitants as well [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 [23,26,27].

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 [28,29].

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 [30,31]. Interference
with nigrostriatal dopamine pathways may lead to parkinsonian-type symptoms such as rigidity
and tremor [17,31]. Other neurotransmitter systems (gamma aminobutyric acid, epinephrine,
serotonin, and acetylcholine) also appear to be involved, either directly or indirectly [28,32].

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 [17,33].
This in itself may represent a primary skeletal muscle defect or a direct toxic effect by neuroleptics
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 [33]. 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 [34]. Genetic studies
have shown that the presence of a specific allele of the dopamine D2 receptor gene is over-
represented in NMS patients [35]. 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 [4,36].

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 [37]. 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 [16].
●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 [38,39].
●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) [3,20]. 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 [37].
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 [3,4,17,20,40,41]. 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 [33,40]. 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) [41]. 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 [3,5,20]. 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 [3,42]. (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 [20,43].

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 [44]. 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 [17,45]. 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.

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.

Related disorders — NMS is one of a group of acute dysautonomias that share common
features: rigidity, hyperpyrexia, and dysautonomia [5,7,44,46]. These entities are usually
distinguishable, if only by the implicated drugs.
Serotonin syndrome — The most commonly diagnosed related disorder is serotonin syndrome
[44,47,48]. This is usually caused by use of selective serotonin reuptake inhibitors and has a
similar presentation that is difficult to distinguish from NMS [18]. Typical features in these patients
that are not often seen in NMS patients are shivering, hyperreflexia, myoclonus, and ataxia
[49,50]. 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. (See "Serotonin syndrome (serotonin toxicity)".)

Malignant hyperthermia — A rare genetic disorder, malignant hyperthermia is distinguished

from NMS by its clinical setting: occurring with use of potent halogenated inhalational anesthetic
agents and succinylcholine. 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 malignant hyperthermia 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 [17,33,46]. (See "Malignant
hyperthermia: Clinical 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 [51,52]. 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 [4,16]. One reviewer
found it impossible to distinguish between the two disorders in 22 percent of cases [29].
(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 [53]. 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".)

Unrelated 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 neuroleptic use. These diagnoses
have serious prognostic and treatment implications and should not be overlooked [10,44]:

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

●Systemic infections (eg, pneumonia, sepsis)
●Seizures
●Acute hydrocephalus
●Acute spinal cord injury
●Heat stroke (neuroleptics 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
●Acute porphyria

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) [54]. 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. 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 [39].

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 [44]. 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 [55], as well as signal abnormalities in the
cerebellum and basal ganglia that are similar to those seen in malignant hyperthermia [56].
Cerebrospinal fluid is usually normal, but a nonspecific elevation in protein is reported in 37
percent of cases [20].

Electroencephalography may be done to rule out nonconvulsive status epilepticus. In NMS

patients, generalized slow wave activity is seen [4,20].

TREATMENT — The management of patients with NMS should be based upon a hierarchy of
clinical severity and diagnostic certainty [4,29]. 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 [57]. 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 neuroleptic agent or precipitating drug.

●Maintain cardiorespiratory stability. Mechanic ventilation, antiarrhythmic agents, or
pacemakers may be required [58].
 ●Maintain euvolemic state using intravenous fluids. Insensible fluid loss from fever and from
diaphoresis should also be considered [59]. If creatine kinase (CK) is very elevated, high-
volume intravenous fluids with urine alkalinization may help prevent or mitigate renal failure
from rhabdomyolysis [60]. (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 [61]. Nitroprusside may
have advantages by also facilitating cooling through cutaneous vasodilation [62].
(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, clonazepam, lorazepam 0.5 to 1.0 mg) to control agitation, if
necessary [29].

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 [63]. 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 [64].

●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. 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 [65,66]. 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 [67].
●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
[31], apomorphine [68], carbamazepine [69], and benzodiazepines
(lorazepam or clonazepam) [17,44,70].

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 [28]. A retrospective analysis of published
cases indicates that the use of bromocriptine and/or dantrolene appeared to hasten clinical
response [71]. 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 [72].

These and similar analyses are of questionable validity because of publication and other biases
[1,72]. 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 [73]. 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 neuroleptics 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) [74]. In another comprehensive literature review, clinical response occurred after an
average of 4.1 treatments. However, interpretation of this is complicated by the variable timing of
ECT in relation to symptom onset [75]. 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 [75]. Another patient had status epilepticus. Other authors also report uncontrolled
spontaneous seizures and aspiration pneumonia complicating ECT treatment for NMS [74-76].

The use of ECT in this setting is further challenged by the requirement for anesthesia. Because
of concerns for associated malignant hyperthermia, some authors suggest the use of
nondepolarizing agents. However, in over 16 reported cases of NMS patients treated
with succinylcholine, there was no malignant hyperthermia [17,75]. Succinylcholine may also
cause hyperkalemia and cardiac arrhythmias in patients with rhabdomyolysis and autonomic
dysfunction [29].

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 [5,20]. 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 [76]. 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 are 5 to 20 percent [1,6,70,77]. Disease severity and the
occurrence of medical complications are the strongest predictors of mortality [44]. 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 organic brain
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 [77].

RESTARTING NEUROLEPTICS — Patients restarted on neuroleptic 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 [1,5,13,78]. Early resumption of neuroleptic therapy;
use of high-potency, parenteral neuroleptics; and concomitant use of lithium appear to be risk
factors for recurrence [5,78]. Recurrent NMS is also idiosyncratic, with reports of patients with no
sequelae after early resumption of a high-potency neuroleptic, and relapses of NMS occurring on
low-potency agents up to two years later [13,78].

If neuroleptic medication is required, the following guidelines may minimize risk of NMS
recurrence [4,20,78]; 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.

SUMMARY AND RECOMMENDATIONS — Neuroleptic malignant syndrome (NMS) is a life-

threatening neurologic emergency associated with the use of neuroleptic 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 neuroleptic
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 '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, neuroleptic 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 neuroleptic agents may or may not have a recurrent NMS
episode. If neuroleptic medication is required, risk may be minimized by following some
general guidelines. (See 'Restarting neuroleptics' above.)