Neuroleptic Malignant

Syndrome
Leslie V. Simon; Muhammad F. Hashmi; Avery L. Callahan.
Author Information and Affiliations
Last Update: April 24, 2023.

Continuing Education Activity

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

with the use of dopamine-receptor antagonist medications or with rapid withdrawal of
dopaminergic medications. NMS has been associated with virtually every neuroleptic
agent but is more commonly reported with the typical antipsychotics like haloperidol
and fluphenazine. Classic clinical characteristics include mental status changes, fever,
muscle rigidity, and autonomic instability. This activity describes the presentation of
neuroleptic malignant syndrome and highlights the role of the interprofessional team
in the management of affected patients.

Objectives:

● Explain when the diagnosis of neuroleptic malignant syndrome should be

considered.
● Explain how to diagnose neuroleptic malignant syndrome.
● Explain the management of neuroleptic malignant syndrome.
● Explore strategies to optimize care coordination among interprofessional team
members to improve outcomes for patients affected by neuroleptic malignant
syndrome.
Access free multiple choice questions on this topic.

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Introduction

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

with the use of dopamine-receptor antagonist medications or with the rapid
withdrawal of dopaminergic medications. NMS has been associated with virtually
every neuroleptic agent but is more commonly reported with the typical
antipsychotics like haloperidol and fluphenazine. Classic clinical characteristics
include mental status changes, fever, muscle rigidity, and autonomic instability. While
uncommon, NMS remains an important part of the differential diagnosis of fever and
mental status changes because it requires early diagnosis and treatment to prevent
significant mortality and death. Treatment involves immediately discontinuing the
offending agent, aggressive supportive care to manage and prevent complications, and
pharmacologic therapy in severe cases. The empiric medications most frequently used
for refractory NMS include bromocriptine mesylate, a dopamine agonist, and
dantrolene sodium, a muscle relaxant. If the syndrome is due to the rapid withdrawal
of dopaminergic medication, rapid re-institution of the medication may improve
symptoms.[1][2][3]

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Etiology

The primary trigger for NMS is dopamine receptor blockade, most often due to an
antipsychotic agent. NMS is usually associated with high-potency first-generation
neuroleptic agents but also may be caused by low-potency and atypical antipsychotic
agents, antiemetics, tricyclic antidepressants, and lithium. Rapid withdrawal of
dopaminergic drugs, most often used to manage parkinsonian diseases, such as
levodopa and amantadine, also may cause this syndrome. The rapid switching of one
Parkinson medication to another also is associated with the development of NMS.[4]
[5][6]
Medications Associated with Neuroleptic Malignant Syndrome

Typical Neuroleptics

● Haloperidol
● Chlorpromazine
● Fluphenazine
● Thioridazine
● Trifluordazine
● Thiothixene
● Loxapine
● Bromperidol
● Promazine
● Clopenthixol

Atypical Neuroleptics

● Olanzapine
● Clozapine
● Risperidone
● Quetiapine
● Ziprasidone
● Aripiprazole
● Zotepine
● Amisulpride

Antiemetics

● Droperidol
● Domperidone
● Metoclopramide
● Promethazine
● Prochlorperazine
Others

● Tetrabenazine
● Reserpine
● Amoxapine
● Diatrizoate
● Lithium
● Phenelzine
● Dosulepin
● Trimipramine
● Desipramine

Dopaminergic Agents (withdrawal)

● Levodopa
● Amantadine
● Tolcapone
● Dopamine agonists

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Epidemiology

Incidence rates range from 0.01% to 3.2% of patients taking neuroleptic medications.
The incidence is decreasing due to newer agents, which are less likely to cause NMS,
and increased awareness of the condition. Most cases occur in young adults, but this is
most likely because it is the age of first exposure to neuroleptic medications rather
than an age-related risk. Men outnumber women 2:1, also related to the likelihood of
exposure to the causative agent. Incidence due to the withdrawal of dopaminergic
drugs is more likely in the geriatric population based on the likelihood of exposure to
the inciting cause.

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Pathophysiology

The pathophysiology of NMS is complex and incompletely understood. Most

symptoms are attributed to the sudden reduction in central dopaminergic activity due
to a D2 receptor blockade or abrupt withdrawal of D2 receptor stimulation. This
accounts for the characteristic muscle rigidity, hyperthermia, and mental status
changes. Other neurotransmitters are involved, and NMS has features suggestive of
disruption of the sympathetic nervous system. Other theories suggest a calcium-
mediated disruption of the musculoskeletal system, pathophysiologically similar to
malignant hyperthermia. Familial clusters of patients with NMS and genetic testing
suggest a predisposition to the development of NMS in certain individuals.[7][8][9]

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History and Physical

The main risk factor for developing NMS is the initiation or increase in the dosage of
neuroleptic medication. High-potency and long-aging neuromuscular depot forms
carry the greatest risk. The concurrent use of multiple neuroleptic agents or lithium
also increases the risk. Abrupt withdrawal of dopaminergic agents is a less common
but important cause of NMS. Symptoms of NMS develop over one to three days and
include distinctive clinical features: fever, muscle rigidity, mental status changes, and
autonomic rigidity.

The DSM-V criteria for diagnosing NMS are as follows:

Major Criteria (all required)

● Exposure to dopamine-blocking agent

● Severe muscle rigidity
● Fever

Other Criteria (at least two required)

 ● Diaphoresis
● Dysphagia
● Tremor
● Incontinence
● Altered level of consciousness
● Mutism
● Tachycardia
● Elevated or labile blood pressure
● Leukocytosis
● Elevated creatine phosphokinase

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Evaluation

Evaluation should include a comprehensive metabolic panel including electrolytes and

serum creatinine, creatine phosphokinase level, urinalysis for myoglobinuria, and
arterial or venous blood gas to screen for metabolic acidosis. Diagnosis can be made
clinically, but supporting lab work is usually consistent with rhabdomyolysis with an
elevated CK and acutely declining renal function. The elevated CK can be profound
and typically correlates with disease severity. Leukocytosis is common with white
blood cell counts ranging from 10,00 to 40,000 mm3 with a left shift. Transaminases
may also be mildly elevated. In patients where the diagnosis is less clear,
neuroimaging and lumbar puncture may be necessary to exclude structural and
infectious diagnosis from the differential. Additional laboratory testing such as a
lithium level and screening for drugs of abuse may be helpful in selected cases.

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Treatment / Management

NMS is a neurologic emergency, and delays in diagnosis and treatment can lead to
significant morbidity or death. Discontinuing the offending agent is paramount,
followed by supportive therapy. [10][11] This includes aggressive cooling and
correction of volume deficits and any electrolyte imbalances. Patients are prone to
cardiac dysrhythmias and respiratory failure due to chest wall rigidity. Treat with
antiarrhythmic agents and mechanical ventilation as needed. More severe cases are
managed with empiric pharmacologic therapy. Meta-analyses and case reports suggest
that these may shorten the course and reduce morbidity and mortality. Bromocriptine,
a dopamine agonist, given orally or via a gastric tube, is used to reverse the
hypodopaminergic state. Dantrolene, a muscle relaxant may be administered
intravenously or orally in less severe cases. Benzodiazepines also may be useful in
controlling agitation. If the syndrome is due to a rapid withdrawal of dopaminergic
agents, restarting the drug may reduce symptoms. Electroconvulsive therapy also has
been reportedly effective in refractory cases. Patients should be admitted for close
monitoring in an intensive care unit setting.[12]

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Differential Diagnosis

NMS is one of a group of drug-related acute dysautonomias with common features of

fever, rigidity, and autonomic dysfunction. Serotonin syndrome has similar features to
NMS and is most easily distinguished by the causative agent, most frequently the
serotonin-specific reuptake inhibitors. Hyperthermia and muscle rigidity are usually
less severe with serotonin syndrome than with NMS; additionally, serotonin
syndrome is more commonly associated with gastrointestinal symptoms,
hyperreflexia, and myoclonus. Malignant hyperthermia is almost clinically
indistinguishable from NMS, but the history of exposure to depolarizing muscle
relaxants, most commonly succinylcholine, or inhaled anesthetic agents make the
distinction clear in most cases. Malignant catatonia (MC) may present with fever,
rigidity, akinesia, and altered mental status. It is important to distinguish from NMS
because malignant catatonia shows robust responsiveness--reports reveal a full
recovery in up to 80% of patients--with rapid initiation of benzodiazepines and
electroconvulsive therapy.[13] Distinguishing features of malignant catatonic include
increased positive symptoms as compared to NMS and a behavioral prodrome of
automatisms, agitation, or psychosis.

Multiple other medical conditions can mimic NMS, making it easy to misdiagnose.
The most common mimics are central nervous system (CNS) infections such as
meningitis or encephalitis, heatstroke, agitated delirium, toxic encephalopathies,
withdrawal syndromes, metabolic emergencies, and nonconvulsive status epilepticus.
Acute encephalitis, meningitis, or brain abscess must be excluded in patients
presenting with fever and mental status changes to avoid delay in treatment of CNS
infection. This involves lumbar puncture for cerebrospinal fluid analysis and
neuroimaging in certain cases. Patients on antipsychotic drugs are predisposed to
heat-related illnesses, which may resemble NMS. Acute intoxication with many
recreational drugs such as cocaine, MDMA, amphetamines, methamphetamines, and
phencyclidine may have similar features. Abuse of recreational drugs may occur in
the setting of medical therapy with antipsychotics making the clinical picture
ambiguous. Several withdrawal syndromes may present with features similar to NMS,
especially withdrawal from muscle relaxants; the emergence of a withdrawal from an
agent like baclofen is best managed by reinitiation therapy or with benzodiazepines.
Alcohol and benzodiazepine withdrawal also share features with NMS as do the
withdrawal syndromes of other sedatives and hypnotics. Thyrotoxicosis and
pheochromocytoma also have overlapping manifestations in common with NMS.

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Prognosis

Early mortality reports were greater than 30% for NMS; however, increased
awareness, earlier detection, and better supportive care have reduced mortality to less
than 10%. With early recognition and aggressive treatment, most patients will fully
recover in 2 to 14 days. Delayed treatment may result in significant morbidity such as
residual catatonia, parkinsonism, renal, or cardiopulmonary complications. When
fatal, deaths are usually due to cardiac arrhythmias, disseminated intravascular
coagulation, respiratory failure, or renal failure. Many patients may be successfully
restarted on neuroleptic medications, but some will develop recurrent symptoms.
Guidelines for re-initiation of neuroleptic therapy recommend waiting at least two
weeks after resolution of symptoms, using lower-potency agents, starting with low
doses and slowly titrating to effect, and avoiding lithium in conjunction with
neuroleptics. Patients should be instructed to avoid dehydration and should be
carefully monitored for any symptoms of recurrent NMS.

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Enhancing Healthcare Team Outcomes

NMS is a medical emergency that is best managed by an interprofessional team.
These patients are ideally managed in the ICU with very close nursing monitoring and
reporting to the team. A pharmacist trained in toxicology and a toxicologist should be
involved in assisting with treatment and management decisions. The key is hydration
and supportive therapy. There is no specific drug to reverse this disorder. Anecdotal
reports on dantrolene continue to appear but a few case studies indicate that the drug
may neither be effective or safe.[14]

For most patients in whom the offending drug is discontinued, the prognosis is good.
An interprofessional approach to the education of the family, monitoring, and
treatment by clinicians, nurses, and pharmacists will provide the best outcomes.
[Levell 5]

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Review Questions

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