Neuroleptic malignant syndrome

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Neuroleptic malignant syndrome
ICD-10 G21.0
ICD-9 333.92
DiseasesDB 8968

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]

Keywords and synonyms: NMS


The neuroleptic malignant syndrome is an uncommon adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The syndrome is characterized by severe rigidity, fever, tremor, autonomic dysfunction, altered mental status, and elevated serum creatinine phosphokinase. This is a life-threatening condition, with difficulties in diagnosis and treatment. This syndrome can further complicates psychiatric treatment.

Historical Perspective

The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a ‘‘syndrome malin des neuroleptiques.’’2 Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the incidence has decreased to around 0.01% to 0,02%.[1][2][3][4]


The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of antipsychotic drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.

Additionally, this theory is supported by the dopamine receptor imaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the CSF of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting signs and symptoms of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and medications without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with malignant hyperthermia and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and symptoms of NMS is the peripheral skeletal muscle system. The release of calcium is increased from the sarcoplasmic reticulum of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and hyperthermia. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to neuroleptics. Furthermore, it remains unknown why patients who develop NMS are usually able to continue being treated with similar medications and, at times, even the same offending agent.[5][6][7][8]


Potent typical neuroleptics such as fluphenazine, haloperidol, trifluoperazine, chlorpromazine, and prochlorperazine have been most frequently associated with NMS and thought to confer the greatest risk. Although atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most atypical neuroleptics including clozapine, risperidone, olanzapine, quetiapine, aripiprazole, olanzapine aripiprazole, and ziprasidone. Neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone. Neuroleptic malignant syndrome has also been rarely associated with a number of other medications not known to have any central antidopaminergic activity such as lithium, desipramine ,trimipramine, dosulpin,and phenelzine. [9][10][11]

Neuroleptic and Nonneuroleptic Medications Associated With Neuroleptic Malignant Syndrome
Typical Neuroleptics Atypical Neuroleptics Nonneuroleptics with antidopaminergic activity Dopaminergics (withdrawal) Others
a. Haloperidol

b. Fluphenazine

c. Chlorpromazine

d. Prochlorperazine

e. Trifluoperazine

f. Thioridazine

g. Thiothixene

h. Loxapine

i. Perphenazine

J. Bromperido

k. Clopenthixol

l. Promazine

a. Clozapine

b. Risperidone

c. Olanzapine

d. Quetiapine

e. Ziprasidone

f. Aripiprazole

(1) Metoclopromide

2) Tetrabenazine

(3) Reserpine

4) Droperidol

(5) Promethazine

(6) Amoxapine

(7) Diatrizoate

(1) Levodopa

2) Dopamine agonists

(3) Amantadine

4) Tolcapone

(1) Lithium

2) Phenelzine

(3) Dosulepin

4) Desipramine

(5) Trimipramine

Differential Diagnosis

NMS and Serotonin Syndrome

The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.[13]

Features, classically present in NMS, that are useful for differentiating the two syndromes are:[14]

  • Fever
  • Muscle rigidity
  • Laboratory values (WBC and CK)

One the basis of stiffness and fever it can be differentiated from:

Differential Diagnosis of Fever and Stiffness
Disease Diagnosis Treatment
Symptoms Signs Laboratory Findings
  • Not significant
Neuroleptic Malignant Syndrome [17][18]
Viral Meningitis[19][20][21]
Stiff man syndrome
  • Marked rigidity
  • Spasms
    • Intermittent
    • Painful
    • Absent during sleep
Drug induced (Tardive dyskinesia)[22][23][24]
  • History of intake of the offending drug for at least one month
  • Eye deviation
  • Head and neck jerky movements
  • No tonic contraction of the muscles between the spasms
Strychnine poisoning[25][26][27][28]
  • Hx of up to date tetanus immunizations
  • History of intentional or accidental intake
    • Strychnos nux vomica seeds
    • Rodenticide
  • Hypervigilance
  • Anxiety
  • Mydriasis
  • Hypereflexia
  • Clonus
  • Facial and neck stiffness
  • Blood assay
  • Tissue assay
  • Urine assay
  • Initial stabilization
  • High dose Benzodiazepines
  • Intubation and airway securing
Parkinson's disease[31][32]
  • Clinical diagnosis
  • Improvement with dopaminergic therapy confirms diagnosis

Epidemiology and Demographics

The incidence of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking antipsychotic medications. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.[33]

The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.

Risk Factors

Following are the major risk factors for the development of NMS.[34][35][36]

  • Initiation or dose escalation of neuroleptioc medication
  • Use of high dose, high potency intramuscular neuroleptics
  • Concurrent use of multiple neuroleptics
  • physical exhaustion
  • Heat stroke
  • Dehydration
  • hyponatremia
  • thyrotoxicosis
  • psychoactive substances
  • presence of a structural or functional brain disorder such as encephalitis, tumor, delirium, or dementia


There is insufficient evidence to recommend routine screening for NMS.

Natural History, Complication and Prognosis

As with most illnesses, the prognosis is best when identified early and treated aggressively. In these cases NMS is usually not fatal, although there is currently no agreement on the exact mortality rate for the disorder. Studies have given the disorder a mortality rate as low as 5% and as high as 76%, although most studies agree that the correct percentage is in the lower spectrum, perhaps between 10% - 15%. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Poor prognostic factors include:

  • Administration of dopamine antagonists
  • Administration of new atypical antipsychotics[12]


Diagnosis Criteria

DSM-V Diagnostic Criteria for Neuroleptic Malignant Syndrome[12]

  • Patients have generally been exposed to a dopamine antagonist within 72 hours prior to symptom development.
  • Hyperthermia (>100.4°F or >38.0°C on at least two occasions, measured orally), associated with profuse diaphoresis, is a distinguishing feature of neuroleptic malignant syndrome, setting it apart from other neurological side effects of anti psychotic medications.
  • Extreme elevations in temperature, reflecting a breakdown in central thermoregulation, are more likely to support the diagnosis of neuroleptic malignant syndrome.
  • Creatine kinase elevation of at least four times the upper limit of normal is commonly seen. Changes in mental status, characterized by delirium or altered consciousness ranging from stupor to coma, are often an early sign.
  • Affected individuals may appear alert but dazed and unresponsive, consistent with catatonic stupor. Autonomic activation and instability manifested by tachycardia (rate >25% above baseline), diaphoresis, blood pressure elevation (systolic or diastolic >25% above baseline) or fluctuation (>20 mmHg diastolic change or >25 mmHg systolic change within 24 hours), urinary incontinence, and pallor—may be seen at any time but provide an early clue to the diagnosis.
  • A workup, including laboratory investigation, to exclude other infectious, toxic, metabolic, and neuropsychiatric etiologies or complications is essential.
  • Although several laboratory abnormalities are associated with neuroleptic malignant syndrome, no single abnormality is specific to the diagnosis.
  • Findings from cerebrospinal fluid analysis and neuroimaging studies are generally normal, whereas electroencephalography shows generalized slowing.
  • Autopsy findings in fatal cases have been nonspecific and variable, depending on complications.


The first symptom to develop is usually muscular rigidity, followed by high fever and changes in cognitive functions. Other symptoms can vary, but may be unstable blood pressure, confusion, coma, delirium, muscle tremors, etc. Once symptoms do appear, they rapidly progress and can reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.

Laboratory Studies

A raised creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity. The patient may be hypertensive and suffering from a metabolic acidosis.

EEG Studies

A non-generalised slowing on an EEG is reported in around 50% of cases.

Unfortunately, symptoms of NMS are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.[37]


A mnemonic used to remember the features of NMS is: FEVER.[38]


Medical Therapy

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

The single most important step in the treatment of NMS is removal os causative agents. If possible, other potential contributing psychotropic agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.

Supportive care

Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.

  • Discontinue any precipitating antipsychotic medication
  • Maintain cardiorespiratory stability. Mechanical ventilation and cardio consultation may be required.
  • Maintain euvolumic state through administration of intravenous fluids,
  • If CK is elevated then urine alkalinization with high volume fluid should be done to prevent renal failure from rhabomyolysis
  • Cooling blankets should be used to lower fever, more aggressive measures such as ice water gastric lavage may be required.
  • Lower blood pressure if markedly elevated. clonidine may be used.
  • Prescribe heparin or LMWH to prevent deep venous thrombosis
  • If needed, use benzodiazepines (eg, lorazepam 0.5 to 1 mg) to control agitation


Recommendations for the treatment of NMS are based on clinical experience and case reports and randomized control trials were never done. Dantrolene, amantadine, and bromocriptine are commonly used medications. These agents are used in more severe cases and the dose is escalated if the patient gets worse. 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.


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