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


Neuroleptic malignant syndrome (NMS) is a life-threatening, neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs.

Historical Perspective

NLM was known about as early as 1956, shortly after the introduction of the first phenothiazines, and is derived from the French syndrome malin des neuroleptiques.[1]


The mechanism of NMS is thought to depend on decreased levels of dopamine due to:


NMS is caused almost exclusively by antipsychotics, including all types of neuroleptic medicines along with newer antipsychotic drugs.[3] The higher the dosage, the more common the occurrence. Rapid and large increases in dosage can also trigger the development of NMS. Other drugs, environmental or psychological factors, hereditary conditions, and specific demographics may cause greater risk, but to date no conclusive evidence has been found to support this. The disorder typically develops within two weeks of the initial treatment with the drug, but may develop at any time the drug is being taken. NMS may also occur in people taking a class of drugs known as dopaminergics when the dosage is reduced (i.e Levodopa).

Drug Causes

Differential Diagnosis

NMS and Serotonin Syndrome

The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.[5]

Features, classically present in NMS, that are useful for differentiating the two syndromes are:[6]

  • 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 [9][10]
Viral Meningitis[11][12][13]
Stiff man syndrome
  • Marked rigidity
  • Spasms
    • Intermittent
    • Painful
    • Absent during sleep
Drug induced (Tardive dyskinesia)[14][15][16]
  • 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[17][18][19][20]
  • 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[23][24]
  • Clinical diagnosis
  • Improvement with dopaminergic therapy confirms diagnosis

Risk Factors

  • Antipsychotic drug administration
  • Agitation
  • Dehydration
  • Iron deficiency
  • ExhaustionDiagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.

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[4]


Diagnosis Criteria

DSM-V Diagnostic Criteria for Neuroleptic Malignant Syndrome[4]

  • 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.[25]


A mnemonic used to remember the features of NMS is: FEVER.[26]


Although treatment is not always necessary, it will help to cure the disease and prevent fatal developments from occurring. The first step in treatment is generally to remove the patient from any neuroleptic or antipsychotic drugs being taken and to treat fever aggressively. Many cases require intensive care, or some kind of supportive care at the minimum. Depending on the severity of the case, patients may require other treatments to contend with specific effects of the disorder. These include circulatory and ventilatory support, the drugs dantrolene sodium, bromocriptine, apomorphine and electroconvulsive therapy (ECT) if medication fails.


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