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Neuroleptic malignant syndrome

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Synonym: malignant neuroleptic syndrome

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What is neuroleptic malignant syndrome?

Neuroleptic malignant syndrome is a rare but potentially life-threatening idiosyncratic reaction to antipsychotic drugs1 . It causes fever, muscular rigidity, altered mental status and autonomic dysfunction. The syndrome is usually associated with potent neuroleptics such as haloperidol and fluphenazine.

The underlying pathological abnormality is thought to be central D2 receptor blockade or dopamine depletion in the hypothalamus and nigrostriatal/spinal pathways. This leads to an elevated temperature set-point, impairment of normal thermal homeostasis and extrapyramidally induced muscle rigidity. However, this does not explain why it sometimes occurs with low-potency neuroleptic drugs or other medication without known antidopaminergic activity.

It is thought that other mechanisms such as changes in skeletal muscle calcium metabolism or sympathoadrenal hyperactivity may be involved. The condition shares many features with the serotonin syndrome and malignant hyperpyrexia. It presents a diagnostic challenge.


  • Pooled data from 1966 to 1997 suggested the incidence of neuroleptic malignant syndrome (NMS) ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics.

  • As newer neuroleptic agents have become available, the incidence has dropped to around 0.01% to 0.02%.

  • Incidence is higher in those aged under 40 years and in males, probably reflecting use of antipsychotics. However, it can occur at any age in patients receiving precipitating medication3 .

  • A review of the literature between 1990-2008 found 20 cases in patients between the ages of 11-184 .

Important information

Risk factors for developing neuroleptic malignant syndrome2

Use of neuroleptic drugs and genetic/metabolic susceptibility.

Withdrawal of anti-Parkinsonian medication.

Use of high doses and of depot preparations.

Patient agitation or catatonia.

High ambient temperature and dehydration appear to increase risk of the syndrome.

A previous episode of neuroleptic malignant syndrome significantly increases the risk of a future similar reaction5 .

Less commonly, use of other agents with central D2 receptor antagonist activity may cause the syndrome:



Atypical antipsychotics such as clozapine, risperidone.

Anticholinergic drugs.


Amoxapine (tricyclic now discontinued).


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Neuroleptic malignant syndrome symptoms

  • Patients may report dyspnoea (due to hypoventilation caused by muscle rigidity), dysphagia or difficulty walking with the development of a shuffling gait.

  • There may be increasing tremor or involuntary movements.

  • Rarely, there may be oculogyric crises, opisthotonos, seizures or chorea.

Neuroleptic malignant syndrome is most common after initiation or increase in dosage of neuroleptic therapy and in 90% of cases this occurs within 10 days6 . The onset is usually gradual over 1 to 3 days and tends to occur within four weeks of starting or increasing neuroleptic medication. However, it can occur at any time in those taking neuroleptics. There is always a history of taking neuroleptics or other relevant agents within the preceding four weeks.

Symptoms can persist for up to 5 to10 days after discontinuation of the offending drug, or longer if depot medication.


  • There will be hyperthermia with temperature above 38°C.

  • Muscular rigidity (lead-pipe type) will always be present.

  • There is likely to be an alteration in mental status with confusion or agitation and altered consciousness.

  • Autonomic instability may manifest as pallor, tachycardia, fluctuating blood pressure, excessive sweating/salivation, tremor and incontinence.

Important information

Diagnostic features of neuroleptic malignant syndrome7

Neuroleptics within 1 to 4 weeks.

Hyperthermia (above 38°).

Muscle rigidity.

Five of the following:

Changed mental status.


Hypotension or hypertension.



Diaphoresis (excessive sweating) or sialorrhoea.

Increased creatine phosphokinase (CPK) or urinary myoglobin.

Metabolic acidosis.


Exclusion of other illnesses (neuropsychiatric, drug-induced, systemic).

Differential diagnosis

  • Simple dystonic/akathisia reaction to neuroleptics (usually responds rapidly to anticholinergics).

  • Serotonin syndrome.

  • Malignant hyperpyrexia.

  • Recreational drug toxicity, especially cocaine, amfetamines, 3,4-methylenedioxy-N-methylamfetamine (MDMA) - also known as 'ecstasy'.

  • Phenothiazine-related heatstroke (no rigidity and absence of sweating, the cause of pyrexia in this condition).

  • Lethal catatonia (rare psychiatric syndrome - catatonia with rigidity ± raised creatine kinase (CK), usually no autonomic involvement or involuntary movement).

  • Organophosphate poisoning.

  • Heatstroke.

  • Encephalitis (including herpes simplex encephalitis and rabies).

  • Hyperthermic reaction to monoamine-oxidase inhibitors.

  • Polymyositis.

  • Rhabdomyolysis.

  • Other forms of poisoning (for example, strychnine).

  • Other drug toxicity (anticholinergics, selective serotonin reuptake inhibitors).

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Investigations2 6

  • FBC often shows leukocytosis.

  • U&Es may show metabolic disturbance due to acidosis or acute kidney injury.

  • Hypocalcaemia is a frequent association.

  • Arterial blood sample to assess acid-base balance.

  • LFTs may show elevated transaminases and lactate dehydrogenase (LDH) of muscle origin.

  • CK is usually elevated.

  • Urine myoglobin should be checked.

  • Coagulation studies - particularly prothrombin time, activated partial thromboplastin time and international normalised ratio (INR) - should be checked (to detect coagulopathy).

  • A urinary drug screen should be performed (particularly for salicylates, cocaine and amfetamines).

  • If sepsis is suspected then blood and other relevant cultures should be taken.

  • Imaging may be indicated:

    • CXR should be considered if sepsis is suspected.

    • CT scan of the head, in order to exclude other diagnoses.

  • Lumbar puncture may be required to exclude other diagnoses (particularly where there is fever and altered mental status). There are no significant cerebrospinal fluid (CSF) findings in neuroleptic malignant syndrome other than raised protein.

Neuroleptic malignant syndrome treatment8

Neuroleptic malignant syndrome is best considered as a medical emergency and managed in an acute hospital9 .

Airway and breathing need to be protected if there is evidence of compromise. Severe cases may require circulatory and ventilatory support.

  • Agitated patients require intravenous (IV) benzodiazepines. Physical restraint is best avoided or minimised, as it can worsen the hyperthermia.

  • The offending drug should be discontinued.

  • IV fluids should be given for dehydration.

  • If there has been a recent overdose of the agent then activated charcoal may help to prevent absorption.

  • Cooling devices and antipyretics are used to treat hyperthermia.

  • If rhabdomyolysis and acute kidney injury occur then alkalinisation of urine and dialysis are often required.

  • Dopaminergic drugs, such as bromocriptine and amantadine and muscle relaxants, such as dantrolene sodium, are frequently used in severe cases but there is little empirical evidence for their efficacy. However, there are many anecdotal reports of their usefulness.

  • Electroconvulsive therapy (ECT) is sometimes used if medication fails to improve the condition and there appears to be some evidence to support its use.

Prognosis2 10

Mortality has reduced from 20-30% and is now reported as 5-11.6%. Death is usually caused by cardiovascular collapse, respiratory failure, myoglobinuric acute kidney injury, arrhythmias or diffuse intravascular coagulation. Morbidity results from respiratory failure, acute kidney injury, seizures and arrhythmia.

Respiratory changes, severity of hyperthermia, and older age have been found to be associated with a higher mortality1 .

If acute kidney injury develops during an episode of neuroleptic malignant syndrome this increases mortality up to 50%.

Once oral neuroleptics are stopped, the condition can last for 2-14 days; for depot neuroleptics, the period may be up to 21 days.

The outlook is good on the whole if there:

  • Is early recognition of the condition.

  • Is adequate supportive care and treatment.

  • Are no complications.

Complications2 11

Neuroleptic malignant syndrome prevention12

  • Awareness of the condition and consideration of the diagnosis in those with relevant symptoms, on neuroleptics, is central to early diagnosis.

  • Monitoring for features of the syndrome after changes in neuroleptic medication can assist early diagnosis.

  • Early diagnosis and withdrawal of any offending drug will arrest development of worsening symptoms.

  • It is important to give a warning of the risk of recurrence. Patients should be actively encouraged to inform healthcare providers of their susceptibility and given good written information to assist in this process. There is a very good case for use of medical emergency identification jewellery or similar.

Further reading and references

  1. Guinart D, Misawa F, Rubio JM, et al; A systematic review and pooled, patient-level analysis of predictors of mortality in neuroleptic malignant syndrome. Acta Psychiatr Scand. 2021 Oct;144(4):329-341. doi: 10.1111/acps.13359. Epub 2021 Aug 25.
  2. Berman BD; Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011 Jan;1(1):41-7. doi: 10.1177/1941875210386491.
  3. Henderson T; Neuroleptic malignant syndrome in adolescents: four probable cases in the Western Cape. S Afr Med J. 2011 May 25;101(6):405-7.
  4. Neuhut R, Lindenmayer JP, Silva R; Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol. 2009 Aug;19(4):415-22. doi: 10.1089/cap.2008.0130.
  5. Ouyang Z, Chu L; A case of recurrent neuroleptic malignant syndrome. Shanghai Arch Psychiatry. 2013 Aug;25(4):256-8. doi: 10.3969/j.issn.1002-0829.2013.04.008.
  6. Shaikh N, Al-Sulaiti G, Nasser A, et al; Neuroleptic malignant syndrome and closed head injury: A case report and review. Asian J Neurosurg. 2011 Jul;6(2):101-5. doi: 10.4103/1793-5482.92173.
  7. Neuroleptic Malignant Syndrome; National Organization for Rare Diseases, 2004
  8. Frucht SJ; Treatment of movement disorder emergencies. Neurotherapeutics. 2014 Jan;11(1):208-12. doi: 10.1007/s13311-013-0240-3.
  9. Statement on neuroleptic malignant syndrome; Royal College of Psychiatrists and Royal College of Physicians, December 2014
  10. Janati AB, Alghasab N, Osman A; Neuroleptic malignant syndrome caused by a combination of carbamazepine and amitriptyline. Case Rep Neurol Med. 2012;2012:183252. doi: 10.1155/2012/183252. Epub 2012 Jul 24.
  11. Ambulkar RP, Patil VP, Moiyadi AV; Neuroleptic malignant syndrome: A diagnostic challenge. J Anaesthesiol Clin Pharmacol. 2012 Oct;28(4):517-9. doi: 10.4103/0970-9185.101946.
  12. Zarrouf F et al; Neuroleptic malignant syndrome: Don’t let your guard down yet, 2007.

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