Recommendations
Key Recommendations
Suspect NMS if the patient presents within 72 hours of treatment with a dopamine antagonist (or occasionally dopamine agonist withdrawal) and has any of the following features:[35][36]
Hyperthermia (temperature >38℃ [>100.4°F] measured orally on at least two occasions)[38]
Muscle rigidity; a cardinal feature
Described as 'lead pipe' in its most severe form and usually unresponsive to antiparkinsonian agents[38]
Altered mental status[38]
Sympathetic nervous system lability (blood pressure elevation or fluctuation, sweating, or urinary incontinence)[38]
Hypermetabolism (25% increase of heart rate and 50% increase in respiratory rate above baseline)
Creatine kinase (CK) is a key investigation.
NMS is associated with a significant increase in CK (at least 4 times the upper limit of normal range, and typically >1000 units/L).[35][38][43]
If rhabdomyolysis is present (CK >5 times the upper limit of normal range), the patient is at risk of myoglobinuric acute kidney injury and requires urgent treatment with intravenous fluids.[35] See Rhabdomyolysis.
Rule out other potential causes for the patient’s symptoms (such as sepsis); NMS is a diagnosis of exclusion.[35]
Suspect NMS if the patient presents within 72 hours of treatment with a dopamine antagonist (or occasionally dopamine agonist withdrawal) and has any of the following features:[35][36]
Hyperthermia: temperature >38℃ (>100.4°), measured orally on at least two occasions; often associated with profuse diaphoresis[38]
A distinguishing feature of neuroleptic malignant syndrome, setting it apart from other neurological side effects of antipsychotic medications and other dopamine receptor blocking agents[38]
Muscle rigidity
Generalised rigidity, described as 'lead pipe' in its most severe form and usually unresponsive to antiparkinsonian agents, is a cardinal feature and may be associated with other neurological symptoms (e.g., tremor, sialorrhoea, akinesia, dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis)[38]
Altered mental status[38]
Sympathetic nervous system lability: blood pressure elevation or fluctuation, sweating, or urinary incontinence[38]
Hypermetabolism: 25% increase of heart rate and 50% increase in respiratory rate above baseline.
Bear in mind, however, that NMS is a diagnosis of exclusion. Perform a careful assessment, including physical examination and comprehensive tests, to exclude other potential toxic, metabolic, infectious, or neurological causes.[6][12][35]
Severity of NMS is generally determined by the severity of the patient’s clinical features, particularly temperature.[35]
Take a careful drug history to ascertain whether the patient has been treated with a dopamine antagonist (or stopped or rapidly reduced a dopamine agonist) within the last 72 hours.[35][36]
NMS can be caused by any antipsychotic medication but is often associated with the use of first-generation antipsychotics such as haloperidol.[35] NMS can also occur with second-generation antipsychotics such as clozapine, olanzapine, quetiapine, and risperidone.[35][36]
Almost all patients develop symptoms within 30 days, with 16% developing symptoms within 24 hours of drug initiation and 66% within 1 week.[24][38]
Some association has been reported with exposure to dopamine antagonists/modulators other than antipsychotics, including metoclopramide, lithium, tolcapone, amantadine, and certain (particularly tricyclic) antidepressants.[1][2][3][29]
This list of causative drugs is not exhaustive, and you should consult your drug formulary for a complete list of drugs where NMS or NMS-like symptoms have been reported.
Ask about a history of delirium, dementia, brain trauma, Wilson's disease, or Parkinson's disease; they are associated with an increased risk of NMS in the context of treatment with antipsychotics/dopaminergic drugs.[13][26][27] A prior episode of NMS is generally thought to significantly increase risk for subsequent episodes.
Identify key diagnostic features of NMS, including:[35]
Hyperthermia: temperature >38℃ (>100.4°F), measured orally on at least two occasions.[36][38]
May occur simultaneously with excessive sweating or flushing, indicating a disruption of normal thermoregulation, though may be delayed by up to 24 hours after onset of these symptoms.
Muscle rigidity: patients can develop new muscle rigidity, or have worsening of pre-existing muscle rigidity.
Generalised rigidity, described as 'lead pipe' in its most severe form and usually unresponsive to antiparkinsonian agents, is a cardinal feature and may be associated with tremor, akinesia, dystonia, trismus, myoclonus, dysarthria, and dysphagia. Patients may have sialorrhoea and rhabdomyolysis.[38]
Altered mental status: characterised by confusion, delirium, or stupor.[38]
Sympathetic nervous system lability: blood pressure elevation or fluctuation, sweating, or urinary incontinence.[38]
Hypermetabolism: 25% increase of heart rate and 50% increase in respiratory rate above baseline.
Practical tip
Sweating associated with NMS is often described by the patient as being greasy in nature.
Investigations are essential to exclude other diagnoses, and to detect complications of NMS.
Laboratory tests
Always request:
Serum creatine kinase (CK) levels
NMS is associated with a significant increase in serum CK (at least 4 times the upper limit of normal range, and typically >1000 units/L) which indicates muscle damage.[35][38][43]
If rhabdomyolysis is present (CK >5 times the upper limit of normal range), the patient is at risk of myoglobinuric acute kidney injury, particularly if the CK activity is greater than 5000 units/L.[35] See Rhabdomyolysis.
Rhabdomyolysis requires urgent treatment with intravenous fluids.[35] See Management recommendations.
If the initial CK is normal but you have clinical concern about muscle damage, consider a repeat measurement.[35]
Monitor CK daily until the patient’s CK levels and symptoms have resolved.
Blood gas
To check for respiratory failure and metabolic acidosis.[46]
Capillary blood glucose
May be high due to stress response. NMS may also precipitate hyperosmolar hyperglycaemia state.[47]
Hypoglycaemia with liver dysfunction is a late sign of multi-organ failure.
Urea, electrolytes, and creatinine
To evaluate the presence of complications (e.g., acute kidney injury), determine hydration status, and identify any electrolyte disturbances such as hyperkalaemia, hyponatraemia, or hypernatraemia.[35]
Full blood count
Leukocytosis may be present due to NMS-specific immune activation (although bear in mind this is non-specific).[36]
Leukocytosis can also indicate a differential diagnosis (e.g., an infection that might progress or has progressed to sepsis).
Liver function tests
To exclude liver failure.[46]
Clotting screen
To exclude liver failure and disseminated intravascular coagulation.[46]
Myoglobin levels and urinalysis
To detect presence of myoglobinuria; this is a poor prognostic sign. Haemolysed blood on urine dip-stick testing suggests myoglobinuria.[35]
Consider the following:
Urine and blood cultures
Order if you suspect an infection.
Toxicology screen
Order if you suspect drug misuse/overdose/withdrawal of a drug that isn’t an antipsychotic (including prescription and illicit drugs).
Serum iron
In practice, this is not ordered routinely.
Acute, transient low levels have been described.[32] In some cases, transient low serum iron appears to signal imminent worsening of the patient’s condition.
Electrocardiogram (ECG)
Perform a 12-lead ECG for any patient with suspected NMS.[35]
Check the patient’s cardiac rhythm, QT interval, and QRS duration.[35]
Be aware that further ECGs may be required depending on the clinical situation, even if the initial ECG is normal.
In particular, consider repeating the ECG if:[35]
The initial ECG is abnormal
The patient has ongoing symptoms of NMS.
ECG changes can occur at any time in patients with NMS, owing to the dynamic nature of the condition; abnormalities may result from direct cardiac effects and/or metabolic changes.
Imaging
CT brain scan
Order if you suspect brain infection, mass, or bleed as differential diagnoses.[6]
Chest x-ray
Order if you suspect pneumonia.
Other tests
Lumbar puncture
Organise if you suspect meningitis/encephalitis in patients with high fever, altered mental status, and rigidity.
Electroencephalogram (EEG)
Rarely used in practice but may be considered if hyperthermia and tachycardia are not responding to treatment or if the diagnosis is unclear. Bear in mind that non-convulsive status epilepticus can have similar clinical features to NMS; this can be a differential diagnosis or a complication of NMS. See Status epilepticus.
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