quick reference
4 features (in order)
- AMS
- EPS
- Hyperthermia
- Autonomic Instability
four features
1/4: mental status changes in ~70%
- These may be variable. Agitation may occur initially, with later evolution into mutism, catatonia, and coma.
- These symptoms may be obscured in patients who are intubated and sedated, or in patients with poorly controlled schizophrenia (in whom these symptoms may blend into the symptoms of schizophrenia).
2/4: extrapyramidal symptoms, which may include:
- Tremor (similar to Parkinson’s disease), chorea.
- Oculogyric crises (gaze may be fixated upwards).
- Dystonia (which may be refractory to anticholinergic therapies).
- Dysphagia or dysarthria may occur.
- Rigidity is the most common and hallmark extrapyramidal symptom:
- The most severe manifestation is lead-pipe rigidity (stable resistance throughout the range of motion; see video below). However, patients may also have a superimposed tremor on top of the lead pipe rigidity, which creates a pattern of cogwheel rigidity.
3/4: hyperthermia
- Not all patients have hyperthermia:
- ~87% of patients have temperatures >38C.
- ~40% of patients have temperatures >40C (so frank hyperthermia is often absent).
- Delayed onset of hyperthermia may promote diagnostic confusion.
- Similar to other forms of hyperthermia, this is usually not associated with chills, nor responsive to antipyretic therapy.
4/4: autonomic instability with sympathetic activation
- These features seem to be the least frequent:
- Sinus tachycardia and other arrhythmias (~62%).
- Labile hypertension (~42%).
- Diaphoresis (~44%).
- Urinary incontinence.
pathophysiology
NMS is often related to neuroleptic agents (i.e., antipsychotic medications)
- mental status changes
- hyperthermia
- rigidity
- autonomic dysfunction
Result from a deficiency of signaling via D2 dopamine receptors in the brain:
- Dopamine deficiency within striatal dopamine pathways in the basal ganglia may cause Parkinsonian-type symptoms (e.g., lead-pipe rigidity).
- Dopamine deficiency in the hypothalamus may cause autonomic dysfunction.
- Dopamine alterations within the reticular activating system may cause alterations in consciousness (e.g., mutism, coma)
A combination of excess motor tone plus dysautonomia may precipitate other features of neuroleptic malignant syndrome, including rhabdomyolysis and hyperthermia.
Treatment involves both augmentation of D2 signaling in the brain, as well as providing muscle relaxants to reduce peripheral muscle tone.
epidemiology / etiology
causative agents
- Antipsychotics are the most common cause:
- NMS can occur with typical or atypical agents (especially clozapine).
- NMS usually presents within a month of initiating treatment (most often within two weeks), but it can emerge during chronic therapy (often triggered by another illness).
- Antiemetics that block the dopamine receptor:
- Prochlorperazine.
- Promethazine.
- Metoclopramide.
- Withdrawal of dopaminergic Parkinson’s medications.
risk factors
- Personal or family history of NMS.
- Aspects of antipsychotic therapy:
- Rapid up-titration of neuroleptic.
- Higher doses of antipsychotic.
- First-generation (“typical”) antipsychotics have greater risk than atypical antipsychotics. Clozapine and quetiapine have the lowest risk.(Shutter, 2019)
- Multiple antipsychotic agents, coadministration with lithium.
- Underlying dopamine deficiency:
epidemiology
- The risk of NMS is on the order of ~0.01-0.04% among people exposed to antipsychotics.
- There doesn’t appear to be any dramatic age or sex predominance.
- Historical trends towards higher rates among young men may simply represent patients treated with higher doses of neuroleptics.
- There are a few case reports of NMS arising within the ICU, as a nosocomial complication of antipsychotic administration. Diagnosis of nosocomial NMS is challenging (e.g., the development of fever and altered mental status may initially be attributed to sepsis).
Symptoms usually develop gradually over 1-3 days, but timing is extremely variable. NMS likewise takes a while to improve, with resolution usually occurring over two weeks.