• Neuroleptic malignant syndrome (NMS) is rare, but life threatening and often overlooked.
• Associated with new onset, increased dose, or combination of antidopaminergic drugs such as antipsychotics or metoclopramide, or the withdrawal of Parkinson disease medications.
• Four cardinal features: altered mental status, severe “lead pipe” rigidity, fever (often above 40deg), and autonomic instability (hypertension, tachycardia).
• Associated mortality of 5.6%.

Clinical manifestations

• Classically four defining features of NMS, developing over days, often in the following order:
  • Altered mental status: Often the initial symptom, frequently underappreciated. May present as simple agitation, delirium, or may be profoundly obtunded.
  • Muscle rigidity: Severe, bilateral muscle rigidity. Rigidity is described as “lead-pipe” and is smooth throughout range of motion (versus cogwheeling). There may be other extrapyramidal symptoms including tremor, dyskinesia, dystonia.
  • Fever: Common to have a temperature above 40 degrees.
  • Autonomic instability: Primarily sympathetic symptoms including hypertension, tachycardia, tachypnea, diaphoresis (often severe).

Investigations

• Lab work should include basic CBC and chemistry, creatinine, LFTs, CK, tox screen, blood gas, and cultures ± CSF analysis, to rule out competing diagnoses.
• CK often elevated (above 1000) in the context of muscle rigidity leading to rhabdomyolysis.
• Creatinine may be elevated as a consequence of rhabdomyolysis.
• Other non-specific findings: Leukocytosis, hypo/hypernatremia, hyperkalemia, hypocalcemia, hypomagnesemia.

Diagnosis

• Diagnosis is largely based on clinical suspicion based on history of antipsychotic dose changes, clinical presentation, and examination, supported by laboratory markers (elevated CK).
• No diagnostic gold standard exists.
• One diagnostic tool has been proposed (below), though notably, the absence of meeting the diagnostic threshold does not rule out NMS as its presentation may be atypical or its features may continue to develop over time.
• Importantly, the diagnosis should be considered early to initiate treatment before all the diagnostic criteria are met.

Differential diagnosis

Stop the offending agent

• Discontinue any antipsychotics or dopamine acting anti-emetics (metoclopramide).
• If recent withdrawal of Parkinson’s disease medications, restart these medications.

Protect the airway

• May require intubation and higher level of care if significantly obtunded.

Provide supportive care

• Treat hyperthermia with antipyretics and external cooling (cooling blankets, evaporative cooling, ice packs).
• Provide fluids to treat rhabdomyolysis and prevent renal injury. Correct insensible losses of volume.
• Lower blood pressure if markedly elevated.
• Correct electrolyte abnormalities.
• Provide DVT prophylaxis given significant immobility and rigidity.

Benzodiazepines

• Benzodiazepines can control agitation and allow for muscle relaxation.
• Usual dose: lorazepam 1-2mg IV q8hrs as needed.

Specific treatments

• Controversy exists whether dantrolene and bromocriptine are effective, and randomized controlled trials are lacking.
• Their use is primarily supported by their pharmacological effect and various case reports/anecdotes suggesting that these agents cause more rapid clinical improvement and faster overall resolution. However, this is debated in the literature.
• Dantrolene 1-2.5mg/kg IV, may repeat 1mg/kg q6h x 48h (max 10mg/kg/day)
  • Works as a skeletal muscle relaxant by inhibiting calcium release in myocytes.
  • May cause hepatotoxicity and LFTs should be monitored.
• Bromocriptine 2.5mg PO/NG q8-12h, titrated to a max of 45mg/day
  • Works as a dopamine agonist, restoring lost dopaminergic tone.
  • Continue therapy for 10 days after NMS is controlled, then taper slowly.
  • Monitor for hypotension and CNS depression. May exacerbate psychosis by worsening hallucinations.

1. Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015;13(3):395–406.

   
   

2. Gurrera RJ, Mortillaro G, Velamoor V, Caroff SN. A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. J Clin Psychopharmacol. 2017 Feb;37(1):67–71.

   
   

3. Pileggi DJ, Cook AM. Neuroleptic Malignant Syndrome: Focus on Treatment and Rechallenge. Ann Pharmacother. 2016;50(11):973–81.

   
   

4. Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality. Neurocrit Care. 2016;24(1):97–103.

   
   

5. Wijdiks, EFM. Neuroleptic Malignant Syndrome [Internet]. UpToDate; 2019 [cited 2022 May 14]. Available from: www.uptodate.com