Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS) is a life-threatening idiosyncratic reaction to dopamine antagonists (most commonly, but not always, antipsychotics) characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction.^[1] It is hypothesized to be due to excessive dopamine receptor blockade. Certain individuals may be at a higher risk for NMS.

• The incidence rates for NMS are around 0.01%-0.02% among individuals treated with antipsychotics.^[2]

• Most cases of NMS develop within 24 hours after drug initiation and/or within the first week, and virtually all cases develop within 30 days.
  • When recognized and treated early, most patients recover completely.
• The fatality rates of NMS can be up to 10%-20% when it is not recognized.
  • The mean recovery time after drug discontinuation is 7-10 days, with most individuals recovering within 1 week and nearly all within 30 days.^[3]
• The duration may be prolonged when long-acting antipsychotics are implicated. Residual neurological signs may persist for weeks after the acute hyper-metabolic symptoms resolve.
• Individuals generally do not experience a recurrence of NMS when re-challenged with an antipsychotic, but there is a negligible risk, especially when antipsychotics are restarted soon after the episode of NMS.

• Any individual starting a dopamine antagonist has the potential risk for developing NMS.
  • NMS is not specific to any neuropsychiatric disorder and can occur in individuals without a mental disorder who is on a dopamine antagonist.
• Agitation, exhaustion, dehydration, iron deficiency are increased risk factors for NMS.
  • Patients on stable doses may develop NMS during acute illness.^[4]
• High-potency first-generation antipsychotic agents (i.e., haloperidol, fluphenazine), high doses, rapid dose escalation, and parenteral formulations of antipsychotics increase the risk for NMS.^[5]
• Offending drug factors such as parenteral administration, rapid titration, and higher total drug doses are also associated with increased risk, but most cases of NMS occur within the therapeutic antipsychotics dose range.

• Any individual starting an antipsychotic has the potential risk for developing NMS.
• Almost all dopamine antagonists can cause NMS, and higher potency antipsychotics pose a greater risk compared with low-potency agents and atypical antipsychotics.

• Non-psychotropic dopamine antagonists, such as metoclopramide and prochlorperazine are also implicated in NMS.

• NMS can also be seen in patients with Parkinson's disease, when there is withdrawal of L-Dopa or dopamine agonist therapy, dose reductions, or a switch from one dopamine agonist to another.^[6]

• The full pathophysiological process behind NMS is not well understood. NMS can occur from both use of dopamine antagonists or from withdrawal/dose reductions of antiparkinson medications such as L-Dopa or dopamine agonist therapy.
• The dopamine D2 receptor antagonism model of NMS theorizes that excessive central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to hyperthermia, muscle rigidity, autonomic instability, and tremors.
• NMS has similar symptoms as malignant hyperthermia, but are distinctly different conditions with different etiologies.^[7][8] On the contrary, malignant catatonia is thought to be a related to NMS, with NMS essentially being an iatrogenic form of malignant catatonia.

Neuroleptic malignant syndrome (NMS) must be diagnosed promptly to avoid serious injury or death, but there is no consensus on diagnostic criteria for this disorder. The 2011 International Consensus Study of Neuroleptic Malignant Syndrome Diagnostic Criteria proposed the following consensus criteria:^[9]

• A work up to exclude other infectious, toxic, metabolic, and neuropsychiatric etiologies is essential.
  • This may include neuroimaging, lumbar puncture, metabolic testing and drug immunoassays to exclude alternate causes (i.e., a delirium work up)
• Individuals with NMS can have leukocytosis, metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations in serum muscle enzymes and catecholamines. Cerebrospinal fluid analysis and neuroimaging studies are generally unremarkable, whereas electroencephalography shows generalized slowing.
• Standard bloodwork can include serum iron, CK, electrolytes, WBC, temperature, liver transaminases (AST, ALT, LDH).

NMS should be a diagnosis of exclusion and must be differentiated from other serious neurological or medical conditions, including central nervous system infections, inflammatory or autoimmune conditions, status epilepticus, subcortical structural lesions, and systemic conditions (e.g. - pheochromocytoma, thyrotoxicosis, tetanus, heat stroke).

• Anticholinergic and Cholingeric Toxicity
• Serotonin syndrome
• Parkinsonian hyperthermia syndrome
  • Usually following abrupt discontinuation of dopamine agonists
• Alcohol or sedative withdrawal
• Malignant hyperthermia occurring during anesthesia
• Hyperthermia associated with abuse of stimulants and hallucinogens
• Atropine poisoning
• Malignant catatonia
  • Can be indistinguishable from NMS. NMS is considered to be a drug-induced (iatrogenic) form of malignant catatonia.

• Early recognition of NMS is key to good outcomes.
• All dopamine antagonists should be immediately stopped once NMS is suspected.
• Supportive care includes fluid replacement, supporting cardiac, lung, and renal function, and temperature reduction. Cooling blankets and ice packs should also be used for hyperthermia.
• Patients may require an intensive care setting to provide volume resuscitation, treat hyperthermia and manage end-organ dysfunction.^[10]
• Trending and monitoring WBC, CK, temperature, serum iron, and liver transaminases (AST, ALT, LDH) can help monitor the patient's recovery.

• Benzodiazepines (i.e. - IM or IV lorazepam 1–2 mg every 4–6 h) are first-line treatments for muscle rigidity and sympathetic overactivity, including agitation and hyperthermia.^[11]
• Other agents that may be used in the treatment of NMS include:
  • Bromocriptine, a pro-dopaminergic and pro-seroternergic agent
  • Amantadine^[12]
  • Dantrolene
  • L-dopa^[13]
  • The efficacy of dantrolene and dopamine agonists is not well established but may be used in cases of worsening symptoms despite initial management.

• Electroconvulsive therapy may be considered in cases where there is no initial improvement or in severe cases.^[14]

• If use of antipsychotic medications is still required for psychiatric reasons after an episode of NMS, measures should be taken to decrease the risk of recurrence, which is estimated to be between 10%–30%.^[15]
• Prescribers should wait at least 2 weeks for full symptom resolution (or 4 weeks for depot injections), before reintroducing an antipsychotic.
• Use of low-potency antipsychotic agents, low doses, and slow titration is recommended.^[16]

• Tan, C. M., & Kumachev, A. (2023). Neuroleptic malignant syndrome. CMAJ, 195(43), E1481-E1481.
• Berman, B. D. (2011). Neuroleptic malignant syndrome: a review for neurohospitalists. The Neurohospitalist, 1(1), 41-47.