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. It is hypothesized to be due to excessive dopamine receptor blockade. Certain individuals may be at a higher risk for NMS.

Epidemiology

The incidence rates for NMS are around 0.01%-0.02% among individuals treated with antipsychotics.[1] 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.

Prognosis

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. 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.

Risk Factors

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, and iron deficiency are increased risk factors for NMS. Parenteral administration, rapid titration, and higher total drug doses are also associated with increased risk, but most cases of NMS 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 high-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 has similar symptoms as malignant hyperthermia, but are distinctly different conditions with different etiologies.[2][3] 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:[4]

  1. Recent dopamine agonist withdrawal or dopamine antagonist exposure (within the last 72 hours)
  2. Hyperthermia (> 38°C on at least 2 measurements, measured orally)
  3. Rigidity (“lead pipe”)
  4. Mental status alteration (reduced or fluctuating level of conciousness)
  5. Creatine kinase (CK) elevation (at least 4x the upper limit of normal)
  6. Sympathetic nervous system lability, defined by at least 2 of the following:
    • Blood pressure elevation (SBP or DBP ≥ 25% above baseline)
    • Blood pressure fluctuation (≥ 20 mmHg systolic change within 24 hours)
    • Diaphoresis
    • Urinary incontinence
  7. Hypermetabolism, defined as heart rate increase (≥ 25% above baseline) AND respiratory rate increase (≥ 50% above baseline)
  8. Negative work-up for infectious, toxic, metabolic, or neurologic causes

Neurological Symptoms

Other neurological symptoms that can present with NMS include tremors, trismus, dysarthria, dysphagia, akinesia, sialorrhea, and myclonus. Going through a comprehensive neurological exam can help pick out these signs and symptoms.

A work up to exclude other infectious, toxic, metabolic, and neuropsychiatric etiologies is essential. 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).

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. Trending and monitoring WBC, CK, temperature, serum iron, and liver transaminases (AST, ALT, LDH) can help monitor the patient's recovery.

  • Bromocriptine, a pro-dopaminergic and pro-seroternergic agent
  • Amantadine
  • Dantrolene