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Neuroleptic Malignant Syndrome, Emergency Medicine

Basics

Description

- Muscular rigidity and tremor resulting from dopamine blockade in the nigrostriatal pathway - Hyperthermia due to central dopamine receptor blockage in the hypothalamus. - More likely in the setting of benzodiazepine withdrawal - May be indistinguishable from other causes of drug-induced hyperthermia (malignant hyperthermia, serotonin syndrome, anticholinergic toxins, or sympathomimetic poisoning) - Most episodes resolve within 2 wk after cessation of offending agent. - Diagnostic criteria: - Development of elevated temperature and severe muscle rigidity in association with use of antipsychotic/neuroleptic medication - 2 or more of the following: - Diaphoresis - Dysphagia - Tremor - Incontinence - Altered mental status (range from confusion to coma) - Mutism - Tachycardia - Elevated labile BP - Leukocytosis - Lab evidence of muscle injury

- Occurs in ó ł ╝1% of patients treated with neuroleptics (especially haloperidol) - Has also been associated with abrupt withdrawal from dopamine agonists in Parkinson disease - SSRIs or lithium along with neuroleptic medication may be associated with an increased risk - Risk factors: - Rapid drug loading - High-dose antipsychotics - High-potency antipsychotics - IV administration of drug - Dehydration - Prior neuroleptic malignant syndrome (NMS) - Preceding extreme psychomotor agitation or catatonia - Infection or surgery

- Life-threatening condition - Hallmarks of the disease: - Hyperthermia (temperature may be as high as 106 " ô107 é ░F, 41 é ░C) - Altered level of consciousness " östupor - Significant skeletal muscle rigidity " ö " Łlead-pipe rigidity. " Ł - Autonomic instability - Tachycardia - Labile BP - Tachypnea - Profuse sweating - Dysrhythmias

- Measures to control hyperthermia: - Ice packs - Mist and fan - Cooling blankets - Ice water gastric lavage

  • Life-threatening neurologic disorder most often caused by an adverse reaction to a neuroleptic or antipsychotic medication.
  • Mortality can be as high as 20%
  • May develop any time during therapy with neuroleptics " öfrom a few days to many years:Most often occurs in the 1st mo of therapy
  • Muscular rigidity and tremor resulting from dopamine blockade in the nigrostriatal pathway
  • Hyperthermia due to central dopamine receptor blockage in the hypothalamus.
  • More likely in the setting of benzodiazepine withdrawal
  • May be indistinguishable from other causes of drug-induced hyperthermia (malignant hyperthermia, serotonin syndrome, anticholinergic toxins, or sympathomimetic poisoning)
  • Most episodes resolve within 2 wk after cessation of offending agent.
  • Diagnostic criteria:Development of elevated temperature and severe muscle rigidity in association with use of antipsychotic/neuroleptic medication2 or more of the following:DiaphoresisDysphagiaTremorIncontinenceAltered mental status (range from confusion to coma)MutismTachycardiaElevated labile BPLeukocytosisLab evidence of muscle injurySymptoms are not caused by another disease process

Etiology

  • Rare complication of treatment with neuroleptics:PhenothiazinesChlorpromazine (Thorazine)Fluphenazine (Modecate)Prochlorperazine (Compazine)Promethazine (Phenergan)Metoclopramide (Reglan)ButyrophenonesAtypical antipsychoticsRisperidone (Risperdal)Olanzapine (Zyprexa)Quetiapine (Seroquel)Clozapine (Clozaril)Aripiprazole (Abilify)
  • Occurs in ó ł ╝1% of patients treated with neuroleptics (especially haloperidol)
  • Has also been associated with abrupt withdrawal from dopamine agonists in Parkinson disease
  • SSRIs or lithium along with neuroleptic medication may be associated with an increased risk
  • Risk factors:Rapid drug loadingHigh-dose antipsychoticsHigh-potency antipsychoticsIV administration of drugDehydrationPrior neuroleptic malignant syndrome (NMS)Preceding extreme psychomotor agitation or catatoniaInfection or surgery

Diagnosis

Signs and Symptoms

  • Life-threatening condition
  • Hallmarks of the disease:Hyperthermia (temperature may be as high as 106 " ô107 é ░F, 41 é ░C)Altered level of consciousness " östuporSignificant skeletal muscle rigidity " ö " Łlead-pipe rigidity. " ŁAutonomic instabilityTachycardiaLabile BPTachypneaProfuse sweatingDysrhythmias

History

  • Neuroleptic use
  • Discontinuation of antiparkinsonian drugs
  • Change in mental status

Physical Exam

  • Fever
  • Tachycardia, labile BP
  • Delirium
  • Muscle rigidity
  • Diaphoresis

Essential Workup

  • An accurate history (especially current medications) and physical exam confirm the diagnosis.
  • Creatine phosphokinase, WBC determination, liver function tests, and iron level

Diagnosis Tests & Interpretation

Lab

  • Electrolytes, glucose
  • BUN, creatinine
  • PT/PTT, urinalysis, and urine myoglobin
  • Creatine kinase
  • LFTs (lactate dehydrogenase, aspartate transaminase, alkaline phosphatase, etc.)
  • Venous blood gas (VBG)

Imaging

CT scan, EEG if the cause of altered level of consciousness is unclear é á

Diagnostic Procedures/Surgery

Lumbar puncture to rule out other causes of fever or altered mental status é á

Differential Diagnosis

Related disorders é á

  • Malignant hyperthermia
  • Serotonin syndrome
  • Anticholinergic poisoning
  • Sympathomimetic poisoning (cocaine, methamphetamine)
  • Drug intoxication toxicity (PCP, ecstasy MDMA)
  • Withdrawal from intrathecal baclofen therapy

Unrelated disorders é á

  • CNS infection (meningitis, encephalitis)
  • Tetanus
  • Heat stroke
  • Acute dystonia
  • Strychnine poisoning
  • Vascular CNS event
  • Thyrotoxicosis
  • Rabies
  • Alcohol withdrawal
  • Seizures
  • Pheochromocytoma
  • Acute porphyria
  • Acute hydrocephalus
  • Acute spinal cord injury
  • Systemic infections (e.g., pneumonia, sepsis)

Treatment

Pre-Hospital

  • Ventilation may be difficult because of chest wall rigidity
  • Cool the patient and treat seizures if they occur
  • Check fingerstick glucose

Initial Stabilization/Therapy

  • Airway intervention and circulatory support as needed
  • IV, supplemental O2, cardiac monitor
  • Immediate IV benzodiazepines (diazepam, lorazepam, midazolam):May require repeated large doses
  • If symptoms are not controlled within a few minutes, rapid sequence intubation (RSI) and neuromuscular blockade are necessary:Nondepolarizing neuromuscular blockers (vecuronium, rocuronium, pancuronium) are preferable to succinylcholine.
  • Measures to control hyperthermia:Ice packsMist and fanCooling blanketsIce water gastric lavage
  • Aggressive IV fluid therapy with lactated Ringer solution or normal saline

Ed Treatment/Procedures

  • Relief of muscle rigidity
  • Benzodiazepines are the drug of choice
  • Bromocriptine is a dopamine agonist that may play a role in longer-term management
  • Dantrolene is a direct skeletal muscle relaxant that may play a role in longer-term management
  • Neither bromocriptine nor dantrolene has a rapid onset and neither has been shown to alter outcome
  • Amantadine has dopaminergic and anticholinergic effects and can be used as an alternative to bromocriptine
  • Discontinue neuroleptics
  • Recognize complications (rhabdomyolysis, respiratory failure, acute renal failure)

Medication

First Line

  • Diazepam: 5 mg IV q5min
  • Lorazepam: 1 mg IV q5min
  • Midazolam 1 mg IV q5min
  • Rocuronium: 600 " ô1,200 Ä ╝g/kg IV â Ś 1 for RSI
  • Pancuronium: 60 " ô100 Ä ╝g/kg IV â Ś 1 for intubation

Second Line

  • Bromocriptine: 5 " ô10 mg PO TID " ôQID (start 2.5 mg)
  • Dantrolene: 1 mg/kg IV q4 " ô6h â Ś 24 " ô48 hr
  • Amantadine: 100 mg PO BID

Follow-Up

Disposition

Admission Criteria

  • Patients with NMS should be admitted
  • Patients will often require intensive care

Followup Recommendations

Patients and families must be counseled on the future use of any drug that may trigger NMS é á

Pearls and Pitfalls

  • Maintain high clinical suspicion for NMS in patients on neuroleptics with mental status changes, rigidity, fever, or dysautonomia
  • Must rule out other causes of fever and altered mental status (i.e., meningitis, encephalitis)
  • Medication history is essential when considering NMS
  • Discontinuing causative agent is the key step in treatment
  • Aggressive supportive care is essential

Additional Reading

  • Bellamy é áCJ, Kane-Gill é áSL, Falcione é áBA, et al. Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol. J Trauma. 2009;66:954 " ô958.
  • Marx é áJA, Hockberger é áRS, Walls é áRM, et al. Rosens Emergency Medicine: Concepts and Clinical Practice. 7th ed. St. Louis, MO: Mosby; 2009.
  • Seitz é áDP, Gill é áSS. Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: Case reports and a review of the literature. Psychosomatics. 2009;50:8 " ô15.
  • Stevens é áDL. Association between selective serotonin-reuptake inhibitors, second-generation antipsychotics, and neuroleptic malignant syndrome. Ann Pharmacother. 2008;42:1290 " ô1297.
  • Wijdicks é áEFM. Neuroleptic malignant syndrome. In: Aminoff é áMJ, ed. UpToDate. Waltham, MA: 2012.

Codes

ICD9

333.92 Neuroleptic malignant syndrome é á

ICD10

G21.0 Malignant neuroleptic syndrome é á

SNOMED

  • 15244003 Neuroleptic malignant syndrome (disorder)