Author:
Lindsey M.Retterath
Sarah A.Watkins
Nicholas B.Hurst
Description
- Uncommon, but life-threatening disorder associated with antipsychotic (dopamine antagonist) medications, or with dopamine agonist withdrawal
- Mortality can be as high as 20%
- May develop any time during therapy - from days to years
- Most often occurs in the first month of therapy, or after a dosage increase, or with parenteral (IV/IM) depot administration
- Muscular rigidity and tremor result from dopamine blockade in the nigrostriatal pathway
- Fever, delirium, and /or dysautonomia, due to dopamine receptor blockade in the hypothalamus
- May be indistinguishable from other causes of drug-induced hyperthermia (malignant hyperthermia, serotonin syndrome, anticholinergic or sympathomimetic toxicity)
- May have a waxing and waning course
- Most episodes resolve 3-14 d after stopping the offending agent
- Diagnostic criteria:
- Fever + severe muscle rigidity in association with use of antipsychotic/neuroleptic medication
- 2 or more of the following:
- Diaphoresis
- Dysphagia
- Tremor
- Incontinence
- Altered mental status
- Mutism
- Tachycardia
- Nystagmus
- Elevated labile BP
- Leukocytosis
- Lab evidence of muscle injury
- Symptoms not caused by another disease process
Etiology
- Rare complication of treatment with neuroleptics:
- Phenothiazines:
- Butyrophenones:
- Atypical antipsychotics:
- Occurs in ∼1 in 1,000 patients treated with neuroleptics
- Has also been associated with abrupt withdrawal from dopamine agonists in Parkinson disease
- SSRIs, TCAs, carbamazepine, metoclopramide, and lithium may also precipitate NMS; however, it is difficult to distinguish from serotonin syndrome
- Risk factors:
- Rapid drug loading
- High-dose antipsychotics
- High-potency antipsychotics
- IV/IM administration of drug
- Depot preparations
- Dehydration
- Prior neuroleptic malignant syndrome (NMS)
- Preceding extreme psychomotor agitation
- Infection or surgery
- Physical restraints
- History of catatonia
- Low iron level
- Fever
Signs and Symptoms
- Life-threatening condition
- Hallmarks of the disease:
- Fever (may be as high as 106-107°F, 41°C)
- Altered consciousness - may range from confusion to coma
- Severe muscle rigidity - “lead-pipe rigidity”
- Autonomic instability:
- Tachycardia
- Labile BP
- Tachypnea
- Profuse sweating
- Dysrhythmias
History
- Neuroleptic/antipsychotic use
- Discontinuation of antiparkinsonian drugs
- Change in mental status
Physical Exam
- Fever
- Tachycardia, labile BP
- Delirium
- Muscle rigidity
- Diaphoresis
Essential Workup
- Accurate history (esp current medications) and physical exam confirm the diagnosis
- Creatine kinase (CK), WBC count, liver function tests, and iron level
Diagnostic Tests & Interpretation
Lab
- CBC with differential
- Electrolytes (including Ca, Mg)
- Serial CK
- AST/ALT, lactate dehydrogenase, alkaline phosphatase
- Other studies aimed at ruling out other causes
Imaging
CT scan (or MRI), EEG if the cause of altered level of consciousness is unclear
Diagnostic Procedures/Surgery
Lumbar puncture to rule out other causes of fever or altered mental status
Differential Diagnosis
Related disorders:
- Malignant hyperthermia
- Serotonin syndrome (clonus, but no rigidity)
- Anticholinergic toxidrome (no rigidity)
- Sympathomimetic toxidrome
- Lithium toxic encephalopathy (fever is absent)
- Lethal catatonia (no Hx of neuroleptics)
- Heat shock (no diaphoresis, no rigidity)
- Withdrawal from intrathecal baclofen
Unrelated disorders:
- 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)
Prehospital
- 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
- 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:
- Measures to control hyperthermia:
- Ice packs
- Mist and fan
- Cooling blankets
- Ice water gastric lavage
- Paralysis to prevent shivering thermogenesis
- Aggressive IV fluid therapy with crystalloid solution
ED Treatment/Procedures
- Discontinue offending medications
- Keep room cool (no higher than 21-23°C)
- Avoid physical restraints when possible
- Correct electrolyte/pH derangements
- There is no clear consensus on first-line pharmacologic treatment
- For relief of muscle rigidity, benzodiazepines may be indicated; however, paralytics may be necessary
- Bromocriptine is a dopamine agonist that may play a role in longer-term management
- Dantrolene is a direct skeletal muscle relaxant with conflicting evidence for use in NMS, and it may cause severe hepatotoxicity
- 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
- Recognize complications (e.g., 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: 600-1,200 mcg/kg IV × 1 for RSI
- Pancuronium: 60-100 mcg/kg IV × 1 for RSI
Second Line
- Bromocriptine: 5-10 mg PO t.i.d-q.i.d (start 2.5 mg, increase 2.5-7.5 per d to a max of 45 mg daily)
- Dantrolene: 1-10 mg/kg IV q4-6h × 24-48 hr up to cumulative dose 10 mg/kg/24 hr
- Amantadine: 100 mg PO b.i.d
Disposition
Admission Criteria
Patients with NMS should be admitted to an intensive care setting
Follow-up Recommendations
Patients and families must be counseled on the future use of any drug that may trigger NMS
ICD9
333.92 Neuroleptic malignant syndrome
ICD10
G21.0 Malignant neuroleptic syndrome
SNOMED