Basics
Description
- 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 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
- Symptoms are not caused by another disease process
Etiology
- Rare complication of treatment with neuroleptics:
- Phenothiazines
- Chlorpromazine (Thorazine)
- Fluphenazine (Modecate)
- Prochlorperazine (Compazine)
- Promethazine (Phenergan)
- Metoclopramide (Reglan)
- Butyrophenones
- Atypical antipsychotics
- Risperidone (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 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
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 " östupor
- Significant skeletal muscle rigidity " ö " Łlead-pipe rigidity. " Ł
- Autonomic instability
- Tachycardia
- Labile BP
- Tachypnea
- Profuse sweating
- Dysrhythmias
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 packs
- Mist and fan
- Cooling blankets
- Ice 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)