BASICS
DESCRIPTION
- Neuroleptic malignant syndrome (NMS) is a life-threatening condition that may develop during treatment with neuroleptic medications; 2/3 of cases develops within the first 2 weeks of initiating therapy but can happen at any time during therapy.
- Nonneuroleptic medications with antidopaminergic activity have also been implicated but to a lesser degree.
- Characterized by muscular rigidity due to dopamine antagonism in the nigrostriatal pathway
- Signs and symptoms include hyperthermia from the antagonism of hypothalamic thermoregulation (more likely in the setting of benzodiazepine withdrawal); autonomic instability; cognitive changes and elevations of serum creatine phosphokinase are other hallmarks.
- May be indistinguishable from other causes of drug-induced hyperthermia (e.g., malignant hyperthermia, serotonin syndrome, lethal catatonia, anticholinergic toxins, or sympathomimetic poisoning); detailed history is essential to differentiate between these other conditions.
EPIDEMIOLOGY
Incidence
- Variably reported as 0.01 " “3%
- 2,000 new cases annually in the United States
- Predominant sex: male > female
- Predominant age: <40 years
Prevalence
0.15% ‚ ± 0.05% among patients receiving neuroleptics ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- Exact mechanism: unknown
- Most likely due to central dopaminergic blockade of nigrostriatal, hypothalamic, mesocortical/limbic pathways
- Sympathoadrenal hyperactivity and defects in neuronal calcium regulatory proteins may also contribute.
- Most commonly seen in treatment with typical antipsychotics: phenothiazines (e.g., fluphenazine), butyrophenones (e.g., haloperidol), and thiothixene
- May also be seen with atypical antipsychotics (e.g., clozapine, risperidone, olanzapine) (1)[C]
- Nonneuroleptic agents with antidopaminergic activity (e.g., metoclopramide, promethazine, and droperidol) have also been implicated.
- Rare cases have occurred with usage of medications not known to have any central antidopaminergic activity (e.g., lithium, phenelzine, and desipramine).
- Also associated with withdrawal from dopamine agonists in Parkinson disease, CNS shunt failure, and functional hemispherectomy
Genetics
- Some studies show a genetic predisposition to NMS.
- Polymorphisms: loss of DEL allele in 141C Ins/Del of the dopamine D2 receptor gene and Ser9Gly in the dopamine D3 receptor gene
RISK FACTORS
- High-potency neuroleptic medications; newly administered medication or a rapid increase in the dose of an existing agent
- Intramuscular or depot administration of medications
- Concurrent use of multiple neuroleptic agents
- Administration of neuroleptics with other drugs known to cause NMS, such as lithium
- Previous episodes of NMS
- Exposure to heat
- Dehydration/malnutrition
- Presence of an underlying structural/functional brain disorder (tumor, encephalitis, delirium/dementia)
- Postpartum women may be at an increased risk of developing NMS.
DIAGNOSIS
HISTORY
- Neuroleptic use or an increase in dose
- Discontinuation of antiparkinsonian drug
- Mental status changes common
PHYSICAL EXAM
- Extrapyramidal symptoms: dysphagia, short shuffling gait, resting tremor, and significant skeletal muscle rigidity " ”lead-pipe rigidity (these symptoms are less likely with clozapine-induced NMS) (2)[C]
- Hyperthermia (temperature may be as high as 106 ‚ ° to 107 ‚ °F [41 ‚ °C])
- Altered level of consciousness (ranging from mild drowsiness, agitation, or confusion to a severe delirium/coma)
- Autonomic instability (e.g., diaphoresis, flushing, skin pallor, tachycardia, tachypnea, labile BP, urinary incontinence)
DIFFERENTIAL DIAGNOSIS
- Infectious: meningitis, encephalitis, brain abscess, pneumonia/sepsis
- Metabolic: acute renal failure, thyrotoxicosis, pheochromocytoma
- Malignant hyperthermia, severe dystonic reaction
- Serotonin syndrome
- Anticholinergic poisoning, salicylate poisoning
- Sympathomimetic poisoning
- Acute hydrocephalus or spinal cord injury
- Tetanus
- Rabies
- Heat stroke
- Strychnine poisoning
- Cerebrovascular accident
- Acute intermittent porphyria
- Nonconvulsive status epilepticus
- Drug withdrawal: alcohol, benzodiazepines, baclofen, sedatives, and hypnotics
DIAGNOSTIC TESTS & INTERPRETATION
- CBC (evaluate for leukocytosis)
- Elevated creatine phosphokinase (CPK)
- Serum electrolyte abnormalities (hypocalcemia, hypomagnesemia, hypo/hypernatremia, hyperkalemia, metabolic acidosis)
- Consider: lactate dehydrogenase, liver function tests, urine myoglobin, urine drug screen, salicylate level, BUN and creatinine, uric acid, serum iron, and coagulation studies
Initial Tests (lab, imaging)
- Chest x-ray (if aspiration pneumonia is suspected)
- Head CT scan (before lumbar puncture and to rule out underlying brain etiology)
- MRI to detect restricted diffusion in cerebellar hemispheres, basal ganglia, and cerebellum (3)[C]
Diagnostic Procedures/Other
- Lumbar puncture (rule out other causes of fever/altered mental status)
- Urinalysis (rule out UTI)
- Blood culture (as part of sepsis workup)
- Urinary drug screen
- Electroencephalography (rule out nonconvulsive status epilepticus)
TREATMENT
- NMS is a medical emergency. Discontinue offending agent immediately.
- Treat hyperthermia aggressively with cooling baths or ice packs.
- Provide supportive care (4)[C].
- Hydration
- Maintain renal function.
GENERAL MEASURES
- Patients often require ICU admission to control volume status, correct electrolyte abnormalities, protect renal function, and ameliorate muscle rigidity.
- Recognize complications (e.g., rhabdomyolysis, respiratory failure, acute renal failure); mortality can be as high as 50%.
MEDICATION
- Dopamine agonists can be used, but their role in NMS is still uncertain:
- Bromocriptine: 2.5 mg PO every 8 to 12 hours up to max of 40 mg/day; recommended to continue for 10 days and then slowly taper
- Amantadine: 100 mg PO BID; increase, as needed, to a max of 400 mg/day.
- Skeletal muscle relaxant: dantrolene " ”1 to 2.5 mg/kg IV; may be repeated up to max of 10 mg/kg/day
- Benzodiazepines
- Diazepam: 5 mg IV q5min
- Lorazepam: 1 mg IV q5min
- Electroconvulsive therapy may be used for refractory symptoms not responding to medical treatment.
- Neither bromocriptine nor dantrolene has a rapid onset, and neither has been demonstrated to alter outcome.
- If symptoms are due to CNS insult and do not subside on alleviation of insult, consider use of intrathecal baclofen (5,6)[C].
ISSUES FOR REFERRAL
- Involve psychiatry for withdrawal or change of neuroleptic medications.
- All patients should be transferred to an acute care facility where intensive monitoring is available.
- Nephrology should be consulted in the setting of renal failure.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- All patients with the diagnosis of NMS should be admitted, often for intensive care.
- Airway intervention and circulatory support, as needed; ventilation may be difficult because of chest wall rigidity.
- IV fluids, supplemental O2, cardiac monitor, pulse oximetry
- Immediate IV benzodiazepines (e.g., diazepam, lorazepam); may require repeated large doses to control agitation
- If symptoms are not controlled within a few minutes, rapid-sequence intubation and neuromuscular blockade are necessary; nondepolarizing neuromuscular blockers (e.g., vecuronium, rocuronium, pancuronium) are preferable to succinylcholine.
- Cool the patient (ice packs, cooling blankets, ice baths) as quickly as possible; monitor core temperature closely.
- Treat symptoms, such as seizures and high blood pressure, appropriately.
- Aggressive IV fluid therapy with Lactated Ringer solution or NS and alkalinization of urine to prevent renal failure from rhabdomyolysis (high CPK levels) and monitor for appropriate urine output
- Monitor for hyperosmolar hyperglycemic state (HHS).
- Administer heparin/low-molecular-weight heparin to prevent deep venous thrombosis.
IV Fluids
Hydration with IV Lactated Ringer or NS ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Allow at least 15 days after recovery before considering a rechallenge neuroleptic; rechallenge should not be with the medication implicated in the original NMS episode; consider lower potency neuroleptic agent or 2nd-generation antipsychotic. Involve psychiatry for appropriate medication selection and titration.
- For pregnant women, untreated psychosis by discontinuing neuroleptics in the setting of NMS can lead to adverse effect such as miscarriage, stillbirth, prematurity, and small size for gestational age; consider risk and benefit before restarting neuroleptic therapy.
- Start at low dose and titrate gradually.
- Carefully monitor for signs and symptoms of recurrent NMS.
PATIENT EDUCATION
- Discuss risk-to-benefit ratio of restarting therapy versus a recurrence of NMS.
- NMS information service: www.nmsis.org
PROGNOSIS
- Mortality rate is estimated at 5 " “11.6% (25% in 1984).
- Poor prognostic indicators include temperature >104 ‚ °F, renal failure, HHS, and cardiopulmonary complications
- In the absence of complications, the prognosis for recovery is good; most patients recover in 15 days.
- Prognosis is better when NMS is detected early.
COMPLICATIONS
- Rhabdomyolysis (causing acute renal failure and, possibly, disseminated intravascular coagulation)
- Cardiac arrest (cardiac arrhythmia, myocardial infraction)
- Respiratory failure (aspiration pneumonia, pulmonary embolism, chest wall rigidity)
- Dehydration and electrolyte disturbances
- Deep venous thrombophlebitis/thrombosis (due to immobilization)
- Seizure
- Hepatic failure
- Sepsis
- Uncontrolled psychosis; persistent neuropsychiatric complications
- Death
REFERENCES
11 Belvederi Murri ‚ M, Guaglianone ‚ A, Bugliani ‚ M, et al. Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs R D. 2015;15(1):45 " “62.22 Trollor ‚ JN, Chen ‚ X, Sachdev ‚ PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477 " “492.33 Lyons ‚ JL, Cohen ‚ AB. Selective cerebellar and basal ganglia injury in neuroleptic malignant syndrome. J Neuroimaging. 2013;23(2):240 " “241.44 Seitz ‚ DP, Gill ‚ SS. 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(1):8 " “15.55 Wait ‚ SD, Ponce ‚ FA, Killory ‚ BD, et al. Neuroleptic malignant syndrome from central nervous system insult: 4 cases and a novel treatment strategy. Clinical article. J Neurosurg Pediatr. 2009;4(3):217 " “221.66 Strawn ‚ JR, Keck ‚ PEJr, Caroff ‚ SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870 " “876.
ADDITIONAL READING
- Berman ‚ BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41 " “47.
- Neuhut ‚ R, Lindenmayer ‚ JP, Silva ‚ R. Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol. 2009;19(4):415 " “422.
- Perry ‚ PJ, Wilborn ‚ CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry. 2012;24(2):155 " “162.
SEE ALSO
Algorithms: Coma; Delirium ‚
CODES
ICD10
G21.0 Malignant neuroleptic syndrome ‚
ICD9
333.92 Neuroleptic malignant syndrome ‚
SNOMED
Neuroleptic malignant syndrome (disorder) ‚
CLINICAL PEARLS
- NMS is a medical emergency that normally requires critical care for management.
- 2/3 of NMS cases occur within the first 2 weeks of starting a neuroleptic therapy.
- Elevated serum creatinine kinase is the most consistent lab abnormality in patients with NMS.
- Early clinical suspicion is essential as early treatment is necessary to reduce mortality.