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DESCRIPTION
Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are similar syndromes that involve muscle rigidity, extrapyramidal signs, autonomic instability, and altered mental status. Several diagnostic strategies have been published. For NMS, four major criteria plus three minor criteria must be present for diagnosis.
Major Criteria for NMS
- Patient has recently used neuroleptic or other dopamine antagonist or discontinued use of a dopamine agonist (e.g., levodopa).
- Muscular rigidity.
- Hyperthermia above 38°C occurs without another cause.
- Altered mental status (e.g., confusion, delirium, mutism, stupor, coma).
- Creatine kinase is more than three times normal without other obvious causes.
Minor Criteria for NMS
- Other signs of extrapyramidal syndrome (tremor, cogwheeling, acute dystonic reaction, choreiform movement).
- Other signs of autonomic dysfunction exist (e.g., urinary incontinence, dysrhythmia, sweating, pulse above 100 beats/min, blood pressure higher than 150/100 mm Hg or lower than 90/60 mm Hg not counted above).
- Respiratory signs occur (e.g., tachypnea, severe dyspnea, hypoxemia, respiratory failure).
- Leukocytosis is greater than 12,000/mm3.
SS Criteria
- SS has a presentation similar to that of NMS.
- Autonomic instability may include hyperthermia, hyper- or hypotension, salivation, or diarrhea.
- Muscular dysfunction includes shivering, myoclonus, tremor, or rigidity.
- Altered mental status may include confusion, agitation, seizures, or coma.
- SS has been reported after simultaneous use of monoamine oxidase (MAO) inhibitors and clomipramine, lithium, meperidine, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), as well as with the simultaneous use of SSRIs and tricyclic antidepressants, trazodone, or dextromethorphan.
PATHOPHYSIOLOGY
- NMS is believed to be related to CNS dopamine blockade.
- SS is believed to be caused by excessive stimulation of serotonin 1A and 2 receptors.
EPIDEMIOLOGY
- NMS and SS are uncommon.
- Toxic effects with SS are typically mild to moderate.
- Severity of NMS is variable, with death occurring in patients with delayed diagnosis or inadequate management of hyperthermia and rigidity.
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DIFFERENTIAL DIAGNOSIS
Further information on each poison is available in SECTION IV, CHEMICAL AND BIOLOGICAL AGENTS.
Initially, NMS and SS may be indistinguishable; diagnosis is based on the history and course of disease.
Toxicologic Causes of Symptoms Similar to NMS or SS
- Overdose with MAO inhibitors or drug and food interactions
- Agitation, tachycardia, and hyper- and hypotension may accompany MAO inhibitor overdose.
- Many drugs or foods interact with MAO inhibitors and produce a syndrome that involves autonomic dysfunction, altered mental status, and rigidity.
- Malignant hyperthermia is a rare inherited disorder typified by fever, autonomic dysfunction, and severe muscular rigidity that occurs in patients undergoing general anesthesia.
- Anticholinergics and antihistamines cause fever, agitated delirium, altered mental status, tachycardia, and hypertension.
- Sympathomimetics. Severe overdose may cause hyperthermia, tachycardia, and hypertension followed by hypotension, agitation, coma, seizures, and rhabdomyolysis.
- Hallucinogens (LSD, PCP, peyote) may cause agitation associated with hallucinations, hyperthermia, tachycardia, hypertension, and hypotension.
- Withdrawal from ethanol, benzodiazepines, or other sedative hypnotic drugs
- Withdrawal may cause delirium, diaphoresis, and agitation similar to sympathomimetic overdose.
- Seizures also may occur and contribute to hyperthermia.
Other Causes of NMS and SS Symptoms
- Heat stroke and heat exhaustion may present with dehydration, altered mental status, and organ failure.
- Meningitis or other infection causes fever, but is usually identifiable.
- Thyroid storm.
- Neoplasms, connective tissue disease, and granulomatous disease.
SIGNS AND SYMPTOMS
Delirium, agitation, coma, hypotension, multiorgan failure, and death may develop in severe cases.
Vital Signs
- Extreme hypertension, hypotension, and tachycardia may occur with NMS.
- Hypertension and tachycardia are common with SS.
- Hyperthermia may develop with either syndrome and become life threatening with NMS.
HEENT
Dysarthria and salivation may occur.
Dermatologic
Diaphoresis may occur.
Cardiovascular
- Tachycardia is common with NMS or SS.
- Hypertension or hypotension may occur with NMS or SS.
Pulmonary
Tachypnea and respiratory failure may develop with NMS.
Gastrointestinal
Diarrhea is common with SS.
Fluids and Electrolytes
Dehydration is common.
Musculoskeletal
- Rigidity ("lead pipe"), myoclonus, and tremors may occur with NMS or SS.
- Rigidity may affect lower extremities primarily in SS.
- Rhabdomyolysis may develop.
Neurologic
- Seizures may occur.
- Altered mental status occurs in nearly all cases.
- Muscle rigidity, tremor, and myoclonus may occur with either NMS or SS.
- Cogwheeling, dystonic reactions, and choreiform movements may occur with NMS.
PROCEDURES AND LABORATORY TESTS
Essential Tests
- Rectal temperature should be taken to confirm hyperthermia.
- Serum electrolytes, BUN, creatinine, and creatine kinase should be assayed to assess metabolic acidosis and rhabdomyolysis.
- Complete blood count often reveals increased white blood cell count.
- Arterial blood gases may show respiratory alkalosis, respiratory acidosis, or metabolic acidosis.
- Urinalysis may reveal blood and protein if rhabdomyolysis develops.
- Liver and pancreatic tests often reveal elevation of aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase in a hepatocellular pattern.
- ECG may reveal various nonspecific findings.
Recommended Tests
- Serum lithium level should be checked to rule out lithium toxicity.
- Serum acetaminophen and aspirin levels should be checked in an overdose setting to detect occult overdose.
- Urine toxicology screen should be performed in patients with hyperthermia, altered mental status, or autonomic dysfunction of unknown cause.
- Other tests (blood cultures, lumbar puncture, head CT, thyroid functions) should be ordered as needed to evaluate other causes of fever and altered mental status.
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- Focus therapy on airway management, aggressive cooling measures if temperature exceeds 40°C, and general supportive care.
- Dose and time of exposure should be determined for all substances involved.
- Specific treatment should be initiated while supportive care continues.
DIRECTING PATIENT COURSE
The health-care provider should call the poison control center when:
- the cause of hyperthermia syndrome is unclear.
- coingestant, drug interaction, or underlying disease presents unusual problems.
Admission Considerations
All patients with NMS or SS require admission to an intensive care setting.
DECONTAMINATION
- Gastric decontamination may not be necessary unless acute overdose could have occurred.
- Induction of emesis is not recommended.
- Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for substantial ingestion presenting within 1 hour of ingestion or if serious effects are present.
- One dose of activated charcoal (1-2 g/kg) may be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.
ANTIDOTES
There is no specific antidote for NMS or SS.
ADJUNCTIVE TREATMENT
- Initial therapy is expectant and supportive.
- Complications are common and repeated physical and laboratory examination of the patient are crucial.
- Early endotracheal intubation of the patient is strongly advised.
Control of Agitation
A benzodiazepine with which the provider has experience should be administered; the airway must be monitored closely.
- Diazepam. Adult, 5 to 10 mg intravenously; pediatric, 0.2 to 0.5 mg/kg intravenously; doses repeated at 5-minute intervals, titrated to effect
- Lorazepam. Adult, 1 to 2 mg intravenously; pediatric, 0.05 mg/kg intravenously; doses repeated at 5-minute intervals, titrated to effect
Muscle Rigidity and Body Temperature
- Patient's clothing should be removed and intravenous infusion of isotonic crystalloid begun.
- Fluid losses should be replenished, while fluid administration is monitored carefully to avoid fluid overload.
- Cooling fans and wet sheets are effective, especially in a dry climate.
- Cooling blankets or application of ice may be needed in severe cases.
- Sedation and neuromuscular paralysis/mechanical ventilation are important in severe cases and will also help control temperature; in cases of NMS, a nondepolarizing neuromuscular blocking agent should be used and succinylcholine avoided.
- Core temperature should be monitored frequently and cooling discontinued when body temperature decreases to 39°C.
- Agents used to antagonize CNS and musculoskeletal effects of NMS or SS
- Dantrolene
- Dantrolene is used for NMS, but supporting evidence is anecdotal; aggressive supportive care may be equally effective.
- Initial dose is 2 mg/kg intravenously, repeated as needed up to total dose of 10 mg/kg.
- Maintenance dose is 2.5 mg/kg intravenously every 6 hours or 1 mg/kg orally every 12 hours, up to 50 mg/dose.
- Bromocriptine
- Bromocriptine is used in NMS, but supporting evidence is anecdotal.
- Initially the dose is 5 mg orally three times a day; if response is inadequate, the dose may be increased rapidly to a maximum of 20 mg orally four times a day.
- If NMS remits, the medication should be continued for 10 days.
- Cyproheptadine
- This medication has been used for treatment of SS.
- The dose is 4 mg to 8 mg orally and is repeated up to a total dose of 32 mg if signs persist.
- Pediatric dose is 0.25 mg/kg/day in four divided doses; maximum dosage is 12 mg/day.
Tachycardia
- Specific therapy is rarely required.
- Symptoms may improve with control of hyperthermia, agitation, and muscle rigidity.
Hypotension
- Patient should receive 10 to 20 ml/kg 0.9% NaCl and be placed in Trendelenburg position.
- If hypotension is unresponsive, a vasopressor such as dopamine can be administered at an initial rate of 2 to 5 µg/kg per minute, titrated to effect; rates above 20 µg/kg/min are unlikely to provide further benefit.
- High rate of infusion may cause tissue ischemia.
Hypertension
- This often improves with control of agitation.
- If persistent hypertension (higher than 130 mm Hg diastolic, not responsive to sedation) or end-organ injury develops (worsening altered mental status, congestive heart failure, myocardial ischemia, or aortic dissection), a short-acting titratable agent such as nitroprusside can be administered.
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PATIENT MONITORING
Respiratory, cardiac, temperature, and severity of muscle injury should be monitored continuously.
EXPECTED COURSE AND PROGNOSIS
- NMS typically begins gradually with rapid progression over the day or two before presentation.
- SS usually begins more abruptly but is less severe and resolves without sequelae with supportive care.
- Severe NMS may be fatal if not promptly diagnosed and treated; some patients sustain permanent neurologic injury.
Section Outline:
ICD-9-CMNo code is available.
See Also: SECTION II, Hypertension, Hyperthermia, Hypotension, and Tachydysrhythmia (Unexplained) chapters; SECTION III, Dantrolene and Nitroprusside chapters; and SECTION IV, chapters on specific agents.
RECOMMENDED READING
Martin T. Serotonin syndrome. Ann Emerg Med 1996;28:520-526.
Mills KC. Serotonin syndrome. Med Toxicol 1997;13:763-783.
Author: Katherine M. Hurlbut
Reviewer: Luke Yip