eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Critical Care

Neuroleptic Malignant Syndrome

Mary C Mancini, MD, PhD, Professor, Department of Surgery, Louisiana State University Health Sciences Center
Girish G Deshpande, MD, MBBS, FAAP, Assistant Professor, Department of Pediatrics, Division of Critical Care Medicine, Children's Hospital of Illinois at OSF St Francis Medical Center

Updated: Dec 9, 2008

Introduction

Background

Neuroleptic malignant syndrome (NMS), first described in 1963 by Delay et al in the French psychiatric literature, is a rare but potentially lethal complication of treatment with potent neuroleptics.

Neuroleptic drugs (ie, antipsychotic drugs, antischizophrenic drugs) are primarily used to treat schizophrenia and other psychotic states. Traditional drugs have action through inhibition of dopaminergic receptors, whereas the newer agents work by causing blockade of serotonin receptors.

Neuroleptic malignant syndrome often occurs as treatment begins, when physicians progressively increase doses of neuroleptics. No clear relationship has been established between neuroleptic dosage and risk of developing neuroleptic malignant syndrome. A drug's potential for inducing neuroleptic malignant syndrome seems to parallel its antidopaminergic activity.

Pathophysiology

Neuroleptic malignant syndrome pathophysiology is largely speculative. Neuroleptic drugs block dopaminergic receptors, creating a functional dopamine-deficiency state. Dopaminergic receptor blockade in the substantia nigra causes muscle rigidity and alters thermoregulation in the hypothalamus. Increased heat production from muscle rigidity causes fever, impaired heat dissipation (by reducing cutaneous vasodilatation or by sweating), and possibly a higher core temperature set point in the hypothalamus.

MM isoenzyme of creatine kinase increases. Muscle biopsy demonstrates morphologic and histoenzymologic abnormalities in muscle fibers.

Frequency

International

Incidence varies because of differing diagnostic criteria, patient characteristics, and available information. Reported incidence of neuroleptic malignant syndrome in neuroleptic-treated patients ranges from 0.1-5.5%.

Neuroleptic malignant syndrome onset ranges from 1-44 days following administration of neuroleptic drug; mean onset is 10 days. Lazarus et al reported neuroleptic malignant syndrome occurring in 67% of patients within 1 week and 96% of patients within 30 days following administration of neuroleptics.¹

Mortality/Morbidity

Once reported to be 20-30%, the mortality rate is now estimated at 5-11.6%. Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism). Renal failure is associated with a 50% mortality rate.

No consistent long-term physical, neurological, cognitive, or laboratory sequelae have been attributed to neuroleptic malignant syndrome alone, although sequelae may result from such secondary complications as prolonged hypoxia or ischemic encephalopathy. Researchers have noted sporadic cases of prolonged rigidity and long-term neuropsychological deficits.

Sex

The male-to-female ratio is 2:1.

Age

Neuroleptic malignant syndrome occurs in people of all age groups, with a reported mean age of 40 years.

Clinical

History

Symptoms of neuroleptic malignant syndrome include the following:

• Neuroleptics either recently started or dosage recently increased
• Neuroleptic malignant syndrome usually evolves over 24-72 hours.
• Hyperthermia (temperature >38°C)
• Altered mental status
• Rigidity and other extrapyramidal syndrome (EPS) symptoms
• Autonomic dysfunction (eg, urinary incontinence, diaphoresis, sialorrhea)
• Dyspnea, dysphagia

Physical

• General examination findings
  • Hyperthermia
  • Tachycardia
  • Tachypnea, respiratory distress (31% of cases)
  • Hypotension or hypertension
  • Hypoxemia (low pulse oximeter reading)
  • Dehydration (secondary to hyperpyrexia and inadequate oral intake)
• Neuromuscular examination findings
  • Altered mental status (status ranging from drowsiness and confusion to coma)
  • Muscular rigidity (usually lead-pipe type)
  • Autonomic dysfunction (eg, dysrhythmias, urinary incontinence, diaphoresis, sialorrhea, tachycardia, hypotension, hypertension)
  • Other EPS

Causes

• Most common agents
  • Butyrophenones
  • Haloperidol
  • Phenothiazines
  • Thioxanthenes
  • Long-acting neuroleptics (benzamines)
  • Several other agents that reportedly have caused neuroleptic malignant syndrome - Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), anticonvulsants, lithium, and dopamine antagonists (eg, metoclopramide, sulpiride)
• Agent risk factors
  • Rapid initiation of antipsychotic therapy
  • Use of high-potency drugs (drug's potential for inducing neuroleptic malignant syndrome seems to parallel its antidopaminergic activity)
  • Depot preparations
• Host risk factors
  • Age - People of all age groups affected (reported mean age is 40 y)
  • Sex - More common in men (2:1 ratio)
  • Concomitant illnesses
    • Organic brain disease or alcoholism
    • Dehydration, nutritional deficits
    • Affective disorder
    • Severe patient agitation or catatonia
    • History of neuroleptic malignant syndrome
    • Simultaneous use of predisposing drugs (eg, lithium, anticholinergic agents)
• Environmental risk factors: Environmental risk factors may include seasonality. Some investigators report higher incidence of neuroleptic malignant syndrome in summer in connection with heat stroke; other investigators have reported no seasonal clustering.
• Caveats
  • Higher incidence of neuroleptic malignant syndrome with parenteral administration of neuroleptics was noted in one study.
  • Coadministration of anti-Parkinson drugs and neuroleptics effectively prevents neuroleptic malignant syndrome, according to one investigator; however, another investigator found no such benefit. Withdrawal of parkinsonian medication is reported to be one etiological factor for neuroleptic malignant syndrome.
  • Not all patients have recurrent neuroleptic malignant syndrome, even if the same neuroleptic is administered in the same dose after recovery from neuroleptic malignant syndrome.

Differential Diagnoses

Other Problems to Be Considered

Neuroleptic malignant syndrome (NMS) is a diagnosis of exclusion; the following disorders create similar symptomatology:

Primary CNS disorders

Meningoencephalitis
Stroke
Trauma
Tumors
Major psychosis (eg, lethal catatonia)

Systemic disorders

Infections (eg, tetanus)
Metabolic conditions
Endocrinopathies (eg, thyrotoxicosis, pheochromocytoma)
Autoimmune diseases (eg, systemic lupus erythematosus)
Sepsis

Miscellaneous

Heat stroke
Strychnine poisoning
Central anticholinergic syndrome
Sympathomimetic intoxication
Serotonin syndrome
Monoamine oxidase inhibitor (MAOI) overdose
Lithium overdose
Alcohol or sedative-hypnotic withdrawal
Malignant hyperthermia

Workup

Laboratory Studies

No laboratory test result is diagnostic for neuroleptic malignant syndrome (NMS).

• Evidence of increased muscular activity
  • Elevated creatinine kinase (50-100% of cases)
  • Metabolic acidosis
  • Increased transaminases
  • Myoglobinuria
• CBC count showing leukocytosis (70-98% of cases)
• Electrolyte levels that indicate hyperkalemia, metabolic acidosis
• Renal function tests indicating prerenal (dehydration) and renal (myoglobinuria) failure
• Coagulation studies, such as platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT), if thromboembolic phenomenon or diffuse intravascular coagulation (DIC) is suspected
• Cultures from various sites to look for infections
• Cerebrospinal fluid (CSF) analysis to rule out meningitic or encephalitic process

Imaging Studies

• Imaging studies (eg, CT scanning, MRI) of the brain may be performed to rule out other conditions such as intracranial hemorrhage (ICH) or trauma. They per se do not yield any diagnostic information for neuroleptic malignant syndrome.
• Chest radiography is indicated for suspected aspiration pneumonia.

Histologic Findings

• Neuroleptic malignant syndrome has an associated increase of MM isoenzyme of creatine kinase.
• Muscle biopsy reveals morphological and histoenzymological abnormalities in muscle fibers. These findings are nonspecific and are not diagnostic of neuroleptic malignant syndrome.

Treatment

Medical Care

Neuroleptic malignant syndrome (NMS) is a life-threatening medical emergency that requires monitoring and management in an ICU. Tailor intervention levels to the severity of illness.

• Terminate the dopamine antagonist by withdrawing neuroleptic and neuroleptic malignant syndrome–potentiating drugs (eg, anticholinergics, lithium).
• Supportive measures include the following:
  • Reduce body temperature using antipyretics, evaporative cooling, ice packs, and cooled intravenous (IV) fluids.
  • Treat suspected or secondary infections with empiric antibiotics.
  • Consider prophylactic intubation for patients with excessive salivation, swallowing dysfunction, coma, hypoxemia, acidosis, and severe rigidity with hyperthermia.
  • Maintain pulmonary, cardiovascular, and renal functions by monitoring and managing such complications as respiratory failure, renal failure, disseminated intravascular coagulation (DIC), and arrhythmias.
  • Sedate the patient.
• Specific measures include the following:
  • A goal is rapid peripheral muscle relaxation. Rapid control of rigidity averts hyperthermia, rhabdomyolysis, renal failure, pneumonia, respiratory failure, DIC, and cardiovascular collapse.
  • Considering all the disadvantages of dantrolene (vide infra), using nondepolarizing neuromuscular blocking agents (eg, pancuronium, other newer agents) is reasonable, along with such sedatives as benzodiazepines, to achieve rapid, predictable, and effective control of rigidity and hyperthermia.
  • Dantrolene sodium directly relaxes muscles by inhibiting calcium release from the sarcoplasmic reticulum. Its disadvantages include the following: the mean response time is 1.7 days; rigidity and temperature reduction takes longer, effects are erratic, and effects are often incomplete; and dantrolene is a potentially hepatotoxic agent. Because of rigidity relieving action, it may offer another therapeutic modality for treatment of neuroleptic malignant syndrome (NMS).
  • Bromocriptine is a dopamine agonist that overcomes neuroleptic-induced dopaminergic blockade. It has also been used in combination with dantrolene.
  • Other agents that have been tried include amantadine, which enhances presynaptic release of dopamine, and levodopa/carbidopa, which increase presynaptic dopamine stores.
  • Antimuscarinic agents are not recommended because they are not only ineffective but also may worsen hyperthermia.
• Consider electroconvulsive therapy (ECT). In 1987, Addonizio and Susman recommended ECT for persistently psychotic and agitated patients in whom distinguishing between neuroleptic malignant syndrome and lethal catatonia is difficult and in patients who run the risk of neuroleptic malignant syndrome recurring when neuroleptics are restarted.²

Consultations

• Consultation with a psychiatrist may be prudent as the patient is stabilized in the ICU and for further follow-up care after the patient is discharged from the ICU.

Medication

Skeletal muscle relaxants, nonparalytic

This agent is a direct muscle relaxant to control rigidity.

Dantrolene sodium (Dantrium)

Interferes with release of calcium from sarcoplasmic reticulum, thus directly inhibiting muscle contraction. Also prevents or reduces increase in myoplasmic calcium ion concentration that activates acute catabolic process associated with malignant hyperthermia. Available as sodium salt in 25-mg, 50-mg, and 100-mg caps and in 20-mg vial for IV administration.

Dosing

Adult

Spasticity: 25 mg/d PO initially, gradually increase to tid/qid; then increase dose by 25 mg q4-7d; not to exceed 100 mg 2-4 times/d or 400 mg/d
Hyperthermia:
Preoperative prophylaxis: 4-8 mg/kg/d PO divided qid administered 1-2 d before surgery for patients at risk; to prevent recurrence, administer last dose 3-4 h before scheduled surgery; alternatively, 2.5 mg/kg IV infused over 1 h before anesthesia; additional doses may be needed during surgery, especially if prolonged
Crisis : 1 mg/kg IV, may repeat prn; not to exceed a cumulative dose of 10 mg/kg; if physiologic and metabolic abnormalities reappear, repeat regimen
Postcrisis follow-up: 4-8 mg/kg/d PO divided qid for 1-3 d; administer IV when PO therapy is not practical; individualize dosage beginning with 1 mg/kg IV or more as clinical situation dictates

Pediatric

Spasticity: 0.5 mg/kg PO bid initially, increase frequency to tid/qid at 4-d to 7-d intervals; then increase dose by 0.5 mg/kg increments; not to exceed 3 mg/kg 2-4 times/d up to 400 mg/d
Hyperthermia: Administer as in adults

Interactions

Use with verapamil may result in hyperkalemia and myocardial depression; concomitant use of estrogen increases risk of hepatotoxicity; CNS depression is exaggerated when used with CNS depressants; incompatible when mixed with dextrose, saline, or bacteriostatic water solutions

Contraindications

Documented hypersensitivity; active hepatic disease (eg, hepatitis, cirrhosis)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with impaired cardiac or pulmonary function or history of previous liver disease; may cause hepatotoxicity (more common in females or patients >35 y), onset of overt hepatitis typically 3-12 mo after treatment initiation; monitor baseline and periodic liver function; adverse reactions include hepatitis, drowsiness, seizures, dizziness, lightheadedness, confusion, headaches, pleural effusion with pericarditis, tachycardia, hematuria, diarrhea, nausea, vomiting, GI bleeding, severe constipation, dysphagia, rash, photosensitization, acnelike rash, pruritus, urticaria, and abnormal hair growth; avoid alcohol and unnecessary exposure to sunlight; causes drowsiness; may impair ability to perform hazardous functions requiring mental alertness or physical coordination; protect IV from light; use reconstituted injection within 6 h; precipitant forms when IV placed in glass containers

Dopamine agonists

For a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. D2 receptor blockade might cause neuromalignant malignant syndrome by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents (eg, phenothiazines).

Bromocriptine (Parlodel)

Is an ergot alkaloid with dopamine receptor agonist action.

Dosing

Adult

10 mg PO tid initially; if no improvement in 24 h, may increase dose; not to exceed 20 mg PO qid

Pediatric

Limited data available; 1.25 mg PO q12h initially, may gradually increase dose prn; not to exceed 20 mg/d

Interactions

Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects

Contraindications

Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May worsen condition of patient with psychiatric illness, peptic ulcer disease, or preexisting peripheral vascular disease; may result in cardiac decompensation in patients with history of myocardial infarction; adverse reactions include orthostatic hypotension, hallucinations, confusion, delirium, nausea, and vomiting

Amantadine (Symmetrel)

Has been tried in NMS because it increases synaptic dopamine activity. As an antiviral, actions include inhibition of influenza A virus uncoating, prevention of virus penetration into host, and inhibition of M2 protein in the assembly of progeny virions. Exhibits antiparkinsonian activity by blocking reuptake of dopamine into presynaptic neurons and by causing direct stimulation of postsynaptic receptors.

Dosing

Adult

Data limited; several case reports describe using 100 mg PO bid

Pediatric

Not established; 5 mg/kg/d PO qd or divided bid has been used for influenza A prophylaxis; not to exceed 150 mg/d (age 1-9 y) or 200 mg/d (age >10 y)

Interactions

Drugs with anticholinergic or CNS stimulant activity increase amantadine toxicity; the concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with liver disease, epilepsy, history of recurrent eczematoid dermatitis, or uncontrolled psychosis; may increase seizure activity or EEG disturbances with preexisting seizure disorders; decrease dosage with renal impairment and with active seizure disorders; adverse reactions include orthostatic hypotension, edema, dizziness, confusion, insomnia, difficulty in concentration, restlessness, hallucinations, seizures, livido reticularis, nausea, vomiting, xerostomia, and urinary retention; avoid alcohol; may cause drowsiness; may impair ability to perform activities requiring mental alertness or coordination; do not abruptly discontinue therapy because may precipitate a parkinsonian crisis

Levodopa and carbidopa (Sinemet)

Levodopa is a metabolic precursor of dopamine. Few reports of its use in combination with carbidopa (vide infra) in NMS exist because of its dopaminergic action. Crosses the blood-brain barrier and is converted to dopamine by enzyme action, thus restoring dopamine levels in the extrapyramidal centers such as substantia nigra.
Carbidopa, a dopamine decarboxylase inhibitor, does not cross the blood-brain barrier. Diminishes the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing levodopa's availability in the CNS and enhancing its effectiveness.
A variety of dosage ratios are available (ie, 1:10 carbidopa to levodopa, 1:4 carbidopa to levodopa). Also available as IR and SR dosage forms.

Dosing

Adult

25 (carbidopa)/250 (levodopa) mg PO tid/qid
Alternatively, 500-1000 (based on levodopa component) mg/d PO divided q6-12h; increase by 100-750 mg/d q3-7d until response; not to exceed 8000 mg/d

Pediatric

Not established

Interactions

Antacids increase bioavailability of levodopa; benzodiazepines, hydantoins, methionine, papaverine, and pyridoxine decrease levodopa effectiveness; iron salts and anticholinergics decrease GI absorption of levodopa; MAOIs may increase hypertensive reaction; may decrease metoclopramide effects; methyldopa may have additive hypotensive effects

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with severe cardiovascular or pulmonary disease, asthma, occlusive cerebrovascular disease, renal or hepatic or endocrine disease, affective disorders, major psychoses, cardiac arrhythmias, and chronic wide-angle glaucoma

Follow-up

Deterrence/Prevention

• Because neuroleptic malignant syndrome (NMS) usually develops while the dose is being increased, be alert to this possibility until a steady dose is achieved.
• Know the risk factors and be vigilant for neuroleptic malignant syndrome development.

Complications

• Respiratory failure
• Aspiration pneumonia
• Renal failure
• Cardiovascular collapse and arrhythmias
• Thromboembolism and disseminated intravascular coagulation (DIC)

Prognosis

• Prognosis depends on how early patient is treated and on the presence of such associated complications as respiratory or renal failure.
• The mortality rate once reported at 20-30% is now estimated at 5-11.6%.
• The mortality rate rises to about 50% if neuroleptic malignant syndrome is complicated by renal failure.

Patient Education

• Explain and educate the patient and caretakers about possible adverse effects of medications.

Miscellaneous

Medicolegal Pitfalls

• Several other drugs in addition to neuroleptics can cause this potentially lethal condition.
• Know the risk factors for neuroleptic malignant syndrome (NMS) if a patient must be started on neuroleptics.
• Monitor the patient on close follow-up in the outpatient department while the dose of neuroleptics is being increased.
• Explain this serious complication of the therapy to the patient and the patient's caregiver.
• Explore the possibility of a recent neuroleptic administration in any patient who presents with the symptom complex of hyperthermia, rigidity, and altered mentation. Necessary investigations may be performed to rule out other treatable and potentially serious conditions that could cause similar symptomatology.
• Treatment is mainly supportive; it is directed toward controlling the rigidity and hyperthermia and toward preventing other complications (eg, respiratory failure, renal failure). Remember that development of renal failure increases the mortality rate to 50%.

References

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Keywords

neuroleptic malignant syndrome, NMS, neuroleptics, antidopaminergic activity, serotonin, schizophrenia, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism, hypoxia, ischemic encephalopathy, urinary incontinence, diaphoresis, sialorrhea, hypertension, respiratory distress, dehydration, hypotension, butyrophenones, haloperidol, phenothiazines, thioxanthenes, long-acting neuroleptics, benzamines, tricyclic antidepressants, monoamine oxidase inhibitors, MAOIs, anticonvulsants, lithium, domatine antagonists

Contributor Information and Disclosures

Author

Mary C Mancini, MD, PhD, Professor, Department of Surgery, Louisiana State University Health Sciences Center
Mary C Mancini, MD, PhD is a member of the following medical societies: American Heart Association, American Medical Association, American Thoracic Society, Association for Academic Surgery, Association for Surgical Education, International College of Surgeons, International Society for Heart and Lung Transplantation, New York Academy of Sciences, Phi Beta Kappa, and Southern Thoracic Surgical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Girish G Deshpande, MD, MBBS, FAAP, Assistant Professor, Department of Pediatrics, Division of Critical Care Medicine, Children's Hospital of Illinois at OSF St Francis Medical Center
Girish G Deshpande, MD, MBBS, FAAP is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Medical Editor

G Patricia Cantwell, MD, Associate Clinical Professor, Department of Pediatrics, University of Miami; Director of Pediatric Critical Care Medicine, Miller School of Medicine, Jackson Children's Hospital
G Patricia Cantwell, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Barry J Evans, MD, Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center
Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.

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