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

Neuroleptic Malignant Syndrome

Author: Mary C Mancini, MD, PhD, Professor, Department of Surgery, Louisiana State University Health Sciences Center
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
Contributor Information and Disclosures

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.

More on Neuroleptic Malignant Syndrome

Overview: Neuroleptic Malignant Syndrome
Differential Diagnoses & Workup: Neuroleptic Malignant Syndrome
Treatment & Medication: Neuroleptic Malignant Syndrome
Follow-up: Neuroleptic Malignant Syndrome
References
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References

  1. Lazarus A. Neuroleptic malignant syndrome. Hosp Community Psychiatry. Dec 1989;40(12):1229-30. [Medline].

  2. Addonizio G, Susman VL. ECT as a treatment alternative for patients with symptoms of neuroleptic malignant syndrome. J Clin Psychiatry. Mar 1987;48(3):102-5. [Medline].

  3. Bismuth C, de Rohan-Chabot P, Goulon M, Raphael JC. Dantrolene--a new therapeutic approach to the neuroleptic malignant syndrome. Acta Neurol Scand Suppl. 1984;100:193-8. [Medline].

  4. Cawrse N, Wilson S, Williams M, Burge T. Neuroleptic malignant syndrome in the burns patient?. Burns. Aug 2006;32(5):647-9. [Medline].

  5. Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin Neuropharmacol. Apr 1996;19(2):157-64. [Medline].

  6. Ellenhorn MJ, Schonwald S, Ordog G. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams & Wilkins; 1997:663-4, 1187-1190.

  7. Haddad LM, Shannon MW, Winchester JF. Clinical Management of Poisoning and Drug Overdose. 3rd ed. Philadelphia, PA: WB Saunders; 1998:139-40, 633-4, 639-40.

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Further Reading

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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

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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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