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Neuroleptic Malignant Syndrome

Author: Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital
Contributor Information and Disclosures

Updated: Aug 18, 2009

Introduction

Background

The neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to a neuroleptic medication. The syndrome is characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction.

Although potent neuroleptics (eg, haloperidol, fluphenazine) are more frequently associated with NMS, all antipsychotic agents, typical or atypical, may precipitate the syndrome. For example, these agents have been associated with NMS: prochlorperazine (Compazine), promethazine (Phenergan), clozapine (Clozaril), and risperidone (Risperdal). NMS has also been associated with non-neuroleptic agents that block central dopamine pathways such as metoclopramide (Reglan), amoxapine (Ascendin), and lithium.1

Pathophysiology

All medications implicated in NMS have dopamine D2-receptor antagonist properties. NMS has been noted following withdrawal of anti-Parkinson medication. The clinical syndrome is thought to be secondary to decreased dopamine activity in the central nervous system (CNS) either from blockade of dopamine D2-receptors or from decreased availability of dopamine itself, and NMS shares similarities with malignant hyperthermia and the serotonin syndrome. Blockade of dopamine neurotransmission in the nigrostriatum and hypothalamus results in muscular rigidity and altered thermoregulation, respectively. Sympathetic nervous system activation or dysfunction may play a significant role in the pathogenesis of NMS.2,3

Frequency

United States

Incidence is uncommon, with rates ranging from 0.02-12.2% of patients treated with a neuroleptic medication. Prospective studies and pooled data from the literature report an incidence of 0.07-0.2%. Because of increased awareness of this syndrome and efforts at prevention, the incidence is probably less now than in the past.

Mortality/Morbidity

  • The incidence of mortality, once reported at 20-30% is now estimated at 5-11.6%. Death usually results from respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or diffuse intravascular coagulation (DIC).
  • Morbidity from NMS includes rhabdomyolysis, pneumonia, renal failure, seizures, arrhythmias, DIC, and respiratory failure.

Sex

NMS has been reported to be more common in males, most likely because of increased use of neuroleptics in males. The male-to-female ratio is 2:1.

Age

No age predilection for NMS exists. NMS may occur in patients of any age who are receiving neuroleptics or other precipitating medications.

Clinical

History

  • Neuroleptic malignant syndrome (NMS) is more likely to develop following initiation of neuroleptic therapy or an increase in the dose.
  • The onset can be within hours, but, on average, it is 4-14 days after initiation of therapy. However, NMS can occur at any time during neuroleptic use, even years after initiating therapy.
  • Of those patients who develop NMS, 90% of them do so within 10 days.
  • NMS is a heterogeneous syndrome that spans a broad severity continuum. The diagnosis is made on clinical grounds based on the presence of certain historical, physical, and laboratory findings. The diagnosis is confirmed, but not necessarily excluded, by the presence of the following 5 criteria:
    • Recent treatment with neuroleptics within past 1-4 weeks
    • Hyperthermia (temperature above 38°C)
    • Muscular rigidity
    • At least 5 of the following:
      • Change in mental status
      • Tachycardia
      • Hypertension or hypotension
      • Diaphoresis or sialorrhea
      • Tremor
      • Incontinence
      • Increased creatinine phosphokinase (CPK) or urinary myoglobin level
      • Leukocytosis
      • Metabolic acidosis
      • Exclusion of other drug-induced, systemic, or neuropsychiatric illness
  • Clinical signs
    • Hyperthermia
    • Profuse diaphoresis
    • Generalized rigidity (lead pipe)
    • Mental status changes
    • Autonomic instability
  • Atypical NMS4
    • Patients with NMS may present with atypical features that don't include muscle rigidity or hyperthermia at the onset.
    • Hyperthermia and muscle rigidity may develop over time or not at all.
    • Atypical presentation of NMS may be more common after treatment with the atypical class of antipsychotics.

Physical

  • Hyperthermia
  • Diaphoresis
  • Generalized muscular rigidity (lead pipe)
  • Tachycardia
  • Hypertension or hypotension
  • Tremor
  • Incontinence
  • Altered mental status
  • Tachypnea

Causes

  • All classes of neuroleptics (dopamine D2-receptor antagonists) are associated with NMS, and dopamine receptor blockade is considered the cause of NMS.
    • Experimental blockade of dopamine in the striatum can cause rigidity, tremor, and rhabdomyolysis.
    • Blockade of dopamine in the hypothalamus can cause impaired temperature regulation and hyperthermia.
    • This theory does not explain why only some patients develop NMS. It also does not explain why patients rechallenged with neuroleptics do not always redevelop NMS.
  • Risk factors for developing NMS include the following:
    • Increased ambient temperature
    • Dehydration
    • Patient agitation or catatonia
    • Rapid initiation or dose escalation of neuroleptic
    • Withdrawal of anti-Parkinson medication
    • Use of high-potency agents and depot intramuscular preparations
    • History of organic brain syndrome or affective disorder
    • History of NMS
    • Concomitant use of predisposing drugs (eg, lithium, anticholinergic agents)

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

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  2. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. Feb 1999;156(2):169-80. [Medline].

  3. Jauss M, Krack P, Franz M, Klett R, Bauer R, Gallhofer B, et al. Imaging of dopamine receptors with [123I]iodobenzamide single-photon emission-computed tomography in neuroleptic malignant syndrome. Mov Disord. Nov 1996;11(6):726-8. [Medline].

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Further Reading

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Keywords

neuroleptic malignant syndrome, neuroleptic medication, NMS, idiosyncratic reaction, muscular rigidity, autonomic dysfunction, haloperidol, fluphenazine, antipsychotic agents, prochlorperazine, promethazine, clozapine, risperidone, metoclopramide, amoxapine, lithium, dopamine D2-receptor antagonist, withdrawal of anti-Parkinson medication

respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, diffuse intravascular coagulation, DIC, rhabdomyolysis, pneumonia, renal failure, seizures, hyperthermia, profuse diaphoresis, sialorrhea, metabolic acidosis, dopamine receptor blockade, impaired temperature regulation

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Contributor Information and Disclosures

Author

Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital
Theodore I Benzer, MD, PhD is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians
Disclosure: Nothing to disclose.

Medical Editor

Mark S Slabinski, MD, FACEP, FAAEM, Vice President, EMP Medical Group
Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Ohio State Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

 
 
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