Neuroleptic Malignant Syndrome 

  • Author: Joseph Tonkonogy, MD, PhD; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych (UK)   more...
 
Updated: Oct 18, 2011
 

Background

Neuroleptic malignant syndrome (NMS) refers to the combination of hyperthermia, rigidity, and autonomic dysregulation that can occur as a serious complication of the use of antipsychotic drugs. Delay first used the term in 1960, after observing patients treated with high-potency antipsychotics.[1]

Even the newer atypical antipsychotics, which are not classified accurately as neuroleptics, can cause NMS. The list of atypical antipsychotic drugs that may cause NMS include olanzapine, risperidone, paliperidone, aripiprazole, ziprasidone, amisulpride, and quetiapine. Clozapine may also be associated with the development of NMS, but it appears to be less likely to manifest with extrapyramidal features, including rigidity and tremor. In general, over the past 30 years, the syndrome has been associated with a variety of drugs that lead to decreased dopamine receptor activation.[2]

While some clear risk factors for neuroleptic malignant syndrome are present, the low incidence of this syndrome and the consequent difficulty in studying it in a controlled, prospective manner make clinical features, predisposing conditions, treatment, and prognosis difficult to define.

Following is a case vignette of a patient with neuroleptic malignant syndrome that developed several days after the start of treatment with the atypical antipsychotic olanzapine.

A 66-year-old white male was hospitalized for increasingly aggressive behavior. He had no prior psychiatric admissions. On the day of admission after he sustained a fall, a CT scan of the brain revealed a subarachnoid hemorrhage at the right superior sulcus and a possible hemorrhagic contusion at the left frontal lobe. Over the course of hospitalization, the patient had a series of CT scans showing resolution of the hemorrhage. He was started on olanzapine for intermittent agitation. Olanzapine was titrated to 7.5 mg daily.

Ten days later the patient became abruptly somnolent with body temperature reaching 39.7 º C and severe muscle rigidity in both upper and lower extremities. He had severe diaphoresis and fluctuation of blood pressure and pulse. Laboratory data revealed elevation of white blood cells to 14800 K/L, creatine phosphokinase to 2800 U/L (normal < 174 U/L), and mild elevation of serum alanine and aspartate aminotransferase. MRI of the brain, CSF studies, and chest radiograph were unremarkable. A presumptive diagnosis of neuroleptic malignant syndrome was made. Olanzapine was immediately discontinued and supportive care was initiated.

Intravenous lorazepam was given as needed every 4 hours for behavioral agitation along with a fixed 0.5 mg intravenous push twice daily. The patient received a total of 8.5 mg of lorazepam in the first 24 hours and 3 mg the next day. Fever and muscular rigidity resolved in 24 hours. All other manifestations of neuroleptic malignant syndrome resolved in 9 days.

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Pathophysiology

The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome.[3]

Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome.

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Epidemiology

Frequency

United States

Neuroleptic malignant syndrome is associated with the use of various antipsychotic medicines, most frequently neuroleptics (the older antipsychotics). Development of neuroleptic malignant syndrome appears to be independent of the conditions that these medicines treat.

The syndrome can occur after any duration of treatment, although two thirds of cases occur within the first week. The frequency has been variably reported as 0.07–2.2% of patients taking neuroleptics.[4] Data largely come from case control studies rather than prospective randomized trials.

International

The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial variation. The one large randomized trial conducted in China showed an incidence of 0.12% in patients taking neuroleptics.[5] A retrospective study conducted in India showed an incidence of 0.14%.[6]

Mortality/Morbidity

Mortality from neuroleptic malignant syndrome is very difficult to quantify due both to the case report designs of most of the literature and to the inconsistency of the diagnostic parameters used.

  • In some series, mortality rates as high as 76% have been reported. Most series suggest, however, that the mortality rate is 10-20%. When reporting bias is factored in, the true rate of mortality from neuroleptic malignant syndrome might be much lower.
  • Studies have also found that the mortality rate has been decreasing over the past 2 decades. Mortality is generally higher in patients who develop severe muscle necrosis and resulting rhabdomyolysis.

Race

No data suggest geographic or racial variation.

Sex

Incidence is higher in males.

Age

  • Incidence is higher in persons younger than 40 years. Differential incidence simply might reflect a population that has a high rate of antipsychotic usage.
  • Some small case series looking at neuroleptic malignant syndrome in elderly patients suggest that onset might occur after a longer duration of antipsychotic use.
  • Although NMS is rare in children, studies suggest that clinicians should maintain a high level of suspicion in children. Symptoms of NMS in children are consistent with those described in adults.[7]
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Contributor Information and Disclosures
Author

Joseph Tonkonogy, MD, PhD  Clinical Professor of Psychiatry, University of Massachusetts Medical School; Consulting Staff, Departments of Psychiatry, University of Massachusetts Medical School

Joseph Tonkonogy, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Neuropsychiatric Association, International Neuropsychological Society, Massachusetts Medical Society, Royal Society of Medicine, Society for Neuroscience, and United Council for Neurologic Subspecialties, Certification Behavioral Neurology and Neuropsychiatry

Disclosure: Nothing to disclose.

Coauthor(s)

Darius P Sholevar, MD  Fellow, Cardiovascular Disease, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Alan D Schmetzer, MD  Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training Director in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Midtown Mental Health Cener at Wishard Health Services

Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for Convulsive Therapy

Disclosure: Eli Lilly & Co. Grant/research funds Other

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harold H Harsch, MD  Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin

Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: lilly Honoraria Speaking and teaching; Forest Labs None None; Pfizer Grant/research funds Speaking and teaching; Northstar None None; Novartis Grant/research funds research; Pfizer Honoraria Speaking and teaching; Sunovion Speaking and teaching; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research; Merck Honoraria Speaking and teaching

Chief Editor

Iqbal Ahmed, MBBS, FRCPsych (UK)  Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Iqbal Ahmed, MBBS, FRCPsych (UK) is a member of the following medical societies: Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric Association, American Psychiatric Association, American Society of Clinical Psychopharmacology, and Royal College of Psychiatrists

Disclosure: Nothing to disclose.

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