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Neuroleptic Malignant Syndrome Differential Diagnoses

  • Author: Theodore I Benzer, MD, PhD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Mar 24, 2016
 
 

Diagnostic ConsiderationsOther neuroleptic-induced reactionsLethal catatoniaSerotonin syndromeMalignant hyperthermiaMedical mimics

Neuroleptic malignant syndrome (NMS) is a heterogeneous condition that spans a broad severity continuum. The diagnosis is made on clinical grounds and is based on the presence of certain historical, physical, and laboratory findings. The diagnosis is confirmed by the presence of recent treatment with neuroleptics (within the past 1-4 weeks), hyperthermia (temperature above 38°C), and muscular rigidity, along with at least five of the following features:

  • Change in mental status
  • Tachycardia
  • Hypertension or hypotension
  • Diaphoresis or sialorrhea
  • Tremor
  • Incontinence
  • Increased creatine phosphokinase (CPK) or urinary myoglobin level
  • Leukocytosis
  • Metabolic acidosis
  • Autonomic instability

In addition, diagnosis of neuroleptic malignant syndrome requires exclusion of other drug-induced, systemic, or neuropsychiatric illness. The clinician must rule out another medication reaction that might be a more likely cause of the patient’s symptoms than use of a neuroleptic. Exposure to other psychotropic drugs can result in disorders very similar to neuroleptic malignant syndrome. Medical conditions must also be considered.

Diagnostic criteria created by a consensus of an international multispecialty expert panel, including psychiatrists, neurologists, anesthesiologists, and emergency physicians, were released in 2011. In addition to hyperthermia and rigidity, at least two other clinical features of neuroleptic malignant syndrome, including leukocytosis and laboratory evidence of muscle injury, should be present. Although the criteria require validation before being used in clinical settings, they can provide guidance for clinicians.[7]

Neuroleptic syndrome also has been associated with the rapid removal of medications with dopaminergic properties.[30] Medications in these classes often are used to treat Parkinson disease and include levodopa, bromocriptine, and amantadine. In such cases, dopaminergic drugs should be started as soon as possible to prevent rhabdomyolysis and renal failure.[31] Evaluation and treatment is otherwise the same as in neuroleptic syndrome involving other drugs.

Antipsychotics can cause a variety of reactions that can be confused with neuroleptic malignant syndrome. These neuroleptic-induced reactions often occur with increasing medication dosages and include the following:

  • Acute dystonia - Abnormal contraction or spasm of a group of skeletal muscles, often involving the head or neck
  • Acute akathisia - Motor restlessness, particularly involving the legs
  • Tardive dyskinesia - Involuntary, rhythmic movements starting with mouth movements
  • Parkinsonism, or pseudoparkinsonism - Classically presents as the triad of tremor, muscular rigidity, and akinesia

Despite the term neuroleptic-induced, these conditions also can be caused, although less frequently, by many of the newer, nontraditional antipsychotic medications, which also have some dopamine-blocking activity. For more information, see Medication-Induced Dystonic Reactions and Neuroleptic Agent Toxicity .

Lethal catatonia (LC) is a similar condition that might be confused with neuroleptic malignant syndrome. Lethal catatonia occurs in people with schizophrenia or during manic episodes. Neuroleptics might either improve or worsen the symptoms of lethal catatonia.

Distinguishing lethal catatonia from neuroleptic malignant syndrome can be difficult, although a detailed history might reveal episodes of catatonia while a patient is not taking neuroleptics. Lethal catatonia also tends to have a prodrome of excitement and agitation prior to the onset of rigidity, while neuroleptic malignant syndrome tends to begin with rigidity.[32]

The serotonin syndrome is similar to neuroleptic malignant syndrome. It is characterized by the triad of altered mental status, autonomic dysfunction, and movement disorder (tremor and abnormal involuntary movement) following exposure to serotonergic agents.[33]

Diagnosis may be especially challenging in patients taking both serotonergic and neuroleptic agents, who may meet criteria for both syndromes.[34] However, laboratory findings characteristic of neuroleptic malignant syndrome (eg, elevated creatine kinase level, liver function test results, and white blood cell count, coupled with a low serum iron level) do not occur in serotonin syndrome.[35]

The proposed mechanism of serotonin syndrome is excessive 5-hydroxytryptamine (5-HT or serotonin) stimulation. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used medications in this class. Given the increasing use of SSRIs, the serotonin syndrome might become increasingly prevalent.

The serotonin syndrome can be distinguished from neuroleptic malignant syndrome in most cases by a detailed history of medication use, with particular attention to recent dosage changes and the presence of tremor and abnormal movements but the absence of severe rigidity. Treatment of this condition includes removal of the offending drug and supportive management, though 5-HT1A antagonists might have a role.[33, 36]

Malignant hyperthermia (MH) occurs after administration of halogenated inhalational anesthetics (eg, halothane) or depolarizing muscle relaxants (eg, succinylcholine) to genetically susceptible individuals.[37] An underlying defect is an autosomal dominant mutation in the ryanodine receptor, which leads to excessive calcium release from the sarcoplasmic reticulum in skeletal muscle when one of the above agents is administered. A multifactorial pattern of inheritance also has been postulated.

Malignant hyperthermia can be distinguished readily by history. Treatment is based on supportive care, use of dantrolene to decrease calcium release, and subsequent avoidance of precipitating medications. No evidence shows that neuroleptic malignant syndrome occurs more frequently in patients susceptible to malignant hyperthermia.

General medical conditions that might mimic neuroleptic malignant syndrome include the following:

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Theodore I Benzer, MD, PhD Assistant Professor in Medicine, Harvard Medical School; Director of the ED Observation Unit, 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, American College of Emergency Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Mary C Mancini, MD, PhD, MMM Professor and Chief of Cardiothoracic Surgery, Department of Surgery, Louisiana State University School of Medicine in Shreveport

Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Society of Thoracic Surgeons, Phi Beta Kappa

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.

Acknowledgements

Iqbal Ahmed, MBBS, FRCPsych (UK) Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of the Health Sciences; 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.

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.

G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami, Leonard M Miller School of Medicine; Medical Director, Palliative Care Team, Director, Pediatric Critical Care Transport, Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Manager, FEMA, Urban Search and Rescue, South Florida, Task Force 2; Pediatric Medical Director, Tilli Kids – Pediatric Initiative, Division of Hospice Care Southeast Florida, Inc

G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society

Disclosure: Nothing to disclose.

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.

Girish G Deshpande, MD, MBBS, FAAP Associate Professor of Pediatrics, Interim Director and Division Chief of Critical Care Medicine, Department of Pediatrics, University of Illinois College of Medicine at Peoria; Consulting Staff, 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.

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.

Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Roudebush VA Medical Center

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: Nothing to disclose.

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

Disclosure: Nothing to disclose.

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.

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

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.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and 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.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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