Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome
Definition
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal condition that can occur in people who take neuroleptic medication to treat schizophrenia, mania, delusional disorder, and other types of mental illnesses. There is evidence that sympathetic nervous system activation or dysfunction may be significantly associated with the underlying pathogenesis of NMS. NMS, which is characterized by motor dysfunction, extremely high fever, and changes in consciousness, is most commonly associated with older generation typical neuroleptics such as haloperidol (Haldol) and chlorpromazine (Largactil). However, the newer, atypical antipsychotic agents, such as cloza-pine (Clozaril), resperidone (Risperdal), and olanza-pine (Zyprexa), also have been associated with NMS symptoms. NMS additionally has been reported in patients with Parkinson’s disease who have had their medications (such as levodopa) rapidly withdrawn.
Non-neuroleptic agents associated with NMS block central dopamine pathways and include metoclo-pramide (Reglan), lithium, and amoxapine (Ascendin). The syndrome also shares features with malignant hyperthermia and the serotonin syndrome.
Description
NMS is believed to be related to the dopaminergic system. Dopamine is a neurotransmitter that transmits messages between nerve cells in the brain. It regulates mood, emotion, motivation, and movement. Neuroleptic antipsychotic drugs act as antagonists at dopamine receptors, meaning that they block the receptors, thereby preventing dopamine from attaching to the receptors and causing its response from the decreased availability of dopamine itself. Sometimes, blocking these receptors can result in movement disorders and difficulty regulating body heat, both of which are symptoms associated with NMS. NMS typically begins within the first two to four weeks after a patient starts taking antipsychotic medications or is put on a higher dose of the medication.
Demographics
Neuroleptic malignant syndrome occurs in between 0.02% and 2.44% of people who are treated with neuroleptic medications, although there is no universal agreement on this statistic. The mortality rate with NMS is between 5% and 11.6%, also with no complete consensus on this figure. Mortality from the condition has declined over the years but remains significant. Death generally results after respiratory failure, diffuse intravascular coagulation (DIC), cardiovascular collapse, myoglobinuric renal failure, and arrhythmias. There is a predilection toward males but none associated with age. There is a 2:1 male-to-female ratio, which is thought to occur because men are treated with neuroleptic agents more frequently than women.
Causes and symptoms
Causes
Although researchers have identified several risk factors for NMS, the precise cause is unknown. Genetic factors may play a role, however, and NMS has been reported to run in families. Researchers have identified alterations or deletions to the CYP2D6 genes in people with NMS. Changes to these genes may affect the way neuroleptics are metabolized by the liver, resulting in higher blood concentrations.
Symptoms
The Diagnostic and Statistical Manual of Mental Disorders (or DSM-IV) lists muscle rigidity and a high temperature as the primary symptoms of NMS. Other clinical signs are profuse diaphoresis, changes in mental status, and autonomic instability. The diagnosis is confirmed, but not excluded, when the following are observed:
- Recent treatment with neuroleptics within the past one to four weeks
- Hypothermia (above 38°C)
- Muscular rigidity
- Exclusion of other drug-induced, system, or neuropsychiatric illness
- At least five of the following: Change in mental status; Tachycardia (abnormally rapid heartbeat); Hypertension or hypotension; Diaphoresis or sialorrhea; Leu-kocytosis; Tremor; Incontinence; Increased creatine phosphokinase (CPK) or urinary myoglobin; and Metabolic acidosis
Diagnosis
Early diagnosis of NMS is essential to prevent fatality. Physicians begin by ruling out conditions with similar symptoms. Laboratory studies include a complete blood count; urine myoglobin; CPK; arterial blood gas; liver function tests; blood cultures; serum and urine toxic screening for cocaine, amphetamines, and other gents; blood urea nitrogen; and calcium and
KEY TERMS
Atypical antipsychotic —A class of newer generation antipsychotic medications that are used to treat schizophrenia and other psychotic disorders.
Dopamine —A neurotransmitter in the brain that helps regulate emotion and movement.
Dopamine agonist —A drug that binds to dopamine receptors and produces effects that are similar to dopamine.
Dopamine antagonist —A substance that binds to dopamine receptors, preventing dopamine from binding and triggering its response.
Electroencephalogram —A diagnostic technique that measures electrical activity in the brain.
Neuroleptic drugs —The class of drugs used to treat schizophrenia, mania, and other types of mental disorders.
Parkinson ’s disease—A degenerative condition of the central nervous system that results in reduced dopamine production, leading to symptoms such as tremors, muscle rigidity, and difficulty with balance and coordination.
phosphate levels. Blood tests of patients with NMS reveal high levels of creatine kinase, a muscle enzyme, as well as abnormally high levels of leukocytes (white blood cells). An electroencephalogram (EEG), which measures electrical activity in the brain, will show a slowing of brain function. Chest radiography is performed to rule out aspiration pneumonia. A lumbar puncture, sometimes with a preceding CT scan, is performed to diagnose meningitis in patients who have high fever and altered mental status.
Treatments
Because little research has been done on NMS, treatment guidelines are limited. The first line of treatment is to discontinue the medication that is believed to be causing the condition, exclude other medical conditions, begin aggressive supportive care, and administrate pharmacotherapies, such as benzodiaze-pines (diazepam ), muscle relaxants, and dopamine agonists (bromocriptine), which can be used to control symptoms. After the medication is stopped, most patients will improve within two weeks, although symptoms may persist for as long as several months. Doctors typically recommend waiting for at least two weeks after the patient’s symptoms have improved before restarting antipsychotic medications, to prevent a relapse of NMS. After that period, atypical antipsychotic medications are preferred over the older generation antipsychotic drugs, because they are associated with a lower risk of NMS.
Patients should be carefully monitored while recovering from NMS. Doctors will check the patient’s creatine kinase levels, as well as his or her overall health, and will ensure that the patient receives adequate nutrition and hydration and does not progress to kidney failure.
Prognosis
With early diagnosis and treatment, mortality from NMS can be prevented. However, because the condition can recur at any time, patients must be monitored over the long term.
Prevention
The only way to entirely prevent NMS is to avoid the use of neuroleptic drugs. But because NMS is rare, and because many patients rely on these drugs for the treatment of mental disorders, avoiding these drugs is neither practical nor feasible in many cases. However, using the newer atypical antipsychotics and/or lowering the dose may reduce the risk of NMS.
Resources
BOOKS
Bruton, Laurence, John Lazo, and Keith Parker. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: The McGraw-Hill Companies, 2006.
Caroff, Stanley N., MD, Paul E. Keck, Jr., MD, and Arthur Lazarus. Neuroleptic Malignant Syndrome and Related Conditions. 2d ed. Arlington, VA: American Psychiatric Publishing, 2003.
Kring, Ann M., Gerald C. Davison, John M. Neale, and Sheri L. Johnson. Abnormal Psychology. Hoboken, NJ: John Wiley & Sons, 2006.
Meyer, Jerrold S., and Linda F. Quenzer. Psychopharma-cology: Drugs, the Brain and Behavior. Sunderland, MA: Sinauer Associates, Inc., 2005.
ORGANIZATIONS
Mental Health America, 2000 N. Beauregard Street, Sixth Floor, Alexandria, VA 22311. Telephone: (800) 433-5959. http://www.nmha.org
National Institute of Mental Health, Public Information and Communications Branch, 6001 Executive Boulevard, Room 8184, MSC 9663, Bethesda, MD 20892-9663. Telephone: (866) 615-6464. http://www.nimh.nih.gov
National Parkinson Foundation, 1501 N.W. 9th Avenue/Bob Hope Road, Miami, FL 33136-1494. Telephone: (800) 327-4545. http://www.parkinson.org
Neuroleptic Malignant Syndrome Information Service, Box 1069, Sherburne, NY 13460-1069. Telephone: (888) 667-8367. http://www.nmsis.org
Stephanie N. Watson