Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group of antipsychotic drugs or major tranquilizers (neuroleptics). These drugs are commonly prescribed for the treatment of schizophrenia and other neurological, mental, or emotional disorders. Several of the more commonly prescribed neuroleptics include thioridazine, haloperidol, chlorpromazine, fluphenazine and perphenazine.
The syndrome is characterized by high fever, stiffness of the muscles, altered mental status (paranoid behavior), and autonomic dysfunction. Autonomic dysfunction alludes to defective operations of the components of the involuntary (autonomic) nervous system, leading to wide swings of blood pressure, excessive sweating and excessive secretion of saliva.
A genetic basis for the disorder is suspected but not proven. It does appear to be clear that a defect in the receptors to dopamine (dopamine D2 receptor antagonism) is an important contributor to the cause of neuroleptic malignant syndrome.
Symptoms of neuroleptic malignant syndrome usually include very high fever (102 to 104 degrees F), irregular pulse, accelerated heartbeat (tachycardia), increased rate of respiration (tachypnea), muscle rigidity, altered mental status, autonomic nervous system dysfunction resulting in high or low blood pressure, profuse perspiration, and excessive sweating.
Other symptoms may include liver or kidney failure, abnormally high potassium levels (hyperkalemia), major destruction of skeletal muscle tissue (rhabdo-myolysis) or blood clots in veins and arteries.
Neuroleptic malignant syndrome comes about, most likely, as a result of “dopamine D2 receptor antagonism”. Dopamine is a chemical substance (neurotransmitter) found in the brain and elsewhere in the central nervous system that acts to convey messages from one cell to another. In some way, the use of a particular drug blocks the receptor in the brain cell for dopamine.
When the dopamine receptors in the hypothalamus or another bundle of nerve fibers (nigrostriatal pathways) and/or the spinal cord are blocked, increased muscle rigidity is the result. The interference with the dopamine receptors in the hypothalamus is also probably responsible for high body temperature, as well as the swings in blood pressure.
Some clinicians believe that neuroleptic malignant syndrome may be related to malignant hyperthermia, a genetic disorder characterized by an abnormal reaction to anesthesia drugs. (See related disorders section for more information about malignant hyperthermia.)
Neuroleptic malignant syndrome may affect any person taking neuroleptic drugs. Men appear to be at higher risk than women. Some clinicians believe that the stronger neuroleptic medications are more likely to precipitate an attack of NMS.
Although two-thirds of cases are thought to occur within the first week of start of treatment, the syndrome may begin at any time during treatment.
Recurrence of an attack of NMS is not uncommon. The risk of recurrence is closely related to the time elapsed between the end of the original episode of neuroleptic malignant syndrome and the beginning of renewed administration of an antipsychotic drug. If the waiting period is two weeks or less, about 63% will have a recurrence. If the waiting period is more than two weeks, the percentage of patients experiencing a relapse drops to about 30.
The diagnosis of neuroleptic malignant syndrome is based on the presence of characteristics that include treatment with neuroleptic drugs within the past 1-4 weeks. high body temperature (greater than 38 degrees centigrade); muscle rigidity; and at least five of the following:
Change in mental status
Rapid heart beat (tachycardia)
Low or high blood pressure (hypo- or hypertension)
Excessive sweating (diaphoresis)
Excessive saliva production (sialorrhea)
Increased creatine phosphokinase, or increased urinary myoglobin
Increased number of white blood cells (leukocytosis)
Increased concentrations of metabolic acids in blood and urine
Exclusion of other drug-induced psychiatric or systemic illness.
Treatment of neuroleptic malignant syndrome consists of withdrawal of
neuroleptic medications under a doctor's supervision, immediate measures to restore appropriate water and nutrient levels, and steps to lower the individual's body temperature. Medications prescribed as treatment may include skeletal muscle relaxants, such as dantrolene; stimulators of dopamine production and activity, such as bromocriptine; and/or continuous perfusion of central nervous system depressants, such as diazepam.
Complications that may result from neuroleptic malignant syndrome, such as kidney (renal) insufficiency, deficiency of oxygen reaching the tissues (hypoxia), and/or decreased alkalinity of the blood and tissues (acidosis) can be extremely serious and must be treated immediately. Once patients have recovered from neuroleptic malignant syndrome, about 87% will be able to tolerate an antipsychotic at some point in the future. Physicians usually switch to a different antipsychotic class and to an atypical antipsychotic. Such patients must be carefully monitored since recurrences of neuroleptic malignant syndrome are not infrequent.
Electroconvulsive treatments have been prescribed for patients with neuroleptic malignant syndrome with varied results.
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Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malignant syndrome and related conditions (2nd ed). Washington, DC: American Psychiatric Publishing, 2003.
Rowland LP, ed. Merritt’s Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:697.
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1568; 1577-78.
Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry/V. 5th ed. William & Wilkins. Baltimore, MD; 1989:783-85; 1624-25.
Waldorf S. AANA journal course. Update for nurse anesthetists. Neuroleptic malignant syndrome. AANA J. 2003;71:389-94.
Hadad E. Weinbroum AA, Ben-Abraham R. Drug-induced hyperthermia and muscle rigidity: a practical approach. Eur J Emerg Med. 2003;10:149-54.
Rodnitzky RL. Drug-induced movement disorders in children. Semin Pediatr Neurol. 2003;10:80-87.
Kogoj A, Velikonja I. Olanzapine induced neuroleptic malignant syndrome – a case review. Hum Psychopharmacol. 2003;18:301-09.
Kawanishi C. Genetic predisposition to neuroleptic malignant syndrome: implications for antipsychotic therapy. Am J Pharmacogenetics. 2003;3:89-95.
Ikebe S, Harada T, Hashimoto T, et al. Prevention and treatment of neuro-leptic malignant syndrome in Parkinson’s disease: a consensus statement of the malignant syndrome research group. Parkinsonism Relat Disord. 2003;9 Suppl 1:S47-49.
Mizuno Y, Takubo H, Mizuta E, et al. Malignant syndrome in Parkinson’s disease: concept and review of the literature. Parkinsonism Relat Disord. 2003;9 Suppl 1:S3-9.
Farver DK. Neuroleptic malignant syndrome induced by atypical antipsychotics. Expert Opin Drug Saf. 2002;2:21-35.
Kontaxakis VP, Havaki-Kontaxaki BJ, Christodoulou NG, et al. Olanzpine-associated neuroleptic malignant syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:897-902.
Caroff SN, Mann SC, Campbell EC, et al. Movement disorders associated with atypical antipsychotic drugs. J Clin Psychiatry. 2002;63 Suppl 4: 12-19.
Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251 Suppl1:I8-13.
Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q. 2001;72:325-36.
Fink M. Catatonia: syndrome or schizophrenia subtype? Recognition and treatment. J Neural Transm. 2001;108:637-44.
FROM THE INTERNET
Sholevar DP, Sholevar EH. Neuroleptic Malignant Syndrome. eMedicine. Last Updated: November 6, 2002. 17pp.
Benzer T. Neuroleptic Malignant Syndrome. eMedicine. Last Updated: July 25, 2002. 13pp.
NINDS Neuroleptic Malignant Syndrome Information Page. Reviewed 1-23-2002. 2pp.
Caroff SN, Mann SC, Campbell EC. What is NMS? Neuroleptic Malignant Syndrome.
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