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10/15/2015

Neuroleptic Malignant Syndrome: Practice Essentials, Background,
Pathophysiology

Neuroleptic Malignant Syndrome
Author: Theodore I Benzer, MD, PhD; Chief Editor: Asim Tarabar, MD
more... Updated: Feb 12, 2015

Practice Essentials
Neuroleptic malignant syndrome (NMS) is a rare, but lifethreatening, idiosyncratic
reaction to neuroleptic medications that is characterized by fever, muscular
rigidity, altered mental status, and autonomic dysfunction. NMS often occurs
shortly after the initiation of neuroleptic treatment, or after dose increases.

Signs and symptoms
The key to diagnosis is that NMS occurs only after exposure to an neuroleptic
drug. On average, onset is 414 days after the start of therapy; 90% of cases occur
within
10 days. However, NMS can occur years into therapy. Once the syndrome starts,
it usually evolves over 2472 hours.
Cardinal features are as follows:
Severe muscular rigidity
Hyperthermia (temperature
>38°C) Autonomic instability
Changes in the level of consciousness
A summary of the clinical features of neuroleptic malignant syndrome includes
the following:
Muscular rigidity (typically, “lead pipe”
rigidity) Hyperthermia (temperature >38°C)
Diaphoresis
Pallor
Dysphagia
Dyspnea
Tremor
Incontinence
Shuffling gait
Psychomotor agitation
Delirium progressing to lethargy, stupor, coma
Other general examination findings indicative of autonomic dysregulation
include the following:
Diaphoresis
Sialorrhea
Tachycardia
Tachypnea, respiratory distress (31% of
cases) Increased or labile blood pressure
Hypoxemia (low pulse oximeter
reading) See Clinical Presentation for more
detail. Diagnosis
No laboratory test result is diagnostic for NMS. Laboratory studies are used to
assess severity and complications or rule out other diagnostic possibilities. A
summary of the laboratory abnormalities that may be found in neuroleptic
malignant syndrome includes the following:
Increased LDH
Increased creatine kinase (50100% of cases)
Increased AST and ALT
Increased alkaline
phosphatase Hyperuricemia
Hyperphosphatemia
Hyperkalemia
Myoglobinemia
Leukocytosis (7098% of cases)
Thrombocytosis
Proteinuria
Decreased serum iron
[1]
Increased CSF
protein Hypocalcemia
Myoglobinuria
Metabolic acidosis
See Workup for more detail.

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Pathophysiology The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. and muscle cell breakdown. The syndrome was first described by Delay and colleagues in 1960. and prognosis difficult to define. over the past 30 years. and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. cutaneous vasodilation.Management Treatment of NMS is mainly supportive; it is directed toward controlling the rigidity and hyperthermia and preventing complications (eg. Traditional agents (eg. prospective manner make clinical features. haloperidol) act through inhibition of dopaminergic receptors. resulting in increased contractility. chlorpromazine. altered mental status. including rigidity and tremor. [5] A drug's potential for inducing NMS seems to parallel its antidopaminergic activity. is uncertain. In this model. NMS has also been precipitated by the abrupt withdrawal of antiParkinson medication. symptoms will report t o f ind out > resolve in 12 weeks. The value of other interventions. muscular rigidity. However. while nigrostriatal blockade results in muscular rigidity. respiratory failure. treatment. the low incidence of this syndrome and the consequent difficulty in studying it in a controlled. Atypical antipsychotic drugs that may cause NMS include the following: Olanzapine Risperidone Paliperidone Aripiprazole Ziprasidone Amisulpride Quetiapine The secondgeneration antipsychotic agent clozapine may also be associated with the development of NMS. however. idiosyncratic reaction to neuroleptic medications that is characterized by fever. renal failure). NMS frequently occurs shortly after the initiation of neuroleptic treatment. Successful treatment requires prompt recognition. See Neuroleptic Agent Toxicity for discussion of the range of adverse effects seen with therapeutic doses and overdoses of these drugs. and electroconvulsive therapy. nigrostriatal pathways. though not as potent as those of the traditional agents. In V iew our 2015 Wom en as P hysician Leaders most cases. which effectively decreases the domaminergic activity of the brain. predisposing conditions. aggressive supportive care. The mean onset is 10 days after starting the new medication. exclusion of other medical conditions. sweating). bromocriptine. and while they are not classified accurately as neuroleptics they can cause NMS. Onset of NMS may also follow dose increases of an established medication. Of note. withdrawal of neuroleptic agent. such as dantrolene. . amantadine. Peripherally. rigidity. See Treatment and Medication for more detail. Background Neuroleptic malignant syndrome (NMS) is a rare. whereas the secondgeneration (atypical) agents work by causing blockade of serotonin receptors.[4] In general. which can contribute to hyperthermia. central D2 receptor blockade in the hypothalamus. While some clear risk factors for NMS have been identified. NMS has been associated with a variety of drugs that lead to decreased dopamine receptor activation. These agents also have dopamineblocking properties. it appears to be less likely to produce extrapyramidal features. and administration of certain pharmacotherapies (see Treatment and Medication). Episodes precipitated by longacting depot injections of neuroleptics can last as long as a month. No clear relationship has been established between neuroleptic dosage and risk of developing neuroleptic malignant syndrome. What deters female physicians from The most important becoming leaders? intervention is to discontinue all neuroleptic agents. [2] Monitoring and management in an ICU is recommended. but lifethreatening. antipsychotics lead to increased calcium release from the sarcoplasmic reticulum. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heatdissipating mechanisms (eg. and autonomic dysfunction. rhabdomyolysis. [3] Neuroleptic drugs are primarily used to treat schizophrenia and other psychotic states. in patients treated with highpotency antipsychotics.

7] The resulting sympathoadrenal hyperactivity and dysregulation leads to . D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. [6.Beyond these direct effects.

12% in patients taking neuroleptics. 20] Sex and agerelated variations in incidence Neuroleptic malignant syndrome has been reported to be more common in males. including male sex (2:1 ratio) and age younger than 40 years. Case reports have been published on neuroleptic malignant syndrome occurring in identical twins as well as in a mother and two of her daughters. While that has not been proven in controlled studies. Because of increased awareness of this syndrome and efforts at prevention. [9] The clearest risk factors for neuroleptic malignant syndrome relate to the time course of therapy. the risk of recurrence is strongly related to the elapsed time between the episode and restarting antipsychotics. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. . [15] Data largely come from case control studies rather than prospective randomized trials. the incidence is probably lower now than in the past. [18] Onset of neuroleptic malignant syndrome ranges from 144 days after initiation of neuroleptic drug therapy; mean onset is 10 days.14%. [43. The one large randomized trial conducted in China showed an incidence of 0. haloperidol decanoate. 44] Given the potentially life threatening nature of neuroleptic malignant syndrome. fluphenazine decanoate. However. [19.[43] Delaying reintroduction of antipsychotic medication until at least 2 weeks after the resolution of symptoms is typically recommended. Epidemiology In the United States. [16] The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics. Etiology All classes of antipsychotics have been associated with neuroleptic malignant syndrome. including lowpotency neuroleptics. and the newer (or atypical) antipsychotics. several such states have been proposed as risk factors for neuroleptic malignant syndrome. Lazarus et al reported neuroleptic malignant syndrome occurring in 67% of patients within 1 week and 96% of patients within 30 days following administration of neuroleptics. Other potential risk factors include the following: Dehydration [12] Agitation [12] Exhaustion Malnutrition Organic brain syndromes Nonschizophrenic mental illness Lithium use Past history of electroconvulsive therapy Warm and humid environments Inconsistent use of neuroleptics Postpartum period [13] Genetic factors also might play a role. [17] A retrospective study conducted in India showed an incidence of 0. using an atypical antipsychotic rather than a traditional agent. Neuroleptic malignant syndrome has been reported most frequently in patients taking haloperidol and chlorpromazine. Strongly associated factors are as follows[10] : Highpotency neuroleptic use Highdose neuroleptic use Rapid increase in neuroleptic dose Depot injectable (longacting) neuroleptic use (ie. No data suggest geographic or racial variation.2% of patients taking neuroleptics. [45] The majority of patients who develop neuroleptic malignant syndrome will be able to tolerate an antipsychotic at some point in the future. The risk of recurrence may be reduced by switching to a different antipsychotic class and. those features may simply indicate the higher usage of potent neuroleptics in this population. fluphenazine enanthate.[8] Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome. Lithium at toxic levels may also reportedly cause neuroleptic malignant syndrome. in a given region. risperdal consta) Prior episodes of neuroleptic malignant syndrome Recent episode of catatonia [11] A number of demographic features have been implicated. if possible. [14] In patients who have experienced an episode of neuroleptic malignant syndrome.072. reintroduction of antipsychotic treatment must be approached cautiously. highpotency neuroleptics. The maletofemale ratio is 2:1.autonomic dysfunction. neuroleptic malignant syndrome has been variably reported as occurring in 0. especially neuroleptics. although that most likely reflects greater neuroleptic usage rather than greater susceptibility.

The mortality rate rises to about 50% if neuroleptic malignant syndrome is complicated by renal failure. Complications Complications of neuroleptic malignant syndrome include dehydration from poor oral intake. the mortality rate is estimated at 511. the syndrome may last 710 days after discontinuation of the drug. Although NMS is rare in children. acute renal failure from rhabdomyolysis. Patients who have previously experienced episodes of neuroleptic malignant syndrome are at risk for recurrences. In those who have received depot neuroleptics (eg. and deep venous thrombosis and pulmonary embolism from rigidity and immobilization. clinicians should explain and educate the patient and caretakers about possible adverse effects of the medications. No consistent longterm physical. but the syndrome may occur in patients of any age who are receiving neuroleptics or other precipitating medications.The reported mean age of patients experiencing neuroleptic malignant syndrome is 40 years.6%. because the literature on this subject consists largely of case reports and because the diagnostic parameters used have been inconsistent. In patients who develop neuroleptic malignant syndrome after taking an oral agent. However. Most series suggest. is now estimated at 511. mortality rates as high as 76% have been reported. the true rate of mortality from neuroleptic malignant syndrome might be much lower. which is very important because most patients taking neuroleptics require them to maintain a reasonable functional status. [21] Prognosis The prognosis in patients with neuroleptic malignant syndrome depends on how promptly treatment is instituted and on the presence of associated complications. Studies have also found that the mortality rate has been decreasing over the past 2 decades. however. Some small case series suggest that onset in elderly patients might occur after a longer duration of antipsychotic use. After an episode of neuroleptic malignant syndrome. arrhythmias. The mortality rate in patients with neuroleptic malignant syndrome. cardiovascular collapse. In some series. DIC). In the absence of rhabdomyolysis. the majority of these patients will be able to tolerate another antipsychotic. educational approaches can help patients and their relatives to understand what has happened to the patient.6%. [20] Differential incidence simply might reflect a population that has a high rate of antipsychotic usage. or aspiration pneumonia. why . Most patients taking antipsychotic medicines are being treated for a severe and persistent psychiatric disorder; a high likelihood exists that a patient will relapse while off antipsychotics. and with good supportive care. especially if antipsychotics are restarted shortly afterward. renal failure. thromboembolism. [22] Renal failure is associated with a 50% mortality rate. renal failure. cognitive. that the mortality rate is 1020%. the syndrome may last up to a month. although sequelae may result from such secondary complications as prolonged hypoxia or ischemic encephalopathy. Symptoms of NMS in children are consistent with those described in adults. once reported at 2030%. the prognosis for recovery is good. When reporting bias is factored in. Avoiding antipsychotics can cause complications related to uncontrolled psychosis. respiratory failure. or laboratory sequelae have been attributed to neuroleptic malignant syndrome alone. A summary of the potential complications of neuroleptic malignant syndrome includes the following: Rhabdomyolysis Renal failure Cardiovascular arrhythmias and collapse Aspiration pneumonia Respiratory failure Seizure Pulmonary embolism and deep venous thrombosis (DVT) Hepatic failure Disseminated intravascular coagulation (DIC) Decompensation of psychiatric disease following the withdrawal of neuroleptics Mortality/morbidity Mortality from neuroleptic malignant syndrome is very difficult to quantify. Mortality is caused by one or more complications (eg. Currently. studies suggest that clinicians should maintain a high level of suspicion in children. Patient Education When prescribing neuroleptic medications. fluphenazine). neurological. Researchers have noted sporadic cases of prolonged rigidity and longterm neuropsychological deficits.

MD Instructor. Leonard M Miller School of Medicine; Medical Director. American College of Emergency Physicians. American Trauma Society. National Association of EMS Physicians. MMM is a member of the following medical societies: American Association for Thoracic Surgery. MD is a member of the following medical societies: American Academy of Pediatrics. American College of Medical Toxicology. This education may help patients and their relatives to decide about giving consent to restart antipsychotics. University of Illinois College of Medicine at Peoria; . MBBS. MD. Department of Emergency Medicine. Michael J Burns. Department of Surgery. American College of Emergency Physicians Disclosure: Nothing to disclose. Girish G Deshpande. Coauthor(s) Mary C Mancini. Department of Pediatrics. Policy Core. FAAP Associate Professor of Pediatrics. Pediatric Critical Care Transport. Massachusetts General Hospital Theodore I Benzer. American Surgical Association. Helpful Web sites for patients include the following: Neuroleptic Malignant Syndrome Information Service NINDS Neuroleptic Malignant Syndrome Information Page (National Institute of Neurological Disorders and Stroke) Clinical Presentation Contributor Information and Disclosures Author Theodore I Benzer. Uniformed Services University of the Health Sciences; Clinical Professor of Psychiatry. American Neuropsychiatric Association. Department of Emergency Medicine. For patient education information. Injury Research Center. YaleNew Haven Hospital Disclosure: Nothing to disclose. Jackson Memorial Medical Center; Medical Manager. University of Miami. Yale University School of Medicine; Consulting Staff. Timothy E Corden. Acknowledgements Iqbal Ahmed. PhD is a member of the following medical societies: Alpha Omega Alpha. Clinical Professor of Geriatric Medicine. MD. American Heart Association. PhD. and changes of consciousness) and the importance of immediately seeking medical care if these arise. University of Hawaii. FEMA. Medical Toxicology. PICU. and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Harvard University Medical School. Task Force 2; Pediatric Medical Director. Palliative Care Team. and Wisconsin Medical Society Disclosure: Nothing to disclose. Society of Thoracic Surgeons. Inc G Patricia Cantwell. Division of Hospice Care Southeast Florida. Chief Editor Asim Tarabar. and Wilderness Medical Society Disclosure: Nothing to disclose. Tilli Kids – Pediatric Initiative. American Society of Clinical Psychopharmacology. If they give consent. Phi Beta Kappa. MD is a member of the following medical societies: American Academy of Clinical Toxicology. FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine. Division of Pediatric Critical Care Medicine. Chair of Quality and Safety. MD. Urban Search and Rescue. G Patricia Cantwell. Society of Critical Care Medicine. American Academy of Pediatrics. Director. Director of Toxicology. they have to be aware of the early signs of neuroleptic malignant syndrome (eg. MD. and the possibility of recurrence if antipsychotic therapy is restarted. Society of Critical Care Medicine. MD. MD. Medical College of Wisconsin; Associate Director. Department of Emergency Medicine. hyperthermia. MBBS. MD Associate Professor of Pediatrics. South Florida. MD Assistant Professor. American Association for Geriatric Psychiatry. American College of Surgeons. PhD Assistant Professor in Medicine. Chief. Department of Emergency Medicine. see Neuroleptic Malignant Syndrome. Department of Psychiatry. MD. American Psychiatric Association. and Royal College of Psychiatrists Disclosure: Nothing to disclose. Holtz Children's Hospital. Director. FCCM Professor of Clinical Pediatrics. Louisiana State University School of Medicine in Shreveport Mary C Mancini.the neuroleptic malignant syndrome has developed in the past. MMM Professor and Chief of Cardiothoracic Surgery. FRCPsych (UK) is a member of the following medical societies: Academy of Psychosomatic Medicine. FRCPsych (UK) Faculty. Interim Director and Division Chief of Critical Care Medicine. Harvard Medical School; Director of the ED Observation Unit. CoDirector. Tripler Army Medical Center; Clinical Professor of Psychiatry. Beth Israel Deaconess Medical Center Michael J Burns. Phi Beta Kappa Disclosure: Nothing to disclose. John A Burns School of Medicine Iqbal Ahmed. Children's Hospital of Wisconsin Timothy E Corden. PhD. MBBS. rigidity.

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