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Emergency Medicine > TOXICOLOGY
Neuroleptic Malignant Syndrome
Article Last Updated: Sep 20, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Theodore I Benzer, MD, PhD, Instructor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Department of Emergency Medicine, Massachusetts General Hospital
Theodore I Benzer is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians
Editors: Mark S Slabinski, MD, FACEP, FAAEM, Mid-Atlantic Regional Director, Emergency Medicine Physicians, Ltd; John T VanDeVoort, PharmD, ABAT, Director of Pharmacy, Sacred Heart Hospital; Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Author and Editor Disclosure
Synonyms and related keywords:
neuroleptic malignant syndrome, neuroleptic medication, NMS, idiosyncratic reaction, muscular rigidity, autonomic dysfunction, haloperidol, fluphenazine, antipsychotic agents, prochlorperazine, promethazine, clozapine, risperidone, metoclopramide, amoxapine, lithium, dopamine D2-receptor antagonist, withdrawal of anti-Parkinson medication, respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, diffuse intravascular coagulation, DIC, rhabdomyolysis, pneumonia, renal failure, seizures, hyperthermia, profuse diaphoresis, sialorrhea, metabolic acidosis, dopamine receptor blockade, impaired temperature regulation
Background
The neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to a neuroleptic medication. The syndrome is characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction. Although potent neuroleptics (eg, haloperidol, fluphenazine) are more frequently associated with NMS, all antipsychotic agents, typical or atypical, may precipitate the syndrome. For example, these agents have been associated with NMS: prochlorperazine (Compazine), promethazine (Phenergan), clozapine (Clozaril), and risperidone (Risperdal). NMS has also been associated with non-neuroleptic agents that block central dopamine pathways such as metoclopramide (Reglan), amoxapine (Ascendin), and lithium.
Pathophysiology
All medications implicated in NMS have dopamine D2-receptor antagonist properties. NMS has been noted following withdrawal of anti-Parkinson medication. The clinical syndrome is thought to be secondary to decreased dopamine activity in the central nervous system (CNS) either from blockade of dopamine D2-receptors or from decreased availability of dopamine itself, and NMS shares similarities with malignant hyperthermia and the serotonin syndrome. Blockade of dopamine neurotransmission in the nigrostriatum and hypothalamus results in muscular rigidity and altered thermoregulation, respectively. Sympathetic nervous system activation or dysfunction may play a significant role in the pathogenesis of NMS.
Frequency
United States
Incidence is uncommon, with rates ranging from 0.02-12.2% of patients treated with a neuroleptic medication. Prospective studies and pooled data from the literature report an incidence of 0.07-0.2%. Because of increased awareness of this syndrome and efforts at prevention, the incidence is probably less now than in the past.
Mortality/Morbidity
- The incidence of mortality, once reported at 20-30% is now estimated at 5-11.6%. Death usually results from respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or diffuse intravascular coagulation (DIC).
- Morbidity from NMS includes rhabdomyolysis, pneumonia, renal failure, seizures, arrhythmias, DIC, and respiratory failure.
Sex
NMS has been reported to be more common in males, most likely because of increased use of neuroleptics in males. The male-to-female ratio is 2:1.
Age
No age predilection for NMS exists. NMS may occur in patients of any age who are receiving neuroleptics or other precipitating medications.
History
- Neuroleptic malignant syndrome (NMS) is more likely to develop following initiation of neuroleptic therapy or an increase in the dose.
- The onset can be within hours, but, on average, it is 4-14 days after initiation of therapy. However, NMS can occur at any time during neuroleptic use, even years after initiating therapy.
- Of those patients who develop NMS, 90% of them do so within 10 days.
- NMS is a heterogenous syndrome that spans a broad severity continuum. The diagnosis is made on clinical grounds based on the presence of certain historical, physical, and laboratory findings. The diagnosis is confirmed, but not necessarily excluded, by the presence of the following 5 criteria:
- Recent treatment with neuroleptics within past 1-4 weeks
- Hyperthermia (temperature above 38°C)
- Muscular rigidity
- At least 5 of the following:
- Change in mental status
- Tachycardia
- Hypertension or hypotension
- Diaphoresis or sialorrhea
- Tremor
- Incontinence
- Increased creatinine phosphokinase (CPK) or urinary myoglobin level
- Leukocytosis
- Metabolic acidosis
- Exclusion of other drug-induced, systemic, or neuropsychiatric illness
- Clinical signs
- Hyperthermia
- Profuse diaphoresis
- Generalized rigidity (lead pipe)
- Mental status changes
- Autonomic instability
Physical
- Hyperthermia
- Diaphoresis
- Generalized muscular rigidity (lead pipe)
- Tachycardia
- Hypertension or hypotension
- Tremor
- Incontinence
- Altered mental status
- Tachypnea
Causes
- All classes of neuroleptics (dopamine D2-receptor antagonists) are associated with NMS, and dopamine receptor blockade is considered the cause of NMS.
- Experimental blockade of dopamine in the striatum can cause rigidity, tremor, and rhabdomyolysis.
- Blockade of dopamine in the hypothalamus can cause impaired temperature regulation and hyperthermia.
- This theory does not explain why only some patients develop NMS. It also does not explain why patients rechallenged with neuroleptics do not always redevelop NMS.
- Risk factors for developing NMS include the following:
- Increased ambient temperature
- Dehydration
- Patient agitation or catatonia
- Rapid initiation or dose escalation of neuroleptic
- Withdrawal of anti-Parkinson medication
- Use of high-potency agents and depot intramuscular preparations
- History of organic brain syndrome or affective disorder
- History of NMS
- Concomitant use of predisposing drugs (eg, lithium, anticholinergic agents)
Encephalitis
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Renal Failure, Acute
Rhabdomyolysis
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Toxicity, Amphetamine
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Toxicity, Cocaine
Toxicity, Cyclic Antidepressants
Toxicity, Lithium
Toxicity, MDMA
Toxicity, Medication-Induced Dystonic Reactions
Toxicity, Methamphetamine
Toxicity, Monoamine Oxidase Inhibitor
Toxicity, Neuroleptic Agents
Toxicity, Selective Serotonin Reuptake Inhibitor
Withdrawal Syndromes
Other Problems to be Considered
Parkinsonism
Pheochromocytoma
Serotonin syndrome
Strychnine toxicity
Dystonic reactions
Lethal catatonia
Lab Studies
- Complete blood count (CBC)
- Blood cultures
- Liver function tests (LFTs)
- Blood urea nitrogen (BUN) and creatinine levels
- Calcium and phosphate levels
- Creatine kinase level
- Urine myoglobin level
- Arterial blood gas (ABG) level
- Prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR)
- Serum and urine toxicologic screening (eg, salicylates, cocaine, amphetamines)
Imaging Studies
- Perform chest radiography, if aspiration pneumonia is a concern.
- Perform a head CT to evaluate for a structural lesion or before a lumbar puncture (LP). No universal agreement exists on the absolute need for a CT scan before the LP in patients without clinical evidence of a structural lesion; the decision is left to the individual practitioner.
Procedures
- The LP is indicated to rule out meningitis in patients exhibiting fever and altered mental status.
Prehospital Care
- Any patient being evaluated by prehospital personnel requires assessment of the airway, breathing, and circulation (ABCs).
- Any patient with altered mental status should receive thiamine, dextrose (or rapid glucose determination), and naloxone.
- Prehospital personnel must assess the patient's safety and, if necessary, restrain the patient. Restraint use in agitated, hyperthermic patients can increase the risk of significant morbidity and mortality in various disease states (eg, NMS, cocaine intoxication, amphetamine abuse). Chemical restraints (eg, benzodiazepines), if available, may be preferable in such situations.
Emergency Department Care
Successful treatment requires prompt recognition, withdrawal of neuroleptic agent, exclusion of other medical conditions, aggressive supportive care, and administration of certain pharmacotherapies. - A careful history should be taken before starting a new neuroleptic medication.
- NMS may recur when medications are restarted.
- Monitor a patient carefully while administering neuroleptic medication to prevent excessive agitation and dehydration because these conditions may predispose a patient to NMS.
- Benzodiazepines and physical restraints may be useful.
- Stop all neuroleptics.
- Correct volume depletion and hypotension with intravenous fluids.
- Methods to reduce the temperature include the following:
- Cooling blankets
- Antipyretics
- Cooled intravenous fluids
- Ice packs
- Evaporative cooling
- Various pharmacotherapies to reduce rigidity (see below)
- When rhabdomyolysis occurs, maintain vigorous hydration and alkalinize the urine with intravenous NaHCO3 to prevent renal failure.
- Electroconvulsive therapy (ECT) has been used to treat NMS. It can help with the alteration of temperature, level of consciousness, and diaphoresis. It may also be useful in treating the underlying psychiatric disease in patients who are unable to take neuroleptics. ECT with anesthesia has generally been safe with no increased incidence of malignant hyperthermia from succinylcholine administration.
Consultations
- Consultation with a neurologist may be needed if the diagnosis is in question.
- Consultation with a psychiatrist can be helpful to manage the underlying psychiatric disease once the neuroleptics have been withdrawn.
- Consultation with a nephrologist is needed if the patient develops rhabdomyolysis and renal failure.
Pharmacotherapy recommendations are from noncontrolled prospective and retrospective studies and case reports; no controlled studies exist. The mortality rate has declined from approximately 20% to less than 10%. The decrease may be due to improved supportive care modalities. Whether the addition of dantrolene to dopamine agonists will improve the prognosis is unclear. A recent review of case reports indicates that combining dantrolene with other pharmacotherapy prolongs the recovery period. Using dantrolene as monotherapy seemed to be associated with increased mortality. Dopaminergic medications can be especially useful if the NMS was caused by withdrawal of anti-Parkinson medication.
Drug Category: Dopamine agonists
Dopamine agonists reverse the dopamine D2-receptor blockade produced by neuroleptics. In retrospective studies, agonists appear to decrease mortality and shorten the course of NMS.
| Drug Name | Bromocriptine (Parlodel) |
|---|
| Description | Semisynthetic, ergot alkaloid derivative. Strong, dopamine D2-receptor agonist. Partial dopamine, D1-receptor agonist.
May relieve akinesia, rigidity, and tremor associated with Parkinson disease. Stimulates dopamine receptors in the corpus striatum.
Approximately 28% is absorbed from the GI tract and metabolized in the liver. Approximate elimination half-life is 50 h with 85% excreted in feces and 3-6% eliminated in urine.
Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess dosage titration q2wk. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.
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| Adult Dose | 7.5-30 mg/d PO divided tid (2.5-10 mg/dose); not to exceed 100 mg/d |
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| Pediatric Dose | <15 years: Not recommended
>15 years: Not established |
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| Contraindications | Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders |
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| Interactions | Toxicity may increase with ergot alkaloids, erythromycin, isometheptene, phenylpropanolamine (recalled from US market), and ethanol; amitriptyline, butyrophenones, zotepine, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | Caution in renal or hepatic disease, breastfeeding women, cardiovascular disease, and concomitant antihypertensive therapy |
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| Drug Name | Amantadine (Symmetrel) |
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| Description | May act to release dopamine from dopaminergic terminals and other central sites. |
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| Adult Dose | 100-300 mg PO bid |
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| Pediatric Dose | <1 year: Not established
1-9 years: 4.4-8.8 mg/kg/d PO; not to exceed 150 mg/d PO qd or divided bid
9-12 years: 100 mg PO bid
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Drugs with anticholinergic or CNS stimulant activity increase toxicity; concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, seizures, and those receiving CNS stimulant drugs; do not discontinue this medication abruptly |
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| Drug Name | Levodopa and carbidopa (Sinemet) |
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| Description | Large neutral amino acid absorbed in proximal small intestine by saturable carrier-mediated transport system. Absorption is decreased by meals, which include other large neutral amino acids. Only patients with meaningful motor fluctuations need consider a low protein or protein redistributed diet. Greater consistency of absorption achieved when levodopa taken >1 h after meals. Nausea often is reduced if levodopa is taken immediately following meals. Some patients with nausea benefit from additional carbidopa in doses up to 200 mg/d. Half-life of levodopa/carbidopa is approximately 2 h.
Provide at least 70-100 mg/d carbidopa. When more carbidopa required, substitute 25/100 tab for each 10/100 tab. When more levodopa required, substitute 25/250 tab for the 25/100 or 10/100 tab.
Sustained-release formulation of levodopa/carbidopa is more slowly absorbed and provides more sustained levodopa levels than the immediate-release dosage form. Effective as immediate-release formulation when levodopa is required initially and may be more convenient when fewer intakes are desired.
Most patients have been adequately treated with 2-8 tab/d (divided doses) at intervals of 4-8 h while awake. Higher doses (>12 tab/d) and intervals <4 h have been used but are not usually recommended. If <4 h interval used or if divided doses are not equal, give smaller doses at end of day. Allow at least a 3-d interval between dosage adjustments. May administer as whole or half tab, which should not be crushed or chewed.
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| Adult Dose | 25/250 mg PO tid/qid |
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| Pediatric Dose | Not established; 10/100 mg/d PO suggested if patient aged 6-10 y; increase by 1 tab qod prn; not to exceed 60/600 mg/d |
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| Contraindications | Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions |
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| Interactions | Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects; toxicity increases with antacids and MAOIs |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Certain adverse CNS effects (eg, dyskinesias) may occur at lower dosages and earlier in therapy with SR form; caution in MI, arrhythmias, asthma, and peptic ulcer disease; high-protein diets should be distributed throughout the day to avoid fluctuations in levodopa absorption; short-term adverse effects include nausea, hypotension, and hallucinations; long-term adverse effects include motor fluctuations and dyskinesia (chorea) |
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Drug Category: Skeletal muscle relaxant
These agents stimulate muscle relaxation by modulating skeletal muscle contractions at site beyond myoneural junction and acting directly on muscle itself.
| Drug Name | Dantrolene (Dantrium) |
|---|
| Description | Inhibits ionized calcium release from sarcoplasmic reticulum and results in direct muscle relaxation. Used to treat NMS-associated muscular rigidity and hyperthermia.
Based on retrospective studies, the addition of dantrolene to bromocriptine does not appear to offer additional advantage. Dantrolene therapy alone appears to shorten the duration of illness, but use is controversial. Reduction of fever and rigidity is not immediate but occurs over a mean of 1.7 d. When rapid rigidity reduction is necessary, alternative means (eg, neuromuscular paralysis) may be preferable. A recent review of case reports indicates that adding dantrolene to other medication prolongs the course of NMS. Therapy with dantrolene alone had increased mortality. The only benefit to dantrolene was in patients who prior to NMS had been on a neuroleptic monotherapy.
Most patients respond to 400 mg/d or less. |
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| Adult Dose | 1-3 mg/kg IV initial, followed by 10 mg/kg/d PO/IV in divided doses |
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| Pediatric Dose | 0.5 mg/kg PO/IV bid initial, increase to 0.5 mg/kg bid/qid, then by increments of 0.5 mg/kg to 3 mg/kg bid/qid prn; not to exceed 100 mg qid |
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| Contraindications | Documented hypersensitivity; active hepatic disease (hepatitis and cirrhosis) |
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| Interactions | Toxicity may increase with the coadministration of clofibrate and warfarin; coadministration with estrogen may increase hepatotoxicity in women >35 y; coadministration with verapamil may lead to hyperkalemia |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | May cause hepatotoxicity (use only for recommended indications); caution in impaired pulmonary function and severe cardiac insufficiency; may cause photosensitivity with exposure to sunlight; unlabeled use for NMS; G-6-PD deficiency |
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Further Inpatient Care
- Additional evaluation and treatment should be in an inpatient setting, preferably an ICU.
- The patient must be monitored closely to rule out underlying infection.
- Adequate hydration must be maintained.
- Rhabdomyolysis must be diagnosed and treated aggressively with alkalinization and hydration to prevent renal failure.
- The patient's psychiatric disease must be evaluated and treated during withdrawal of the neuroleptic medication.
- Challenge with an atypical antipsychotic may be appropriate since these drugs have a lower incidence of neuroleptic malignant syndrome (NMS).
- Treatment with ECT may be useful to treat the underlying psychiatric disease after an episode of NMS.
Further Outpatient Care
- NMS may be prolonged. If the patient is discharged, close follow-up care should be given to monitor residual symptoms. If neuroleptics are to be reinstituted, they should be administered at relatively low initial doses.
Transfer
- If NMS is diagnosed in a psychiatric facility, the patient should be transferred to an acute care medical facility where intensive monitoring and treatment is available.
Deterrence/Prevention
- Take a careful history before starting a new neuroleptic medication. NMS frequently recurs when medications are restarted.
- Monitor a patient carefully while administering neuroleptic medication to prevent excessive agitation and dehydration because these conditions may predispose a patient to NMS.
- Benzodiazepines and physical restraints may be useful.
Complications
- Rhabdomyolysis
- Renal failure
- Seizures
- Respiratory failure
- Aspiration pneumonia
- Decompensation of psychiatric disease with the withdrawal of neuroleptics
- DIC
Prognosis
- Increased mortality, up to 50%, is seen in patients who develop renal failure during an episode of NMS.
- In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and with good supportive care, the prognosis for recovery is good.
- The syndrome may last 7-10 days after discontinuing oral neuroleptics and up to 21 days after using depot neuroleptics (eg, fluphenazine).
Patient Education
- After an episode of NMS, the patient must be told that he or she is at risk for recurrence if rechallenged with a neuroleptic medication. The patient should report this reaction to all health care providers.
Medical/Legal Pitfalls
- Failure to consider this diagnosis and to institute prompt therapies
- Failure to consider other non-NMS diagnoses as the cause of similar symptoms
- Failure to obtain a prior history of NMS before instituting medical therapies with any medications known to cause NMS
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Neuroleptic Malignant Syndrome excerpt Article Last Updated: Sep 20, 2007
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