Hospital Medicine

Neuroleptic malignant syndrome

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Neuroleptic Malignant Syndrome

I. What every physician needs to know.

Neuroleptic malignant syndrome (NMS) is a rare, potentially fatal complication of treatment with dopamine antagonists (e.g., neuroleptics such as haloperidol) or less commonly acute withdrawal of dopamine agonists (e.g., Parkinson's medications such as carbidopa-levodopa). The classic clinical presentation is a tetrad of fever, muscle rigidity, altered mental status, and autonomic dysfunction. Accompanying laboratory abnormalities may include elevated serum creatinine kinase and white blood cell count. The challenge of the syndrome is that there is no one diagnostic test; NMS remains a diagnosis of exclusion.

Given the strong association of NMS with neuroleptics, the presumed mechanism is of dopaminergic blockade affecting the hypothalamic (fever, dysautonomia) and striatal (muscle rigidity, parkinsonism) dopaminergic receptors. Yet, this theory does not fully explain the syndrome as only a small minority of patients taking neuroleptics develop NMS, i.e., dopamine blockade via neuroleptics is necessary but not sufficient to develop the syndrome. Other neurotransmitter systems are likely also involved including gamma aminobutyric acid (GABA), epinephrine, serotonin, and acetylcholine.

NMS has rarely been associated with medications that do not have central anti-dopaminergic activity including, lithium and certain tricyclic antidepressants (desipramine).

II. Diagnostic Confirmation: Are you sure your patient has Neuroleptic Malignant Syndrome?

Since there is no one diagnostic test that defines NMS, the diagnosis rests on strong clinical suspicion, clinical history, and the patient's constellation of clinical findings.

There are no widely accepted diagnostic criteria, although most published criteria, require the following:

  • Current or prior treatment with medications linked to NMS: neuroleptics (both typical and atypical), antiemetic’s such as metoclopramide or promethazine, or acute withdrawal of dopamine agonists such as carbidopa-levodopa

  • Fever

  • Muscle rigidity

  • Exclusion of other potential medical or psychiatric etiologies for the signs and symptoms

  • Other features which may or may not be present include:

    • Elevated serum creatine kinase

    • Change in level of consciousness from delirium and agitation to coma

    • Dysautonomia: typically tachycardia, elevated or labile blood pressure

    • Leukocytosis

    • Diaphoresis or sialorrhea

    • Dysphagia

    • Incontinence

A. History Part I: Pattern Recognition:

A typical patient with NMS will have a history of neuroleptic use (or other associated medications), however, it is important to note that NMS is often idiosyncratic. While NMS may be more likely to present within the first 2 weeks of exposure and after higher doses, rapid dose escalation, or depot forms of medication, the disorder can present after a single dose or after years of a stable neuroleptic dose.

Symptoms tend to evolve over 1 to 3 days. In a review of 340 cases, 82% of patients initially presented with either mental status changes or rigidity then went on to develop hyperthermia and autonomic dysfunction.

Mental status changes often present as agitated delirium and confusion but may also involve a depressed level of consciousness and, in the most severe forms, a comatose state.

Fever and muscular rigidity are often defining symptoms. Muscular rigidity is usually generalized and may range from hypertonicity to dramatic, lead-pipe rigidity with stable resistance through all ranges of movement.

Autonomic dysfunction may present in a number of ways, but typically involves tachycardia, labile blood pressure, hypertension, tachypnea, and less often dysrhythmias. Sialorrhea, diaphoresis, and urinary incontinence may be further representations of dysautonomia.

B. History Part 2: Prevalence:

NMS remains rare. Estimates of incidence range from 0.02-3.23%, though are hampered by nonuniform diagnostic criteria and retrospective studies prone to selection bias.

NMS tends to be seen in men more than woman with a mean age of 40 (fitting with patterns of neuroleptic usage), although patients of all ages have been described.

Predisposing factors remain unclear but are thought to include dehydration, higher doses of high potency neuroleptics, rapid dose escalation, depot formulations, and concomitant lithium use. Other possible risk factors include extreme agitation, use of restraints, and underlying brain disease. In addition, familial clusters of NMS have been described suggesting a possible genetic predisposition.

C. History Part 3: Competing diagnoses that can mimic Neuroleptic Malignant Syndrome.

A number of other drug-related or systemic diagnoses may mimic the presentation of NMS. In addition, patients who have pre-existing extrapyramidal effects and rigidity from neuroleptics, may develop a new fever secondary to a pneumonia or urinary tract infection which may initially raise the question of NMS. Clinicians should have a low threshold for suspecting possible NMS though it remains a diagnosis of exclusion.

The disorders most closely related to NMS because they include fever, rigidity, and dysautonomia, include: serotonin syndrome, malignant hyperthermia, and malignant catatonia.

  • Serotonin syndrome. Caused by excess serotonergic activity typically due to selective serotonin reuptake inhibitors (SSRIs) so a careful review of a patient's medications will help raise the suspicion. Rigidity and fever tend to be less severe than in NMS and patients often have additional symptoms of nausea, vomiting, diarrhea, shivering, myoclonus, and hyperreflexia, which are atypical for NMS.

  • Malignant hyperthermia. Clinical presentation is identical to NMS, but the diagnosis should be apparent based on history as malignant hyperthermia develops after exposure to halogenated inhalational anesthetic agents and succinylcholine, and is often genetic with autosomal dominant inheritance.

  • Malignant catatonia. May not be distinguishable from NMS, but sometimes will have an identifiable behavioral prodrome 2-3 weeks prior to presentation of emotional withdrawal, depression, anxiety, or agitation. Patients with malignant catatonia may be more likely to demonstrate waxy flexibility, dystonic posturing, or stereotyped repetitive movements.

Other disorders which should also be considered in the differential:

  • Heat stroke. Neuroleptics suppress central heat loss mechanisms and patients are susceptible to heat stroke if exposed to hot environments or physical exertion. Typically heat stroke can be distinguished from NMS by the absence of rigidity, the presence of hot dry skin without sweating, and by history of exercise or heat exposure.

  • Central nervous system infections, such as meningitis or encephalitis, may mimic NMS. Complaints of headache and meningismus on exam should suggest CNS infection. Evaluation with lumbar puncture confirms the diagnosis. NMS patients typically have a normal spinal fluid profile, or a slightly elevated protein, while patients with meningitis or encephalitis will usually demonstrate cerebrospinal fluid (CSF) leukocytosis, elevated protein, and potentially low glucose.

  • Central anticholinergic syndrome. May be distinguished from NMS on review of the patient's medication history. On exam, rigidity is usually not present, creatinine kinase is often normal, patients are not diaphoretic, and patients with anticholinergic poisoning will often demonstrate blotchy red skin, dilated pupils, and bladder distension.

Further diagnosis to consider:

  • Seizures

  • Acute intoxication with cocaine, ecstasy

  • Withdrawal states (particularly alcohol, benzodiazepines, and intrathecal baclofen)

  • Thyrotoxicosis

D. Physical Examination Findings.

As described above, the classic tetrad of the syndrome is fever, muscular rigidity, altered mental status, and dysautonomia.

E. What diagnostic tests should be performed?

There are no physical examination findings that will confirm the diagnosis of NMS, but some combination of the core features of the syndrome should be present (fever, rigidity, altered mental status, and dysautonomia).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No one laboratory test is diagnostic for NMS, however there are common laboratory abnormalities found.

  • Creatine kinase levels often are elevated secondary to skeletal muscle damage and typically correlate with the degree of rigidity the patient has, i.e., if it is early in the disease process and rigidity is not well developed, CK may be only mildly elevated. CK levels usually will be >1,000 IU/L.

    • With a significant degree of muscle breakdown, myoglobinuric acute renal failure may result from rhabdomyolysis and myoglobin will be detected on a urinalysis.

  • Leukocytosis with or without a left shift is often present.

  • Electrolyte abnormalities: hypocalcemia, hypomagnesemia, hypo and hypernatremia, hyperkalemia, and metabolic acidosis.

  • Mild abnormalities of liver transaminases and alkaline phosphatase.

  • Low serum iron.

Of note it is also useful to ensure there is no evidence of alternative explanations for a patient presenting with fever, so laboratory studies such as blood cultures and urinanalysis with culture should be included, and a lumbar puncture should be considered.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies will confirm the diagnosis of NMS, yet imaging may suggest alternative diagnoses such as an underlying systemic infection or an underlying structural mass lesion. Depending on the clinical scenario, a chest radiograph may be useful to look for pneumonia, and in patients presenting with fever, rigidity, and/or altered mental status brain imaging should be done with at least a non-contrast head computed tomography (CT).

Patients with NMS should have normal imaging studies.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Magnetic resonance imaging (MRI) of the brain is usually not necessary if other clinical and exam findings are strongly indicative of NMS.

III. Default Management.

Once NMS is suspected, it is essential to discontinue all neuroleptics or other dopamine antagonists. Supportive therapy is the mainstay of treatment with aggressive intravenous hydration, lowering hyperthermia, close monitoring and repletion of electrolyte derangements, and careful monitoring and support of cardiac, respiratory, and renal function.

Monitoring for potential complications is also important, especially renal failure from rhabdomyolysis, deep venous thrombosis or pulmonary embolism due to immobilization and dehydration, and aspiration pneumonia due to altered mental status. Other complications may include cardiac arrhythmias, myocardial infarction, disseminated intravascular coagulation (DIC), and seizures from hyperthermia and metabolic derangements.

To prevent complications and to allow for close monitoring, most patients should initially be placed in an intensive care unit with telemetry and deep venous thrombosis prophylaxis should be started (e.g., heparin 5,000 units SC q8hrs).

The role of pharmacotherapy in the treatment of NMS remains uncertain as there are no randomized or even controlled, prospective trials. The most commonly used agents in severe cases of NMS, despite the lack of clear efficacy, are dantrolene, bromocriptine, and amantadine.

Dantrolene is a direct muscle relaxant which inhibits calcium release from the sarcoplasmic reticulum thereby decreasing calcium available for ongoing muscle contraction. Dantrolene may be used in severe cases to reduce muscle rigidity. Typical initial doses are 1-2 mg/kg intravenously every 6-12 hours, but maximum dose of 10 mg/kg/day should not be exceeded due to risk of hepatotoxicity.

Bromocriptine and amantadine are dopamine agonists. Bromocriptine is typically started at 2.5 mg orally or via nasogastric tube two to three times a day, and, if needed, the dose can be increased up to a total of 45 mg/day. Side effects may include nausea, vomiting, hypotension, and psychosis. Amantadine is initiated at 200-400 mg/day in divided doses.

Electroconvulsive therapy (ECT) has also been used as a treatment option for medically refractory cases. ECT has the advantage of also being a treatment for malignant catatonia which can be challenging to distinguish from NMS. The efficacy of ECT has not been proved, but case series have reported success. The main complications of ECT are cardiovascular (arrhythmia, cardiac arrest) and status epilepticus.

A. Immediate management.

The most important treatment is to stop the offending neuroleptic agent as soon as you suspect the diagnosis.

B. Physical Examination Tips to Guide Management.

Patients with NMS will typically have fever, dysautonomia, encephalopathy, and rigidity, and these features can be followed throughout the hospital course. Close monitoring of vital signs is important and fever should be treated with antipyretics or other cooling methods. Dysautonomia including tachycardia, blood pressure lability, and even in arrhythmias or bradycardia should also be closely monitored and may necessitate intervention such as a temporary pacemaker.

Patients' underlying encephalopathy can be expected to wax and wane though any significant changes in exam, such as progression from a waxing and waning delirium to a comatose state, should prompt further investigations to ensure no underlying metabolic derangement, new infection, or other complication such as seizure.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Creatinine kinase (CK). Typically elevated and when significant muscle breakdown is present and CK is >10,000 IU/L, patients are at risk for rhabdomyolysis induced acute renal failure. CK should be trended at least initially on a daily basis to ensure a downward trend.

Basic metabolic panel with magnesium, calcium, phosphate. Initially should be checked at least twice a day as patients are at risk for renal failure and electrolyte derangement. Renal failure should be treated with intravenous hydration and electrolytes should be closely monitored and repleted as needed.

Liver function tests. Liver transaminases, lactate dehydrogenase, and alkaline phosphatase may be slightly elevated in NMS. If a patient is being treated with dantrolene, LFTs should be followed every day or every 2 days to ensure there is no upward trend which could suggest dantrolene induced hepatotoxicity.

D. Long-term management.

Given the typical rapid resolution of NMS, there is no long-term management of the disorder. However, one of the long-term issues is when and how to restart neuroleptics (please see Section VI. B for further details).

E. Common Pitfalls and Side-Effects of Management.

Dehydration: Patients commonly present with dehydration, a potential predisposing risk factor for NMS, but hyperthermia and insensible losses from autonomic dysfunction can worsen dehydration unless aggressively treated with intravenous fluid hydration.

Deep venous thrombosis/pulmonary embolus: Due to immobility from acute illness and the underlying muscular rigidity, patients with NMS are at risk for developing deep venous thrombosis. Patients should be treated with anticoagulant prophylaxis such as heparin 5,000 units subcutaneously every 8 hours.

Renal failure: Acute renal failure due to rhabdomyolysis should be treated with early and aggressive intravenous fluid hydration and even alkalinization of the urine with bicarbonate in severe cases.

Hyperthermia and metabolic derangements can lead to complications such as seizure or arrhythmia which should be monitored closely and treated appropriately. Hyperthermia can be treated with scheduled antipyretics such as acetaminophen or cooling protocols.

Pharmacotherapy: If the patient with NMS is not responding to typical supportive management, pharmacotherapy may be required which carries its own potential complications. The most serious complication of dantrolene is hepatotoxicity, whereas the dopamine agonists can lead to hypotension or psychosis.

Electroconvulsive shock therapy: For medically refractory patients, or for those with suspected malignant catatonia, ECT may be an option. The most notable risks of ECT include cardiac arrhythmia, myocardial infarction, and status epilepticus.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Standard management which consists of stopping neuroleptics or offending agents and supportive therapy would remain unchanged. Patients with pre-existing renal failure will still be at risk for worsening acute renal failure and should be aggressively hydrated.

B. Liver Insufficiency.

In patients with liver insufficiency, supportive therapy is the safest treatment option, but if pharmacotherapy is required, dantrolene should be avoided due to potential hepatotoxicity. Bromocriptine should also be used with caution in patients with hepatic impairment.

C. Systolic and Diastolic Heart Failure.

The aggressive IV fluid management required in NMS may need to be done cautiously in patients with systolic heart failure, and may necessitate close monitoring for complications such as pulmonary edema or arrhythmia.

Pharmacotherapy with bromocriptine should also be used cautiously in patients with cardiovascular disease as well as amantadine or dantrolene, all of which can potentially induce cardiac arrhythmia.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

NMS is rarely associated with disseminated intravascular coagulation (DIC). Patients with underlying hematologic or coagulation issues are theoretically at higher risk of this complication of NMS and should be monitored with laboratory studies. Dantrolene and amanatadine may also be contraindicated in this population or only used with extreme caution due to potential leukopenia and thrombocytopenia with dantrolene and leukopenia or agranulocytosis with amantadine.

K. Dementia or Psychiatric Illness/Treatment.

Dopamine antagonists should be held or avoided all together during treatment for NMS. Agitated or anxious patients should instead be treated with frequent verbal reassurance, reorientation, benzodiazepines, or physical restraints, as necessary.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

If serum creatinine trends upwards on laboratory studies ensure patient has IV fluids running and consider alkalinization of the urine.

For cardiac arrhythmias ensure potassium >4 mEq/L and magnesium >2 mg/dL.

For seizures lasting >3 minutes treat with lorazepam 2mg intravenously once and search for any underlying treatable etiologies, such as hyperthermia or electrolyte derangement.

B. Anticipated Length of Stay.

Most episodes of NMS resolve within 1 to 2 weeks, although patients on depot forms of neuroleptics may have a longer course.

C. When is the Patient Ready for Discharge.

  • Euthermia

  • Stable vital signs without blood pressure lability, hypertension, tachycardia or bradycardia

  • Improvement in muscular rigidity and patient able to mobilize

  • Improvement in cognition

  • Downtrending serum creatine kinase, ideally <1,000 IU/L without active renal failure

  • Stable serum electrolytes without frequent repletion

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Primary care physician within 1 to 2 weeks from hospital discharge to ensure continued improvement and stable vital signs.

Psychiatrist within 2 weeks for consideration of re-challenging with neuroleptic treatment or an alternative therapy.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None if the patient is stable with normalized laboratory studies prior to hospital discharge. If patient has persistent electrolyte disturbances or evidence of renal insufficiency on hospital discharge, a full chemistry panel should be performed prior to the clinic visit.

E. Placement Considerations.

Most patients should be able to recover and return to their prior level of function. Some patients may exhibit persistent residual symptoms such as catatonia, parkinsonism, or other morbidity due to renal or cardiopulmonary complications. Such patients should be evaluated for skilled nursing or acute rehabilitation.

F. Prognosis and Patient Counseling.

The majority of patients recover within 2 weeks, however, NMS can be life-threatening. Mortality rates when initially reported before 1970 were as high as 76%. With improved recognition of the syndrome and treatment, more recent mortality rates are closer to 10%. Myoglobinemia and renal failure are strong predictors of mortality.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

NMS is an idiosyncratic reaction. Nonetheless, if a patient requires antipsychotics, it is generally recommended to use a different neuroleptic than the one that led to the development of NMS. Case series have found relapse rates with re-challenge ranging from 10-90%. Since the majority of patients who develop NMS have underlying psychiatric comorbidities requiring treatment, most patients require treatment with neuroleptics in the future. Neuroleptics can typically be safely introduced after waiting a period of 2 weeks (or 6 weeks for a depot form) and only with slow titration and close monitoring.

To prevent a recurrent episode of NMS, most experts recommend:

  • Waiting at least 2 weeks before restarting a neuroleptic

  • Choosing a low-potency or atypical neuroleptic, such as quetiapine

  • Starting at a low dose and titrating slowly ideally in a monitored setting or with close follow-up

  • Avoiding other presumed risk factors such as concomitant lithium use and dehydration

VII. What's the evidence?

Berman, B. "Neuroleptic malignant syndrome". The Neurohospitalist. vol. 1. 2011. pp. 41-47.

Gurrera, RJ, Simpson, JC, Tsuang, MT. "Meta-analytic evidence of systematic bias in estimates of neuroleptic malignant syndrome incidence". Compr Psychiatry. vol. 48. 2007. pp. 205-11.

Reulbach, U, Dutsch, C, Biermann, T. "Managing an effective treatment for neuroleptic malignant syndrome". Crit Care. vol. 11. 2007. pp. R4.

Strawn, JR, Keck, PE, Caroff, SN. "Neuroleptic malignant syndrome". Am J Psychiatry. vol. 164. 2007. pp. 870-6.

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