Updated (2003) by Ronald Gurrera, M.D., Associate Chief of Psychiatry and Assistant Professor of Psychiatry, Harvard Medical School at the Brockton VAMC and Harvard South Shore Psychiatry Residency Training Program
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Incidence and mortality. Neuroleptic Malignant Syndrome (NMS) occurs in approximately 0.1% of hospitalized patients treated with antipsychotic medications. When it was first recognized more than 40 years ago, the mortality rate was 10% or greater. Improved clinician education, leading to more prompt and effective clinical intervention, is credited with a dramatic reduction in the lethality of the disorder over time. Nonetheless, patients with acute NMS can be gravely ill, and fatalities still occur.
Diagnosis. The syndrome is characterized by a tetrad of clinical signs: hyperthermia, increased muscle tone, labile autonomic hyperactivity, and altered mental status. Diagnostic criteria vary from one academic institution to another, but those provided by the appendix in DSM-IV are reasonable. The diagnosis of NMS is generally one of exclusion, as patients at risk for NMS often have one or more potentially treatable medical processes (e.g., infection) capable of producing clinical findings that can be confused with NMS.
Etiology and pathogenesis. The etiology of NMS is not established. The most widely accepted view is that NMS is caused by antipsychotic medication-induced dopamine antagonism in the hypothalamic thermoregulatory center, but this mechanism fails to account for many well documented features of the disorder [1]. Incidence and recurrence rates are consistent with a genetic vulnerability, but to date no specific genetic defect has been linked to this disorder [1].
Risk factors. In a recent critical review of the NMS literature [2], the following risk factors emerged, in decreasing order of importance: previous h/o NMS episode, male gender, and youthful age (20-40 years). Premorbid brain disorders of various types have also been implicated as risk factors, but the significance of these isolated reports is unclear [2]; acute encephalitis may be more ominous than other causes of brain dysfunction [3].
Antipsychotic medication class. All antipsychotic medications, including newer agents, have been associated with NMS. Among case reports with adequate diagnostic reporting and no confounding effect of concomitant old generation antipsychotics, there have been at least 19 reports with clozapine, 21 with risperidone, and 9 with olanzapine [4]. There is at least one case report with quetiapine [5]. A recent review of anecdotal data [6] indicates that the clinical presentation of NMS associated with newer antipsychotic agents may be only slightly different, or perhaps not different at all, from that related to older drugs. These preliminary observations, which were based upon spontaneous reports from clinicians in the field, suggest that extrapyramidal signs may be less prominent or severe during NMS associated with newer, compared to older, antipsychotic medications. However, no adequately controlled comparison is available.
MANAGEMENT.
If you have made, or seriously ruled in, the diagnosis of acute NMS, prompt action is imperative. Acute NMS is an incipient, or actual, medical emergency, depending on the patient=s clinical condition and the pace at which the syndrome is advancing. Unfortunately there is no clear consensus yet on the management of acute NMS because there have been no prospective, controlled studies comparing treatments that have been advocated by individuals working in this field. Despite the lack of an established treatment protocol, however, there is a general management approach that has the support of leading NMS experts. If you seriously suspect that your patient has acute NMS, you should:
1. Immediately discontinue all antipsychotic medications.
2. Evaluate the patient=s fluid balance and hydrate accordingly.
3. If signs persist or worsen after steps 1 and 2, consider adding a minor tranquilizer (lorazepam and diazepam have received the most attention in anecdotal reports). Dosing in the range of lorazepam 1-2 mg IM or IV, 3-4 times per day, has been suggested [7-9] based largely upon anecdotal data. Others have suggested even higher dosing [10].
4. If signs persist or worsen after step 3, consider adding bromocriptine or dantrolene. In choosing between these options, some experts have advocated reserving dantrolene for medically severe cases in which increased muscle tone is prominent, while preferring to use bromocriptine in severe cases with prominent mental status changes. The rationale invoked to support these choices is that dantrolene is a ryanodine receptor (skeletal muscle sarcoplasmic reticulum calcium channel) blocker, and bromocriptine is a dopamine agonist with central activity. However, one should be aware that both agents are potentially toxic, and that evidence supporting their use is controversial. Studies indicate that these agents have some benefit [11,12], no benefit [13], or an adverse impact [14] in acute NMS. The largest review to date [15] found inconsistent effects from dantrolene and bromocriptine, similar to previous reviews indicating no clear benefit [16,17].
4a. Bromocriptine dosing of 2.5-5 mg PO or per NG tube TID (not to exceed 30 mg/day total) has been suggested [7]. Amantadine is a weak dopamine agonist with some anecdotal support for its use in acute NMS. Amantadine dosing of 100 mg PO or per NG tube 3-4 times per day has been suggested [7], and this agent may be tried first as a potentially safer alternative to bromocriptine.
4b. Dantrolene dosing of 1 mg/kg IV QID has been suggested [7].
5. If signs persist or worsen after step(s) 4a and/or 4b, ECT can be considered, in the form of 6-10 bilateral treatments [7,10].
It is important to emphasize that the management of acute NMS is empirical, and that the above is intended only only as a general treatment guideline. Each NMS case is unique. Consideration of your patient=s individual circumstances, condition and history take precedence over these general management suggestions.
PLEASE NOTE: There is a 24-hour NMS hotline for clinicians who are seeking up-to-date information about NMS and its management. The hotline is staffed by nationally recognized experts in this area; it is organized by the Neuroleptic Malignant Syndrome Information Service under the auspices of the Malignant Hyperthermia Association of the United States. Medical professionals can call toll-free at 888-667-8367, or visit the website at www.nmsis.org.
Since your patient has a history of NMS, a consideration of the risks associated with rechallenge is essential. Estimates of NMS recurrence rate are quite high, between 25%-75%, depending on the study [18-22]. All estimates to date have been based upon retrospective methodologies, however, so while the risk associated with rechallenge appears considerable, the data are inconclusive. Risk factors for recurrence on rechallenge are likely to be similar to those associated with de novo risk, but no controlled studies have been done and recommendations are based on anecdotal reports and small case series.
The usual recommendation is to wait at least two weeks after all signs and symptoms (e.g., fever, rigidity, elevated CPK) have disappeared before initiating a re-challenge, but this conventional advice is based principally upon a single retrospective study [23]. Most experts would recommend using a less potent and/or atypical antipsychotic medication in a rechallenge situation, but there is little objective data to support this conventional advice: there are no objective data to indicate that a different antipsychotic compound in and of itself is likely to reduce risk of recurrence [24]. However, this strategy may have the practical advantage of reducing the likelihood of a subsequent tort claim in the event that NMS does recur.
If the patient's psychiatric condition compels a re-challenge, the most important aspects of the clinical management are close monitoring of objective clinical signs (vital signs, muscle tone, CPK); careful consideration of the patient's competency to consent to a re-challenge; and education of other involved care givers regarding early signs of NMS [25]. When initiating a rechallenge, one should be on guard for early signs of recurrence and act promptly. Given the diagnostic and management challenges associated with this disorder, appropriate consultation should be considered at key decision points.
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