Atypical Neuroleptic Malignant Syndrome: Diagnostic Controversies and

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Atypical Neuroleptic Malignant Syndrome: Diagnostic Controversies and Considerations

Lara S. Picard, Pharm.D., Shane Lindsay, Pharm.D., Jeffrey R. Strawn, M.D., Rakesh M. Kaneria, M.D., Nick C. Patel, Pharm.D., Ph.D., and Paul E. Keck, Jr., M.D.

Neuroleptic malignant syndrome (NMS) is a serious and potentially fatal adverse effect of antipsychotic drugs. The diagnosis of NMS commonly requires core symptoms of hyperthermia and muscle rigidity. Although diagnostic criteria for NMS have been established and are widely accepted and used, it should be recognized that atypical presentations pose a diagnostic dilemma, as hyperthermia and/or muscle rigidity may be absent or develop slowly over several days, leading to impairment or a significant delay in diagnosis and treatment. Evidence from case reports and retrospective evaluations supports a concept of atypical NMS, particularly with regard to treatment with atypical antipsychotics. However, it remains unclear whether these atypical presentations represent early or impending NMS. Furthermore, it is unclear whether dysfunction in other neurotransmitter systems, in addition to dopamine, may be involved in the pathogenesis of NMS induced by atypical antipsychotics. In patients receiving any antipsychotic, clinicians should carefully evaluate any features of NMS and should not prematurely exclude a diagnosis of NMS in cases where severe rigidity or hyperthermia is not initially apparent.

Key Words: neuroleptic malignant syndrome, NMS, antipsychotics, neuroleptics, dopamine.
(Pharmacotherapy 2008;28(4):530–535)


Diagnostic Criteria for Neuroleptic Malignant Syndrome

Atypical Neuroleptic Malignant Syndrome Core Symptoms

Recommendations and Future Research Conclusion

From the Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy (Drs. Picard and Lindsay), and the Department of Psychiatry, College of Medicine (Drs. Strawn, Kaneria, and Keck), University of Cincinnati, Cincinnati, Ohio; the Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Athens, Georgia (Dr. Patel); the Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia (Dr. Patel); and Lindner Center of HOPE, Mason, Ohio (Dr. Keck).

Address reprint requests to Dr. Nick C. Patel, UGA Clinical Pharmacy Program, Medical College of Georgia, CJ- 1020, 1120 15th Street, Augusta, GA 30912–2450; e-mail:

Neuroleptic malignant syndrome (NMS), a serious and potentially fatal adverse effect of antipsychotic drugs, is characterized by muscle rigidity, hyperthermia, autonomic instability, mental status changes, and evidence of muscle injury (e.g., elevated creatine kinase levels).1–3 Risk of developing NMS appears to be associated with a number of pharmacologic factors, including the use of first-generation antipsychotics, particularly high potency agents. Elevated doses and rapid titration contribute to the risk. In addition, many clinical and systemic risk factors, such as agitation, dehydration, physical restraint, iron deficiency, preexisting central dopamine abnormalities, and history of NMS are thought to increase the risk for NMS.1–3 Development of NMS typically occurs early after the start of an antipsychotic drug; it is uncommon for NMS to emerge after 30 days of treatment unless the dosage is increased or an additional antipsychotic


drug has been administered.4 In the absence of complications, NMS is typically self-limiting after discontinuation of the offending agent and treatment of the syndrome, with most cases resolving within 7–30 days.4

Treatment of NMS includes early recognition, discontinuation of dopamine-blocking agents, supportive care, and several drug-specific inter- ventions, such as bromocriptine, amantadine, and dantrolene.5, 6 If unrecognized or untreated, severe complications (e.g., aspiration pneumonia, acute renal failure, cardiac arrest, pulmonary embolism, disseminated intravascular coagula- tion) or death may result.4 In fact, although NMS is estimated to occur in 0.01–0.02% of patients treated with antipsychotic drugs and is usually self-limited, the mortality estimates remain at approximately 10%.3

Goals of treatment are prevention of compli- cations and complete resolution without sequelae. Achievement of these goals is usually facilitated by prompt and accurate diagnosis and careful differential diagnosis, including consid- eration of diseases that can mimic NMS. These diseases include, but are not limited to, malig- nant hyperthermia, serotonin syndrome, central nervous system infections, intoxication states, agitated delirium, and benign extrapyramidal symptoms.3 A definitive diagnosis and thus appropriate treatment may be delayed when a patient does not present with classic signs of NMS. For example, cases of NMS have been reported in which hyperthermia or muscle rigidity were not present7–10 and, therefore, have been labeled atypical. Atypical presentations, due to lack of recognition, may prolong the course of NMS and increase the risk of complications, long-term sequelae, and death. Conversely, an incorrect diagnosis of atypical NMS may result in premature discontinuation of potentially beneficial drugs, negatively affecting patient outcomes.

Diagnostic Criteria for Neuroleptic Malignant Syndrome

Diagnosis of NMS is not a simple or straight- forward matter. Much of the reason for this stems from a lack of consensus on the precise definition of NMS, which is reflected in the availability of numerous sets of published diagnostic criteria. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) identifies the core features of NMS as severe muscle rigidity and elevated

temperature associated with the use of a neuroleptic drug.11 In addition, two or more of the following symptoms should be present for a diagnosis of NMS: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or laboratory evidence of muscle injury (elevated creatine kinase level).11 These core features and symptoms must not be due to another substance or a neurologic or other general medical condition, and they are not better accounted for by a mental disorder.11

In addition to the DSM-IV-TR criteria for NMS, four other sets of diagnostic criteria have been promulgated. The second set resembles the DSM-IV-TR criteria in that recent use of a neuroleptic (within 1–4 wks), muscle rigidity, and fever of at least 38°C are required.12 In addition to these core symptoms, at least five of the following symptoms are needed: change in mental status, tachycardia, hypertension or hypotension, diaphoresis or sialorrhea, tremor, incontinence, increased levels of creatine kinase or urinary myoglobin, leukocytosis, and metabolic acidosis. In contrast, the third set requires only three criteria to be met for a diagnosis of NMS: elevated temperature (> 37.4°C), severe extra- pyramidal symptoms, and autonomic dysfunction.13 The fourth set of diagnostic criteria require extrapyramidal symptoms and fever (≥ 37°C) in the presence of three minor symptoms within a 48-hour period.14

In contrast to the other diagnostic criteria, which all identify elevated temperature and muscle rigidity as major symptoms, the fifth set of criteria allow the diagnosis of NMS in patients with either three major symptoms (hyperthermia, rigidity, elevated creatine kinase level) or with two major and four minor symptoms (tachycardia, diaphoresis, tachypnea, abnormal blood pressure, leukocytosis, altered consciousness).15 This set of criteria does not require concurrent hyper- thermia and muscle rigidity for a diagnosis of NMS.15

Although the DSM-IV-TR diagnostic criteria for NMS are widely used in both clinical and research settings, it should be recognized that atypical presentations arise that do not fit these criteria and present a diagnostic dilemma. In atypical presentations, symptoms of hyperthermia and/or muscle rigidity may be absent or may develop slowly over many days. It is possible for these symptoms to be milder in an atypical case than in a typical case; this may suggest that the

532 PHARMACOTHERAPY Volume 28, Number 4, 2008

patient is experiencing common adverse effects from the antipsychotic drug rather than impending NMS.16 If so, use of DSM-IV-TR or other strict criteria may impair or significantly delay definitive diagnosis and appropriate treatment, at which time the acute severity of NMS may be increased. The fifth set of criteria,15 which are broader than the other published criteria, may be more sensitive and allow for inclusion of atypical presentations.

Because a variety of medical conditions may present with similar symptoms to NMS, the diagnosis of NMS remains one of exclusion.3, 17 In addition, the differential diagnosis may be further complicated in patients with atypical presentations. This may be especially true when patients have an altered mental status and cannot provide a precise history or accurate picture of their symptomatology.

Atypical Neuroleptic Malignant Syndrome

Core Symptoms

The concept of atypical NMS is controversial, and some have argued that there is insufficient evidence to support a diagnosis of NMS in many of these cases.18 In addition, there is overlap between characteristics of NMS and the more benign adverse effects of second-generation antipsychotics. For example, 3% of patients who receive clozapine experience transient benign hyperthermia, and 25% of patients receiving clozapine or risperidone have hemodynamic changes during initial titration of the drug.18 In addition, a series of studies involving patients with psychosis found that creatine kinase levels were elevated in 29 of 37 patients who started treatment with clozapine.19 Despite this overlap between the relatively benign adverse effects of antipsychotic drugs and diagnostic features of NMS, a growing body of literature suggests the existence of atypical presentations of NMS.

These findings support a spectrum-based concept of NMS, with treatment dictated by the stage and features of the clinical presentation (Figure 1).3, 20

In several case reports of putative NMS, partic- ularly those associated with second-generation antipsychotics, extreme temperature elevations and/or extrapyramidal dysfunction have been absent.7–10, 21 In addition, a review of 21 cases of risperidone-induced NMS in which temperature was recorded found that two patients did not display hyperthermia throughout the course of illness.22 In a case of olanzapine-induced NMS, the patient’s body temperature fluctuated over time, including a 10-day period in which the patient was afebrile.23 Aripiprazole, at high doses, has also been reported to cause NMS without hyperthermia or with only low-grade temperature elevations, although several clinical and systemic factors, such as concurrent infection, confound many of the reported cases.24 Lack of muscular rigidity has been described in putative NMS case reports associated with clozapine, olanzapine, risperidone, and aripiprazole.7–10 Similarly, a review of NMS cases from 1980–1985 found that 11% of patients lacked muscle rigidity,15 and a review of clozapine-associated NMS cases revealed that muscle rigidity was absent in 36% of patients.25

In 2000, 164 cases of NMS induced by a first- generation antipsychotic (115 patients), clozapine (19 patients), olanzapine (9 patients), or risperidone (21 patients) were evaluated.21 Second-generation antipsychotics were found more likely than first-generation antipsychotics to be associated with an NMS presentation that lacked one of the core symptoms, especially hyperthermia. Specifically, 106 (92%) of the 115 patients with NMS induced by a first-generation antipsychotic had a temperature elevation of 38°C or greater. This was significantly higher than the frequency of temperature elevation observed in cases of NMS reportedly induced by

Stage: Symptoms:


Rigidity, Rigidity, tremor mutism,


Mild rigidity,


Moderate rigidity, catatonia or confusion,
T 38–40°C,

HR 100–120 bpm


Severe rigidity, catatonia or confusion,
T ≥ 40°C,

HR ≥ 120 bpm

catatonia or stupor confusion,

T ≤ 38°C,
HR ≤ 100 bpm

Figure 1. Spectrum-based concept of neuroleptic malignant syndrome. T = temperature; HR = heart rate; bpm = beats/minute. (Adapted from reference 20.)


atypical antipsychotics, as only 37 (76%) of these 49 patients had hyperthermia (p<0.05). Patients without a recorded body temperature above 38°C made up 29%, 22%, and 17% of the cases induced by risperidone, olanzapine, and clozapine, respectively. Rates of muscle rigidity were comparable in cases associated with first- generation and second-generation agents (91% and 88%, respectively). Of interest, although not statistically significant, clozapine was associated with a lower rate of rigidity (79%) than olanzapine (89%) or risperidone (95%).21 Thus, there may be some association between features of the syndrome and the likelihood of the agent to induce extrapyramidal symptoms.

Such evidence from case reports and retrospective evaluations supports a concept of atypical NMS. However, it remains unclear whether these atypical presentations represent early or impending NMS. Similarly, it is difficult to determine whether an atypical presentation represents a prodrome of a typical presentation.


Many signs and symptoms of NMS have been proposed to be due to abrupt and profound dopamine D2-receptor blockade.3, 26–28 This hypothesis is supported by the observation that dopamine D2 antagonists cause NMS, and dopamine agonists are often effective in treating NMS. Muscle rigidity is thought to be caused by dopamine blockade in the nigrostriatal region, and extreme muscle rigidity can produce hyper- thermia. In addition, hypothalamic dopamine blockade may result in impaired temperature regulation26 and precipitate the autonomic changes associated with NMS.29

The lack of hyperthermia or muscle rigidity in atypical cases of NMS raises the possibility of differences in pathophysiology. A research group reported that patients with NMS had significantly higher circulatory levels of epinephrine and serotonin during the acute phase of NMS compared with levels obtained after remission.30 Other researchers observed significantly higher levels of norepinephrine and its major metabolite, 3-methoxy-4-hydroxyphenylethyl-eneglycol, during the acute phase, but significantly lower levels of -aminobutyric acid.31 Collectively, these findings suggest that dysfunction in these neurotransmitter systems, in addition to dopamine, may be involved in the pathogenesis of NMS. It is possible that second-generation antipsychotics may cause NMS through interactions with these

neurotransmitter systems. In addition, given the very different extrapyramidal-symptom profiles of many second-generation antipsychotics compared with first-generation antipsychotics, it is possible that nigrostriatal and hypothalamic dopamine blockade may not be comparable or as extensive, and thus the secondary rigidity or hyperthermia may be less severe in NMS associated with second- generation versus first-generation antipsychotics. Finally, it is possible that serotonin receptor antagonist properties of second-generation antipsychotics contribute to the heterogeneity of atypical NMS presentations associated with these agents, particularly with regard to muscle rigidity. Serotonin 5-HT2-receptor blockade in the nigrostriatal pathway increases dopamine release in this area and thus decreases extrapyramidal symptoms.32

Recommendations and Future Research

Because there is considerable variability in the presentation of NMS, dichotomous sets of diagnostic criteria, such as those in the DSM-IV- TR, may not be sensitive to subsyndromal or atypical presentations. Thus, these criteria may interfere with prompt diagnosis and treatment. More flexible criteria that allow for diagnosis based on major and/or minor symptoms may be more sensitive in capturing the spectrum of NMS presentations. Clearly, additional studies are needed to determine which set of diagnostic criteria provide the most sensitivity and speci- ficity in diagnosing both classical and atypical presentations of NMS. In addition, the patho- physiology of NMS is poorly understood, and the roles of dopamine and other neurotransmitters in the pathogenesis need to be elucidated in order to determine which treatment modalities are likely to produce the best possible patient outcomes.

If a patient receiving a second-generation antipsychotic has hyperthermia, muscle rigidity, delirium, or autonomic instability, an evaluation for atypical NMS is likely warranted. Rating scales, such as the Sachdev NMS scale,16 may aid in evaluation, particularly because newer rating scales do not require clinical features, such as rigidity, hyperthermia, and mental status change, to be dichotomized as present or absent. Instead, these newer scales account for the severity of these features. In particular, the Sachdev NMS scale includes oral temperature, severity of extra- pyramidal symptoms, autonomic instability, level of consciousness, catatonic characteristics, and laboratory data (elevation in creatine kinase

534 PHARMACOTHERAPY Volume 28, Number 4, 2008

level, white blood cell count). Although this NMS rating scale requires psychometric validation, it does have clinical utility in that it provides a measure of NMS symptom severity that can aid in the diagnostic and monitoring processes. Thus, a delirious patient with a low-grade fever and extreme rigidity could still be considered to have NMS, whereas with conventional criteria, such a patient would not be considered to have NMS.

Although the concept of atypical NMS remains controversial and may relate to various pharma- cologic properties of second-generation anti- psychotics or clinical factors (e.g., earlier recognition in which more fulminate forms of NMS are abated), accumulating evidence strongly suggests that NMS is heterogeneous in severity, etiology, and course. Moreover, the notion that the syndrome may represent a spectrum of disorders has gained increasing attention in the literature3, 20 and among clinicians. Recently, the relationship between variable clinical features and treatment outcomes has been explored.33, 34 For example, benzodiazepines may be more effective in less severe forms (e.g., lacking severe hyperthermia), whereas dantrolene and electroconvulsive therapy may be more effective for patients with severe rigidity.3 However, because of variability in the course of NMS, it is difficult to say whether atypical forms of the syndrome respond differently to certain treatments or whether they are associated with different prognoses. These observations have led to a suggestion that treatment approaches be based on the stage of syndrome.3


Atypical cases of NMS support a spectrum- based concept of the syndrome. Flexible diagnostic criteria with regard to the presence of core symptoms may be more sensitive in the detection of NMS cases. In patients receiving any antipsychotic, clinicians should carefully evaluate any features of NMS in a patient treated with these agents and should not prematurely exclude a diagnosis of NMS in cases where severe rigidity or hyperthermia are lacking.


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