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A Woman in Her 60s With Fever and Altered Mental Status in a Psychiatric Hospital FREE TO VIEW

Benjamin C. Kalivas, MD; Andrew J. Goodwin, MD
Author and Funding Information

aDivision of General Internal Medicine, Medical University of South Carolina, Charleston, SC

bDivision of Pulmonary, Critical Care, Sleep and Allergy Medicine, Medical University of South Carolina, Charleston, SC

CORRESPONDENCE TO: Benjamin C. Kalivas, MD, Division of General Internal Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, Ste 807-CSB, MSC 623, Charleston, SC 29425


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(6):e171-e174. doi:10.1016/j.chest.2016.06.022
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A woman in her 60s with a history of hepatitis C with cirrhosis and major depressive disorder with psychotic features was admitted to the inpatient psychiatric unit for suicidal ideation. She was initially treated with a combination of sertraline and paliperidone. The paliperidone was subsequently changed to risperidone and ultimately to olanzapine. She developed worsening mental status and was then treated for catatonia with benzodiazepines. Over 2 days, her mental status continued to worsen and she developed fever and tachycardia. She was transferred to the ICU and endotracheally intubated for inability to protect her airway. She was started on lactulose via orogastric tube but showed no improvement in her mental status after 2 days despite having two or three bowel movements per day.

Vital signs were as follows: temperature, 38.1°C; pulse, 125 beats/min; BP, 155/80 mm Hg; respiratory rate, 24 breaths/min; oxygen saturation, 100% while on volume control at 6 cm3/kg; fraction of inspired oxygen, 0.4; and positive end-expiratory pressure, 5. She opened her eyes in response to sound but did not follow commands and did not require sedation to tolerate an endotracheal tube. Her pupils were sluggishly reactive and her sclera were icteric. Her chest had symmetric expansion with inspiration and was clear to auscultation throughout. Her cardiac examination results were normal. She had no abdominal distention or evidence of ascites. Her liver was not palpable and there were no facial grimacing in response to palpation. All extremities were rigid and without clonus. Hyporeflexia was present throughout.

A complete blood count produced normal results except for a hemoglobin concentration of 10.8 g/dL. The results of a comprehensive metabolic panel were normal except for a bicarbonate level of 18 mM and an albumin level of 2.7 g/dL. The serum ammonia level was 94 μM. Urinalysis results were normal, and a chest radiograph demonstrated appropriate placement of the endotracheal and orogastric tubes and no other abnormalities. Creatine kinase peaked at 348 International Units/L (upper limit of normal, 240 International Units/L). Cerebrospinal fluid analysis revealed a hemorrhagic tap with 36,026 RBCs/μL, 22 WBCs/μL, protein at 84 g/dL, and glucose at 93 g/dL. Extensive microbiologic studies of the cerebrospinal fluid, serum, and respiratory secretions produced negative results. Brain magnetic resonance imaging with angiography indicated no pathology, including encephalitis or hemorrhage, and an EEG was consistent only with encephalopathy.

What is the diagnosis?

Diagnosis: Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a potentially lethal condition that can go unrecognized in the ICU. Its features can be variable and include altered mental status, fever, and autonomic instability, which are also present in many conditions commonly encountered in the ICU. Although the syndrome’s early association with first-generation antipsychotic medication use gave rise to its name, observational studies have since demonstrated that NMS is associated with additional classes of medications (Table 1). These include second-generation, or “atypical,” antipsychotics, antiemetics, and even the cessation of dopaminergic agents used in the treatment of Parkinson’s disease. The common feature linking each of these medications to NMS is a reduction in dopaminergic signaling, suggesting a potential key mechanistic feature of NMS. This is further substantiated by the observation that a “loss of function” allele of the dopamine D2 receptor gene is more common in patients with NMS than in those who do not develop the syndrome. Thus, early recognition of NMS and prompt avoidance of risk factors is an important component of effective management.

Table Graphic Jump Location
Table 1 Medications Associated With NMS

NMS = neuroleptic malignant syndrome.

Previous estimates suggest that NMS occurs in one of every 10,000 patients treated with antipsychotic medications, although misdiagnosis may underestimate the true incidence rate. An increase in the number of available antipsychotic medications combined with a rapid rise in their off-label indications has resulted in a dramatic increase in their use since the mid-1990s. Indeed, more than 50 million prescriptions for atypical antipsychotic medications were issued in the United States in 2011 alone. This pattern of use is particularly evident in ICUs as physicians have recently increased the focus on the negative consequences of delirium, including increased mortality and long-term cognitive effects. As such, while there is little evidence indicating that antipsychotics improve patient outcomes in delirium, survey data suggest that 40% of ICU physicians prescribe typical and 10% prescribe atypical antipsychotics for sedation. Thus, critically ill patients are frequently exposed to antipsychotics and commonly have conditions whose symptoms may mask NMS, potentially leading to underrecognition.

The older definition of NMS as described in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was based on strict diagnostic criteria. Specifically, it required that a patient exhibit rigidity and hyperthermia in the setting of antipsychotic use and two or more minor features including the following: dysautonomia, evidence of muscle injury, tremor, and changes in the level of consciousness, among others. No alternative explanation could be present for these features. However, as our understanding of NMS has improved, it is recognized that NMS can be present with a variety of combinations of these signs or symptoms. Conversely, isolated hyperthermia, rigidity, or dysautonomia has also been described with antipsychotic medication use but does not always progress to NMS. Therefore, the definition of NMS in the more recent edition of the DSM (DSM-V) has been changed and now allows the diagnosis to be made with any combination of these classic signs or symptoms if they occur during exposure to medications with known associations with NMS and have no alternative medical or psychiatric cause (Table 2).

Table Graphic Jump Location
Table 2 Clinical Features of NMS

See Table 1 legend for expansion of abbreviation.

When assessing a patient with fever and/or encephalopathy in the ICU, it is important to keep NMS high on the list of possible diagnoses and to investigate for additional signs to confirm this diagnosis. Although not completely specific, generalized rigidity is present in more than 80% of patients with NMS and is an uncommon finding in other conditions treated in the ICU. Its presence can narrow the differential diagnosis to a few possibilities including CNS infection, malignant hyperthermia, cocaine intoxication, malignant catatonia, intrathecal baclofen withdrawal, and serotonin syndrome. Because of frequent concomitant use of selective serotonin reuptake inhibitors and antipsychotic medications, NMS and serotonin syndrome are often considered simultaneously in patients with fever, encephalopathy, and rigidity. The presence of hyperreflexia, clonus, and/or ocular clonus is classically associated with serotonin syndrome but not NMS and can be used to distinguish one from the other. Thus, a careful neuromuscular examination should be an essential part of every evaluation of a critically ill patient with fever and encephalopathy.

There are no laboratory studies specific for NMS; however, several laboratory findings may provide corroborative diagnostic value. Serum creatine kinase can be moderately elevated (more than four times the upper limit of normal) to severely elevated (> 100,000 International Units/L) in this syndrome, depending on the degree of associated muscle rigidity, and patients with significant rhabdomyolysis may also exhibit myoglobinuria and associated acute kidney injury. However, as noted in the DSM-V definition, creatine kinase elevation is not an absolute requirement in diagnosing NMS. Electrolyte derangements including hyperkalemia, hypocalcemia, and hypomagnesemia are common nonspecific findings in NMS, as is leukocytosis. Reduced serum iron levels have also been described as highly sensitive (95%) in case series, although this finding is also nonspecific in the acutely ill. Cerebrospinal fluid glucose levels and cell counts are normal in NMS, while protein is elevated in roughly one-third of patients.

The most important treatment intervention in NMS is to stop the causative agent or, if NMS is related to cessation of dopaminergic agents, to restart the agent at previous baseline dosage. Patients with NMS are at risk for numerous complications including dehydration, renal failure, respiratory failure, hyperthermia-related seizures, and cerebrovascular accidents. Thus, supportive care including intravenous hydration, mechanical ventilation, cooling blankets, and blood pressure reduction may be required for some patients. Benzodiazepines are also recommended, if necessary, to control agitation. Recommendations for specific therapy for NMS are controversial and based on case reports, due to a paucity of prospective clinical trials. One proposed treatment is dantrolene, a skeletal muscle relaxant used for malignant hyperthermia, which is reported to reduce muscle rigidity and hyperthermia in NMS. In addition, both bromocriptine and amantadine have been used as each possesses dopaminergic activity. The optimal treatment duration for each of these options has not been rigorously tested, although some have advocated for 10 days of therapy followed by tapering. Electroconvulsive therapy has been attempted in patients who do not respond to pharmacologic therapy. Published case series have suggested that mortality rates are lower among patients receiving electroconvulsive therapy vs supportive care alone; however, a lack of methodologic rigor precludes drawing firm conclusions from these data.

With appropriate supportive care and management of the culprit medication, the average time to resolution of NMS symptoms is 7 to 11 days. Prolonged courses have been described, however, in the setting of underlying brain abnormalities or with the use of depot preparations of the offending medication. The majority of patients experience no residual neurologic impairment after recovery although those who experience hypoxemia or prolonged, severe hyperthermia may develop chronic sequelae. In severe cases or in patients who develop secondary organ dysfunction, NMS has been associated with death. More recent case series have reported mortality rates ranging from 5 to 20%, while older data have suggested mortality rates as high as 50%. Some have reported that the NMS-like syndrome related to the withdrawal of Parkinson disease therapy follows a less severe course and may be a distinct syndrome. Accordingly, this clinical scenario has been labeled “Parkinsonism hyperpyrexia” or the “malignant syndrome in Parkinson disease,” although whether it is truly a distinct clinical entity remains unclear. Survivors of NMS related to antipsychotic medication use often still have a clinical need for their use after the resolution of symptoms. The reported relapse rate of NMS after reexposure to antipsychotic medications is highly variable and ranges from 10 to 90%. Although early reexposure, use of parenteral preparations, and cotreatment with lithium have been suggested as risk factors, relapse appears to be idiosyncratic and can occur at any time or with any agent. It is, however, recommended that patients not be rechallenged with culprit medications for at least 2 weeks after symptom resolution.

Clinical Course

The patient was initially started on intravenous antibiotics targeting hospital-acquired pneumonia; however, these were discontinued after 48 hours when she failed to demonstrate overt signs of infection and her mental status did not improve. Because NMS was clinically suspected, olanzapine was discontinued. After 4 days, her rigidity improved and she began to follow commands. She was successfully extubated and transferred back to the psychiatry department for consideration of alternative treatment regimens.

  • 1.

    NMS is a potentially lethal condition, to be considered in ICU patients with fever and encephalopathy. The current diagnostic definition reflects that NMS does not always exhibit all previously recognized features of the syndrome.

  • 2.

    The presence of rigidity in patients in the ICU should increase the suspicion for NMS in the setting of culprit medication use.

  • 3.

    The presence or absence of hyperreflexia, clonus, or ocular clonus can help to differentiate between NMS and serotonin syndrome.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.


Figures

Tables

Table Graphic Jump Location
Table 1 Medications Associated With NMS

NMS = neuroleptic malignant syndrome.

Table Graphic Jump Location
Table 2 Clinical Features of NMS

See Table 1 legend for expansion of abbreviation.

References

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