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Atypical Neuroleptic Malignant Syndrome Associated With Olanzapine

from Pharmacotherapy

Roy R. Reeves, D.O., Ph.D., Raphael A. Torres, M.D., Vincent Liberto, M.D., Roy H. Hart, M.D.

Abstract and Introduction

Abstract

Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of antipsychotic agents. It generally is characterized by fever, altered mental status, rigidity, and autonomic dysfunction. A 53-year-old man developed NMS without rigidity while taking olanzapine. Such atypical cases may support either a spectrum concept of NMS or the theory that NMS secondary to atypical antipsychotics differs from that caused by conventional neuroleptics. More flexible diagnostic criteria than currently mandated by the the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision, may be warranted.

Introduction

Neuroleptic malignant syndrome (NMS) is an uncommon side effect of antipsychotic drugs, usually characterized by fever, altered mental status, rigidity, and autonomic dysfunction. The pathophysiology of NMS is not fully understood. Reduction in dopaminergic activity secondary to neuroleptic-induced dopamine blockade is considered the chief mechanism.[1] This syndrome was first described in 1960 during clinical trials with haloperidol.[2] Since that time, NMS has been associated with virtually all dopamine-blocking agents. Because many atypical antipsychotic agents have weaker dopamine blockade and lower rates of extrapyramidal side effects than conventional antipsychotic agents,[3] it has been suggested that atypical antipsychotic agents are less likely to cause NMS. However, this remains unproven, and cases of NMS associated with clozapine, risperidone, olanzapine, and quetiapine have been reported.[4-27]

A 53-year-old African-American nonsmoking man with a long history of paranoid schizo-phrenia had been in stable condition for approximately 3 years while taking olanzapine 10 mg/day. His medical history was unremarkable except for heat stroke over a year earlier, during which he had a high fever and weakness after prolonged exertion in hot weather. The patient was taking olanzapine at the time; no other details are available. During those 3 years the patient had intermittent employment and did not require hospitalization. Then, after experiencing a number of stressors, he became progressively more paranoid and isolated. He lost his job and, after a series of intrusions, caused his wife to lose hers. Under financial stress, the couple decided to move to Mississippi to live with the wife's relatives.

The 4-day drive from Tacoma, Washington, was stressful for the patient, and he became increasingly paranoid. He heard voices and other sounds underlying road noises and felt that other drivers were following him. He began taking extra olanzapine to control these symptoms. How much extra he took was unknown (he had filled a prescription for 30 10-mg tablets 2 weeks previously), but when he arrived in Mississippi he had taken all his tablets. After noting that he was coughing and had a fever, his wife took him to the emergency room, where his temperature was 102.9°F. He was diagnosed with sinusitis and treated with amoxicillin 250 mg 3 times/day. He complained that he was still hearing voices, and he was prescribed olanzapine 5 mg 3 times/day.

Over the next 2 days his wife gave him the drugs as prescribed, but he became increasingly paranoid and confused. He returned to the hospital the following day but would not allow anyone to examine him because he was so paranoid. He was given olanzapine 10 mg and lorazepam 2 mg. Approximately 45 minutes later, physical examination found him to be lethargic and diaphoretic, with a temperature of 104°F, blood pressure 85 mm Hg, heart rate 80-115 beats/minute, and respiratory rate 20 breaths/minute. He was confused and oriented to person only, but with no other abnormalities and no source of infection. Neurologic examination revealed symmetric movement of all extremities and symmetric reflexes. Muscle tone was normal. Laboratory tests revealed white blood cell count 5.7 x 103/mm3, hemoglobin 11.4 g/dl, hematocrit 33.9%, platelet count 105 x 103/mm3, sodium 132 mEq/L, potassium 3.0 mEq/L, chloride 95 mEq/L, glucose 117 mg/dl, blood urea nitrogen 21 mg/dl, creatinine 1.5 mg/dl, creatine kinase 1388 IU/L, aspartate amino-transferase 56 IU/L, and lactate dehydrogenase 271 IU/L. Urinalysis, drug screen, and chest radiograph showed no abnormalities.

The patient was admitted to the intensive care unit (hospital day 1) and treated with intra-venous hydration. All antipsychotic drugs were withheld. Computed tomography of the head, lumbar puncture, thyroid function studies, rapid plasma reagin, human immunodeficiency virus testing, and electroencephalogram results were unremarkable. On day 2 the patient's blood pressure was stable at 105/62 mm Hg, and his temperature was 102°F. His mental status slightly improved, in that he was oriented to person and place, although still unable to perform cognitive tasks. His creatine kinase declined to 1203 IU/L, and his electrolytes became closer to normal. Intravenous fluids were continued, and on day 3 his electrolytes and renal and hepatic function tests were within normal limits. At that point, the patient's temperature was 100.9°F, blood pressure 135/85 mm Hg, and creatine kinase 551 IU/L. He was less confused and scored 17 of 30 possible points on the Mini-Mental State Examination. However, he continued to express paranoid ideations. On day 4 he was afebrile with normal cognitive functioning and his creatine kinase level was 211 IU/L. At no point did he have rigidity or increased muscle tone. He received no intramuscular injections.

During his illness the patient's white blood count fell as low as 3.3 x 103/mm3. His red blood cell count, hemoglobin, hematocrit, and platelet count were also slightly low. A complete evaluation for causes of pancytopenia found that the abnormalities were consistent with anemia of chronic disease, and no active treatment was recommended. This probably explains the failure of his white blood count to elevate, as often occurs with NMS.

The patient continued to hallucinate and was paranoid after his condition stabilized, so he was transferred to a psychiatric unit and started on risperidone 1 mg twice/day. His psychotic symptoms improved moderately, and 2 days later the dosage was increased to 3 mg at bedtime. He complained of headache with each dose, so risperidone was replaced with ziprasadone 20 mg twice/day. The dosage was increased to 40 mg twice/day, which fully alleviated the patient's hallucinations and improved his paranoia such that he was suitable for discharge. He has experienced no adverse effects with this drug.

Discussion

Although over 1000 cases of NMS have been reported,[28] many features of the syndrome remain controversial. Several diagnostic criteria have been proposed, but no single set of criteria has been adopted for general use. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV),[29] the diagnosis of NMS should be assigned only to patients who develop severe muscle rigidity and elevated temperature while receiving a neuroleptic drug and who display two or more of the following signs and symptoms: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and laboratory evidence of muscle injury.

Alternative diagnostic criteria that also requires fever and rigidity have been proposed by two groups of investigators.[30,31] However, operational criteria suggested by a third group[32] permit a probable diagnosis of NMS even if one of three criteria for a definite diagnosis (hyperthermia, severe extrapyramidal effects, autonomic dysfunction) is absent, provided the two other criteria are clearly met and the patient displays one of the following characteristic signs: clouded consciousness as evidenced by delirium, mutism, stupor, or coma; leukocytosis with a white blood cell count above 15 x 103/mm3; and creatine kinase level above 300 IU/ml. A fourth group[33] suggests that NMS can be considered highly probable in patients who either meet three major manifestations (fever, rigidity, elevated creatine kinase) or have two of these major manifes-tations in association with at least four of the following minor manifestations: tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, and leukocytosis. Similarly, another group[34] developed diagnostic guidelines for NMS that involve combinations of major and minor criteria exhibited by patients who either are receiving or have recently received a neuroleptic drug or another dopamine antagonist.

Our patient did not fully meet the criteria for diagnosis of NMS under the requirements of the DSM-IV or the second and third guidelines described above.[30,31] However, our patient did fulfill the diagnostic criteria of the remaining three guidelines.[32-34] Despite this patient's lack of muscular rigidity, NMS is the best explanation for his symptoms. A complete medical work-up excluded concomitant medical illness, all other criteria for NMS were present, and onset and remittance of the syndrome coincided with increased dosing and discontinuation of olanzapine. Because he had taken extra olanzapine during his drive from Washington, olanzapine overdose or anticholinergic delirium must be considered in the differential diagnosis. However, this seems unlikely to have caused his illness because his symptoms continued to worsen over the 3 days before admission, during which time his wife administered his drugs as prescribed. Moreover, several signs and symptoms typically associated with anticholinergic toxicity were notably absent, including flushed dry skin, dry mucous membranes, blurred vision, mydriasis, decreased bowel sounds, and urinary retention. Olanzapine overdose in premarketing trials (67 patients, one of whom ingested 300 mg of this agent) was characterized by drowsiness and slurred speech, but patients did not undergo changes in laboratory analytes, electrocardiogram, or vital signs.[35]

The controversy as to whether our patient actually had NMS centers on his lack of muscular rigidity. Of the 16 cases of olanzapine-associated NMS documented in English-language reports or abstracts,[9-24] the presence of rigidity is clearly documented for 15 of the involved patients. In the other instance,[22] muscle tone was not noted in the medical record and thus was unknown to the author. However, NMS without rigidity has been documented in patients receiving antipsychotics other than olanzapine (although the diagnosis might be questioned in some cases). A review of NMS cases from 1980-1985 found that 11% of patients lacked rigidity.[33] A review of all cases of clozapine-associated NMS before 1999 revealed that rigidity was absent in 36% of patients and was mild or limited to the neck in 15%.[5] Two investigators[36] recently reported a clozapine-treated patient who met one of the above sets of criteria for NMS, even though this patient did not develop rigidity or creatine kinase elevation. Risperidone-induced NMS without rigidity has been described.[37] A search of the medical literature found 71 reports of NMS associated with atypical antipsychotics, of which 23 (32.4%) of the patients lacked rigidity.

These findings raise the question of whether NMS induced by atypical antipsychotic agents differs from NMS caused by conventional antipsychotics. If the primary cause of NMS with conventional antipsychotic agents is secondary to dopamine D2 blockade, atypical antipsychotics might cause NMS by a different mechanism because their dopamine2-blocking properties are relatively weak. Insufficient evidence exists to truly define the concept of atypical NMS with new antipsychotics.[38] In clozapine-induced NMS, fever and rigidity are less likely to occur and, when present, may not be extreme.[5] As more information is gathered on NMS caused by atypical agents, it may become possible to define such a syndrome. Due to overlap between features of NMS and the adverse effects of atypical antipsychotics, potential may exist for diagnostic confusion. For example, approximately 3% of patients receiving clozapine develop benign hyperthermia, and 25% of patients have autonomic instability during initial titration of clozapine or risperidone.[39]

Cases of this type may support a spectrum concept of NMS.[40] Possibly, NMS is not a single entity with a uniform presentation, or it may represent the extreme end of neuroleptic-related toxic reactions. Incomplete or atypical presentations of the syndrome may represent early or impending NMS.[41]

This is an area with many unanswered questions requiring further research. It would appear that one should not always require the presence of strict DSM-IV or similar criteria to consider a diagnosis of NMS. Any patient under treatment with an atypical antipsychotic who exhibits unexplained fever, alteration of cognition, rigidity, or autonomic instability should be evaluated for atypical NMS and receive appropriate treatment. Adherence to a rigid diagnostic paradigm for NMS may interfere with prompt diagnosis and treatment, especially because this condition may present in a variety of ways. In our opinion, diagnostic requirements based on flexible major and minor criteria would be more sensitive than rigid paradigms in a clinical setting, and still retain diagnostic specificity. We recommend continued vigilance of MedWatch reporting so that the pool of cases can be expanded. This may facilitate a true delineation of variations in the frequency and presentation of this rare condition.

Acknowledgements

Supported in part by the South Central Veterans Administration Health Care Network Mental Illness Research, Education, and Clinical Center.

Reprint Address Address reprint requests to Roy R. Reeves, D.O., Ph.D., VA Medical Center (116A), 1500 East Woodrow Wilson Drive, Jackson, MS 39216; e-mail: roy.reeves2@med.va.gov.