A case of neuroleptic malignant syndrome (NMS) in a nursing facility resident that was initially misdiagnosed as a urinary tract infection is presented. The author reviews the etiology and diagnosis of NMS, including the differential diagnosis, and discusses how other syndromes can generate similar symptoms.

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The Case

Mrs. F is a 64-year-old female resident in a skilled nursing facility (SNF) with a history of early-onset dementia of the Alzheimer’s type, who was noted by staff at the facility to be more confused and restless. The patient developed a fever with a Tmax of 102.2 degrees F, and was evaluated by her primary care physician in the SNF. The nursing staff also reported that she had difficulty swallowing with dysphagia. Upon examination, a urinalysis was ordered, and the patient was diagnosed with a UTI. Review of symptoms and physical exam did not elicit a cough or any respiratory symptoms. A chest x-ray was negative for infiltrate. A course of antibiotics was started for her infection. She had been on her medication course of risperidone 2 mg twice a day, lorazepam 1 mg three times a day, and trazodone 50 mg twice a day since being discharged from an inpatient geriatric psychiatric unit two months earlier. The medical doctor also added quetiapine 12.5 mg twice a day to her medication regimen for breakthrough agitation.

Two days later a psychiatric evaluation was ordered for worsening agitation and anxiety with restlessness. On evaluation by the psychiatrist, the patient was reported by the nursing staff to be more lethargic and disorganized than her baseline. The patient exhibited restlessness and was very fidgety. Poor eye contact and resistance with questioning and commands were noted. On physical exam there was moderate to severe lead-pipe rigidity of both arms at the wrists and elbows.

A creatinine phosphokinase (CPK) level was ordered and found to be elevated at 800 IU/L. The white blood cell count was elevated on her complete blood count without a left shift. Her liver transaminases were also mildly elevated from a normal baseline with an aspartate aminotransferase (AST) of 68 and an alanine aminotransferase (ALT) of 58. Her renal function was normal, and she had no myoglobin in her serum or urine. She had a normal computed tomography scan of her head.

The risperidone and quetiapine were stopped immediately. The lorazepam was increased to 4 mg per day. She was given oral and intravenous fluids in the facility. A follow-up CPK the next day showed a level of 400 IU/L, and it continued to trend down, returning to normal in the next three days. Her temperature normalized in the next two days, and her rigidity was significantly improved. On exam, the patient was alert and much calmer. Two weeks later, she began to become psychotic and agitated again, and so was restarted on risperidone 0.5 mg three times daily. On follow-up up to two months later she did not exhibit any evidence of NMS.

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Discussion
A large percentage of patients in skilled nursing facilities are treated with antipsychotic agents for a variety of disorders ranging from dementia with psychosis to schizophrenia. Neuroleptic malignant syndrome is a rare but dangerous complication of antipsychotic medication use,1 a form of drug-induced hyperthermia.2 The presentation and course of NMS can be variable and can range from benign and self-limiting to fatal in some cases if not recognized and diagnosed rapidly. The incidence of NMS varies from 0.02% to 3.23% but has been declining. It is more commonly seen with conventional antipsychotics than with the newer atypical agents. Neuroleptic malignant syndrome occurs in all ages and is found to be more common in males.3,4

The etiology appears to be related to specific antidopaminergic activity of antipsychotic medications. Central dopamine systems are involved in temperature regulation, as well as in regulation of muscle tone and movement. It is postulated that dopamine blockade in the nigrostriatal pathway can cause rigidity.5 Antipsychotic-induced blockade of dopamine receptors in the hypothalamus can lead to autonomic impairment and impairment of thermoregulation, causing hyperthermia through decreased heat discharges. The hypermetabolic state in NMS may be a result of an excess of noradrenaline (norepinephrine) relative to dopamine.6 Increased risk of NMS has been correlated with dehydration, use of restraints, preexisting abnormalities of CNS dopamine activity or receptor function, and iron deficiency.7 Nearly all case series of NMS patients have reported physical exhaustion and dehydration prior to the onset of NMS.8

The clinical presentation is characterized by mental status changes, muscle rigidity, hyperthermia, and autonomic dysfunction.4 The DSM-IV-TR criteria for NMS require severe muscle rigidity and elevated temperature associated with use of neuroleptic medication. In addition, it includes at least two of the following: diaphoresis, dysphagia, tremor, incontinence, changes in consciousness with increased confusion, mutism, tachycardia, labile blood pressure, leukocytosis, or laboratory evidence of muscle injury (eg, elevated CPK) (Table). The elevated CPK level resulting from muscle breakdown can progressively lead to renal damage and rhabdomyolysis.9 The differential diagnosis of NMS must include a broad range of illnesses presenting with fever.4

Cases such as the ones presented above can be complicated because the fever and leukocytosis can be explained by other causes such as a UTI. Therefore, if one does not carefully assess for rigidity or if rigidity exists from other causes (eg, advanced dementia, Parkinson’s disease), then it can easily be missed. Treatment includes stopping the offending agents (eg, antipsychotics) and using supportive measures including cooling and hydration. Treatment with dopamine agonists can be considered, with bromocriptine being the most common agent used at a dose of 2.5 mg every 8 hours. Treatment with benzodiazepines (eg lorazepam) can also be considered.10

Restarting antipsychotic treatment after resolution of an NMS episode has been associated with a likelihood of developing NMS again as high as 30%.4 Nevertheless, most patients who require antipsychotics can be safely treated again with such agents. Precautions should include waiting at least two weeks after recovery from NMS before rechallenge with antispychotics, using low doses with a gradual titration, and closely monitoring patients for early signs of NMS.11

Conclusion

Clinicians in SNFs must be aware of the clinical features of NMS, and keep a high index of suspicion and be vigilant in detecting early signs, as its presentation can mimic other illnesses. Primary management of NMS lies in prevention through conservative use of antipsychotics, reduction of risk factors, early diagnosis, prompt discontinuation of offending medications, and medical management. Early recognition and treatment of NMS minimizes complications. For mild cases, supportive care and careful clinical monitoring may be sufficient. In severe cases, more aggressive measures should be taken, including empirical trials of specific pharmacological agents.