Neuroleptic Malignant Syndrome in an Older Woman With Schizophrenia

Currently, 85% of US elders with schizophrenia reside in the community and the remainder in LTC facilities or other residential care settings.³ In 2005, 1.2 million new nursing home admissions were reported in the United States; 2.7% of these new admissions were older adults with schizophrenia or bipolar disorder, according to a study by Grabowski and colleagues.³ According to the World Health Organization, schizophrenia affects about 24 million people worldwide, equivalent to seven of every 1000 adults.⁴ In the United States, the current generation of older adults with schizophrenia has spent considerably more time in the community than earlier generations due to the 1963 Community Mental Health Centers Act, which led to considerable deinstitutionalization.⁵ As a result, adults of this generation may find themselves in LTC facilities staffed by individuals who are unprepared to provide necessary psychiatric assessments and interventions.^5,6 This is of particular concern when an older adult with schizophrenia is experiencing an uncommon and potentially life-threatening adverse reaction (such as NMS) to his or her antipsychotic medication. Although many patients with mental disorders are treated with the newer generation of antipsychotic medications (atypical antipsychotics), NMS and its milder, partial form do occur and need to be part of a clinician’s differential diagnosis when an older adult develops new-onset fever and muscular rigidity as well as other symptoms, such as autonomic dysfunction, mutism, dysphagia, diaphoresis, increased confusion, urinary incontinence, and leukocytosis. 

In this case report, we describe an uncommon presentation of NMS in an older woman with schizophrenia. A brief discussion of the prevalence of NMS, its risk factors in older adults, and approaches to treatment is also provided. 

Case Report 

A 66-year-old woman with paranoid schizophrenia and Alzheimer’s dementia had recently moved from the community into an LTC facility. After 3 months, she was brought to a local hospital’s emergency department (ED) because of a productive cough and chest pain, and bacterial pneumonia was diagnosed. She was started on azithromycin 250 mg by mouth twice daily. The patient’s other chronic illnesses included hypertension, hypothyroidism, osteoarthritis, and chronic obstructive pulmonary disease. For 10 years, the patient was taking clozapine 200 mg orally before meals and at bedtime. Her other regularly scheduled medications included escitalopram, levothyroxine, buspirone, donepezil, omeprazole, diltiazem, and acetaminophen. As part of the protocol to monitor risk of adverse clozapine-induced cardiovascular events, the LTC facility’s supervising pharmacy required weekly monitoring of the patient’s complete blood count (CBC) and white blood cell (WBC) differential. Although patients who complete 1 year or more of continuous therapy with clozapine and experience no abnormal blood events during that time can be monitored every 4 weeks, the LTC facility’s associated pharmacy decided to monitor the patient’s WBC count weekly because she was new to the facility. Despite her WBC count being elevated at 12,000/µL (reference range, 4500-10,000/µL) at the time of the pneumonia, it rapidly returned to normal with antibiotic therapy. 

Approximately 1 week later, a physician and a nurse practitioner from a different local hospital’s LTC service saw the patient during a routine certification visit. At that time, the patient presented with profuse diaphoresis; muscular rigidity, including cogwheeling; dysphagia; poor appetite and weight loss; a fixed gaze; and mutism. A diagnosis of NMS was strongly suspected, resulting in urgent transport to the ED. She returned from the ED approximately 10 hours later with a urinary tract infection (UTI) diagnosis, for which she was started on ciprofloxacin. During the next routine CBC, which coincided with the patient’s ciprofloxacin regimen, her WBC was >12,000/µL, her previous symptoms remained, and she continued to be afebrile. A test for the patient’s creatine phosphokinase (CPK) level was normal at 34 µL (reference range, 10-120 µL). Upon completion of the antibiotic therapy 3 days later, the patient’s WBC level had climbed to 14,000/µL. She returned to the LTC facility and was started on a different antibiotic (amoxicillin 500 mg by mouth three times a day) for her UTI and amantadine for her NMS. The patient has since fully recovered and continues taking a lower dose of clozapine for her schizophrenia. It has been suggested that a lower dose of an initial antipsychotic can be reinstituted after an adequate drug-free period.⁷ 

Our case patient had an uncharacteristic presentation. She had been taking clozapine, an atypical agent, for 10 years. In addition, she remained afebrile and lacked elevated CPK levels. In this case, presence of bacterial pneumonia and an immediate subsequent UTI may have triggered the presentation of NMS by causing elevated serum concentrations of clozapine.⁸ The use of ciprofloxacin, a potent inhibitor of the cytochrome P450 1A2 (CYP1A2) enzyme, may have increased the effects of the clozapine.⁹ Further discussion of this drug-drug relationship is provided in the Risk Factors section. 

Discussion 

French psychiatrist and neurologist Jean Delay and colleagues first described NMS in relation to the use of haloperidol in 1960.¹⁰ Explanation of the syndrome was expanded upon in the medical literature in 1968,¹¹ yet it was not fully recognized by American physicians until the 1980s.¹² The Physicians’ Desk Reference did not report NMS as an adverse reaction of neuroleptic therapy until 1985.¹³ What follows is a review of the prevalence, risk factors, pathophysiology, diagnosis, and treatment of NMS.

Prevalence of NMS 

As neuroleptic medications are sometimes used outside of psychiatric care, NMS may be overlooked and therefore underrecognized^14,15; however, historically, the prevalence of NMS has been thought to be between 0.5% to 2.4% of patients taking neuroleptics,¹⁴ with some estimates reaching as high as 3.23%.¹⁶ A recent review by Hall and colleagues¹⁴ found that the prevalence of NMS has dropped to between 0.02% and 0.2%, which may be attributed to the advent of atypical antipsychotic medications, also known as second-generation antipsychotics, and an increased recognition and understanding among clinicians of this uncommon event. In the United States, approximately 2000 cases of NMS are diagnosed annually, resulting in a 10% mortality rate and an associated $70 million in healthcare expenditures.¹⁵ Higher rates of NMS have been associated with typical neuroleptic agents, such as haloperidol,^13,14 but there are documented cases of NMS associated with atypical agents as well, including clozapine, risperidone, and olanzapine.¹⁷ Milder or partial forms of NMS have been documented with ziprasidone and aripripazole, which are among the most recently introduced atypical antipsychotics.^10,12,15,18 Additionally, quetiapine has been implicated in both NMS and in its milder, partial form.^12,17 

Other drugs associated with NMS include the antiemetic prochlorperazine; the sedative promethazine; the antiemetic and gastroprokinetic agent metoclopramide; and anesthetics, such as droperidol.^14,15 All of these agents antagonize dopamine in a fashion similar to atypical antipsychotics. 

A spectrum concept has been proposed with severe NMS at one end and mild NMS at the other,¹² with the more severe cases requiring treatment in an intensive care unit.¹³ According to the review by Hall and colleagues,¹⁴ the reported mortality rate for NMS ranges between 4% and 20%, with the rate increasing to 50% in the presence of renal failure. Other fatalities have resulted from sudden cardiorespiratory arrest, aspiration pneumonia, pulmonary emboli, and disseminated intravascular coagulation.¹⁵ 

Risk Factors 

Case reports of NMS among older adults highlight elders as a vulnerable population due to predisposing factors, such as dehydration, malnutrition, exhaustion,and underlying electrolyte abnormalities.^14,15 While environmental considerations, such as hot summer weather, have been suggested as a contributor to hyperthermia in NMS patients, the condition has been reported to occur during winter months and in areas with cold climates.¹⁵ NMS tends to occur more commonly in men.^14,16 Other predisposing factors include dementia, traumatic brain injuries, infections, and coadministration of lithium, some antidepressants (eg, venlafaxine), and anticholinergic agents.¹³ Bacterial pneumonia has been found to increase serum concentrations of clozapine.⁸ 

Coadministration of medications other than neuroleptics account for more than half of the cases of NMS.¹³ Medications with anticholinergic properties are thought to significantly increase the risk of NMS partly due to the many medications with anticholinergic properties that are commonly prescribed to nursing home residents.⁷ A review by Hall and colleagues⁷ found that 30% to 60% of nursing home residents are taking a minimum of one medication with significant anticholinergic properties, and approximately 15% of elders in LTC are taking multiple medications with anticholinergic properties. These authors identified that coadministration of a number of classes of drugs with anticholinergic properties are associated with NMS. These include antiemetics, antispasmodics, bronchodilators, antiarrhythmic agents, antihistamines, antihypertensive drugs, antiparkinson agents, corticosteroids, skeletal and smooth muscle relaxants, antiulcer drugs, and psychotropics.

In our case patient, it appears a drug-drug interaction between clozapine and ciprofloxacin may have induced NMS. Ciprofloxacin belongs to the class of CYP450 enzymes, which are essential for the metabolism of many medications. There have been several recent studies that suggest CYP450 enzymes may inhibit metabolism of clozapine, thereby increasing serum concentration of this agent and causing severe adverse reactions or therapeutic failure.^9,19,20 This relationship is not well understood, but Brouwers and associates²⁰ have suggested using another antibacterial agent in combination with clozapine therapy or reducing clozapine dosage to minimize risk. 

Pathophysiology of NMS 

It has been suggested that the cause of NMS may be multifactorial.⁶ The pathophysiology of NMS is not entirely understood, although it has been established that acute reduction of dopamine activity in the brain is the basic underlying mechanism.^13-16 Currently, NMS is thought to be caused by central or peripheral dopaminergic blockade resulting in muscle rigidity and core temperature elevation.¹⁴ Dopamine blockade in the nigrostriatal pathway is the source of the muscular rigidity or lead-pipe rigidity (ie, a type of increased muscle tone in which pathologic resistance to passive extension of a joint is constant throughout the range of motion²¹), while blockade in the hypothalamus can result in hyperthermia.¹⁶ It is unlikely the dopaminergic blockade theory is the sole explanation given serotonergic, noradrenergic, and cholinergic pathways are also implicated.¹⁴ It is thought that glutamate also plays a role, which explains why the drug amantadine (an N-methyl-D-aspartate S-type glutamate receptor antag-onist) is used to treat NMS.¹⁴ 

Diagnosing NMS  

There has been controversy surrounding the diagnostic criteria of NMS largely due to the varying symptoms and degrees of severity in presentations.¹² There are several sets of criteria by which to diagnose NMS: the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV)²²; the Adityanjee Criteria²³; the Levenson Criteria²⁴; and the Pope Criteria.²⁵ According to the DSM-IV, a diagnosis of NMS requires two essential features to be present: severe muscle rigidity and fever (temperature >99ºF).²² Two or more other symptoms must also be present, such as diaphoresis, dysphagia, tremor, incontinence, altered levels of consciousness with increased confusion, mutism, tachycardia, elevated or labile blood pressure, hypersalivation, leukocytosis, or laboratory evidence of muscle injury, as in the case of elevated CPK levels.²¹ 

Muscle rigidity and fever are essential diagnostic features of these four sets of criteria. Rigidity is usually generalized throughout the body and is described as lead-pipe or unbreakable in quality.^14,15 However, the classic symptom of muscular rigidity has been absent in some documented cases of NMS,¹⁴ or in other cases, has been localized to the tongue, facial muscles, or masticatory muscles, causing dysarthria or dysphagia.^7,12 Temperature elevations are usually accompanied by profuse diaphoresis, and it is the febrile state that constitutes NMS as a medical emergency because it can lead to brain damage of the cerebellum or death.¹⁵ However, fever can instead be mild, delayed in presentation, or absent entirely.^12,14 

While elevated CPK levels and leukocytosis are thought to be characteristic of NMS, they are not required to make the diagnosis, as was the case described by Murray and colleagues.²⁶ Although elevated CPK levels are commonly noted during the progression of NMS and are considered an essential symptom to diagnose NMS per the Levenson Criteria,²⁴ this symptom is generally considered to be nonspecific and not pathognomonic for the syndrome.^6,23,25 The duration of reported symptoms varies from 1 to 44 days and does not appear to be dose-related.¹⁴ In addition, these symptoms can occur when drug concentrations in the blood are in therapeutic ranges, rather than at toxic levels.¹³ 

Though not included specifically on any of the diagnostic criteria lists, patients can present with a fixed gaze resembling mutism, while others can be agitated, more psychotic, or delirious.¹³ Furthermore, it has been reported in more than 80% of cases that mental status changes or muscular rigidity preceded other signs and symptoms of NMS, suggesting an incipient form of NMS may exist.¹⁵

Differential diagnosis. Because the symptoms of NMS are nonspecific, the differential diagnosis of NMS has been described as “baffling,”¹³ encompassing a broad range of disorders that are beyond the discussion of this case report. It is important to note that as NMS progresses and remains undiagnosed, patients may show more severe symptoms of agitation, psychosis, or delirium, and clinicians may mistakenly assume the patient is experiencing an exacerbation of his or her primary psychiatric illness. For example, Kohen¹⁶ reported a case of a 66-year-old woman with Alzheimer’s dementia who resided in a skilled nursing facility and whose NMS was misdiagnosed as a UTI. The case patient experienced restlessness, confusion, and agitation, for which her attending physician added quetiapine 12.5 mg twice daily to her medication regimen. Within 2 days of taking quetiapine, the patient’s symptoms worsened and an elevated CPK level was noted. Quetiapine was discontinued immediately, leading to resolution of her NMS. This mistake may lead to inappropriate treatment, such as erroneous prescription of further antipsychotic medication, which would only worsen the patient’s clinical picture. 

Nursing home personnel often have limited formal education and training in psychiatric disorders and psychopathology.⁵ With regard to our case patient, the nursing personnel recognized a change in her status, but were limited in understanding all the possible explanations for this change. The
patient presented with symptoms during a summer with record high temperatures, which may have explained the diaphoresis. A documented UTI may have led staff to attribute behavioral or mental status changes to the infection, similar to the Kohen¹⁶ case report. Muscle rigidity with mutism or psychosis may have been erroneously interpreted as a worsening of the patient’s schizophrenia or Alzheimer’s disease. What follows is an explanation of the diagnoses that were considered as part of the differential diagnosis for our case patient and why they were ruled out; these included heat stroke, serotonin syndrome, and anticholinergic delirium. 

Heat stroke is characterized by pyrexia, confusion, rapid breathing, and agitation, and it typically occurs during the summer months, which is when our case patient exhibited her symptoms.²⁷ However, patients with heat stroke have skin that is dry. In cases of NMS, patients present with diaphoresis and noticeably wet skin.¹² 

Patients with serotonin syndrome present with altered mental status, similar to NMS; however, they are typically restless and agitated,²⁸ whereas akinesia and muscular rigidity are hallmarks of NMS. Patients with serotonin syndrome have demonstrated rigidity in rare cases. Nausea, vomiting, and diarrhea are characteristic of serotonin syndrome but are not typically present in NMS. Further, serotonin syndrome has a rapid onset, usually within 24 hours, whereas NMS develops over the course of 24 to 72 hours, or longer, after administration of a neuroleptic agent.^12,14  

Anticholinergic delirium was considered given the patient’s medication regimen. The features of anticholinergic delirium include confusion, pyrexia, dry skin, mydriasis, and decreased secretion of body fluids.⁷ In contrast, diaphoresis and wet skin are typically present with NMS.¹² 

Treatment 

Once a diagnosis of NMS is established, discontinuation of the causative antipsychotic medication is widely considered the first step toward amelioration.^12-15 Once the agent is discontinued, NMS remits in approximately 7 to 10 days, and nearly all patients recover within 30 days.¹⁵ Our case patient’s clozapine was not discontinued when NMS was suspected because the treating psychiatrist was concerned about a relapse of her schizophrenia. In addition, NMS is not an absolute contraindication to continued antipsychotic therapy. 

Because complications of NMS and of withdrawal of the neuroleptic agent can be severe and life-threatening, emergency transfer to a hospital for supportive care is often warranted.¹⁵ General supportive measures should be initiated, including daily monitoring of CPK levels, rehydration and cooling, stabilization of blood pressure, correction of fluid and electrolyte imbalances, deep venous thrombosis prophylaxis, and nutritional support.^12-15 These measures are often sufficient to resolve NMS. Patients who must be restarted on their neuroleptic medication should be carefully monitored to minimize the risk of recurrence. Precautionary measures include waiting at least 2 weeks to resume therapy, using less potent therapies, starting with a lower dose of medications and titrating upward gradually, avoiding concomitant administrating of lithium, and avoiding dehydration.²⁹ 

There are conflicting reports of the benefit of using dopamine agonists (ie, bromocriptine, amantadine) and muscle relaxants (ie, dantrolene) as treatment.¹² Dantrolene, bromocriptine, or amantadine may be considered for patients with CPK elevations or hyperthermia upon presentation, or those who do not respond to withdrawal of the neuroleptic agent with supportive care within a couple of days.²⁹ Dantrolene can be prescribed to reduce core body temperature and peripheral muscle rigidity by inhibiting calcium release from the muscle sarcoplasmic reticulum.^13-15 Amantadine has been effective in some cases, as reported by Lazarus and colleagues,¹³ and it is thought to reverse the dopamine receptor blockade associated with NMS. Bromocriptine may reduce hyperthermia and alleviate rigidity and heat production via action on thermoregulatory centers in the hypothalamus.¹³ 

Conclusion 

Although NMS is a rare disorder, patients are at risk of developing it whenever dopamine antagonists are prescribed. Because the symptoms are nonspecific, staff can easily overlook NMS and its milder, partial form, yet the condition can become life-threatening if left untreated. Thus, NMS should remain a concern of staff at LTC facilities, which will house increasing numbers of older adults with chronic and persistent mental illness. It is important for healthcare professionals to become familiar with this potentially lethal adverse event of neuroleptics and be vigilant to its early signs and symptoms to ensure early and optimal intervention. 

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