Neuroleptic Malignant Syndrome in a Medically Ill Older Woman
A 77-year-old Caucasian woman suffered from obsessive-compulsive disorder and recurrent major depressive disorder. She was treated with a complex regimen of psychotropic medications. She called her psychiatrist complaining of insomnia, and trazodone 100 mg at bedtime was prescribed in order to improve sleep adding to an already complicated regimen. After taking one dose of trazodone, she awoke with muscle stiffness, dizziness, ataxia, and difficulty swallowing. Trazodone was immediately discontinued, but her physical symptoms persisted and worsened. She suffered from an increase in obsessive thoughts and developed bladder and bowel incontinence.
The patient was admitted to an inpatient psychiatric unit at another hospital where her medication regimen was reduced due to concerns that her symptoms were drug induced. Sustained-release bupropion (150 mg orally daily), buspirone (15 mg orally twice daily), alprazolam (0.25 mg orally 3 times daily), methyl- phenidate (orally, unknown dose), and risperidone (2 mg orally daily) were all discontinued. She was discharged home and was prescribed fluvoxamine (300 mg orally at bedtime), clorazepate (3.75 mg orally 3 times daily), and quetiapine (25 mg orally daily), which she discontinued after 3 days. She continued to take lorazepam 1 mg 3 times daily and zolpidem 10 mg at bedtime. Despite these changes, the patient continued to deteriorate, and 5 days after discharge her daughter brought her to our emergency department (ED) for further evaluation and management.
The patient presented confused and disoriented. Her vital signs included a temperature of 37.3º C, a heart rate of 103 beats/min, a respiratory rate of 18 breaths/min, and a blood pressure of 164/99 mm Hg. Her medical history was significant for hypothyroidism, chronic atrial fibrillation, recurrent urinary tract infections (UTIs), and at least two prior cerebrovascular events. An electrocardiogram revealed atrial fibrillation with rapid ventricular response. A computed tomography (CT) scan of her brain identified an old infarction of the left lentiform nucleus and several patchy areas of decreased attenuation in the periventricular and subcortical white matter, consistent with small vessel ischemia. Her laboratory studies were remarkable for a positive UTI (white blood cells > 25/HPF, leukest +3, cloudy), and a thyroid-stimulating hormone (TSH) level of 0.019 µU/mL (0.400-5.500 µU/mL).
The ED physician admitted the patient to the internal medicine service after administering 2 doses of haloperidol 5 mg intravenously (IV) in hopes of improving her delirium. Medications on admission were lorazepam (1 mg orally 3 times daily), laxative (1000 mg orally daily), levothyroxine (0.25 mg orally daily), zolpidem (10 mg orally at bedtime), and aspirin (325 mg orally daily). Magnetic resonance imaging (MRI) of the brain revealed no new infarct, and further laboratory reports confirmed the abnormal thyroid function (TSH 0.025 µU/mL [0.400-5.500 µU/mL], T4 12.6 µg/dL [5.0-11.0 µg/dL], T3 90 ng/dL [94-170 ng/dL], T3 U 53% [23-37%], free thyroxine index 17.3 µg/dL [6.0-11.0 µg/dL]) and an elevated creatinine kinase (539 U/L [30-220 U/L]). Psychiatry was consulted the following day. The evaluation noted very limited communication, bilateral stiffness, and cogwheeling of the patient’s upper extremities with tongue fasciculations, involuntary jaw movements, and variations in heart rate (68-100 beats/min) and systolic blood pressure (100-160 mm Hg).
The psychiatry service recommended all nonessential medications be stopped, IV fluids started, and lorazepam be given (0.5 mg IV every 6 hours) for her involuntary movements and potential neuroleptic malignant syndrome (NMS). The consultation cited the muscle rigidity, elevations in creatine phosphokinase, autonomic instability, and the recent use of haloperidol in a medically ill woman with a history of cerebrovascular accidents as indications of the diagnosis of NMS. Unfortunately, the medical service, although appreciative of psychiatry’s input, was not entirely convinced of a diagnosis of NMS. The patient had other factors, including a UTI, as a cause of delirium. Diphenhydramine (25 mg IV every 6 hours as needed) was added to address a new erythematous rash on the patient’s chest and both lower extremities. Lorazepam was discontinued for one day, but as the patient deteriorated it was restarted at a lower dose (0.5 mg IV every 8 hours). An electroencephalogram was performed that revealed encephalopathy with intermittent slow waveforms, particularly in the left temporal lobe. A transthoracic echocardiogram was unremarkable with an ejection fraction of 60%.
The patient’s mental status and extrapyramidal symptoms did not improve, even after the lorazepam dose was resumed. However, after the dose was increased to 1 mg IV every 8 hours on day 9, the patient’s mental status cleared dramatically, her stiffness and cogwheeling improved, and her vital signs began to stabilize. Concomitant with the increase in lorazepam, a single positive blood culture out of three prompted an aggressive antibiotic regimen (ampicillin/ sulbactam 3 g IV every 8 hours). On day 13, the patient had a setback, manifesting with significantly increased tone and perseverant speech. A bolus dose of lorazepam (1.5 mg) followed by a continuation of the scheduled dosing led to improvement, and the following morning her IV fluids were discontinued. Unfortunately, on day 15, the patient once again appeared disoriented and lethargic.
Evaluation revealed a left lower lobe infiltrate on chest CT and a fungal infection in the urinary tract. Between hospital days 16 and 21, the patient was treated aggressively for both infectious etiologies and NMS. Infectious disease (ID) was consulted, and multiple antibiotics including nitrofurantoin, fluconazole, amoxicillin, ampicillin/sulbactam, clindamycin, piperacillin/tazobactam, and vancomycin were employed at various points. On day 18, the lorazepam was increased to 2 mg IV every 8 hours. Amantadine (100 mg orally daily) and zolpidem (5 mg orally at bedtime) were added, and intravenous fluids were resumed. Between days 20 and 21, the patient was more alert, but her stiffness returned and her blood pressure fluctuated dramatically (95/48 to 198/88 mm Hg.). This perplexing change of events coincided with a primary team decision to lower the lorazepam dose from 2 mg to 1 mg orally 3 times daily on day 20, and then from 1 mg to 0.5 mg orally 3 times daily on day 21. On recommendation from the psychiatry consultant, the lorazepam dose was increased to 1 mg 3 times daily, and on day 22 the patient’s tone and deep tendon reflexes improved.
Over the ensuing 5 hospital days, the patient’s mental status improved and her physical symptoms remained stable. This improvement coincided with an increase in the amantadine dose to 100 mg twice daily on day 23. A family meeting on hospital day 24 suggested a history of previous mild but undiagnosed NMS episodes, as relatives recalled prior hospitalizations complicated by extreme rigidity, mutism, and fever. Convinced she was no longer suffering from any infections, the internal medicine team discontinued all antibiotics. Unfortunately, the patient suffered yet another setback on hospital day 27 when she presented once again with limb rigidity and cogwheeling. Both of these symptoms increased, and by day 28 she was once again mute. To treat this, amantadine was increased to 200 mg orally twice daily, and by the next day the patient was improving mentally and physically. This improvement continued over the next 2 days, while discharge planning was performed. After 31 days of hospitalization, with some residual muscle rigidity and mild deficits in attention, the patient was discharged to an extended-care facility close to her home in West Virginia for rehabilitation. As part of discharge planning, the psychiatry service provided detailed instructions to the extended-care facility for continued care of the patient, including the current maintenance of benzodiazepine dosing, attention to hydration, and avoidance of all antipsychotics. She continued to show improvement, and after several months moved back to live with her daughter.
Neuroleptic malignant syndrome is an idiosyncratic and life-threatening reaction to typical and atypical antipsychotic medications. It has been believed that blockade of the postsynaptic dopamine D2 receptors, a common feature of all antipsychotic agents, is related to the etiology of the disorder.1-6 There is increased risk of NMS in those patients with diseases associated with central dopaminergic hypoactivity, such as Parkinson’s disease, dementia, and those who are treated chronically with dopamine-blocking agents.3 The pathognomonic symptoms of NMS include fever, rigidity, and tremor, and are related to dysfunction of the autonomic system, extrapyramidal system, and frontal cortex. Characteristic—but not mandatory—laboratory findings include an elevated creatine phophokinase and leukocytosis. Any patient receiving dopamine antagonists can develop NMS, particularly with rapid dose escalation.
Disorders that affect deep brain structures, such as strokes and neurodegenerative disease, substance abuse, catatonic states, dehydration, or agitation can increase the risk.2 The differential diagnosis can be challenging with disorders of similar presentation, including serotonin syndrome, catatonia, hyperthermia, and infections with delirium. Early recognition of the risk factors and evolving symptoms of NMS in order to arrive at an accurate diagnosis and provide aggressive treatment is vital. Neuroleptic malignant syndrome is associated with significant morbidity and mortality.
Issues Relevant to the Case Patient
This unfortunate case illustrates the complexity of treating the older patient with both psychiatric and neurologic pathology. Ultimately, the liberal use of neuroleptic psychotropics should be carefully considered in cases where there is increased risk of NMS. In this instance, haloperidol was employed to “treat the patient’s delirium” in the ED, but it may actually have worsened her condition and contributed to the patient’s prolonged hospital course. For this particular patient, several complications bear discussion. First, the patient’s medication history requires the differentiation of NMS and serotonergic syndrome, given that both share symptoms of fever and confusion but require different treatment.1-3
On presentation, the patient had been treated primarily with selective serotonin reuptake inhibitors. She had distant but no recent contact with antipsychotic medications until she came to the ED. Given that these two syndromes share common clinical findings, it is reasonable to consider each carefully in the differential before medicating and potentially confusing the situation.1 Indeed, given the frequency of psychotropic combinations, all too often one is dealing with a combination of syndromes requiring slightly different approaches.1,2 Of interest, some evidence suggests that a high 5HT/dopamine neurotransmitter ratio may be more important for the development of NMS than the effects of dopaminergic antagonism alone.4
Second, by MRI this patient also suffered from what appeared to be a remote left lenticular stroke. Although there is no direct evidence that remote cerebral damage has any influence on an NMS presentation, a few case reports have suggested that striatal damage is associated with increased risk for the development of NMS.3,5 Certainly, corpus striatum injury is intimately involved in the pathophysiology of movement disorders,6 so at the very least this injury could have independent effects that mimic NMS symptoms, thus confusing the presentation. Third, for this case in particular, a history suspicious for prior NMS episodes must be given credence early to prevent delay in therapy. Collateral information, so crucial in all medical treatment, is an absolute necessity in psychiatric conditions. Unfortunately, it is all too often incomplete or untimely. Despite conscientious effort, much of this patient’s remote history was not obtained until late in her hospital course. However, even without this information, the patient’s consistent response to NMS treatments and her relevant known risk factors for NMS must be respected.
Finally, chronic illness and system failure should not be counted on to explain global dysfunction. Fever and dehydration can follow infection and allergic response, adding multifactorial fuel; however, as demonstrated in this case, a complicated mixture of conditions can lead to “missing the forest for the trees” or at least a significant grove. The simplest explanation is often the answer; multiple systems can simultaneously fail and lead to a myriad of symptoms. However, this should never exclude the possibility that something more unusual and perhaps more elegantly fundamental is an important cause. Indeed, as we become increasingly familiar with NMS, it may turn out to be less of a zebra after all.
Diagnosis and Treatment
Patients who have been on a conventional or atypical antipsychotic agent or those who abruptly stop dopaminergic agents are at risk for NMS.7 Observing closely for autonomic instability, hyperpyrexia, extrapyramidal symptoms, and mental status changes are key symptoms. For some, elevated creatinine phosphokinase, increased white blood cell count, and low plasma iron may be identified. More susceptible patients may include those with dehydration, physical illness, many medicine prescriptions, and a substance abuse history. When treating patients with NMS, lowering body temperature and providing adequate fluids are critical support measures. Others may wait until the temperature is > 39 degree C.8 Cooling blankets are often recommended if temperatures rise above 38 degree C and certainly if above 39 degree C. We initiated bromocriptine, a central dopamine agonist assisting in stabilization of heart rate, blood pressure, and body temperature, in our patient. In other cases of similar severity,9 dantrolene, an agent originally used in malignant hyperthemia, has been recommended. By slowing the flow of calcium from the sarcoplasmic reticulum to the muscle cytoplasm, it may allow muscle relaxation.10 Its ability to decouple oxidative phosphorylation may limit excess heat production. For some patients, both bromocriptine and dantrolene are used, although efficacy is not assured.9 Recently, pulse therapy with methylprednisolone was given to patients with Parkinson’s disease who had developed NMS after discontinuing their antiparkinsonian agents. In addition, all patients received levodopa, bromocriptine, and dantrolene. Patients recovered more quickly when methylprednisolone rather than placebo was added to the other three agents.11 Dantrolene does not easily dissolve in water and requires some preparation time.
In summary, although mortality has been lowered by safer medications, early identification, and rapid treatment, NMS still occurs. Elderly patients on anti- psychotic medication or those who abruptly stop taking parkinsonian agents are at great risk, particularly if they are dehydrated, taking many medications, or have complications such as urinary tract infections. With rapid identification, treatment can be effectively initiated. Treating only individual signs and symptoms, blood pressure fluctuating, extrapyramidal symptoms or elevated temperature, white blood cell count, and altered mental status may only delay seeing the more important target of NMS.