The Twilight Zone: Oxybutynin Overuse Exacerbating Delirium

Background

Overactive bladder (OAB) is a common diagnosis in older patients and the first-line pharmacological treatment is antimuscarinic therapy, such as oxybutynin chloride (Ditropan). ¹ The adverse effect profile of oxybutynin has been well-studied and it has been linked to central nervous system (CNS) adverse effects, including somnolence, memory impairment, confusion, and in severe cases, psychosis.^2-5 As a tertiary amine, it easily crosses the blood–brain barrier to exert anticholinergic activity in the CNS, increasing the likelihood of psychiatric adverse effects relative to other anticholinergics. ⁶ According to the 2019 American Geriatrics Society Beers Criteria, anticholinergic medications should be avoided in patients 65 or older due to their uncertain effectiveness and possible risk of inducing or exacerbating delirium and major neurocognitive disorder. ⁷ Providers should interpret these guidelines with caution, as there is evidence that some anticholinergics may be both efficacious and safe in older adults with urgency incontinence.^8,9

Many older patients who were prescribed oxybutynin for OAB years ago continue on anticholinergic therapy in the absence of patient-reported adverse effects. Anticholinergic-induced CNS adverse effects may be underreported as they are often unrecognized by patients. ¹⁰ In these cases, the adverse effects may manifest in a variety of patient presentations and with interesting histories. We present a case of an older man with a history of major neurocognitive disorder in which oxybutynin overuse led to repeated episodes of delirium and subsequent hospitalizations.

Case Report

Our patient is a 73-year-old man experiencing homelessness with a history of major neurocognitive disorder with behavioral disturbance secondary to traumatic brain injury who presented to the emergency department in a confused state after getting lost while driving. The patient stated that he began to feel like he was in “a twilight zone” while driving in an area he knew well, and found himself just going around in circles. He could not specifically remember the events preceding his arrival at the emergency department, but described seeing “fluorescent lights” that he was following while driving, although he was not able to elaborate.

The details of his neurocognitive disorder and past psychiatric history were reviewed to assess for contributing factors to this delirium episode. The patient suffered a traumatic brain injury during a motorcycle accident as a teenager and lost consciousness for three days. Since that incident, he reported suffering near daily headaches, narcolepsy, and short-term memory loss. He also had a long history of post-traumatic stress disorder after serving in the army for several years. He had a history of alcohol use disorder as an adult which has remained in full sustained remission since his 40s. In his mid-50s, he was involved in a second motor vehicle accident and experienced an exacerbation of agitation, mood lability, and cognitive impairment. He was started on valproic acid, which largely controlled his symptoms, but after 15 years was switched to risperidone due to elevated bilirubin. Neuropsychological testing results obtained shortly after this second accident demonstrated impairments in executive functioning and he received a diagnosis of dementia secondary to traumatic brain injury. Additional neuropsychological testing performed and repeated within the past three years of this report demonstrated some additional cognitive declines in processing speed, attention, and memory over the next two decades that had stabilized in recent years, consistent with major neurocognitive disorder secondary to traumatic brain injury.

Additional medical history includes type two diabetes mellitus, obstructive sleep apnea, atrial fibrillation, hypertension, hyperlipidemia, gastroesophageal reflux disease, and benign prostatic hyperplasia for which he underwent transurethral resection of the prostate, with reports of urinary incontinence since this operation. Accordingly, he was taking glipizide, modafinil, apixaban, amlodipine, metoprolol, atorvastatin, omeprazole, tamsulosin, trazodone, and risperidone, which were prescribed by providers within our healthcare system. Medications were reconciled with the patient’s pharmacy on admission.

On admission, his vitals and labs were within normal limits. Computerized tomography (CT) scan of the head demonstrated stable ventriculomegaly and cortical volume loss consistent with his history of neurocognitive disorder and no acute intracranial processes were detected. On evaluation, he was disorganized, disoriented, inattentive, and agitated, with circumstantial thought process and impaired insight into current circumstances. Still, none of the information gathered from the patient’s history, labs, or imaging offered an explanation for this acute episode. Due to poor outpatient follow-up, we were unable to obtain collateral from the patient’s primary care physician to provide additional context for the current presentation. His delirium was diagnosed clinically in the emergency department and without the use of standardized instruments, such as the Confusion Assessment Method (CAM). Several other causes of delirium were ruled out with a complete medical evaluation, including complete metabolic panel, complete blood count, thyroid function test, liver function tests, venous blood gas, urine drug screen, and electrocardiogram. Although no electroencephalogram was performed to evaluate for possible seizure activity, there was no clinical concern for seizure. Further, there was no immediate clinical concern for stool impaction or urinary retention, so these etiologies of delirium were not evaluated in the emergency department. After this evaluation, the patient was voluntarily admitted to the inpatient psychiatric unit.

The next morning, during the initial psychiatric interview, the patient was agitated about the admission. He displayed pressured speech and disorganized thought process, and was unable to be redirected. He insisted that he was only looking for a place to stay the night and was not aware that he had been admitted to a psychiatric hospital. The patient was disoriented, irritable, and argumentative throughout the first two days when it was determined that he still required inpatient admission.

Notably, he had exhibited similar behaviors during his recent hospitalization one week earlier. At that time, he was admitted after a similar history of confusion while driving, with bystanders reporting that he was driving erratically, swerving off-road, and having delusions of aliens and laser beams. The patient had an extensive history demonstrating poor insight and judgment—while living out of his car, he once lit a candle overnight for warmth, causing the car to set fire. He later reported that he was not aware that cars were flammable. He also insisted that he is prescribed “77 medications,” although he could not recall any of them. Based on this history, it was determined that he was unable to live alone and manage his medications appropriately, and he was subsequently placed in multiple assisted-living facilities over time. Each time, he reported feeling dissatisfied with the facility and, though he was homeless, absconded without notifying facility staff.

During the current admission, he again showed poor insight to his inability to live independently outside of the hospital and declined to consider placement in an assisted-living facility. However, after a few days in the psychiatric unit, he began to display a more linear thought process and improved insight regarding his functional status and living situation. His mental status exams were consistent with his known major neurocognitive disorder, but there was no further evidence of psychosis, agitation, or delirium during the remainder of his admission.

Days later, after experiencing several episodes of urinary incontinence in the unit, the patient requested to restart his outpatient oxybutynin. He stated that it was highly effective for relieving his incontinence. On thorough medication review, it was noted that he had been switched from solifenacin to oxybutynin for OAB four months prior, but this was discontinued shortly thereafter. Despite the fact that oxybutynin had been discontinued, the patient continued to take this medication. Psychoeducation about the cognitive adverse effects of oxybutynin and the rationale for not restarting this medication were provided to the patient.

He initially dismissed the connection between possible cognitive adverse effects and oxybutynin usage, claiming that it only helped his incontinence and denying ever having issues with confusion while taking it. He was then reminded about his repeated admissions to the hospital for getting lost and confused while driving. After additional review of these recent events, he revealed that he would often take additional doses of oxybutynin before driving to prevent incontinence on long drives in the car. The patient then began to connect the episodes of hallucinations, delirium, agitation, and experiences of being in the “twilight zone” to instances when he took excess oxybutynin before a long car ride. After discussion with the patient about treatment alternatives, including non-pharmacological options such as bladder training and posterior tibial nerve stimulation, a trial of mirabegron 25 milligrams daily was initiated for non-invasive treatment of OAB. After continued hospitalization and cessation of oxybutynin overuse, his cognition, mood, and insight continued to improve.

Discussion and Conclusions

As seen in this case report, the importance of obtaining a thorough history regarding the ways in which patients take their medication cannot be overstated. It can, however, be extremely challenging to obtain a clear history from patients with neurocognitive disorders and impaired short-term recall. Therefore, thorough review of prescribed medication is essential in all patients who present in confusional states or with worsening neurocognitive disorder, and requires consideration of all comorbidities and drug interactions. Careful medication review can also reduce polypharmacy in older patients, a known contributor to increased morbidity, reduced quality of life, and high rates of inappropriate medication use. ¹¹ It is equally important to provide proper education to patients about the potential adverse effects of all medications they are prescribed, and perform adequate discharge counseling about how patients should take new outpatient medications. As medication adherence is lower in patients with lower health literacy, cognitive impairment, higher numbers of prescriptions, and multiple care providers and pharmacies, providers should perform targeted efforts to discharge these patients with the adequate means for medication management.^12,13

All providers should also recognize the potential adverse effects of oxybutynin, especially in older patients and in patients with known neurocognitive disorders. Specifically, the anticholinergic-induced CNS effects of oxybutynin should be considered when initiating or continuing anticholinergic therapy. Though the incidence of anticholinergic delirium has not been studied on a wide scale, it has been estimated that 20–50% of Americans aged 65 or older takes at least one medication with anticholinergic properties, and use of medication with anticholinergic effects has been suggested to be associated with the development of neurocognitive disorders, even in patients without known pre-existing neurocognitive disorders.^14-16 While the effect of anticholinergic burden on risk of delirium in healthy older adults has been unclear in past studies, in older patients with pre-existing neurocognitive disorders, there is evidence for an increase in the risk of delirium with higher anticholinergic burden. ¹⁷ When this is seen, it may manifest as a hyperactive delirium with pressured speech, agitation, and visual abnormalities. However, it also has been reported to manifest as hypoactive or mixed delirium, and in more severe cases, it can involve psychotic elements, including visual and auditory hallucinations. This variability in presentation can make it difficult to make the diagnosis purely based on the characteristics of the delirium. Clinicians should consider using other signs of anticholinergic toxidrome to confirm the suspected diagnosis, such as constipation, dry mouth, blurred vision, and odynophagia.^18,19

The neurologic sequelae of anticholinergic therapy may be inappropriately attributed to worsening of known neurocognitive disorders in patients, obscuring the clinical picture. In these patients, it is even more important to monitor anticholinergic administration, as most anticholinergics have been also shown to potentiate symptoms of known neurocognitive impairment.^17,20 This likely occurs by further reducing the already decreased cholinergic activity in brains with major neurocognitive disorder, and secondarily, by augmenting CNS inflammation associated with major neurocognitive disorder, thereby accelerating neurodegeneration. ²¹ However, the pathophysiology remains unclear, and in animal models, anticholinergic medication exposure has been associated with brain atrophy, suggesting the alternate theory that this occurs by reducing hippocampal glucose metabolism and temporal and medial temporal lobe cortical volume. ²² Often, patients may have been prescribed oxybutynin with good effect years prior and continued on the medication because of its efficacy in treating OAB. In these patients, providers must additionally consider the interplay of comorbidities and total anticholinergic burden in adding to the risk of neurologic sequelae, and after administration, if there is any evidence of adverse effects or psychiatric comorbidity, choose alternate therapy accordingly. ²³ Providers should note that patients with higher anticholinergic burden are more likely to experience adverse effects, so they should seek to calculate anticholinergic burden in all patients and opt for non-pharmacologic treatment when possible in patients with higher burden scores. In this patient, who had an anticholinergic burden score of 6, it was crucial to evaluate for any prescribed medications that were linked to delirium or neurologic sequelae, and discontinue them to avoid polypharmacy and excessive anticholinergic burden. To do this, providers should familiarize themselves with commonly used medications that have been linked to anticholinergic delirium, including atropine, scopolamine, benztropine, antihistamines, tricyclic antidepressants, antipsychotics, opiates, and carbamazepine, as well as with the available scales to help quantify anticholinergic burden, of which the Anticholinergic Cognitive Burden (ACB) Scale is the most frequently validated and most widely used. ²⁴ The ACB Scale and the Anticholinergic Drug Scale consider the largest range of relevant medications in estimating total anticholinergic exposure when compared to other commonly used scales, such as the Anticholinergic Risk Scale. However, when using any of these three scales, it is important for providers to note that unlike the Anticholinergic Activity Scale, they are not based on quantifying serum anticholinergic activity. Though this may sacrifice biological precision, there is a poor correlation between serum anticholinergic activity and severity of central adverse effects, ²⁵ so the ACB Scale remains the preferred scale by most providers.

Due to the high incidence of anticholinergic use in older patients, providers who care for these populations should understand standards in the management of anticholinergic delirium. Non-pharmacologic management of general delirium should be trialed first, including frequent re-orientation, decreasing stimuli in the environment, ensuring adequate nutrition and hydration, and sleep enhancement, with avoidance of pharmacological treatment in older adults due to the risk of adverse effects, as per the National American Geriatric Society guidelines. ²⁶

Alternative medications with more favorable adverse effects have become preferred in the older population for management of OAB. Selective M3 antagonists, such as solifenacin, darifenacin, trospium, and fesoterodine, result in few central nervous system adverse effects. ²⁷ However, other than some data which showed no clear effect of solifenacin on cognitive function in older patients with pre-existing cognitive impairment, there are no further analyses investigating these for these four agents. ²⁸ Mirabegron and vibegron, beta-3 adrenoceptor agonists, have been shown to improve irritative urinary symptoms without affecting cognitive function, although it is important to note that these results have only been demonstrated in one randomized control trial assessing cognitive function in patients taking mirabegron at twelve week follow-up with a Montreal Cognitive Assessment thus far, with no data regarding effects on cognitive function for vibegron. Mirabegron is contraindicated in severe liver disease, chronic kidney disease, uncontrolled hypertension, and in pregnancy, and it is important to counsel patients about the adverse effect profile when weighing safer alternatives, such as pelvic floor muscle therapy and bladder training.^28-32 It is crucial that providers who care for older patients or patients with neurologic and psychiatric conditions not only understand the CNS adverse effect profiles of commonly used medications but also viable alternatives to these medications in older adults, including physical therapy, bladder training, and posterior tibial nerve stimulation.