Challenges for emergency departments: Anti-amyloid therapy and amyloid-related imaging abnormalities in persons with dementia

Abstract

Anti-amyloid therapies (AAT) offer promise to persons with Alzheimer's dementia (AD).^{1, 2} The number of persons undergoing AAT will grow in the coming years, and many could potentially present to U.S. emergency departments (ED) with serious adverse treatment reactions, particularly amyloid-related imaging abnormalities (ARIA), which manifest as intracerebral edema or hemorrhage with varying symptoms.³ There are currently no evidence-based clinical policies or care guidelines for the pre-hospital and ED management of ARIA, and current disparities in access to brain imaging and neuroradiology expertise,^{4, 5} and neurology consultation,⁶ may result in persons on AAT finding themselves at EDs without the necessary expertise or resources to optimally manage their clinical presentation.^4-8 Consequently, they may undergo unnecessary tests or treatments, hospitalization, and transfers to another hospital. Further, potential adverse interactions between AAT and anticoagulants or thrombolytics would complicate the time-sensitive ED management of acute conditions.^{9, 10} The goal of this paper was to outline potential challenges for ED care of persons on AAT and recommend a framework for development of guidelines to address these challenges.

Current recommendations for aducanumab and lecanemab restrict their use to mild cognitive impairment (MCI) or mild AD dementia confirmed with amyloid beta (Aβ) biomarkers (amyloid PET or CSF Aβ).^{11, 12} Recent 2021 U.S. population estimates of persons ≥65 years suggest 5.7 million Aβ+ persons with MCI and 2.45 million Aβ+ persons with mild AD.¹³ These estimates are projected to increase by 76% and 128%, respectively, by 2060.¹⁴ The percentage eligible for AAT is uncertain, but estimates range from 9% to 57% based on rates of contraindications (e.g., anticoagulant therapy, stroke/TIA/seizure within the last year).^15-17 Therefore, we estimate 0.72 to 4.6 million persons in the U.S. currently eligible for AAT.

Most of the attention on adverse effects of AAT has centered on ARIA, which can manifest as either brain edema (ARIA-E) or brain hemorrhage, most commonly microhemorrhages or hemosiderin deposits (ARIA-H).⁸ A recent meta-analysis of 19 studies with a pooled sample of 9429 patients yielded a pooled incidence of 6.5% for AIRA-E and 7.8% for ARIA-H,¹⁸ although this report was published before results from the lecanemab and donanemab phase 3 trials were released, both of which reported higher raw proportions of treatment group participants with ARIA-E (12.6%; 24.0%) and ARIA-H (17.3%; 31.4%), respectively.^{1, 2} ARIA may be asymptomatic in approximately 80% of cases,^{3, 18} and can present with a wide range of clinical symptoms, including headache, confusion, dizziness (i.e., lightheadedness or vertigo), seizures, visual disturbances, focal neurologic deficits, or systemic viral (influenza-like) symptoms.^{3, 8} In the lecanemab and donanemab trials, ARIA screening was accomplished by routinely scheduled MRI, with additional unscheduled MRIs by investigator discretion in the donanemab trial. One would not expect patients on AAT without symptoms or indications for emergent imaging to receive a screening MRI in the ED. More likely, patients undergoing brain imaging would have complaints or symptoms suspicious for ARIA or other neurological conditions. The potential number of persons receiving AAT presenting to the ED for evaluation of ARIA will likely be toward the upper end of the above estimates.

The pre-hospital response and triaging of persons receiving AAT with new neurologic complaints will be challenging for emergency medical services (EMS), as well as for outpatient primary care providers and urgent care clinics. Given the urgency of symptomatic ARIA, the default action would be to recommend these persons be evaluated in the ED. If the first medical response is with EMS, persons with focal neurologic complaints would be managed as an acute stroke, given existing pre-hospital EMS protocol for stroke.¹⁹ With the current lack of EMS education or pre-hospital guidelines regarding ARIA, an acute neurologic deficit due to an adverse reaction to AAT will likely not be entertained early on in a person's presentation.

The ED clinician will be faced with three challenges in determining if a patient on AAT has neurologic findings due to ARIA, stroke, or other alternative diagnoses: The first is verifying that the patient is on AAT, especially in situations where the patient cannot provide a history. As AAT are currently administered by infusion, available medication records may not provide this information. The second is recognition of ARIA with its wide range of symptoms. The third is accessing and utilizing optimal tools and resources for diagnosis and management of ARIA, and its impact on the management of other conditions.

Determination of ARIA on neuroimaging can be difficult and resource dependent. The ideal ED that can efficiently address this clinical situation are those with 24/7 access to (a) MRI imaging with recommended sequences required for diagnosis,^{3, 8} potentially with access to the patient's pre-treatment imaging for comparison and to a scanner identical to pre-treatment assessment²⁰; (b) a neurologist and/or radiologist with expertise to diagnose ARIA; and (c) a consulting neurologist to provide expert management of ARIA.^{3, 6-8} Most ED patients will not have access to this level of care. A 2008 report found only 66% of U.S. EDs had MRI availability in-house and 20% of EDs depended on mobile MRI services, and it was unclear which facilities had 24/7 MRI access.²¹ While MRI access may have since increased nationally, we know of no report to verify this, although recent studies revealed disparities in MRI access in Minnesota,⁵ disparities in imaging in general,⁴ and particularly for cerebrovascular imaging.²² Many of these ED patients will have to be transferred to facilities with appropriate radiology resources. Some patients on AAT may also be under the care of a behavioral neurologist or neuropsychiatrist who are geographically distant and difficult to access for consultation and/or follow-up after an ED visit.

Another important concern involves any ED patient on AAT who presents with an acute ischemic stroke within the treatment window for thrombolytic therapy. The risk versus benefit of thrombolytic agents is presently unclear for these patients, given the very limited data on the safety of these agents in patients on AAT. Presently, we are aware of one case report of a patient treated with t-PA for an acute ischemic stroke who had received three doses of lecanemab and subsequently diagnosed with multiple cerebral hemorrhages, although it is unclear if the lecanemab was an etiologic factor in the hemorrhage.^{10, 23} There are additional clinical scenarios where patients on AAT present with other clinical indications for anti-platelet or anticoagulation therapy, such as an acute pulmonary embolism or acute cardiovascular event. More research is needed regarding these situations. However, the decision to administer these types of medications will likely fall on the treating ED physician who may not be familiar with the potential risks in patients on AAT.

The coming years will offer better estimates of the number of persons at risk for adverse effects of AAT. Despite uncertainties of current estimates, EDs must prepare for the possibility of increasing visits by patients with possible ARIA or other adverse treatment reactions. These patients will be at risk of unnecessary testing and treatments, hospitalizations, and/or hospital transfers, all of which have associated adverse outcomes among older persons with dementia.^24-27 For individuals whose symptoms have other etiologies, the long wait times and chaotic ED environment can be a trying experience for older persons with dementia.²⁸ Even when appropriate consultants and neuroimaging are available, work up of these symptoms would almost certainly increase ED length of stay with associated risk of delirium and other adverse events, and hospitalization to facilitate MRI and/or neurology consult carries similar risks.^{24, 26}

Risks associated with AAT may also be underestimated among racial minorities, given their low representation in the aducanumab, lecanemab and donanemab trials.²⁹

Ultimately, challenges for EDs treating patients on AAT will be dynamic, numerous and complex as implications of their use evolve over time. Interdisciplinary guidance and partnerships will be critical in facing the AD treatment landscape ahead.

AXL and REK were responsible for the concept and design of this manuscript. RDS and ASR contributed original material. All authors were responsible for the preparation and revision of the manuscript. All authors have reviewed the manuscript and approved its submission to JAGS.

The authors have no conflicts of interest.

REK is supported by R01 AG037561 (as PI) and 1P20AG068024 (as co-I). The study sponsors had no role in the study design; the collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication. The research presented in this paper is that of the authors and does not reflect the respective official policies of the individual funding organizations.