Donanemab-Associated Amyloid-Related Imaging Abnormalities Presenting as Acute Stroke Mimic and SeizureKey clinical message:Amyloid-related imaging abnormalities may present as an acute neurological emergency in patients treated with anti-amyloid monoclonal antibodies. While often asymptomatic, some cases lead to seizure, encephalopathy, and focal neurological deficits. Prompt recognition and MRI evaluation are essential to prevent inappropriate interventions, guide supportive or steroid therapy, and ensure patient safety.Introduction:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. The pathophysiology of AD is strongly associated with the deposition of β-amyloid, making β-amyloid a major therapeutic target1. More recently, monoclonal antibodies directed against β-amyloid plaques, including lecanemab and donanemab, have emerged as novel therapeutic agents2,3. However, these therapies carry risks, particularly the development of amyloid-related imaging abnormalities (ARIA)4. This occurs due to an inflammatory response, causing extravasation of proteinaceous fluid and vasogenic edema (ARIA-E) or microhemorrhages and hemosiderin deposition (ARIA-H)5. In this case report, we describe two patients treated with anti-amyloid monoclonal antibodies who developed ARIA. The first patient presented like an acute stroke mimic, and the second patient presented with a seizure. This case series underscores the importance of awareness and timely recognition of this complication to prevent misdiagnosis and inappropriate treatment.Case presentationCase 1Case history/examination/initial managementWe report a 74-year-old woman with a past medical history of early-onset Alzheimer’s dementia, who had recently initiated intravenous donanemab therapy. Surveillance MRI brain demonstrated a small amount of left temporal edema, frontal, and temporal lobe microhemorrhages. Based on these asymptomatic imaging findings, discontinuation of donanemab was planned. She presented to our emergency department with an acute onset of speech disturbance. The evening before the hospital visit, she was at her baseline. The following morning, her family noted incomprehensible speech, naming difficulty, and nonsensical output. She had never experienced similar symptoms before. Since the onset, there was partial improvement but no resolution. There were no other associated focal neurological deficits, such as weakness or sensory loss. At baseline, she was awake, alert, oriented to person and place, and ambulated independently, though she had chronic dementia-related deficits causing inattention. Neurological examination revealed impaired naming (4/6 objects correct), intact repetition with paraphasic errors, and frequent errors on fluency testing. Reading was mostly preserved, with one error noted on complex sentences. Comprehension was intact. Orientation was limited to person. No additional focal deficits were found.Differential Diagnosis, Investigations, and ManagementA non-contrast CT head revealed left temporal vasogenic edema, unchanged from the prior outpatient MRI performed 10 days ago, without any significant mass effect. CT angiography of the head and neck demonstrated no evidence of large vessel occlusion or new stenosis. Given the history of donanemab infusion, MRI findings of vasogenic edema/microhemorrhages, and acute language disturbance, the most likely diagnosis was of symptoms from amyloid-related imaging abnormalities (ARIA), specifically ARIA-E with concomitant ARIA-H. Differential considerations included acute ischemic stroke, seizure with post-ictal aphasia, though these were less consistent with the clinical course and imaging. The patient was monitored closely with supportive management. Antithrombotic therapy was avoided due to concern for ARIA-H.Outcome and Follow-UpBy the following day, the patient’s symptoms improved significantly; she was oriented to person, place, and year, with only mild residual anomia and word-finding difficulty. Inpatient MRI was deferred, and follow-up imaging was obtained as an outpatient. The first follow-up MRI confirmed progression of ARIA-E and ARIA-H, predominantly involving the left temporal lobe. A subsequent MRI one month later demonstrated a reduction in left temporal lobe edema (Figure 1).Case 2Case history/examination/initial managementA 73-year-old male presented to the emergency department with acute altered mental status, left gaze deviation, and left-sided weakness. He has a past medical history of early Alzheimer’s dementia, receiving monthly donanemab infusions, and hypertension. At baseline, he was fully oriented and independent despite memory changes from dementia. On the morning of the presentation, while at work, he experienced dizziness and a mild headache. His wife brought him home, where she noticed confusion, delayed responsiveness, and slurred speech, prompting her to call emergency medical services. On arrival to the emergency room, he had a blood pressure of 189/91 mmHg and blood glucose of 195 mg/dL. He was lethargic but arousable to verbal stimuli, oriented only to self, and demonstrated slow speech without significant dysarthria. He inconsistently followed simple commands. He had a left gaze preference crossing midline and left upper extremity weakness (4/5 strength). CT head showed no acute intracranial hemorrhage or infarct. His routine EEG showed continuous right-sided epileptiform periodic discharges. The patient received intravenous lorazepam 2 mg and levetiracetam 2 g.Differential Diagnosis, Investigations, and ManagementLevetiracetam was transitioned to divalproex sodium 750 mg twice daily due to agitation. The patient had a complicated course in the ICU. MRI Brain showed right occipital lobe hyperintensity and left frontal hyperintensity on FLAIR sequence. Our differential diagnosis included ARIA-E and posterior reversible encephalopathy syndrome (PRES). The patient was started on intravenous dexamethasone 6 mg every 6 hours with a two-week taper and improved after the steroids. Follow-up MRI showed improvement in vasogenic edema in the left frontal and right occipital lobes compared to prior imaging (Figure 2). Given that the patient improved with steroids, a diagnosis of ARIA-E was made.Outcome and Follow-UpAfter initial improvement, the patient had a complicated hospital course, ultimately requiring a tracheostomy. The patient was discharged to a long-term care facility.DiscussionAmyloid-Related Imaging Abnormalities (ARIA) have been reported in patients receiving novel monoclonal antibody therapies for Alzheimer’s disease2,3. Most patients who develop ARIA during monoclonal antibody treatment remain asymptomatic, but in certain cases, the condition can be clinically significant and even life-threatening. Reported symptoms with lecanemab include headache, dizziness, and gait disturbance, which are more common. More severe manifestations such as status epilepticus, focal neurological deficits, and encephalopathy can also occur6. Interestingly, lecanemab has been associated with the development of ischemic strokes in a prior case report7. Aducanumab is another anti-amyloid therapy that has been discontinued since 2024 due to reduced efficacy8.Donanemab, a monoclonal antibody that binds to pyroglutamate modified Aβ peptide and is approved for the treatment of mild dementia in Alzheimer’s disease. Donanemab effectively cleared amyloid plaques. However, it has been associated with both asymptomatic ARIA and symptomatic cases, including headache, confusion, and, in rare instances, fatal outcomes. 36.8% of treated patients experienced ARIA8. Overall, both lecanemab and donanemab have been associated with serious adverse effects; however, donanemab has the potential to cause more adverse effects9. Importantly, APOE4 homozygotes appear to have an increased risk of ARIA, particularly with edema and effusion2. Although PRES and ARIA share overlapping clinical features, ARIA occurs exclusively with anti-amyloid therapies or in the setting of cerebral amyloid angiopathy4,10. It has been hypothesized that ARIA may represent a variant within the broader spectrum of PRES 11.In our report, Patient 1 developed expressive aphasia, initially presenting as an acute stroke mimic, which was ultimately attributed to ARIA. Patient 2 presented with seizures, a recognized though rare complication of ARIA. In this case, the differential diagnosis also included PRES, given the patient’s hypertension at presentation and associated vasogenic edema. However, the clinical improvement with steroids, recent history of donanemab infusion, and characteristic imaging findings were most consistent with ARIA-E.Management of ARIA typically includes corticosteroids in more severe cases, while milder cases may be managed with supportive care such as acetaminophen or NSAIDs12. In our cases, patient 1 was managed conservatively with symptomatic treatment; corticosteroids were not initiated due to the mild, resolving nature of her symptoms, and a repeat MRI was recommended in four weeks with outpatient neurology follow-up. In contrast, Patient 2 required a dexamethasone taper due to significant symptoms and the development of seizures.ConclusionARIA can present with a wide spectrum of clinical manifestations, including acute stroke mimic and seizure, as demonstrated in our patients. Failure to recognize ARIA in this context carries the risk of inappropriate treatment with anticoagulation or thrombolysis, which may significantly worsen outcomes. This report underscores the importance of maintaining a high index of suspicion for ARIA in patients receiving anti-amyloid monoclonal antibody therapy. It highlights the need for greater awareness of its symptomatic presentations among clinicians to prevent misdiagnosis and inappropriate treatment.Figure captions:Figure 1. MRI brain showing edema and microhemorrhages in case 1. The top row represents the T2 FLAIR sequence, and the bottom row represents the GRE/SWAN sequence. (A) and (D) represents the initial MRI brain of the patient obtained outpatient before presentation. (B) and (E) represents the MRI obtained in four weeks, showing worsening edema and hemorrhage. (C) and (F) indicates the MRI performed eight weeks after the first MRI of the brain. The blue arrows represent the areas of vasogenic edema, and the green arrowhead indicates microhemorrhages. (FLAIR- fluid attenuated inversion recovery, GRE- gradient echo, SWAN- susceptibility weighted angiography)Figure 2. MRI brain of case 2. A indicates an initial MRI brain FLAIR sequence showing right occipital lobe vasogenic edema. B represents the repeat MRI brain performed in a week, which shows the resolving vasogenic edema as indicated by the arrows. (FLAIR- fluid attenuated inversion recovery).References:1. Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Euro J of Neurology . 2018;25(1):59-70. doi:10.1111/ene.134392. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA . 2023;330(6):512. doi:10.1001/jama.2023.132393. Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med . 2023;388(1):9-21. doi:10.1056/NEJMoa22129484. 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