Ischemic stroke associated with amyloid‐related imaging abnormalities in a patient treated with lecanemab

Abstract

INTRODUCTION

Anti‐amyloid antibody therapies such as lecanemab are increasingly being used to treat Alzheimer's disease (AD). These therapies are associated with a high rate of amyloid‐related imaging abnormalities (ARIA).

METHODS

We review the case history of a patient who developed ARIA associated with lecanemab treatment.

RESULTS

In addition to microhemorrhages and cerebral edema that are recognized features of ARIA, the patient developed several ischemic strokes. The patient also experienced frequent electrographic seizures without overt clinical seizures. The patient demonstrated clinical and radiographic improvement after steroid treatment.

DISCUSSION

Our case suggests that ischemic strokes may be a feature of ARIA and highlights the importance of having a high clinical suspicion for seizures in ARIA. As anti‐amyloid therapies are likely going to be increasingly used to treat AD, it is important to appreciate the spectrum of clinical and radiographic findings that can result as side effects from this class of therapies.

Highlights

• We report a patient who developed severe amyloid‐related imaging abnormalities (ARIA) after treatment with lecanemab.

• Our report suggests that ischemic strokes may be a novel imaging feature of ARIA.

• Our report highlights the need for high clinical suspicion for seizures in ARIA.

1. BACKGROUND

Alzheimer's disease (AD) is the most common cause of dementia in the United States. ¹ Based on the hypothesis that AD is mediated in part by pathologic accumulation of amyloid beta (Aβ), ² , ³ anti‐amyloid antibodies have been developed as disease‐modifying treatments for early‐stage AD and have been proven effective in clearing cerebral amyloid. ⁴

Lecanemab, an intravenous (IV) monoclonal antibody targeting Aβ protofibrils, was approved by the US Food and Drug Administration for use in AD based on data from a phase III clinical trial in which lecanemab demonstrated statistically significant reduction in rates of cognitive and functional decline among patients with early AD over the 18‐month study period. ⁵ Amyloid‐related imaging abnormalities (ARIA) are a recognized and potentially severe side effect of anti‐amyloid antibody therapies, including lecanemab. Two forms of ARIA have been described: ARIA‐E (edema) is characterized by vasogenic edema, and ARIA‐H (hemorrhage) is characterized by the presence of intraparenchymal microhemorrhages, superficial siderosis, and/or rarely cerebral macrohemorrhage. ⁶ , ⁷ , ⁸ , ⁹ The risk of ARIA peaks 3 to 4 months after initiation of therapy. ¹⁰ ARIA are hypothesized to result from binding of anti‐amyloid antibodies to amyloid deposits in cerebral vasculature, which compromises vascular integrity. ¹¹

While most patients with ARIA remain asymptomatic, patients less commonly may experience headaches, dizziness, or potentially serious symptoms including seizures, focal neurologic deficits, and encephalopathy. Most cases of ARIA‐E spontaneously resolve, and ARIA‐H will stabilize with cessation of anti‐amyloid therapy. ¹⁰ , ¹² The optimal management of ARIA is unclear, though prior studies have suggested that steroid treatment hastens recovery. ¹² , ¹³ With lecanemab now used in clinical practice, novel presentations of ARIA may be encountered. Here, we present a case of multiple ischemic strokes and subclinical seizures related to ARIA after lecanemab treatment, representing novel findings in the setting of ARIA.

2. RESULTS

2.1. Initial presentation

A 71‐year‐old man with medical history of mild hypertension was evaluated for 4 years of insidious onset, slowly progressive episodic memory impairment. At baseline, his Mini‐Mental Status Examination (MMSE) was 27/30, with points off only for delayed recall on verbal list memory. On more detailed psychometric testing, he had mildly reduced semantic and lexical fluency, but other components of his language examination including confrontation naming were normal. He also performed normally on tasks of attention, calculation, visuospatial function, and executive function. His family reported mild functional impairment in his instrumental activities of daily living consistent with a diagnosis of mild dementia.

RESEARCH IN CONTEXT

1. Systematic review: The authors reviewed the literature using traditional methods (e.g., PubMed) and did not find any previous reports of ischemic stroke associated with amyloid‐related imaging abnormalities (ARIA). Relevant citations related to stroke and ARIA have been cited.

2. Interpretation: The authors present a case of a patient who developed ARIA associated with lecanemab treatment. In addition to microhemorrhages and cerebral edema that are recognized features of ARIA, the patient also developed several ischemic strokes, which have not been associated with ARIA. The patient was also noted to have several subclinical seizures on electroencephalogram. This case highlights the possibility of ischemic stroke as a new feature of ARIA and demonstrates the importance of having a high clinical suspicion for seizures in patients with ARIA.

3. Future directions: Additional investigation is needed to determine the incidence of ischemic stroke in ARIA, and further studies examining the mechanisms of cerebral infarction in cases of ARIA will be important for guiding medical management.

Magnetic resonance imaging (MRI) revealed mild cortical atrophy, including subtle atrophy of the medial temporal lobe structures (Figure 1A). He had minimal vascular disease on brain imaging, though he did have prominent perivascular spaces. He had three microhemorrhages in his right temporal lobe visible on susceptibility‐weighted imaging (SWI) (Figure 1B). Because his history, mental status testing, and imaging findings were felt to be most consistent with underlying AD, he underwent additional work‐up for anti‐amyloid therapy treatment.

FIGURE 1.

Baseline magnetic resonance imaging. A, Coronal T2‐weighted images showing mild hippocampal atrophy and prominent perivascular spaces. B, Axial susceptibility‐weighted images showing three microhemorrhages seen at baseline prior to lecanemab treatment. Microhemorrhages indicated by red arrows.

Cerebrospinal fluid (CSF) biomarkers revealed low Aβ42 (623 pg/mL; reference range > 834), elevated phosphorylated tau 181 (46.5 pg/mL, reference range ≤ 21.6), and elevated phosphorylated tau 181/Aβ42 ratio (0.075, reference ≤ 0.028), all consistent with a biomarker diagnosis of AD. He was heterozygous for the ε3 and ε4 alleles in the APOE gene.

He was started on lecanemab infusions approximately 2 months after his baseline MRI. Lecanemab was dosed at the standard 10 mg/kg of body weight at every‐other‐week intervals. Several days after his third infusion, he developed a gradual onset bifrontal headache. This headache persisted for 6 days, at which point he experienced an episode of confusion lasting approximately 30 minutes. The next day—1 week after his third infusion—his headache became severe, prompting presentation to the emergency department (ED).

2.2. Hospital course

Head computed tomography (CT) in the ED showed a large region of hypodensity in the right parietal and temporal lobes with 3 mm of midline shift. CT angiogram of his head and neck showed mild intracranial and extracranial atherosclerosis, no large vessel occlusion, and no evidence of vasculitis. MRI revealed large areas of parenchymal edema with leptomeningeal enhancement in his right greater than left parietal, temporal, and occipital lobes (Figure 2A,B). Gradient recalled echo (GRE) sequence revealed a new microhemorrhage in the right temporal lobe (Figure 2C). His overall presentation was consistent with severe ARIA‐E and mild ARIA‐H. ⁶ , ¹⁴ Diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging also revealed a small focus of restricted diffusion in the right occipital lobe consistent with an ischemic stroke (Figure 2D,E). He was admitted to the inpatient stroke service for further management. His initial Montreal Cognitive Assessment (MoCA) score on admission was 21/30 (2 points off for executive/visuospatial function, 1 point off for language/fluency, 5 points off for delayed recall on a verbal list memory task, and 1 point off for orientation).

FIGURE 2.

Magnetic resonance imaging at initial presentation for amyloid‐related imaging abnormalities (ARIA). A, Axial T2/fluid‐attenuated inversion recovery sequence showing edema in the right more than left temporal, parietal, and occipital lobes consistent with ARIA edema. B, Coronal T1 sequences after gadolinium administration showing leptomeningeal enhancement in the areas of edema. C, New microhemorrhage not present at baseline, as indicated by white arrow. D, Area of diffusion restriction (white arrow) in the right occipital lobe on diffusion‐weighted imaging. E, Apparent diffusion coefficient (ADC) map showing reduced ADC signal in the area of diffusion restriction.

On hospital day one, continuous electroencephalogram (EEG) monitoring was initiated which revealed three focal seizures without obvious clinical correlate. His electrographic seizures were associated with abundant lateralized periodic discharges in the right temporo‐occipital region. He received a 3 g loading dose of levetiracetam followed by maintenance therapy with 500 mg every 12 hours. He continued to experience electrographic seizures along with abundant lateralized discharges on the ictal‐interictal continuum. His levetiracetam dose was increased to 1500 mg every 12 hours, after which he had no evidence of seizure on EEG.

His stroke workup was notable only for a mildly elevated low density lipoprotein level of 154 mg/dL (reference < 129 mg/dL). Transthoracic echocardiogram showed normal ejection fraction, but moderately dilated left atrium. Telemetry monitoring did not reveal any cardiac arrhythmia. He was started on atorvastatin for secondary stroke prevention. He was initially given two doses of aspirin 81 mg daily for his ischemic stroke, but antiplatelet therapy was stopped after further discussion regarding the risks/benefits of antiplatelet therapy in the setting of new microhemorrhages and the proposed mechanism of stroke being vascular inflammation in the setting of ARIA (see Discussion).

During his hospital admission, he received 4 days of IV methylprednisolone at 1 g/day. He was discharged on a prolonged taper of oral prednisone starting with 60 mg daily, decreasing by 10 mg every week. At hospital discharge, his MoCA score improved to 25/30, with points missed only for delayed recall on the verbal list memory.

2.3. Post‐discharge course

Further lecanemab treatments were discontinued. Repeat brain MRI 2 weeks after hospital discharge revealed several new microhemorrhages in the right temporo‐occipital region. At his outpatient follow‐up appointment, he noted improvement in his cognitive symptoms. Approximately 1 month after hospital discharge, he again developed a severe headache and was referred for ED evaluation. An MRI of his brain revealed a new punctate infarct in his right occipital lobe, but otherwise improving cerebral edema and no obvious new microhemorrhages on GRE (Figure 3A,B). His new ischemic stroke was again attributed to ongoing inflammation and his prednisone taper was prolonged. Repeat clinical evaluations at 1 and 2 months after hospital discharge revealed slowly improving cognitive and functional status and that he had recovered close to his status prior to initiation of lecanemab.

FIGURE 3.

Follow‐up imaging hospital discharge. A) T2/fluid‐attenuated inversion recovery (FLAIR) showing resolving edema at 1 month after hospital discharge. B, New punctate area of diffusion restriction on diffusion‐weighted imaging (white arrow) at 1 month after hospital discharge. C, T2/FLAIR showing essentially resolved edema at 5 months after hospital discharge. D, Axial susceptibility‐weighted images at 5 months after hospital discharge showing several microhemorrhages that had developed in the preceding months. Microhemorrhages present prior to lecanemab treatment are indicated by white arrows. Microhemorrhages that developed in the intervening few months are indicated by asterisks.

At approximately 5 months after hospital discharge, the patient presented back to the ED for headache and several episodes of confusion. An MRI revealed near complete resolution of cerebral edema (Figure 3C). He did accumulate several new microhemorrhages in the preceding months (Figure 3D). Continuous EEG monitoring revealed lateralized periodic discharges. His confusion was attributed to subclinical seizures and lacosamide 100 mg twice daily was added, in addition to levetiracetam for seizure prophylaxis. His confusional episodes resolved with addition of lacosamide.

Also, approximately 5 months after hospital discharge, the patient developed acute left monocular vision loss. Fundoscopic examination revealed optic disc edema, inferior greater than superior arcuate defects with spared central vision, and an anatomically small optic cup‐to‐disc ratio in the contralateral eye. Sedimentation rate was normal (2 mm/hour, reference 0–20 mm/h) as were C‐reactive peptide levels (0.10, reference range ≤ 0.8 mg/dL). Fluorescein angiogram showed leakage in the left inferior optic disc but did not reveal evidence of vasculitis of the retinal vasculature. MRI with and without gadolinium contrast of the orbits did not reveal pathological optic nerve enhancement. To fully assess for the possibility of ongoing central nervous system inflammation, he underwent a repeat lumbar puncture, which revealed no nucleated cells, mildly elevated CSF protein of 55 (55 mg/dL, reference range 15–45 mg/dL), and normal CSF glucose (59 mg/dL, reference range 45–70 mg/dL). Given the small optic cup‐to‐disk ratio and lack of evidence of inflammation, the patient's vision loss was diagnosed as non‐arteritic ischemic optic neuropathy (NAION), which was felt to be coincidental and unrelated to lecanemab or ARIA.

As part of this repeat lumbar puncture obtained 9 months after his initial lumbar puncture and 6 months after stopping lecanemab, we also re‐assessed his CSF AD biomarkers. His CSF biomarkers at this timepoint (which were performed at a separate laboratory from his initial lumbar puncture), revealed a normal Aβ42 (959 pg/mL; reference range ≥ 835) and elevated phosphorylated tau 181 (36.1 pg/mL, reference range ≤ 21.6), which was lower compared to his pre‐lecanemab baseline (46.5 pg/mL, reference range ≤ 21.6).

3. DISCUSSION

We describe a patient who developed ARIA after receiving his third dose of lecanemab. As anti‐amyloid therapies are likely going to be increasingly used to treat this common condition, it is important for clinicians to appreciate the spectrum of clinical and radiographic findings that can result as side effects from this class of therapies.

Ischemic infarcts as seen in our patient have not been described with lecanemab or as an imaging finding of ARIA. Most likely, the ischemic strokes resulted from thrombosis in the setting of vessel wall inflammation due to amyloid plaque clearance. Cerebral amyloid angiopathy‐related inflammation (CAA‐ri) and ARIA are proposed to share pathologic mechanisms, ¹¹ , ¹⁵ and ischemic strokes are frequently encountered in CAA, ¹⁶ , ¹⁷ supporting the idea that the strokes in our patient resulted from an inflammatory response to amyloid plaques in the cerebral vasculature. Our patient's pre‐lecanemab imaging showed three cortical microhemorrhages, and it should be noted that the phase III clinical trial of lecanemab excluded patients with > 4 microhemorrhages.

We did entertain other potential stroke etiologies including vascular compression from surrounding cerebral edema and cardioembolism induced by lecanemab. As our patient has relatively few cardiovascular risk factors, no history of prior strokes, and no definitive etiology elucidated after his initial stroke evaluation, we felt that it was unlikely that his infarcts were purely coincidental and unrelated to lecanemab. It will be important to further investigate the incidence of ischemic stroke as a feature of ARIA as well as the associated symptoms and imaging characteristics to guide management decisions. Understanding the relationship between ARIA and ischemic stroke is particularly important given that severe cerebral hemorrhages caused by thrombolysis have been reported in a patient treated with lecanemab. ¹⁸ It remains to be determined whether ischemic stroke represents a direct side effect of lecanemab, or whether it is the result of a more general inflammatory state. Further research is needed to understand the mechanism by which ischemic stroke occurs in ARIA, as well as the immunological and inflammatory reactions associated with anti‐amyloid therapies.

We also highlight the importance of having a heightened clinical suspicion for ARIA in patients treated with anti‐amyloid therapies. While he presented to the ED because of severe headache and a confusional episode, his symptoms started with only a mild headache over several days. Despite these relatively mild clinical symptoms, imaging revealed severe ARIA‐E, and EEG captured numerous subclinical seizures. Although no clinical seizures were observed, his epileptic activity in the setting of previous confusion, worse cognition, and risk for future clinical seizures justified treatment with an anti‐seizure medication. Epileptic activity has been reported in cases of ARIA, ¹³ , ¹⁴ , ¹⁵ and this case further highlights that EEG monitoring should be routinely considered for patients with ARIA to guide decision making regarding anti‐seizure medications. Although there is little evidence to guide optimal management of ARIA, our patient was treated with high‐dose steroids and reassuringly demonstrated clinical and radiographic improvement in serial clinical follow‐up. Given this patient's second infarction which necessitated the extension of his steroid taper, it is possible that more prolonged courses of steroids are beneficial for stroke prevention in patients with ARIA. Additional case reports and studies will be important for determining ideal treatment regimens.

We also note that our patient had a repeat CSF evaluation at 6 months after stopping lecanemab. His repeat CSF evaluation revealed normalized Aβ42 and a lowered but still elevated level of phosphorylated tau 181. These CSF biomarker changes are consistent with observations from the lecanemab clinical trial at 12 and 18 months of treatment. ⁵ The results of this repeat CSF evaluation in our patient suggest biomarker improvement after just three doses of lecanemab that are maintained despite severe ARIA and 6 months without further anti‐amyloid treatment.

AUTHOR CONTRIBUTIONS

All authors contributed to care of this patient and discussions regarding the management of the patient. Alec W. Gibson, Holly Elser, and Michael H. Guo drafted the manuscript. All authors edited the manuscript and provided final approval.

CONFLICT OF INTEREST STATEMENT

D.A.W serves as a paid consultant to Eli Lilly and has previously served as a paid consultant to GE Healthcare and Qynapse. He serves on a data safety monitoring board (DSMB) for Functional Neuromodulation and GSK. He receives research support paid to his institution from Biogen. I.N. has served as a paid consultant for Eisai and does educational speaking for PeerView. All other authors report no competing interests. Author disclosures are available in the supporting information.

CONSENT

The patient provided informed consent for this study.

Supporting information

Supporting Information

Gibson AW, Elser H, Rosso M, et al. Ischemic stroke associated with amyloid‐related imaging abnormalities in a patient treated with lecanemab. Alzheimer's Dement. 2024;20:8192–8197. 10.1002/alz.14223