Fatal Iatrogenic Cerebral Amyloid-Related Encephalitis in a patient treated with lecanemab for Alzheimers disease: neuroimaging and neuropathology

We report the case of an elderly woman in good general health aside from early-stage Alzheimers disease who was enrolled in a randomized controlled trial of the novel therapeutic monoclonal antibody lecanemab where she was treated with the placebo, and subsequently in the open label extension study where she received lecanemab infusions every two weeks. After the third infusion, she suffered a seizure followed by aphasia and progressively worsening encephalopathy. Magnetic resonance imaging revealed multifocal cerebral edema and an increased burden of cerebral microhemorrhages compared to pre-trial imaging, consistent with Amyloid Related Imaging Abnormality (ARIA). She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and expired after five days in the hospital. The family requested an autopsy and consented to evaluation of her brain for research. Post-mortem MRI confirmed extensive microhemorrhagic changes in the temporal, parietal and occipital lobes, some of which were visible on gross inspection of the brain. Autopsy confirmed APOE genotype of E4/E4 and the presence of typical neuropathological features of Alzheimers disease along with severe cerebral amyloid angiopathy with inflammatory features, including perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of {beta}-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. Cerebral microhemorrhages were associated with arterioles harboring {beta}-amyloid deposits and having degenerative morphologies. We conclude from these results that the patient likely died as a result of severe cerebral amyloid angiopathy with marked microvascular degeneration and meningoencephalitis. Further study of the mechanism of ARIA and the neuropathological changes associated with plaque clearance are needed.