Donanemab Infusion and Recurrent Seizures in a Patient With Alzheimer's Disease and Epilepsy in the Absence of Amyloid-Related Imaging Abnormalities (ARIA).

Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.