Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease

We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Initial presentation: The patient was 79 years old and in good general health prior to the admission in question.She had early-stage Alzheimer's disease, no clinical history of hypertension and took fluoxetine for mild depression, omeprazole for gastroesophageal reflux, along with atorvastatin and vitamins.The patient's study partner reported that she complained of headaches and "brain fog" for the last several weeks.The headaches were most severe immediately after infusions of an experimental drug in a clinical trial and lasted one to two days during which she mostly stayed in bed.Her study partner additionally reported that in the days prior to the precipitating event she was more easily disoriented than typical.On the day in question, she was brought by EMS to the hospital for what her study partner described as a seizure.While eating at a restaurant, she looked and turned to the left, became stiff and her speech became slurred.She then had 30 seconds of generalized convulsion after which she slumped out of her chair due to flaccid left hemiplegia.When the EMS team evaluated her, her Glasgow Coma Scale was less than 8 and she was hypoxic (SpO2 ~80%) prompting intubation in the field with fentanyl and midazolam.Upon arrival in the ER her blood pressure was 126/99, rapid glucose screen was normal.She was sedated with propofol infusion.An emergent CT scan of the head was interpreted as: "extensive low-density within the periventricular region bilaterally; no intracranial hemorrhage, mass or acute territorial infarcts."The treating team initially felt her presentation was most worrisome for a stroke.The ER team and consulting neurologist considered administering a thrombolytic agent but decided to forego this treatment based on the unclear history and suboptimal neurological exam due to sedation from the recent intubation.The family informed the treating team that the patient "was getting some experimental medication for dementia at a research center --she got 3 doses in the last six weeks."Medical history: She had mild dementia, but was independent, living with a roommate who was also her study partner.She participated in a randomized trial of an anti-β-amyloid immunotherapy called lecanemab for approximately 18 months during which time she was receiving the placebo.She felt no obvious side effects nor obvious benefits during the randomized portion of the study.She then enrolled in the open-label extension of the trial where she was guaranteed to receive the active drug and had received three infusions (10mg/kg) at two-week intervals.Preconditions of the study included documentation of pathological levels of β-amyloid by PET imaging; her imaging prior to enrollment in the open label extension continued to show amyloid positivity (see supplementary figure 6).Her other medical problems were gastroesophageal reflux, right knee replacement and a small meningioma which had been stable in size for decades.She notably had no prior history of seizures, no tobacco, alcohol, or sedative use.
Examination: Her initial examination upon arrival to the hospital was limited due to recent intubation, but once admitted to the ICU and sedatives were paused, she was unable to follow commands and was agitated, but regained motor function on the left as she was noted to withdraw from noxious stimulation symmetrically in all extremities.She had no obvious cranial nerve defect.
Diagnostic evaluations: Initial labs were notable for leukocytosis (22,100/mm 3 with a 92% neutrophilic predominance) which returned to nearly normal within 24 hours.Platelet count was normal (205,000/mm 3 ), and she was not anemic (Hgb 12.8 g/dL).A chemistry panel showed normal renal function and normal liver function tests, but she developed elevated transaminases on hospital day 2 (AST 109 IU/L, ALT 78 IU/L, alkaline phosphatase 101 U/L, and total bilirubin 0.8 mg/dL).All sputum, blood and urine cultures were negative during the hospitalization.
Her EKG showed she was in atrial fibrillation.Echocardiogram was normal (EF 55%, normal valves, wall motion and chamber dimensions).Her apolipoprotein genotype was homozygous APOE4/4.EEG on hospital day 1 interpreted as follows: No posterior dominant rhythm; background consisted of 4-5 hz activity that appeared symmetric.There were frontal sharp waves that appeared rhythmic consistent with a FIRDA pattern.Photic stimulation evoked a driving response at certain flash frequencies.
The key sequences from the MRI are available in the attached imaging summary.Post-contrast images were also obtained and were uninformative.
A baseline MRI was obtained before enrollment in the open label extension of the clinical trial (a little more than six weeks prior to her acute event) and is included in this material for additional context.
No CSF analysis was performed.
Hospital course: She was started on heparin infusion after atrial fibrillation was identified on day 1.Anticoagulation was monitored with factor Xa levels -the highest was 2.5x the upper limit of the reference range and this was stopped on day 2.She was also started on ceftriaxone out of concern for aspiration pneumonia.Her home medications of aspirin, atorvastatin, metoprolol and fluoxetine were continued while an inpatient.The patient's clinical trial physician raised a concern for the possibility of amyloid-related imaging abnormality (ARIA) as a side effect from the experimental drug.She was started on Keppra 500 mg BID and 1 g daily of solumedrol which was continued for four doses over three days.On the third day, the patient was extubated with instructions not to reintubate, in line with requests in her living will.She remained "agitated and restless" according to nursing staff, mute aside from occasional unintelligible mutterings, she was unable to follow commands, but spontaneously moved all extremities.To manage agitation, she was sedated using dexmedetomidine infusions on days 3-5.She was also given 25mg quetiapine on days 3-5 for agitation and occasional doses of lorazepam for anxiolysis to assist with diagnostic testing.She was started on a nicardipine infusion on day three for blood pressure management.Repeat CT head showed neither worsening nor improvement in the white matter hypodensities and no new pathology.At the end of hospital day 3, her breathing deteriorated, and she became more hypoxic.A loop diuretic was administered, and she was placed on high-flow oxygen with bilevel positive airway pressure.Her antibiotic regimen was broadened to piperacillin/tazobactam.She also required a diltiazem infusion to control tachycardia.She developed an elevated highly sensitive troponin level (504 pg/ml) which was attributed to the rapid atrial fibrillation and downtrended on subsequent testing.Late in hospital day 4, she had an aspiration event, developed respiratory distress and hypotension, and subsequently developed renal injury (Cr 2.1 mg/dL, BUN 48 mg/dL), leukocytosis (20,000/mm 3 ), and worsened transaminitis (AST 2398 IU/L, ALT 1854 IU/L, alkaline phosphatase 187 U/L, tBili 2.4 mg/dL).Consistent with her wishes to forego invasive life support measures, the family and treating team instituted comfort-oriented care measures and the patient died in about one day.

Autopsy:
The general autopsy found bronchopneumonia with diffuse alveolar damage.It also noted atherosclerosis, left ventricular myocardial hypertrophy and nephrosclerosis.Atherosclerotic plaque occupied about 60-70% of the intimal surface of the abdominal aorta and approximately 60% of the proximal anterior descending coronary artery, interpreted as moderate stenosis.The heart weighed 370 grams.Microscopy examination of the heart showed mild to moderate arteriolosclerosis consistent with hypertensive small vessel disease.There was no infarction.Hyalinizing arteriolosclerosis and focal glomerulosclerosis was present in the kidneys.
The brain was removed and immersion fixed in 10% formaldehyde prior to coronal sectioning into roughly 1 cm coronal slabs.For histological analysis, 16 blocks of tissue were paraffin embedded.The locations of the tissue blocks is shown in supplementary figure 7 and include the right middle frontal gyrus, right anterior superior and middle temporal gyrus, the right mid-to-posterior middle and inferior temporal gyri, the left striate region, the right anterior cingulate gyrus with corpus callosum, the right striatum, right basal ganglia at anterior commissure, right thalamus, left mid hippocampus, left amygdala, caudal midbrain/rostral pons, pons, medulla, left cerebellar cortex with dentate nucleus, right parietal cortex (with hemorrhage), and right inferior temporo-parietal cortex with hemorrhages.Microscopic neuropathological analysis was conducted independently by Dr. Coyne and Dr. Harmsen.The results were discussed by consensus conference.
On gross evaluation, the brain weighed 1320 grams.The left cerebral hemisphere was mildly full in comparison to the right, and the cortical gyri were widened and flattened against the leptomeninges, consistent with moderate cerebral cortical edema.The large blood vessels arose normally and were of normal configuration with intermittent nonocclusive atheromatous plaques.Numerous black petechial hemorrhages were appreciated on the surface of the cortex, most prominently in the left temporal lobe but also in the right temporal lobe and in the bilateral parietal and occipital lobes.Additionally, numerous punctate hemorrhages were also found on the cut surfaces of the cortex of all lobes, with the highest concentration of these being in the inferior temporal lobes.No laminar necrosis nor infarctions were found.The bilateral hippocampi were mildly atrophic.
Three blocks of tissue were submitted to Vanderbilt's VANTAGE genomics core for DNA extraction and sequencing to assess APOE genotype.A control panel was simultaneously genotyped to ensure correct allelic discrimination.All three replicates returned identical results, homozygous C/C at rs429358 and homozygous C/C at rs7412, consistent with a homozygous E4 genotype.