Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome

Abstract

Background: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). Methods: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. Results: We included 49 patients (74% men, mean age 43 years [range, 27–84]); 15 from our database (6% [95% CI, 3%–10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7–32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59–99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. Conclusions: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Iatrogenic cerebral amyloid angiopathy: An illustrative case of a newly introduced disease

“…In this case, it could be argued that there is no spatial proximity between the cerebellar surgical site and the haemorrhage locations, the latter occurring far from the point of application of the contaminating dural graft. However, this is in line with a recent collection of cases published by Kaushik et al [5]. Furthermore, the widespread distribution of radiological CAA features on MRI and the diffuse presence of beta‐amyloid deposits detected with 18F‐Flutemetamol PET reinforce the hypothesis of prion‐like dissemination of dural‐derived amyloid.…”

Seed to Bleed: Iatrogenic Cerebral Amyloid Angiopathy

“…One observation is that once introduced into the central nervous system, Aβ fibrils can circulate widely before depositing: The reported neurosurgical cases show no consistent relationship between site of human tissue exposure-often quite distant from the brain as in the case of spinal surgeries-and site of CAA-related hemorrhage. 2 Another striking insight is that the preferential sites of Aβ propagation appear to be the cerebral vessels rather than the brain parenchyma, as the predominantly observed pathology has been CAA rather than the mature parenchymal plaques characteristic of Alzheimer disease. 6 Studies in transgenic mice found a similar predilection for vascular Aβ deposition regardless of whether the inoculated amyloid was in the form of Alzheimer disease, CAA, or both.…”

“…A body of literature—now including the report in the current issue of Stroke from Leiden University Medical Center and collaborating investigators in the Netherlands 2 —firmly places Aβ (beta-amyloid) on this list. Transmissibility of brain amyloidosis via intracerebral injection of exogenous Aβ was observed in marmosets (a nonhuman primate that expresses human-like Aβ) as early as 1993 and over the early 2000’s in injected transgenic mice expressing human amyloid precursor protein.…”

“…An initial 2015 report found extensive Aβ deposition with severe CAA in 4 of 8 autopsied brains from individuals previously diagnosed with iatrogenic Creutzfeldt-Jakob disease due to childhood treatment with pituitary-derived human growth hormone. 5 The 18 new individuals reported by the Leiden University Medical Center investigators together with additional probable or possible iatrogenic CAA (iCAA) cases identified from systematic literature review 2,6 bring the number of reported cases to 49, with more likely to emerge as echoes of the neurosurgical use of human tissue primarily during the 1970s and 1980s. These 49 individuals include some with equivocal evidence of human tissue seeding, such as those whose neurosurgical procedures did not use human tissue (where the source of amyloid may have been contaminated instruments) or with traumatic brain injury without explicit documentation of neurosurgery.…”

“…From a clinical standpoint, the impact of iCAA is devastating to those who develop early onset intracerebral hemorrhage (mean age of first presentation 43, earliest age 27), 2 but fortunately quite narrow when considered against the overall burden of CAA. Widespread recognition of Creutzfeldt-Jakob disease has led to worldwide standards for discontinuation of high-risk tissues 7 and decontamination of potentially exposed instruments, 8 which should allow iCAA to dwindle away.…”