A Rare Case of Iatrogenic Prion-like Pathogenesis of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is the most common cause for a lobar intracerebral hemorrhage in older (>50 years) patients. Histopathologically this means an accumulation of β-amyloid in the vascular walls of small cerebral and subarachnoid arterial vessels. The effect is an increased susceptibility for bleeding events (1). Rarely, these can be genetically determined forms rather the far most commonly occurring spontaneous forms. The Dutch variant has been thoroughly studied. In 2015, initial reports came out of the iatrogenic transmission of fibrillary Aβ aggregates after treatment with growth hormones extracted from cadavers, after which a prion-like increase in β-amyloid and deposits in cerebral vessels as in CAA was observed (2). We report the case of a patient aged 35 at the time of his diagnosis, in whom we identified iatrogenic cerebral amyloid angiopathy (iCAA) (3, 4).

Previous medical history

In 1985, At the age of three months, our patient underwent neurosurgical clipping of an aneurysm of the posterior cerebral artery, which had become symptomatic as an obstructive hydrocephalus. During cranial trepanation the dura mater was injured on the left temporal side and was patched with lyophilized human cadaver dura mater. The patient subsequently developed symptomatic epilepsy, which was treated medically. With this treatment the patient remained seizure-free for years. He gained a special needs school leaving certificate and lived independently. The family history did not indicate any neurodegenerative disorders or intracranial bleeds.

Case description

The first cranial image available to us was taken because of an epileptic seizure with a fall when the patient was 17 years old. It showed an only residual expansion of the interior cerebrospinal fluid spaces. Cranial magnetic resonance tomography with blood sensitive sequences when the patient was 28 for the first time showed three microbleeds in the left hemisphere. Diagnostic cerebral angiography did not indicate any cerebral vasculitis or aneurysms.

Further MRI scans at the age of 33–35 years showed clearly progressive hemorrhagic injury and changes to the white matter (Figure a-c). At the age of 35 years our patient presented with acute hemiparesis and left-sided hemihypesthesia. Computed tomography detected an acute lobar intracerebral hemorrhage, which was evacuated neurosurgically by means of osteoplastic trepanation. The immunohistologic work-up showed a deposit of β-amyloid in the vascular walls of the smallest cerebral arteries (Figure d) without any signs of inflammation. Only very few amyloid plaques were identifiable in the cerebral parenchyma. Deposits of phosphorylated tau protein were not seen.

Figure: magnetic resonance imaging and histopathologic work-up.

a), b) clearly defined and progressive, initially left hemispheric, now also right hemispheric cerebral microbleeds, superficial cortical siderosis (a, Arrow), white matter lesions (b, Arrow), and enlarged perivascular spaces (b, Circle) at age 35.

c) At this point in time, cerebellar microbleeds (Circle) as well as cerebellar superficial siderosis (Arrow) are identifiable (curved arrow: artifacts owing to the clip)

d) Immunohistochemical confirmation of β-amyloid in vascular walls (Arrow), staining for β-amyloid, 400 x enlargement, antibody dilution 1:50; DakoCytomation, Glostrup, Denmark

Examination of cerebrospinal fluid at the age of 37 showed a reduction of Aβ 40 (2742 pg/mL, normal range 7 231–17 404 pg/L) and Aβ 42 (163 pg/mL, normal range > 489.5 pg/L). Furthermore, the total tau concentration was 510.0 pg/mL (normal range <382 pg/mL). A comprehensively analyzed exome-based diagnostic genetic examination did not yield any potentially causative genetic variants in the genes APP, PSEN1, PSEN2, TTR, COL4A1/A2, NOTCH3, and other genes associated with cerebral microangiopathy or amyloidosis as well as an ApoE3/4 genotype. The patient experienced a total of six further bilateral lobar intracerebral bleeds in the following six years, which did not, however, require neurosurgery. Today the patient is living with the consequences of the intracerebral bleeds, which manifest as global aphasia and left-side spastic hemiparesis as well as epileptic seizures. He requires nursing care in everyday life and is living in a care home.

Discussion

iCAA is caused by iatrogenically transmitted fibrillary Aβ aggregates as the pathogen, which, according to the prion hypothesis can induce further conformity changes before multiplying and spreading in the brain (3, 4). The main transmission routes under discussion are (3, 4):

• Use of a human cadaver dural graft

• Use of embolization material with human cadaver dura mater grafts in neuroradiologic procedures

• Treatment with human cadaver growth hormone

• Use of contaminated neurosurgical instruments.

The latency period between the transmission/infection and disease onset is three to four decades (3, 4). According to a recently published literature review the clinical course resembles the spontaneous type of CAA, with an occasionally much younger age at manifestation observed and to be noted (3).

To our knowledge, this is the first case of iCAA in Germany after a dural graft was used (5). The exact number of dural grafts used in Germany is not known. Future studies should determine the actual number of grafts used in Germany so as to be able to estimate the possible prevalence of iCAA. Because of the long latency period between the underlying exposure and the occurrence of clinical symptoms, further cases may be expected for some time.

Our case was notable because of:

• The long radiologic and clinical observation period even before symptoms developed and a diagnosis was made

• The high degree of diagnostic certainty

• The asymmetric onset ipsilaterally to the dural graft, which potentially indicates a prion-like protein aggregation and spread.

Especially in younger patients with CAA, targeted history taking after neurosurgery is needed to reach a diagnosis, in addition to genetic assessment, since more cases can be expected to be identified in future.