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Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in the wall of small cortical and leptomeningeal vessels in cerebral amyloid angiopathy (CAA). Sporadic CAA is prevalent in an ageing population and is a major cause of intracerebral haemorrhage and dementia. There is evidence of Aβ transmission through medical procedures, such as injection of cadaver-derived growth hormone (GH) or cadaveric dura mater graft in humans, in the context of iatrogenic Creutzfeldt-Jakob disease (iCJD).1 Interestingly, there is increasing evidence to suggest that Aβ transmission may also occur in the absence of iCJD through neurosurgical procedures.2 3
This paper describes a case of early onset, pathologically proven CAA presenting with multiple symptomatic intracerebral haemorrhages occurring three decades after cardiac surgery involving a cadaveric dura mater patch.
A young male with multiple intracerebral haemorrhages underwent an extensive multimodal evaluation including clinical examination, cerebral MRI, amyloid positron emission tomography using 18F-florbetapir, apolipoprotein E (APOE) genotype, genetic testing for mutations or duplication causing hereditary CAA (amyloid precursor protein (APP), gelsolin, transthyretin and cystatin 3) and neuropathological examination of a brain biopsy. Sporadic CAA was confirmed pathologically. Childhood exposure to cadaveric dura mater was suspected based on the surgical history for congenital heart disease, then confirmed. The patient’s informed consent was obtained.
A man aged 34 years presented with multiple symptomatic lobar intracerebral haemorrhages. He had a medical history of transposition of the great arteries, requiring neonatal cardiac surgery with the Rashkind procedure. At 2 years of age, the patient underwent repeat surgery with a Senning procedure. A cadaveric dura mater patch was implanted to repair the atrial defect (1980). He was well up to 34 years of age when he experienced sudden onset of impaired speech. Cerebral MRI showed an acute left frontal lobar intracerebral haemorrhage with multiple strictly lobar cerebral microbleeds and focal cortical superficial siderosis (figure 1) indicative of underlying CAA. Amyloid positron emission tomography showed increased widespread cortical florbetapir uptake (global standardised uptake value ratio=1.20), thus confirming amyloid deposition. The APOE genotype was ε3/ε3. The patient had no pre-existing cognitive impairment, as assessed by the Informant Questionnaire on Cognitive Decline in the Elderly (<3.4). There was no familial history of intracerebral haemorrhage or Alzheimer’s disease. APP, gelsolin, transthyretin and cystatin 3 gene testing proved negative for mutation or duplication causing hereditary CAA.
Three years later, the patient had a recurrent lobar intracerebral haemorrhage causing sudden onset of aphasia and right-sided weakness. Cerebral MRI revealed an acute, extensive, left parietal intracerebral haemorrhage associated with an increased number of lobar cerebral microbleeds and disseminated cortical superficial siderosis. Neurological deterioration occurred a few hours after admission with loss of consciousness. Emergency haematoma evacuation and a diagnostic biopsy of surrounding leptomeninges and brain parenchyma were performed. The pathological examination confirmed CAA affecting medium-sized and large-sized leptomeningeal and cortical vessels with capillary involvement. The vessel walls were thickened by total amyloid replacement of the media (Vonsattel grade 2). The vessels were stained with Congo red and anti-Aβ antibodies. Moderate parenchymal Aβ deposits and amyloid plaques were also observed in the cortex without tau pathology. There was no evidence of abnormal prion protein deposition in available tissue samples.
The patient subsequently improved despite persistent aphasia and cognitive impairment, but had another right frontal lobar intracerebral haemorrhage at 39 years of age causing headache and disorientation.
This is a case of early onset CAA with initial symptoms presenting three decades after cardiac implantation of a cadaveric dura mater patch. Iatrogenic CAA was suspected based on childhood exposure to cadaveric dura through cardiac surgery. The probability of a causal relationship was high (no risk factor for sporadic CAA, negative genetic test results for hereditary CAA, absence of tau pathology). However, although rarely reported in subjects under 50 years of age, sporadic CAA cannot be completely ruled out as we were unable to prove the presence of Aβ seed in the dural patch. Contamination through surgical equipment rather than the dural patch per se is another potential mechanism.
Prior to our findings, there were a few cases of suspected iatrogenic early onset CAA, but almost all of these were reported after neurosurgical procedures.2 3 Most cases came to light three decades postexposure as in our patient.
Cerebral Aβ transmission through direct contact between Aβ seeds contained in cadaveric donor dural membrane graft and host brain has been hypothesised based on previous reports of early onset CAA following cadaveric exposure through neurosurgical procedures. It has been shown experimentally that intracerebral injections of misfolded Aβ can seed Aβ deposition in APP transgenic mice.4 Our report suggests that Aβ seeds may also be transmitted via blood from a peripheral source (cardiac dural patch) and could subsequently spread in host brain. It has been demonstrated that intravenous5 administration of Aβ seeds could promote CAA in mice. Only one previous case of early onset CAA without iCJD has been reported in humans following a non-neurosurgical procedure involving external carotid embolisation using lyophilised cadaveric dura.2
Apart from its significance in terms of Aβ transmissibility in humans, our case may also have clinical implications. Iatrogenic CAA should be considered especially in patients with early onset CAA without gene mutation. Clinicians should focus on prior neurosurgical procedure as a potential source of Aβ seed exposure. It is important to note that, as cadaveric dura grafts were also used in orthopaedic, otological, dental, urological, gynaecological and cardiac procedures before they were banned in the early 1990s, the spectrum of potential exposure might be broader based on potential transmission via blood, as suggested in our particular case. Exposure to cadaveric human growth hormone may also be considered.
Our report provides further evidence that Aβ seeds are transmissible in humans by direct contact between cadaveric dura and host brain through neurosurgical procedures and via blood through non-neurosurgical procedures using cadaveric dura. The resulting iatrogenic CAA may have dramatic consequences with multiple intracerebral haemorrhages occurring three decades later. These findings should be brought to the attention of the medical community and require confirmation in large-scale collaborative studies.
The authors would like to thank the CHU de Toulouse.
Twitter @Mélanie Planton, @Francois Chollet
Contributors NR: design and conceptualised study; supervised the study; collected the data; analysed and interpreted the data; wrote the manuscript; revised the manuscript; prepared the figures. AS and EU-C: analysed and interpreted the data; revised the manuscript; prepared the figures. MP, LC, PP, J-FA, AV, M-BD, FC, FB and J-MO: analysed and interpreted the data; revised the manuscript. JP: design and conceptualised study; analysed and interpreted the data; revised the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests NR was supported by a Fulbright Scholarship, and received an Arthur Sachs Scholarship from the Harvard University Committee on General Scholarship, and a Philippe Foundation research grant. PP reports personal fees from Lilly/Avid and from GE Healthcare. JP has received speaker honoraria from Lilly, Roche and Novartis.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.