2025 Volume 12 Pages 317-321
Iatrogenic cerebral amyloid angiopathy is a rare yet clinically relevant condition that may develop decades after cadaveric dura mater transplantation. We present the case of a 48-year-old man who experienced recurrent, bilateral, multilobar intracerebral hemorrhages approximately 40 years after childhood dura mater transplantation. Pathological examination confirmed amyloid β protein deposition around small cerebral blood vessels in the brain parenchyma. Genetic testing excluded mutations associated with hereditary cerebral amyloid angiopathy. According to the patient's operative record, at age 7 years, a left parietal bone tumor and the adjacent dura mater were removed, and a cadaveric dural patch was transplanted onto the intact brain surface. This case suggests that exogenous amyloid β protein can be transmitted through cadaveric dura mater, even when placed on intact brain tissue with preserved glymphatic and dural lymphatic drainage function, manifesting decades after transplantation.
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid proteins on the walls of brain blood vessels. This deposition leads to vascular fragility, which increases the risk of cerebral hemorrhage.1) CAA is predominantly observed in older adults, with early onset before the age of 55 being relatively rare.2) Recently, early-onset CAA has been linked not only to genetic risk factors associated with hereditary CAA but also to childhood head surgery involving cadaveric dura mater transplantation.3-6) Such cases are termed iatrogenic CAA (iCAA) or acquired CAA.7-9)
We present a case of iCAA that caused recurrent, bilateral, multilobar cerebral hemorrhage approximately 40 years after childhood dura mater transplantation. Notably, the brain tissue was not manipulated during any neurosurgical procedure in childhood, which represents a previously unreported occurrence.
A 48-year-old man was admitted to our hospital with symptoms of consciousness disturbance, aphasia, and right hemiplegia. At the age of 7 years, he had undergone neurosurgery involving cadaveric dural transplantation in the left parietal lobe after skull bone tumor resection. Intraoperative findings showed that the bone tumor was mildly adherent to the dura mater, but the inner part of the dura mater appeared normal without invasion, and the arachnoid membrane was intact. The bone tumor and the underlying dura mater were removed, and a cadaveric dura mater (LYODURA; B. Braun, Melsungen, Germany) was placed on the intact arachnoid for dura mater replacement. Pathology of the bone tumor revealed an eosinophilic granuloma. At 45 years of age, the patient experienced a subcortical hemorrhage in the right parietal lobe and subsequently underwent craniotomy for hematoma removal. Neither before the cerebral hemorrhage nor before this visit were there any symptoms characteristic of Creutzfeldt-Jakob disease (CJD), such as rapidly progressive dementia, myoclonus, visual disturbances, cerebellar ataxia, pyramidal or extrapyramidal signs, or akinetic mutism. The patient had no history of hypertension or medication use, or relevant family medical history.
On arrival, the patient's Glasgow Coma Scale score was E2 V2 M5, indicating a decreased level of consciousness. He exhibited aphasia and had a Manual Muscle Testing score of 1/5 in both the right upper and lower limbs. Blood tests did not reveal any abnormalities suggestive of a bleeding tendency. A head computed tomography (CT) scan showed a 60-mm diameter subcortical hemorrhage in the left frontal lobe with midline shift, and three-dimensional CT angiography of the head showed no abnormalities (Fig. 1). Emergency craniotomy was performed for hematoma evacuation. During the procedure, no abnormal vessels or vascular malformations were identified. A sample of the brain parenchyma was sent for pathological examination. Congo red staining revealed amyloid deposits in small blood vessels within the brain parenchyma, and immunostaining confirmed the presence of amyloid β protein (Aβ) 40 (Fig. 2). These findings led to a diagnosis of CAA-related subcortical hemorrhage. Genetic testing revealed no mutations in the genes of amyloid precursor protein (APP), presenilin (PSEN) 1, or PSEN2, which are known to be associated with hereditary CAA. The patient's apolipoprotein E (ApoE) genotype was ε2/ε4.
(A) The head computed tomography scan performed at the time of examination showed a subcortical hemorrhage with a maximum diameter of 60 mm in the left frontal lobe. The arrow in the figure indicates a subcortical hemorrhage in the right parietal lobe, which occurred when the patient was aged 45 years. (B) Three-dimensional computed tomography angiography of the head, performed at the time of examination, revealed no obvious vascular malformations, aneurysms, or venous sinus thrombosis.
Pathological images of the brain parenchyma. (A) Hematoxylin-eosin staining revealed circumferential wall thickening of the arteries. (B) Congo red staining showed amyloid deposits in small vessels within the brain parenchyma. (C) Immunohistochemistry testing was positive for amyloid β protein 40 at the site of amyloid deposition. Scale bar = 100 μm.
Susceptibility-weighted imaging on magnetic resonance imaging (MRI) performed on post-operative day (POD) 29 showed old hemorrhages in the surgically treated left frontal and right parietal lobes, and in the right frontal and occipital lobes, in addition to other numerous microhemorrhages (Fig. 3). Diffusion-weighted imaging did not show marked brain atrophy or high signal intensity in the cerebral cortex or basal ganglia, which are characteristic of CJD. On POD 42, the patient was transferred to another rehabilitation facility with a modified Rankin Scale (mRS) score of 4. He underwent rehabilitation for the next 5 months, but there was little to no dramatic relief of symptoms such as aphasia and right hemiplegia, and his mRS score remained at 4. Owing to difficulties in being discharged from the hospital and returning home, he was admitted to a nursing home. There was no recurrence of cerebral hemorrhage during this time.
Magnetic resonance imaging on post-operative day 29. (A) Susceptibility-weighted imaging showed subcortical hemorrhages in the right parietal lobe and left frontal lobe, which had been surgically treated. These images also revealed untreated old hemorrhages in the right frontal and occipital lobes, along with other numerous microbleeds. The arrow in the figure indicates the cadaveric dura mater graft site from when the patient was aged 7 years. (B) Diffusion-weighted imaging showed bleeding and evidence of previous hemorrhage, but no significant brain atrophy or high signal intensity in the cerebral cortex or basal ganglia, which are characteristic of Creutzfeldt-Jakob disease.
To the best of our knowledge, this is the first reported case of iCAA resulting from the application of cadaveric dura mater to an intact brain surface. This case highlights the potential risk of iCAA development from exposure to cadaveric dura mater, even when the brain remains intact.
The patient had received cadaveric dura mater grafts in childhood and later experienced recurrent subcortical hemorrhage in his 40s. This case led to the diagnosis of iCAA, based on the proposed diagnostic criteria, including onset before the age of 55 years, a history suggestive of potential exposure such as dura mater grafting, the presence of lobar hemorrhages or microbleeds, confirmation of Aβ deposition, and exclusion of mutations in APP, PSEN1, and PSEN2.10) Regarding the possibility of iatrogenic CJD, it was considered unlikely, given the symptoms were not rapidly progressive, and there were no symptoms or imaging findings consistent with CJD.
Transmission of pathogenic proteins, such as prions or Aβ, from humans to humans has been reported not only through the surgical use of cadaveric dura mater but also through contaminated medical instruments or the administration of human cadaveric derivatives.11-13) In this case, the cadaveric dura mater was grafted in childhood, from which transmission of Aβ is presumed. The mechanism of Aβ spread from the cadaveric dura mater is speculated to be direct spread from the brain surface or through the blood and cerebrospinal fluid pathways.7,9) Recent discoveries have revealed that the glymphatic system and meningeal lymphatic organs play crucial roles in maintaining cerebrospinal fluid circulation, immunity, and the clearance of waste products such as Aβ.14,15) The mechanism of Aβ transmission from cadaveric dura mater to brain tissue is believed to involve neurosurgical manipulation disrupting the glymphatic and perivascular drainage systems, thereby facilitating the accumulation of waste products in the central nervous system.6,16) Although prior studies have established a link between cadaveric dura mater use and iCAA, most have focused on cases when the dura mater was applied to damaged or compromised brain tissue, such as traumatic brain injury or tumor resection.8) The present case shows, for what is, to our knowledge, the first time, that even when the arachnoid membrane and brain surface are intact and the glymphatic and dural lymphatic drainage systems are functional, contact between pathogenic dura mater and the intact meninges can seed Aβ into a healthy, young brain.
Regarding ApoE protein, the ε2 and ε4 alleles have been associated with the severity of CAA; the ε2 allele is associated with vascular inflammation or disruption, whereas the ε4 allele is linked to promote Aβ deposition on vessel walls.17,18) This case is distinctive owing to having the ApoE genotype ε2/ε4. However, the association between ApoE genotype and the severity of cerebral bleeding in iCAA remains unclear because individuals with the ε3/ε3 genotype can also exhibit similar patterns.8) Another characteristic of this case is that the initial brain hemorrhage occurred on the opposite side of the cadaveric dura patch. It is generally believed that in iCAA, bleeding is more likely to occur on the same side as the surgical procedure.8) However, there have also been reports of cases when bleeding occurs on the opposite side, as in this case.4) This may support the possibility that Aβ can spread not only through direct propagation but also through blood and cerebrospinal fluid to remote areas.7,9)
Given the historical prevalence of dura mater grafts performed in the 1980s, there is a high likelihood that similar cases will be observed as these patients age.11) Young individuals with a history of childhood head surgery who present with subcortical hemorrhage should be examined for iCAA. Future research should focus on specific epidemiological studies that examine the long-term effects of dura mater grafts, elucidate the pathophysiology, and develop effective treatment strategies. Moreover, establishing a support system for health issues related to dura mater graft use remains a crucial challenge.
ConclusionsWe encountered a case of recurrent subcortical hemorrhage in a patient in their 40s due to iCAA. This case suggests that exogenous Aβ can be transmitted through cadaveric dura mater to intact brain tissue with preserved glymphatic and dural lymphatic drainage function, potentially manifesting decades after transplantation.
The authors thank Dr. Katsuaki Sato at Noto General Hospital for his expertise in pathological diagnosis, and Dr. Kensaku Kasuga at Niigata University for his expertise in genetic testing.
Informed consent for genetic testing and the publication of this case report, including any accompanying images, was obtained from the patient's family.
All authors have no conflict of interest.
