1 Introduction
LyoduraⓇ was a commercially available cadaveric dura mater patch that was marketed worldwide by B. Braun Melsungen AG/Germany from 1969 to 1996 and widely used in neurosurgery for dural repair. Since 1987, it has been incriminated as a main agent of iatrogenic Creutzfeldt–Jakob disease (iCJD) by transmission of prions (). More recently, it has also been associated with iatrogenic cerebral amyloid angiopathy (iCAA) by transmission of fibrillary amyloid aggregates (). The mechanism with which the disease unfolds is unclear but is believed to occur in a prion like manner. Misfolded proteopathic seeds are believed to induce misfolding in other cells which in turn are also able to induce protein misfolding, thus reaching distant parts of the brain. After this first incubation phase, a second plateau phase follows during which neurotoxicity and clinical events occur (). Its clinical and neuroradiological manifestations include stroke, seizures, transient focal neurological episodes, cognitive impairment, intraparenchymal and subarachnoid hemorrhages, cerebral microbleeds, and cortical superficial siderosis (). iCAA may serve as a model disease to provide insights into sporadic CAA.
2 Discussion
To date, no certain numbers of cadaveric dura mater use were available, which precludes reliable risk assessment. It has been estimated, though, for Japan, Australia, South Korea, and more vaguely for the USA. For unknown reasons, its usage has been regionally diverse. In Japan, app. 20.000 patches have been used annually in the 1980s while in the USA < 10% of app. 4000 patches have been used annually (Table 1). Pikija et al. recently reported the numbers for the pediatric population from a single institution in central Europe. Over a period of 25 years, 34 patients were definitely exposed to LyoduraⓇ during neurosurgical procedures. The authors report an incidence rate as high as 12% () for iCAA, which is in stark contrast to the incidence of iCJD after the use of cadaveric dura mater (Table 1). The authors state that for a number of reasons they most likely underestimated the true incidence: (1) MRI which might uncover subtle signs of CAA not visible on CT is not globally available and historically a young imaging modality. (2) Patients displaying only mild or clinically barely noticeable symptoms might not be picked up. (3) Many patients may have been misclassified as sporadic CAA and (4) many patients may have been lost to follow-up.
Table 1
| Number of cases, Incidence | USA | Australia | Korea | Japan |
|---|---|---|---|---|
| Estimated LyoduraⓇ use, n | < 100/year () | ~2,208–2,478 () | ~57.434 () | ~200.000 () |
| iCJD cases (confirmed LyoduraⓇ), n | 4 () | 5 () | 2 () | 142 () |
| iCJD incidence (confirmed LyoduraⓇ) | NA | 0.23–0.43% () | 0.02–0.09% () | 0.03% () |
| iCAA cases (confirmed LyoduraⓇ), n | 2 () | 1 () | 0 | 4 (–) |
Estimated LyoduraⓇ use per country, reported cases, and incidences for iCJD and iCAA.
In addition, several aspects may indicate that the number of patients at risk may be still be higher: (1) Although the authors did not find a case of iCAA associated with other sources of cadaveric dura mater, other brands of cadaveric dura mater () and locally grafted cadaveric dura mater () have been implicated with the occurrence of iCJD. It is conceivable that these kinds of grafts were also a source of amyloid transmission. (2) Further, lyophilized cadaveric dura mater has been used in other procedures notably as an embolization agent in head and neck applications (). (3) Other routes of infections (contaminated neurosurgical instruments (), blood transfusion (, )) also seem possible but unproven. (4) While the spectrum of underlying conditions leading to cadaveric dura mater use in the cohort described by Pikija et al. roughly matches Japanese patients treated with LyoduraⓇ who developed iCJD () (tumor surgery and hemorrhage/trauma being the most common) Japanese patients' age was way outside the pediatric spectrum (mean age at surgery 44 years). However, a 20-year-old having received a cadaveric dura mater patch in 1995 may likely still be alive today and even be considered for the diagnosis of iCAA ().
Although the authors did not find a case of iCAA associated with other sources of cadaveric dura mater, other brands of cadaveric dura mater () and locally grafted cadaveric dura mater () have been implicated with the occurrence of iCJD. It is conceivable that these kinds of grafts were also a source of amyloid transmission. Further, lyophilized cadaveric dura mater has been used in other procedures, notably as an embolization agent in head-and-neck applications (). Other routes of infection [contaminated neurosurgical instruments () and blood transfusion (, )] also seem possible but unproven.
While the spectrum of underlying conditions leading to cadaveric dura mater use in the cohort described by Pikija et al. roughly matches Japanese patients treated with LyoduraⓇ who developed iCJD () (tumor surgery and hemorrhage/trauma being the most common), Japanese patients' age was way outside the pediatric spectrum (mean age at surgery: 44 years). However, a 20-year-old patient having received a cadaveric dura mater patch in 1995 may potentially still be alive today and even be considered for the diagnosis of iCAA (). As for now, iCAA cannot reliably be differentiated from sporadic CAA (besides age of onset and history of exposure). Although preliminary, p-tau levels in CSF may be used for differentiation (). Further, there is evidence that some hemorrhagic MRI markers occur in a centrifugal manner from the site of surgery (, ).
The mean incubation period for iCJD is 12 years (1.3–30 years) (). The latency period for iCAA is reported to be much longer (mean: 34 years, range: 25–46 years) (). A broad peak of occurrence of iCJD was reported in the mid-to-late 1990s and early 2000s (). If the latency for iCAA is superimposed, a peak could be expected in the 2020s.
The last reported number of patients included in the international registry for iCAA, the largest collection of patients with iCAA so far, is 88 (). This indicates that the gap between expected and reported cases is still wide (Table 1). Neuroradiologists, neurologists, and neurosurgeons have to identify the remaining patients.
Statements
Author contributions
TT: Funding acquisition, Writing – review & editing, Formal analysis, Investigation, Data curation, Validation. UJ-K: Supervision, Methodology, Writing – review & editing, Validation, Investigation, Conceptualization, Data curation, Formal analysis, Writing – original draft.
Funding
The author(s) declared that financial support was received for this work and/or its publication. We acknowledge financial support for the article processing charges by Land Schleswig–Holstein within the funding program Open Access Publikationsfonds.
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References
1.
DuffyPWolfJCollinsGDeVoeAGStreetenBCowenD. Letter: possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med. (1974) 290:692–3. doi: 10.1056/NEJM197403212901220
2.
BanerjeeGSamraKAdamsMEJaunmuktaneZParry-JonesARGrieveJet al. Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon. J Neurol Neurosurg Psychiatry. (2022) 93:693–700. doi: 10.1136/jnnp-2022-328792
3.
SandbergMKAl-DoujailyHSharpsBClarkeARCollingeJ. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. (2011) 470:540–2. doi: 10.1038/nature09768
4.
Fandler-HöflerSKaushikKStortiBPikijaSMallonDAmblerGet al. Clinical-radiological presentation and natural history of iatrogenic cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. (2025) 96:832–41. doi: 10.1136/jnnp-2024-335164
5.
PikijaSTomaARadlbergerRGriessenauerCJHeckerCTrinkaEet al. Iatrogenic cerebral amyloid angiopathy in patients treated with cadaveric dura mater during childhood neurosurgery: a retrospective cohort study. Euro J of Neurology. (2025) 32:e70091. doi: 10.1111/ene.70091
6.
HannahELBelayEDGambettiPKrauseGParchiPCapellariSet al. Creutzfeldt–Jakob disease after receipt of a previously unimplicated brand of dura mater graft. Neurology. (2001) 56:1080–3. doi: 10.1212/WNL.56.8.1080
7.
PocchiariMMasulloCSalvatoreMGenuardiMGalganiSHarveyIet al. Creutzfeldt-Jakob disease after non-commercial dura mater graft. Lancet. (1992) 340:614–5. doi: 10.1016/0140-6736(92)92153-7
8.
CaroppoPMarucciGMaccagnanoEGobboCLBizzozeroITiraboschiPet al. Cerebral amyloid angiopathy in a 51-year-old patient with embolization by dura mater extract and surgery for nasopharyngeal angiofibroma at age 17. Amyloid. (2021) 28:142–3. doi: 10.1080/13506129.2020.1854715
9.
FrolSJensen-KonderingUIhanA. Regarding “Optimization and evaluation of new decontamination procedures inactivating human prions” recently published by Herzog and colleagues. J Hosp Infect. (2025) S0195670125001719. doi: 10.1016/j.jhin.2025.05.022
10.
ZhaoJRostgaardKLauwersEDahlénTOstrowskiSRErikstrupCet al. Intracerebral hemorrhage among blood donors and their transfusion recipients. JAMA. (2023) 330:941. doi: 10.1001/jama.2023.14445
11.
DiFrancescoJCTabaee DamavandiPPretnar-OblakJFrolSde la Riva JuezPAlbajar GomezIet al. Iatrogenic cerebral amyloid angiopathy after red blood cell transfusion?Eur J Neurol. (2024) 31:e16366. doi: 10.1111/ene.16366
12.
YamadaMNoguchi-ShinoharaMHamaguchiTNozakiIKitamotoTSatoTet al. Dura mater graft-associated Creutzfeldt-Jakob disease in Japan: clinicopathological and molecular characterization of the two distinct subtypes. Neuropathology. (2009) 29:609–18. doi: 10.1111/j.1440-1789.2008.00987.x
13.
Jensen-KonderingUMargrafNGPikijaSRak-FrattnerKMalojcicBFrolSet al. Cerebrospinal fluid β-amyloid and τ levels in patients with iatrogenic cerebral amyloid angiopathy, sporadic cerebral amyloid angiopathy, Alzheimer disease, and controls. J Am Heart Assoc. (2025) 14:e041908. doi: 10.1161/JAHA.125.041908
14.
Jensen-KonderingU. Spatial colocalization of imaging markers in iatrogenic cerebral amyloid angiopathy with the site of surgery: a metaanalysis. J Neurol Sci. (2024) 458:122931. doi: 10.1016/j.jns.2024.122931
15.
BrownPBrandelJPSatoTNakamuraYMacKenzieJWillRGet al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis. (2012) 18:901–7. doi: 10.3201/eid1806.120116
16.
KaushikKBanerjeeGSellimiA. An international registry for iatrogenic cerebral amyloid angiopathy. In:DichigansMGreenbergSM, editors. 9th International CAA Conference. Munich: International CAA Association (2024). p. 149–50.
17.
BrownPPreeceMBrandelJPSatoTMcShaneLZerrIet al. Iatrogenic Creutzfeldt–Jakob disease at the millennium. Neurology. (2000) 55:1075–81. doi: 10.1212/WNL.55.8.1075
18.
BrookeFJBoydAKlugGMMastersCLCollinsSJ. Lyodura use and the risk of iatrogenic Creutzfeldt–Jakob disease in Australia. Med J Australia. (2004) 180:177–81. doi: 10.5694/j.1326-5377.2004.tb05863.x
19.
JeonBHKimJKimGKParkSCKimSCheongHK. Estimation of the size of the iatrogenic Creutzfeldt-Jakob disease outbreak associated with cadaveric dura mater grafts in Korea. Epidemiol Health. (2016) 38:e2016059. doi: 10.4178/epih.e2016059
20.
NakamuraYAsoEYanagawaH. Relative risk of Creutzfeldt-Jakob disease with cadaveric dura transplantation in Japan. Neurology. (1999) 53:218–218. doi: 10.1212/WNL.53.1.218
21.
KellieJFCampbellBCVWatsonRPraegerAJNairGMurugasuAet al. Amyloid-β (Aβ)-related cerebral amyloid angiopathy causing lobar hemorrhage decades after childhood neurosurgery. Stroke. (2022) 53:e369–74. doi: 10.1161/STROKEAHA.121.038364
22.
MullerC. Case report of iatrogenic cerebral amyloid angiopathy after exposure to Lyodura: an Australian perspective. Front Neurosci. (2023) 17:1185267. doi: 10.3389/fnins.2023.1185267
23.
TanakaFUminoMMatsukawaMKishiSKogueRKawadaNet al. Iatrogenic cerebral amyloid angiopathy after childhood brain surgery: novel findings of MRI and CT. Neurol Int. (2025) 17:64. doi: 10.3390/neurolint17050064
24.
HatakeyamaYKimuraAMTsuboguchiSRatanovMNakamuraKHatakeyamaMet al. A case of cerebral amyloid angiopathy with ipsilateral tau and contralateral amyloid PET uptake related to cadaveric dura mater implanted in childhood. Eur J Nucl Med Mol Imaging. (2025) 52:2737–9. doi: 10.1007/s00259-024-07030-z
25.
KawarabayashiTNakamuraTTakatamaSMiyamotoNIwaiTNaitoIet al. A case of the iatrogenic transmission of vascular Aß40 amyloid. Amyloid. (2025) 32:81–3. doi: 10.1080/13506129.2024.2419857
26.
YoshikiKHiroseGKumahashiKKohdaYIdoKShioyaAet al. Follow-up study of a patient with early onset cerebral amyloid angiopathy following childhood cadaveric dural graft. Acta Neurochir. (2021) 163:1451–5. doi: 10.1007/s00701-021-04751-0
Summary
Keywords
LyoduraⓇ, cadaveric dura mater, iatrogenic Creutzfeldt–Jakob disease (iCJD), iatrogenic cerebral amyloid angiopathy (iCAA), intracerebral hemorrhage
Citation
Turloff T and Jensen-Kondering U (2025) Iatrogenic cerebral amyloid angiopathy: more cases to come. Front. Neurol. 16:1741885. doi: 10.3389/fneur.2025.1741885
Received
07 November 2025
Accepted
28 November 2025
Published
15 December 2025
Volume
16 - 2025
Edited by
Luis Rafael Moscote-Salazar, Colombian Clinical Research Group in Neurocritical Care, Colombia
Reviewed by
Pratiksha Baliga, Mahatma Gandhi Mission Institute of Health Sciences, India
Updates
Copyright
© 2025 Turloff and Jensen-Kondering.
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*Correspondence: Ulf Jensen-Kondering, Ulf.Jensen-Kondering@uksh.de
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.