Iatrogenic cerebral amyloid angiopathy: More cases to come

Till TurloffUlf Jensen-Kondering^*

• Institute of Neuroradiology, University of Lübeck, Lübeck, Germany

Lyodura® was a commercially available cadaveric dura mater patch that was marketed worldwide by B. Braun Melsungen AG/Germany from 1969-1996 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 (1). More recently, it has also been associated with iatrogenic cerebral amyloid angiopathy (iCAA) by transmission of fibrillary amyloid aggregates (2). Its clinical and neuroradiological manifestations include stroke, seizures, transient focal neurological episodes, cognitive impairment, intraparenchymal and subarachnoid hemorrhages, cerebral microbleeds, cortical superficial siderosis (3). iCAA may serve as a model disease to provide insights into sporadic CAA. Up to now, 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 (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% (4) 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 (e.g. lack of neuroimaging, mild symptoms not yet clinically noticeable, loss to follow-up) they most likely underestimated the true incidence. In addition, several aspects may indicate that the number of patients at risk may be still be higher.Although the authors did not find a case of iCAA associated with other sources of cadaveric dura mater, other brands of cadaveric dura mater (5) and locally grafted cadaveric dura mater (6) 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 (7). Other routes of infections (contaminated neurosurgical instruments (8), blood transfusion (9,10)) 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 (11) (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 (3). As for now, iCAA cannot reliably be differentiated from sporadic CAA (besides age of onset and history of exposure) but early data indicate a role for CSF biomarkers (12).Mean incubation period for iCJD is 12 years (1.3-30 years) (13). The latency period for iCAA is reported much longer (mean 34 years, range 25-46 years) (3). A broad peak of occurrence of iCJD was reported in the mid-to late 1990 and early 2000 (13). If the latency for iCAA is superimposed, a peak could be expected in the 2020s.The last reported numbers of patients included in the international registry for iCAA, the largest collection of patients with iCAA so far, is 88 (14). That indicates and Table 1 suggests that the gap between expected and reported cases is still wide. Neuroradiologists, neurologists and neurosurgeons have to identify the remaining patients. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. UJK conceptualized the paper. Material preparation, data collection and analysis were performed by UJK and TT. The first draft of the manuscript was written by UJK. UJK and TT commented on previous versions of the manuscript. UJK and TT read and approved the final manuscript. We acknowledge financial support for the article processing charges by Land Schleswig-Holstein within the funding programme Open Access Publikationsfonds.