**4. Discussion**

In general, all vascular interventions involving the thoracic or the supra-aortal regions bear the risk of clinically (in)conspicuous cerebral ischemic lesions, as reported for transcatheter aortic valve implantation or in carotid angioplasty [29,30]. Thus, all patients undergoing thoracic or supra-aortal interventions are prone to dementia and cognitive dysfunction [31,32]. Our prospective study on the occurrence of procedure-associated brain lesions following catheter-based embolization of PAVMs in patients with HHT suggests

that this procedure carries a very low risk of cerebrovascular incidents in this patient population. Although our study can only be considered preliminarily, only one individual exhibited newly formed, clinically inconspicuous, small and diffuse cerebral emboli at 4 h after the interventional procedure, and this patient was unique amongs<sup>t</sup> the patients in our cohort due to the presence of corroded tungsten coils from previous interventions. Embolization of the vessel had to be performed proximally and distally to the corroded coils and thus, when forwarding the catheter through the corroded coils, the risk of additional small displaced fragments was unavoidable.

To our knowledge, this is the first study to report on the incidence of peri-procedural cerebrovascular incidents following catheter-based embolization of PAVMs. Although the incidence of ischemic stroke ranges between 9 and 18% in patients with HHT and patent PAVMs [19,20,33–35], our findings sugges<sup>t</sup> that embolization therapy does not significantly impact the rate of further cerebrovascular incidents. Indeed, the one event noted in our series can be ascribed to the embolization material used previously (tungsten coils) rather than to the embolization procedure itself. Given the relatively high number of participants and the high number of complex PAVMs warranting re-embolization therapy due to reperfusion, our results confirm that embolization therapy is safe and highly effective for the treatment of PAVMs in patients with HHT [36–38].

Available data regarding the occurrence of peri-interventional cerebrovascular incidents measured with DWI sequences in cMRI sugges<sup>t</sup> that new ischemic brain lesions occur in up to 34% of patients treated for carotid stenting [23]. However, neurovascular interventions are more prone to acute cerebral embolism. Moreover, studies investigating the implementation of protection devices during carotid stenting have not shown statistically significant reductions in the incidence of acute peri-interventional embolism [30,39,40].

There were some limitations to this study. First, as in all interventional studies, evaluation of peri-procedural complications requires expertise and experience. This was a single-center study with procedures performed and assessed by only a few, very experienced interventional radiologists. It is possible that a greater number of cerebrovascular incidents might have occurred in this same patient cohort, had the interventions been performed by less experienced physicians. However, it should be noted that PAVMs are a complex pathology that warrant a certain degree of interventional experience by the treating physician, and that intervention would usually be undertaken at dedicated institutions by experienced personnel. Second, we only evaluated safety in terms of cerebrovascular incidents. Further studies are needed to evaluate the incidence of other potential complications, such as chest pain, hemoptysis, and hemothorax. Moreover, cMRI readings could not be blinded, since examiners were instructed to carefully look for new, small ischemic lesions in the brain, therefore being aware of the embolization therapy and patient's disease.

In conclusion, to our knowledge, this is the first study to investigate the safety of catheter embolization of PAVMs in patients with HHT in terms of cerebrovascular incidents. Although further multi-center studies in larger patient populations are required to confirm our preliminary results, our observational study reveals a very low rate of clinically inconspicuous cerebral ischemia in patients with HHT undergoing interventional treatment for PAVMs.

**Author Contributions:** All referenced authors approved to the submitted version of this manuscript and all authors agree to be personally responsible for each respective contribution and ensure the accuracy and integrity of the submitted work. All authors confirm the submitted article is appropriately investigated, resolved and documented. Conceptualization: G.S., P.R.; Methodology: P.R., G.S.; Software: P.R.; Validation: P.R., G.S.; Formal Analysis: A.B., G.S., P.R., F.F., A.M., P.F.; Investigation: G.S., P.R.; Resources: G.S., A.B.; Data Curation: P.R., A.M., F.F., P.F.; Writing—Original Draft Preparation: P.R., G.S.; Writing—Review & Editing: G.S., A.B., F.F., A.M., P.F.; Visualization: P.R., G.S., P.F., A.M., F.F.; Supervision: G.S.; Project Administration: G.S.; Funding Acquisition: not applicable. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research did not receive any specific funding.

**Institutional Review Board Statement:** Institutional Review Board approval of the corresponding ethics committee was obtained.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical reasons.

**Conflicts of Interest:** The authors declare no conflict of interest. There are no sponsors to declare in the choice of this research project, neither in the design of the study, the collection, analyses or interpretation of data, nor in the writing of the manuscript, nor in the decision to publish the results.
