The International PERForator ANeurysm Registry (PERFAN)

1. Background and current state of research Lenticulostriate and basilar perforator aneurysms are extremely rare subtypes of intracranial aneurysms. Recent years have seen an increase in their diagnosis due to advancements in imaging technology. However, their low incidence has left a significant gap in the understanding of their natural history, diagnostic evaluation, management, and clinical outcomes. To date, the available literature consists mainly of case reports or small case series, with only a limited number of systematic reviews, such as those on lenticulostriate aneurysms (112 cases) and basilar perforator aneurysms (54 patients). The most common presentation of perforator aneurysms is rupture, although unruptured aneurysms may be diagnosed as an incidental finding or as the cause of compressive symptoms. Initial angiography fails to identify approximately 30%-60% of perforator aneurysms. Various treatment approaches have been reported, including surgery and various endovascular techniques such as coiling, embolization with liquid embolic agents, flow-diverters, and even electrothrombosis with a microguidewire. However, all invasive strategies have inherent periprocedural risks that must be carefully weighed against the reported overall high rate of favorable outcomes in conservatively managed patients. Despite the growing interest and knowledge in this field, an international multicenter registry that includes baseline patient characteristics, imaging, follow-up protocols, treatment strategies, and outcomes for both ruptured and unruptured intracranial perforator aneurysms is still lacking.
2. Research questions, hypotheses and aims The research questions of this exploratory study are:

• To conduct a comparative analysis of clinical characteristics and outcomes among patients with intracranial lenticulostriate and basilar perforator aneurysms treated conservatively, endovascularly, and surgically.
• To assess the size and exact location of lenticulostriate and basilar intracranial perforator aneurysms.
• To gather information regarding the specific type of endovascular treatment employed.
• To compare patients with predominantly perimesencephalic SAH harboring a perforator aneurysm and those without an aneurysm.
• To investigate the occurrence of spontaneous occlusion in aneurysms treated conservatively.
• To perform a core lab analysis of lenticulostriate and basilar intracranial perforator aneurysms using different imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), 2D digital subtraction angiography (DSA), and 3D DSA.
• To review and document observed changes of lenticulostriate and basilar perforator aneurysms (e.g. size) on follow-up imaging.
• To examine the association between aneurysm size and the incidence of bleeding.

1. Methods 3.1 Study population This is an international, multicenter, mixed-retrospective-prospective exploratory observational study. So far, in Switzerland, the Inselspital, the University Hospital Basel, the University Hospital Lausanne, the Regional Hospital of Lugano and the Cantonal Hospital St. Gallen are participating in this study and have received ethical approval. In addition, since the start of the study in early November 2023, already 15 international centers have expressed their interest in participating. More centers worldwide will be contacted via a distribution list [European Society of Minimally Invasive Neurological Therapy (ESMINT); Society of Neurointerventional Surgery (SNIS)] and invited to participate. The investigators estimate that approximately 20-30 centers worldwide will participate with an estimated total sample size of 200-300 patients by 2025. The analysis will be based on a survey (see below for included data) specifically designed for this study and completed by local neuroradiologists, neurologists or neurosurgeons involved in the management of intracranial perforator aneurysms. The primary treating physician will review the clinical records of patients with intracranial perforator aneurysms treated conservatively, endovascularly, or surgically. Study lead and coordination as well as radiological and statistical analysis will be performed by the team at the Inselspital, Bern, Switzerland. 3.2 Baseline characteristics, imaging variables, treatment variables, and outcome variables Data include:

• Age, sex, relevant comorbidities such as e.g. hypertension, arteriovenous malformation (AVM), Moya-Moya, initial clinical presentation (incidental vs. hemorrhagic). In case of hemorrhagic presentation the type of bleeding [SAH, perimesencephalic subarachnoid hemorrhage (pmSAH), intraventricular hemorrhage (IVH), or intracerebral hemorrhage (ICH)] will be documented.
• Type of initial diagnostic modality (CT, MRI, DSA).
• Perforator aneurysm identified on initial diagnostic modality.
• Type of treatment (surgical vs. endovascular). In case of endovascular treatment specific type [coiling, n-butyl cyanoacrylate (NBCA), ethylene vinyl alcohol (EVOH), flow-diverter, Electro-coagulation, other].
• Pre- and post-treatment modified Rankin Scale (mRS). Clinical endpoints include:
• mRS at 3 months after initial diagnosis of an intracranial perforator aneurysm
• mRS at last follow-up (including time-point of last follow-up after diagnosis)
• Rupture/re-rupture of the index aneurysm as a time-event outcome Safety endpoints include:
• Death during the acute hospital stay
• Death up to 90 days (related to the index aneurysm)
• Ischemic stroke (imaging based)
• Periprocedural and postprocedural complications in patients submitted to endovascular or surgical treatment. Efficacy Endpoint
• For patients receiving treatment, assessment of aneurysm occlusion after treatment and available follow-ups. 3.3 Data transfer and storage (Medical-Blocks® and REDCap) Imaging data from all external participating centers will be securely transferred via and stored on Medical-Blocks® (https://mb-neuro.medical-blocks.ch). This cloud-based platform for storage, anonymization and exchange of medical images in the neuro field (MB-Neuro) is provided by the Inselspital Bern. The platform provides the necessary interfaces to communicate with other secure and advanced IT environments via various Application Programming Interfaces (APIs). Secure Sockets Layers (SSL) with 256-bit encryption is used, which complies with the regulations of KlinV. (Verordnung über klinische Versuche) Art. 18 and HFV (Humanforschungsverordnung) Art. 5 of the Swiss Ordinance on the Storage of Health-Related Personal Data and Biological Materials. The clinical datasets will be provided in an anonymized fashion (matching the anonymized imaging data) by the physician primarily involved in patient management from the participating centers and entered and stored in REDCap.

1. Sample size and statistical analyses

This is an exploratory study. The investigators estimate that approximately 20-30 centers worldwide will participate with an estimated total sample size of 200-300 patients.

Categorical variables will be presented as numbers and percentages, and continuous variables as medians, interquartile range (IQR). Fisher's exact will be used for categorical and Mann-Whitney U test or Kruskal-Wallis test for continuous variables. Logistic regression results will be displayed as odds ratios (OR) for simple regression or adjusted OR (aOR) for multinomial regression analyses, with their corresponding 95% confidence intervals (CIs). As this is an exploratory study, no conclusions about significance can be drawn. Therefore, a p-value < 0.05 will be interpreted as a trend. All analyses will be performed using established statistic software, including R 4.01 or newer, Python 3.83 or newer, Stata 16 and/or Statistical Package for the Social Sciences (SPSS) 27.00 or newer.