慢性硬腦膜下血腫潛在分子機制探索：從臨床機器人立體定位輔助手術治療到第一型血鐵質氧化酶在血管新生和微血管滲漏的關鍵作用

Abstract

顱內出血(Intracranial Hemorrhage)是一項重大臨床挑戰，臨床醫師們需要在有效控制出血造成的顱內壓升高、中樞神經系統次級傷害與降低手術風險之間努力取得平衡。此外，若病患需要接受積極侵入性的手術治療，在術後重新恢復使用抗凝血藥物以預防缺血性中風之時機與可能面臨再出血高復發率的矛盾困境中，也常會令臨床醫師陷入兩難，尤其是針對大多擁有諸多共病症且好發於高齡族群的慢性硬腦膜下血腫(Chronic Subdural Hematomas, CSDH)顱內出血患者，因此，本論文針對顱內出血這個臨床重要議題，從以下兩方面進行探討： 1）從臨床處置角度出發，深入分析比較臨床上最新的機器人立體定位輔助(Robotic Stereotactic Assistance, ROSA)手術，探討其在顱內出血手術處置中的有效性與安全性； 2）從轉譯醫學研究角度深入，特別針對顱內出血中的CSDH病患族群進行臨床檢體分析，希望能找到影響此出血疾病的關鍵分子，並進一步探討顱內出血的致病機轉。 在第一個臨床處置部分，使用了ROSA手術來評估其對自發性顱內出血手術結果的影響，並建立標準化手術流程。研究結果顯示，ROSA手術顯著提升了手術精確度，減少術中失血，縮短手術時間，並改善術後恢復率。得益於穩定的機械手臂，結合精確的GPS (Global Positioning System) 導航和即時影像的神經外科規劃導引系統，所有手術患者均無重大併發症，且術後神經學功能均獲得改善。此外，基於累積的臨床經驗，我更進一步建立了ROSA手術顱內出血吸除與置放導管溶栓的臨床治療流程，將以術前計畫、術中程序及術後管理三大要點分述之。 為了更深入了解顱內出血，我對93名CSDH患者收集手術檢體並進行了一項回溯性分析。該分析顯示，第一型血鐵質氧化酶 (Heme Oxygenase-1, HO-1) 是與CSDH厚度獨立負相關的風險因子。隨著HO-1濃度增加100 ng/mL，CSDH厚度約減少8.9 mm。同時，我進一步深入探討CSDH的分子醫學致病機轉，特別關注 HO-1在血管新生與微血管滲漏…等病理過程中之作用。雞胚絨毛尿囊膜(Chorioallantoic Membrane, CAM)實驗結果顯示，低HO-1濃度的血腫上清液會促進血管新生與微血管滲漏。值得注意的是，高HO-1濃度的血腫上清液中，並無此現象．這表明CSDH上清液中的HO-1可能有助於穩定新生膜 (Neomembranes) 上之新生血管，減少血管過度滲透性，並防止進一步的微血管滲漏。此外，後續針對內皮前驅細胞(Endothelial Progenitor Cells, EPCs)、纖維母細胞向肌纖維母細胞轉化(Fibroblast-to-Myofibroblast Transition, FMT)及人類硬腦膜纖維母細胞的實驗也支持HO-1在新生膜上針對新生血管的作用。結果顯示，HO-1可以影響EPCs與纖維母細胞的分化，調節FMT過程，並抑制人類硬腦膜纖維母細胞的遷移能力，進而支持其在維持血管穩定性及防止血腫過度增厚方面的重要性。 總結來說，這項從臨床到基礎轉譯醫學研究的整合型研究，不僅增進了我們對顱內出血之血腫病理學及手術處置的理解，也為未來的相關研究奠定了基礎。持續改良新手術技術與提高血腫液中HO-1之濃度是否將有助於改善顱內出血之預後。

Intracranial Hemorrhage (ICH) presents a significant clinical challenge, requiring clinicians to carefully balance effective control of the elevated intracranial pressure caused by the hemorrhage, prevention of secondary damage to the central nervous system, and minimizing the risks associated with surgery. Additionally, for patients requiring aggressive invasive surgical treatment, the timing of resuming anticoagulation therapy for ischemic stroke prevention postoperatively, while facing the dilemma of high recurrence rates of rebleeding, often presents a clinical conundrum. This dilemma is particularly relevant in patients with chronic subdural hematomas (CSDH), which predominantly affect the elderly population with multiple comorbidities. Therefore, this thesis explores the important clinical issue of intracranial hemorrhage from the following two perspectives: 1. From a clinical management perspective, an in-depth analysis and comparison of the latest robotic stereotactic assistance (ROSA) surgery was conducted to evaluate its efficacy and safety in the management of ICH. 2. From a translational research perspective, clinical specimen analyses were performed on CSDH patient populations, with the aim of identifying key molecules influencing this hemorrhagic condition and further investigating the pathogenic mechanisms of intracranial hemorrhage. In the clinical management section, ROSA surgery was employed to assess its impact on surgical outcomes in spontaneous intracranial hemorrhage, and a standardized surgical protocol was established. The results demonstrated that ROSA surgery significantly enhanced surgical precision, reduced intraoperative blood loss, shortened operation times, and improved postoperative recovery rates. The stable robotic arm, combined with precise Global Positioning System (GPS) navigation and real-time image-guided neurosurgical planning, contributed to the fact that none of the surgical patients experienced major complications, and postoperative neurological function improved in all cases. Additionally, based on accumulated clinical experience, a clinical treatment protocol was developed for ROSA-guided hematoma aspiration and catheter-based thrombolysis, with a focus on preoperative planning, intraoperative procedures, and postoperative management. To gain further insight into intracranial hemorrhage, surgical specimens from 93 CSDH patients were collected for a retrospective analysis. The analysis revealed that heme oxygenase-1 (HO-1) was an independent risk factor negatively associated with CSDH thickness. As HO-1 concentrations increased by 100 ng/mL, CSDH thickness decreased by approximately 8.9 mm. Additionally, an in-depth investigation of the molecular pathogenesis of CSDH was conducted, particularly focusing on the role of HO-1 in pathological processes such as angiogenesis and microvascular leakage. The results from the chick chorioallantoic membrane (CAM) assay indicated that low HO-1 concentrations in hematoma supernatant promoted angiogenesis and microvascular leakage. Notably, these effects were absent in supernatants with high HO-1 concentrations. This suggests that HO-1 in CSDH supernatant may help stabilize the neomembrane vasculature, reduce excessive vascular permeability, and prevent further microvascular leakage. Furthermore, subsequent experiments involving endothelial progenitor cells (EPCs), fibroblast-to-myofibroblast transition (FMT), and human dural fibroblasts supported the role of HO-1 in modulating neovascularization on the neomembrane. The results indicated that HO-1 could influence the differentiation of EPCs and fibroblasts, regulate the FMT process, and inhibit the migration ability of human dural fibroblasts, thereby supporting its importance in maintaining vascular stability and preventing excessive hematoma thickening. In conclusion, this integrated study, ranging from clinical to translational research, not only enhances my understanding of hematoma pathophysiology and surgical management in intracranial hemorrhage but also lays the foundation for future related research. Continued improvements in novel surgical techniques and elevating HO-1 concentrations in hematoma fluid may potentially improve intracranial hemorrhage outcomes.