THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion

Intraoperative Cerebrospinal Fluid Leak in Extradural Spinal Tumor Surgery

Objective Patients with extradural spine tumors are at an increased risk for intraoperative cerebrospinal fluid (CSF) leaks and postoperative wound dehiscence due to radiotherapy and other comorbidities related to systemic cancer treatment. In this case series, we discuss our experience with the management of intraoperative durotomies and wound closure strategies for this complex surgical patient population. Methods We reviewed our recent single-center experience with spine surgery for primarily extradural tumors, with attention to intraoperative durotomy occurrence and postoperative wound-related complications. Results A total of 105 patients underwent tumor resection and spinal reconstruction with instrumented fusion for a multitude of pathologies. Twelve of the 105 patients (11.4%) reviewed had intraoperative durotomies. Of these, 3 underwent reoperation for a delayed complication, including 1 epidural hematoma, 1 retained drain, and 1 wound infection. Of the 93 uncomplicated index operations, there were a total of 9 reoperations: 2 for epidural hematoma, 3 for wound infection, 2 for wound dehiscence, and 2 for recurrent primary disease. One patient was readmitted for a delayed spinal fluid leak. The average length of stay for patients with and without intraoperative durotomy was 7.3 and 5.9 days, respectively, with a nonsignificant trend for an increased length of stay in the durotomy cases (p=0.098). Conclusion Surgery for extradural tumor resections can be complicated by CSF leaks due to the proximity of the tumor to the dura. When encountered, a variety of strategies may be employed to minimize subsequent morbidity