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. 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 (thrombospondin type 1 domain containing protein 1) 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 was identified that segregated with the 9 affected (3 suffered subarachnoid hemorrhage and 6 had unruptured IA) and was absent in 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 subarachnoid hemorrhage (1.6% [95% confidence interval, 0.8%-3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89 040 chromosomes in Exome Aggregation Consortium (ExAC) database (P<0.0001). 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 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

A Criteria to Reduce Interhospital Transfer of Traumatic Brain Injuries in Greater East Texas.

BACKGROUND: Traumatic brain injury (TBI) due to single-level falls (SLF) are frequent and often require interhospital transfer. This retrospective cohort study aimed to assess the safety of a criteria for non-transfer among a subset of TBI patients who could be observed at their local hospital, vs mandatory transfer to a level 1 trauma center (L1TC). METHODS: We conducted a 7-year review of patients with TBI due to SLF at a rural L1TC. Patients were classified as transfer/non-transfer according to the Brain Injuries in Greater East Texas (BIGTEX) criteria. The primary outcome measure was the occurrence of a critical event defined as deteriorating repeat head computed tomography (CT) scan or neurological status, neurosurgical intervention, or death. RESULTS: Of the 689 included patients, 63 (9.1%) were classified as non-transfer. Although there were 4 cases with a neurological change and one with a head CT change among the non-transfer group, there were no neurosurgical procedures or deaths. The Cox Proportional Hazard model showed a near 3-fold increased risk of experiencing a critical event if classified as a non-transfer. The multivariable regression model showed patients with an Abbreviated Injury Scale (AIS) of 3 was twice as likely to experience a critical event, with an AIS of 4, three times, and 3 times more likely to be classified to transfer. DISCUSSION: The BIGTEX criteria identify a subset of patients who can safely be observed at their local hospital. To confirm the safety and efficacy of this transfer criteria recommendation, a prospective study is warranted.

Angiogram-negative subarachnoid hemorrhage: relationship between bleeding pattern and clinical outcome.

BACKGROUND: Angiogram-negative subarachnoid hemorrhage (anSAH) accounts for 15% of spontaneous SAH. Recent studies suggest the outcome and diagnostic yield in anSAH differ based on initial bleeding pattern. We present a single-center experience in managing patients with SAH and negative initial digital-subtracted angiogram (DSA). METHODS: Records of all patients with anSAH were reviewed. Bleeding pattern was determined from computed tomography (CT) and was categorized as perimesencephalic (PMN), diffuse, cortical, or xanthochromia (blood not detectable by CT). Diagnostic yield, in-hospital complications, and outcome parameters were analyzed. RESULTS: Of 352 patients admitted with spontaneous SAH from 2003 to 2008, 68 (19.3%) had negative initial DSA. Mean age was 59.5 ± 14, and 33 were female. By CT, 27 (39.7%) patients exhibited PMN SAH, 33 (48.5%) diffuse SAH, 6 (8.8%) cortical SAH, and 2 (2.9%) xanthochromia only. Sixty-one patients had good Hunt and Hess (H/H) grades (I-III) and seven had poor grades (IV-V). Additional diagnostic studies included repeat angiogram (54), brain and C-spine magnetic resonance imaging (20), and repeat CTA (15). A structural bleeding cause was determined in six (8.8%) patients, 4 of which had diffuse SAH and 2 cortical SAH. Among these, two aneurysms (2.9%) were detected and surgically clipped, and both had diffuse SAH. Twenty-nine patients (42.6%) experienced medical complications, with infection (18), cardiovascular problems (12), and vasospasm (10) being the most frequent events. Additional surgeries included 13 ventriculoperitoneal shunts, 4 tracheostomies, and 9 gastric tube placements. Favorable outcome (mRS = 0-2) was recorded in 49 (72.1%) patients and unfavorable (3-6) in 19 (17.49%), with 1 (1.2%) in-hospital death. Multivariable logistic regression revealed older age and diffuse bleeding pattern were significant predictors of unfavorable outcome. CONCLUSIONS: The overall incidence of true aneurysms in patients with angiogram-negative SAH is low (2.9%). Initial bleeding pattern strongly correlates with diagnostic yield and clinical outcome. Diffuse bleeding pattern is associated with significantly higher diagnostic yield, more in-hospital complications, and worse clinical outcome. Patients with initial imaging characteristics other than diffuse pattern SAH developed few disease related complications, with the majority of in-hospital adverse events treatment related.

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.

Resolution of extra-axial collections after decompressive craniectomy for ischemic stroke.

Extra-axial fluid collections are known consequences of decompressive hemicraniectomy. Studies have examined these collections and their management. We retrospectively reviewed 12 consecutive patients who underwent decompressive hemicraniectomy for the treatment of malignant cerebral edema after infarction and evaluated the evolution, resolution and treatment of post-operative extra-axial fluid collections. All patients underwent standard-sized frontotemporoparietal hemicraniectomy with duraplasty as treatment for medically intractable malignant cerebral edema at an average of 3 days after the stroke (median 2 days). Their 30-day mortality was 25%. Three patients developed some extra-axial fluid collections after craniectomy: two patients developed the collections early in their post-operative course, 3 days and 5 days after the craniectomy. Both experienced spontaneous resolution of the collections without corrective cranioplasty or shunt placement at 34 days and 58 days after surgery. The third patient developed a collection 55 days after the operation related to a subgaleal bacterial infection. In the final analysis, 18% of patients developed extra-axial collections and all resolved spontaneously. The incidence of extra-axial collections after decompressive hemicraniectomy following ischemic stroke was lower in our retrospective series than has been reported by others. The collections resolved spontaneously, suggesting that early anticipatory, corrective treatment with cerebrospinal fluid diversion or cranioplasty may not be warranted.

Craniectomy-associated Progressive Extra-Axial Collections with Treated Hydrocephalus (CAPECTH): redefining a common complication of decompressive craniectomy.

Extra-axial fluid collections following decompressive craniectomy have been observed in a variety of patient populations. These collections have traditionally been thought to represent extra-axial signs of hydrocephalus, but they often occur even in settings where hydrocephalus has been optimally treated. This study aims to elucidate the phenomenon of extra-axial fluid collections after decompressive craniectomy in patients with treated hydrocephalus, in order to improve identification, classification, prevention and treatment. We retrospectively reviewed all patients at a single institution undergoing decompressive craniectomy for refractory intracranial pressure elevations from June 2007 through December 2009. We identified 39 patients by reviewing clinical reports and imaging. Any patient who died on or prior to the third post-operative day (POD) was excluded. The analysis focused on patients with extra-axial collections and treated hydrocephalus. Twenty-one of 34 (62%) patients developed extra-axial collections and 18 of these developed collections despite ventricular drainage. Subgroup analysis revealed that seven of seven patients (100%) with subarachnoid hemorrhage, and 11 of 14 (79%) with traumatic brain injury developed collections. Extra-axial collections may develop after decompressive craniectomy despite aggressive treatment of communicating hydrocephalus. In these patients, the term "external hydrocephalus" does not appropriately capture the relevant pathophysiology. Instead, we define a new phenomenon, "Craniectomy-associated Progressive Extra-Axial Collections with Treated Hydrocephalus" (CAPECTH), as progressive collections despite aggressive cerebral spinal fluid (CSF) drainage. Our data indicate that early cranioplasty can help prevent the formation and worsening of this condition, presumably by returning normal CSF dynamics.

Idiopathic syrinx in the pediatric population: a combined center experience.

OBJECT: Discovery of a syrinx in a child, without a readily identifiable proximate cause such as a Chiari malformation, tumor, or site of tethering, is often a cause of concern for families and a source of consternation for clinicians. There is a paucity of data describing the natural history of an idiopathic syrinx in the pediatric population. The authors present the combined data of 2 major pediatric neurosurgical centers to describe their experience with this condition. METHODS: Data were collected at Children's Hospital Boston and St. Louis Children's Hospital according to institutional review board-approved protocols and captured visits over a 2.5-year interval (October 2006-March 2009), with records reviewed if the patient had a preexisting diagnosis of syrinx. Patients were identified by ICD-9 codes derived from departmental databases. All pediatric patients (age < 19 years) in whom idiopathic syrinx had been diagnosed, as defined by MR imaging findings (dilated central canal in the spinal cord of ≥ 1 mm in axial dimension and extending over at least 2 vertebral levels), were included. RESULTS: Forty-eight patients met the criteria for idiopathic syrinx during this period, and in 32 of them detailed follow-up imaging was available. Discovery of a syrinx was incidental in 6 patients, whereas the others were referred for imaging because of the presence of pain, neurological symptoms, scoliosis, or skin markings. The average age at the first MR imaging session was 9.7 years, with a mean syrinx size of 4 mm (range 1.2-9.4 mm). The majority (52%) of patients had a thoracic syrinx, with the average lesion spanning 7.1 vertebral levels. The average follow-up was 23.8 months (range 2-64 months), and subgroups of patients with < 3 years and ≥ 3 years of follow-up were independently reviewed. Overall, symptoms improved in 34% and worsened in 9%; 57% of the patients remained asymptomatic or stable. Radiographically (in the subgroup of 32 patients with detailed follow-up imaging), syrinx size decreased in 25% of patients, increased in 12.5%, and remained unchanged in 62.5%, with no apparent correlation between change in syrinx size and clinical symptoms. CONCLUSIONS: Clinically, children with an idiopathic syrinx remained asymptomatic, stable, or improved in 91% of cases. The majority of syringes (87.5%) remained stable or shrank over time, with no apparent correlation between changes in size and changes in symptoms. Although longer follow-up is needed, these data suggest that the natural history of an idiopathic syrinx in children is benign, and that repeated imaging may not be necessary.