Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1 ^−/− ) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye–induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1 ^−/− mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B ₂ and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease α _IIb β ₃ activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5–13 mice/group or 7–10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (α _IIb β ₃ ) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) may be complicated by hydrocephalus in 6.5%–67% of cases. Some patients with aSAH develop shunt dependency, which is often managed by ventriculoperitoneal shunt placement. The objectives of this study were to review published risk factors for shunt dependency in patients with aSAH, determine the level of evidence for each factor, and calculate the magnitude of each risk factor to better guide patient management. METHODS: The authors searched PubMed and MEDLINE databases for Level A and Level B articles published through December 31, 2014, that describe factors affecting shunt dependency after aSAH and performed a systematic review and meta-analysis, stratifying the existing data according to level of evidence. RESULTS: On the basis of the results of the meta-analysis, risk factors for shunt dependency included high Fisher grade (OR 7.74, 95% CI 4.47–13.41), acute hydrocephalus (OR 5.67, 95% CI 3.96–8.12), in-hospital complications (OR 4.91, 95% CI 2.79–8.64), presence of intraventricular blood (OR 3.93, 95% CI 2.80–5.52), high Hunt and Hess Scale score (OR 3.25, 95% CI 2.51–4.21), rehemorrhage (OR 2.21, 95% CI 1.24–3.95), posterior circulation location of the aneurysm (OR 1.85, 95% CI 1.35–2.53), and age ≥ 60 years (OR 1.81, 95% CI 1.50–2.19). The only risk factor included in the meta-analysis that did not reach statistical significance was female sex (OR 1.13, 95% CI 0.77–1.65). CONCLUSIONS: The authors identified several risk factors for shunt dependency in aSAH patients that help predict which patients are likely to require a permanent shunt. Although some of these risk factors are not independent of each other, this information assists clinicians in identifying at-risk patients and managing their treatment.

Brain deformation models have proven to be a powerful tool in compensating for soft tissue deformation during image-guided neurosurgery. The accuracy of these models can be improved by incorporating intraoperative measurements of brain motion. We have designed and implemented a passive intraoperative stereo vision system capable of estimating the three-dimensional shape of the surgical scene in near real-time. This intraoperative shape is compared with the cortical surface in the co-registered preoperative magnetic resonance (MR) volume for the estimation of the cortical motion resulting from the open cranial surgery. The estimated cortical motion is then used to guide a full brain model, which updates a preoperative MR volume. We have found that the stereo vision system is accurate to within approximately 1 mm. Based on data from two representative clinical cases, we show that stereopsis guidance improves the accuracy of brain shift compensation both at and below the cortical surface.

OBJECT: This article introduces a classification scheme for extensive traumatic anterior skull base fracture to help stratify surgical treatment options. The authors describe their multilayer repair technique for cerebrospinal fluid (CSF) leak resulting from extensive anterior skull base fracture using a combination of laterally pediculated temporalis fascial-pericranial, nasoseptal-pericranial, and anterior pericranial flaps. METHODS: Retrospective chart review identified patients treated surgically between January 2004 and May 2014 for anterior skull base fractures with CSF fistulas. All patients were treated with bifrontal craniotomy and received pedicled tissue flaps. Cases were classified according to the extent of fracture: Class I (frontal bone/sinus involvement only); Class II (extent of involvement to ethmoid cribriform plate); and Class III (extent of involvement to sphenoid bone/sinus). Surgical repair techniques were tailored to the types of fractures. Patients were assessed for CSF leak at follow-up. The Fisher exact test was applied to investigate whether the repair techniques were associated with persistent postoperative CSF leak. RESULTS: Forty-three patients were identified in this series. Thirty-seven (86%) were male. The patients’ mean age was 33 years (range 11–79 years). The mean overall length of follow-up was 14 months (range 5–45 months). Six fractures were classified as Class I, 8 as Class II, and 29 as Class III. The anterior pericranial flap alone was used in 33 patients (77%). Multiple flaps were used in 10 patients (3 salvage) (28%)—1 with Class II and 9 with Class III fractures. Five (17%) of the 30 patients with Class II or III fractures who received only a single anterior pericranial flap had persistent CSF leak (p < 0.31). No CSF leak was found in patients who received multiple flaps. Although postoperative CSF leak occurred only in high-grade fractures with single anterior flap repair, this finding was not significant. CONCLUSIONS: Extensive anterior skull base fractures often require aggressive treatment to provide the greatest long-term functional and cosmetic benefits. Several vascularized tissue flaps can be used, either alone or in combination. Vascularized flaps are an ideal substrate for cranial base repair. Dual and triple flap techniques that combine the use of various anterior, lateral, and nasoseptal flaps allow for a comprehensive arsenal in multilayered skull base repair and salvage therapy for extensive and severe fractures.