BackgroundAneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients.MethodSAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients.ResultsFollowing SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes.ConclusionSAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.

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Brain arteriovenous malformations (AVMs) are a heterogeneous group of rare lesions that can pre sent with headaches, seizures, neurological deficits, and intracranial hemorrhages. Risks of hemorrhage have been estimated in the range of 2%-4% per year. 8,15,32,47 Risk factors for future ruptures have been identified, but their use to inform decision making is errorprone, given the methodological problems with AVM observational studies and the modest relative risks. The comments were categorized as items related to the design, the conduct, and the analysis and interpretation of the trial. results Thirty-one articles or letters were identified. The pragmatic design, with heterogeneity of patients and lack of standardization of the treatment arm, were frequently stated concerns. The choice of outcome measures was repeatedly criticized. During the trial, low enrollment rates, selection bias, and premature interruption of enrollment were frequent comments. The short follow-up period, the lack of subgroup analyses, the lack of details on the results of the various treatments, and a contentious interpretation of results were noted at the analysis stage. A fundamental problem was the primary hypothesis testing conservative management. The authors believe that other trials are needed. Future trials could be pragmatic, test interventions stratified at the time of randomization, and look for long-term, hard clinical outcomes in a large number of patients. coNclusioNs In the authors' view, the ARUBA trial is a turning point in the history of brain AVM management; future trials should aim at integrating trial methodology and clinical care in the presence of uncertainty.