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      Neuroinflammation as a Target for Intervention in Subarachnoid Hemorrhage

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          Abstract

          Aneurysmal subarachnoid hemorrhage (SAH) is a sub-type of hemorrhagic stroke associated with the highest rates of mortality and long-term neurological disabilities. Despite the improvement in the management of SAH patients and the reduction in case fatality in the last decades, disability and mortality remain high in this population. Brain injury can occur immediately and in the first days after SAH. This early brain injury can be due to physical effects on the brain such as increased intracranial pressure, herniations, intracerebral, intraventricular hemorrhage, and hydrocephalus. After the first 3 days, angiographic cerebral vasospasm (ACV) is a common neurological complication that in severe cases can lead to delayed cerebral ischemia and cerebral infarction. Consequently, the prevention and treatment of ACV continue to be a major goal. However, most treatments for ACV are vasodilators since ACV is due to arterial vasoconstriction. Other targets also have included those directed at the underlying biochemical mechanisms of brain injury such as inflammation and either independently or as a consequence, cerebral microthrombosis, cortical spreading ischemia, blood–brain barrier breakdown, and cerebral ischemia. Unfortunately, no pharmacologic treatment directed at these processes has yet shown efficacy in SAH. Enteral nimodipine and the endovascular treatment of the culprit aneurysm, remain the only treatment options supported by evidence from randomized clinical trials to improve patients’ outcome. Currently, there is no intervention directly developed and approved to target neuroinflammation after SAH. The goal of this review is to provide an overview on anti-inflammatory drugs tested after aneurysmal SAH.

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          Most cited references106

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          Spontaneous subarachnoid haemorrhage

          Subarachnoid haemorrhage is an uncommon and severe subtype of stroke affecting patients at a mean age of 55 years, leading to loss of many years of productive life. The rupture of an intracranial aneurysm is the underlining cause in 85% of cases. Survival from aneurysmal subarachnoid haemorrhage has increased by 17% in the past few decades, probably because of better diagnosis, early aneurysm repair, prescription of nimodipine, and advanced intensive care support. Nevertheless, survivors commonly have cognitive impairments, which in turn affect patients' daily functionality, working capacity, and quality of life. Additionally, those deficits are frequently accompanied by mood disorders, fatigue, and sleep disturbances. Management requires specialised neurological intensive care units and multidisciplinary clinical expertise, which is better provided in high-volume centres. Many clinical trials have been done, but only two interventions are shown to improve outcome. Challenges that remain relate to prevention of subarachnoid haemorrhage by improved screening and development of lower-risk methods to repair or stabilise aneurysms that have not yet ruptured. Multicentre cooperative efforts might increase the knowledge that can be gained from clinical trials, which is often limited by small studies with differing criteria and endpoints that are done in single centres. Outcome assessments that incorporate finer assessment of neurocognitive function and validated surrogate imaging or biomarkers for outcome could also help to advance the specialty.
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            Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis

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              Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group.

              In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/538836
                URI : https://frontiersin.org/people/u/528970
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                02 May 2018
                2018
                : 9
                : 292
                Affiliations
                [1] 1Adult Critical Care Unit, Hospital Paulistano – United Health Group , São Paulo, Brazil
                [2] 2Keenan Research Center for Biomedical Science, Department of Surgery, Li Ka Shing Knowledge Institute, University of Toronto , Toronto, ON, Canada
                [3] 3Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, Department of Surgery, Li Ka Shing Knowledge Institute, University of Toronto , Toronto, ON, Canada
                Author notes

                Edited by: Fernando Testai, University of Illinois at Chicago, United States

                Reviewed by: Adel Helmy, University of Cambridge, United Kingdom; Elisa R. Zanier, Istituto Di Ricerche Farmacologiche Mario Negri, Italy

                *Correspondence: Airton Leonardo de Oliveira Manoel, airtonleo.manoel@ 123456gmail.com

                Specialty section: This article was submitted to Neurocritical and Neurohospitalist Care, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2018.00292
                5941982
                29770118
                ae2133ac-edd9-445e-b094-13cf24fa5027
                Copyright © 2018 de Oliveira Manoel and Macdonald.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 February 2018
                : 16 April 2018
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 102, Pages: 12, Words: 8819
                Categories
                Neuroscience
                Review

                Neurology
                neuroinflammation,subarachnoid hemorrhage,early brain injury,secondary brain injury,vasospasm,delayed cerebral ischemia

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