Inflammation: a Good Research Target to Improve Outcomes of Poor-Grade Subarachnoid Hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disease [1] and should be treated as a systemic disorder needing intensive care, not merely as an intracranial disorder, especially in poor-grade SAH patients [2]. Aging and poorer admission clinical grade are the most important predictors of poor outcomes [3]. In our recent series treated with early aneurysmal obliteration by endovascular coiling or surgical clipping, SAH patients over age 75 had 3month modified Rankin scales 3–6 (poor outcomes) in 73.1% of cases with admission World Federation of Neurological Surgeons (WFNS) grades I–III and in 77.4% of cases with admission WFNS grades IV–V (poor grade), while SAH patients under age 75 had 3-month poor outcomes only in 13.1% of cases with admission WFNS grades I–III but still in 59.3% of cases with admission WFNS grades IV–V (unpublished data). All acute SAH patients with > 10mm ischemic brain lesion on diffusion-weighted magnetic resonance imaging or prolonged mean transit time > 6.385 s in the whole brain on computed tomography perfusion may have irreversible brain damage and resulted in poor outcomes irrespective of any treatment including cerebrospinal fluid drainage and decompressive craniectomy to control intracranial pressure in addition to early aneurysmal obliteration [4, 5]. The other patients with WFNS grade V had poor outcomes in 70–80%, even though the maximal treatment was undergone [4–6]; however, it should be noticed that no treatment caused poor outcomes in all grade V patients [6]. There are poor evidence and no guidelines available for the treatment of poor-grade SAH patients. From a basic research point of view, admission poor clinical grade indicates that severe early brain injury (EBI) is arising at admission and possibly leads to poor outcomes directly or associated with delayed cerebral ischemia [1]. Although EBI is multifactorial and includes multiple pathologies including neuroinflammation [7], oxidative stress [8], neuronal apoptosis [9], blood-brain barrier disruption [10], microvascular constriction, andmicrothrombi [11], the pathologies may interact with each other. Delayed cerebral ischemia may be caused by cerebral vasospasm, cortical spreading depolarization, and microcirculatory dysfunction [12], which may occur secondary to EBI [13]. Although cerebral vasospasm remains an important cause of delayed cerebral ischemia [14], microcirculatory disturbance and cortical spreading depolarization may be more important than cerebral vasospasm as to the impact on functional outcomes especially in poor-grade SAH patients [15]. Thus, many basic researchers have worked hard to overcome EBI, which is believed eventually to improve outcomes of poor-grade SAH patients. It is no doubt that an abrupt elevation of intracranial pressure by a rupture of cerebral aneurysm is an essential trigger of the development of EBI. Even though the amount and distribution of blood in the subarachnoid space are similar, an abrupt increase in intracranial pressure disrupts cerebral perfusion associated with early, pronounced, and sustained disruption of cerebral autoregulation as well as neuronal damage, possibly leading to more severe EBI and poorer outcomes [16]. Severe SAH induced glial and endothelial injuries contributing to increased blood-brain barrier permeability immediately after SAH by endovascular perforation in rats [17]. Severe SAH-induced intracranial pressure elevation and brain injury also activate the sympathetic nervous system, release catecholamines, and induce systemic inflammation and extracerebral organs injury [18]. In endovascular perforation SAH models using adhesion molecule knockout mice, it was demonstrated that SAH resulted in early intravascular inflammation with the recruitment of circulating neutrophils to the vessel/brain interface and that the inhibition of neutrophilendothelial interaction prevented systemic inflammation from accumulating and activating microglia to cause neuronal cell death [19]. Extravasated blood components such as thrombin, platelets, and leukocytes also activate microglia, which is an * Hidenori Suzuki [email protected]