Early Brain Injury After Subarachnoid Hemorrhage: Incidence and Mechanisms

Abstract

Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.

Keywords: aneurysm; secondary brain injury; stroke; subarachnoid hemorrhage.

Figure 1.

Characteristic secondary disturbances mediated by pathways that occur during the EBI period and lead to loss of neuronal integrity. Major mediators of each process are outlined. Several mediators function in producing the phenotypes of EBI through multiple mechanisms and are listed on separate pathways. NFkB = Nuclear factor kappa B, TLR-4 = Toll-like receptor 4, iNOS = Inducible nitric oxide synthase, NLRP3 = NLR family pyrin domain containing 3, Bcl2/Bax = B-cell lymphoma 2/Bcl-2-associated X protein, PI3k/Akt = Phosphoinositide 3-kinase/Akt, AIM2 = Absent in melanoma 2, eNOS = Endothelial nitric oxide synthase, L-type VDCC = L-type voltage dependent calcium channel, CaSR = Calcium-sensing receptor, H2S = Hydrogen sulfide, AQP4 = Aquaporin-4, HIF-1a = Hypoxia inducible factor 1 subunit alpha, VEGF = Vascular endothelial growth factor, MMP-9 = Matrix-metalloproteinase-9, ZO-1 = Zonula occludens-1, TREM-1 = Triggering receptor expressed on myeloid cells-1, Figure created using Biorender.com.

Figure 2.

MMP-9 stimulation in EBI leads to the degradation of ZO-1 and other components of the ECM, causing disruption of the BBB and allowing unregulated paracellular movement. Figure created using Biorender.com.

Figure 3.

Hemorrhagic blood products stimulate neuroinflammation through TLR-4 signaling, which occurs in a MyD88-dependent manner early in EBI and a TRIF-dependent manner later in EBI. Figure created using Biorender.com.

Figure 4.

Polarization of M0 to the M1 phenotype is mediated by numerous signaling molecules associated with neuroinflammation, while IL-4 primarily mediates polarization to the M2 phenotype. Figure created using Biorender.com.