Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating stroke subtype with high morbidity and mortality, accounting for approximately 5% of all strokes. Despite advances in diagnosis and management, mortality remains high (35%, range 20-67%), and significant morbidity affects about 20% of survivors. Delayed cerebral ischemia (DCI), a feared complication, affects 20-40% of aSAH patients and is an independent predictor of poor prognosis. DCI is classically defined as new neurological deficits, impaired consciousness, or infarct on imaging starting 3-4 days post-bleed, peaking around 7-8 days. Earlier onset is linked to higher mortality and infarct load. Numerous treatment modalities targeting DCI's pathophysiological pathways have been studied, yet outcomes remain largely unchanged. The definition and pathophysiology of DCI have been extensively debated. While symptomatic vasospasm was once considered paramount, its lack of clear correlation with outcomes and the observation of DCI in patients with minimal vasospasm shifted focus to early brain injury (EBI) and its association with autoregulatory failure and neuroinflammation as primary contributors to DCI. This review will discuss the current understanding of the pathophysiological mechanisms of EBI and its relationship to DCI, clinical outcomes, and future research directions for improved aSAH management.

Several studies have explored risk factors for aSAH and DCI, including modifiable factors like smoking and pre-morbid diabetes mellitus, and non-modifiable factors such as female sex and poor-grade aSAH. Genetic studies have investigated the heritability of aSAH (estimated at 41%), identifying potential genetic variants and utilizing genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) to explore risk variants. However, results across different studies have been inconsistent, highlighting the complexities of gene-environmental interactions. One promising study revealed the angiogenic and pro-inflammatory gene neuregulin 1 (NRG1) as a predictor of DCI, while another identified hypermethylation of INSR and CDHR5 genes as significantly associated with reduced mRNA expression in DCI patients. The development of polygenic risk scores (PRS) shows promise for risk stratification, but further research is necessary to refine these scores and improve their clinical utility.

This is a review article, not an original research study. Therefore, there is no specific methodology section detailing data collection and analysis. The authors systematically reviewed existing literature on the pathophysiology of early brain injury (EBI) and its association with delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH). Their review synthesizes findings from numerous studies, including clinical trials, observational studies, and genetic analyses, to provide a comprehensive overview of the current understanding of this complex clinical problem. The authors utilized existing data from published research to explore the mechanisms of EBI and its connection to DCI, including the role of autoregulation, neuroinflammation, vasospasm, microthrombosis, and blood-brain barrier (BBB) breakdown. They reviewed the existing literature on various diagnostic tools, such as imaging techniques (CT, MRI, CT perfusion), physiological monitoring (brain tissue oxygenation [PbtO2], cerebral microdialysis), and clinical grading scales (Hunt and Hess, World Federation of Neurosurgical Societies [WFNS], Fisher scale, SEBES, VASOGRADE, HAIR). The authors assessed the predictive capabilities of each tool and the strengths and limitations of each scale. This approach allowed the authors to present the current consensus on the pathophysiology of aSAH complications, and highlight the need for further research focusing on EBI and microcellular mechanisms.

The review emphasizes the importance of early brain injury (EBI) as a key driver of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Large vessel vasospasm, once considered the primary mechanism, is now understood as one component of a multifactorial process. The initial insult (ictus) causes a surge in intracranial pressure (ICP), leading to decreased cerebral perfusion pressure (CPP) and transient global cerebral ischemia. This triggers a sympathetic catecholamine surge, causing further injury through endothelin activation, cytokine release, and systemic complications. EBI is characterized by impaired autoregulation, neuroinflammation, glutamate accumulation, and damage to the blood-brain barrier. Microthrombi formation from platelet aggregates contributes to microvascular dysfunction and ischemia. Cortical spreading depolarization leads to cytotoxic edema and neuronal cell death. The Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) has emerged as a valuable radiographic marker of EBI and predictor of DCI and poor outcomes. Volumetric analysis of global cerebral edema (GCE) also shows promise as a predictor of poor outcomes. Multimodal monitoring, including brain tissue oxygen (PbtO2), cerebral microdialysis, and electroencephalography (EEG), can aid in early detection of DCI and guide personalized management. However, results from invasive multimodal monitoring have shown some variability. Several clinical and radiological grading scales exist to predict DCI, but none fully incorporate the role of EBI. Genetic factors also play a significant role in susceptibility to aSAH and DCI, but further research is needed to identify and characterize these factors.

This review successfully highlights the shift in understanding of DCI pathophysiology from a primary focus on vasospasm to a more nuanced appreciation of the complex interplay of EBI and its associated mechanisms. The emphasis on EBI as a pivotal factor in DCI development and the subsequent focus on microcellular milieu changes provides crucial insights for future therapeutic strategies. The discussion of predictive models and advanced neuromonitoring techniques offers valuable tools for risk stratification and personalized treatment. The review underscores the limitations of current clinical and radiological scales, emphasizing the need for more comprehensive tools that integrate clinical, radiological, and biological data. The ongoing debate regarding the interpretation of multimodal monitoring data underscores the challenges in translating these technologies into routine clinical practice. The extensive review of the literature on genetic predisposition to aSAH and DCI highlights the complex interplay of genetic and environmental factors and demonstrates the need for larger, more comprehensive studies. The review successfully emphasizes the need for translational research to bridge the gap between preclinical findings and clinical applications.

This review comprehensively summarizes the current understanding of EBI's pathophysiology and its association with DCI after aSAH. The shift towards focusing on early brain injury and microcellular mechanisms, including impaired autoregulation, neuroinflammation, and microthrombosis, is significant. Advanced monitoring tools and predictive models are promising, yet further research is critical to develop more robust and reliable diagnostic tools and ultimately lead to improved outcomes for aSAH patients. Future research should concentrate on developing novel therapeutics targeting EBI and exploring the complexities of gene-environment interactions.

As a review article, this study is limited by the inherent biases and limitations of the studies included in the review. The quality and generalizability of the included studies may vary, and publication bias could influence the results. Furthermore, the lack of standardized methodologies across the reviewed studies may impact the synthesis of results. There is also a lack of consistently robust results in several areas, such as the predictive value of multimodal neuromonitoring, due to inconsistencies in methodology and interpretation. The review is limited by the current literature available at the time of writing, and further research is needed to clarify the roles of specific mechanisms in DCI development. Future studies should include larger sample sizes with more rigorous methodology and standardized measures to enhance the generalizability of the findings.