Pathophysiology of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Review

Abstract

Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.

Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Is There a Relevant Experimental Model? A Systematic Review of Preclinical Literature

“…The year of publication ranged from 1979 to 2020. Fifty-nine studies (76%) were published between 2,000 and 2020, 27 of which were published following the 2010 article that defined DCI ( 3 ). Fifty-three different teams were identified.…”

“…The current consensus suggests that the origin of DCI is a multifactorial and complex process. It not only includes the narrowing of cerebral arteries (i.e., vasospasm) but also the activation of others pathways, including a neuroinflammatory reaction that promotes perfusion mismatch with neurovascular uncoupling, as well as other pathological phenomena such as microthrombosis, cortical spreading depolarization and breakdown of the blood-brain barrier ( Figure 1 ) ( 2 , 3 ). All these local and systemic inflammatory responses are involved in the genesis and development of DCI.…”

Neutrophil Extracellular Trap Biomarker Titers and Delayed Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage

“…36,37 Whatever the immediate trigger of the inflammatory response to aSAH may be, the concept of NET-induced thrombus formation as a result of it is intriguing, as it provides a framework that links inflammation, thrombus formation, and DCI. 5,38 We found high levels of MPO-DNA complexes in all patients with aSAH, not only in those with DCI. While lower levels of MPO-DNA complexes have been measured in the general population 39 , the high levels in our study may reflect an overall inflammatory environment after aSAH, in line with high levels of C-reactive protein in all our patients.…”

“…3 Most DCI occurs 4 to 14 days after the initial hemorrhage and is strongly associated with poor outcome. 4,5 However, effective prediction and prevention measures of DCI are lacking. 5 While DCI development might be preceded by clinical deterioration, angiographic vasospasm, increase in transcranial doppler flow velocities, or electroencephalographic changes, DCI often occurs silently and is mostly identified in retrospect.…”

Adverse Events and Complications in Continuous Intra-arterial Nimodipine Infusion Therapy After Aneurysmal Subarachnoid Hemorrhage

“…Many survivors remain dependent on daily life activities. However, effective protective measures and adequate treatment for DCI are still the subject of research (4,5).…”