Pathophysiology of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Review

William S Dodd, Dimitri Laurent, Aaron S Dumont, David M Hasan, Pascal M Jabbour, Robert M Starke, Koji Hosaka, Adam J Polifka, Brian L Hoh, Nohra Chalouhi, William S Dodd, Dimitri Laurent, Aaron S Dumont, David M Hasan, Pascal M Jabbour, Robert M Starke, Koji Hosaka, Adam J Polifka, Brian L Hoh, Nohra Chalouhi

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.

Keywords: delayed cerebral ischemia; intracranial aneurysm; stroke; subarachnoid hemorrhage.

Conflict of interest statement

None.

Figures

Figure 1. Vascular dysfunction after subarachnoid hemorrhage.
Figure 1. Vascular dysfunction after subarachnoid hemorrhage.
Transient global ischemia and free hemoglobin toxicity are the ultimate sources of vascular dysfunction leading to microthrombosis and vasospasm. Perturbation of the NO pathway is a pivotal mechanism connecting vascular dysfunction to inflammation and cortical spreading ischemia. The glymphatic system and meningeal lymphatic vessels are also emerging as a possible mediator of delayed cerebral ischemia. CBF indicates cerebral blood flow; CSF, cerebrospinal fluid; ICP, intracranial pressure; ROS, reactive oxygen species; SAH, subarachnoid hemorrhage; and SDs, spreading depolarizations.
Figure 2. Mechanisms of inflammatory response after…
Figure 2. Mechanisms of inflammatory response after subarachnoid hemorrhage.
Subarachnoid hemorrhage elicits an inflammatory response from resident CNS glia directly through TLR4 and CD163 receptor signaling. Reactive microglia then contribute to inflammatory cytokine production, vasospasm, and neuronal apoptosis. The endothelium of the cerebrovasculature also contributes to inflammation by recruiting circulating leukocytes. Neutrophils, monocytes, and lymphocytes all enter the CNS after SAH and promote vasospasm and inflammatory cytokine release. CD163 indicates cluster of differentiation 163; CNS, central nervous system; SAH, subarachnoid hemorrhage; and TLR4, toll‐like receptor 4.
Figure 3. Spreading depolarizations after subarachnoid hemorrhage…
Figure 3. Spreading depolarizations after subarachnoid hemorrhage and potential therapeutic targets.
Spreading depolarizations cause cerebral ischemia by increasing metabolic demand in injured tissue unable to compensate with increased perfusion. SAH itself also promotes the development of spreading depolarizations by the release of K+ and glutamate from extravasated erythrocytes and platelets. A couple of promising therapeutic agents to prevent spreading depolarizations/cortical spreading ischemia are ketamine and cilostazol. Ketamine works through inhibiting NMDA receptors and the propagation of spreading depolarizations. Cilostazol reduces ischemia by improving neurovascular response to depolarization. DCI indicates delayed cerebral ischemia; NMDA, N‐methyl‐D‐aspartate; and SAH, subarachnoid hemorrhage.

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