Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need

Abstract

Background-Delayed cerebral ischemia (DCI) is among the most dreaded complications following aneurysmal subarachnoid hemorrhage (SAH). Despite advances in neurocritical care, DCI remains a significant cause of morbidity and mortality, prolonged intensive care unit and hospital stay, and high healthcare costs. Large artery vasospasm has classically been thought to lead to DCI. However, recent failure of clinical trials targeting vasospasm to improve outcomes has underscored the disconnect between large artery vasospasm and DCI. Therefore, interest has shifted onto other potential mechanisms such as microvascular dysfunction and spreading depolarizations. Animal models can be instrumental in dissecting pathophysiology, but clinical relevance can be difficult to establish.Methods-Here, we performed a systematic review of the literature on animal models of SAH, focusing specifically on DCI and neurological deficits.Results-We find that dog, rabbit and rodent models do not consistently lead to DCI, although some degree of delayed vascular dysfunction is common. Primate models reliably recapitulate delayed neurological deficits and ischemic brain injury; however, ethical issues and cost limit their translational utility.Conclusions-To facilitate translation, clinically relevant animal models that reproduce the pathophysiology and cardinal features of DCI after SAH are urgently needed.

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

“…GCaMP mice) or invasive electrophysiology [36][37][38][39] It is worth commenting on our choice of a mouse model. There are several mouse models of subarachnoid hemorrhage [40,41]; however, a perfect SAH model does not exist and there is not yet a consensus about which model to use for each experimental condition [42]. We chose to base our study on the anterior prechiasmatic injection model which recapitulates early brain injury, leads to early elevations in ICP, and results in a significant clot burden at the base of the skull [9].…”

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

“…For induction of SAH, we used the anterior prechiasmatic injection approach. 9,10 There are several mouse models of subarachnoid hemorrhage 11,12 ; however, a perfect SAH model does not exist and there is not yet a consensus about which model to use for each experimental condition. 13 We based our study on the anterior prechiasmatic injection model because it recapitulates early brain injury, leads to early elevations in ICP, and results in a significant clot burden at the base of the skull.…”

Proposed Definition of Experimental Secondary Ischemia for Mouse Subarachnoid Hemorrhage

“…A recent literature review suggests that animal models, with the exception of primates, do not fully recapitulate the progression of DCI in humans [27]. Especially delayed/ secondary neurological deficits were not detected in most mice, dog, rat, or rabbit models, but the incidence in primate models was similar to the incidence of delayed cerebral ischemia in humans.…”

“…Especially delayed/ secondary neurological deficits were not detected in most mice, dog, rat, or rabbit models, but the incidence in primate models was similar to the incidence of delayed cerebral ischemia in humans. The majority of animal models could not faithfully reproduce a pathophysiological situation, which was severe enough to cause infarction, regardless of the method and species [27]. Similarly, the mean overall mortality rate in experimental mouse models of aSAH is significantly lower than the reported human case fatality [11].…”