Spreading depolarisation and angiographic spasm are separate mediators of delayed infarcts

Abstract In DISCHARGE-1, a recent phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarisation variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (1) extravascular blood volumes, (2) predefined spreading depolarisation variables, or proximal vasospasm assessed by either (3) digital subtraction angiography or (4) transcranial Doppler-sonography; and whether spreading depolarisations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarisation variables, as our primary interest was to investigate spreading depolarisations. Standardised path coefficients (pc) were 0.22 for the path from extravascular bloodcomponent to depolarisationcomponent (P=0.010); and 0.44 for the path from depolarisationcomponent to the first principal component of delayed infarct volume (P<0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P=0.36). Thus, the role of spreading depolarisations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarisationcomponent as mediator (pc from bloodcomponent to depolarisationcomponent =0.23, P=0.03; pc from depolarisationcomponent to delayed infarctcomponent =0.29, P=0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (pc from intraventricular haemorrhage to vasospasmcomponent =0.24, P=0.03; pc from vasospasmcomponent to delayed infarctcomponent =0.35, P<0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarisations that trigger (1) neuronal cytotoxic oedema and (2) spreading ischaemia. The statistical mediator role of spreading depolarisation variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarisations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarisation-induced spreading ischaemia by reduced upstream blood supply.