Houman Khosravani, MD, PhD

Vagal A, Aviv R, Sucharew H, Reddy M, Hou Q, Michel P, et al. Collateral Clock Is More Important Than Time Clock for Tissue Fate: A Natural History Study of Acute Ischemic Strokes. Stroke. 2018

“We hold these truths to be self-evident” is stated in the Declaration of Independence, and some say that with the passage of time, all becomes self-evident. Thus, what is the impact of time, and what is the truth behind the function and abundance of collateral circulation? These answers are critical to the late-window management of acute stroke. The topic will be one that keeps on giving, and an important contribution to this topic comes from a recent paper by Vagal et al.

In both early and extended time-windows brought about by DAWN and DEFUSE 3, the presence and functional capacity of robust collaterals has become uniquely important. The ischemic penumbra can persist for prolonged periods of time (up to 48 hrs), and its survival rests in part with the collateral circulation. The ability to assess this important aspect of tissue health is key in the evolution of thinking that is taking place: a move from time-window to tissue-health window. At the forefront of this assessment is perfusion imaging — in the case of this research, using CT perfusion. Understanding how time affects the natural history of the penumbra stands to inform assessment and decision-making in the era of EVT for patients within 24 hrs of symptom onset. Vagal et al. explore time from stroke onset and infarct growth in untreated acute ischemic stroke patients within this time window with the purpose of understanding how collaterals affect this evolution. However, it is important to note that data in this study were collected in the era of TPA first up to 3 hrs, then up to 4.5 hrs, and IA-TPA up to six hours (spanning 2003-2011) — thus, prior to the current EVT era. Nonetheless, patients who met inclusion criteria did not receive any therapy allowing for assessment of the penumbra’s natural history.

In a multicenter, retrospective study involving four institutions, CT/CTA/CTP images were reviewed as collected in the first 24 hrs, subsequent 24-48 hrs, and within 5 days (CT or MRI) for the Final Infarct Volume (FIV). The presence of collaterals and penumbra salvaged in these untreated patients was assessed: penumbra salvage being FIV subtracted from baseline penumbral volume, and infarct growth being the quantity calculated by subtracting baseline core volume from FIV. Of the 110 patients meeting inclusion criteria, 94 had adequate perfusion imaging with most of the occlusions being in the M1, followed by the ICA, with a median NIHSS of 13, ASPECTS 7; 51% spontaneously recanalized.

No correlation was detected between time of imaging from stroke onset and salvaged penumbra or between time and infarct growth. 61% of patients had good CTA collaterals of varying degree and 39% had poor collaterals. Penumbral salvage was lower in patients with poor collaterals. No interaction was found between collateral status and time in association with infarct growth or penumbral salvage. In patients with LVO, as with others, lack of correlation between time and penumbral salvage and infarct growth persisted. Recanalization status did not impact collateral scores, penumbral salvage, and infarct growth. Overall, however, better collaterals were associated with larger penumbral salvage and decreased infarct growth. Spontaneous recanalized patients did better.

This study adds to the growing body of work that suggests collaterals and reperfusion success are heavier weighted variables in saving the penumbra rather than time from onset to reperfusion. The pace and degree of infarct appears to largely depend on collaterals, but it is important to note, and pointed out by the authors, that this interaction is complex and dynamic. Thus emerges the concept of “collateral clock” (and by corollary — collateral structure and function), which may be oversimplified by time alone.

This research has important relevance to the extended time windows because collateral status is not a primary concern in perfusion-based selection for EVT within 24 hrs. Taken together, better assessment, consideration, and quantification of collaterals during the triage phase will be beneficial in selecting patients who should undergo EVT … only becoming more evident with the passage of time.