CT perfusion based rCBF <38% volume is independently and negatively associated with digital subtraction angiography collateral score in anterior circulation large vessel occlusions

Abstract

Background

Collateral status (CS) is an important biomarker of functional outcomes in patients with acute ischemic stroke secondary to large vessel occlusion (AIS-LVO). Pretreatment CT perfusion (CTP) parameters serve as reliable surrogates of collateral status (CS). In this study, we aim to assess the relationship between the relative cerebral blood flow less than 38% (rCBF <38%), with the reference standard American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score (CS) on DSA.

Methods

In this prospectively collected, retrospectively reviewed analysis, inclusion criteria were as follows: (a) CT angiography (CTA) confirmed anterior circulation large vessel occlusion from 9/1/2017 to 10/01/2023; (b) diagnostic CT perfusion; and (c) underwent mechanical thrombectomy with documented ASITN CS. The ratios of the CTP-derived CBF values were calculated by dividing the values of the ischemic lesion by the corresponding values of the contralateral normal region (which were defined as rCBF). Spearman’s rank correlation and logistic regression analysis were performed to determine the relationship of rCBF <38% lesion volume with DSA ASITN CS. p ≤ .05 was considered significant.

Results

In total, 223 patients [mean age: 67.77 ± 15.76 years, 56.1% (n = 125) female] met our inclusion criteria. Significant negative correlation was noted between rCBF <38% volume and DSA CS (ρ = −0.37, p < .001). On multivariate logistic regression analysis, rCBF <38% volume was found to be independently associated with worse ASITN CS (unadjusted OR: 3.03, 95% CI: 1.60–5.69, p < .001, and adjusted OR: 2.73, 95% CI: 1.34–5.50, p < .01).

Conclusion

Greater volume of tissue with rCBF <38% is independently associated with better DSA CS. rCBF <38% is a useful adjunct tool in collateralization-based prognostication. Future studies are needed to expand our understanding of the role of rCBF <38% within the decision-making in patients with AIS-LVO.

Background

Acute ischemic stroke caused by large vessel occlusion (AIS-LVO) is associated with severe functional deficits and poor outcomes. The outcomes in patients with AIS-LVO not only depend on successful arterial recanalization following mechanical thrombectomy (MT) but also on the extent of distal vascular bed tissue reperfusion. ¹ The tissue reperfusion depends on a number of factors, one of them is the degree of collateral blood flow [or collateral status (CS)]. ²

Multiple scoring systems have been described to estimate the CS derived from single-phase CT angiogram (CTA), multi-phase CTA (mCTA), CT perfusion data, and digital subtraction angiography (DSA).^3–19 DSA derived 5-point American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASINT/SIR) scale is considered the reference standard test in quantifying CS.^20–22 DSA CS is an excellent marker in predicting the outcomes in AIS-LVO. However, DSA CS can only be assessed intraoperatively, which prevents pre-planning of the intervention. This limitation makes it important to have reliable pretreatment surrogate CS markers derived from readily available baseline imaging when trying to decide on the best treatment approach in individual patients.

Recently, Potreck et al. ²³ studied the performance of all CTP-derived markers including hypoperfusion intensity ratio (HIR), and the cerebral blood volume (CBV) index in estimating CS, and found that volume of brain parenchyma with relative cerebral blood flow less than 38% (rCBF <38%) best estimates good CS. However, this study used mCTA as the reference for CS as opposed to the reference standard DSA ASITN CS. ²³

In this study, we aim to investigate the relationship between rCBF <38% lesion volume as a pretreatment CTP CS marker with the reference standard DSA CS based on ASITN criteria, which has not been performed to date. We hypothesize that lower rCBF <38% lesion volume is associated with more robust CS on DSA.

Methods

Study design

Retrospective analysis of prospectively maintained stroke databases was performed, and we identified consecutive patients from two comprehensive stroke centers from 01 September, 2017 to 01 October, 2023 who met our inclusion criteria. This study was approved through the institutional review board and follows the STROBE checklist guidelines as an observational study. ²⁴

The study was conducted in accordance with the Declaration of Helsinki and the Health Insurance Portability and Accountability Act (HIPAA). Informed consent was waived by the institutional review boards given the retrospective study design. The decisions to administer IV thrombolysis and/or perform MT were made on an individual basis based on consensus stroke team evaluation per institutional protocols.

Data collection

Baseline and clinical data were collected through electronic records and stroke center databases for each patient including but not limited to demographics, site of occlusion, baseline CT parameters at first presentation, and outcome measures.

CTP image acquisition

Whole brain pretreatment CTP was performed on the Siemens Somatom Force (Erlangen, Germany) with the following parameters: 70 kVP, 200 effective mAs, rotation time 0.25 s, average acquisition time 60 s, collimation 48 × 1.2 mm, pitch value 0.7, and 4D range 114 mm × 1.5 s.

CTP source images were then post-processed using commercial RAPID perfusion software, version 5.2.2 (iSchemaView, Menlo Park, CA) to generate rCBF <38% lesion volume.

Imaging analysis

All the CTAs and CTPs were assessed by board certified neuroradiologists (9 years of working experience) for diagnostic adequacy and timing of contrast bolus, where only those deemed diagnostic adequate were included in the study. The volume of brain parenchyma in the territory of LVO rCBF <38% was derived from CTP data.

The DSA CS was independently assessed by a board certified neuroradiologist (9 years of working experience) and the performing neurointerventionalist. Any discrepancies were resolved based on consensus review. ASITN grades included: Grade 0: non-existing or barely visible pial collaterals on the ischemic site during any point of time; Grade 1, partial collateralization of the ischemic site until the late venous phase; Grade 2, partial collateralization of the ischemic site by the late venous phase; Grade 3, complete collateralization of the ischemic site by the late venous phase; and Grade 4, complete collateralization of the ischemic site before the venous phase.^20–22

The ratios of the CTP-derived CBF values were calculated by dividing the values of the ischemic lesion by the corresponding values of the contralateral normal region (which were defined as rCBF). Good rCBF <38% was defined as <27 mL, ²³ and good ASITN CS was defined as 3 or greater.^20–22

Statistical analysis

The objective of this study is to assess the relationship between rCBV <42% lesion volume with follow-up volume. Categorical data was described using contingency tables including counts and percentages; continuous variables were summarized with mean (± standard deviation). A student t test was used in the data analysis for continuous variables, the Mann–Whitney U test was used in the data analysis for ordinal data, and the chi square test was used for categorical data.

Spearman’s rank correlation coefficient was used to assess correlation between the volume of tissue with rCBF <38% lesion volume and DSA ASITN CS.

The outcome measure of DSA CS was dichotomized into a nominal variable for logistic regression analysis as poor DSA CS (ASITN 0–2) and robust DSA CS (ASITN 3–4). The univariable and multivariable logistic regression models were used to estimate the relationship between rCBF <38% lesion volume with DSA ASITN CS. The multivariable logistic regression model considered confounding variables: age, sex, admission Alberta Stroke Program Early CT Score (ASPECTS), administration of intravenous tissue-type plasminogen activator (IV tPA), premorbid modified Rankin Scale (mRS), admission national institute of health stroke scale (NIHSS), prior history of transient ischemic attack or stroke, atrial fibrillation, diabetes mellitus, hyperlipidemia, heart disease, and hypertension. The outcomes were reported as unadjusted and adjusted odds ratio (OR), 95% confidence interval, and p value. Statistically significant analysis was described as p ≤ .05, p < .01, and p < .001.

Results

A total of 223 consecutive patients, mean age of study population was 67.77 ± 15.76 years, and 125 (56.05%) females met our inclusion criteria. In total, 80 (35.87%) patients received intravenous tissue plasminogen activator administered (IV tPA).

Of 223 patients, 162 (72.65%) had M1 occlusion, 45 (20.18%) had proximal M2 occlusion, and 16 (7.17%) had distal ICA occlusion. Patient demographic and stroke treatment details are presented in Table 1.

Table 1.

Demographics of study participants.

Study demographics	Total (n = 223)	DSA ASITN CS (0–2) (n = 151)	DSA ASITN CS (3–4) (n = 72)	p value
Age in years (mean ± standard deviation)	67.77 ± 15.76	68.17 ± 15.90	66.93 ± 15.53	.583
Sex [numbers (%)]				.636
Female	125 (56.05%)	83 (54.97%)	42 (58.33%)
Male	98 (43.95%)	68 (45.03%)	30 (41.67%)
Race [numbers (%)]				.268
African American	90 (40.36%)	62 (41.06%)	28 (38.89%)
Caucasian	117 (52.47%)	78 (51.66%)	39 (54.17%)
Asian	7 (3.14%)	3 (1.99%)	4 (5.56%)
Other	9 (4.04%)	8 (5.30%)	1 (1.39%)
Prior history of stroke or transient ischemic attack [numbers (%)]	44 (19.73%)	29 (19.21%)	15 (20.83%)	.775
Admission NIH stroke scale (mean ± standard deviation)	15.65 ± 6.82	16.30 ± 6.82	14.29 ± 6.66	.040*
Premorbid modified Rankin score (mRS) (mean ± standard deviation)	0.63 ± 1.07	0.55 ± 1.02	0.80 ± 1.14	.105
Admission Alberta stroke program early CT score (ASPECTS) (mean ± standard deviation)	8.64 ± 1.86	8.43 ± 2.03	9.07 ± 1.30	.005*
Intravenous tissue plasminogen activator administered (IV tPA) [numbers (%)]	80 (35.87%)	51 (33.77%)	29 (40.28%)	.344
Segment occlusion [number (%)]				<.001*
Supraclinoid internal carotid artery	16 (7.17%)	14 (9.27%)	2 (2.78%)
Middle cerebral artery, M1 segment	162 (72.65%)	122 (80.79%)	40 (55.56%)
Middle cerebral artery, proximal M2 segment	45 (20.18%)	15 (9.93%)	30 (41.67%)
rCBF <38%	31.30 ± 36.78	37.80 ± 39.44	17.67 ± 25.74	<.001*

Statistically significant difference was assessed using unpaired student t test for continuous variables and chi square test for categorical variables. Statistically significant results are highlighted with asterisks*.

There was significant negative correlation between the volume of tissue with rCBF<38% and DSA CS (ρ = −0.37, p < .001). Statistically significant higher mean volume of tissue with rCBF <38% was found in patients with poor DSA CS (mean = 37.80 ± 39.44), compared to patients with robust DSA CS (mean = 17.67 ± 25.74) (Figure 1).

Figure 1.

Box and whisker plot distribution of rCBF <38% lesion volume (in ml) in patients with poor DSA CS of 0–2 and robust DSA CS of 3 or greater. Box plot represents median and interquartile range, whereas whiskers represent minimum and maximum values. Statistically significant difference was present between mean rCBF <38% in patients with poor DSA CS (mean = 37.80 ± 39.44), and patients with robust DSA CS (mean = 17.67 ± 25.74).

Univariable logistic regression analysis of volume of rCBF <38% with poor DSA CS showed unadjusted OR of 3.03 (95% CI: 1.60–5.69, p < .001) (Table 2).

Table 2.

Multivariate logistic regression model in predicting good collateral status as defined by DSA ASITN CS of 3 or greater.

Variables	Univariate analysis unadjusted odds ratio [OR (95% confidence interval)]	Multivariate logistic regression analysis
		Adjusted OR	95% confidence interval		p value
			Lower	Upper
rCBF <38% lesion volume of <27 mL)	3.03 (1.60–5.69)	2.73	1.351	5.502	<.01
Age	0.99 (0.97–1.00)	0.991	0.968	1.013	.42
Sex	0.80 (0.50–1.30)	0.982	0.517	1.865	.956
Race	0.99 (0.72–1.40)	0.880	0.558	1.387	.582
Hypertension	0.74 (0.41–1.27)	0.622	0.290	1.337	.224
Hyperlipidemia	1.04 (0.65–1.70)	1.068	0.566	2.015	.839
Diabetes mellitus	1.15 (0.68–2.00)	1.001	0.481	2.083	.998
Heart disease	1.00 (0.63–1.64)	0.890	0.441	1.798	.745
Atrial fibrillation	1.17 (0.72–1.91)	1.375	0.659	2.866	.396
Prior stroke or transient ischemic attack	1.06 (0.59–1.91)	0.986	0.457	2.128	.971
Intravenous tissue plasminogen activator administered (IV tPA)	1.23 (0.76–2.03)	1.323	0.697	2.512	.392
Admission NIH stroke scale	0.96 (0.93–0.98)	0.965	0.919	1.014	.161
Premorbid modified Rankin score (mRS)	1.17 (0.94–1.46)	1.317	0.967	1.792	.080

On multivariable logistic regression analysis accounting for age, sex, admission ASPECTS, administration of tPA, premorbid mRS, admission NIH stroke scale, prior history of TIA or stroke, atrial fibrillation, diabetes mellitus, hyperlipidemia, heart disease, and hypertension, good rCBF <38% was found to be independently associated with good DSA ASITN CS with adjusted OR: 2.73 (95% CI: 1.34–5.50, p < .01) (Table 2).

Discussion

Our study demonstrates that volume of tissue with rCBF <38% is independently associated with poor DSA ASITN CS. This is the first study exploring associations of volume of rCBF <38%, as a baseline CTP CS parameter, with DSA CS.

Recently, Potreck et al. ²³ reported that amongst all CTP markers, volume of rCBF <38% best estimated the CS in anterior circulation AIS-LVO cases. rCBF <38% was better associated with CS compared to CTP-derived CBV index and HIR. It is important to note that in this study, authors used mCTA CS ²⁵ as reference standard. They also used the CTP data to calculate this score, which would theoretically overestimate the association as the test variables and outcomes are derived from the same source data. Hence, we conducted this study to assess the association of volume of rCBF <38% with reference standard DSA ASITN CS with a comparable sample size. Our study shows that volume of rCBF <38% has significant negative correlation with DSA CS (ρ = −0.37, p < .001), and furthermore was independently associated with reference standard ASITN CS (adjusted OR: 2.73, 95% CI: 1.34–5.50, p < .01). The correlation coefficient is smaller than what was reported by Potreck et al. ²³ (ρ = −0.66, p < .001), which is attributable to their study limitations of using the same source data to derive their testing variables and outcome measures, and considering mCTA CS as their reference standard. Even though studies have reported significant correlations between mCTA CS and DSA ASITN CS,^26–28 mCTA CS is not considered as the reference standard in estimating CS. Nevertheless, our findings further validate that volume of tissue with rCBF <38% less than 27 mL indicates good CS. rCBF quantifies the velocity of blood flow within the infarct core, relative to normal contralateral side, and hence potentially estimates the collateral blood flow.^23,29

In our study cohort 151 (67.71%) cases had poor DSA CS, and this distribution is similar to the distribution reported in the literature.^27,30 As expected, patients with good DSA CS had significantly lower NIH stroke scale (mean: 14.29 ± 6.66 vs 16.30 ± 6.82, p < .001) and had higher premorbid modified Rankin score (mRS ³¹ ) (0.80 ± 1.14 vs 0.55 ± 1.02, p > .05). Furthermore, robust DSA CS had a higher Alberta stroke program early CT score (ASPECTS ³² ) (mean: 8.43 ± 2.03 vs 9.07 ± 1.30, p < .01) (Table 1).

There are certain limitations to this study. First, DSA CS has a modest inter- and intra-observer agreement. ³³ Third, volume of tissue with rCBF <38% derived using CTP data may not be accessible to smaller stroke centers and centers that may forego CTP for MT eligibility, particularly in the setting of large cores. ³⁴ Nevertheless, a large sample size of 223 patients derived from two comprehensive stroke centers is the strength of this study.

Our results further validate the role of volume of tissue rCBF<38% in estimating CS, and that it can be used as an adjunct marker in complex AIS-LVO cases where decision is more nuanced. Future studies are needed to expand our understanding of the adjunct role of rCBF <38% with other similar pretreatment imaging-based markers in clinical evaluation and decision-making in patients with AIS-LVO.

Appendix.

Abbreviations

AIS

Acute ischemic stroke

ASPECTS

Alberta stroke program early CT score

DSA

Digital subtraction angiography

CS

Collateral status

rCBF <38%

Relative cerebral blood flow less than 38%

tPA

Tissue plasminogen activator

LVO

Large vessel occlusion

mRS

Modified Rankin score

mCTA

Multi-phase CT angiogram

NIHSS

National institute of health stroke scale

MT

Mechanical thrombectomy

ORCID iDs

Dhairya A Lakhani https://orcid.org/0000-0001-7577-1887

Manisha Koneru https://orcid.org/0000-0001-5012-6793

Burak Berksu Ozkara https://orcid.org/0000-0002-8769-3342

Licia Luna https://orcid.org/0000-0003-3539-4831

Vivek S Yedavalli https://orcid.org/0000-0002-2450-4014