Capillary Index Score and Correlation with Outcomes in Acute

Ischemic Stroke: a Meta-analysis

Manoj Jagani, Waleed Brinjikji, Mohammad H. Murad, Alejandro A. Rabinstein, Harry J. Cloft, and
David F. Kallmes

Abstract
Background and PurposeThe capillary index score (CIS) has been recently introduced as a metric
for rating the collateral circulation of ischemic stroke patients. Multiple studies in the last five years have
evaluated the correlation of good CIS with clinical outcomes and suggested the use of CIS in selecting
patients for endovascular treatment. We performed a meta-analysis of these studies comparing CIS with
Journal of Vascular and Interventional Neurology, Vol. 9

clinical outcomes.
MethodsWe conducted a computerized search of three databases from January 2011 to November 2015
for studies related to CIS and outcomes. A CIS = 0 or 1 is considered poor (pCIS) and a CIS = 2 or 3 is
considered favorable (fCIS). Using random-effect meta-analysis, we evaluated the relationship of CIS to
neurological outcome (modified Rankin scale score 2), recanalization, and post-treatment hemorrhage.
Meta-regression analysis of good neurological outcome was performed for adjusting baseline National
Institutes of Health Stroke Scale (NIHSS) between groups.
ResultsSix studies totaling 338 patients (212 with fCISs and 126 with pCISs) were included in the anal-
ysis. Patients with fCIS had higher likelihood of good neurological outcome [relative risk (RR) = 3.03; con-
fidence interval (CI) = 95%, 2.054.47; p < 0.001] and lower risk of post-treatment hemorrhage (RR =
0.38; CI = 95%, 0.190.93; p = 0.04) as compared with patients in the pCIS group. When adjusting for
baseline NIHSS, patients with fCIS had higher RR of good neurological outcome when compared with
those with pCIS (RR = 2.94; CI = 95%, 1.237, p < 0.0001). Favorable CIS was not associated with higher
rates of recanalization.
ConclusionsObservational evidence suggests that acute ischemic stroke patients with fCIS may have
higher rates of good neurological outcomes compared with patients with pCIS, independent of baseline
NIHSS. CIS may be used as another tool to select patients for endovascular treatment of acute ischemic
stroke.

Introduction
The degree of collateral circulation has been identified
as a major factor in determining the outcomes of acute
ischemic stroke secondary to large vessel occlusion [1].
Adequate collateral blood flow mitigates infarct growth
and post-treatment hemorrhage and increases the likeli-
hood of recanalization and reperfusion [27]. Many
studies have shown that the presence of good collaterals
is associated with good clinical outcome [5,6,814].
The capillary index score (CIS) has recently been pro-
posed as a method of rating the collateral circulation of
acute ischemic stroke patients [9]. CIS was suggested to
improve patient selection for endovascular treatment,
and it is thought to be a reliable predictor of patients
who will achieve a good clinical outcome following
endovascular treatment [8]. Several studies have been
published in the last five years for evaluating the useful-
ness of the CIS and its correlation with clinical out-
comes [813]. However, the relatively small individual
study sizes and the still small number of studies limit the
ability of clinicians to determine the practicality of CIS
in patient selection or as a predictor of outcomes. Due to
these pitfalls, we performed a systematic review and a
meta-analysis of studies that evaluated CIS in relation to
outcomes in patients undergoing intra-arterial therapy
for acute ischemic stroke.

Vol. 9, No. 3, pp. 713. Published January, 2017.

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Journal of Vascular and Interventional Neurology, Vol. 9
Figure 1. Quantification of the Cis. in each image, the ischemic area is divided into three sectors. Sectors with no capil-
lary blush: 0. Sectors showing capillary blush: 1. Patient in (a) receives a Cis = 1. Patient in (b) receives a Cis = 2.
Patient in (c) receives a Cis = 3. Adapted from [11].
Methods
Literature Search
To identify comparative studies on the CIS and out-
comes, an experienced librarian searched the three data-
bases Ovid EMBASE, Ovid MEDLINE and Web of Sci-
ence for articles from January 2011 to November 2015.
The keywords capillary index score, mechanical throm-
bectomy, stroke, acute ischemic stroke, collaterals, and
outcome were used for the search. Both published
manuscript and abstract presentations were included in
the search. After the initial search was complete, the ref-
erences of the identified articles were assessed to find
any other relevant articles.
The initial studies were, then, further evaluated by two
authors for inclusion in the meta-analysis. The inclusion
criteria were the following: 1) studies properly assigning
CISs as described by Al-Ali et al. [9], 2) studies com-
paring CISs with some relevant clinical outcomes
between two separate groups (i.e., favorable CIS and
unfavorable CIS), 3) studies reporting separate outcome
data for the two groups, and 4) studies with 20 or more
patients. Favorable CIS was defined as a CIS of 2 or 3,
and unfavorable CIS was defined as a CIS of 0 or 1.
Studies were excluded if they: 1) did not stratify out-
comes by CIS or 2) had less than 20 patients.
Capillary Index Score
The CIS was initially described by Al-Ali et al. as a
method to evaluate the adequacy of collateral flow in the
ischemic area [9]. CIS assumes that capillary blush on a
cerebral angiogram indicates viable tissue. The CIS is
used only in cases of intra-cerebral internal carotid
8
artery or M1 branch of the middle cerebral artery occlu-
sions. To determine the CIS on a digitally subtracted
angiogram, the bilateral common carotid arteries and the
dominant vertebral artery are injected and assessed
through the venous phase for capillary blush. The ische-
mic area is divided into three equal parts, and each part
is given a score of 0 or 1. A score of 0 indicates
no capillary blush, while a score of 1 indicates normal
capillary blush. The scores for the three parts are added
up to give a CIS range of 03. A CIS = 0 or 1 is consid-
ered poor (pCIS), and a CIS = 2 or 3 is considered favor-
able (fCIS). The higher scores indicate that greater
ischemic area is potentially viable for recovery follow-
ing recanalization. An example of how CIS is calculated
is shown in Figure 1.
Outcomes
Each study separated the patients into two groups of
favorable CIS and poor CIS. Studied outcomes included
rates of good neurological outcome, recanalization, and
post-recanalization hemorrhage. Good neurological out-
come was defined as a modified Rankin scale score
(mRS) 2 at 90 days. Recanalization was defined as
thrombolysis in cerebral infarction 2b or thrombolysis
in myocardial infarction 2. We also extracted data on
baseline National Institutes of Health Stroke Scale
(NIHSS) scores and time to recanalization when availa-
ble for each group.
Risk of Bias Assessment and Evaluation of
Study Characteristics
Risk of bias assessment was performed using the New-
castle-Ottawa Scale. This is a tool used for assessing the
quality of non-randomized studies included in system-
 Jagani et al.
Journal of Vascular and Interventional Neurology, Vol. 9
Figure 2. Flow chart of literature assessment.
atic reviews and/or meta-analyses. Each study is judged
on eight items categorized into three groups: 1) selection
of the study groups, 2) comparability of the study
groups, and 3) ascertainment of the outcome of interest
[15]. Factors examined in our assessment of risk of bias
were the following: 1) similar baseline NIHSS between
groups, 2) similar time to revascularization between
groups, 3) use of angiographic core labs, 4) patient-
reported mRS scores at 90 days, and 5) similar revascu-
larization techniques between groups.
Statistics
We extracted a 2 2 table for each binary outcome from
each study. Random-effect meta-analysis was used for
pooling across studies [16]. The I2 statistic was used to
express the proportion of inconsistency that is not attrib-
utable to chance [17]. Meta-analysis results were
expressed as relative risk (RR) and 95% of confidence
interval (CI). We planned to explore the impact of publi-
cation bias by constructing funnel plots and testing their
symmetry if a sufficient number of studies (>20) was
available. A meta-regression analysis for good neurolog-
ical outcome was performed for adjusting baseline
NIHSS between groups in studies which included such
data. Meta-analysis was conducted using Stata (Stata-
Corp. 2015. Stata Statistical Software: Release 14. Col-
lege Station, TX: StataCorp LP).
9
Results
Literature Search
Fifteen articles were found on the initial literature
search. Of these articles, eight were excluded (53.3%)
after reading the abstract because they did not use the
CIS or did not include any clinical outcome data. One
additional article was excluded, because only percen-
tages of the patients in each group were given. In total,
six studies were included in the meta-analysis: four were
published in full text and two were abstract presenta-
tions given at conferences. A flow chart that describes
the study selection process is shown in Figure 2. Not all
of the studies provided data on all outcomes. In addition,
data regarding good neurological outcome from [13]
were excluded because it was defined as mRS 3. The
largest study contained 146 patients (106 with fCISs and
40 pCISs), and the smallest study included 26 patients.
The studies and the available outcomes from each are
summarized in Table 1. In total, 338 patients were inclu-
ded in this study, 212 in the fCIS group and 126 in the
pCIS group.
Baseline NIHSS and Time to Recanalization
The baseline NIHSS scores were significantly different
between the two groups (p = 0.003). The mean baseline
NIHSS score in the fCIS group was 17.5 (16.118.9)
and 19.5 (18.220.8) in the pCIS group (p = 0.003). The
time to recanalization was not statistically different
between the two groups with the mean in fCIS group
 10

Table 1. Studies Included in Meta-analysis

Authors, Year fCIS (n) pCIS (n) Good Neu- Recan- Post-Treat- Baseline Baseline Time to Time to Risk of Bias
rologi- alization ment Hem- NIHSS NIHSS Recanaliza- Recanaliza-
cal Outcome orrhage in fCIS in pCIS tion in fCIS tion in
group group group (min) pCIS group
(min)
Jagani et al., 2015 13* 14* 18 6 16 6 336 176 355 121 H
[11]
Al-Ali et al., 2013 [9] 11 15 18 9 22 7 380* 399* M
Al-Ali et al., 2014 13 15 19 4 20 3 L
[10]
Al-Ali et al., 2015 [8] 48 30 18 5 20 4 237 49 252 57 L
Labeyrie et al., 2015 106 40 16 5 19 6 340 79 304 93 M
[12]
Teleb et al., 2014 21 12 H
[13]
*
No standard deviation available.
Journal of Vascular and Interventional Neurology, Vol. 9

Figure 3. Forest plot for good neurological outcome.

being 332 min (264.8397.2) and the mean in the pCIS
group being 326.5 min (246.5406.6).
Outcomes
Favorable CISs were associated with higher RR of good
neurological outcome (RR = 3.03; CI = 95%, 2.054.47;
p < 0.001) compared with pCIS [Figure 3 (forest plot)].
Fifty-nine percent (112 of 191) of patients with fCIS had
good neurological outcome compared with 18% (21 of
114) of patients with pCIS. On meta-regression adjust-
ing for baseline NIHSS, patients with fCIS had higher
RR of good neurological outcome when compared with
those with pCIS (RR = 2.94; CI = 95%, 1.237, p <
0.0001).
There was lower risk of post-treatment intra-cerebral
hemorrhage within the fCIS group (RR = 0.38; CI =
95%, 0.190.93; p = 0.04). Favorable CIS was not asso-
ciated with higher rates of recanalization (RR = 1.18; CI
= 95%, 0.991.41; p = 0.06). These data are summarized
in Table 2. Forest plots for hemorrhage and recanaliza-
tion are provided in Figures 4 and 5.
Study Heterogeneity
The I2 values were <50% for the three main outcomes:
1) good neurological outcome (I2 = 38%), 2) post-treat-
 Jagani et al. 11

Table 2. Meta-analysis Results: Outcomes

Outcome RR (fCIS versus pCIS) 95% CI P Value I2
Good Neurological Outcome (mRS 2) 3.03 2.054.47 <0.001 38%
Post-Treatment Hemorrhage 0.38 0.160.93 0.04 0%
Recanalization 1.18 0.991.41 0.06 0%
Journal of Vascular and Interventional Neurology, Vol. 9

Figure 4. Forest plot for post-treatment hemorrhage.

Figure 5. Forest plot for recanalization.


ment hemorrhage (I2 =0%), and (3) recanalization (I2 =
0%). These values indicate relatively low heterogeneity
among the studies.
Dicussion
We conducted a systematic review and meta-analysis of
five studies reporting on 338 patients and found that
patients with favorable CISs had higher rates of good
neurological outcome (mRS 2) following endovascu-
lar therapy for acute ischemic stroke when compared
with those with a poor CIS, even when adjusting for
baseline NIHSS. Patients with fCIS had significantly
lower rates of post-treatment hemorrhage and trended
toward higher recanalization rates as well. These find-
Journal of Vascular and Interventional Neurology, Vol. 9
ings are important as they suggest that CIS is a poten-
tially useful tool in predicting outcomes following endo-
vascular treatment of acute ischemic stroke.
Proposed applications of the CIS are in patient selection
and prognostication. Many of the individual studies and
this meta-analysis found fCIS and good neurological
outcome to be strongly correlated. The relationship of
collateral grade to clinical outcome supports the hypoth-
esis that fCIS can identify viable ischemic tissue that
may be amenable to revascularization; however, there is
no guarantee that the tissue will recover with or without
endovascular intervention. In addition, identifying
patients with pCIS can be valuable. Reperfusing patients
with pCIS can be harmful because reperfusing nonviable
tissue may lead to hemorrhagic transformation and
edema, as demonstrated in our study. Our findings reaf-
firm the importance of collaterals and CIS in predicting
clinical outcomes, independent of baseline NIHSS. It is
important to point out, however, that fCIS cannot be the
sole determinant in patient selection for endovascular
therapy. The degree of collateral flow can help predict
the likelihood of good outcomes, but the absence of
good flow should not prevent endovascular therapy[6].
In patients with pCIS, 18% still recovered with good
neurological outcome.
A number of studies have been published examining
efficacy of other collateral grading systems in predicting
outcomes of endovascular therapy for treatment of acute
ischemic stroke. In general, poor collaterals are associ-
ated with lower rates of good neurological outcomes and
higher rates of hemorrhage, similar to those seen with
the CIS [3,18,19]. In a large meta-analysis of 19 studies
over the last 15 years that compared collateral grades
with outcomes, Leng et al. found that good pre-treat-
ment collateral status almost doubled the rate of good
neurological outcome as compared with patients with
poor collaterals (RR = 1.98; CI = 95% ,1.642.38; p <
12
0.001) [14]. Of the 19 studies, the majority graded col-
laterals using DSA imaging, primarily on the American
Society of Interventional and Therapeutic Neuroradiol-
ogy and the Society of Interventional Radiology scale
[20]. One potential advantage of the CIS scoring method
over traditional DSA-based collateral scoring methods is
the fact that the scale is easily quantifiable with high
rates of inter-observer agreement [11]. Furthermore, the
scale evaluates the functionality of collaterals by assess-
ing capillary perfusion rather than the presence of collat-
erals alone.
In addition, several studies have used collateral grading
methods based on CT angiography and CT perfusion
techniques [2124]. One advantage of CT-based collat-
eral scores is the fact that they rely on non-invasive
imaging and can, thus, be used for patient selection prior
to conventional angiography. These scores may be more
advantageous because they truly evaluate the enhance-
ment and extent of collateral vessels in the ischemic ter-
ritory. To date, no studies have been performed compar-
ing the accuracy of CTA-based scoring systems and the
CIS in predicting good neurological outcome following
endovascular therapy.
Limitations
This study has several limitations. First, there were a rel-
atively small number of studies included in analysis.
This may be due to the relatively short time since the
introduction of the CIS. In addition, not all studies had
each of the investigated outcomes, further adding to the
small size and limiting the power of the meta-analysis.
Each of the studies included was retrospective and non-
randomized, further limiting certainty in the observed
estimates. Baseline NIHSS scores were lower in the
fCIS group and likely played a role in the association of
the score results and outcome. It is important to point
out, however, that in meta-regression of good neurologi-
cal outcomes adjusting for baseline NIHSS, fCIS was
still significantly association with good neurological
outcome. Differences in grading the CIS, quality of
angiogram scored, and rater experience among the inclu-
ded studies could not be evaluated. Publication bias was
not assessed because our meta-analysis incorporated less
than 10 studies. Overall, the quality of the evidence (i.e.,
confidence in the estimates of effect) is low.
Conclusion
Observational evidence suggests that acute ischemic
stroke patients with favorable CISs had higher rates of
good neurological outcomes, independent of baseline
NIHSS. These findings suggest that CIS can be used as
 Jagani et al.
a tool to prognosticate outcomes of endovascular treat-
ment of acute ischemic stroke. It is important to point
out that nearly 20% of patients with a pCIS had good
neurological outcome following endovascular treatment,
thus suggesting that CIS should not be used as the only
tool for patient selection at this time.
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