Original Contribution

Original Contribution
Relevance of Blood–Brain Barrier Disruption After
Endovascular Treatment of Ischemic Stroke
Dual-Energy Computed Tomographic Study
Arturo Renú, MD; Sergio Amaro, MD; Carlos Laredo, MSc; Luis San Román, MD;
Laura Llull, MD; Antonio Lopez, MD; Xabier Urra, MD; Jordi Blasco, MD;
Laura Oleaga, MD; Ángel Chamorro, MD
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Background and Purpose—Computed tomographic (CT) high attenuation (HA) areas after endovascular therapy for acute
ischemic stroke are a common finding indicative of blood–brain barrier disruption. Dual-energy CT allows an accurate
differentiation between HA areas related to contrast staining (CS) or to brain hemorrhage (BH). We sought to evaluate
the prognostic significance of the presence of CS and BH after endovascular therapy.
Methods—A prospective cohort of 132 patients treated with endovascular therapy was analyzed. According to dual-energy
CT findings, patients were classified into 3 groups: no HA areas (n=53), CS (n=32), and BH (n=47). The rate of new
hemorrhagic transformations was recorded at follow-up neuroimaging. Clinical outcome was evaluated at 90 days with
the modified Rankin Scale (poor outcome, 3–6).
Results—Poor outcome was associated with the presence of CS (odds ratio [OR], 11.3; 95% confidence interval, 3.34–38.95)
and BH (OR, 10.4; 95% confidence interval, 3.42–31.68). The rate of poor outcome despite complete recanalization was
also significantly higher in CS (OR, 9.7; 95% confidence interval, 2.55–37.18) and BH (OR, 15.1; 95% confidence
interval, 3.85–59.35) groups, compared with the no-HA group. Patients with CS disclosed a higher incidence of delayed
hemorrhagic transformation at follow-up (OR, 4.5; 95% confidence interval, 1.22–16.37) compared with no-HA patients.
Conclusions—Blood–brain barrier disruption, defined as CS and BH on dual-energy CT, was associated with poor clinical
outcomes in patients with stroke treated with endovascular therapies. Moreover, isolated CS was associated with delayed
hemorrhagic transformation. These results support the clinical relevance of blood–brain barrier disruption in acute
stroke. (Stroke. 2015;46:00-00. DOI: 10.1161/STROKEAHA.114.008147.)
Key Words: blood–brain barrier ◼ stroke ◼ thrombolytic therapy
E
ndovascular therapy (ET) is an increasingly used therapeutic strategy in acute ischemic stroke.1 The administration of contrast material during ET often results in high
attenuation areas on postprocedural brain computed tomography (CT) related to blood–brain barrier (BBB) breakdown,
although their clinical significance is conflicting.2–8 Early
differentiation between contrast enhancement and brain
hemorrhage may be of assistance to detect bleeding complications and anticipate the start of antithrombotic therapy
after thrombolysis.9 However, in the early post-ET period,
this distinction is not feasible using conventional post-treatment CT.2–5,10
Dual-energy CT (DE-CT) is a relatively new technique that
allows for a reliable differentiation between tissue high attenuation areas related to iodine contrast material extravasation
and parenchymal hemorrhage.11–13 The technique is based on
the different attenuation effects of normal brain tissue, iodine,
and blood at different irradiation energy levels. In patients
receiving ET, DE-CT has shown a good accuracy for early differentiation between hemorrhage and contrast extravasation,
but these studies did not address specifically the prognostic
implications of this segregation.12,14,15
Brain ischemia induces time-dependent changes in microvascular integrity and these changes may lead to the extravasation of contrast molecules and cellular blood elements from
microvessels leading to hemorrhagic complications.16,17 Thus,
the ability of DE-CT to differentiate between contrast and
brain hemorrhage after ET may allow discriminating between
different grades BBB disruption. The aim of the study was to
evaluate the prognostic significance of the presence of contrast
Received November 14, 2014; final revision received December 23, 2014; accepted January 13, 2015.
From the Department of Neuroscience, Comprehensive Stroke Center, Hospital Clinic, University of Barcelona, August Pi I Sunyer Biomedical Research
Institute (IDIBAPS), Barcelona, Spain (A.R., S.A., C.L., L.L., X.U., Á.C.); and Radiology Department, Hospital Clinic, Barcelona, Spain (L.S.R., A.L.,
J.B., L.O.).
Guest Editor for this article was Tatjana Rundek, MD, PhD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
114.008147/-/DC1.
Correspondence to Ángel Chamorro, MD, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. E-mail [email protected]
© 2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.008147
1
2 Stroke March 2015
staining (CS) or brain hemorrhage after ET in a cohort of
patients studied with DE-CT.
Materials and Methods
Patients
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Patients were part of a prospectively collected registry of acute ischemic stroke treated with ET at a single Comprehensive Stroke Center.
A total of 203 patients were treated from May 2010 to June 2013, of
whom 132 who were evaluated with a DE-CT scan after ET were included in the study. A contemporary group of 71 patients was not included because DE-CT was not performed (n=46 because of DE-CT
equipment unavailability, n=7 because of early clinical deterioration
resulting in death before post-ET neuroimaging, and n=18 because
of preference for brain MRI). According to our institutional protocol,
the patients and their legal representatives signed a written informed
consent accepting to receive ET and to be included in the registry. The
study protocol was approved by the local Clinical Research Ethics
Committee.
All treated patients had a CT angiography that confirmed a proximal artery occlusion and ruled out a malignant profile, as previously
reported.18 In patients with symptoms lasting >4.5 hours, the presence
of mismatch was also required. Type (primary or rescue therapy after systemic thrombolysis), duration of the interventional procedure,
and final vessel patency were prospectively recorded. Iopromide
(Ultravist, Bayer HealthCare Pharmaceuticals; 300 mgI/mL; molecular weight, 791.12 Da), a low-osmolar nonionic monomeric
x-ray contrast medium, was used for the therapeutic angiographic
procedures. Final vessel patency was graded on digital subtraction
angiography according to the thrombolysis in cerebral infarction classification (grade 0, no perfusion; grade 1, penetration with minimal
perfusion; grade 2a, partial filling of the entire vascular territory;
grade 2b, complete filling, but the filling is slower than normal; grade
3, complete perfusion). Recanalization was defined as complete if a
2b-3 grade was obtained at the end of ET.
After the procedure, patients were admitted into an intermediate care
Stroke Unit. Demographics, neuroimaging data, concomitant therapies,
clinical course, and functional outcome were prospectively collected.
The Alberta Stroke Program Early CT Score was assessed on baseline
CT, and qualifying strokes were classified according to the Trial of Org
10 172 in Acute Stroke Treatment (TOAST) criteria. Functional outcome was scored with the modified Rankin Scale at 3 months, and poor
outcome was defined as a modified Rankin Scale score >2.
DE-CT Imaging and Follow-Up Imaging Studies
According to our protocol for endovascular procedures, a complete
postinterventional DE-CT data set was acquired after ET. Images
were obtained through a 64-channel multidetector dual-source CT
equipment (Somatom Definition FLASH; Siemens), which uses 2 xray tubes optimized independently and 2 stellar detectors in the same
gantry. The implemented protocol allowed simultaneous imaging acquisition at 100 kV/250 mAs and 140 kV/250 mAs, and a 20×0.6 mm
collimation (total dose ≈3 mSv effective, similar to that required for
single source CT). The information obtained was rebuilt in 3 different
series, 2 sets corresponding to 100 and 140 kV, respectively (slice
thickness of 1.5 mm), and a third set corresponding to a mixture map
of both energies (100 kV/140 kV) simulating a conventional CT of
120 kV. Subsequent postprocessing was performed through commercial software (syngo.CT Dual-Energy Brain Hemorrhage; Siemens).
The software uses a 3-material decomposition algorithm aimed to differentiate normal brain parenchyma, hemorrhage, and iodine contrast
to finally obtain an iodine map (for displaying only iodine) and a
virtual noncontrast map (to visualize brain parenchyma and hemorrhage). Iodine maps and virtual noncontrast maps were used to differentiate between high attenuation areas related to CS alone and to
brain hemorrhage in concordance with previously published data, as
shown in Figure 1.12
Follow-up imaging by CT/MRI angiography was performed at 48
to 72 hours of stroke in 110 patients. Bleeding complications were defined on brain imaging according to the European Cooperative Acute
Stroke Study criteria as hemorrhagic infarction and parenchymal
hematoma type 1 and parenchymal hematoma type 2. Investigators
blinded to clinical data evaluated DE-CT, and investigators blinded to
DE-CT group classification evaluated follow-up imaging studies and
modified Rankin Scale.
Statistics
Continuous variables were reported as mean (SD) or median (interquartile range) and were compared with the Student t test, ANOVA,
Figure 1. Dual-energy computed tomographic (CT) classification of parenchymal
high attenuation areas after endovascular therapy. High attenuation areas were
defined as areas with higher density than
the normal white matter or surrounding
gray matter in plain CT. Absence high
attenuation areas in plain CT (A). A hyperattenuation only seen on the iodine overlay
image was classified as contrast staining
alone (B); a hyperattenuation only seen on
the virtual noncontrast (VNC) maps was
classified as hemorrhage (C). When contrast staining and brain hemorrhages were
found together, the patient was classified in
the brain hemorrhage group (C).
Renú et al BBB Disruption After Endovascular Therapy 3
Table 1. Demographics, Baseline, and Procedure-Related Variables According to DE-CT Classification
DE-CT Classification
No-HA (n=53)
CS (n=32)
BH (n=47)
P Value*
Age, mean (SD), y
68 (14)
68 (13)
65 (14)
0.612
Men, n (%)
26 (49)
18 (56)
19 (40)
0.373
Hypertension, n (%)
32 (60)
17 (53)
28 (60)
0.787
Diabetes mellitus, n (%)
14 (26)
5 (16)
10 (21)
0.503
Atrial fibrillation, n (%)
14 (26)
11 (34)
16 (34)
0.640
Previous antithrombotic treatment, n (%)
24 (45)
10 (31)
27 (57)
0.071
Baseline SBP, mean (SD), mm Hg
146 (23)
145 (23)
149 (25)
0.730
Glucose, median (IQR), mg/dL
125 (112–151)
123 (101–149)
119 (103–151)
0.400
Pre-angio NIHSS, median (IQR)
13 (10–19)
15 (13–19)
16 (12–21)
0.238
9 (8–10)†
8 (7–9)
8 (7–9)
0.006
ASPECTS, median (IQR)
Primary ET, n (%)
21 (40)
Time to ET onset, median (IQR), min
Duration of ET procedure, median (IQR), min
13 (41)
20 (43)
0.956
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260 (180–365)
279 (210–382)
278 (206–400)
0.574
27 (15–58)†
40 (17–76)
47 (23–91)
0.029
49 (93)
29 (91)
44 (94)
0.885
7 (13)
1 (3)
2 (4)
0.132
Type of ET treatment
Stent retrievers, n (%)
Merci device, n (%)
Local alteplase, n (%)
0 (0)
1 (3)
1 (2)
0.475
Device passes per procedure, median (IQR)
1 (1–4)†
3 (1–4)
3 (2–5)
0.028
Recanalization 2b-3 (yes), n (%)
46 (87)
26 (81)
37 (79)
Time to recanalization
0.555
0.049
Recanalization <4′5 h, n (%)
23 (43)†
7 (22)
8 (17)
…
Recanalization 4′5–6 h, n (%)
13 (25)
12 (38)
18 (38)
…
Recanalization >6 h or absence, n (%)
17 (32)
13 (41)
21 (45)
TOAST classification
…
0.516
7 (13)
7 (22)
6 (13)
…
Cardioembolic origin, n (%)
Atherothrombotic origin, n (%)
25 (47)
17 (53)
27 (57)
…
Other pathogeneses, n (%)
21 (40)
8 (25)
14 (30)
…
0 (0)†
10 (31)
28 (60)
<0.001
25 (53)
<0.001
Associated subarachnoid HA areas, n (%)
Associated SAH, n (%)
0 (0)†
Time to DE-CT, median (IQR), min
627 (417–1016)
0 (0)
441 (224–635)
409 (268–668)
0.001
ASPECTS indicates Alberta Stroke Program Early CT Score; BH, brain hemorrhage; CS, contrast staining; CT, computed tomography; DE-CT, dual-energy CT; ET,
endovascular therapy; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; no-HA, no high attenuation areas; SAH, subarachnoid hemorrhage; SBP,
systolic blood pressure; and TOAST, Trial of Org 10 172 in Acute Stroke Treatment.
*P value for difference between the 3 groups by 1-way ANOVA, Kruskal–Wallis test and χ2/Fisher exact test when applicable.
†P values <0.05 for difference between no-HA group and CS/BH groups by t test, Mann–Whitney U test and χ2/Fisher exact test when applicable.
Mann–Whitney, or Kruskal–Wallis tests as appropriate. Categorical
variables were compared with the χ2 and Fisher exact tests.
Multivariate logistic regression analyses adjusted for variables with a
P<0.10 on univariate analysis were built to assess the value of DE-CT
groups to predict the bleeding risk and the functional outcome at 90
days, using a conditional forward procedure. Age, type of ET (primary versus rescue), and time from symptom onset to recanalization
(when applicable) were forced in the final models used for prediction of clinical outcomes for their prognostic relevance; time from
ET conclusion to DE-CT acquisition was also forced because of the
significant imbalance between groups. The analysis was performed
using SPSS Version 19.0 and the level of significance was established
at the 0.05 level (2-sided).
Results
Main Characteristics of the Study Population
Overall, 132 patients were included in the analysis, of whom
53 (40%) had no high attenuated areas after ET (no-HA
group), 32 (24%) disclosed CS alone (CS group), and 47
(36%) disclosed brain hemorrhage or a combination of hemorrhage and CS (BH group). Descriptive data on demographics and baseline variables according to DE-CT classification
are shown in Table 1. Of note, CS and BH groups disclosed a
higher proportion of use of antithrombotics before admission,
lower baseline Alberta Stroke Program Early CT Score, longer
time from stroke onset to recanalization, and shorter delays to
DE-CT acquisition, in comparison with no-HA group. High
attenuated subarachnoid areas were exclusively observed in
CS and BH groups and were classified as subarachnoid hemorrhage only in the BH group.
The location of arterial occlusions before ET, the modality
of ET (rescue versus primary ET), and the type of ET techniques were similar across DE-CT–defined groups, as shown
in Table 1. Of note, the most widely used thrombectomy
4 Stroke March 2015
Table 2. Multivariate Models for the Prediction of Outcomes
8.7 (3.84–19.91)
<0.001
BH (vs no-HA)
10 (4.03–24.70)
<0.001
Baseline NIHSS (per IQR)
1.6 (1.20–2.16)
0.002
3 (1.52–5.95)
0.002
0.3 (0.15–0.82)
0.016
Baseline glucose levels (per IQR)
1.6 (1.18–2.17)
0.003
Hypertension (vs no)
1.6 (0.85–3.20)
0.139
Age/y
1.0 (0.98–1.03)
0.810
Time to DE-CT (per IQR)
1.2 (0.90–1.63)
0.227
higher glucose, and systolic blood pressure levels at baseline, hypertension, diabetes mellitus, absence of recanalization, and duration of ET procedure (Table I in the
online-only Data Supplement). The rate of poor outcome
was increased in CS (odds ratio [OR], 5.32; 95% confidence
interval [CI], 2.05–13.77) and BH (OR, 5.94; 95% CI, 2.50–
14.12) groups in comparison with no-HA group, and the
effect remained significant in multivariate logistic regression analysis (Table 2). Moreover, more patients with CS
or BH shifted into worse categories of the modified Rankin
Scale using ordinal regression analysis (Table 2).
Complete recanalization was obtained in 109 (83%)
patients, although in 50 (46%) patients it was not followed
by good outcome. Poor outcome despite complete recanalization was associated with higher baseline National
Institutes of Health Stroke Scale, primary ET, hypertension,
diabetes mellitus, baseline glucose levels, and baseline systolic blood pressure in univariate analyses (Table II in the
online-only Data Supplement). The rate of poor outcome
despite complete recanalization was significantly higher in
CS (58%; OR, 4.91; 95% CI, 1.72–13.99) and BH (68%;
OR, 7.50; 95% CI, 2.81–20.03) compared with the no-HA
group (22%) in univariate analysis, and this association
remained significant also in multivariate regression models
(Table 2).
CS (vs no-HA)
9.7 (2.55–37.18)
0.001
CS After ET and the Risk of Delayed Hemorrhagic
Transformation
BH (vs no-HA)
15.1 (3.85–59.35)
<0.001
OR (95% CI)
P Value
CS (vs no-HA)
12.6 (3.55–44.98)
<0.001
BH (vs no-HA)
11.3 (3.60–35.65)
<0.001
Poor outcome (mRS>2) at day 90
Baseline NIHSS (per IQR)
1.7 (1.13–2.61)
0.011
Primary ET (vs rescue)
3.2 (1.21–8.52)
0.019
Recanalization 2b-3 (yes vs no)
0.2 (0.06–0.77)
0.017
Baseline glucose levels (IQR)
1.9 (1.22–2.90)
0.004
Hypertension (vs no)
2.3 (0.89–5.83)
0.086
Age/y
1.0 (0.98–1.05)
0.384
Time to DE-CT (per IQR)
1.2 (0.75–1.77)
0.507
mRS (ordinal; 0–6) at day 90
CS (vs no-HA)
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Primary ET (vs rescue)
Recanalization 2b-3 (yes vs no)
Poor outcome despite complete
recanalization
Baseline NIHSS (per IQR)
1.6 (1.01–2.55)
0.044
Primary ET (vs rescue)
2.6 (0.89–7.40)
0.081
Time to recanalization (per IQR)
1.5 (0.98–2.44)
0.061
Hypertension (vs no)
2.5 (0.90–6.95)
0.078
Age/y
1.0 (1.00–1.09)
0.052
Baseline glucose levels (per IQR)
1.9 (1.18–2.95)
0.008
Time to DE-CT (per IQR)
1.2 (0.71–1.92)
0.531
Delayed HT
CS (vs no-HA)
4.5 (1.22–16.37)
0.024
Prior antithrombotic therapy (vs no)
2.2 (0.63–7.77)
0.216
Cardioembolism (vs no)
3.8 (1.03–14.17)
0.046
Baseline ASPECTS score (>7 vs ≤7)
1.8 (0.39–7.97)
0.455
BH indicates brain hemorrhage; CI, confidence interval; CS, contrast
staining; DE-CT, dual-energy computed tomography; ET, endovascular
therapy; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS,
National Institutes of Health Stroke Scale; no-HA, no high attenuation areas;
and OR, odds ratio.
devices were stent retrievers (92%). The duration of the
endovascular procedure and the number of device passes
were highly correlated (Spearman ρ, 0.643; P<0.001), and
both variables were significantly higher in CS and BH groups
(Table 1).
Clinical Outcomes After ET According to DE-CT–
Defined Groups
Poor outcome at 90 days occurred in 67 (51%) patients
and was associated with increased baseline stroke severity,
Overall, hemorrhagic transformation (HT) was seen in 55
(50%) patients, of whom 27 (25%) had hemorrhagic infarction and 28 (26%) had parenchymal hematoma. The presence
of HT at follow-up neuroimaging was significantly associated
with baseline Alberta Stroke Program Early CT Score, prior
antithrombotic treatment, and cardioembolic pathogenesis
and was also marginally associated with poor prognosis (58%,
versus 40%; P=0.056).
Delayed HT was evaluated in 71 patients without signs of
brain hemorrhage as classified by DE-CT after ET, of whom
44 pertained to the non-HA group and 27 to the CS group. In
this subset of patients, the use of antithrombotics after DE-CT
did not differ between CS and no-HA groups (data not shown),
and was neither associated with delayed HT (Table III in the
online-only Data Supplement). Patients with CS after ET disclosed a higher incidence of delayed HT at follow-up neuroimaging compared with no-HA patients (OR, 3.1; 95% CI,
1.01–9.57; P=0.048). This association remained significant
in multivariate models adjusted by baseline Alberta Stroke
Program Early CT Score, prior antithrombotic therapy, and
cardioembolism (Table 2). Representative cases of delayed
HT are shown in Figure 2.
Discussion
The present study demonstrated a consistent association
between post-ET BBB disruption, as evidenced by CS and
BH on DE-CT images, and poor clinical outcomes. Moreover,
the study also showed that the identification of isolated CS on
DE-CT was a reliable harbinger of delayed HT. Collectively,
these results supported the feasibility and clinical relevance of
Renú et al BBB Disruption After Endovascular Therapy 5
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Figure 2. Representative cases of contrast
staining, brain hemorrhage, and absence
of early blood–brain barrier disruption
as detected by dual-energy computed
tomography (CT), and relationship with
hemorrhagic transformation at follow-up
neuroimages. DWI indicates diffusionweighted imaging; and VNC, virtual
noncontrast.
DE-CT to identifying early BBB disruption in patients with
acute stroke receiving ET.
In agreement with previous studies, signs of BBB disruption were found in ≈60% of patients.3,6,7 However, the
use of plain CT in most previous studies was a major drawback because of the limited ability of the technique to discriminate between CS and early HT. An intact BBB allows
the passage of lipid-soluble molecules with molecular
weights <400 Da.19 Thus, the leakage in the brain tissue
of iodinated contrast materials such as iopromide (a watersoluble molecule with a molecular weight of 791.12 Da)
in patients without BH is consistent with early BBB disruption. Indeed, brain ischemia induces a time-dependent
and gradual process of increased microvascular permeability that allows the leakage of a range of small molecules
to larger cellular blood elements from microvessels into
the extracellular space.16,17 As illustrated in Figure 1, this
gradual process of BBB disruption can be captured using
DE-CT because of its ability to differentiate intracranial
hemorrhage from isolated extravasation of iodinated contrast material.
In our series, both CS and early BH as classified by DE-CT
were markers of poor clinical outcomes even despite complete recanalization in patients selected with the use of multimodal neuroimaging.18 Moreover, the risk of delayed HT
was increased in patients disclosing isolated CS in DE-CT.
Overall, these data suggest that early BBB disruption is a predictor of poor outcomes and complement previous studies of
BBB permeability using other neuroimaging strategies such as
dynamic contrast-enhanced MR or CT imaging.20,21 Our data
give further support to the potential role of therapies aimed to
protect the BBB in combination with reperfusion therapies to
heighten the chances of successful outcome after ET, in addition to strategies for improving the selection of patients to be
treated and for shortening the time from stroke onset to complete reperfusion.1
The pathophysiology of cerebral hemorrhage associated
with reperfusion therapies involves the disruption of the
BBB, procedure-related direct vessel damage, and the toxicity secondary to thrombolytic drugs.22 In our series, the presence of signs of BBB disruption in DE-CT was associated
with longer duration of the procedures and higher number
of thrombectomy device passes, as well as with preintervention stroke severity and longer duration of ischemia. Longer
procedure times were highly correlated with the number of
passes of thrombectomy devices, as a marker of direct procedure-related vessel damage, and probably with enhanced
exposure to intra-arterial contrast. The contribution of iodinated contrast material to the development of brain edema or
HT is controversial. In experimental models of brain ischemia, intra-arterial administration of iodinated contrast material may increase intracerebral hemorrhage,23 although this
deleterious effect depends on the osmolarity of the contrast
used.24 In patients with acute stroke treated with intra-arterial
alteplase, the number of microcatheter injections of contrast
is related to an increase in the risk of intracranial hemorrhage,
6 Stroke March 2015
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suggesting that contrast toxicity or pressure-related damage
consequent to microcatheter injections may be potential contributors to BBB disruption.25
The main strength of the study is that the use of DE-CT
allowed us to investigate separately the prognostic relevance of isolated CS as an intermediate step between the
absence of BBB disruption and early HT. Besides the role
of DE-CT as a biomarker of BBB injury, the differentiation
between CS and BH may be relevant to balance the risks
and benefits of post-ET antithrombotic management.9,13
Nonetheless, the study has several limitations. First, the
assessment of BBB disruption through the presence of
high attenuation areas after ET is an indirect evaluation
of a multifaceted and time-dependent process.7,26 Second,
DE-CT has several technical limitations.27 The presence
of a fourth material (eg, calcium) other than normal brain
parenchyma, iodine or blood, as well as certain artifacts
(eg, metallic artifacts, beam hardening) may impair the
discriminatory accuracy of the 3-material decomposition
algorithm used in the image postprocessing, although this
limitation was irrelevant in our series. Finally, the presence of high attenuation areas after ET was related to
longer procedure times and to a shorter delay from procedure to the acquisition of DE-CT, although this limitation
was addressed by including these 2 potentially confounding variables in the multivariate analysis for outcome
prediction.
Conclusions
DE-CT allows an early grading of BBB disruption and adds
relevant prognostic information in patients with acute stroke
treated with ET. Moreover, DE-CT identifies a subgroup of
patients with increased risk of delayed HT. These findings
support the clinical relevance of early loss of BBB integrity after brain ischemia in patients with acute stroke treated
endovascularly.
Sources of Funding
This study was funded by grants from the Spanish Ministry of Economy
and Competitiveness for grant to Dr Amaro (PI13/01268, funded as
part of the Plan Nacional Investigación, Desarrollo e Innovación and
cofinanced by Instituto Salud Carlos III–Subdirección General de
Evaluación and by Fondo Europeo de Desarrollo Regional).
Disclosures
None.
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Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2016
Relevance of Blood−Brain Barrier Disruption After Endovascular Treatment of Ischemic
Stroke: Dual-Energy Computed Tomographic Study
Arturo Renú, Sergio Amaro, Carlos Laredo, Luis San Román, Laura Llull, Antonio Lopez,
Xabier Urra, Jordi Blasco, Laura Oleaga and Ángel Chamorro
Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2016
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ONLINE SUPPLEMENT.
Title
Relevance of blood brain barrier disruption after endovascular treatment of ischemic stroke: a
Dual-Energy CT study.
Running head
BBB disruption after endovascular therapy
Authors
Arturo Renú M.D.1; Sergio Amaro M.D.1; Carlos Laredo MSc.1; Luis San Román M.D.2;
Laura LLull M.D.1; Antonio Lopez M.D.2; Xabier Urra M.D.1; Jordi Blasco M.D.2; Laura
Oleaga M.D.2 ; Ángel Chamorro, M.D.1
Affiliations
1
Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, University of
Barcelona and August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona,
Spain. 2Radiology Department, Hospital Clinic, Barcelona, Spain.
Corresponding author
Ángel Chamorro MD; Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain.
Email: [email protected] Tel.: + 34 93 227 54 14; fax: + 34 93 227 57 83.
Supplemental Tables:
Supplemental Table I: Demographics, baseline and procedure related variables according to
clinical outcome at day 90.
Supplemental Table II: Demographics, baseline and procedure related variables according to
the presence of poor outcome despite complete recanalization.
Supplemental Table III: Demographics, baseline and procedure related variables according to
the presence of delayed hemorrhagic transformation.
1
Supplementary Table I
Demographics, baseline and procedure related variables according to clinical outcome
at day 90.
Good outcome
Poor outcome
N=65
N=67
Age (years), mean (SD)
65 (14)
68 (13)
0.211
Males, n (%)
34 (52)
29 (43)
0.299
Smoking, n (%)
14 (22)
18 (27)
0.475
Hypertension, n (%)
32 (49)
45 (67)
0.037
Diabetes, n (%)
9 (13)
20 (30)
0.026
Dyslipidemia, n (%)
26 (40)
31 (46)
0.467
Atrial Fibrillation, n (%)
18 (28)
23 (34)
0.410
Previous Antithrombotic treatment, n (%)
25 (36)
36 (54)
0.079
Baseline SBP (mmHg), mean (SD)
141 (23)
153 (23)
0.006
116 (101-133)
127 (113-155)
0.003
12 (9-17)
16 (13-22)
0.000
ASPECTS, median (IQR)
8 (7-9)
8 (7-9)
0.396
Systemic rTPA + ET , n (%)
47 (72)
31 (46)
0.002
Primary ET, n (%)
18 (28)
36 (54)
0.002
263 (185-329)
277 (208-405)
0.200
30 (15-59)
47 (20-91)
0.034
59 (91)
50 (75)
0.015
p
Glucose (mg/dl), median (IQR)
Pre-angio NIHSS, md (IQR)
Time to ET onset (min), md (IQR)
Duration of ET procedure (min), md (IQR)
Recanalization 2b-3 (yes), n (%)
TOAST classification
0.173
2
Atherothrombotic origin, n (%)
Cardioembolic origin, n (%)
Other etiologies, n (%)
Time to DE-CT (min), median (IQR)
23 (35)
20 (30)
0.173
6 (9)
14 (21)
0.173
36 (55)
33 (49)
0.173
497 (352-839)
441 (244-750)
0.166
DE-CT: Dual Energy CT ; ET: endovascular therapy ; SBP: systolic blood pressure.
3
Supplementary Table II
Demographics, baseline and procedure related variables according to the presence of
poor outcome despite complete recanalization.
Good outcome
Poor outcome
p
N=59
N=50
64 (14.3)
69 (12.3)
0.075
Males, n (%)
29 (49)
20 (40)
0.338
Smoking, n (%)
13 (22)
12 (24)
0.808
Hypertension, n (%)
27 (46)
34 (68)
0.020
Diabetes, n (%)
9 (15)
17 (34)
0.022
Dyslipidemia, n (%)
25 (42)
24 (48)
0.556
Atrial Fibrillation, n (%)
15 (25)
17 (34)
0.327
Previous Antithrombotic treatment, n (%)
22 (37)
26 (52)
0.123
Baseline SBP (mmHg), mean (SD)
141 (24)
153 (24)
0.010
119 (101-135)
128 (112-157)
0.018
13 (9-18)
18 (14-22)
<0.001
ASPECTS 8-10, n (%)
44 (75)
30 (61)
0.137
Systemic rTPA+ ET , n (%)
41 (70)
24 (48)
0.023
Primary ET, n (%)
18 (31)
26 (52)
0.023
Time to ET onset (min), md (IQR)
263 (180-331)
276 (225-384)
0.259
Time to ET ending (min), md (IQR)
300 (225-395)
332 (280-414)
0.139
30 (15-59)
33 (15-80)
0.304
Age (years), mean (SD)
Glucose (mg/dl), median (IQR)
Pre-angio NIHSS, md (IQR)
Duration of ET procedure (min), md (IQR)
4
Time to recanalization (min), median (IQR)
300 (225-395)
332 (280-414)
TOAST classification
0.083
Atherothrombotic origin, n (%)
23 (39)
14 (28)
Cardioembolic origin, n (%)
6 (10)
13 (26)
Other etiologies, n (%)
30 (51)
23 (46)
538 (352-848)
483 (363-750)
Time to DE-CT (min), median (IQR)
0.139
0.406
SBP: systolic blood pressure; ET: endovascular therapy; DE-CT: Dual Energy CT.
5
Supplementary Table III
Demographics, baseline and procedure related variables according to the presence of
delayed hemorrhagic transformation.
No HT
HT
N=54
N=17
Age (years), mean (SD)
68 (15)
71 (12)
0.355
Males, n (%)
28 (60)
11 (65)
0.353
Smoking, n (%)
14 (26)
3 (18)
0.485
Hypertension, n (%)
32 (59)
9 (53)
0.646
Diabetes, n (%)
14 (26)
3 (18)
0.485
Dyslipidemia, n (%)
25 (46)
8 (47)
0.956
Atrial Fibrillation, n (%)
13 (24)
9 (53)
0.025
Previous Antithrombotic treatment, n (%)
21 (39)
10 (59)
0.148
Baseline SBP (mmHg), mean (SD)
149 (24)
139 (21)
0.125
126 (111-154)
122 (116-137)
0.968
15 (10-20)
15 (11-17)
0.840
ASPECTS, median (IQR)
9 (7-10)
8 (8-9)
0.403
ASPECTS 8-10, n (%)
38 (73)
13 (76)
0.782
Systemic rTPA+ ET , n (%)
34 (63)
10 (59)
0.759
Primary ET, n (%)
20 (37)
7 (41)
0.759
262 (186-372)
217 (170-284)
0.205
30 (16-60)
45 (16-59)
0.666
p
Glucose (mg/dl), median (IQR)
Pre-angio NIHSS, md (IQR)
Time to ET onset (min), md (IQR)
Duration of ET procedure (min), md (IQR)
6
Recanalization 2b-3 (yes), n (%)
45 (83)
15 (88)
0.626
Time to recanalization (min), median (IQR)
287 (240-395)
261 (230-300)
0.241
Time to DE-CT (min), median (IQR)
514 (352-848)
598 (289-679)
0.808
DE-CT classification group
0.043
No- high attenuation areas
37 (68)
7 (41)
Contrast staining
17 (32)
10 (59)
Antithrombotic use after DE-CT
No antithrombotic, n (%)
0.324
2 (4)
0 (0)
Antiplatelets, n (%)
21 (39)
4 (24)
Unfractioned Heparin, n (%)
31 (57)
13 (76)
TOAST classification
0.032
Cardioembolic origin, n (%)
24 (44)
13 (77)
Atherothrombotic origin, n (%)
8 (15)
1 (6)
Other etiologies, n (%)
22 (41)
3 (18)
SBP: systolic blood pressure; ET: endovascular therapy; DE-CT: Dual Energy CT.
7
Abstract
31
Abstract
虚血性脳卒中の血管内治療と血液−脳関門破壊の関連性
二重エネルギー CT 研究
Relevance of Blood-Brain Barrier Disruption After Endovascular Treatment of Ischemic Stroke
Dual-Energy Computed Tomographic Study
Arturo Renú, MD; Sergio Amaro, MD; Carlos Laredo, MSc, et al.
Department of Neuroscience, Comprehensive Stroke Center, Hospital Clinic, University of Barcelona, August Pi I Sunyer Biomedical Research
Institute (IDIBAPS), Barcelona, Spain.
背景および目的：急性虚血性脳卒中の血管内治療後のコ区間（ CI ）：3.34 ∼ 38.95 ］および BH（ OR ＝ 10.4，95%
ンピューター断層撮影（ CT ）高吸収（ HA ）領域は，血液− CI：3.42 ∼ 31.68 ）の存在と関連していた。完全再開通
脳関門破壊を示す一般的な所見である。二重エネルギーが得られたにもかかわらず転帰不良であった率も，CS
(dual-energy) CT を使用すると，造影剤の滲み出し（CS）に群（ OR ＝ 9.7，95% CI：2.55 ∼ 37.18 ）および BH 群
関連する HA 領域と脳出血（ BH ）に関連する HA 領域を正（ OR ＝ 15.1，95% CI：3.85 ∼ 59.35 ）の方が非 HA 領域
確に鑑別することができる。本研究では，血管内治療後の群よりも有意に高かった。追跡調査時の遅発性出血性変化
CS および BH の予後因子としての意義について評価した。の発生率は，CS 群の患者の方が非 HA 領域群よりも高かっ
方法：血管内治療を行った患者 132 例の前向きコホートをた（ OR ＝ 4.5，95% CI：1.22 ∼ 16.37 ）
。
解析した。二重エネルギー CT 所見に従って患者を非 HA 結論：二重エネルギー CT 上で CS および BH と確認され
領域群（ n ＝ 53 ）
，CS 群（ n ＝ 32 ）
，および BH 群（ n ＝た血液−脳関門の破壊は，血管内治療を行った脳卒中患者
47 ）の 3 群に分類した。新規の出血性変化の発生率は，追の臨床転帰不良と関連していた。また，CS 単独では遅発
跡調査の神経画像検査で記録した。臨床転帰は 90 日目の性出血性変化と関連していた。上記の結果は，急性脳卒中
改変 Rankin スケール（転帰不良：3 ∼ 6 ）で評価した。
における血液−脳関門の破壊が臨床的な関連をもつことを
結果：転帰不良は CS［オッズ比（OR ）＝ 11.3，95% 信頼裏付けている。
Stroke 2015; 46: 673-679. DOI: 10.1161/STROKEAHA.114.008147.
A
高吸収領域なし
内皮細胞
星状膠細胞
管腔
神経細胞
周皮細胞
B
造影剤の滲み出し
造影剤
C 脳出血
密着結合
二重エネルギー・コンピューター
断層撮影（ CT ）による血管内治
療後の脳実質の高吸収領域の分
類。高吸収領域は，単純 CT で
正常な白質もしくは周囲の灰白
質よりも密度が高い領域とした。
A：単純 CT で高吸収領域が認
められない。B：造影画像上の
図1
みで認められる高吸収領域を「造
影剤の滲み出し」群に分類した。
C：疑似単純画像（ VNC ）マップ
のみで認められる高吸収領域を
「脳出血」群に分類した。C：造
影剤の滲み出しと脳出血の両者
が検出された患者は脳出血群に
含めた。
血液
単純CT
STR-J_10-2_ab7_main.indd
STR-J
10-2 ab7 main.indd 31
疑似単純画像
造影画像
血液−脳関門
2015-8-25 14:53:37

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