ORIGINAL ARTICLE

Frequency and outcome of total anterior circulation strokes without

intracranial large-vessel occlusion
E. Giralt-Steinhauera, A. Oisa, S. Abilleirab, X. Urrac, P. Cardona-Portelad, M. Gomise, M. Castellanosf,
bregash, A. Pellise
C. Molinag, J. Martı-Fa i, D. Ca
novasj, M. Gomez-Chocok, J. Kuprinskil,m, D. Cochon and
a
J. Roquer on behalf of the Cat-SCR Consortium

a
Neurovascular Research Group, Neurology Department, Hospital del Mar, Barcelona; bStroke Programme, Catalan Agency for Health
Information, Assessment and Quality (CAHIAQ), Barcelona; cHospital Clınic, Barcelona; dHospital Universitari de Bellvitge, Barcelona;
e
Hospital GermansTrias i Pujol de Badalona, Badalona; fHospital Universitari JosepTrueta de Girona, Girona; gHospital Universitari de

EUROPEAN JOURNAL OF NEUROLOGY

la Valld’Hebron, Barcelona; hHospital Universitari de la Santa Creu i Sant Pau, Barcelona; iHospital Universitari Joan XXIII de
Tarragona, Tarragona; jHospital Parc Taulı de Sabadell, Barcelona; kHospital Moises Broggi, Barcelona; lHospital Universitari Mutua
Terrassa, Barcelona, Spain; mHealthcare Sciences, MMU, Manchester, UK; and nHospital de Granollers, Granollers, Spain

Keywords:
intravenous
thrombolysis, ischaemic
stroke, prognosis
Received 11 March 2016
Accepted 16 September 2016
European Journal of
Neurology 2016, 0: 1–7
doi:10.1111/ene.13187
Background and purpose: The percentage of patients with clinical total ante-
rior circulation infarct (TACI) syndrome treated with reperfusion therapies in
the absence of intracranial large-vessel occlusion (ILVO) was determined and
their characteristics and outcome are described.
Methods: Data from a population-based, prospective, externally audited reg-
istry of all stroke patients treated with intravenous thrombolysis (IVT) and
endovascular therapies in Catalonia from January 2011 to December 2013
were used. Patients with a baseline TACI and initial stroke severity measured
by the National Institute of Health Stroke Scale (NIHSS) ≥ 8, evaluated less
than 4.5 h post-onset, for whom a vascular study prior to treatment was avail-
able (n = 1070) were selected. Clinical characteristics, outcome and radiologi-
cal data for patients treated with IVT alone (n = 605) were compared between
those with detected ILVO (n = 474) and non-ILVO patients (n = 131).
Results: A total of 1070 patients met study criteria; non-ILVO was found in
131 (12.2%). Analysing the 605 patients treated only with IVT, no significant
differences were found between non-ILVO and ILVO patients in age, sex, risk
factors, time-to-treatment and type of radiological studies performed.
Although non-ILVO patients had lower initial stroke severity (P < 0.001) and
a better prognosis (P = 0.001), 51.3% had a poor outcome and 16% were
deceased at 90 days. In 66.4% of patients without ILVO, a recent anterior ter-
ritorial infarct was detected.
Conclusions: Intracranial artery patency was observed in 12.2% of TACI
patients evaluated within 4.5 h. Although absence of ILVO was associated with
slightly better prognosis, more than half had a poor outcome at 3 months.

occlusion [1–5], a condition that carries a particularly

Introduction
Recent trials have demonstrated the usefulness of
advanced recanalization therapies in the first hours of
an ischaemic stroke (IS) due to acute large-vessel
Correspondence: A. Ois, Neurologıa, Hospital del Mar, Passeig
Marıtim 25 29, Barcelona, Spain (tel.: 932483235, fax: 932483236;
e-mail: egiralt@imim.es).
high rate of death and disability [6–8].
Few stroke scales may be useful to identify patients
with an intracranial large-vessel occlusion (ILVO).
The Oxfordshire Community Stroke Project (OCSP)
developed a simple classification for acute stroke
based on clinical features, which correlates with func-
tional outcome [9,10]. Previous studies have demon-
strated that a classification as total anterior

© 2016 EAN 1
2 E. GIRALT-STEINHAUER ET AL.
circulation infarct (TACI) is associated with worse
prognosis and is more likely than other subtypes to
have proximal ILVO [11]. Moreover, high National
Institutes of Health Stroke Scale (NIHSS) scores are
correlated with the presence of an ILVO, but the best
cut-off point is still controversial [12,13]. Recently, the
Rapid Arterial Occlusion Evaluation (RACE) scale
has been reported to identify these patients in pre-hos-
pital settings, administered by medical emergency
technicians [14].
However, in clinical practice it is not unusual to
find patients presenting with acute severe neurological
symptoms without an identifiable ILVO. Although
favourable outcomes and small radiological lesions
are expected in such patients, this remains to be deter-
mined [15,16].
In this subset of severely affected patients, the
absence of a visible occlusion can lead to uncertainty
about diagnosis and therapeutic approaches. Some of
these patients may be withdrawn from intravenous
thrombolysis (IVT), assuming a ‘stunned brain’ syn-
drome with delayed recovery [17].
The aim of this prospective observational study was
to quantify the frequency of total anterior circulation
ischaemic stroke patients evaluated within 4.5 h of
onset and treated with reperfusion therapies who do
not have a visible arterial occlusion, and to analyse
their clinical characteristics, outcomes and radiological
data.
Methods and patients
Participating hospitals and study design
Data from the SONIIA database, a population-based,
prospective registry that includes data from all IVT
and endovascular treatments for IS performed in Cat-
alonia (Spain) [18], were used. Data collection
involved all Catalan hospitals with the capacity to
deliver these reperfusion therapies. At each hospital,
designated local investigators were charged with
requesting the informed consent, including all consec-
utive patients with IS undergoing reperfusion thera-
pies in the registry, and collecting the study data.
Inclusion criteria for this study were the following:
(i) IS patients evaluated within the first 4.5 h after
stroke onset between January 2011 and December
2013; (ii) clinical combination of higher cerebral dys-
function, homonymous visual field defect and motor
and/or sensory deficit involving at least two of three
body areas (face, arm and leg) (OCSP clinical classifi-
cation of TACI); (iii) baseline stroke severity ≥8 as
measured by the NIHSS; and (iv) availability of a vas-
cular study previous to reperfusion therapies that
included at least one of intracranial two-dimensional
colour-coded duplex ultrasonography, computed
tomography angiogram (CTA), magnetic resonance
angiogram (MRA) and/or angiography.
Patients were classified as ILVO if the vascular
study showed an occlusion in the terminal internal
carotid artery and/or a proximal or distal occlusion of
the first/second division of one or more of the follow-
ing arteries: middle cerebral artery (MCA), anterior
cerebral artery (ACA) and/or posterior cerebral
artery.
Age, sex, pre-stroke modified Rankin Scale (mRS)
score, time to IVT, vascular risk factors (hypertension,
diabetes, hyperlipidaemia) and prevalence of atrial fib-
rillation were obtained from patients, their caregivers
and/or medical records and entered online by each
research coordinator, using a structured questionnaire.
Severe extracranial internal carotid disease was defined
as significant ipsilateral stenosis (≥70%) or occlusion,
recorded at the time the first vascular study was per-
formed. At 3 months, local investigators recorded the
stroke aetiology, following the Trial of ORG 10172 in
Acute Stroke Treatment classification (TOAST) [19], or
identified the event as a stroke mimic.
Patients underwent computed tomography (CT) or
magnetic resonance imaging (MRI) between 24 and
36 h after thrombolysis (control neuroimaging) and
additional scans in the case of clinical deterioration.
Since information about final ischaemic lesion are
lacking in the registry, research coordinators at each
site were asked to retrospectively review radiological
data for each of these patients.
Recent infarction on imaging in the appropriate
hemisphere was classified according to six categories:
no ischaemic lesion, lacunar stroke (single acute
infarction ≤1.5 cm on CT scan or ≤2 cm on MRI with
greatest diameter within the territory of basal pene-
trating arteries in axial imaging) [20], large lesion
(>33% of the MCA territory or deep and cortical
lesions), non-large lesion (≤33% of the MCA territory
or exclusively subcortical infarct >1.5 cm) [21], lesions
in the ACA territory, and lesions in the posterior cere-
bral artery or in two or more territories.
Outcome measures
The outcome was determined by mRS score at
3 months. Three-month follow-up data were obtained
during a patient visit to the hospital or from tele-
phone interview, if patients failed to attend the visit.
Poor outcome was defined as moderate to severe dis-
ability or death (mRS 3–6) at 3-month follow-up or
worsening by 1 point in those patients with pre-stroke
disability (previous mRS > 2).
© 2016 EAN
 TOTAL ANTERIOR INFARCT WITHOUT ARTERIAL OCCLUSION
Secondary outcomes included NIHSS at 24–36 h;
early neurological deterioration (END), defined as an
increase in the NIHSS score ≥4 points in the first 24–
36 h after admission; dramatic recovery, defined as at
least a 10-point improvement in the NIHSS score or a
score of 0–1 at 24–36 h; symptomatic intracranial
haemorrhage (SICH), defined as any intracranial
haemorrhage on imaging studies and an increase of 4
points or more in the NIHSS score; mortality at 24–
36 h; mortality at 3 months and a recurrent stroke
during the 3 months follow-up.
Statistical analysis
The registry coordinator identified the total number
of patients who fulfilled the inclusion criteria; of these
the percentage of patients without ILVO was assessed.
Subsequently, a comparative analysis was performed,
restricted to patients treated with isolated IVT,
between patients with and without ILVO. Patients
with endovascular therapies were excluded from this
second analysis to avoid heterogeneities and difficul-
ties in comparison.
Percentages were used to describe categorical vari-
ables and means (standard deviation) or medians (in-
terquartile range) to describe continuous variables.
Comparative analysis was performed using the Pear-
son chi-squared test (categorical variables), the t test
(normal continuous variables) or the Mann–Whitney
U test (when normality was difficult to assume). Two-
tailed P values < 0.05 were considered statistically sig-
nificant. Binary outcomes were analysed for patients
without ILVO using logistic regression and reported
as adjusted odds ratios (aORs) with 95% confidence
intervals (CIs) to indicate statistical precision. All sta-
tistical analysis was done using SPSS software pack-
age version 18 (SPSS Inc., Chicago, IL, USA). The
SONIIA registry satisfies all requirements mandated
by Spain’s law on the protection of personal data.
Inclusion in the registry is subject to the patient’s per-
mission.
Results
Of the 1070 patients treated with any reperfusion ther-
apy, non-ILVO was found in 131 patients (12.2%)
(Fig. 1).
Demographic and clinical baseline characteristics
Demographic data, vascular risk factors, time from
stroke onset to treatment, type of vascular study and
follow-up neuroimaging performed on 605 patients
who received IVT alone are presented in Table 1.
© 2016 EAN
3
Total anterior infarct syndromes
Total cohort and NIHSS ≥ 8, arriving in less
n = 1070 than 4.5 h and with an
arterial study available
n = 465 Endovascular therapies
Stroke cohort treated
with isolated IVT
n = 605
With intracranial large-
vessel occlusion
n = 474
Without intracranial large-
vessel occlusion
n = 131
Figure 1 Flowchart of patients’ inclusion.
There were no significant differences in these parame-
ters between ILVO (n = 474) and non-ILVO patients
(n = 131). Differences regarding stroke subtypes were
identified (P = 0.041): more cardioembolic strokes
were found in the ILVO group (57.5% vs. 49.2%)
and more undetermined aetiology in the non-ILVO
group (33.3% vs. 26%).
Clinical outcome
Overall, the absence of major arterial occlusions had a
significant relationship to many of the outcome vari-
ables (Table 2). Data on 3-month primary outcomes
were available for 124 of 131 non-ILVO patients. Com-
pared to the ILVO TACI group, fewer non-occluded
patients had a poor outcome (51.6% vs. 68.4%, respec-
tively; P = 0.001); even after excluding stroke mimics
(n = 7), this difference persisted (53.8% vs. 68.4%,
respectively; P = 0.003). The NIHSS scores at admis-
sion and at 24–36 h were significantly lower in the non-
ILVO patients than in the ILVO group (both
P < 0.001), and there was a significantly higher propor-
tion of dramatic recovery in the non-ILVO group
(41.9% vs. 29%, respectively; P = 0.006). There were no
significant differences between the groups in the occur-
rence of END (P = 0.710), SICH (P = 0.727), mortality
at 24–36 h (P = 0.463) and stroke recurrence during the
3-month follow-up (P = 0.561). Although 90-day mor-
tality was higher in the ILVO group (26.6%), a non-neg-
ligible 16.1% of the non-ILVO patients died within the
first 90 days (P = 0.016). A subgroup analysis was
undertaken to assess the predictors of poor outcome in
non-ILVO patients (Table 3). Diabetes mellitus (aOR
2.65; 95% CI 1.06–6.63, P = 0.037), previous known
atrial fibrillation (aOR 4.16; 95% CI 1.52–11.34,
P = 0.006) and higher initial stroke severity (aOR 1.16;
4 E. GIRALT-STEINHAUER ET AL.

Table 1 Clinical and radiological charac-

Non-ILVO n = 131 ILVO n = 474 P value
teristics of patients according to intracra-
Age, mean (SD) 75.5 (10.9) 75.0 (11.4) 0.639 nial arterial status in patients treated with
Female sex, n (%) 66 (50.4) 247 (52.1) 0.726 IVT
Pre-stroke mRS ≤ 2, n (%) 115 (87.8) 418 (88.2) 0.901
Hypertension, n (%) 94 (71.8) 364 (76.8) 0.234
Hyperlipidaemia, n (%) 63 (48.1) 199 (42) 0.212
Diabetes mellitus, n (%) 41 (31.3) 114 (24.1) 0.093
Previous known AF, n (%) 34 (26) 141 (29.7) 0.397
Initial severity NIHSS, median (IQR) 16 (12–20) 18 (15–21) <0.001
Severe carotid disease, n (%) 26 (19.8) 84 (17.7) 0.577
Time from stroke onset to 144.6 (57.6) 138.9 (54.5) 0.274
treatment (min), mean (SD)
Vascular study performed, n (%) 0.766
Intracranial 2D color-coded 28 (21.4) 104 (21.9)
duplex ultrasound
CT angiography 101 (77.1) 359 (75.7)
MR angiography 2 (1.5) 7 (1.5)
Arteriography 0 (0) 4 (0.8)
Control neuroimaging, n (%) 0.677
CT 97 (74) 369 (77.8)
MRI 1 (0.8) 6 (1.3)
Both 30 (22.9) 94 (19.8)
No neuroimaging performed 3 (2.3) 5 (0.8)
Stroke mimic, n (%) 7/131 (5.3) 0/474 (0)
Stroke aetiology, n (%) 0.041
Atherothrombotic 16/120 (13.3) 69/447 (15.4)
Cardiac embolism 59/120 (49.2) 257/447 (57.5)
Small-artery disease 1/120 (0.8) 0/447 (0)
Other determined aetiology 4/120 (3.3) 5/447 (1.1)
Undetermined 40/120 (33.3) 116/447 (26)

AF, atrial fibrillation; CT, computed tomography; ILVO, intracranial large-vessel occlusion;
IQR, interquartile range; IVT, intravenous thrombolysis; MRI, magnetic resonance imaging;
mRS, modified Rankin Score; NIHSS, National Institutes of Health Stroke Scale; Bold
values indicates a statistically significant result.

95% CI 1.05–1.28, P = 0.004) were independently asso- P < 0.001) and fewer had MRIs performed (10% vs.
ciated with poor outcome. 24.8%, P = 0.148), respectively.

Radiological data Discussion

Finally, neuroimaging data on recent infarction were
available for 128 of 131 non-ILVO patients. It was
found that 78.9% of patients had visible ischaemic
changes (66.4% with an anterior territorial infarct,
9.4% posterior infarcts or lesions in multiple territories
and 3.1% with a lacunar infarction). In 27 of 128
(21.1%) patients no recent infarct was visible [seven of
these 27 (25.9%) underwent a control MRI]. This per-
centage was higher than the 28 of 465 (6%) patients
without lesion and with ILVO [two of these 28 (7.1%)
underwent a control MRI] (P < 0.001) (Table 4).
Detailed examination of the characteristics of these 20
patients, after excluding the seven cases finally diag-
nosed as stroke mimics, compared to patients without
ILVO but with a visible lesion showed that they were
older (81.3 vs. 75 years, P = 0.01), had a lower initial
stroke severity (median NIHSS 14 vs.17, P = 0.019),
lower NIHSS value at 24–36 h (median NIHSS 2 vs. 9,
The actual percentage of patients presenting with sev-
ere anterior circulation syndromes without an ILVO
was unknown. In this large, robust, multicentre cohort
of consecutive acute TACI patients treated with reper-
fusion therapies, this condition was observed to occur
in 12.2% of patients.
Importantly, our study showed that, despite all
patients without ILVO receiving IVT, a significant
proportion (more than 50%) did not achieve a favour-
able outcome, with a 16% mortality rate at 3 months.
However, our data did not show significant differences
in age, sex or vascular risk factors compared to those
with ILVO; predictors for prompt identification of
these non-occluded patients could not be reliably
determined. Comparing the two groups, those without
ILVO were more likely to have milder neurological
deficit at presentation and at 24–36 h, with a higher
percentage of dramatic recovery.

© 2016 EAN
 TOTAL ANTERIOR INFARCT WITHOUT ARTERIAL OCCLUSION 5

Table 2 Outcome measures according to intracranial arterial status an absence of artery occlusion had developed a cere-
in patients treated with IVT bral infarction, mostly in the anterior territory.
Non-ILVO In about 20% of patients, no acute infarct was
n = 131 ILVO n = 474 P value detected, although only seven were diagnosed as
stroke mimic by local investigators. In agreement with
Poor outcome 64/124 (51.6) 301/440 (68.4) 0.001
at 3 monthsa previous studies, a low percentage of our patients pre-
Secondary outcomes sented lacunar or posterior infarcts despite the initially
NIHSS 24–36 h, 7 (3–17) 14 (6–20) <0.001 high severity that simulates a TACI syndrome [25,26].
median (IQR)b Finally, two important questions arise. First, do
END, n (%)b 10/129 (7.8) 40/455 (8.8) 0.710
patients with clinically severe IS who have no demon-
Dramatic recovery 54/129 (41.9) 132/455 (29) 0.006
at 24–36 h, n (%)b strated ILVO at presentation benefit from IVT? Our
SICH, n (%)c 8/128 (6.3) 25/465 (5.4) 0.727 study was not designed to address this issue, because
Mortality, first 24–36 h, 3/131 (2.3) 17/474 (3.6) 0.463 all patients were treated. However, a recent retrospec-
n (%) tive study compared 256 non-ILVO patients on CTA/
Mortality at 3 months, 20/124 (16.1) 117/440 (26.6) 0.016
MRA (103 patients treated with IVT and 153 patients
n (%)a
Recurrent stroke 2/124 (1.6) 11/440 (2.5) 0.561 who were not) and found better clinical outcomes in
at 3 months, n (%)a the treatment group [27]. Secondly, what can be
offered to these patients, who are not candidates for
END, early neurological deterioration; ILVO, intracranial large-ves-
endovascular therapies because of the absence of a
sel occlusion; IQR, interquartile range; IVT, intravenous thromboly-
sis; NIHSS, National Institutes of Health Stroke Scale; SICH,
symptomatic intracranial haemorrhage; Bold values indicates a sta-
tistically significant result. Table 4 Radiological lesions in control neuroimaging for both
a
Outcome data at 3 months were available for 124/131 non-ILVO groups
patients and 440/474 ILVO patients.
b
Secondary outcome data at 24–36 h, except for mortality, were Non-ILVO ILVO
available for 129/131 non-ILVO patients and 455/474 ILVO patients. Radiological lesions n = 128 n = 465
c
Information about SICH at 24–36 h were available for 129/131
No infarct, n (%) 27 (21.1) 28 (6)
non-ILVO patients and 465/474 ILVO patients.
Infarct, n (%) 101 (78.9) 437 (94)
Anterior territory 85 (66.4) 384 (82.5)
MCA large infarct 27 (21.1) 219 (47.1)
In the subgroup analysis regarding only those MCA non-large infarcts 54 (42.2) 162 (34.8)
patients without ILVO, independent predictors for ACA 4 (3.1) 3 (0.6)
poor outcome were the same as those described for Posterior or multiple territories 12 (9.4) 45 (9.7)
general stroke patients, such as NIHSS score, previous Lacunar infarct 4 (3.1) 8 (1.7)

known atrial fibrillation or diabetes mellitus [22–24]. ACA, anterior cerebral artery; ILVO, intracranial large-vessel occlu-
Furthermore, almost 80% of patients presenting with sion; MCA, middle cerebral artery.

Table 3 Bivariate and multivariate analysis

Bivariate analysis
according to poor outcome at 3 months in
patients without ILVO Good Multivariate analysis,
outcome Poor outcome adjusted
Factors analysed n = 60 (48%) n = 64 (52%) P value OR (95% CI)*

Age, mean (SD) 73.8 (12.1) 76.6 (9.5) 0.143 1.01 (0.98–1.05)
Female sex, n (%) 30 (50) 33 (51.6) 0.862 0.85 (0.36–1.98)
Pre-stroke mRS ≤2 56 (93.3) 54 (84.4) 0.115
Hypertension, n (%) 39 (65) 50 (78.1) 0.105
Hyperlipidaemia, n (%) 27 (45) 32 (50.0) 0.577
Diabetes mellitus, n (%) 12 (20.0) 24 (37.5) 0.032 2.65 (1.06–6.63)
Previous known AF, n (%) 7 (11.7) 25 (39.1) <0.001 4.16 (1.52–11.34)
NIHSS, median (IQR) 14 (11–17) 17 (14–21) 0.001 1.16 (1.05–1.28)
Severe carotid 8 (13.3) 16 (25) 0.1
disease, n (%)

AF, atrial fibrillation; CI, confidence interval; ILVO, intracranial large-vessel occlusion; IQR,
interquartile range; mRS, modified Rankin Score; NIHSS, National Institutes of Health
Stroke Scale; OR, odds ratio.
*Including age, sex and significant variables in the bivariate analysis (P < 0.05).

© 2016 EAN
6 E. GIRALT-STEINHAUER ET AL.
treatable occlusion, to improve their outcomes? In our
opinion, this remains an open question.
This study has some limitations. First, although the
cases were prospectively included and data accuracy
was assured through quality controls, vascular status
and radiological lesions were retrospectively reviewed.
Considering the inclusion of centres with different
baseline vessel-imaging protocols, non-detection of
ILVO could be due to a lower sensitivity of the vascu-
lar technique used. To limit this possibility, those
patients evaluated exclusively using a transcranial
blind-Doppler were excluded. Regarding the other
techniques, no differences were found according to the
type of study used. Moreover, another technical issue
was the resolution of follow-up radiological studies; it
has to be taken into account that the overall number
of control MRI performed was low (approximately
20% in each group). Furthermore, the radiological
categories were simple, and even if a few lesions were
misclassified it would probably not alter the overall
study conclusions. Secondly, an exact picture of acute
severe stroke treatment implementation across Cata-
lan hospitals cannot be offered, because the registry
does not include data about patients who did not
receive reperfusion therapies.
In conclusion, the lack of visible ILVO in clinically
severely affected patients in a multicentre cohort trea-
ted with reperfusion therapies is described for the first
time. Compared to ILVO stroke patients treated only
with IVT, the absence of ILVO was associated with
slightly better outcomes. Nonetheless, more than half
had an unfavourable prognosis.
Acknowledgements
Elaine M. Lilly, PhD, provided assistance in the Eng-
lish translation.
This work was supported by grants from ISC III
FEDER (RD12/0042/0020), Redes Tem aticas de
Investigacion Cooperativa (RETICS-INVICTUS
RD012/0014) and FEDER (Fondo Europeo de Desar-
rollo Regional).
Disclosure of conflicts of interest
The authors report no disclosures.
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