Perspectives in Medicine (2012) 1, 185193

Bartels E, Bartels S, Poppert H (Editors):

New Trends in Neurosonology and Cerebral Hemodynamics an Update.
Perspectives in Medicine (2012) 1, 185193

journal homepage: www.elsevier.com/locate/permed

Transcranial Doppler in acute stroke management

A real-time bed-side guide to reperfusion and
collateral ow
Christopher Levi a,b,, Hossein Zareie a, Mark Parsons a

a
Centre for Translational Neuroscience & Mental Health Research, University of Newcastle & Hunter Medical Research Institute,
Australia
b
Director, Acute Stroke Services, John Hunter Hospital, Newcastle, NSW, Australia

KEYWORDS Summary
Transcranial Doppler; Introduction: Assessment of cerebral hemodynamics with transcranial Doppler (TCD) can pro-
Acute ischemic vide real-time, bed-side assessment of important prognostic variables in acute stroke such as the
stroke; status of collateral ow and vessel recanalization status. In acute middle cerebral artery (MCA)
Collateral ow; occlusion, anterior cerebral artery (ACA) ow diversion (FD) is correlated with leptomeningeal
Recanalization; collateral ow and may be a clinically useful prognostic indicator. Continuous TCD monitor-
Microembolic signals ing of MCA recanalization may also provide useful prognostic information including changes in
ow pattern and the occurrence of microembolic signals (MES). We present studies examining
associations between ACA FD, MCA recanalization and MES patterns on the characteristics of
ischemia and infarction in acute MCA stroke.
Methods: Patients studied were consecutive sub-6 h from onset internal carotid artery (ICA) ter-
ritory ischemic stroke cases. A subset of these cases with MCA occlusion were studied with 2 h of
continuous MCA monitoring. All patients underwent baseline multimodal computed tomographic
(CT) scanning, baseline diagnostic TCD, and 24 h post stroke magnetic resonance (MR) imaging.
All MCA occlusion patients studied with continuous monitoring were treated with intravenous
thrombolysis. ACA ow diversion was dened as ipsilateral mean velocity of 30% or greater than
the contralateral artery. Recanalization status was assessed using the Thrombolysis In Brain
ischemic (TIBI) grading system and MES counted off-line by experienced observers. Lep-
tomeningeal collateralisation (LMC) was graded on CT angiography. Infarct core and penumbral
volumes were dened using CT perfusion thresholds. Infarct volume, reperfusion, and vessel
status were measured at 24 h using MR techniques. In patients undergoing recanalization moni-
toring, comparison was made between those with and without major reperfusion. Multivariable
regression analysis was performed to assess for any associations between ACA ow diversion,
TIBI grades and MES on infarction controlling for other important clinical variables.

Corresponding author at: Department of Neurology, John Hunter Hospital, Locked Bag No. 1., Hunter Regional Main Centre, 2310 NSW,

Australia. Tel.: +61 249855593; fax: +61 249213488.

E-mail address: christopher.levi@hnehealth.nsw.gov.au (C. Levi).

2211-968X 2012 Published by Elsevier GmbH. Open access under CC BY-NC-ND license.
doi:10.1016/j.permed.2012.02.044
186 C. Levi et al.

Results: Flow diversion: 53 patients qualied for FD analysis. ACA FD was associated with good
collateral ow on CT angiography (p < 0.001) and was an independent predictor of admission
infarct core volume (p < 0.001), and 24 h infarct volume (p < 0.001). The likelihood of a favourable
outcome (modied Rankin score 02) was higher (Odds ratio = 27.5, p < 0.001) in those with ow
diversion.
Recanalization monitoring: 27 patients with MCA occlusion treated with intravenous thrombolysis
were included in the analysis of recanalization patterns (16 cases with major reperfusion, 11 cases
of non-reperfusion). Major TIBI grade improvement ( 3 grades overall) was associated with
major reperfusion (p = 0.04) excellent 90 day clinical outcome (p = 0.03), improvement in clinical
outcome at 24 h (p = 0.049) and attenuated infarct growth (p = 0.06). MES did not associate with
reperfusion status or outcome variables.
Conclusions: ACA FD is independently associated with the smaller infarction volumes and more
favourable 90 day clinical outcome. Flow diversion may provide enhanced perfusion of ischemic
tissue, offering some protection against infarct expansion and buying-time for effective reper-
fusion and tissue salvage.
Major TIBI grade improvement associates with major reperfusion, favourable 24 h and 90 day clin-
ical outcomes along with a trend to smaller infarct volumes in patients treated with intravenous
thrombolysis.
Acute bedside transcranial Doppler assessment of ACA FD and recanalization aids prognostication
and therapeutic decision making in acute stroke.
2012 Published by Elsevier GmbH. Open access under CC BY-NC-ND license.

Introduction clinical surrogates such as reperfusion and infarct core

growth.
Leptomeningeal collateralisation (LMC) is a recognised
Reperfusion therapies in acute ischemic stroke are becoming
determinant of tissue fate in patients with acute ante-
both more widely used and more varied. In routine clini-
rior circulation ischemic stroke [914]. The status of LMC
cal practice, intravenous thrombolysis is generally regarded
as measured on catheter angiography in middle cerebral
as rst-line therapy and is being delivered to over
artery occlusion (MCAO) has been shown to inuence brain
20% of ischemic stroke patients in many centers [1].
perfusion and clinical outcomes [12,15]. Collateral ow
Advances in endovascular therapies, in particular, the var-
in MCAO measured using CT angiography (CTA) has been
ious mechanical thrombectomy techniques [2,3], are being
demonstrated to inuence the volume of ischemic penum-
increasingly applied and, although generally regarded as
bra measured on CT perfusion (CTP) and clinical outcome
second-line treatment options based on the limited ran-
[16]. In MCA occlusion, ow is commonly diverted from the
domised evidence, have signicant potential advantages
distal internal carotid artery (ICA) to the ACA [11,1720].
over intravenous thrombolysis. With this increase in ther-
This ow diversion (FD) can be detected using TCD, where
apeutic options comes a need for development of validated
typically, a higher velocity ow in the ipsilateral ACA can be
methods for both selection of patients for specic thera-
measured as compared with that of the contralateral ACA
pies and also, the identication of patients not responding
[17,2024]. A retrospective review of data of patients with
to intravenous thrombolysis. Advanced MR and CT imag-
a proximal MCA occlusion from the CLOTBUST trial demon-
ing are well suited to guide initial patient selection for
strated that ACA FD was associated with earlier and better
reperfusion therapy. Both techniques can provide informa-
neurological improvement, supporting the hypothesis that
tion on the characteristics of vessel occlusion, collateral
FD may provide nutrient ow to the ischemic brain [23].
ow and the extent of both hypoperfusion and established
To further clarify the potential clinical role for TCD in
infarction [4,5]. Both techniques have been used in ran-
selecting patients for reperfusion therapies we investigated
domised clinical trials and are now commonly used in routine
clinical practice to identify likely responders to reperfu-
1. The relationship between ACA-FD on TCD, LMC status
sion therapy [6]. However, imaging methods for identifying
on CTA, and measures of the acute perfusion lesion and
non-responders to intravenous thrombolysis have been
extent of infarction.
less well studied and currently no well validated or generally
2. The relationship between TCD features of recanalization
accepted approach exists.
and major reperfusion, infarct growth attenuation and
Transcranial Doppler is well suited to the task of iden-
clinical outcomes.
tifying both collateralisation and the time course and
completeness of recanalization of the arteries of the circle
of Willis [7]. Numerous studies [8] have examined charac-
teristics and patterns of recanalization and its association
Patients and methods
with early neurological improvement. Recent advances in
multimodal CT and MR imaging now allow more detailed Patients
investigation and understanding of the potential role for TCD
in guiding acute stroke therapy, where correlation is possi- The overall study population is a prospective cohort of
ble between important TCD characteristics and important consecutive TCD examinations in acute anterior circulation
TCD correlates of collateral ow, reperfusion and outcome in acute stroke
ischemic stroke patients presenting within 6 h of symptom
onset. The cohort was collected between June 2007 and
January 2010. Eligibility criteria were presence of a demon-
strated occlusion of either MCA or ICA on baseline acute CTA
in a patient undergoing assessment for potential suitability
for intravenous thrombolytic therapy. A subgroup of patients
with MCA occlusion and baseline TIBI grades 3 treated with
intravenous thrombolysis was used to study recanalization
features and MES characteristics. Patients were excluded if
a pre-morbid Rankin score (mRS) was greater than 3 or seri-
ous co-morbid illness limited the patients life expectancy,
if posterior circulation stroke was suspected, of tempo-
ral acoustic windows were inadequate, if unilateral ACA
hypoplasia or aplasia was evident on CTA (dominant ACA
at least twice the size of the contralateral ACA [25,26]).
Stroke severity was measured using the National Institutes
of Health Stroke Scale (NIHSS). Patient outcome was deter-
mined using the NIHSS at 24 h from stroke onset modied
Rankin scale at 90 days blind to imaging data. The study was
approved by the institutional ethics committee and individ-
ual patient consent was obtained.
Baseline TCD examination
TCD ultrasound was performed using a digital power-motion
Doppler unit (PMD 100, Spencer Technologies) with 2-MHz
pulsed wave diagnostic transducers. The initial TCD exami-
nation was performed immediately prior to commencement
of intravenous t-PA, or immediately following CT scanning
in the case of those not eligible for thrombolysis. The
insonation protocol was as follows: initially the non-affected
MCA was insonated from a depth of 6045 mm as a unidi-
rectional signal towards the probe. This included M1 and
M2 segments to determine the depths and velocity ranges
and continued to bifurcation, terminal ICA (TICA), ACA and
PCA. The proximal ACA waveform was determined from a
depth of 6070 mm as a unidirectional signal away from the
probe. Next, the affected MCA waveform was determined
and then the bifurcation, TICA, ACA and PCA. Flow mea-
surements for ACA FD were taken at ACA A1 segment (depth
6070 mm) as a ow away from the probe. The ophthalmic
arteries (depths: 4050 mm) and ICA siphons (5565 mm)
were then checked for ow direction and pulsatility through
the transorbital windows bilaterally [27].
Peak systolic, diastolic and mean ow velocities and pul-
satility indices were measured off-line. FD was considered
present when the ipsilateral ACA mean blood ow velocity
was at least 30% greater than that of the contralateral ACA
[20,22]. All TCD studies and measurements were attended
by an experienced sonographer (DQ) who remained blind to
CT and MR imaging data. Baseline measurements and ves-
sel segment insonation were checked where appropriate by
another experienced sonographer (CRL).
Middle cerebral artery TCD monitoring and
recanalization characteristics
Unilateral TCD monitoring was also performed using the
digital power-motion Doppler unit (PMD 100, Spencer
Technologies) with a 2-MHz pulsed wave transducer xed
in place using the Spencer Marc series head frame. The
187
monitoring protocol was as follows: after determining TIBI
grade of 3 or less, the sample volume length was set at
10 mm and insonation depth set immediately distal at the
site of the commencement of attenuation in MCA waveform.
Power output was set at the maximum permitted level;
monitoring commenced immediately after commencement
of intravenous thrombolysis and continued for 2 h. Contin-
uous off-line review of recanalization status was performed
by an experienced neurosonologist (HZ) and documentation
of TIBI grades made a 5 minutely intervals through the 2 h
monitoring period. Sudden major improvement in TIBI grade
was dened as increase of 3 TIBI grades in <15 min. Full
recanalization was dened as achievement of TIBI grades 4
or 5. All TCD analyses were performed blind to CT and MR
imaging analyses.
MES were counted at off-line review of the by consen-
sus human expert assessment (HZ and CRL) using standard
acoustic and spectral criteria and also using PMD TCD criteria
and related embolic signatures [28,29].
Brain imaging
CT scans were obtained with a multidetector scanner (16-
slice Philips Mx8000). Whole brain noncontrast CT was
performed: 120 kV, 170 mA, 2 s scan time, contiguous 6-mm
axial slices. Perfusion CT (CTP) followed, comprising two
60-s series. Each series consisted of one image per slice per
second, commencing 5 s after intravenous administration of
40 ml of non-ionic iodinated contrast at a rate of 5 ml/s via
a power injector. Each perfusion series covers a 24 mm axial
section acquired as two adjacent 12-mm slices. The rst sec-
tion was at the level of the basal ganglia/internal capsule,
and the second was placed directly above, towards the ver-
tex. Thus, the two perfusion CT series allows assessment of
two adjacent 24 mm cerebral sections [30].
CT angiography
CTA was performed after CTP, using the parameters 120 kV,
125 mA, slice thickness 1.5 mm, pitch 1.5:1, helical scan-
ning mode, intravenous administration of 70 ml of non-ionic
contrast at 4 ml/s. Bolus-tracking software was used to
maximise image acquisition at peak contrast arrival. Data
acquisition was from base of skull to the top of lateral
ventricles. Patients were selected if complete occlusion on
CTA was present. Contrast within the distal MCA (beyond
the occlusion) was presumed secondary to retrograde lling
via leptomeningeal collaterals. Collateral status was divided
into good, moderate or poor based on degree of
reconstitution of the MCA up to the distal end of its occlu-
sion on CTA [16]. Moderate ow and poor collateral ow
were graded together as reduced.
MRI
Follow-up imaging used a 1.5 T MRI (Siemens Avanto). The
stroke MRI protocol included an axial spin-echo T2-weighted
series, an axial isotropic diffusion-weighted echoplanar
spin-echo sequence (DWI), time of ight MR angiography
188
(MRA), and perfusion-weighted imaging (PWI) with an axial
T2*-weighted echoplanar sequence [31].
Assessment of perfusion lesions and nal infarct
volumes
De-identied CTP and perfusion MR data were analysed with
MIStar software using an identical deconvolution algorithm
to generate both CTP and MR perfusion maps, including
mean transit time (MTT) and cerebral blood volume (CBV)
[30,31]. A MTT delay of >145% compared with the contra-
lateral hemisphere was used to calculate automated CTP
MTT lesion volumes [32]. Within the CTP MTT lesion, base-
line infarct core volume was determined from CBF maps
using an automated threshold of <40% normal tissue [5].
Thus, penumbral volume was determined from the differ-
ence between the baseline CTP MTT lesion and CBF lesions,
and the CTP mismatch ratio was calculated from MTT Flow diversion
lesion volume/CBF lesion volume (using the above thresh-
olds for MTT and CBF lesion volumes). The same software
was used to measure 24 h infarct volume using automated
signal intensity thresholds for MR-DWI, or Hounseld unit
thresholds for CT [31]. The follow-up infarct maps were co-
registered with baseline CTP maps to obtain volumes from
the same spatial position and axis orientation. To determine
reperfusion, the automated threshold (MTT delay of >145%
compared with contra-lateral hemisphere) was used to cal-
culate 24 h MR (or CTP)-MTT lesion volumes. The MR-MTT
maps were co-registered with baseline CTP so that MR-MTT
volumes were obtained from the same spatial position and
axis orientation as the CTP-MTT maps. All lesion volumes
were obtained from the average of measurements taken on
separate occasions by a stroke neurologist and stroke fel-
low. Reperfusion was dened as major in patients with
>80% reduction in baseline-24 h MTT lesion volume and/or
complete vessel recanalization [30,31]. All imaging analyses
were performed blind to TCD data.
During the study a subgroup of patients were included
in the randomised Tenecteplase in Stroke trial receiving
either intravenous tenecteplase (0.1 mg/kg or 0.25 mg/kg
as a bolus dose) or standard alteplase therapy within 6 h of
symptom onset [33].
Statistical analysis
Statistical analysis was performed using Stata (Ver-
sion 10, College Station, TX 2007). Statistical comparisons
between patients with and without FD were performed for
the total sample (ICAOs and MCAOs, n = 53) as well as for
the MCAOs alone (n = 42). Comparisons between patients
with major reperfusion and no reperfusion were made in
the subgroup pf patients with MCA occlusion treated with
intravenous thrombolysis. Differences in continuous mea-
surements were tested using the MannWhitney U test and
differences in categorical outcomes were tested using the
Fishers exact test with two tailed p values. The impact of
FD and TIBI grade on admission and 24 h perfusion lesions,
infarct volumes and clinical outcome was examined using
regression analyses to adjust for potential confounding fac-
tors.
C. Levi et al.
Results
Among 90 consecutive patients assessed for intravenous
thrombolysis eligibility within 6 h of stroke onset, 53 (42
of whom received thrombolytic therapy) were included
in the analysis for ACA FD. A subgroup of 27 patients
with MCA occlusion treated with intravenous thrombolysis
was included in the analysis of recanalization character-
istics. Patients were excluded due to lack of evidence of
ICA or MCA occlusion on CTA [17], absence of temporal
windows [11], incomplete or poor quality CTA [4], PCA occlu-
sion [1] or aplastic or hypoplastic ACA [3], and non-stroke
[1]. Occlusion site was determined by CTA and included
42 M1/M2 occlusions and 11 intracranial ICA occlusions.
Baseline characteristics of the main sample and MCA throm-
bolysis subgroup are shown in Tables 1 and 2.
Signicant FD to the ACA was present in 24/53 (45%) patients
and to the PCA in 8/38 (21%) patients. Because adequate
insonation of both PCAs was not possible in 15/53 (28%) of
patients, further analysis of PCA FD was not undertaken. The
differences in admission and outcome variables between
groups dened by the presence or absence of FD are dis-
played in Table 3.
The presence of ACA FD was strongly associated with a
CTA good collateral ow grade; 18 of 23 (78%) with good CTA
collaterals had an ACA ratio greater than 1.3. However, 23
of 26 (88%) with reduced CTA collaterals had an ACA FD ratio
less than 1.3 (Odds ratio 27.6, p < 0.001).
Twenty-four hour core infarct expansion ( core >5 ml
between baseline and 24 h imaging) was also strongly
Table 1 Baseline characteristics of all patients presenting
with acute anterior circulation ischemic stroke studied with
TCD (n = 53).
Variables
Age, yearsa 72 (6579)
Male genderb 30 (56.6)
Admission National Institution Health 17 (4.9)
Stroke Score; mean (SD)
History of hypertensionb 39 (74)
Atrial brillation by history or ECGb 22 (42)
History of myocardial infarction or 23 (43)
ischemic heart diseaseb
History of previous strokeb 13 (25)
History of diabetes mellitusb 8 (15)
Current smokingb 8 (15)
Time from symptom onset to hospital 79 (60114)
arrival in minutesa
Time from hospital arrival to CT in 32 (2050)
minutesa
Time from CT to transcranial Doppler 44 (2752)
ultrasound in minutesa
a
Median (IQR) values.
b Values are n (%); SD, standard deviation.
TCD correlates of collateral ow, reperfusion and outcome in acute stroke 189

Table 2 MCAO thrombolysis subgroup baseline characteristics by 24 h reperfusion status.

Baseline characteristics Major reperfusion Non-reperfusion p

n = 16 n = 11

Mean age 71 years SD 18.1 55.7 SD 19.1 p = 0.02

Female 56% 33%
Mean NIHSS 15.8 SD 5.1 18.2 SD 3.7 p = 0.18
Median infarct core volume 17.6 ml Range: 0.488.8 34.4 ml Range: 0.477 ml p = 0.15
Median perfusion lesion volume 110.6 ml Range: 30.3141.2 144 ml Range: 59.1169.8 ml p = 0.007
Good collateral grade 50% 40% p = 0.30
ACA ow diversion 44.40% 50% p = 0.80
Mean systolic BP 152 mmHg SD 20.5 150.6 mmHg SD 26.8
Mean diastolic BP 87 mmHg SD 11.1 86.7 mmHg SD 15.4
Risk factors
AF 50% 20%
HT 61% 60%
DM 11% 20%
HC 27% 50%
Current smoking 17% 20%
Antithrombotic medication (%)
Antiplatelet 27% 10%
Warfarin 11% 0%

associated with ACA FD where only 6 of 22 patients (27%)
with an ACA FD ratio of greater than 1.3 had infarct
core growth compared with 22 of 28 (78%) with ACA FD
ratios of less than 1.3 (Odds ratio 9.7, p < 0.001). The
presence of ACA FD may indicate a subgroup of patients
with better collateral ow and a relatively stable ischemic
penumbra.
After adjusting for occlusion site, stroke onset time to CT,
age and gender, the two predictors of baseline infarct core
volume on linear regression analysis were FD (p < 0.001) and
acute NIHSS (p = 0.002). Predictors of penumbral volume,
after adjusting for occlusion site, acute NIHSS, onset time
to CT and gender, FD (p < 0.001) and younger age (p = 0.016)
(r2 = 0.3707) remained signicant.

Table 3 Differences in admission and outcome variables between groups dened by the presence or absence of TCD detected
ow diversion (FD).

All patients (n = 53)

MCAO and ICAO (n = 53) MCAO only (n = 42)

FD+ FD p FD+ FD p
24 29 23 19

Good collaterals according to CTAb 21/24 (87.5) 6/29 (20.7) <0.001 20/23 (87) 6/19 (32) <0.001
Admission NIHSSa 16 (1218.5) 18 (1622) 0.024 16 (1219) 17 (1319) 0.454
Admission infarct core volumea 6.4 (415) 52.2 (2680) <0.001 6.2 (416) 36.1 (2158) 0.001
Admission penumbral volumea 95.3 (78113) 65.5 (3376) <0.001 93.9 (78113) 69 (2579) 0.002
Total perfusion lesiona 107.6 (87130) 118 (85146) 0.357 104 (86131) 105 (48142) 0.859
Mismatch ratioa 12.4 (827) 1.95 (1.83.4) <0.001 12.3 (7.527) 2.7 (1.94) <0.001
Thrombolysisb 22/24 (91.7) 20/29 (69) 0.086 21/23 (91) 17/19 (89) 1.000
Major recanalization/reperfusionb 16/23 (69.7) 16/29 (55) 0.392 16/22 (73) 12/19 (63) 0.737
Infarct expansion (ml)a 2.3 (0.5 to 15) 38 (969) 0.001 1.9 (0.5 to 5) 23 (384) 0.006
Final infarct volume (ml)a 14 (725) 92 (46142) <0.001 14 (720) 65 (25143) <0.001
24 h NIHSSa 4 (112) 17 (825) <0.001 3 (112) 12 (419) 0.016
90 day mRS 2b 18/24 (75.0) 6/29 (21.7) <0.001 17/23 (74) 6/19 (32) 0.012
FD+, anterior cerebral artery ow diversion positive; FD, anterior cerebral artery ow diversion negative; CTA, computed tomography
angiography; NIHSS, National Institute of Health Stroke Scale; mRS, modied Rankin score; mismatch ratio calculated by dividing mean
transit time lesion volume by cerebral blood volume lesion volume.
a Median (IQR) values.
b Values are n (%).
190 C. Levi et al.

Table 4 Predictors of favourable clinical outcome in patients following acute anterior circulation ischemic stroke.

Variable mRS 02 Unadjusted analysis Adjusted analysis

n (%) (stepwise regression)
Odds ratio (CI) p value Odds ratio (CI) p value

Recanalization/reperfusion
No (n = 20) 3 (15.0) 1.00 1.00
Yes (n = 32) 21 (65.6) 10.3 (2.366.7) <0.001 21.1 (2.01208) 0.005
Flow diversion
No (n = 29) 6 (20.7) 1.00 1.00
Yes (n = 24) 18 (75.0) 10.8 (2.751.3) <0.001 27.5 (3.01451) <0.001
Age 0.98 (0.941.02) 0.385
Gender
Female (n = 23) 14 (60.9) 1.00
Male (n = 30) 10 (33.3) 0.33 (0.091.14) 0.085
Admission National Institute of Health 0.78 (0.660.90) <0.001 0.83 (0.671.01) 0.061
Stroke Scale score
Stroke onset time to thrombolysis 0.99 (0.981.00) 0.136
Stroke onset time to transcranial Doppler 1.00 (0.991.00) 0.685
ultrasound
Thrombolysis
No (n = 11) 1 (9.1) 1.00
Yes (n = 42) 23 (54.8) 11.6 (1.4547.6) 0.014
Middle cerebral artery occlusion
No (n = 11) 0 (0.0) 1.00
Yes (n = 42) 24 (57.1) 18.9 (2.8) <0.001
CI, condence interval (95%); mRS, modied Rankin score.

Predictors of 24 h infarct volume after adjusting for
occlusion site, therapy with thrombolytic agent, and
stroke onset to thrombolytic treatment time were: FD
(p < 0.001), major reperfusion (p < 0.001) and lower acute
NIHSS (p = 0.02) (r2 = 0.6689).
Independent predictors of a favourable clinical outcome,
as measured by 90 day mRS 02, were FD (OR 27.5,
p < 0.001), major reperfusion (OR 21.1, p = 0.005; Table 4).
All patients with ICAO as the site of vessel occlusion had a
poor outcome.
Recanalization monitoring subgroup
The characteristics of the patients with MCA occlusion
treated with intravenous thrombolysis are shown in Table 2.
Patients with major reperfusion post-thrombolysis were sig-
nicantly older than those with non-reperfusion (71 years
vs 56 years, p = 0.02); however, the major reperfusion
patients showed smaller perfusion lesion (111 ml vs 144 ml,
p = 0.007) and a trend towards smaller infarct core volumes
(18 ml vs 34 ml, p = 0.15) at baseline. TCD monitoring times
were not signicantly different between groups (major
reperfusion, 103 min; non-reperfusion, 124 min; p = 0.34).
Consistent with other studies, patients with major reperfu-
sion showed smaller median 24 h infarct core volumes (28 ml
vs 46 ml, p = 0.005), lower 24 h mean NIHSS score (12.1 vs
16.7, p = 0.009), and a higher proportion of patients with
favourable 90 day functional outcomes (mRS 02, 63% vs
10%, p = 0.002).
The TIBI grade proles for each case is shown in Fig. 1A
and B. Major TIBI grade change (improvement by 3 grades
during the post-thrombolysis monitoring period) was associ-
ated with major reperfusion (p = 0.04) along with higher odds
of attenuation of infarct core growth (p = 0.06), improve-
ment in NIHSS score (p = 0.049) and excellent 90 day
functional outcome (mRS 01; p = 0.03). Major sudden TIBI
grade change (improvement of 3 grades over 15 min) was
associated with a trend towards excellent functional out-
come (mRS 01; p = 0.09).
MES were detected in 36% proportion of cases over-
all, 37% in the patients with major reperfusion and 33% in
patients with non-reperfusion (p = 0.55). There was no asso-
ciation between the presence of microemboli and major
TIBI grade change, 24 h infarct core volume or clinical
outcomes.
Discussion
This is the rst description of the relationship between
TCD features of leptomeningeal collateralisation and
recanalization, hyperacute brain perfusion status, and their
relationships to tissue fate and clinical outcomes in acute
ischemic stroke. Our data demonstrate that the ACA FD is
associated with improved LMC and is independently associ-
ated with 24 h infarct volume and 90 day clinical outcome in
acute anterior circulation stroke patients with identiable
large artery occlusion. ACA FD may therefore dene a group
of patients who have a greater tolerance to ICA or MCA occlu-
sion and, potentially, a longer-lived ischemic penumbra.
Our data also demonstrate that in MCA occlusion patients
treated with intravenous thrombolysis, major improvement
in TIBI grade is associated with major reperfusion at 24 h
TCD correlates of collateral ow, reperfusion and outcome in acute stroke
A. Major Reperfusion Cases
5
4.5
4 Patients with ICA occlusion are more likely to have com-
3.5
TIBI Grade
3
2.5
2
1.5
1 MCA occlusion showing no FD (derived from Table 2).
0.5
0
Monitoring
Time 0
Time
Time 60
Time 120
B. Non-reperfusion cases
TIBI 0 mins
Monitoring
TIBI 60
TIBI 120
Time
Figure 1 Comparison of TIBI grade change over time post
intravenous thrombolysis between patients with major reperfu-
sion (A) and non-reperfusion (B). Reperfusion measured at 24 h
post intravenous thrombolysis using MR perfusion. Major reper-
fusion dened as >80% reperfusion of baseline perfusion lesion
volume.
along with improved 24 h and 90 day clinical outcome and
a trend towards less infarct core growth.
Flow diversion
Although denitions and indices of ACA ow diversion vary in
the literature [17,2023] the ACA asymmetry index used by
Zanette [20], based on comparison between digital cerebral
angiography and TCD performed within 6 h of stroke onset, is
likely to be the most reliable and easily applicable measure
in hyperacute stroke. The same asymmetry index was used
to dene TCD FD in the retrospective analysis of the CLOT-
BUST trial. In this study, FD was observed in 83% of patients
with MCAO treated with tissue plasminogen activator ther-
apy. This patient population excluded cases with ICAO and
also those cases with early TCD measured recanalization,
but noted that FD was associated with early neurological
improvement [23]. To date no other published acute stroke
studies have correlated TCD FD with CT angiographic mea-
sures of collateral ow, nor have examined associations with
perfusion lesion volumes and long-term functional outcome.
We did not nd any signicant association between the
presence of FD and the total volume of the perfusion lesion
despite the admission NIHSS being lower in patients with
ACA FD. In contrast, we demonstrated a strong and inde-
pendent association between FD and the volume of the CTP
dened infarct core. This nding suggests the importance
191
of collateral ow and its TCD correlate in predicting acute
infarct volume [34] and clinical outcome.
promised ACA collateral ow. This was demonstrated in the
results, where, 55% of patients with combined ICA + MCA
occlusion showed no FD as opposed to 42% of patients with
When accompanied by major reperfusion, FD signicantly
increased the chances of a favourable outcome in keeping
with other reports of a potential synergistic effect between
LMC and major reperfusion [12,16]. In our study, 43% of FD
positive patients who did not undergo major reperfusion had
a favourable outcome suggesting that LMCs are capable, in
some patients, of perfusing the territory of an occluded
5
artery to a level sufcient to avoid infarction even with-
4.5
out complete recanalization [11], ACA FD therefore appears
4
to be a rapid onset internal protection mechanism for the
3.5
ischemic area, mitigating infarct core expansion.
3
TIBI Grade
2.5
1.5
Recanalization monitoring
1
0.5 TCD is recognised to accurately reect recanalization status
0 of the MCA when compared to catheter angiography [35]
and TCD dened TIBI recanalization grades recognised
to correlate with baseline stroke severity and clinical
recovery [36]. There is, however, limited data describing
recanalization characteristics in the initial hours following
acute MCA stroke and no data correlating TCD recanaliza-
tion characteristics with reperfusion status and the extent
of early infarction. Alexandrov et al. [37] described a cohort
of 65 patients treated with intravenous tissue plasminogen
activator within 3 h of stroke onset and monitored with
TCD post-thrombolysis. Similar to our ndings, major
improvements in TIBI grades (in this study over time periods
of less than 30 min) were associated with signicantly
lower 24 h post-thrombolysis NIHSS. Using transcranial
colour coded duplex (TCCD) the Duplex Sonography in
Acute Stroke Study group performed TCCD 30 min and 6 h
post-thrombolysis in patients with a variety of ICA and MCA
occlusion patterns [38]. In this patient group, cases showing
recanalization assessed by TIBI grade change also showed
signicant improvements in 24 h NIHSS when compared to
those without TCCD features of recanalization.
Studies examining use of transcranial ultrasound in guid-
ing clinical decision in acute stroke are also limited. In the
small sample of patients entered into the Intervention Man-
agement of Stroke (IMS) trial, MCA blood ow velocity ratios
comparing the affected to unaffected artery accurately
identied angiographic lesions amenable to endovascular
therapy [39]. The clinical relevance and application of this
nding are uncertain.
We have identied only one study evaluating the use
of TCCD as a decision-assistance aid in identifying intra-
venous thrombolysis treated patients who require triage
to endovascular reperfusion therapy. Sekoranja et al. [40]
examined patients treated with intravenous thrombolysis
for MCA occlusion (TIBI grade 03 at baseline) monitored
with intermittent TCCD. At 30 min post-commencement of
intravenous thrombolysis, lack of improvement by at least
1 TIBI grade was used to shift management to endovascu-
lar management. Although uncontrolled, the study showed
192
that favourable long-term outcome (mRS 02) was achieved
in the acceptable proportions of patients (59%) where intra-
venous therapy alone was continued. This assuming a TIBI
grade of at least 3 was achieved at 30 min post-intravenous
thrombolysis. For those patients triaged to endovascular
therapy on the basis of lack of any TIBI improvement
at 30 min, 56% of patients had a favourable long-term
outcome.
MES were commonly detected during the process of
recanalization; however, in this relatively small sample of
patients, the occurrence of MES did not associate with more
effective reperfusion, 24 h infarct volumes neither improved
early nor improved late clinical outcomes.
Conclusion
The growth in endovascular reperfusion therapy options in
acute stroke is driving a need for more sophisticated imag-
ing approaches to gauge both the time-frame of survival of
the ischemic penumbra and the effectiveness of rst-line
intravenous thrombolytic therapies. In MCA stroke the use
of TCD to gauge the adequacy of collateral ow and the
effectiveness of thrombolysis-induced recanalization holds
promise as a clinically useful test. Further validation is
needed through both observational studies using both clini-
cal and imaging outcome measures and ideally, randomised
studies evaluating TCD-guided decision assistance.
Acknowledgements
We would like to thank the patients and family members
involved in this study and members of the John Hunter
Hospital acute stroke team, in particular Debbie Quain,
neurosonologist. This work was supported by: Hunter New
England Local Health District, Hunter Medical Research
Institute, University of Newcastle, the National Stroke
Foundation (Australia) and the National Health & Medical
Research Council (Australia).
References
[1] Quain DA, Parsons MW, Loudfoot AR, Spratt NJ, Evans MK,
Russell ML, et al. Improving access to acute stroke therapies: a
controlled trial of organised pre-hospital and emergency care.
Med J Aust 2008;189(October (8)):42933.
[2] Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP,
et al. Safety and efcacy of mechanical embolectomy in acute
ischemic stroke: results of the MERCI trial. Stroke 2005;36(July
(7)):14328.
[3] The Penumbra Pivotal Stroke Trial Investigators. The Penumbra
Pivotal Stroke Trial: safety and effectiveness of a new genera-
tion of mechanical devices for clot removal in intracranial large
vessel occlusive disease. Stroke 2009;40(August (8)):27618.
[4] Parsons MW, Christensen S, McElduff P, Levi CR, Butcher KS,
De Silva DA, et al. Pretreatment diffusion- and perfusion-MR
lesion volumes have a crucial inuence on clinical response to
stroke thrombolysis. J Cereb Blood Flow Metab 2010;30(June
(6)):21425.
[5] Bivard A, McElduff P, Spratt N, Levi C, Parsons M. Dening the
extent of irreversible brain ischemia using perfusion computed
tomography. Cerebrovasc Dis 2011;31(3):23845.
C. Levi et al.
[6] Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS,
Peeters A, et al. Effects of alteplase beyond 3 h after stroke
in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPI-
THET): a placebo-controlled randomised trial. Lancet Neurol
2008;7(April (4)):299309.
[7] Alexandrov AV, Demchuk AM, Wein TH, Grotta JC. Yield
of transcranial Doppler in acute cerebral ischemia. Stroke
1999;30(August (8)):16049.
[8] Zanette EM, Roberti C, Mancini G, Pozzilli C, Bragoni M, Toni
D. Spontaneous middle cerebral artery reperfusion in ischemic
stroke. A follow-up study with transcranial Doppler. Stroke
1995;26(3):4303.
[9] Bang OY, Saver JL, Buck BH, Alger JR, Starkman S, Ovbiagele B,
et al. Impact of collateral ow on tissue fate in acute
ischemic stroke. J Neurol Neurosurg Psychiatry 2008;79(June
(6)):6259.
[10] Bozzao L, Fantozzi LM, Bastianello S, Bozzao A, Fieschi C.
Early collateral blood supply and late parenchymal brain dam-
age in patients with middle cerebral artery occlusion. Stroke
1989;20(June (6)):73540.
[11] Brozici M, van der Zwan A, Hillen B. Anatomy and func-
tionality of leptomeningeal anastomoses: a review. Stroke
2003;34(November (11)):275062.
[12] Christoforidis GA, Mohammad Y, Kehagias D, Avutu B, Slivka AP.
Angiographic assessment of pial collaterals as a prognostic indi-
cator following intra-arterial thrombolysis for acute ischemic
stroke. AJNR Am J Neuroradiol 2005;26(August (7)):178997.
[13] Roberts HC, Dillon WP, Furlan AJ, Wechsler LR, Rowley HA,
Fischbein NJ, et al. Computed tomographic ndings in patients
undergoing intra-arterial thrombolysis for acute ischemic
stroke due to middle cerebral artery occlusion: results from the
PROACT II Trial * editorial comment: results from the PROACT
II Trial. Stroke 2002;33(June (6)):155765.
[14] Maas MB, Lev MH, Ay H, Singhal AB, Greer DM, Smith WS, et al.
Collateral vessels on CT angiography predict outcome in acute
ischemic stroke. Stroke 2009;40(September (9)):30015.
[15] Kucinski T, Koch C, Eckert B, Becker V, Kromer H, Heesen C,
et al. Collateral circulation is an independent radiological pre-
dictor of outcome after thrombolysis in acute ischemic stroke.
Neuroradiology 2003;45(January (1)):118.
[16] Miteff F, Levi CR, Bateman GA, Spratt N, McElduff P,
Parsons MW. The independent predictive utility of computed
tomography angiographic collateral status in acute ischemic
stroke. Brain 2009;132(August (Pt 8)):22318.
[17] Brass LM, Duterte DL, Mohr JP. Anterior cerebral artery velocity
changes in disease of the middle cerebral artery stem. Stroke
1989;20(December (12)):173740.
[18] Ishikawa S, Handa J, Meyer JS, Huber P. Hemodynamics of
the circle of Willis and the leptomeningeal anastomoses:
an electromagnetic owmeter study of intracranial arte-
rial occlusion in the monkey. J Neurol Neurosurg Psychiatry
1965;28(April):12436.
[19] Mattle H, Grolimund P, Huber P, Sturzenegger M, Zurbrugg HR.
Transcranial Doppler sonographic ndings in middle cerebral
artery disease. Arch Neurol 1988;45(March (3)):28995.
[20] Zanette EM, Fieschi C, Bozzao L, Roberti C, Toni D, Argentino C,
et al. Comparison of cerebral angiography and transcra-
nial Doppler sonography in acute stroke. Stroke 1989;20(July
(7)):899903.
[21] Demchuk AM, Christou I, Wein TH, Felberg RA, Malkoff M,
Grotta JC, et al. Specic transcranial Doppler ow ndings
related to the presence and site of arterial occlusion. Stroke
2000;31(January (1)):1406.
[22] Kim Y, Sin DS, Park HY, Park MS, Cho KH. Relationship
between ow diversion on transcranial Doppler sonography
and leptomeningeal collateral circulation in patients with
middle cerebral artery occlusive disorder. J Neuroimaging
2009;19(January (1)):236.
TCD correlates of collateral ow, reperfusion and outcome in acute stroke
[23] Kim YS, Meyer JS, Garami Z, Molina CA, Pavlovic AM,
Alexandrov AV. Flow diversion in transcranial Doppler ultra-
sound is associated with better improvement in patients
with acute middle cerebral artery occlusion. Cerebrovasc Dis
2006;21(12):748.
[24] Kaps M, Damian M, Teschendorf U, Dorndorf W. Transcranial
Doppler ultrasound ndings in middle cerebral artery occlu-
sion. Stroke 1990;21:5327.
[25] Kayembe KN, Hazama SMF. Cerebral aneurysms and variations
in the circle of Willis. Stroke 1984;15(5):84650.
[26] Kwon HMLY. Transcranial Doppler sonography evaluation of
anterior cerebral artery hypoplasia or aplasia. J Neurol Sci
2005;231(12):6770.
[27] Demchuk AMA. Acute ischemic stroke. In: Alexandrov,
editor. Cerebrovascular ultrasound in stroke prevention
and treatment. New York: Blackwell Publishing; 2004.
p. 17080.
[28] Markus HS, Ackerstaff R, Babikian V, Bladin C, Droste D, Grosset
D, et al. Intercenter agreement in reading Doppler embolic
signals. A multicenter international study. Stroke 1997;28(July
(7)):130710.
[29] Saqqur M, Dean N, Schebel M, Hill MD, Salam A, Shuaib A,
et al. Improved detection of microbubble signals using power
M-mode Doppler. Stroke 2004;35(1):e147.
[30] Parsons MW, Pepper EM, Chan V, Siddique S, Rajaratnam S,
Bateman GA, et al. Perfusion computed tomography: predic-
tion of nal infarct extent and stroke outcome. Ann Neurol
2005;58(November (5)):6729.
[31] Parsons MW, Pepper EM, Bateman GA, Wang Y, Levi CR.
Identication of the penumbra and infarct core on hypera-
cute noncontrast and perfusion CT. Neurology 2007;68(March
(10)):7306.
[32] Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen
M, Goldsher D. Perfusion-CT assessment of infarct core and
penumbra: receiver operating characteristic curve analysis in
130 patients suspected of acute hemispheric stroke. Stroke
2006;37(April (4)):97985.
193
[33] Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle
A, Attia J, et al. Acute ischemic stroke: imaging-guided
tenecteplase treatment in an extended time window. Neurol-
ogy 2009;72(March (10)):91521.
[34] Parsons MW, Christensen S, McElduff P, Levi CR, Butcher KS, De
Silva DA, et al. Pretreatment diffusion- and perfusion-MR lesion
volumes have a crucial inuence on clinical response to stroke
thrombolysis. J Cereb Blood Flow Metab 2010;30(June (6)):
121425.
[35] Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I,
Grotta JC, et al. Transcranial doppler ultrasound criteria for
recanalization after thrombolysis for middle cerebral artery
stroke. Stroke 2000;31(5):112832.
[36] Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA,
Hill MD, et al. Thrombolysis in Brain Ischemia (TIBI) transcra-
nial Doppler ow grades predict clinical severity early recovery,
and mortality in patients treated with intravenous tissue plas-
minogen activator. Stroke 2001;32(January (1)):8993.
[37] Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A,
Grotta JC. Speed of intracranial clot lysis with intravenous
tissue plasminogen activator therapy: sonographic classica-
tion and short-term improvement. Circulation 2001;103(June
(24)):2897902.
[38] Wunderlich MT, Goertler M, Postert T, Schmitt E, Seidel G,
Gahn G, et al. Recanalization after intravenous thrombol-
ysis: does a recanalization time window exist? Neurology
2007;68(17):13648.
[39] Saqqur M, Shuaib A, Alexandrov AV, Hill MD, Calleja S, Tom-
sick T, et al. Derivation of transcranial Doppler criteria
for rescue intra-arterial thrombolysis: multicenter experience
from the Interventional Management of Stroke study. Stroke
2005;36(4):8658.
[40] Sekoranja L, Loulidi J, Yilmaz H, Lovblad K, Temperli P, Comelli
M, et al. Intravenous versus combined (intravenous and intra-
arterial) thrombolysis in acute ischemic stroke: a transcranial
color-coded duplex sonography guided pilot study. Stroke
2006;37(7):18059.