From the Department of Neurological Sciences, University La Sapienza,
Rome, Italy.
Correspondence and reprint request to Dr Danilo Toni, Department of Neurological Sciences, I Chair of Neurology, University La Sapienza, Viale dell'Università 30, 00185 Rome, Italy. E-mail s.u.roma{at}iol.it
Methods—Ninety-three patients underwent CT scan within 5 hours of
a first-ever ischemic hemispheric stroke, and TCD serial
examinations at 6, 24, and 48 hours after stroke onset. We classified
TCD findings as follows: normal; middle cerebral artery (MCA) asymmetry
(asymmetry index between affected and contralateral MCAs below –21%);
and MCA no-flow (absence of flow signal from the affected MCA in the
presence of ipsilateral anterior and posterior cerebral artery signals
through the same acoustic window). We considered early deterioration
and early improvement to be a decrease or an increase of 1 or more
points, respectively, in the Canadian Neurological Scale score over the
same period.
Results—At 6-hour TCD examination, MCA asymmetry and MCA no-flow
were present in 6 (22%) and 2 (7%), respectively, of 27 improving
patients; in 20 (43%) and 10 (22%) of 46 stable patients, and in 9
(45%) and 8 (40%) of 20 deteriorating patients. TCD findings were
normal in the remaining patients (P=0.001). At serial
TCD, we detected early (within 24 hours)
recanalization (from no-flow to asymmetry or normal
and from asymmetry to normal) in 2 (25%) improving patients, in 7
(23%) stable patients, and in 5 (29%) deteriorating patients and late
(between 24 and 48 hours) recanalization in 4
(50%) improving patients, in 6 (20%) stable patients, and in none of
the deteriorating patients (P=0.03,
Conclusions—TCD examination within 6 hours after stroke can help
to predict both early deterioration and early improvement. Serial TCD
shows that propagation of arterial occlusion is rarely
related to early deterioration, whereas the fact that it can detect
early recanalization (within 24 hours) in
deteriorating patients and both early and late
recanalization (after 24 hours) in improving
patients suggests the existence of individual time frames for tissue
recovery.
In a previous study,10 three fourths of
patients with subsequent progressing course had signs of precocious
brain edema, ie, early hypodensity and/or mass
effect,15 16 at admission CT scan performed
within 6 hours of stroke onset. Moreover, in a subgroup of patients
submitted to angiography immediately after CT scan, we observed an
intra- and/or extracranial arterial occlusion in 91% of
deteriorating and in 71% of nondeteriorating patients, with collateral
blood supply in one third and in two thirds, respectively, of the
cases. Hence, we hypothesized that arterial occlusion with
an ineffective collateral blood supply16 had led
to precocious brain edema that was ultimately responsible for early
deterioration.
In a subsequent study,11 we observed an inverse
situation in early improving patients. Early CT hypodensity was
present in only 29% of patients, and angiography showed an
intracranial and/or extracranial arterial occlusion in half
of improving patients, with collateral blood supply in 80% and
arterial patency (ie, normal angiograms or nonstenosing
plaques in the internal carotid artery) in the remaining half of the
patients. Since almost all of the latter presented a CT
territorial infarct, generally considered to be caused by an embolic
arterial occlusion,17 we presumed
that these patients also had had an arterial occlusion,
with arterial reopening occurring before angiography.
Therefore, the presence of effective collateral blood supply, with
preservation of neuronal function, and very early
recanalization, with rapid restoration of an
adequate perfusion, were the proposed mechanisms underlying early
improvement.
However, we were aware that both in deteriorating and in improving
patients we had taken a photograph antecedent to any clinical change,
not knowing whether any modifications in blood supply that might have
been related to the changing clinical picture had subsequently
occurred.
In the present study we monitored with TCD the evolution of
arterial status of acute ischemic stroke patients,
and investigated whether TCD data obtained at hospital admission and
their modification within the first 48 hours of stroke onset were
related to early neurological deterioration or improvement.
The routine examination of patients admitted to our Stroke Unit and the
classification of early and repeat CT findings are detailed
elsewhere.20 For the purposes of this study,
patients underwent the first TCD after the admission CT scan, ie,
within 6 hours of stroke onset. Early deterioration and early
improvement were defined as a decrease and an increase of 1 or more
points, respectively, in the Canadian Neurological Scale
(CNS)21 score from hospital admission to 48 hours
after stroke onset; the remaining patients were considered stable. The
investigators who determined the CNS score were blind to TCD
results.
We followed patients for 30 days, during which we calculated the
fatality rate; we then evaluated the residual activities of daily
living of survivors, considering a Barthel
Index22 score <60 to be a poor functional
outcome.
Statistical Analysis
Table 1
Findings at baseline and at the time of repeat CT scans (88 patients)
or autopsy (5 patients) according to TCD findings at 6 hours and to
their modifications at 24 and 48 hours are shown in Table 2
At the 6-hour TCD, MCA asymmetry and MCA no-flow were detected in 8
(30%) improving patients, as compared with 30 (65%) stable and 17
(85%) deteriorating patients (P=0.001). Among patients with
an abnormal 6-hour TCD, serial TCD showed
recanalization within 24 hours in 2 (25%)
improving patients, 7 (23%) stable patients, and 5 (29%)
deteriorating patients and between 24 and 48 hours in 4 (50%)
improving patients, 6 (20%) stable patients, and none of the
deteriorating patients (P=0.03
Among the baseline clinical characteristics, admission CT, and 6-hour
TCD findings, logistic regression selected normal 6-hour TCD as a
predictor of early improvement (odds ratio [OR], 0.17; 95%
confidence interval [CI], 0.06 to 0.46) and abnormal 6-hour TCD as an
independent predictor of early deterioration (OR, 5.02; 95% CI, 1.31
to 19.3). No other variable was selected by this analysis,
even when repeated to take into account spontaneous
recanalization. Predictive values, sensitivity, and
specificity of 6-hour TCD findings regarding early improvement and
early deterioration are shown in Table 3
Normal 6-hour TCD was the only independent predictor of early
improvement, while abnormal TCD was a predictor of early deterioration.
The presence or absence of early CT hypodensity, previously identified
as predictors of the early clinical course,10 11
did not add to the prediction, and the overall accuracy of TCD findings
in predicting early clinical course was higher than that of CT
findings.14 Unfortunately, while CT can be
performed in all acute patients, TCD cannot, owing to the absence of
the acoustic window in a sizable number of
cases.18 23
Intracerebral and systemic mechanisms have been
proposed by various authors as possibly being responsible for early
deterioration.5 7 8 10 12 13 14 As to
intracerebral mechanisms, we investigated whether in
addition to brain edema, which we previously had suggested as the main
cause of early deterioration,10 a propagation of
arterial occlusion might contribute to this clinical
course. In our series, only 1 deteriorating patient showed a TCD change
from asymmetry to no-flow between 24 and 48 hours after stroke onset,
with early cortical hypodensity at the first CT and a final infarct
involving the whole MCA territory. These data indicate an occlusion of
the distal portion of the MCA and suggest either a subsequent
retrograde propagation of the occlusion to the MCA main stem or, more
likely, that a new embolus lodged next to the initial occlusion.
On the other hand, the serial TCD examinations showed a
recanalization within 24 hours of stroke onset in 5
deteriorating patients. Because we did not perform TCD examinations at
shorter time intervals, we do not know the exact time of
recanalization, but we may argue that it was too
delayed to save brain tissue. However, for 3 of these patients who had
no or only limited early CT hypodensity and an extended final infarct,
we cannot rule out the possibility that a reperfusion
injury24 might have supervened, thus damaging
tissue that was still partially viable at hospital entry.
We can presume neither reperfusion injury nor thrombus propagation for
the 11 deteriorating patients with asymmetry or no-flow at the 6-hour
TCD and no modifications in the subsequent examinations. The remaining
3 deteriorating patients with normal TCD at entry had early hypodensity
at the first CT and an extended territorial infarct at the repeat
CT.17 This led us to hypothesize that these
patients also had had an arterial occlusion, probably
without adequate collateral blood supply,10 16
that was no longer present by the time the first TCD was
performed.
The questions raised by serial TCD findings on the possible mechanisms
underlying early improvement are somewhat more complex. Although in the
majority of patients improvement started within 24 hours, none of them
had a transient ischemic attack. Seventy percent of improving
patients had a normal 6-hour TCD. The fact that lacunar infarcts or
permanently normal CT scans were detected in only one fourth of these
cases, a frequency similar to that of stable patients, allows us to
exclude lacunar stroke as a main cause of early improvement. The other
three fourths of patients had a territorial infarct at the repeat CT
scan. At least a part of these infarcts can be explained by presuming
an occlusion of a few MCA branches, undetected by TCD because it was
insufficient to markedly modify the MCA velocity. This was, in fact,
what we observed in 38% of normal TCD findings in a previous study in
which TCD and digital arterial subtraction angiography were
compared.25 There remain, however, half of the
improving patients with normal 6-hour TCD and subsequent territorial
infarct, for whom very early recanalization before
the first TCD can be hypothesized.
Finally, in half of the improving patients with MCA occlusion at the
6-hour examination, TCD documented recanalization
between 24 and 48 hours after stroke onset. This indicates that in a
minority of patients delayed recanalization may be
related to improvement, suggesting a more prolonged survival of the
ischemic penumbra.26
In conclusion, TCD performed a few hours after stroke onset may help to
predict the clinical course in the subsequent 48 hours. Serial TCD
examinations suggest that early deterioration is rarely, if ever,
related to a propagating arterial occlusion. The occurrence
of early recanalization (within 24 hours) in
patients with a deteriorating course and that of both early and late
recanalization (after 24 hours) in patients with an
improving deficit confirm that there is not a fixed and universal time
frame for tissue recovery but rather an individual therapeutic
window.27
Received February 16, 1998;
revision received March 10, 1998;
accepted March 16, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Early Spontaneous Improvement and Deterioration of Ischemic Stroke Patients
A Serial Study With Transcranial Doppler Ultrasonography
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—The purpose
of our study was to investigate whether emergency
transcranial Doppler (TCD) findings and their
modifications over the first 48 hours are related to early neurological
changes in acute ischemic stroke patients. 
2 for
trend, improving versus nonimproving irrespective of the timing of
recanalization). One deteriorating patient (5%)
developed a no-flow from an initial MCA asymmetry. Logistic regression
selected normal TCD (odds ratio [OR], 0.17; 95% confidence interval
[CI], 0.06 to 0.46) as an independent predictor of early improvement
and abnormal TCD (asymmetry plus no-flow) (OR, 5.02; 95% CI, 1.31 to
19.3) as an independent predictor of early deterioration.
Key Words: stroke, acute • stroke, ischemic • ultrasonography, Doppler • pathogenesis • prognosis
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The growing consensus
in favor of an emergency hospital referral of ischemic stroke
patients1 2 3 has made the study of the clinical
course over the first hours of stroke onset of the utmost relevance. We
now have the opportunity to witness clinical courses that in the past
had already begun or even been completed by the time patients were
hospitalized. Hence, it would theoretically be possible to prevent or
to counteract a neurological deterioration, or to plan a nonintensive
treatment of patients who are likely to improve spontaneously.
Understanding the mechanisms underlying these 2 clinical
evolutions4 5 6 7 8 9 10 11 12 13 14 is obviously the necessary
prerequisite to achieve these goals.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
We studied 93 acute ischemic hemispheric stroke patients
hospitalized within 5 hours from stroke onset, who underwent TCD
examination with a TC 2–64 EME device equipped with a 2-MHz probe. The
anterior cerebral artery (ACA), the middle cerebral artery (MCA), and
the posterior cerebral artery (PCA) were explored through the temporal
window, and the mean flow velocity of each artery was recorded. TCD
findings were classified as follows18,19: (1) MCA
no-flow, when the flow signal from the symptomatic MCA was
absent, while those from the ipsilateral ACA and PCA were detected
through the same acoustic window; (2) MCA asymmetry, when the flow
velocity in the symptomatic MCA was reduced by 21% or more
when compared with the contralateral MCA; and (3) normal MCA, when flow
velocities were the same or MCA asymmetry was less than 21%. This 21%
threshold value of MCA asymmetry was the upper limit of the confidence
intervals (5% of the distribution in the right tail) in a reference
sample of normal subjects.18 TCD was then
repeated after 24 and 48 hours, and after comparing these data with
those at entry, we considered the modification of TCD findings from
no-flow to asymmetry or normal and from asymmetry to normal as
arterial recanalization. Reverse
changes were considered indexes of propagation of a preexisting
arterial occlusion or of a new occlusion.
Univariate tests (,2
2 for trend, Fisher's exact test, and ANOVA)
were used to analyze the following: clinical characteristics on
admission, CT scan and TCD findings, risk factors for stroke in past
medical history, and clinical outcome. To look for independent
predictors of the improving course (stable or deteriorating=0,
improving=1) and deteriorating course (stable or improving=0,
deteriorating=1), baseline clinical and CT findings (early hypodensity
or mass effect: no=0, yes=1) and 6-hour TCD data (normal=0, abnormal,
ie, asymmetry or no-flow, =1), which during the univariate
tests were trend related (P
0.1) to improvement or
deterioration, were taken as independent variables in the logistic
regression analysis. This model was adjusted according to the
therapies administered. A further logistic regression analysis
with the same variables was performed only in patients with MCA
asymmetry and MCA no-flow at the 6-hour TCD to ascertain whether
recanalization at 24 and 48 hours was independently
associated with early improvement or deterioration. Finally, we
calculated predictive values, sensitivity, specificity, and accuracy of
the variables found by logistic regression to be related to the 2
clinical courses.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Of 93 patients studied, 46 (49%) remained stable, 20 (22%)
deteriorated, and 27 (29%) improved during the first 48 hours of
hospitalization. Of the latter, 25 (92%) started improving, but none
of them recovered, within 24 hours. 
shows the demographic data,
baseline clinical characteristics, risk factors for stroke in the
medical history, and 30-day clinical outcome of the 3 groups of
patients. Deteriorating patients were older and had the highest mean
serum glucose levels at entry, whereas improving patients were younger
and had the lowest admission serum glucose levels. At the end of
follow-up, 6 (22%) improving patients had died or were dependent
compared with 26 (56%) stable and 18 (90%) deteriorating patients
(P=0.0002).
View this table:
[in a new window]
Table 1. Demographic Data, Baseline Characteristics, Risk
Factors for Stroke, and Clinical Outcome . At baseline CT, early hypodensity was
found in 8 (30%) improving, 27 (59%) stable, and 16 (80%)
deteriorating patients (P=0.04). At repeat CT or autopsy
territorial infarcts were detected in 22 (81%) improving, 40 (86%)
stable, and 20 (100%) deteriorating patients. The size of the
territorial infarcts varied significantly: improving patients had
mainly small lesions, while medium- and large-sized infarcts prevailed
among stable and deteriorating patients (P=0.01).
View this table:
[in a new window]
Table 2. Baseline and Repeat CT and Autopsy Findings
According to TCD Findings at 6 Hours and to Their Changes at 24 and 48
Hours 2
for trend, improving versus nonimproving, irrespective of the timing of
recanalization). Finally, the TCD finding of 1
(5%) deteriorating patient changed from asymmetry at 6 hours to
no-flow at the 48-hour control. .
The overall accuracy of normal TCD in predicting early improvement was
71% (95% CI, 62 to 80), whereas the accuracy of MCA asymmetry and
that of MCA no-flow in predicting early deterioration were 60% (95%
CI, 50 to 70) and 74% (95% CI, 65 to 83),
respectively.
View this table:
[in a new window]
Table 3. Predictive Values, Sensitivity, and Specificity of
6-Hour TCD Findings With Respect to Early Clinical Course
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The frequency of early improvement and deterioration, the baseline
clinical and CT characteristics, and the clinical evolution of this
series of patients are similar to those reported in previous
studies.5 6 9 10 11 Approximately half of all acute
ischemic stroke patients either worsen or improve within the
first 48 hours of stroke onset, and this early clinical change is
predictive of long-term bad and good outcomes,
respectively.11
Acknowledgments
This work was supported in part by Consiglio Nazionale delle
Ricerche, grant No. 93051602086. We gratefully acknowledge Dr Cinzia
Roberti and Dr Giovanni Mancini for performing transcranial
Doppler examinations, the resident staff for their care and
selection of the patients, and Lewis Baker for having revised our
English.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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