351
Does Cerebral Infarction After a Previous
Warning Occur in the Same Vascular Territory?
J.P.M. Cillessen, MD; L.J. Kappelle, MD; J.C. van Swieten, MD;
A. Algra, MD; and J. van Gijn, MD, FRCPE
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
Background and Purpose: The aim of this study was to compare the territory of cerebral infarcts on
follow-up with that of the preceding transient ischemic attack or nondisabling stroke.
Methods: The Dutch TIA Trial was a randomized, double-blind, controlled trial, in which the secondary
preventive effects of two doses of aspirin were compared in patients with a transient ischemic attack or
nondisabling stroke. On the basis of clinical symptoms and computed tomography, qualifying events were
classified as pertaining to the left carotid, right carotid, or vertebrobasilar circulation.
Results: In 2,993 patients the territory of the qualifying event was that of the left carotid in 1,281 (43%),
the right carotid in 1,090 (36%), and the vertebrobasilar in 444 (15%); the territory was uncertain in 178
(6%). On follow-up (mean, 2.6 years), 184 of the 2,371 patients with a baseline event in the carotid
circulation suffered a recurrent ischemic stroke (7.8%), as did 28 of the 444 patients in the vertebrobasilar
group (6.3%); 117 of these 212 infarcts (55%; 95% confidence interval, 49-62) occurred in the same
territory (108 in the ipsilateral carotid and nine in the vertebrobasilar territory) as the event at baseline,
compared with 39% to be expected by chance alone (95% confidence interval, 32-45). In the carotid groups
patients were significantly more likely to have a subsequent ischemic event in the same territory as at entry
than patients in the vertebrobasilar group (relative risk, 1.8; 95% confidence interval, 1.1-3.2). The
average interval between the qualifying event and the subsequent stroke was significantly shorter (mean,
167 days; 95% confidence interval, 77-257) if the vascular territory was the same.
Conclusions: These results suggest that single artery disease accounts for at most one half of the strokes
on follow-up, relatively more often in the carotid territory, and that recurrent strokes from the same
arterial lesion occur sooner than strokes associated with other lesions. (Stroke 1993;24:351-354)
KEY WoRDs * carotid artery diseases * cerebral ischemia, transient * cerebrovascular disorders
T ransient ischemic attacks (TIAs) are brief episodes of focal loss of brain function attributed
to ischemia, primarily caused by thromboemboli from large arteries or the heart. By convention, they
last shorter than 24 hours and leave no persistent
neurological deficit.' Nevertheless, differences between
TIAs, reversible ischemic neurological deficits (recovery
after 1 day to 6 weeks), and nondisabling strokes are
quantitative rather than qualitative, and these time
limits are highly artificial.2'3 In terms of pathophysiology
and management, it is more relevant to classify ischemic
deficits of the brain according to the territory (carotid
or vertebrobasilar arterial system)' or to the type of the
vessels involved (small or large vessels).4
An even more practical but unanswered question is
how often recurrent strokes occur in the same vascular
territory as the initial event. The aim of this study was to
compare the territory of cerebral infarcts on follow-up
with that of the preceding TIA or nondisabling stroke in
a large series of patients who took part in the Dutch
TIA Trial.5,6
From the University Department of Neurology, Utrecht, The
Netherlands.
Address for correspondence: J.P.M. Cillessen, MD, Department
of Neurology, University Hospital Utrecht, Heidelberglaan 100,
3584 CX Utrecht, The Netherlands.
Received August 27, 1992; final revision received November 20,
1992; accepted November 25, 1992.
Subjects and Methods
The Dutch TIA Trial was a multicenter trial performed in the Netherlands between 1986 and 1990 that
enrolled 3,150 patients in 63 different hospitals. In this
randomized, double-blind, controlled trial the secondary preventive effects of 283 mg acetylsalicylic acid in
patients with a TIA or a nondisabling stroke were
compared with those of 30 mg.5'6 At the same time 50
mg atenolol was tested versus placebo in eligible patients (half of the total number of patients enrolled in
the aspirin part of the trial). All patients had a transient
or permanent focal neurological deficit; in the latter
case they had to be independent in most of their daily
activities (modified Rankin grade 3 or less).78 Patients
with events of a presumably cardioembolic origin, including atrial fibrillation, cardiac valve disease, or recent myocardial infarction, were excluded, as were
patients with disorders of blood coagulation. At entry
the history of each patient was recorded on a checklist
in everyday language.9 A computed tomographic (CT)
scan of the brain was mandatory, except in case of
transient monocular blindness. All CT scans were reviewed by at least two neurologists. Visualized infarcts
were categorized by the territories of the major cerebral
artery involved (anterior, middle, and posterior cerebral
artery; vertebrobasilar artery) or, in some cases, as
being in the border zones between either the anterior
352
Stroke Vol 24, No 3 March 1993
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and middle or between the middle and posterior cerebral artery.
For the purpose of this study patients from different
treatment arms were not separately distinguished. Furthermore, 157 patients were excluded. Twenty-three
patients had a cause of their symptoms other than
ischemia (for instance, an intracerebral hematoma or an
intracerebral tumor). In 131 patients CT was not available. Three patients were excluded because they had
infarcts in both the carotid and the vertebrobasilar
territories, and either could have been responsible for
the qualifying event.
On the basis of symptoms and CT, qualifying events
were classified as pertaining to the left carotid, right
carotid, or vertebrobasilar circulation. If CT showed an
infarct not appropriate to the symptoms, the clinical
features prevailed. Patients with isolated hemianopia,
patients with a combination of hemianopia and sensory
dysphasia, and patients with purely sensory symptoms
and a lacunar infarct in the thalamus were classified in
the vertebrobasilar group. The same applied if at least
two of the following symptoms were present: vertigo,
dysarthria, dysphagia, diplopia, and ataxia. Patients
with aphasia, transient monocular blindness, or unilateral motor deficit in the absence of "vertebrobasilar"
symptoms were classified as events in the carotid territory. Events that could not be confidently classified in
either the vertebrobasilar or the carotid territory were
classified as uncertain.
During the period of follow-up, which had a mean
duration of 2.6 years, the occurrence of outcome events
was closely monitored. Patients were seen every 4
months by their neurologists or, if they could not be
examined at the hospital, by their general practitioner.
For a diagnosis of stroke during follow-up, relevant
clinical features had to persist for more than 24 hours
and had to correspond with a new infarct or a hemorrhage on CT. In cases in which CT scanning was normal
or if no CT scan was available, an additional requirement was an increase in handicap of at least one grade
on the modified Rankin Scale.7,8 Two investigators
independently adjudicated whether the stroke on follow-up should be classified as a carotid or as a vertebrobasilar territory event; in case of disagreement a
third neurologist arbitrated. To describe the stroke-free
interval the Kaplan-Meier technique of survival analysis
was used.10 The Mantel-Haenszel X 2 test was used when
appropriate.
Results
The qualifying event was classified in the territory of
the left carotid artery in 1,281 patients (43%), in that of
the right carotid artery in 1,090 patients (36%), and in
the vertebrobasilar territory in 444 patients (15%).
Thirty-four patients with an infarct in the border zone
between the territories of the middle and the posterior
cerebral artery and 144 patients with normal CT scans
were classified as uncertain, because it was not possible
to classify these in the territory of either the carotid
artery or the vertebrobasilar system; these patients were
excluded from further analysis. Relevant infarcts on the
baseline CT scan were found in 781 of the 2,993 patients
(26%).
A fatal or nonfatal stroke during the follow-up period
occurred in 259 of the 2,815 patients with a classifiable
TABLE 1. Occurrence and Site of Ischemic Stroke on Follow-up
According to Vascular Territory of Qualifying Event
Qualifying
event
(n =2,815)
Left carotid
(n = 1,281)
Right carotid
(n = 1,090)
Vertebrobasilar
(n=444)
Ischemic stroke on follow-up
Left
Right
Total
carotid carotid Vertebrobasilar
(n =212) (n= 103) (n =77)
(n =32)
92
6
23
8
15
92
30
7
28
12
7
Diagonal indicates subsequent strokes that were in same vascular territory as qualifying event.
qualifying event (9.2%). In 25 patients no CT was made
after the recurrent stroke or it was not available, and in
22 patients CT showed a hemorrhage; these patients
were excluded from the analysis. Consequently, a confirmed ischemic stroke on follow-up occurred in 212 of
the 2,815 patients (7.5%); this number comprised 184 of
the 2,371 patients (7.8%) who had had a carotid event at
baseline and 28 of the 444 patients (6.3%) with a
vertebrobasilar event at baseline (Table 1). This difference was not statistically significant.
The presumed territory of the 212 ischemic strokes
on follow-up was the carotid circulation in 180 patients
(85%) and the vertebrobasilar territory in 32 patients
(15%). This overall distribution was therefore similar to
that of the events at baseline. Approximately half of the
subsequent ischemic strokes occurred in the same territory (left carotid, right carotid, or vertebrobasilar) as
the baseline event (117 of 212 or 55%; Table 1). The
territory of the subsequent event was the same as that
for the baseline event in 108 of the 184 patients with a
carotid baseline event (59%) and in nine of the 28
patients with a vertebrobasilar baseline event (32%).
This higher proportion of a similarly located subsequent
ischemic stroke in the carotid territory was statistically
significant: relative rate, 1.8 (95% confidence interval
[CI], 1.1-3.2). In 53 of the 184 patients with a carotid
baseline event (29%) the territory of the event on
follow-up was that of the contralateral carotid.
The average interval between the qualifying event
and the subsequent ischemic stroke was 423 days (415
days in patients with a carotid baseline event and 475
days in those with a vertebrobasilar qualifying event,
which difference was not statistically significant). In the
patients with a subsequent ischemic event in the same
territory the interval was 348 days, versus 515 days in
patients with a subsequent infarct in another territory
(Figure 1). This difference of 167 days was significant
(95% CI, 77-257).
Discussion
A new ischemic event in the same vascular territory
as the baseline event occurred twice as often in patients
with initial symptoms in the supply area of the carotid
artery as in those with a qualifying event in the vertebrobasilar territory, whereas the overall stroke rate in
the two groups was similar. Second, recurrent strokes in
the same vascular territory as the baseline event oc-
Cillessen et al Vascular Territory of Subsequent Cerebral Infarcts
TERRITORY OF THE SUBSEQUENT
Although the overall proportions of carotid and vertebrobasilar events on follow-up were similar to those at
baseline (85% versus 15%), patients who had a qualifying carotid circulation event were significantly more
likely to have a stroke in the same territory than
NFARCT
It
ory as with
event
n
tory as with
tD
ax
0
CL
3vent
'a
0
Q)
UX
..........
200
400
600
1000
800
1000
800
time (in days)
rualafying
FIGURE 1. Graph shows interval between q ..lfying event
event
and ischemic stroke on follow-up according to elationoftheir
vascular territories (Kaplan-Meier curve, n=2 12).
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
curred significantly earlier than those in different
territories.
In this hospital-based study the proporti' on of patients
with a TIA or a nondisabling stroke in the ssupply area of
the carotid artery at entry was 79% compaLred with 15%
in the supply area of the vertebrobasilar syrstem and 6%
with uncertain territory. In community-i based studies
the incidence of carotid TIAs varied betwteen 61% and
80%, and that of vertebrobasilar TIAs vatried between
20% and 32%, with 7% uncertain.11,12 Hlospital-based
studies of patients with TIAs or minor str(okes reported
70-78% carotid events, 22-28% vertebrot)asilar events,
and 2-4% with uncertain vascular terriltory.13-15 The
exclusion of patients in whom cardioem bolism was a
possible cause of the cerebral ischemia in our study has
probably not influenced these proportiions, because
strokes in such patients have been shown to involve the
carotid territory in 70% and the vertebr(obasilar territory in 23%.16
The annual stroke rate of 3.5% was the same as that
in the Oxfordshire Community Stroke Pr oject (OCSP)
study of hospital-referred TIAs17 but s5 omewhat less
(ESPS)
than in the European Stroke Prevention S
in which the stroke recurrence rate was 4.61% per year in
the group treated with antiplatelet agents 14The stroke
carotid
rate in our study was similar for patients with
with a carotid
or with a vertebrobasilar qualifying eve]nt. This iS in
agreement with findings from a retrospecti ve study from
the Mayo Clinic, based on a medical r(
linkage
system between hospitals.11 In contrast, in theESPS and
in the Ticlopidine-Aspirin Stroke Study (TASS), the
patients with a vertebrobasilar TIA as qu alifying event
had a lower stroke risk than patients M
a carotid
TIA18,'9; possibly patients with nonisci temic attacks
were inadvertently included in these trialIs because the
symptoms resembled those of vertebrob; asilar attacks.
The overall proportion of subsequent infaircts occurring
in the vascular territory of the original e' vent was 55%
(95% CI, 49-62), in agreement with prm evious studies
(M.L. Dyken, personal communication).'L7,20 This proportion is higher than that expected by chance alone
(39%; 95% CI, 32-45).
wtudy
a
ecord
vith
353
patients with a vertebrobasilar arterial event. This difference may be explained in several ways. First, it may
be a reflection of a greater tendency of carotid artery
atherosclerotic lesions to lead to recurrent thromboemboli. Patients with carotid lesions associated with a
stenosis of 70% or more are now known to be particularly liable to ipsilateral stroke.2122 Because angiographic or ultrasound studies of the extracranial portion
of the internal carotid artery were at that time not
included in the study protocol, we cannot assess the
importance of this factor. During the follow-up period
carotid endarterectomy was reported in 1% of all patients included. Second, patients with atherosclerosis of
the vertebrobasilar arterial system might have more
coincidental abnormalities in the carotid arteries than
vice versa. Finally, because most of the information was
obtained from the history, our criteria for the classification of the events according to the supply area of the
carotid or the vertebrobasilar artery may have been
imprecise.
The risk of ischemic stroke was greatest soon after the
qualifying event; more than half of the recurrent events
occurred within the first year (Figure 1). This high rate
of early strokes has also been reported in other studies.17 A new finding in our study is the relatively high
risk of stroke in the same vascular territory in patients
with original symptoms in the carotid circulation. This
may be explained by the inclusion of patients with
severe stenosis of the internal carotid artery, as the
interim results of the European Carotid Surgery Trial
(ECST) and the North American Symptomatic Carotid
Endarterectomy Trial (NASCET) clearly showed an
early reduction of the risk of ipsilateral ischemic stroke
after carotid endarterectomy in patients with severe
(70-99%) carotid stenosis.21,22 Our study shows that in
general the territory of the contralateral carotid artery
is also at considerable risk, although strokes in that area
tend to occur somewhat later. It is still uncertain if
atheromatous lesions in the asymptomatic artery should
be operated on, but some ongoing trials will probably
provide an answer in the near future.23
Our study emphasizes that after a TIA or nondisabling stroke the danger of a subsequent stroke is by no
means restricted to the same arterial territory, particularly when the patient has a vertebrobasilar TIA. This
underscores the need for a regimen of medical treatment that can prevent strokes even more effectively
than the 22% reduction now achieved with antiplatelet
agents.24 Regarding local treatment of atherosclerosis,
the carotid arterial system is most often affected, and it
has recently become clear that only in symptomatic
lesions associated with severe stenosis (70-99%) does
the benefit of endarterectomy clearly outweigh the
risks,21'22 whereas the reverse applies to lesions with a
stenosis of less than 30%.21 The continued follow-up
and randomization of patients with symptoms from
intermediate degrees of stenosis will further define the
role of local and distant lesions in the pathogenesis of
recurrent stroke.
354
Stroke Vol 24, No 3 March 1993
Acknowledgments
We wish to thank Dr. H.P. Adams Jr. (Iowa City, Iowa) and
Dr. J.D. Banga (Utrecht, The Netherlands) for helpful comments during the preparation of this article.
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Does cerebral infarction after a previous warning occur in the same vascular territory?
J P Cillessen, L J Kappelle, J C van Swieten, A Algra and J van Gijn
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Stroke. 1993;24:351-354
doi: 10.1161/01.STR.24.3.351
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1993 American Heart Association, Inc. All rights reserved.
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