Progress Reviews
Are Lacunar Strokes Really Different?
A Systematic Review of Differences in Risk Factor Profiles Between
Lacunar and Nonlacunar Infarcts
Caroline Jackson, BSc; Cathie Sudlow, DPhil, MRCP
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Differences in risk factors between lacunar and nonlacunar infarcts might support a distinct
arterial pathological process underlying lacunar infarction.
Methods—We did a systematic review of studies comparing risk factors in patients with lacunar versus nonlacunar
infarction. For each risk factor, we calculated study-specific and pooled relative risks (RRs) for lacunar versus
nonlacunar infarction.
Results—A total of 16 of 28 studies included risk factors in their ischemic stroke subtype definitions. Hypertension and
diabetes appeared commoner among patients with lacunar versus nonlacunar infarction. However, analyses confined to
studies using risk factor–free ischemic subtype definitions found only a marginal excess of hypertension with lacunar
versus nonlacunar infarction (RR, 1.11; 95% CI, 1.04 to 1.19) and no difference for diabetes (RR, 0.95; 95% CI, 0.83
to 1.09). Atrial fibrillation and carotid stenosis were associated more with nonlacunar than lacunar infarction but less
so when only studies using risk factor–free classifications were considered. Otherwise, there was no evidence of
differences in risk factor profiles.
Conclusions—Risk factor–free ischemic stroke subtype classification methods should be used for comparing risk factor
profiles between lacunar and nonlacunar subtypes. (Stroke. 2005;36:891-904.)
Key Words: lacunar infarction 䡲 meta-analysis 䡲 risk factors 䡲 stroke
A
pproximately one quarter of ischemic strokes are caused
by lacunar infarcts: small, deep cerebral infarcts, from 2
to 20 mm in diameter.1 These are presumed to result from the
occlusion of single, small, perforating arteries supplying the
deep subcortical areas of the brain. If the occlusive arterial
pathology is distinct from the atherothromboembolic processes that occlude larger arteries, causing most other types of
ischemic stroke, the best strategies for the investigation and
treatment of patients with lacunar infarction might differ from
those for patients with other ischemic stroke subtypes.
Current knowledge of the arterial pathology of lacunar
infarction is based largely on Fisher’s meticulous clinicopathological studies, in which he serially dissected the vascular
supply of a total of 68 lacunar infarcts in 18 postmortem
brains.2– 6 He found that most symptomatic lacunar infarcts
were associated with occlusion of perforating arteries ⬇200
to 800 ␮m in diameter by atheromatous plaques, with or
without complicating thrombus. Most asymptomatic lacunar
infarcts were associated with occlusion of perforating arteries
⬇40 to 200 ␮m in diameter by “lipohyalinosis,” a destructive
small vessel lesion characterized in the acute phase by
fibrinoid necrosis and in the healed phase by loss of normal
wall architecture, collagenous sclerosis, and mural foam
See Editorial Comment, pg 902
cells. However, it is difficult to draw firm conclusions from
Fisher’s work because the number of patients included was
small, most of the lacunar infarcts were asymptomatic, and
infarcts related to stroke symptoms were studied months or
even years after the acute event.
Further progress in understanding the arterial pathology of
lacunar stroke has been limited. Pathological studies are rare
because autopsy rates are declining, lacunar strokes have a
low-case fatality rate,1 and tracing the vascular supply of
subcortical lesions is technically difficult and time consuming.7 Difficulties in imaging the small perforating intracranial
arteries have made informative imaging studies scarce.
An alternative approach has been to compare the risk factor
profiles of patients with lacunar infarcts versus those with
nonlacunar infarcts because this may reveal differences suggestive of distinct arterial pathologies. However, these studies have
tended to have methodological limitations: sample sizes were
generally small; risk factors were inconsistently defined; and
studies used a variety of different classification methods to
define ischemic stroke subtypes (see Appendix A).
Some used a classification based primarily on the clinical
features of the stroke syndrome (most commonly the Oxford7
Received August 6, 2004; accepted August 31, 2004.
From the Division of Clinical Neurosciences, University of Edinburgh, United Kingdom.
Correspondence to Dr Cathie Sudlow, Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK EH4
2XU. E-mail [email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000157949.34986.30
891
892
Stroke
April 2005
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
shire Community Stroke Project [OCSP] classification8),
usually refined by the results of brain imaging (ie, if a
patient’s computed tomography [CT] or magnetic resonance
[MR] brain scan showed an infarct that was relevant to the
presenting syndrome but whose site and size suggested a
different ischemic stroke subtype classification from the
clinical features alone, the patient was reclassified in line with
the imaging findings).
Other studies used the clinical and imaging features of
the presenting stroke but also included risk factors in their
ischemic stroke subtype definitions (most commonly the
Trial of Org 10172 in Acute Stroke Treatment [TOAST]
classification9). This could bias the results of a comparison
of the prevalence of such risk factors between subtypes. It
might also bias comparisons between subtypes of risk
factors not explicitly included in the definitions because many vascular risk factors are associated with each
other.
A few studies relied on imaging findings alone to classify
ischemic stroke subtypes, regardless of the patients’ symptoms. Some patients in these studies may have been classified
on the basis of asymptomatic or remotely symptomatic
visible infarcts, whereas those with a definite ischemic stroke
but no visible infarct would have been excluded.
In this article, we report the findings of a systematic review
of studies comparing the prevalence of a variety of risk
factors in patients with lacunar versus those with nonlacunar
ischemic stroke.
Methods
Study Identification
We sought studies published in English up to and including June
2003 comparing the prevalence of risk factors among patients with
stroke attributable to lacunar versus nonlacunar cerebral infarction.
We identified studies by comprehensive textword and MeSH-based
electronic searches of Medline and Embase, designed to retrieve
articles about ischemic stroke subtypes, especially lacunar strokes
(for details see Appendix B, available online only at http://www.strokeaha.org); perusal of reference lists of all relevant articles
identified, searching within books on cortical and subcortical stroke,
and discussions with colleagues.
We subsequently decided to include only those studies published
from 1985 onward because the few earlier studies we identified had
very limited access to brain imaging (at that time, CT scanning), and
this was often restricted to younger patients. We excluded studies
among highly selected groups of patients, for example, randomized
controlled trials, and studies in which the definitions used to classify
ischemic stroke subtypes were unclear or in which there were data
inconsistencies.
Data Extraction
We extracted information from each study on the population studied
(community- or hospital-based; inpatients or outpatients; consecutive recruitment or not), ischemic stroke subtype definitions, risk
factor definitions, and the numbers of lacunar and nonlacunar
patients with each of the following risk factors: hypertension;
diabetes; smoking; alcohol consumption; raised cholesterol concentration; previous transient ischemic attack (TIA); atrial fibrillation
(AF); and carotid stenosis.
We included in the nonlacunar patient group all the nonlacunar
ischemic stroke patients apart from the small proportion of patients
with an “unusual” cause of stroke (eg, nonatherosclerotic vasculopathies or hematological disorders), for studies in which these were
categorized separately. Both authors independently extracted data
from the articles, resolving any disagreements by discussion.
Statistical Analyses
We grouped studies according to whether the classification used to
define ischemic stroke subtypes: included the risk factor under study;
included various risk factors, but not specifically the risk factor
under study; was based on brain imaging alone; or was based on the
clinical features of the stroke syndrome, usually refined by brain
imaging, but did not include risk factors. For each risk factor, we
calculated study-specific and pooled relative risks (RRs) with 95%
CIs for lacunar versus nonlacunar infarction using Cochrane RevMan software.10 We used standard ␹2 tests to assess statistical
heterogeneity between studies. In a post hoc sensitivity analysis, we
confined our analyses to community-based studies or studies that had
recruited consecutive patients from hospital admissions and outpatient clinics.
Results
Included Studies
We identified 41 potentially relevant studies. From these, we
excluded 2 that were published before 1985,11,12 5 for which
it was not clear how ischemic stroke subtypes were defined,13–17 1 with data inconsistencies,18 and 5 that included
highly selected groups of patients.19 –23 This left 28 studies
including 21 980 patients, of whom 5379 had a lacunar
infarction.24 –51
The characteristics of the studies included are summarized in Table 1. Sixteen (16 216 patients) used classification methods that included risk factors in the definitions of
ischemic stroke subtypes.24,27,28,30 –33,36,40,42– 45,48 –50 Ten of
these (10 705 patients) used the TOAST classification,28,31–33,40,43– 45,48,50 which considers the presence of
hypertension and diabetes to favor a diagnosis of lacunar
infarction, whereas carotid stenosis of ⬎50% and potential
sources of cardiac embolism such as AF should be absent
for this diagnosis. One study (1262 patients) defined
ischemic stroke subtypes on the basis of the site and size of
infarction on brain imaging alone.39 Ten studies (4502
patients) defined ischemic subtypes on the basis of the
clinical features of the stroke syndrome, generally modified by the site and size of any relevant infarct seen on
brain imaging but not including risk factors (Table 1;
Appendix).29,34,35,37,38,41,46,47,51,52
Five studies (2522 patients) were community based,
whereas 23 (19 458 patients) were hospital based, mostly
recruiting hospital admissions (Table 1). The mean age of the
patients was higher in the community than in the hospitalbased studies (73 versus 66 years), and the proportion of
males was higher in the hospital-based studies. Almost all
patients studied had CT or MR brain imaging. Three studies
excluded presumed cardioembolic stroke,25,30,41 2 excluded
infratentorial infarcts,41,51 and 1 excluded total anterior circulation and posterior circulation strokes (Table 1).38 Table 2
shows the definitions given for the various risk factors
studied.
Hypertension
A total of 25 studies (20 850 patients, 5034 with lacunar
infarction) presented data on hypertension.24 –33,35,36,39 –51
Most defined hypertension on the basis of raised blood
Jackson and Sudlow
TABLE 1.
Risk Factors for Lacunar Versus Nonlacunar Infarction
893
Characteristics of Studies Included
Stroke Population Recruited
Mean %
Age Male
% With
CT/MR
Brain
Scan¶
Ischemic
Stroke
Subtype
Classification
Nonlacunar
Comparison
Group
Risk
Factors
Studied
Total Ischemic
Stroke Patients
Included (lacunar
infarct patients)†
Study
Year*
Ankara40
2002 Consecutive admissions to neurology
department with complete evaluation
65
60
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, AF, smoking, HC
264 (66)
Athens48
2000
Consecutive admissions
71
58
100%#
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, TIA, AF, smoking,
HC
850 (177)
Barcelona36
1999
Consecutive admissions
66
57
100%
Risk factor–based
All nonlacunar ischemic strokes‡
HBP, DM, TIA, smoking, HC
2720 (399)
Besançon39
2000
Consecutive admissions
69
57
100%
Imaging-based
All nonlacunar ischemic strokes
with a single visible infarction on
CT/MRI
HBP, DM, TIA, AF, smoking,
alcohol, HC
1262 (243)
Boston45
2000
Consecutive admissions
69
54
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes
HBP, DM, AF smoking,
alcohol, HC
410 (109)
Buenos Aires44 2001
Consecutive admissions
64
64
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, AF, smoking,
alcohol, HC
234 (105)
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Cincinnati49
1999
Admissions or autopsied cases
(among blacks)
NR
NR
97%#
Risk factor–based (NINDS)
All nonlacunar ischemic strokes‡
HBP, DM, smoking
167 (39)
Edinburgh38
1999
Consecutive admissions and
neurovascular clinic outpatients
NR
NR
NR
Risk factor–free
Partial anterior circulation strokes
(TACI and POCI excluded)
Ipsilateral CS
608 (215)
Erlangen31
2001
Community-based (13% of original
cohort excluded because of
incomplete investigation)
73
44
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, smoking
522 (120)
Germany28
2001
Admissions (multicenter)
68
58
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, TIA, smoking,
alcohol, HC
4842 (1028)
Izmir32
1997
Consecutive admissions to stroke
care unit
63
56
100%
Risk factor–based (TOAST)
All nonlacunar ischemic strokes
HBP, DM, TIA, smoking, HC,
ipsilateral CS
1529 (198)
L’Aquila46
1998 Community-based (unknown No. of
original cohort excluded because of
lack of brain imaging)
74
53
100%
Risk factor–free
Nonlacunar ischemic strokes,
excluding CE strokes or strokes of
uncertain or mixed etiology
HBP, DM, smoking, HC,
ipsilateral CS
393 (242)
London29
2001
Community-based
72
48
NR
Risk factor–free
All nonlacunar ischemic strokes
HBP, DM, AF, smoking,
alcohol
862 (282)
Lund (a)41
1989
Consecutive admissions of minor
stroke patients to neurology
department who were examined
using CT, brain, and catheter
angiography
58
75
100%
Risk factor–free
Nonlacunar ischemic strokes
excluding potentially CE strokes
HBP, DM, TIA, smoking,
alcohol, HC, ipsilateral CS,
contralateral CS
122 (61)
Lund (b)34
1994
Consecutive admissions with brain
imaging, carotid ultrasound, and
echocardiography
73
55
100%
Risk factor–free
All nonlacunar ischemic strokes
AF, ipsilateral CS
166 (49)
Maastricht (a)25 1991
Admissions, excluding infratentorial
infarcts
70
NR
100%
Risk factor–free
Atherothrombotic infarcts
(excluding CE strokes for all
comparisons except AF)‡
HBP, DM, AF, ipsilateral CS,
contralateral CS
247 (103)
Nonlacunar ischemic strokes
HBP, DM
869 (287)
Maastricht (b)26 1996
NR
NR
NR
NR
Risk factor–free
Manchester37
1998
Acute stroke admissions
NR
NR
56%§
Risk factor–free
Oxford35
1990
Community-based
73
49
85%§
Risk factor–free
Nonlacunar carotid territory
ischemic strokes
HBP, DM, TIA, AF, smoking
304 (102)
Riyadh24
1999 Consecutive admissions who had CT
brain
59
68
Risk factor-based
All nonlacunar ischemic strokes
HBP, DM, AF, smoking
756 (248)
Risk factor-based (NINDS)
All nonlacunar ischemic strokes‡
HBP, DM, TIA, smoking
442 (72)
Risk factor–free
All nonlacunar carotid territory
ischemic strokes
HBP, DM, TIA, AF, smoking
517 (170)
Risk factor-based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, TIA, smoking
448 (133)
100%
All nonlacunar ischemic strokes AF, ipsilateral CS, contralateral
(excluding POCI for CS
CS
comparisons)
305 (80)
Rochester42
1999
Community-based
76
41
Rome51
1995
Consecutive stroke patients
hospitalized within 12 hours of onset
of event
67
58
San Diego43
1993
Consecutive admissions to and
outpatients seen at hospital
61
66
Seoul (a)30
1999
Admissions who had a CT or MRI
and catheter angiography
61
76
100%
Risk factor–based
Seoul (b)33
2001 Admissions within 7 days of onset of
event
62
63
100%#
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, TIA, smoking, HC
969 (215)
Taiwan50
1997
Consecutive admissions
66
57
Most
Risk factor–based (TOAST)
All nonlacunar ischemic strokes‡
HBP, DM, AF smoking,
alcohol, HC, ipsilateral CS
637 (195)
Texas47
1991
Inpatients and outpatients seen in
neurology department
61
75
100%
Risk factor–free
Nonlacunar carotid territory
infarcts, excluding CE and
unclassified infarcts
HBP, DM, TIA, smoking,
ipsilateral CS, contralateral CS
109 (55)
USA27
1987
Admissions (multicenter)
68
47
Risk factor-based (NINDS)
All nonlacunar ischemic strokes
HBP, DM, TIA, AF
1273 (337)
92%#
100%
98%#
97%#
Large vessel infarcts, excluding CE HBP, DM, smoking, alcohol
strokes‡
153 (49)
*Year of publication.
†Total of 28 studies with 21 980 ischemic stroke patients included in the lacunar vs nonlacunar comparisons, and 5379 patients with lacunar ischemic stroke.
‡Ischemic strokes with unusual causes excluded (generally⬍5% of ischemic stroke patients studied).
§Siriraj score or Guy’s Hospital Stroke Diagnostic Scale was used to distinguish between ischemic and hemorrhagic stroke in the absence of brain imaging.
¶% of the total No. of ischemic stroke patients included (shown in final column), except where otherwise stated.
#% of total cohort studied (all ischemic strokes⫾hemorrhagic strokes).
NINDS indicates National Institute of Neurological Disorders and Stroke; TACI, total anterior circulation infarct, POCI, posterior circulation infarct; HBP, hypertension; DM,
diabetes mellitus; HC, hypercholesterolemia; CS, carotid stenosis; NR, not reported; CE, cardioembolic.
894
Stroke
TABLE 2.
April 2005
Definitions of Risk Factors in Studies Included*
Hypertension
Diabetes
Severe Carotid Stenosis
Pre/post
Stroke
Cutoff
(mm Hg)
Pre/post
Stroke
Cutoff
(mmol/L)
Smoking
Alcohol†
Raised
Cholesterol
(mmol/L)
Ankara40
Pre or post
160/90
Pre or post
Fasting ⬎7.8
or random
⬎11.1
Current smoking or
within 5 years
ND
⬎5.7
ND
ND
Athens48
Pre
160/90
Pre
Fasting ⬎6.0
Current daily
smoking or within
previous year
ND
⬎6.5
ND
ND
Pre or post
160/90
Pre or post
Fasting ⬎6.1
Current smoking or
within 5 years
ND
⬎6.5 or
triglycerides
⬎1.71
ND
ND
Study
Barcelona36
Besançon39
Cutoff
Method of
Measurement
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
NR
NR
NR
NR
NR
NR
NR
ND
ND
Boston45
Pre or post
140/90
NR
NR
⬎10 cigarettes/day
⬎2 units/day
NR
ND
ND
Buenos Aires44
Pre or post
140/90
Pre or post
Random ⬎11
⬎10 cigarettes/day
⬎2 units/day
⬎5.7
ND
ND
Cincinnati49
Pre
NR
Pre
NR
Current smoking
ND
ND
ND
ND
Edinburgh38
ND
ND
ND
ND
ND
ND
ND
⬎70%
Ultrasound
Erlangen31
Pre or post
160/95
Pre or post
Fasting ⬎6.7
Current smoking
ND
ND
ND
ND
Germany28
Pre
160/90
Pre or post
NR
Current smoking
Daily alcohol
consumed
⬎5.7 before
stroke or
lipid-lowering
medication
ND
ND
Izmir32
Pre
160/90
Pre
Fasting ⬎6.0
Regular smoking
ND
⬎6.5
⬎50 %
Ultrasound, MRA
or catheter
angiography
Pre or post
150/90
Pre
Fasting ⬎7.8
Daily smoking within
at least last 2
months
ⱖ2 units/day for
women and ⱖ3
units/day for men
⬎5.7
⬎50%
Ultrasound
London29
Pre
160/95
Pre
Fasting ⬎7.8
Ever smoked
ND
ND
ND
ND
Lund (a)41
Pre or post
160/90
NR
NR
NR
Alcohol abuse
NR
ⱖ50%
Catheter
angiography
L’Aquila46
ND
ND
ND
ND
ND
ND
ND
ⱖ50%
Ultrasound
Maastricht (a)25
Pre or post
160/90
Pre or post
NR
ND
ND
ND
ⱖ50%
Ultrasound
Maastricht (b)26
NR
NR
NR
NR
ND
ND
ND
ND
ND
Manchester37
ND
ND
ND
ND
ND
ND
ND
⬎70%
Ultrasound
Oxford35
Pre
160/90
NR
NR
Ever smoked
ND
ND
ND
ND
Riyadh24
Pre or post
160/90
Pre or post
Fasting ⬎7.7
NR
ND
ND
ND
ND
Rochester42
NR
NR
NR
NR
NR
ND
ND
ND
ND
Rome51
NR
NR
NR
NR
NR
ND
ND
ND
ND
San Diego43
NR
NR
NR
NR
ⱖ5 cigarettes/day at
time of stroke
ND
ND
ND
ND
Lund (b)34
Seoul (a)30
Pre
NR
Pre
NR
Current smoking
⬎7.5 units/day
ND
ND
ND
Seoul (b)33
Pre or post
160/90
Pre or post
Fasting ⬎6.1
Current smoking
ND
⬎5.7
ND
ND
NR
NR
NR
NR
NR
NR
⬎6.2
ⱖ50%
Ultrasound, MRA
or catheter
angiography
Taiwan50
Texas47
NR
NR
NR
NR
NR
ND
ND
ⱖ50%
Ultrasound
USA27
Pre
NR
Pre
NR
ND
ND
ND
ND
ND
*Definitions for previous TIA and AF not shown.
†Values converted from grams into United Kingdom units where necessary.
ND, no data, indicates that the risk factor concerned was either not studied or extractable data were not given in the publication(s); NR, not reported, even though
the risk factor concerned was studied; MRA, magnetic resonance angiography.
pressure before or after the stroke (Table 2). Overall, hypertension was commoner among patients with lacunar infarcts
(pooled RR lacunar versus nonlacunar infarction, 1.22; 95% CI,
1.20 to 1.25; Figure 1). However, there was substantial statistical
heterogeneity between results of the individual studies
(␹224df⫽105.70; P⬍0.00001), partly arising from the different
methods used to define ischemic stroke subtypes (Figure 1). The
apparent excess of hypertension in lacunar infarction was confined to studies in which the presence of hypertension favored a
diagnosis of lacunar infarction (pooled RR, 1.25; 95% CI,
1.21 to 1.28) and studies including risk factors other than
hypertension in the definitions of ischemic stroke subtypes
(pooled RR, 1.28; 95% CI, 1.23 to 1.34; Figure 1). Among
studies defining ischemic stroke subtypes using a risk factor–
free classification, the increased prevalence of hypertension
among those with lacunar infarction was marginal (pooled
RR, 1.11; 95% CI, 1.04 to 1.19), with no statistical heterogeneity between studies (Figure 1).
Jackson and Sudlow
Risk Factors for Lacunar Versus Nonlacunar Infarction
895
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Figure 1. RRs (lacunar vs nonlacunar) for hypertension, grouped by ischemic stroke subtype classification method. The RR for each
study is shown as a square, with size denoting statistical weight of the study. Horizontal lines represent 95% CIs. Diamonds represent
pooled RRs, with 95% CIs represented by the width of the diamonds. N indicates total number of lacunar or non-lacunar patients; n,
number of lacunar or non-lacunar patients with hypertension; RR, relative risk; CI, confidence interval. Heterogeneity between four
groups: ␹23df⫽18.22; P⫽0.0004.
Diabetes Mellitus
Atrial Fibrillation
A total of 25 studies (20 851 patients, 5035 with lacunar
infarction) presented data on diabetes mellitus.24 –33,35,36,39 –51
Only 13 gave a clear definition of diabetes, generally comprising a history of diabetes before the stroke or raised blood
glucose on admission (Table 2). There was a significant
excess of diabetes in lacunar versus nonlacunar infarction
among studies using a classification in which diabetes favors
a diagnosis of lacunar infarction (pooled RR, 1.25; 95% CI,
1.17 to 1.34) and among studies using a classification
including risk factors other than diabetes (pooled RR, 1.20;
95% CI, 1.09 to 1.32). However, among studies with a risk
factor–free classification, there was no difference in the
prevalence of diabetes in lacunar versus nonlacunar infarction
(pooled RR, 0.95; 95% CI, 0.83 to 1.09; Figure 2).
Fourteen studies (8087 patients, 2266 with lacunar infarction)
presented data on AF.24,25,27,29,34,35,37,39,40,44,45,48,50,51 Overall,
there was a stronger association between AF and nonlacunar
than lacunar infarction (pooled RR for all 14 studies, 0.35;
95% CI, 0.30 to 0.40; Table 3). There was substantial
heterogeneity between the individual study results
(␹213df⫽85.08; P⬍0.00001), largely explained by different
ischemic subtype classifications (Table 3). The association of
AF with nonlacunar infarction was particularly pronounced
among studies in which the presence of AF favored a
diagnosis of nonlacunar infarction (pooled RR, 0.13; 95% CI,
0.09 to 0.19) and was less extreme for studies using a risk
factor–free classification (pooled RR, 0.51; 95% CI, 0.42 to
0.62; Table 2).
896
Stroke
April 2005
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Figure 2. RRs (lacunar vs nonlacunar) for diabetes, grouped by ischemic stroke subtype classification method. Figure format as in Figure 1. N indicates total number of lacunar or non-lacunar patients; n, number of lacunar or non-lacunar patients with diabetes; RR, relative risk; CI, confidence interval. Heterogeneity between four groups: ␹23df⫽18.22; P⫽0.0004.
Carotid Stenosis
Other Risk Factors
Nine studies (3850 patients, 1074 with lacunar infarction)
presented data on ipsilateral stenosis.25,32,34,37,38,41,46,47,50 Definitions of severe stenosis varied, but ⬎50% or ⬎70%
stenosis on ultrasound were the commonest (Table 2). Four of
the studies using risk factor–free classifications also gave
data on contralateral stenosis.25,37,41,47 Overall, there was an
excess of ipsilateral carotid stenosis among patients with
nonlacunar infarction. The association was more pronounced
among studies in which severe carotid stenosis favored a
diagnosis of nonlacunar infarction (RR, 0.08; 95% CI, 0.03 to
0.25) and was less extreme among studies using risk factor–
free ischemic subtype definitions (RR, 0.35; 95% CI, 0.28 to
0.44). A similar result was observed for contralateral stenosis
(RR, 0.21;95% CI, 0.11 to 0.41; Table 3).
There was no clear association between smoking, excess
alcohol consumption, or history of previous TIA and
lacunar versus nonlacunar infarction, irrespective of the
method used to define ischemic stroke subtypes (Table 3).
Where given, definitions of smoking or alcohol excess
varied considerably between studies (Table 2). The definition of raised cholesterol in most studies was based on
the blood cholesterol concentration after stroke (Table 2).
Although the overall pooled RR of 1.22 (95% CI, 1.15 to
1.30), suggested that raised cholesterol predisposes more
to lacunar than to nonlacunar infarction, studies using risk
factor–free ischemic subtype definitions found no definite
association of raised cholesterol with lacunar versus nonlacunar infarction (Table 3).
Jackson and Sudlow
Risk Factors for Lacunar Versus Nonlacunar Infarction
TABLE 3. Pooled RRs for Risk Factors Other Than Hypertension and Diabetes Studied,
Grouped by Stroke Subtype Classification Method
Risk Factor
AF
Stroke Subtype Classification
AF included in definitions
Other risk factors included in definitions
Imaging-based
Risk factor–free
All groups combined*
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Ipsilateral carotid stenosis
Stenosis included in definitions
Risk factor–free
All groups combined†
Contralateral carotid stenosis
Smoking
Risk factor–free
Other risk factors included in definitions
Imaging-based
Risk factor–free
All groups combined‡
Alcohol
Other risk factors included in definitions
Imaging-based
Risk factor–free
All groups combined¶
Previous TIA
Previous TIA included in definitions
No. of Studies/Ischemic
Strokes/Lacunar Infarcts
RR (95% CI)
Heterogeneity Statistics
6/3668/989
0.13 (0.09 to 0.19)
␹25df⫽7.03; P⫽0.22
1/756/248
0.12 (0.05 to 0.29)
1/1262/243
0.59 (0.47 to 0.74)
6/2401/786
0.51 (0.42 to 0.62)
␹25df⫽11.96; P⫽0.04
14/8087/2266
0.35 (0.30 to 0.40)
␹213df⫽85.08; P⫽⬍0.00001
2/2166/393
0.08 (0.03 to 0.25)
␹21df⫽0.83; P⫽0.36
7/1684/681
0.35 (0.28 to 0.44)
␹26df⫽17.72; P⫽0.007
9/3850/1074
0.30 (0.24 to 0.37)
␹28df⫽27.98; P⫽0.0005
4/661/279
0.21 (0.11 to 0.41)
␹23df⫽4.56; P⫽0.21
15/14943/3153
1.06 (0.99 to 1.12)
␹214df⫽48.97; P⫽⬍0.0001
1/1262/243
1.22 (1.02 to 1.46)
6/2305/911
1.00 (0.92 to 1.08)
␹25df⫽11.79; P⫽0.04
22/18510/4307
1.05 (1.00 to 1.10)
␹222df⫽65.16; P⫽⬍0.00001
5/6276/1486
1.11 (0.96 to 1.29)
␹24df⫽4.42; P⫽0.35
1/1262/243
1.41 (0.98 to 2.04)
2/984/343
0.95 (0.68 to 1.34)
␹21df⫽0.27; P⫽0.60
8/8522/2072
1.12 (0.98 to 1.27)
␹27df⫽7.10; P⫽0.42
8/12964/2546
0.88 (0.78 to 1.00)
␹27df⫽7.03; P⫽0.43
897
898
Stroke
April 2005
TABLE 3.
Continued
Risk Factor
Stroke Subtype Classification
Imaging-based
Risk factor–free
All groups combined§
Raised cholesterol
Other risk factors included in definitions
Imaging-based
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Risk factor–free
All groups combined#
No. of Studies/Ischemic
Strokes/Lacunar Infarcts
RR (95% CI)
Heterogeneity Statistics
1/1262/243
1.11 (0.83 to 1.48)
4/1052/388
1.26 (0.97 to 1.64)
␹23df⫽8.37; P⫽0.04
13/15278/3177
0.95 (0.86 to 1.05)
␹212df⫽21.71; P⫽0.04
9/12455/2492
1.26 (1.18 to 1.35)
␹28df⫽27.98; P⫽0.0005
1/1262/243
1.20 (0.92 to 1.57)
2/515/303
0.75 (0.58 to 0.97)
␹21df⫽0.14; P⫽0.71
12/14232/3038
1.22 (1.15 to 1.30)
␹211df⫽42.79; P⫽⬍0.0001
*Heterogeneity between 4 groups: ␹23df⫽66.1; P⬍0.00001
†Heterogeneity between 3 groups: ␹21df⫽9.4; P⫽0.002
‡Heterogeneity between 3 groups: ␹23df⫽4.4; P⫽0.1
¶Heterogeneity between 3 groups: ␹22df⫽2.4; P⫽0.3
§Heterogeneity between 3 groups: ␹22df⫽6.3; P⫽0.04
#Heterogeneity between 2 groups: ␹22df⫽14.7; P⫽0.0007.
Sensitivity Analysis
When we repeated our analyses including only communitybased studies or studies that had recruited consecutive patients from hospital admissions and outpatient clinics, we
found very similar results for all risk factors (data available
from authors on request).
Discussion
Many studies have explored the association of various risk
factors with different subtypes of ischemic stroke. Their
pooled results must be interpreted carefully, with consideration given to various potential sources of heterogeneity.
Ischemic Stroke Subtype Classification Bias
The most important and striking difference was in the
classification systems used to define ischemic stroke subtypes. Many studies included the risk factors being studied in
their definitions of ischemic stroke subtypes, which may lead
to bias (referred to hereafter as “classification bias”) when
assessing differences in risk factor profiles between lacunar
and nonlacunar ischemic strokes. The most appropriate classification system for investigating possible differences in risk
factors between ischemic stroke subtypes should, ideally, be
free of etiological assumptions about risk factors and so based
solely on the clinical features of the stroke syndrome along
with the appearances on brain imaging (ie, the site and size of
the relevant lesion).8
Classification bias was of particular importance in the
results for hypertension and diabetes. The apparent excess of
hypertension and diabetes among lacunar versus nonlacunar
infarction patients disappeared when only studies using risk
factor–free classifications were considered.
Classification bias also affected the results for AF and
carotid stenosis. The excess of AF and carotid stenosis
among nonlacunar infarction patients was (unsurprisingly)
more extreme among studies in which the presence of AF
or carotid stenosis mitigated against a diagnosis of lacunar
infarction. Emboli from the heart can occasionally occlude
small, perforating cerebral vessels, and so it may be
difficult to ascertain whether AF is causal or simply a
manifestation of generalized vascular disease. Similarly,
although carotid stenosis is more prevalent among nonlacunar infarcts, it does occur in association with some
lacunar infarcts. The similarity of RRs for ipsilateral and
contralateral carotid stenosis supports the concept that
carotid stenosis is unlikely to cause most lacunar infarctions. However, the benefit from carotid endarterectomy
among patients with lacunar infarction and severe carotid
stenosis suggests that artery-to-artery emboli and low flow
Jackson and Sudlow
Risk Factors for Lacunar Versus Nonlacunar Infarction
resulting from carotid stenosis may play an etiological role
in some lacunar infarcts.53
Variation Between Studies in Stroke Patient
Population Studied
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
A further potential source of variability is in the population
of patients studied. Most studies we identified were hospital based. The ideal study population would include all
patients with an incident stroke in a particular geographical
area (ie, a community-based stroke study), regardless of
whether or not they attended hospital. A recent meta-analysis of community-based studies comparing the risk factor
profiles of different ischemic stroke subtypes found only 4
such studies (and all but 1 small study including 102
patients that had not been published previously were
included in our systematic review).54 Community-based
studies should avoid spurious differences in risk factor
profiles between ischemic stroke subtypes arising because
of hospital admission selection bias. But diagnosis of
ischemic stroke subtype will first require appropriately
timed brain imaging to exclude primary intracerebral
hemorrhage, and patients managed entirely outside hospital are unlikely to access such imaging. Thus, for our
purposes here, a series of patients recruited consecutively
from outpatients as well as hospital admissions is unlikely
to be any more biased than a community-based stroke
register. Reassuringly, our results were essentially unchanged by a sensitivity analysis including only those
studies based in the community or studying inpatient
admissions and outpatients.
Potential selection bias could be reduced by using multivariate analysis methods to adjust the results for each risk
factor for the confounding effects of other risk factors (eg,
age, gender, etc). We could calculate only univariate associations because we did not have the individual patient data
necessary for multivariate analyses. However, the few studies
that performed both types of analyses found little difference
between the results of univariate and multivariate
analyses.25,26,29,35,46
Variable Misclassification of Ischemic
Stroke Subtypes
Another source of variation between studies using risk
factor– based classification systems such as TOAST is the
reliance on a number of investigations (such as carotid
ultrasound, transcranial Doppler, echocardiography, etc)
apart from brain imaging to allow assignment of an
ischemic stroke subtype because access to these investigations is bound to vary between centers and according to
patient characteristics such as age. Furthermore, the
TOAST classification does not allow assignment of an
ischemic stroke subtype when there is ⬎1 potential cause
of stroke, which occurred in 7% of ischemic strokes in a
large, hospital-based stroke register.55 In this case, or in
the case of incomplete investigation, patients are placed in
the “undetermined etiology” category. In the studies that
used the TOAST classification, the proportion of patients
in this category varied widely from 8%45 to 41%.33 This
899
must be partly the result of variable access to diagnostic
investigations but could also reflect inconsistent application of the TOAST criteria.56 The large and variable
proportion of patients in the “undetermined” subtype
category (some of which will be lacunar, and others
nonlacunar, in unknown proportions) introduces heterogeneity between the studies. A classification that can assign
a stroke subtype to all (or at least almost all) ischemic
stroke patients in the study population will be less prone to
such heterogeneity, favoring classifications based mainly
on clinical features of the stroke syndrome.8
However, even if all ischemic strokes are assigned a
subtype, there will still inevitably be some misclassification. In particular, some lacunar infarcts will be misclassified as small cortical infarcts and vice versa57 because the
clinical features of the stroke syndrome alone are of
limited accuracy in distinguishing these subtypes, and
frequently, the relevant infarct is not visible on CT or MR
brain scan. The extent of misclassification will depend
partly on the proportion of patients with brain imaging and
the type and timing of imaging used, which varied between
the studies included. Small recent infarcts are more likely
to be seen with diffusion-weighted MRI, but none of the
studies we identified used this technique. The effects of
misclassification of subtypes on risk factor associations are
difficult to predict and will only be clarified by further
studies using modern imaging techniques (including
diffusion-weighted MR whenever possible) in large numbers of patients.
Variable Definitions of Risk Factors
Variability in the definitions used for the risk factors studied
(Table 2) could also account for some of the heterogeneity
between the results of different studies.
Summary
Our results suggest that the controversial assertion that
hypertension and diabetes are particularly associated with
lacunar infarction may arise almost entirely from classification bias. Hypertension and diabetes are risk factors for
ischemic stroke in general, but their presence does not help to
distinguish the ischemic stroke subtype. In addition, although
AF and carotid stenosis are associated more with nonlacunar
than lacunar infarction, this association is not as extreme as
risk factor– based classification systems might suggest. Finally, there is no clear evidence of any association between
smoking, previous TIA, excess alcohol consumption, or
raised cholesterol and lacunar versus nonlacunar ischemic
stroke subtypes.
Acknowledgments
C.S. and C.J. were both funded by the Wellcome Trust, United
Kingdom. We are very grateful to Professors Charles Warlow, Peter
Sandercock, Martin Dennis, and Joanna Wardlaw, to Dr Steff Lewis,
and to the anonymous reviewers for their valuable comments on
earlier versions of this manuscript.
900
Stroke
April 2005
Appendix A
Method
Based on risk factors
as well as
clinical and brain
imaging features
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Based on brain
imaging only
Based on clinical
features and brain
imaging only
Description
TOAST
Ischemic stroke classified into one of 5 categories.
Large-artery atherosclerosis: Clinical findings include cortical, cerebellar, or brain stem dysfunction and on brain imaging
cortical, cerebellar, brain stem or subcortical lesions ⬎1.5 cm are considered to be of potential large-artery atherosclerotic
origin. Diagnosis requires supportive evidence by duplex imaging or arteriography of ⬎50% stenosis of an appropriate
intracranial or extracranial artery. Potential sources of cardiogenic embolism, such as AF should be excluded, and a history of
TIAs in the same vascular territory supports the clinical diagnosis.
Cardioembolism: Clinical and brain imaging findings are similar to those described for large artery atherosclerosis. At least 1
cardiac source of embolism, such as AF, must be identified. Previous TIAs in ⬎1 vascular territory supports the diagnosis.
Potential large-artery atherosclerotic sources of thrombosis or embolism should be absent.
Lacunar: Clinical findings of one of the lacunar syndromes should be present. Brain imaging should be normal or show a
relevant brain stem or subcortical hemispheric lesion of diameter ⬍1.5cm. A history of diabetes mellitus or hypertension
supports the diagnosis. Potential cardiac sources of embolism, such as AF, should be absent, and the large extracranial
arteries should not demonstrate ⬎50% stenosis.
Undetermined etiology: Includes patients with ⱖ2 potential causes of stroke (eg, AF and ⬎50% stenosis of extracranial
arteries).
Other determined etiology: Includes patients with rare causes of stroke (eg, nonatherosclerotic vasculopathies and
hematologic disorders.
NINDS
Large-artery atherosclerosis: Clinical and brain imaging findings as described in TOAST. A history of TIAs is considered more
common than among those with other types of stroke. Clinical diagnosis rests on finding evidence of arterial stenosis or
occlusion at ⱖ1 sites.
Cardioembolism: Clinical and brain imaging findings as described in TOAST. The basis for the clinical diagnosis is the
demonstration of a cardiac–transcardiac source of embolism (such as AF) and no evidence of other causes of stroke.
Lacunar: Clinical findings of a lacunar syndrome with normal brain imaging or relevant lesion. No mention of risk factors that
specifically support a lacunar diagnosis.
Undetermined etiology: Cerebral infarction in the absence of stenosis or occlusion of extracranial or intracranial arteries,
cardiac source of embolism, or other demonstrable mechanism.
Unusual cause: Includes patients with rare causes of stroke (eg, nonatherosclerotic vasculopathies and hematologic disorders.
Site and size of visible infarction on CT or MRI scan used to classify stroke subtypes irrespective of patient’s symptoms.
Patients with a definite ischemic stroke but no visible infarct excluded.
eg, OCSP Clinical stroke syndrome (eg, TACI, PACI, LACI, and POCI) used to assign stroke subtype, then revised in light of site and size
of any relevant infarct seen on CT or MRI scan.
NINDS indicates National Institute of Neurological Disorders and Stroke: Classification of Cerebrovascular Diseases III; TACI, total anterior circulation infarction; PACI,
partial anterior circulation infarction; LACI, lacunar infarction; POCI, posterior circulation infarction.
References
1. Bamford J, Sandercock P, Jones L, Warlow C. The natural history of
lacunar infarction: the Oxfordshire Community Stroke Project.
Stroke. 1987;18:545–551.
2. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol.
1969;12:1–15.
3. Fisher CM. Bilateral occlusion of basilar artery branches. J Neurol Neurosurg Psychiatry. 1977;40:1182–1189.
4. Fisher CM. Thalamic pure sensory stroke: a pathologic study. Neurology.
1978;28:1141–1144.
5. Fisher CM. Capsular infarcts. The underlying lesions. Arch Neurol. 1979;
36:65–73.
6. Fisher CM, Tapia J. Lateral medullary infarction extending to the lower
pons. J Neurol Neurosurg Psychiatry. 1987;50:620 – 624.
7. Lammie GA. Pathology of lacunar infarction. In: Donnan GA, Norrving
B, Bamford J, Bogousslavsky J, eds. Subcortical Stroke. New York:
Oxford University Press. 2002; 37– 46.
8. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification
and natural history of clinically identifiable subtypes of cerebral
infarction. Lancet. 1991;337:1521–1526.
9. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL,
Marsh EE III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172
in Acute Stroke Treatment. Stroke. 1993;24:35– 41.
10. Cochrane Collaboration. Cochrane Revman software version 4.2; 2003.
Available at http://www.cochrane-net.org/revman. Accessed February 18,
2004.
11. Mohr JP, Caplan LR, Melski JW, Goldstein RJ, Duncan GW, Kistler JP,
Pessin MS, Bleich HL. The Harvard Cooperative Stroke Registry: a
prospective registry. Neurology. 1978;28:754 –762.
12. Pullicino P, Nelson RF, Kendall BE, Marshall J. Small deep infarcts
diagnosed on computed tomography. Neurology. 1980;30:1090 –1096.
13. Cupini LM, Pasqualetti P, Diomedi M, Vernieri F, Silvestrini M, Rizzato
B, Ferrante F, Bernardi G. Carotid artery intima-media thickness and
lacunar versus non-lacunar infarcts. Stroke. 2002;33:689 – 694.
14. Dulli D, D’Alessio DJ, Palta M, Levine RL, Schutta HS. Differentiation
of acute cortical and subcortical ischaemic stroke by risk factors and
clinical examination findings. Neuroepidemiology. 1998;17:80 – 89.
15. Jeng JS, Chung MY, Yip PK, Hwang BS, Chang YC. Extracranial carotid
atherosclerosis and vascular risk factors in different types of ischaemic
stroke in Taiwan. Stroke. 1994;25:1989 –1993.
16. Loeb C, Gandolfo C, Mancardi GL, Primavera A, Tassinari T. The
lacunar syndromes: a review with personal contributions. In: Lechner A,
Meyer JS, Ott E, eds. Cerebrovascular Disease: Research and Clinical
Management. Amsterdam, The Netherlands: Elsevier; 1986:107–156.
17. Spolveri S, Baruffi MC, Cappelletti C, Semerano F, Rossi S, Pracucci G,
Pracucci G, Inzitari D. Vascular risk factors linked to multiple lacunar
infarcts. Cerebrovasc Dis. 1997;8:152–157.
18. Falcone RA, Shapiro EP, Jangula JC, Johnson CJ. Transoesophageal
echocardiographic findings in subcortical and cortical stroke. Am J
Cardiol. 2000;85:121–124.
19. Boiten J, Rothwell PM, Slattery J, Warlow CP. Ischemic lacunar stroke in
the European Carotid Surgery Trial. Risk factors, distribution of carotid
stenosis, effect of surgery and type of recurrent stroke. Cerebrovasc Dis.
1996;6:281–287.
20. Cerrato P, Imperiale D, Priano L, Mangiardi L, Morello M, Marson AM,
Carra F, Barberis G, Bergamasco B. Transoesophageal echocardiography
in patients without arterial and major cardiac sources of embolism:
differences between stroke subtypes. Cerebrovasc Dis. 2002;13:
174 –183.
Jackson and Sudlow
Risk Factors for Lacunar Versus Nonlacunar Infarction
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
21. Inzitari D, Eliasziw M, Sharpe BL, Fox AJ, Barnett HJ. Risk factors and
outcome of patients with carotid artery stenosis presenting with lacunar
stroke. North American Symptomatic Carotid Endarterectomy Trial
Group. Neurology. 2000;54:660 – 666.
22. Lee TI, Hsu WC, Chen CJ, Chen ST. Etiologic study of young ischemic
stroke in Taiwan. Stroke. 2002;33:1950 –1955.
23. Nagai Y, Kitagawa K, Sakaguchi M, Shimizu Y, Hashimoto H,
Yamagami H, Narita M, Ohtsuki T, Hori M, Matsumoto M. Significance
of earlier carotid atherosclerosis for stroke subtypes. Stroke. 2001;32:
1780 –1785.
24. Awada A, al Rajeh S. The Saudi Stroke Data Bank. Analysis of the first
1000 cases. Acta Neurol Scand. 1999;100:265–269.
25. Boiten J, Lodder J. Lacunar infarcts. Pathogenesis and validity of the
clinical syndromes. Stroke. 1991;22:1374 –1378.
26. Boiten J, Luijckx GJ, Kessels F, Lodder J. Risk factors for lacunes.
Neurology. 1996;47:1109 –1110.
27. Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB. The Stroke Data
Bank: design, methods, and baseline characteristics. Stroke. 1988;19:
547–554.
28. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S,
Glahn J, Brandt T, Hacke W, Diener HC. Risk factors, outcome, and
treatment in subtypes of ischaemic stroke. Stroke. 2001;32:2559 –2566.
29. Hajat C, Dundas R, Stewart JA, Lawrence E, Rudd AG, Howard R, Wolfe
CD. Cerebrovascular risk factors and stroke subtypes: differences
between ethnic groups. Stroke. 2001;32:37– 42.
30. Kim JS, Choi-Kwon S. Risk factors for stroke in different levels of
cerebral arterial disease. Eur Neurol. 1999;42:150 –156.
31. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B,
Heuschmann P. Epidemiology of ischaemic stroke subtypes according to
TOAST criteria. Incidence, recurrence and long-term survival in
ischaemic stroke subtypes: a population study. Stroke. 2001;32:
2735–2740.
32. Kumral E, Ozkaya B, Sagduyu A, Sirin H, Vardarli E, Pehlivan M. The
Ege Stroke Registry: a hospital-based study in the Aegean region, Izmir,
Turkey. Analysis of 2000 stroke patients. Cerebrovasc Dis. 1998;8:
278 –288.
33. Lee BI, Nam HS, Heo JH, Kim DI, The Yonsei Stroke Team. Yonsei
Stroke Registry. Analysis of 1000 patients with acute cerebral infarctions.
Cerebrovasc Dis 2001;12:145–151.
34. Lindgren A, Roijer A, Norrving B, Wallin L, Eskilsson J, Johansson B.
Carotid artery and heart disease in subtypes of cerebral infarction. Stroke.
1994;25:2356 –2362.
35. Lodder J, Bamford JM, Sandercock PA, Jones LN, Warlow CP. Are
hypertension or cardiac embolism likely causes of lacunar infarction?
Stroke. 1990;21:375–381.
36. Marti-Vilalta JL, Arboix A. The Barcelona Stroke Registry. Eur Neurol.
1999;41:135–142.
37. Mead GE, Shingler H, Farrell A, O’Neill PA, McCollum CN. Carotid
disease in acute stroke. Age Ageing. 1998;27:677– 682.
38. Mead GE, Wardlaw JM, Lewis SC, McDowall M, Dennis MS. Can
simple clinical features be used to identify patients with severe carotid
stenosis on Doppler ultrasound? J Neurol Neurosurg Psychiatry. 1999;
66:16 –19.
39. Moulin T, Tatu L, Vuillier F, Berger E, Chavot D, Rumbach L. Role of
a stroke data bank in evaluating cerebral infarction subtypes: patterns and
outcome of 1776 consecutive patients from the Besancon stroke registry.
Cerebrovasc Dis. 2000;10:261–271.
901
40. Murat SM, Erturk O. Ischaemic stroke subtypes: risk factors, functional
outcome and recurrence. Neurol Sci. 2002;22:449 – 454.
41. Norrving B, Cronqvist S. Clinical and radiological features of lacunar vs
non-lacunar minor stroke. Stroke. 1988;20:59 – 64.
42. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers
DO. Ischemic stroke subtypes: a population-based study of incidence and
risk factors. Stroke. 1999;30:2513–2516.
43. Rothrock JF, Lyden PD, Brody ML, Taft-Alvarez B, Kelly N, Mayer,
Wiederholt WC. An analysis of ischemic stroke in an urban southern
California population. The University of California, San Diego, stroke
data bank. Arch Intern Med. 1993;153:619 – 624.
44. Saposnik G, Gonzalez L, Lepera S, Luraschi A, Sica RE, Caplan LR, Rey
RC. Southern Buenos Aires stroke project. Acta Neurol Scand. 2001;22:
449 – 454.
45. Saposnik G, Caplan LR, Gonzalez LA, Baird A, Dashe J, Luraschi A,
Llinas R, Lepera S, Linfante I, Chaves C, Kanis K, Sica RE, Rey RC.
Differences in stroke subtypes among natives and caucasians in Boston
and Buenos Aires. Stroke. 2000;31:2385–2389.
46. Schmal M, Marini C, Carolei A, Di Napoli M, Kessels F, Lodder J.
Different vascular risk factor profiles among cortical infarcts, small deep
infarcts, and primary intracerebral haemorrhage point to different types of
underlying vasculopathy. A study from the L’Aquila Stroke Registry.
Cerebrovasc Dis. 1998;8:14 –19.
47. Tegeler CH, Shi F, Morgan T. Carotid stenosis in lacunar stroke. Stroke.
1991;22:1124 –1128.
48. Vemmos KN, Takis CE, Georgilis K, Zakopoulos NA, Lekakis JP,
Papamichael CM, Zis VP, Stamatelopoulos S. The Athens Stroke Registry: results of a five-year hospital-based study. Cerebrovasc Dis. 2000;
10:133–141.
49. Woo D, Gebel J, Miller R, Kothari R, Brott T, Khoury J, Salisbury S,
Shukla R, Pancioli A, Jauch E, Broderick J. Incidence rates of first-ever
ischemic stroke subtypes among blacks: a population-based study. Stroke.
1999;30:2517–2522.
50. Yip PK, Jeng JS, Lee TK, Chang YC, Huang ZS, Ng SK, Chen RC.
Subtypes of ischemic stroke. A hospital-based stroke registry in Taiwan
(SCAN-IV). Stroke. 1997;28:2507–2512.
51. Toni D, Fiorelli M, De Michele M, Bastianello S, Sacchetti M, Montinaro
E, Zanette EM, Argentino C. Clinical and prognostic correlates of stroke
subtype misdiagnosis within 12 hours from onset. Stroke. 1995;26:
1837–1840.
52. Boiten J, Lodder J. Risk factors for lacunar infarction. In: Donnan GA,
Norrving B, Bamford J, Bogousslavsky J, eds. Subcortical Stroke. New
York: Oxford University Press. 2002; 87–97.
53. Kelly J, Hunt BJ, Rudd A, Lewis RR. Should patients with lacunar stroke
and severe carotid stenosis undergo endarterectomy? QJM. 2002;95:
313–319.
54. Schulz UGR, Rothwell PM. Differences in vascular risk factors between
etiological subtypes of ischemic stroke: importance of population-based
studies. Stroke. 2003;34:2050 –2059.
55. Moncayo J, Devuyst G, Van Melle G, Bogousslavsky J. Coexisting
causes of ischemic stroke. Arch Neurol. 2000;57:1139 –1144.
56. Goldstein LB, Jones MR, Matchar DB, Edwards LJ, Hoff J, Chilukuri V,
Armstrong SB, Horner RD. Improving the reliability of stroke subgroup
classification using the Trial of ORG in Acute Stroke Treatment
(TOAST) criteria. Stroke. 2001;32:1091–1097.
57. Mead GE, Lewis SC, Wardlaw JM, Dennis M, Warlow CP. Should
computed tomography appearance of lacunar stroke influence patient
management? J Neurol Neurosurg Psychiatry. 1999;67:682– 684.
902
Stroke
April 2005
Editorial Comment
Time to Burn the TOAST
There will be a rediscovery of the worth of the nowalmost-abandoned autopsy and clinical pathological
conference and the realization that MRI, computed
tomography, and ultrasonography cannot substitute for
direct postmortem examination of the brain and blood
vessels.1
James F. Toole
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
The observations of many 20th century stroke studies led
their authors to question whether there were any significant
special risk factors, like hypertension, for little strokes. By
assuming the onerous and painstaking task of systematically
reviewing all of the pertinent literature, Jackson and Sudlow
have accomplished a unique task, the proof of a negative!2
There are no specific etiological diagnostic risk factors for
small-vessel occlusion (lacune), the most common variety of
stroke in the TOAST (Trial of ORG 10172 in Acute Stroke
Treatment) tabulation.3 TOAST was the standard classification system for clinical definition of ischemic strokes.
Even BT (before TOAST), the common knowledge of
most experienced clinicians was that family history, age,
smoking, hypertension, cardiac or systemic atherosclerosis,
previous stroke, diabetes, obesity, and cachexia of any cause
are pertinent to general health and probably to the incidence
of stroke. And they knew that big strokes are worse than little
strokes, especially for debilitated older patients. In 1993, the
TOAST stroke investigators recognizing “the etiology of
ischemic stroke affects prognosis, outcome, and management,” proposed a “classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial.”3
Their premise was “determining the cause of stroke does
influence choices for management.”
Their Table 1 illustrates the range of their causal conclusions, 5 major categories, segregated with modest hedging.
For large-artery atherosclerosis, there is an (embolus/thrombosis) choice, and for cardioembolism, a choice of (high-risk/
medium-risk). These, along with small-vessel occlusion (lacune) and stroke of other determined etiology, are adorned
with an asterisk whose footnote indicates the premise that
“investigators are allowed to express their certainty by
classifying the likelihood of diagnosis as probable or possible. . . . because most etiological diagnoses in stroke are not
based on pathological confirmation and are thus presumptive.” The reliability test of the system was that “two
physicians agreed in their final diagnosis of subtype of
ischemic stroke in 19 of 20 [independently assessed]
patients.”
In 1998, the authors of the TOAST system reported their
therapeutic trial of danaparoid. “Subtypes of acute ischemic
stroke were also a pre-specified end point. . . . The effects of
the severity of stroke on admission or the cause [italics ours]
of stroke on outcomes at 3 months are listed in Table 3”
(Table 2).4 The diffident asterisks and graded choices have
been replaced by unqualified “cause.” “Subtypes are determined by the Clinical Coordination Center.” Their terminal
extension of this democratic method was, “A panel of three
physicians who are not aware of the treatment allocation
ascertained the most likely cause of death” (82 deaths, 0
autopsies). (Recall the story of the kindergarten teacher who
explained to her class that she could not ascertain by
inspection the sex of their new pet gerbil. The bright girl in
the first row solved the conundrum; “Let’s vote!”) This
article established the unfortunate precedent of verbal slippage from possible to probable, then often via risk factor or
mechanism to cause, a noun that should carry the rigorous
onus of homology to Koch’s postulate.5,6 The same slippage
is evident in the recent classification of posterior circulation
strokes.7
Review of the projected TOAST criteria for the choice of
cause is pertinent.3
Large-artery atherosclerosis requires big symptoms, multiple or severe, forebrain or hindbrain, big lesion, and imaging
evidence of stenosis ⬎50% of an appropriate artery, intracranial or extracranial. It is well known that such vasculopathy is
commonplace in the absence of stroke, a fact underlined by
the secondary need to “exclude potential sources of cardiogenic embolism.” Conversely, it is certain that such strokes
do occur in the absence of conspicuous arteriographic
pathology.
Cardioembolism “presumably due to an embolus arising in
the heart.” This presumption automatically magnifies the
incidence of cardioembolism by arbitrarily purging the possibility of any other cause for stroke while lumping together
with atrial fibrillation 23 listed less common sources of
cardioembolism. It has been proved only that the incidence of
stroke is reduced by coumadin in patients with atrial
fibrillation.8
Small-vessel occlusion (lacune). Walter Alvarez first
called special attention to the clinical phenomenology of
“little strokes.”9,10 Two score years ago, before computed
TABLE 1. TOAST Classification of Subtypes of Acute
Ischemic Stroke
Large-artery atherosclerosis (embolus/thrombosis)*
Cardioembolism (high-risk/medium-risk)*
Small-vessel occlusion (lacune)*
Stroke of other determined etiology*
Stroke of undetermined etiology
a. Two or more causes identified
b. Negative evaluation
c. Incomplete evaluation
TOAST indicates Trial of Org 10172 in Acute Stroke Treatment.
*Possible or probable depending on results of ancillary studies.
Jackson and Sudlow
Risk Factors for Lacunar Versus Nonlacunar Infarction
903
TABLE 2. Influence of Stroke TOAST Subtype on Rates of Favorable and Very Favorable
Outcomes at 3 Months After Stroke*
TOAST Subtype
No. (%) of Patients
Treated With ORG 10172
No. (%) of Patients
Treated With Placebo
P
Odds Ratio
(95% CI)
1.77 (1.04–3.03)
Favorable Outcome
Atherosclerosis†
77/113 (68.1)
64/117 (54.7)
0.04
Cardioembolism
97/143 (67.8)
85/123 (69.1)
0.82
0.94 (0.56–1.59)
144/158 (91.1)
134/148 (90.5)
0.86
1.07 (0.49–2.34)
11/13 (84.6)
14/17 (82.4)
0.87
1.18 (0.16–8.60)
150/210 (71.4)
167/226 (73.9)
0.56
0.88 (0.58–1.35)
Small vessel†
Other cause
Undetermined
Very Favorable Outcomes
Atherosclerosis†
49/113 (43.4)
34/117 (29.1)
0.02
1.87 (1.08–3.22)
Cardioembolism
69/143 (48.3)
58/123 (47.2)
0.86
1.04 (0.64–1.69)
Small vessel†
93/158 (58.9)
93/148 (62.8)
0.48
0.85 (0.53–1.34)
7/13 (53.8)
10/17 (58.8)
0.79
0.82 (0.19–3.59)
97/210 (46.2)
101/226 (44.7)
0.75
1.06 (0.73–1.55)
Other cause
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Undetermined
*The TOAST (Trial of ORG 10172 [danaparoid sodium, the low-molecular-weight heparinoid] in Acute Stroke
Treatment) subtypes are determined by the Clinical Coordinating Center. CI indicates confidence interval.
†Atherosclerosis refers to large-artery atherosclerosis and small-vessel to small-artery occlusive disease (lacuna).
tomography, Miller Fisher first sponsored the term “lacune”
and the impression that lacunes are caused by a specific lesion
called lipohyalinosis, conditioned by vascular hypertension.11–14 He further came to believe, “These data support the
proposition that small penetrating branch artery disease tends
to occur where it gives rise to symptoms rather than being
distributed by chance.” In his 1991 review, he claimed to
have defined 70, although only 65 specific syndromes are
listed, and several of these are multiple-lesion or redundant.15
Here he also opined “MRI has made dependence on clinical
detail more or less obsolete.” General use of computed
tomography and magnetic resonance imaging has made
certain that little lesions are not always associated with acute
symptoms, and that the syndromes do not always meet rigidly
prescribed clinical patterns.14,16
Miller Fisher’s careful pathological observations in 22 new
“lacunar infarcts” included only 4 with lipohyalinosis.15 Four
empty-vessel cases were presumed to represent lysed emboli,
rather than spasm or other mechanism. The other 14 cases
included “stenosing atheroma with super-imposed thrombus,
5; stenosing atheroma, 5; mural atheroma of the basilar
artery, 2; microaneurysm, 1; and inconclusive, 1.” Evidently
there is no longer a specific vascular occlusive pathology of
little strokes. Jackson and Sudlow now show that there are no
specific clinical risk factors.2
It follows that smallness of lesion by clinical estimate or
imaging is the only criterion for lacunes. The best common
sense hypothesis for the prevalence of small strokes is that
simply because they are very narrow, the tiny lumina of
myriad small terminal arteries/arterioles are most readily
brought to complete occlusion by any partial obstruction:
atheroma, or clot, or circulating detritus. TOAST provides no
rationale for arbitrarily limiting the lacune label to crosssectional diameters less than 1.5 cm.
Stroke of other determined etiology solicits a vote for
long-shot risk-factor diseases involving blood vessels or
coagulation that require exclusion of the more common
conditions. Unproven, such cases may offer excuse for
therapeutic failure or complication. Nevertheless, there are
too few to complicate most large-scale clinical studies
anyway.
Stroke of undetermined etiology is the uncontroversial
democratic vote of maximal insecurity, either too poor or too
rich; incomplete or absent basis for exculpation of a cause, or
conversely, 2 or more adequate but mutually exclusive
causes. It would not be fair to vote for one or the other. (Cf.
kindergarten simile.)
We accept the hope that therapeutic efficacy may differ
among various sorts of pathology. Different strokes may need
different pokes. But the fact is that every clinician’s best
operational diagnosis is based on integration of hard data,
some measurable with real numbers: chronological history of
symptom details, clinical examination, and laboratory and
imaging data. The specious character of TOAST is the
translation of a majority guess into an autonomous causal
power, a factoid, “an invented fact believed to be true because
of its appearance in print.”17 Even a 0.05 correlation coefficient between phenomenon X and some aspect of stroke does
not become a scientifically proven cause by endowing the
association with the pejorative title of risk factor. “Impression” is not the singular form of the noun “data.” Consistently
reliable guessing provides no proof of validity. After a decade
of the routine TOAST classification system, we question
whether it has contributed to the efficacy of stroke treatment
or prevention.
Instead of including the intervening variable of each
clinician’s analogical estimate, we submit that it is valid, and
essentially more reliable, to record for each case the original
data points, a computerized census of the bases of each
operational diagnosis. Without prejudice regarding mechanism, it is now possible to measure the volume and vascular
location of every stroke, including dynamic magnetic reso-
904
Stroke
April 2005
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
nance imaging variant techniques.18 –22 Correlations can be
sought only after the facts are recorded. Retrievable details of
interest beyond age and sex might include duration of onset,
stepwise or continuous, multiple lesions in brain or other
organs, specific nature of cardiac abnormalities, stroke adjacent to or away from previous infarction, severity details of
systemic disease like hypertension and diabetes, ad infinitum
and ad libitum. Cholesterol can be spared.23,24
As Toole points out, stroke investigators have neglected
modern opportunities for neuropathological auditing of disease process and therapeutic endeavors. For example, several
studies have indicated that microhemorrhage may be associated with ischemic infarction.25–29 Is there anything different
about the brains of patients who have gross hemorrhage from
tissue plasminogen activator treatment?30 To our knowledge,
no one has looked.
In the last decade or so, our colleagues in neurology who
are concerned with dementia, movement disorders, and multiple sclerosis have accomplished powerful conceptual and
practical new information by aggressive recruitment of autopsy material. The unfortunate fact is that many stroke
patients do not survive long.31–33 Whether they die in acute
hospital, nursing facility, or home, early or late, how does
their neuropathological status relate to their intensive clinical
evaluation and therapeutic effort? Patients and families are
certain to cooperate if solicited with sincerity and grace. The
predominant know-it-all separation of clinical stroke specialists from the fine tissue neuropathology of stroke seems to us
to be improvident, if not unforgivable. We welcome Dr
Toole’s hopeful prediction.
William M. Landau, MD
Abdullah Nassief, MD
Department of Neurology
Washington University School of Medicine
Saint Louis, Mo
References
1. Toole JF. Stroke research and the 21st century. Arch Neurol. 2000;57:55.
2. Jackson C, Sudlow C. Are lacunar strokes really different? A systematic
review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke. 2005;36:891–901.
3. Adams Jr, HP, Bendixen BH, Kapelle LJ, Biller J, Love BB, Gordon DL,
Marsh EE 3rd. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke. 1993;24:35– 41.
4. The Publications Committee for the Trial of ORG 10172 in Acute Stroke
Treatment (TOAST) Investigators. Low molecular weight heparinoid
ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a
randomized controlled trial. JAMA. 1998;279:1265–1272.
5. Susser M. What is a cause and how do we know one? A grammar for
pragmatic epidemiology. Am J Epidemiol. 1991;133:635– 648.
6. Landau WM. Letter to the editor: causes of stroke. Ann Neurol. 1992;32:
596 –597.
7. Caplan LR, Wityk RJ, Glass TA, Tapia J, Pazdera L, Chang HM, Teal P,
Dashe JF, Chaves CJ, Breen JC, Vemmos K, Amarenco P, Tettenborn B,
Leary M, Estol C, Dewitt LD, Pessin MS. New England Medical Center
posterior circulation registry. Ann Neurol. 2004;56:389 –398.
8. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of
antithrombotic therapy in atrial fibrillation: analysis of pooled data from
five randomized controlled trials. Arch Intern Med. 1994;154:
1449 –1457.
9. Alvarez WC. Small unrecognized strokes: a cause of puzzling indigestion. Proc Staff Meet Mayo Clinic. 1935;10:293–295.
10. Alvarez WC. Little strokes. Philadelphia and Toronto: JB Lippincott;
1966.
11. Fisher CM. Lacunes: small, deep, cerebral infarcts. Neurology. 1965;15:
774 –784.
12. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch
Neurol. 1979;36:65–73.
13. Landau WM. Au clair de lacune: holy, wholly, holey logic. Neurology.
1989;39:725–730.
14. Millikan C, Futrell N. The fallacy of the lacune hypothesis. Stroke.
1990;21:1251–1257.
15. Fisher CM. Lacunar infarcts—a review. Cerebrovasc Dis. 1991;1:
311–320.
16. Tuszynski MH, Petito CK, Levy DE. Risk factors and clinical manifestations of pathologically verified lacunar infarctions. Stroke. 1989;20:
990 –999.
17. Merriam-Webster’s Collegiate Dictionary. Springfield, Massachusetts:
Merriam-Webster; 1998.
18. Lövblad, K-O, Baird AE, Schlaug G, Benfield A, Siewert B, Voetsch B,
Connor A, Burzynski C, Edelman RR, Warach S. Ischemic lesion
volumes in acute stroke by diffusion-weighted magnetic resonance
imaging correlate with clinical outcome. Ann Neurol. 1997;42:164 –170.
19. Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME.
Correlation of perfusion- and diffusion-weighted MRI with NIHSS score
in acute (⬍6.5 hour) ischemic stroke. Neurology. 1998;50:864 – 870.
20. Ay H, Oliveira-Filho J, Buonanno FS, Ezzeddine M, Schaefer PW,
Rordorf G, Schwamm LH, Gonzalez RG, Koroshetz WJ. Diffusionweighted imaging identifies a subset of lacunar infarction associated with
embolic source. Stroke. 1999;30:2644 –2650.
21. Gerraty RP, Parsons MW, Barber PA, Darby DG, Desmond PM, Tress
BM, Davis SM. Examining the lacunar hypothesis with diffusion and
perfusion magnetic resonance imaging. Stroke. 2002;33:2019 –2024.
22. Caviness VS, Makris N, Montinaro E, Sahin NT, Bates JF, Schwamm L,
Caplan D, Kennedy DN. Anatomy of stroke, part 1: an MRI-based
topographic and volumetric system of analysis. Stroke. 2002;33:
2549 –2556.
23. Landau WM. Is cholesterol a risk factor for stroke? No. Arch Neurol.
1999;56:1521–1524.
24. Bowman TS, Sesso HD, Ma J, Kurth T, Kase CS, Stampfer MJ, Gaziano
JM. Cholesterol and the risk of ischemic stroke. Stroke. 2003;34:
2930 –2934.
25. Constantinides P. Pathogenesis of cerebral artery thrombosis in man.
Arch Path. 1967;83:422– 428.
26. Kwa VIH, Franke CL, Verbeeten B Jr, Stam J. Silent intracerebral
microhemorrhages in patients with ischemic stroke. Ann Neurol. 1998;
44:372–377.
27. Ogata J, Masuda J, Yutani C, Yamaguchi T. Mechanisms of cerebral
artery thrombosis: a histopathological analysis on eight necropsy cases.
J Neurol Neurosurg Psychiatry. 1994;57:17–21.
28. Wardlaw JM, Dennis MS, Warlow CP, Sandercock PA. Imaging
appearance of the symptomatic perforating artery in patients with lacunar
infarction: occlusion or other vascular pathology? Ann Neurol. 2001;50:
208 –215.
29. Kidwell CS, Chalela JA, Saver JL, Starkman S, Hill MD, Demchuk AM,
Butman JA, Patronas N, Alger JR, Latour LL, Luby ML, Baird AE, Leary
MC, Tremwel M, Ovbiagele B, Fredieu A, Suzuki S, Villablanca JP,
Davis S, Dunn B, Todd JW, Ezzeddine MA, Haymore J, Lynch JK, Davis
L, Warach S. Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA. 2004;292:1823–1830.
30. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after
intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28:
2109 –2118.
31. Yamamoto H, Bogousslavsky J. Mechanisms of second and further
strokes. J Neurol Neurosurg Psychiatry. 1998;64:771–776.
32. Hartmann A, Rundek T, Mast H, Paik MC, Boden-Albala B, Mohr JP,
Sacco RL. Mortality and causes of death after first ischemic stroke: the
northern Manhattan stroke study. Neurology. 2001;57:2000 –2005.
33. de Jong G, van Raak L, Kessels F, Lodder J. Stroke subtype and mortality: a follow-up study in 998 patients with a first cerebral infarct. J Clin
Epidemiology. 2003;56:262–268.
Editorial Comment−− Time to Burn the TOAST
William M. Landau and Abdullah Nassief
Stroke. 2005;36:902-904
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/36/4/902
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/