Published online before print March 10, 2005, doi: 10.1161/01.STR.0000157949.34986.30
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2005;36:891.)
© 2005 American Heart Association, Inc.
Progress Reviews |
Are Lacunar Strokes Really Different?
A Systematic Review of Differences in Risk Factor Profiles Between Lacunar and Nonlacunar Infarcts
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 cathie.sudlow{at}ed.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
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.
Key Words: lacunar infarction • meta-analysis • risk factors • stroke
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Approximately 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 µm in diameter by atheromatous plaques, with or without complicating thrombus. Most asymptomatic lacunar infarcts were associated with occlusion of perforating arteries 40 to 200 µm 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 cells.7 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.
See Editorial Comment, pg 902
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 Oxfordshire 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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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 hospital-based 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 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).
|
Diabetes Mellitus
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).
|
Atrial Fibrillation
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).
|
Carotid Stenosis
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).
Other Risk Factors
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).
Sensitivity Analysis
When we repeated our analyses including only community-based 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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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 resulting from carotid stenosis may play an etiological role in some lacunar infarcts.53
Variation Between Studies in Stroke Patient Population Studied
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 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.
Received August 6, 2004; accepted August 31, 2004.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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.[CrossRef]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[Abstract]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[Abstract]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
40. Murat SM, Erturk O. Ischaemic stroke subtypes: risk factors, functional outcome and recurrence. Neurol Sci. 2002; 22: 449–454.[CrossRef][Medline] [Order article via Infotrieve]
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.[Medline] [Order article via Infotrieve]
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.[CrossRef][Medline] [Order article via Infotrieve]
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.
Related Article:
Stroke 2005 36: 902-904.
This article has been cited by other articles:
 |
|
 |
|
  W. M. Landau What Is a Lacune? Dogged deja vu doggerel Stroke, July 1, 2009; 40(7): e498 - e499. [Full Text] [PDF]
|
|
|
|
|
|
E. L. Bailey, J. McCulloch, C. Sudlow, and J. M. Wardlaw Potential Animal Models of Lacunar Stroke: A Systematic Review Stroke, June 1, 2009; 40(6): e451 - e458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. N. Doubal, B. Dhillon, M. S. Dennis, and J. M. Wardlaw Retinopathy in Ischemic Stroke Subtypes Stroke, February 1, 2009; 40(2): 389 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y Bejot, M Caillier, D Ben Salem, G Couvreur, O Rouaud, G-V Osseby, J Durier, C Marie, T Moreau, and M Giroud Ischaemic stroke subtypes and associated risk factors: a French population based study J. Neurol. Neurosurg. Psychiatry, December 1, 2008; 79(12): 1344 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B Norrving Lacunar infarcts: no black holes in the brain are benign Practical Neurology, August 1, 2008; 8(4): 222 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bejot, A. Catteau, M. Caillier, O. Rouaud, J. Durier, C. Marie, A. Di Carlo, G.-V. Osseby, T. Moreau, and M. Giroud Trends in Incidence, Risk Factors, and Survival in Symptomatic Lacunar Stroke in Dijon, France, From 1989 to 2006: A Population-Based Study Stroke, July 1, 2008; 39(7): 1945 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Park, N Yasuda, S Toyonaga, E Tsubosaki, H Nakabayashi, and K Shimizu Significant associations of metabolic syndrome and its components with silent lacunar infarction in middle aged subjects J. Neurol. Neurosurg. Psychiatry, June 1, 2008; 79(6): 719 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Khan, L. Porteous, A. Hassan, and H. S Markus Risk factor profile of cerebral small vessel disease and its subtypes J. Neurol. Neurosurg. Psychiatry, July 1, 2007; 78(7): 702 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Viehman, J. L. Saver, D. S. Liebeskind, S. Starkman, L. K. Ali, B. Buck, T. Razinia, and B. Ovbiagele Utility of Urinalysis in Discriminating Cardioembolic Stroke Mechanism Arch Neurol, May 1, 2007; 64(5): 667 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. O. Pruissen, S. A.M. Gerritsen, T. J. Prinsen, J. M. Dijk, L. J. Kappelle, A. Algra, and on behalf of the SMART Study Group Carotid Intima-Media Thickness Is Different in Large- and Small-Vessel Ischemic Stroke: The SMART Study Stroke, April 1, 2007; 38(4): 1371 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Liem, J. van der Grond, J. Haan, R. van den Boom, M. D. Ferrari, Y. M. Knaap, M. H. Breuning, M. A. van Buchem, H. A.M. Middelkoop, and S. A.J. Lesnik Oberstein Lacunar Infarcts Are the Main Correlate With Cognitive Dysfunction in CADASIL Stroke, March 1, 2007; 38(3): 923 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Labovitz, B. Boden-Albala, W. A. Hauser, and R. L. Sacco Lacunar infarct or deep intracerebral hemorrhage: Who gets which? The Northern Manhattan Study Neurology, February 20, 2007; 68(8): 606 - 608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohira, E. Shahar, L. E. Chambless, W. D. Rosamond, T. H. Mosley Jr, and A. R. Folsom Risk Factors for Ischemic Stroke Subtypes: The Atherosclerosis Risk in Communities Study Stroke, October 1, 2006; 37(10): 2493 - 2498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Wardlaw, S. C. Lewis, S. L. Keir, M. S. Dennis, and S. Shenkin Cerebral Microbleeds Are Associated With Lacunar Stroke Defined Clinically and Radiologically, Independently of White Matter Lesions Stroke, October 1, 2006; 37(10): 2633 - 2636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Dijk, Y. van der Graaf, M. L. Bots, D. E. Grobbee, A. Algra, and on behalf of the SMART study group Carotid intima-media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study Eur. Heart J., August 2, 2006; 27(16): 1971 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Hankey Potential New Risk Factors for Ischemic Stroke: What Is Their Potential? Stroke, August 1, 2006; 37(8): 2181 - 2188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H.A. Halkes, L. J. Kappelle, J. van Gijn, I. van Wijk, P. J. Koudstaal, and A. Algra Large Subcortical Infarcts: Clinical Features, Risk Factors, and Long-Term Prognosis Compared With Cortical and Small Deep Infarcts Stroke, July 1, 2006; 37(7): 1828 - 1832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E L L M De Schryver, A Algra, R C J M Donders, J van Gijn, and L J Kappelle Type of stroke after transient monocular blindness or retinal infarction of presumed arterial origin J. Neurol. Neurosurg. Psychiatry, June 1, 2006; 77(6): 734 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sacco, C. Marini, R. Totaro, T. Russo, D. Cerone, and A. Carolei A population-based study of the incidence and prognosis of lacunar stroke Neurology, May 9, 2006; 66(9): 1335 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-J. Ariesen, A. Algra, and L. J. Kappelle Antiplatelet Drugs In the Secondary Prevention After Stroke: Differential Efficacy in Large Versus Small Vessel Disease? A Subgroup Analysis From ESPS-2 Stroke, January 1, 2006; 37(1): 134 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jackson and C. Sudlow Comparing risks of death and recurrent vascular events between lacunar and non-lacunar infarction Brain, November 1, 2005; 128(11): 2507 - 2517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-H. Lee and K.-C. Chang Editorial Comment--Are We in Another Unavoidable 'Diagnose and Adios' Era? Stroke, September 1, 2005; 36(9): 1852 - 1853. [Full Text] [PDF]
|
|
|
|
|
|
W. M. Landau and A. Nassief Editorial Comment-- Time to Burn the TOAST Stroke, April 1, 2005; 36(4): 902 - 904. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||