Differing risk factors and outcomes in ischemic stroke subtypes: focus on lacunar stroke

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Future Neurol. (2011) 6(2), 201–22110.2217/FNL.11.1 © 2011 Future Medicine Ltd

Stroke is the third most common cause of death and the most common worldwide cause of serious acquired adult physical dependency [1]. It consumes at least 5% of healthcare resources and, as people live longer, is likely to remain highly prevalent even if the incidence of stroke declines. A total of 80% of strokes are ischemic, and of these, 25% (20% of all strokes) are of the lacunar type [2,3]. Occasionally, small hemorrhages deep in the brain can also cause lacunar stroke symptoms, and therefore overall, approximately 20% of strokes are of the lacunar clinical type. As most lacunar strokes are not hemorrhagic and most of what we know regarding causes and treatment of lacunar stroke comes from studies on lacunar ischemic stroke, the rest of this article will focus on nonhemorrhagic lacunar stroke.

Lacunar ischemic stroke is defined as a small cerebral infarct, 3–20 mm in diameter, lying in the deep white or grey matter or pons, presumed to result from the occlusion of a single small perforating artery [3–6], and associated with specific neurological syndromes (Figures 1 & 2) [3,5,6]. Although a recognized stroke subtype for many years, the vascular pathology underlying lacunar ischemic stroke (and whether it is indeed different to other types of ischemic stroke) is still unknown and hotly debated [7–10]. Hence, prevention and treatment may be suboptimal. However, as many stroke treatment and prevention trials did not differentiate the patients by

stroke subtype, we do not know whether some drugs work better or worse in lacunar stroke compared with large artery atherothromboembolic stroke, for example. Information on longterm disease progression is limited and associations with risk factors, many of which are very common in older people, are debated [11].

Lacunar stroke is rarely fatal (which may be why it has received relatively less research attention than the usually more severe large artery athero thromboembolic stroke), but it is disabling, with 30% of survivors being left dependent [5]. The scant longterm data suggest that up to 25% have a clinically apparent recurrent stroke within 5 years [12,13], and 15–20% develop dementia [12,14,15]. Recurrent stroke after a lacunar stroke is more likely to be lacunar than nonlacunar [11,16,17], adding support to the concept that lacunar stroke is different to other stroke subtypes.

Lacunar stroke is associated with white matter lesions (WMLs) [18–22], lacunes [23,24], microhemorrhages [25] and enlarged perivascular spaces (EPVS) [26] seen on brain CT scanning or magnetic resonance (MR) imaging (Figure 3). WMLs are associated with cognitive decline (without [15,27,28] or with stroke [29,30]), increased risk of future stroke [23,31,32], worsening of WMLs and lacunes [16] and may progress rapidly after lacunar stroke [33–35]. Whether lacunar stroke on its own is associated with the risk of cognitive decline and dementia more than other stroke

Differing risk factors and outcomes in ischemic stroke subtypes: focus on lacunar stroke

Joanna M WardlawBrain Research Imaging Centre, Edinburgh, SINAPSE Collaboration, c/o Division of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK n Tel.: +44 131 537 2943 n Fax: +44 131 332 5250 n [email protected]

Lacunar stroke has been a recognized stroke subtype for many years but its pathophysiology remains unknown, so prevention and treatment are suboptimal. Most lacunar strokes result from an intrinsic cerebral small vessel disease, probably part of a systemic disorder. Hypertension, diabetes and other vascular risk factors (but not atrial fibrillation and ipsilateral carotid stenosis) are equally common in lacunar as in large artery atherothromboembolic stroke, which, together with other factors, suggests that the patient’s response to vascular risk factors, not the vascular risk factors per se, determines whether they develop small vessel or large artery stroke. Inflammation and endothelial failure are probably involved in the pathogenesis of lacunar stroke, but their role needs to be clarified. The cerebral venules as well as arterioles are abnormal in this condition. The disorder may not be primarily ischemic; instead, arteriolar thrombosis may be a late-stage phenomenon secondary to chronic arteriolar wall damage resulting from leakage of plasma components across the BBB. Accurate diagnosis of lacunar stroke, avoiding risk factor-based classifications, is required to underpin future research.

Keywords

n ischemic stroke n lacunar stroke n lacune n leukoaraiosis n small vessel disease n stroke n white matter disease

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subtypes [36], or whether any increased risk in lacunar stroke is through an association with WMLs and lacunes, is unclear at present, but either way, the added risk of dementia and disability greatly increases the public health burden of lacunar disease over that of the stroke alone. Cerebral small vessel disease is also associated with symptoms that provide further evidence that it is a diffuse process affecting the brain, such as dizziness or unsteadiness [37,38]. Thus, lacunar stroke is part of a diffuse process in terms of the symptoms, disease distribution and appearance on imaging or pathology (Figure 4).

Much has been written about lacunar stroke over the last 50 years, particularly in the last 15 years. Probably the most significant contributions to this field have come from the meticulous and very precise pathological work of C Miller Fisher, an outstanding neuropathologist and

neurologist, who performed most of his clinical and neuropathological research on lacunar stroke at the Massachusetts General Hospital (MA, USA) between the 1950s and the 1970s. He published a landmark review of lacunar infarcts in 1991 [6]. This article examines the key points that he made in that review, discusses new knowledge that has emerged since 1991, reflects on changes in thinking about lacunar stroke and highlights what information is still missing.

Fisher started his work in the 1950s, using careful recording of clinical stroke features combined with detailed pathological dissection of specimens from patients who died between a few days to many years after their stroke. Between 1955 and 1975, even the Massachusetts General Hospital, which served a large population and had a major research interest in stroke, only 20 clinicopathological–vascular investigations were performed by him, and these few cases form the basis of his publications. The introduction of CT scanning in 1973, followed by MR imaging in the early 1980s, completely changed the practice of stroke neurology. As Fisher said, postmortem examinations on patients with stroke “virtually ceased when CT scanning was introduced” – no further vascular pathology studies were made in his hospital after that point [6]. Images are compelling and often more persuasive than the evidence on which they are based. With CT and MRI, the perceived need for postmortems and the postmortem rate rapidly declined. Some pathology studies have been published since then (e.g., [39–42]; not intended to be an exhaustive list), but they suffer from the same problem: small numbers of patients examined at varying times after the stroke, many patients had never had a clinically evident stroke or if they had had a clinically evident stroke, then it was unclear from the publication if and how the lesion found at autopsy related to the symptoms [43]. Most studies rely on retrospective case note reviews to identify whether various risk factors, such as hypertension, were present in life (prospective recording of risk factors in life using standardized measurements is more reliable). This perspective is not intended to be critical of pathology, but simply to recognize that even very detailed pathological examination as a means of determining the cause and associations of lacunar stroke has serious limitations, and we need to take a wider view. The result is that our understanding of lacunar pathology is largely based on a series of dissections that took place more than 50 years ago, in very few patients, often years after the event.

Acu

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une’FLAIR

FLAIR T2

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Figure 1. CT and MRI scans of typical acute and old lacunar infarcts. Lacunar infarction appearances on MRI. Left column: DWI and FLAIR images of an acute lacunar infarct in the left centrum semiovale. The symptoms of right arm and leg weakness started 18 h prior to scanning. Note that on FLAIR imaging, the acute lacunar infarct would be indistinguishable from other white matter lesions, showing that the acute stroke can only be confirmed with certainty using diffusion imaging. Right column: FLAIR and T2-weighted image of an old cavitated lacunar infarct. The patient had experienced left-sided arm and leg sensory disturbance 4 months previously. DWI: Diffusion-weighted imaging; FLAIR: Fluid-attenuated inversion recovery.

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Differing risk factors & outcomes in ischemic stroke subtypes: focus on lacunar stroke Review

Where are we now? There is ongoing debate concerning both the relative roles of atherothromboembolism versus intrinsic cerebral microvascular disease and the likely causes of the latter (e.g., some form of microatheroma or vasospasm, or possibly BBB disruption secondary to endothelial damage or dysfunction). We are still hampered by a lack of pathological specimens, and those that we have

are usually latestage and so are from long after the acute event. Imaging, particularly with MR, has provided much new information on features in the brain associated with lacunar stroke, but has also posed new questions. More information is coming from epidemiology studies, but until recently these have largely relied on clinical diagnosis (and CT scanning) to differentiate lacunar from other subtypes of stroke. However,

Acute lacunar infarctionon DWI <2 cm in diameter, hyperintense on DWI, FLAIR and T2,hypointense on T1, in theterritory of a perforatingarteriole

Lacunar on FLAIRimaging, also knownas silent infarct if notassociated with priorsymptoms CSF-containinghole, >3 mm and <2 cm diameter

White matter lesions onFLAIR imagingHyperintense areas onFLAIR and T2, not CSFsignal, in periventricular and deep white and graymatter, may coalesce if severe

Enlarged perivascularspaces on weightedimagingHyperintense on T2,<3 mm diameter,round or linear, in whiteand deep gray matter.May also be visible on T1,but not other sequences

Figure 3. Examples of other features of cerebral small vessel disease on MRI. From left to right: magnetic resonance diffusion imaging shows an acute lacunar infarct in the lateral part of the right thalamus; FLAIR image shows an old lacune in the genu of the internal capsule; FLAIR image shows multiple periventricular and deep white matter lesions; T2-weighted image shows multiple enlarged perivascular spaces in the basal ganglia and hemispheric white matter. CSF: Cerebrospinal fluid; DWI: Diffusion-weighted imaging; FLAIR: Fluid-attenuated inversion recovery.

Figure 2. CT and MRI scans of acute and old lacunar ischemic strokes in a patient scanned 12 h after onset of symptoms of right face and arm and leg weakness. There was a history of left arm and leg weakness 1 year previously but the patient had not sought medical advice at the time and there was no imaging. (A) CT scan shows subtle hypointensity indicating acute lacunar infarct in the left centrum semiovale (white arrowhead) and immediately anterior an old lacune (white arrow). (B) Diffusion-weighted imaging of the acute hyperintense infarct and old infarct anteriorly. (C) T2-weighted imaging. Note that the computed tomography and magnetic resonance images are obtained at slightly different tilt angles relative to the brain and therefore the lesions appear slightly different.


Review Wardlaw

approximately 20% of patients with lacunar stroke diagnosed on clinical findings alone actually have a recent cortical infarct on imaging that is responsible for their recent stroke (and ~20% of patients with a mild cortical stroke clinically have a recent lacunar infarct on imaging [44–47]; see [47] for a summary of studies), meaning that clinical diagnosis of stroke subtype is unreliable. Thus, many epidemiological studies of lacunar stroke will have misdiagnosed approximately 20% of patients (‘noise’) unless sensitive imaging has been used to make a positive diagnosis of the recent stroke. This is probably enough to have had an important impact on ascertaining associations with apparent risk factors. This may be particularly problematic for stroke classification systems that use risk factors to assign a diagnosis such as the Trial of ORG 10172 in Acute Stroke (TOAST) classification [48], which uses risk factors such as embolic sources and hypertension when deciding the stroke subtype. Another commonly used clinical stroke subtype classification is the Oxfordshire Community

Stroke Project (OCSP) classification [5], which uses only clinical features to assign the stroke subtype, thereby avoiding biasing studies of risk factor associations [11,49]. Greater use of MR with diffusionweighted imaging is improving diagnosis of stroke subtypes, as diffusionweighted imaging is more sensitive to small stroke lesions.

Studies of small vessel morphology and function in other vascular beds (e.g., direct observation of the retina, kidneys, forearm or via measurement of plasma markers of endothelial function) are also providing important information on risk factors and possible causes of lacunar stroke. Indeed, just as large artery atheroma is a systemic condition that affects multiple arteries and vascular territories throughout the body, even if only one organ (e.g., the heart) is symptomatic, lacunar stroke may be part of a systemic small vessel disease [50] that shows up first in the brain, possibly because the brain is more sensitive to failure of a small arteriole than most other organs. By contrast, large artery atheroma tends to present first with cardiac disease, possibly because the coronary arteries are at the smaller end of large arteries, they require less atheroma to cause narrowing and the heart is more sensitive to failure of a mediumsized artery than is a leg muscle or the gut.

Definitions & terminologyFisher was keen to stress the importance of using clear terminology when describing lacunar disease (Box 1 & Figure 3). Describing lacunar stroke, perhaps more than other types of cerebrovascular disease, has been hampered by variable use of termino logy and lack of definitions. In patho logy, it remains a problem [51]. Terms to describe lacunar lesions and related small vessel disease features as seen on brain imaging are also used imprecisely and variably [52]. A lacune (or cerebrospinal fluid [CSF]containing cavity) should not be described as a lacunar infarct or a lacunar stroke, especially without knowledge of associated symptoms (Figures 1–3) [53]; EPVS are frequently mistaken for lacunes and by inference for lacunar infarcts (Figure 3) [52]; many lacunar infarcts that do not cavitate (and as much as 80% may not cavitate to form lacunes [54]) are overlooked as simply being WMLs. It will be difficult to move forward in this field without standardization of clinical, imaging and pathological terminology [52].

What did Fisher see? Fisher described “segmental arterial wall disorganization” (since called ‘lipohyalinosis’, or ‘fibrinoid necrosis’ if acute) where the perforating arteriolar

DiseaseStroke

Dementia

SymptomsFocal (e.g., lacunar stroke)

Diffuse (e.g., dizziness)

AppearanceSolitary

Multiple

T2 FLAIR

10 cm

Figure 4. The spectrum of lacunar disease. The diffuse nature of lacunar disease is evident in its symptomatology (discrete focal neurological events through to cognitive decline and dementia), the appearance on imaging or pathology (discrete lacunar infarcts [arrows] through to extensive coalescent white matter lesions and enlarged perivascular spaces) and the disease (lacunar stroke to dementia). Arrows indicate a solitary lacunar infarct (top row) in a patient with little white matter disease, and a lacunar infarct against a background of multiple white matter lesions (bottom row). FLAIR: Fluid-attenuated inversion recovery.



wall appeared thickened with focal dilation, disintegration and a surrounding ‘infarct’ [6,55]. He suggested that atherosclerosis and presumed embolism were also possible, but that lipohyalinosis affected arterioles of 40–200 µm in diameter and that atherosclerosis and embolism affected arterioles of 200–850 µm in diameter (i.e., the larger perforating arterioles were affected by what was essentially an atherothromboembolic process and the smaller perforating arterioles by an intrinsic destructive vasculopathy of lipohyalinosis/fibrinoid necrosis). He suggested that the larger the affected arteriole, the larger the lacunar infarct and the more likely it was to be symptomatic [6]. Arterioles leading to an infarct but with no obstruction at the time of examination were assumed to have been occluded by an embolus that spontaneously resolved. He did not have a large enough sample of lesions to determine what proportion of lacunar infarcts might be due to atherothromboembolism or intrinsic lipohyalinosis, or what might cause the latter. Hypertension was quite prevalent in the mid20th century, with fewer effective drugs, so he considered lipohyalinosis to be secondary to hypertension. This may be true, but we see a lot of lacunar disease in patients who are not hypertensive or whose hypertension is well treated.

The following is an examination of the evidence now available on various possible risk factors for lacunar stroke and what that might tell us about probable mechanisms (Figure 5) and longterm problems that may result. Potential risk factors for lacunar stroke include all the usual risk factors for stroke in general, as well as some specific ones that are beginning to emerge. General stroke risk factors would include advancing age, hypertension, diabetes, cardioembolic sources such as atrial fibrillation, ischemic heart

disease, possibly other evidence of atheroma such as peripheral vascular disease and carotid or intracranial stenosis. There are two problems that should be kept in mind when considering these results. First, studies of stroke risk factors in stroke patients largely have not distinguished lacunar from other stroke subtypes well enough (because of the 20% misdiagnosis rate [47]) to be certain of the role of these traditional stroke risk factors in lacunar stroke. Second, many studies compared patients with lacunar stroke with agematched normal controls or with agematched controls with similar risk factors but without stroke. Unfortunately, from such comparisons, one can only reliably identify risk factors for stroke in general, not lacunar stroke specifically – to identify risk factors for lacunar stroke speci fically requires a control group with another subtype of ischemic stroke. Lacunar disease associated with monogenetic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is also well known but is beyond the scope of this article. Genetic polymorphisms that might be associated with lacunar stroke (none have yet emerged) are the subject of intense research by the International Stroke Genetics Consortium and other groups and are well covered elsewhere.

General stroke risk factorsMany risk factors are equally shared between lacunar and nonlacunar ischemic stroke subtypes. For example, in a literaturebased systematic review of ten stroke epidemiology studies using risk factorfree definitions of lacunar stroke, there was no clear difference in smoking, prior transient ischemic attack (TIA), excess alcohol consumption, raised cholesterol or diabetes and possibly only a marginal increase in hypertension

Box 1. Definitions of lacunar disease.

LacunenSmall, cerebrospinal fluid-filled cavity, thought to mark the healed cavitated stage of a small region

of infarcted brain, usually in the deeper parts of the brain (e.g., basal ganglia, hemispheric white matter or brainstem)

Lacunar infarctnNoncavitated lesion in subcortical brain regions (same as for lacunes), resulting from abnormality

(‘occlusion’) in a single deep perforating arterioleLacunar strokenStroke symptoms resulting from lacunar lesion in the brain – lacunar stroke is usually ischemic, but

can result from small deep hemorrhagesLacunar syndromenOne of several (up to 58) neurological syndromes resulting from the occurrence of a lacunar stroke

lesion in a specific brain region, the most common being pure motor stroke, pure sensory stroke, sensory–motor stroke and ataxic hemiparesis

See also Figure 2 [6].


Review Wardlaw

(relative risk: 1.11; 95% CI: 1.04–1.19) between lacunar and nonlacunar stroke patients [11]. However, the association between lacunar stroke and hypertension was no different to that for patients with nonlacunar stroke in an individual patient data metaanalysis of comparable cohort studies (1696 patients; adjusted odds ratio [OR]: 1.04; 95% CI: 0.84–1.29) [56]. Similarly, the individual patient data metaanalysis of comparable cohort studies found no difference in previous TIA (2719 patients; OR: 0.82; 95% CI: 0.66–1.02), smoking (1696 patients; OR: 1.17; 95% CI: 0.93–1.47) and alcohol excess (1696 patients; OR: 0.78; 95% CI: 0.58–1.06) between lacunar and nonlacunar stroke [56]. The concept that hypertension or diabetes are specifically associated with lacunar stroke has probably arisen through the use of risk factorbased stroke subtype classification systems [49]. Such classification systems should be avoided in studies that aim to identify risk factors.

Atherothromboembolic disease CardioembolismAtrial fibrillation and ischemic heart disease were less frequent in lacunar than in nonlacunar ischemic stroke in a literaturebased metaanalysis of ten stroke epidemiology studies using risk factorfree definitions of lacunar stroke [11,56]. In an individual patient data metaanalysis of comparative cohort studies of stroke also using risk factorfree definitions of lacunar

stroke and including an updated metaanalysis with literature data, the adjusted OR for atrial fibrillation in patients with lacunar stroke was 0.33 (95% CI: 0.24–0.46), for any cardioembolic source was 0.40 (95% CI: 0.35–0.46) and for ischemic heart disease was 0.75; 95% CI: 0.58–0.97) compared with nonlacunar stroke subtypes [56].

A few individual observational studies suggested that emboli from the large arteries or the heart [57–60] might cause no more than 10–15% of lacunar strokes [61–68]. Studies suggesting stronger associations between lacunar stroke and emboli cited cardiac abnormalities that are not clearly associated with embolism (e.g., left ventricular hypertrophy [60]), had no or an inappropriate control group or may have used a risk factorbased definition. No more than 6% of emboli injected into the internal carotid artery (ICA) in primates entered the perforating arteries, the majority being carried up the middle cerebral artery (MCA) main stem to its cortical branches [69].

Lacunar strokes that are due to emboli may be larger than nonembolic lacunes [58,70,71], which would fit with Fisher’s original pathological observations [72]. However, it should be noted that the few patients who present with more than one lacunar lesion, or a lacunar and a cortical infarct, of similar age but in different arterial territories are more likely to have a proximal cardioembolic source [66]. Furthermore, it should be noted that at

Occlusion Ischemia Endothelial dysfunction

Embolism VasospasmLow flow BBB breakdownAtheroma

Cardiac, aortic arch or carotid artery source. Occlude small deep arteries

Altered endothelial permeability, vessel wall thickening and destruction and brain tissue damage

For example, low bloodpressure, arteriolestenosis or occlusionof both carotid arteries

Suggested possible risk factors for lacunar disease

Macro: occludesmall vessel originsMicro: intrinsic smallvessel wall thickeningor occlusion

Narrows small arterioles,causing ischemia

Figure 5. Summary of current hypotheses as to the causes and mechanisms of lacunar disease.Adapted with permssion from a figure prepared by Emma Bailey, University of Edinburgh (UK).



least one study of patients presenting with an acute lacunar infarct who had a second asymptomatic lacunar infarct of similar (although not necessarily identical) age failed to find any cardioembolic or large artery embolic sources [73].

Large artery atheromaIpsilateral ICA stenosis is a wellestablished risk factor for cortical ischemic stroke. However, it is probably not a frequent risk factor for lacunar stroke. Ipsilateral ICA stenosis is less common in lacunar than in large artery cortical stroke [57,58,61,64,66], summarized in a literaturebased systematic review of ten cohort studies of lacunar stroke [11]. Furthermore, in studies that have examined both ipsilateral and contralateral carotid arteries, patients with lacunar stroke are equally likely to have a stenosis in the contralateral as in the ipsilateral ICA [61] and severe (>50%) stenoses are infrequent on either side, suggesting that carotid stenosis is incidental in the majority of lacunar strokes. The individual patient data metaanalysis of comparable stroke cohort studies confirmed the low frequency of carotid stenosis in both ipsilateral and contralateral carotid arteries in patients with lacunar stroke: ipsilateral carotid stenosis OR: 0.23 (95% CI: 0.19–0.29) and contralateral carotid stenosis OR: 0.29 (95% CI: 0.21–0.41) compared with patients with nonlacunar stroke [56].

There is also a general lack of association between carotid stenosis and WMLs. WMLs are generally distributed symmetrically between the cerebral hemispheres even in patients with asymmetric carotid atheroma, whereas if carotid stenosis caused or contributed to WMLs, then one would expect to see more WMLs in the cerebral hemisphere above a tight carotid stenosis than in the opposite hemisphere where the carotid artery was not stenosed [74,75].

Some small, individual observational studies did find apparent associations between carotid stenosis and lacunar stroke, but in general, these were reporting carotid stenoses as mild as 25% [63], or were taken from carotid endarterectomy trials that only included patients with carotid stenosis.

Conversely, some patients with lacunar stroke do have a tight ipsilateral carotid stenosis, and there is no evidence from the carotid endarterectomy trial data that patients with lacunar stroke benefit any less from carotid endarterectomy than do other stroke subtypes [76]. It is important to distinguish the need to treat a risk factor if present from the low likelihood of finding it. Therefore, patients with lacunar stroke and tight

ipsilateral carotid stenosis should be considered for endarterectomy (or angioplasty) just like any other patient with carotid stenosis, as it would be wrong to deny treatment simply on the grounds that carotid stenosis is not a common risk factor for lacunar stroke. Clearly, the occasional atheromatous embolus can enter a perforating arteriole and cause a lacunar stroke or TIA; therefore, lacunar stroke patients should be investigated for modifiable risk factors and treated just like any other ischemic stroke subtype, at least until we have sufficient data to justify a different approach.

Atheroma in the aortic arch is a cause of any ischemic stroke [77], but it is unclear if it is a more or less frequent cause of lacunar stroke. Transthoracic echocardiography demonstrated aortic arch atheroma in patients with lacunar stroke as a potential embolic source [78]. Transesophageal echocardiography is more sensitive to aortic arch atheroma but is not an investigation that could be justified in every patient with TIA or stroke. While aortic arch atheroma is probably an underdiagnosed cause of stroke, there is currently no specific treatment for it or evidence that the presence of aortic arch atheroma should modify secondary pharmacological prevention. Further studies of stroke subtypes in patients with aortic arch atheroma would be useful.

Further evidence for the lack of association between most lacunar stroke and large artery atherothromboembolism is shown by the lower association of lacunar stroke with ischemic heart disease in combined individual patient data and literaturebased metaanalyses (8412 patients; OR: 0.76; 95% CI: 0.68–0.85) [56], as well as by the lower rate of myocardial infarction during longterm followup after stroke in patients with lacunar compared with other ischemic stroke subtypes (rate ratio: 0.3; 95% CI: 0.1–0.9) [17]. One could speculate that if lacunar stroke is not atherothromboembolic in origin, the inclusion of relatively large proportions of patients with lacunar stroke (as much as 50% in some cases) in some secondary prevention trials of antiplatelet/cholesterollowering drugs (which are primarily aimed at reducing the effects of atheroma) could explain some of the variation between trials in the apparent effectiveness of these treatments. However, note that many trials did not subtype the included patients well enough to be able to reliably examine the effect of treatment in lacunar and nonlacunar stroke subtypes. Future primary treatment and secondary prevention trials should endeavor to subtype stroke patients into lacunar and nonlacunar groups as reliably as possible to look for differential treatment effects.


Review Wardlaw

Intracranial large artery atheroma Intracranial atheromatous stenosis is often mentioned as a cause of stroke, especially in some ethnic groups. Intracranial atheroma might either act as a source of embolism, or the atheroma might occlude the mouth of a perforating arteriole. MCA atheromatous stenosis is said to be common in Chinese Asian, African–American and Mediterranean people [79–81], but uncommon in other populations, such as white northern Europeans [58,82]. It is unclear at present if these differences are true ethnic differences or instead reflect differences in methods of diagnosis and case ascertainment or definition of disease. Some studies may have confused small striatocapsular infarcts (which may be more likely to have underlying MCA atheroma as a cause) with true lacunar stroke. Fisher did not find any examples of perforating arteriolar ostea being occluded by MCA atheroma, although he did see at least one case of this in the basilar artery (he did not mention the ethnicity of his patients) [6].

Intracranial artery stenosis was present with stroke in 49% of Hong Kong Chinese [80] and 12% of Koreans [83], and was associated with an increased risk of future stroke (subtype unspecified) [84] and death [80]. However, even in Asian populations where the prevalence of MCA stenosis is said to be high, two studies found that only 18% [84] and 36% [85] of patients with small subcortical ischemic stroke had ipsilateral MCA stenosis, although we do not know what proportion of other stroke subtypes had ipsilateral MCA stenosis, so it is possible that, as with stenosis of ICA origin in lacunar stroke [61], MCA stenosis could be coincidental. Unfortunately, many studies of intracranial arterial stenosis in western populations were small or contained few patients with lacunar stroke [86,87], as well as only studying the acute phase of stroke when a stenosis might represent a recanalizing embolus [88,89], or did not differentiate stroke subtypes or ethnic origins [86]. Lyrer et al. screened 4382 Swiss patients with stroke to identify 20 patients with MCA stenosis and ipsilateral stroke (0.5%), of which 17 were cortical or large striatocapsular and only five looked like lacunar ischemic stroke on imaging [82]. One autopsy study of 339 European patients who died following stroke found numerous intracranial plaques and stenoses, but these were thought to be causative of the stroke in only 15 patients (5.8%), with little information on stroke subtype [90]. A further analysis of patients with MCA territory stroke in the same autopsy database indicated that MCA stenosis is unlikely to be coincidental, at least in cortical and large

subcortical ischemic stroke [91], but patients with lacunar stroke are likely to be underrepresented in autopsy series.

In the Rotterdam Scan Study, in analyses unadjusted for vascular risk factors, increased MCA flow velocities on transcranial Doppler ultrasound (a surrogate for stenosis if focal) were associated with future stroke risk (subtype unspecified) [92], but all velocities were within normal limits (therefore unlikely to represent stenosis) and there was no association between the side of highest velocity and the side of future stroke. It is possible that the increased velocity was simply a surrogate for higher blood pressure. Also in the Rotterdam Scan Study, arterial stiffness was strongly associated with atherosclerosis at various sites [93], suggesting that intracranial atheroma, arterial stiffness and related features of atheroma may simply be common in older populations, including those with vascular risk factors who are likely to have a stroke, and not necessarily specifically related to lacunar stroke.

Intermediary markers of atheromaThickening of the intimal lining of the carotid arteries can be measured on carotid ultrasound. Intima–media thickness (IMT) is associated with myocardial infarction, large artery stroke and peripheral vascular disease (i.e., it is a marker of large artery atheroma – the greater the IMT, the greater the amount of large artery atheroma). The limited data on IMT in patients with lacunar stroke specifically suggest that any association between intima–media thickening and lacunar stroke is weak [94]. In another study, IMT was greater in large artery stroke than in lacunar stroke [95], suggesting an absence of association. Furthermore, studies looking for associations between IMT and other markers of cerebral small vessel disease, such as WMLs, have failed to find any association both in individual studies of largely asymptomatic cohorts of older people [96] and in systematic reviews of genetic coassociations [97].

DolichoectasiaDiffuse dilatation of the basal intracranial arteries (dolichoectasia) is seen in older patients on brain scanning and is of unknown cause. Dolichoectasia was associated with lacunar disease in several studies [98–100]. Ince and colleagues found dolichoectasia on imaging in 38 out of 387 patients with a first ever ischemic stroke – this was associated with lacunar infarction (42 vs 17%; p < 0.04) but not with hypertension, age, gender, diabetes or prior TIA [99]. Pico and colleagues found dolichoectasia in 63 out of 510



consecutively recruited stroke patients, and also noted that it was more frequent in lacunar than in atherothrombotic stroke (adjusted OR: 2.89; 95% CI: 1.29–6.46); it was also associated independently with increasing age, hypertension and previous myocardial infarction, but not with carotid atheroma [100]. In a separate study of the brains of 381 patients who had died of stroke, intracranial arterial dolichoectasia was found in 23 patients (6%) and was associated with a twofold increase in the prevalence of basilar plaques and ulcerated plaques in the aortic arch, as well as with markers of cerebral small vessel disease such as lacunes, but not with coronary or carotid atheroma. These findings were independent of diabetes, hypertension and age [98]. This suggests that dolichoectasia may be a marker of nonatheromatous arterial wall abnormalities that are associated with lacunar stroke in some patients and may be a clue as to a potential connective tissue abnormality underlying some lacunar strokes. Fisher noted an association between dolichoectasia and lacunar stroke [6], but did not explore it further.

Perforating arteriolar atheroma?Given the lack of association between overt large artery atheroma, intermediary markers of atheroma and lacunar stroke described previously, it seems somewhat unlikely that atheroma should preferentially affect the perforating arterioles in the absence of atheromatous disease elsewhere. However, in this setting we rely on descriptions of the appearance of the arteriolar walls by pathologists, and these are few. Fisher described seeing atherosclerotic plaque causing stenosis of perforating arterioles, sometimes with a superimposed thrombus, within a few millimeters of the parent artery, in perforators arising from the MCA, anterior choroidal artery and basilar artery [6]. Some neuropathologists working today with an interest in lacunar stroke say that the appearance of the perforating arteriolar walls is not a microatheroma [Smith C, Pers. Comm.]. There are no fatty streaks or cholesterol crystals, but atheroma would perhaps appear different in a tiny arteriolar wall compared with its usual appearance in a large artery. Further detailed pathological studies of the perforating arterioles looking for features specifically attributable to atheroma would be helpful. Imaging is not yet sufficiently sensitive to visualize perforating arteriolar wall atheroma, but higher field strength MR scanners (e.g., 7 Tesla) are producing increasingly detailed images and may be able to demonstrate abnormal perforating arteriolar walls in the next decade.

In summary, the majority of lacunar stroke does not appear to be associated with cardioembolism or large artery atheroma, whatever way you look at it. Embolic or atheromatous causes of lacunar stroke probably account for no more than 15–20% of cases at most. That does not mean that potential embolic sources that can be treated should not be sought in patients with lacunar stroke – they should be, just as for any other type of ischemic stroke, and should also be treated. Until we know more about the causes of lacunar stroke and whether they should be treated differently to large artery stroke, patients with lacunar stroke should receive the same investigations and secondary prevention measures, and potentially acute treatments, as for any other ischemic stroke subtype. Meanwhile, it is tempting to speculate that at least some of the embolic strokes in the studies that suggested an association between lacunar stroke and atherothromboembolism or cardioembolism might actually have been among the 15–20% of cortical ischemic strokes that are misdiagnosed as lacunar [47].

Intrinsic cerebral small vessel diseaseIf most lacunar strokes are due to an intrinsic cerebral small vessel disease, then what is its nature and cause? There are several hypotheses as to the possible causes, including vasospasm, low blood flow, endothelial dysfunction or BBB failure (Figure 5). Vasospasm can be induced in animal models with extreme hypertension and causes fibrinoid necrosis [101], but today, few patients have uncontrolled hypertension; most patients with lacunar stroke do not have severe hypertension and the association between hypertension and lacunar versus other ischemic stroke subtypes is weak (relative risk: 1.11; 95% CI: 1.04–1.19) [11]. Medical imaging is not yet sensitive enough to visualize the perforating arterioles in detail, although some emerging techniques and higher field MR scanners appear promising. Small vessels in related vascular beds that can be seen directly might help clarify the cerebral small vessel abnormality. A summary of data on retinal vascular, cerebral blood flow (CBF), endothelial function and BBB studies is presented in the following sections.

Structural changes in microvessels in the retinaRetinal vessels are developmentally related to cerebral vessels and provide a ‘window’ to cerebral small vessels [102,103]. Large studies of nor Large studies of normal populations or those with vascular risk factors or prior stroke show associations between retino pathy and retinal arteriolar narrowing and


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vascular risk factors, previous stroke and associations with future stroke [104,105]. Communitydwelling older subjects with retinal vascular abnormalities (e.g., retinopathy, microaneurysms, soft exudates or arteriovenous nicking) had two to threetimes greater risk of a first ever ischemic stroke (subtype unspecified) [102,106,107]. However, these studies had limitations in terms of the accuracy of stroke diagnosis and particularly of stroke subtype. In some studies, retinal microvascular lesions were also related to other imaging markers of small vessel damage, such as WMLs [108,109], and to systemic markers of inflammation (e.g., fibrinogen and white cell counts) and endothelial dysfunction (e.g., von Willebrand factor and factor VIII) [110]. Two recent cohort studies examined carefully subtyped patients with ischemic stroke and adequate controls. Both simultaneously found that retinopathy was no more common in lacunar than in nonlacunar stroke (and therefore may simply be a marker of exposure to vascular risk factors) [111], but that retinal venules were larger and arterioles were smaller (and hence the ateriovenous ratio was smaller) in patients with lacunar compared with those with cortical ischemic stroke [112,113]. Patients with lacunar stroke have fewer small terminal retinal arteriolar branches than patients with cortical stroke [114], and at retinal arteriolar branch points, the daughter vessels are narrower compared with the parent vessels in patients with more WMLs [114], suggesting faster tapering of the vascular tree in small vessel disease phenotypes. Retinopathy is associated with central cerebral atrophy (i.e., mainly of white matter) but not with cortical atrophy, further suggesting an association between small vessel pathology and subcortical microvasculopathy [115].

The increased venular size is interesting because it was previously observed to be associated with WMLs and inflammatory plasma markers in a nonstroke population [116] and because widened venules (as well as lipohyalinotic arterioles) have been noted in postmortem examinations of subjects with leukoaraiosis [117,118]. Fisher did not comment on venular changes in his pathology studies [6]. The cause of the venular widening is not known. It might represent vasodilatation in response to tissue ischemia, back pressure on the venous system, venular dilation in response to loss of supporting tissue or some other aspect of the small vessel vasculopathy of lacunar disease.

Although some have suggested that retinal vessel diameters might be used to predict risk of future lacunar stroke [119], it is important to note that the average difference in size of the retinal arterioles in lacunar versus nonlacunar stroke was

only 2.6 µm (i.e., 0.0026 mm; 6µm difference for venular width) with large standard deviations, meaning that retinal vessel widths are unlikely to be a practical or reliable method of distinguishing stroke subtypes. Interestingly, these differences in vessel widths were independent of vascular risk factors such as hypertension or diabetes, which were equally prevalent in lacunar and nonlacunar stroke groups. This raises the possibility that differences in susceptibility to small or large vessel disease rather than differences in exposure to risk factors may determine whether someone develops lacunar or cortical stroke.

Reduction in cerebral blood flowLipohyalinosis is associated with arteriolar wall thickening, and this might impair autoregulation and reduce CBF [120], or the thickened walls might simply restrict flow mechanically. The narrow retinal arterioles in lacunar stroke and narrower branch vessels could be consistent with smaller arteriolar diameters in the brain, which could restrict flow. Falling CBF could lead to ischemia, or progressive cerebral damage could lead to less brain tissue to supply. There are very few studies that have studied patients prior to onset or progression of lacunar stroke or white matter disease; most data have come from studies in patients with established small vessel disease. Although patients with established WMLs have impaired autoregulation (see later) [121–123], impaired autoregulation did not predict future stroke risk [92]. Evidence for reduced CBF in WMLs is conflicting: some studies have found reduced CBF [124,125] to also be associated with brain atrophy and WMLs [126], but not others [127–129]. CBF is diffi cult to quan CBF is difficult to quantify [130,131]: ‘reduced’ CBF may be artefactual [132], or, as seems more likely at present, simply the consequence of less tissue to supply. None of this explains what initiates the pathological process or the possible mechanisms for ongoing brain damage once the abnormality is established.

Intracranial artery velocities are known to fall with age, so any study of small vessel disease would need to account for age (it is not clear that many have so far). Using transcranial Doppler in a cohort of patients with lacunar stroke and mild cortical stroke, we found an incremental reduction in MCA velocity per year of increased age and per unit increase in WML score, which suggests that blood flow falls as the amount of brain tissue is reduced, rather than the other way round [133]. While CBF may be altered in lacunar stroke, the differences are small and CBF is hard to measure reliably, meaning that we are not yet at the stage of using CBF to predict stroke risk, whether lacunar or otherwise.



Endothelial dysfunctionDysfunction of the endothelium might make the patient more prone to abnormal cerebral autoregulation or vasospasm or be a marker of endothelial damage [50], which in turn could be a risk factor for lacunar stroke. Endothelial function could be assessed directly in the cerebral circulation by testing autoregulation, in the peripheral circulation by testing forearm blood flow responses [134,135] or indirectly by measuring plasma levels of markers of endothelial activation, inflammation or dysfunction [134]. However, this field is complicated because many patients with stroke have hypertension or diabetes or take medications, all of which affect endothelial function [136,137], and few if any studies appear to have accounted for these factors. Atheromatous large artery disease is also associated with endothelial dysfunction [138]. Unfortunately, many studies of plasma markers of endothelial dysfunction, activation or inflammation either compare patients with lacunar stroke to normal agematched controls or study patients with stroke but without providing data by individual stroke subtypes and do not account for drugs, other atheromatous disease or vascular risk factors. Therefore, it is unclear whether the endothelial changes observed in patients with lacunar ischemic stroke are specific to small vessel stroke or simply reflect age, vascular risk factors, generalized (possibly coincidental) atheroma, drug therapies or the effects of having a stroke.

Systemic markers of endothelial dysfunctionPatients with lacunar stroke have endothelial dysfunction, but this may simply indicate risk factor exposure or the consequences of having any stroke [134]. The same problem occurred in indi The same problem occurred in individual studies. Patients with an isolated lacunar infarction or lacunar infarction plus WMLs had chronically elevated plasma markers of endothelial activation (plasma ICAM1, thrombomodulin and tissue factor pathway inhibitor) compared with agematched normal controls [139]. Creactive protein [140] and ICAM1 were elevated in patients with progression of WMLs [141]. Systemic markers of endothelial dysfunction (e.g., von Willebrand factor and tissue plasminogen activator) and activation of blood coagulation (fibrin ddimer), as well as blood viscosity, fibrinogen and Creactive protein, may predict ischemic stroke [142,143] and recurrent stroke [144]. In patients with lacunar stroke versus agematched nonstroke controls, von Willebrand factor antigen was elevated in patients (141 vs 118% in controls; p = 0.011), especially in patients who also had asymptomatic

lacunes (146%; p = 0.004 vs controls); tissue plasminogen activator activity was increased in patients with extensive WML (0.79 vs 0.44 international units/ml for those with few WMLs; p = 0.016); plasminogen activator inhibitor1antigen levels were lowest in patients with extensive WMLs (27.5 vs 44.0 ng/ml for patients with few WMLs; p = 0.023) [145]. Increased viscosity could promote stasis in the cerebral small vessels and endothelial disruption [146]. Some studies have suggested a link between WMLs and low levels of vitamin B

12 [147], with links to elevated

homocysteine and increased risk of cardiovascular events, although others have not found any difference in homocysteine levels between lacunar and nonlacunar stroke subtypes [148]. These studies may have been too small to detect or refute any differences reliably, and there are issues regarding how vitamin B

12 and related compounds are

measured and the interactions with drugs such as metformin that may not have been taken into account [149]. (In Type 2 diabetes, metformin ameliorates lowgrade inflammation and endothelial activation independent of any effect on glycemic control and reduces macrovascular but not microvascular events [150,151]; the lack of effect on microvascular events may be because metformin impairs vitamin B

12 absorption, which leads to elevated

homocysteine, which might continue to damage small vessels.) In addition, where relevant, without nonlacunar stroke controls, it is unclear whether these patterns were specific to lacunar or simply related to general stroke [152]. Markers of inflammation and endothelial dysfunction are elevated in patients with any stroke subtype and are associated with poorer stroke outcomes and a higher risk of cardiovascular events including recurrent stroke [153], but also with a higher risk of death from any cause, and therefore these may simply be a nonspecific marker of a ‘general sickness factor’ and not even be specific to injured or dysfunctional endothelium [153], and may not be specific at all to lacunar stroke or even general stroke.

Direct assessment of endothelial function in cerebral or peripheral vascular bedsWe systematically reviewed the literature on direct evaluations of cerebral or peripheral (forearm) endothelial dysfunction and found 16 publications, including 974 patients [135]. In lacunar stroke, cerebrovascular reactivity (n = 534) was reduced compared with agematched controls (standardized mean difference [SMD]: 0.94; 95% CI: 0.70–1.17), but not age plus risk factormatched control subjects (SMD: 0.08; 95% CI: 0.36–0.53) or patients with cortical stroke


Review Wardlaw

(SMD: 0.29; 95% CI: 0.11–0.69). Forearm flowmediated dilatation (n = 401) was reduced compared with agematched normal control subjects (SMD: 0.04; 95% CI: 0.75–1.33) and age plus risk factormatched control subjects (SMD: 0.94; 95% CI: 0.61–1.26), but not patients with cortical stroke (SMD: 0.23; 95% CI: 0.08–0.55). We noted that the more the evidence of brain damage, the more impaired the cerebral vascular reactivity (e.g., in the cerebral hemisphere affected by the stroke lesion vs the unaffected side, or in patients with lacunar stroke plus lacunes or WMLs vs those with just one lacunar stroke, cerebral vascular reactivity was more abnormal). This would fit with the notion of changes in CBF or vascular responsiveness being secondary to tissue damage, rather than a precursor, as discussed previously.

BBB failureThe BBB is an important regulator of the cerebral interstitial environment. It is a complex structure that, in its entirety, links the endothelium to the interstitial space via interactions in the small vessel wall and perivascular glial cells. Failure of the BBB would allow blood components into the vessel wall, causing vessel wall and perivascular damage. However, note that the structure and function of the BBB differs at different levels in the arteriolar tree [154]. This means that changes in permeability with aging and with specific disease processes may differentially affect the proximal arterioles and peripheral capillaries. Bearing this in mind, focal evidence of BBB and vessel wall damage has been described in occasional patients presenting with lacunar stroke on detailed MRI [155] where blood appeared to have entered the vessel wall and perivascular space in the vessel at the center of the lacunar lesion. The infarcts were around, rather than at the end of, the abnormal vessel segment, suggesting that a segment of the arteriolar wall had become leaky. Autopsy data suggested that lacunar ‘infarcts’ [156,157] and WMLs [158,159] were actually edema fluid leaking from damaged arterioles, damaging adjacent brain.

Generalized alterations in BBB permeability can be measured in several ways, (e.g., using the CSF:plasma albumin ratio, via other biochemical tests on CSF or using detailed MRI before and after intravenous injection of gadolinium contrast agents). With advancing age, the BBB becomes progressively more permeable [160]; the permeability is more pronounced in patients with Alzheimer’s disease, vascular dementia, WMLs and EPVS on imaging [160,161]. The imaging approach has demonstrated increased permeability of the BBB in patients with ischemic cerebral

small vessel disease at presentation [156,161–164]. Increased BBB permeability has also been seen in numerous experimental models of small vessel disease, mostly using histopathological methods [101,165], including in primates with established WMLs [166] and in rodents in the early stages of and prior to progression of WMLs and lacunar infarcts [167,168].

It is possible that increased BBB permeability also leads to intracerebral hemorrhage and microbleeds. If, as suggested in the previously mentioned pathology studies and experimental models, failure of the microvascular endothelium plays a key role in the development of small vessel wall damage and disintegration – the lipohyalinosis and fibrinoid necrosis – then as well as causing ischemic lesions, actual rupture of the damaged small vessels and parenchymal hemorrhage is entirely possible. However, the picture is complex in light of the emerging knowledge of the association between amyloid angio pathy, intracerebral hemorrhage and microbleeds [25,169,170], as well as limited data on lacunar hemorrhage and infarction specifically. Amyloid deposition is also associated with other markers of small vessel disease, such as WMLs and cerebral atrophy [171].

There are few longterm followup data to determine whether BBB permeability predates the progression of small vessel disease or is simply a secondary effect. We found that patients with worse BBB permeability at presentation with lacunar stroke had more WML progression and were more dependent at 1year followup in a small pilot study [172,173] [Wardlaw JM,

Unpublished Data]. The only other longitudinal study of BBB status prior to progression to overt dementia found that elevated CSF:plasma albumin ratios in normal 85yearold subjects predicted declining cognition and progressive WMLs on followup [174].

The BBB permeability is difficult to measure. Despite some recent promising reports of BBB impairment as a test for Alzheimer’s disease, we are still some way away from having a validated noninvasive test that could be used to predict risk of cerebral small vessel disease. What we can do at present is evaluate other imaging features that are easily seen and relate to risk of recurrent stroke and cognitive decline. For example, WMLs on MRI were associated with an increased risk of stroke (hazard ratio: 3.3: 95% CI: 2.6–4.4), dementia (hazard ratio: 1.9; 95% CI: 1.3–2.8) and death (hazard ratio: 2.0; 95% CI: 1.6–2.7) [175]. WMLs may also be associated with a faster decline in global cognitive



performance, executive function and processing speed [175]. WMLs are also associated with more rapid progression of WMLs and new lacunes, indicating a vicious cycle [16]. EPVS may be frequent in some patients and have largely been overlooked in studies of small vessel disease and WMLs. The perivascular space is an important conduit because it drains the interstitial space to the ventricles [176]. Histologically, they are areas of demyelination around fibrohyalinotic microvessels, with edematous glial swelling indicating perivascular damage [177]. They become plugged with amyloid and inflammatory cells in neurodegenerative conditions. EPVS are markers of cerebral inflammation in other dis orders, such as multiple sclerosis, where an increase in their number is associated with BBB leak in actively inflamed multiple sclerotic lesions [178]. EPVS are also associated with lacunar stroke and WMLs [26], silent lacunes and WMLs [179], cognitive decline [180] and vascular dementia [181]. A link between markers of small vessel disease and inflammation, in addition to the plasma markers, retinal vascular associations and EPVS mentioned previously, is further suggested by studies showing that damage to the BBB in vascular cognitive impairment is associated with elevated systemic markers of inflammation [182]. Whether this BBB dysfunction is due to endothelial inflammation, or a genetic predisposition to respond in this way to vascular risk factors that, in other people, predispose them to large artery atheroma, and the role of inflammation is as yet unclear.

Does size matter?Fisher suggested that larger lacunar infarcts were more likely to result from embolism or perforating arteriolar atheroma, and these larger infarcts were more often in the basal ganglia near the perforating arteriolar origins, while smaller lacunar infarcts were the result of an intrinsic vasculopathy and occurred in the deep white matter further down the perforating arteriolar tree [6]. There has been some support for this observation from more recent studies [70,183], although some ‘larger lacunar infarcts’ may actually have been striatocapsular infarcts, which are often embolic [184]. The preceding sections should have indicated that there is enough of a problem in simply distinguishing whether risk factor profiles differ between lacunar and nonlacunar stroke subtypes, without also considering different lacunar stroke subtypes. More research is needed to identify whether lacunar stroke lesion locations and sizes provide useful clues as to probable etiology.

Future research directionsIn order to take these points further, future studies should take care to clinically subtype stroke accurately and with detailed brain imaging, ideally diffusionweighted imaging, wherever possible. This is essential in epidemiological studies of risk factors and outcomes, studies of cognitive change, clinical trials of new treatments and especially in genetic studies. Otherwise, it will prove very difficult to avoid the 20% of ‘noise’ in the diagnosis of lacunar stroke on clinical grounds, contaminating attempts to discern associations in populations where there are frequently multiple overlapping common disorders and risk factors. Without optimum phenotyping, there is little chance of reliable genotyping. Stroke subtype classification methods that incorporate risk factors should be avoided at all costs and researchers should try to prevent personal beliefs about risk factor associations with lacunar stroke from creeping into their diagnosis of subtype.

Future research should focus on:nThe roles of inf lammation, endothelial

dysfunction and the BBB;

nThe venular side of the cerebral circulation;

nImproved methods for quantifying EPVS, their relationship to inflammation and the temporal relationship between EPVS and other features of small vessel disease;

nTrying to determine whether the size and location of lacunar stroke can be used to differentiate embolic or atheromatous lacunar strokes from those resulting from lipohyalinosis;

nClarifing the longterm risk of recurrent stroke;

nThe risk of progressive lesions on imaging;

nThe risk of cognitive decline and dementia stratified by age, vascular risk factors and features of small vessel disease on imaging (e.g., WMLs, lacunes and EPVS);

nLongitudinal studies, which are required to determine what initiates the microvasculopathy and so whether there might be any more specific primary and secondary prevention and acute treatments than those used for stroke in general.

Until the cause of lacunar stroke is known, it might be better not to refer to lacunar ‘ischemic’ stroke, or ‘ischemic’ WMLs, but just to WMLs and nonhemorrhagic lacunar stroke, because lacunar stroke might not be primarily ischemic at all. Any microvessel occlusion may be a latestage phenomenon secondary to luminal narrowing from endstage vessel wall damage initiated by some other process.


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Vascular risk factors such as carotid stenosis, hypertension, diabetes or hypercholesterolemia should be treated in patients with lacunar stroke just as for any nonhemorrhagic stroke subtype, until we have more information on whether treatment of lacunar stroke should differ from that for other stroke subtypes, which we will learn from new randomized trials. Trials should endeavor to classify stroke subtypes so that any differential effects of treatments in different stroke subtypes can be identified.

ConclusionThere is now an abundance of evidence that lacunar stroke is a different type of disease to large artery atherothromboembolic stroke, with different associations and longterm effects. While some of this knowledge is recent, much of it has been available for many years. However, progress in understanding the pathophysiology and hence in being able to target treatment more effectively has been hampered by imprecise diagnosis of stroke subtypes (additionally biased by use of risk factors), variable use of terminology, assumptions about causation and the falling postmortem rate, among other factors. We need to make sure that in future randomized trials of stroke prevention or treatment, the stroke subtype is routinely identified, so that variation in the effect of treatment between subtypes can be determined. We need to stop thinking about stroke as though the type and severity are just due to exposure to risk factors or the initiating stroke event, and recognize that a large part of the stroke ‘picture’ in any one individual is a consequence of that patient’s response to the insults. So whether or not a patient develops lacunar or large artery stroke may not simply be the consequence of exposure to different vascular risk factors, because hypertension, diabetes and

smoking, among other factors, are all equally prevalent in lacunar and nonlacunar stroke. Instead, it may be that whether or not someone develops large artery atheromatous disease or small vessel disease is more about how they respond to risk factors than about exposure to risk factors per se.

Future perspectiveIn 5–10 years from now, there will be a standardized terminology for describing lacunar stroke. We will understand more about the causes of lacunar stroke and other features of small vessel disease. There will have been more trials conducted just in patients with lacunar stroke. In addition, new primary treatment and secondary prevention stroke trials will have classified the patients into subtypes of ischemic stroke so that the effect of treatment or prevention in different stroke subtypes can be evaluated. This will enable treatment to be targeted specifically at lacunar stroke, rather than just the general vascular risk factormodifying approach presently in use. The incidence of ischemic stroke will have declined somewhat, but because people in many countries are living longer, lacunar stroke will remain common, possibly causing as much as 50% of ischemic stroke. There will be better access to MRI for patients with stroke, which will improve the accuracy of stroke subtype diagnosis. We will know more about the BBB and how it changes in response to aging and common vascular risk factors, as well as about the role of inflammation, individual genetic factors and other factors, such as vitamin and antioxidant levels, which may predispose an individual to small vessel as opposed to large artery atherothromboembolic stroke. Genomewide association studies may even have identified genetic polymorphisms that are responsible for common stroke phenotypes.

Executive summary

Lacunar stroke is a distinct subtype of strokenPatients rarely die soon after lacunar stroke.nAny recurrent stroke is more likely to be another lacunar than nonlacunar stroke.nMost lacunar stroke is caused by an intrinsic microvasculopathy of the cerebral arterioles and venules.nLacunar stroke is associated with other features of cerebral small vessel disease – white matter lesions, enlarged perivascular spaces

and microbleeds.

Lacunar stroke is not primarily caused by atherothromboembolismnCardiac emboli and carotid stenosis cause less than 20% of lacunar stroke.nLacunar stroke and white matter lesions are not associated with carotid stenosis.nIntracranial large artery stenosis is rare in lacunar stroke, although this may vary between ethnic groups.nIntermediary markers of large artery atheroma, such as intima–media thickness, are not associated with lacunar stroke.nLacunar stroke due to emboli may be larger and more often solitary than the majority of lacunar stroke.nPatients with lacunar stroke are less likely to have ischemic heart disease than those with nonlacunar stroke.



Executive summary

Systemic vascular risk factors are no more frequent in lacunar than in nonlacunar strokenHypertension, diabetes, smoking and alcohol use are no more frequent in lacunar than in nonlacunar stroke.nRisk factors should not be used to assign a stroke subtype.nThe development of small vessel versus large artery atherothromboembolic disease may be more related to the individual’s response to

risk factors than to different risk factor exposures.

Lacunar stroke is a focal manifestation of a diffuse cerebral microangiopathynWhite matter lesions are associated with diffuse symptoms such as dizziness and cognitive impairment.nAfter lacunar stroke, patients have increased risk of cognitive decline and dementia.nOn imaging, patients with lacunar stroke have increased risk of worsening white matter lesions and lacunes.nThe microangiopathy has been described as arteriolar lipohyalinosis and fibrinoid necrosis.nThe venules have been neglected but, being dilated, are also abnormal.nPerivascular spaces, very obviously increased in size on MRI in patients with small vessel disease, may have been overlooked

pathologically, but play a vital role in drainage of the interstitial fluid.

Lacunar stroke is associated with abnormal small vessels in other vascular bedsnRetinal arterioles are smaller and venules wider, there are fewer peripheral arteriolar branches and the peripheral arterioles are narrower

in patients with lacunar than with nonlacunar stroke.nSmall vessel disease is probably a systemic condition affecting other organs.

A new approach is required to determine possible etiologies for the microangiopathynThe cause of lacunar stroke is currently unknown.nIt is probably not a small vessel type of atheroma.nCurrent evidence points to an endothelial abnormality initiating the small vessel damage and then the brain damage.nAt present, there is limited evidence that cerebral and peripheral endothelial function is different in lacunar than nonlacunar stroke due

to a lack of appropriate controls.nCerebral blood flow may fall with increasing brain damage from small vessel disease, but there are currently no data to determine

whether changes in cerebral blood flow are a cause or consequence of small vessel disease.nThe BBB becomes increasingly permeable at older ages, in patients with dementia, with white matter lesions and in patients with

lacunar stroke that may predate progression of small vessel disease.nTrue arteriolar narrowing and occlusion may be a late secondary phenomenon.nProgress to date has been delayed by:

– The low autopsy rate; – Assumptions about pathological and imaging appearances; – Bias introduced through use of risk factor-based stroke classification systems; – Misclassification of approximately 20% of lacunar stroke as cortical stroke, and vice versa, in research based mainly on clinical findings and CT scanning; – Nonstandardized terminology for describing clinical, imaging and autopsy findings; – A lack of appropriate stroke controls; – In general, not subtyping stroke in primary treatment and secondary prevention trials.

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Financial & competing interests disclosureJoanna M Wardlaw is part funded by the Scottish Funding Council through the Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration (www.sinapse.ac.uk). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial con-flict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.


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24. Vermeer SE, Longstreth WT Jr, Koudstaal PJ: Silent brain infarcts: a systematic review. Lancet Neurol. 6(7), 611–619 (2007).

n Systematic review of the frequency and associations of silent infarction (i.e., lacunes).

25. Cordonnier C, AlShahi Salman R, Wardlaw J: Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130(8), 1988–2003 (2007).

n Systematic review of the frequency and associations of microbleeds.

26. Doubal FN, MacLullich AM, Ferguson KJ, Dennis MS, Wardlaw JM: Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 41(3), 450–454 (2010).

n Observational study of enlarged perivascular spaces in lacunar and cortical stroke.

27. Deary IJ, Leaper SA, Murray AD, Staff RT, Whalley LJ: Cerebral white matter abnormalities and lifetime cognitive change: a 67year followup of the Scottish Mental Survey of 1932 . Psychol. Aging 18(1), 140–148 (2003).

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38. Colledge N, Lewis S, Mead G, Sellar R, Wardlaw J, Wilson J: Magnetic resonance brain imaging in people with dizziness: a comparison with nondizzy people. J. Neurol. Neurosurg. Psychiatry 72(5), 587–589 (2002).

39. Lammie GA: Pathology of small vessel stroke. Br. Med. Bull. 56(2), 296–306 (2000).

n Review of pathology studies of the causes of lacunar stroke.

40. Ogata J: The arterial lesions underlying cerebral infarction. Neuropathology 19, 112–118 (1999).

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43. Gouw AA, Seewann A, van der Flier WM et al.: Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J. Neurol. Neurosurg. Psychiatry 82(2), 126–135 (2011).



44. Mead GE, Lewis S, Wardlaw JM, Dennis MS, Warlow CP: Should computed tomography appearance of lacunar stroke influence patient management? J. Neurol. Neurosurg. Psychiatry 67, 682–684 (1999).

45. Lindgren A, Staaf G, Geijer B et al.: Clinical lacunar syndromes as predictors of lacunar infarcts. A comparison of acute clinical lacunar syndromes and findings on diffusionweighted MRI. Acta Neurol. Scand. 101(2), 128–134 (2000).

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47. Potter G, Doubal F, Jackson C, Sudlow C, Dennis M, Wardlaw J: Associations of clinical stroke misclassification (‘clinicalimaging dissociation’) in acute ischemic stroke. Cerebrovasc. Dis. 29(4), 395–402 (2010).

48. Adams HP, Jr., Bendixen BH, Kappelle LJ et al.: 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 24(1), 35–41 (1993).

49. Landau WM, Nassief A: Editorial comment – time to burn the TOAST. Stroke 36(4), 902–904 (2005).

50. Thompson CS, Hakim AM: Living beyond our physiological means. Small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis. Stroke 40, E322–E330 (2009).

nn Review of systemic abnormalities in cerebral small vessel disease.

51. Pantoni L, Sarti C, Alafuzoff I et al.: Postmortem examination of vascular lesions in cognitive impairment: a survey among neuropathological services. Stroke 37(4), 1005–1009 (2006).

52. Potter GM, Marlborough FJ, Wardlaw JM: Wide variation in definition, detection and description of lacunar lesions on imaging. Stroke 42(2), 359–366 (2011).

n Systematic review and survey of experts on the definitions and diagnosis of imaging features of lacunar stroke.

53. Wardlaw JM: What is a lacune? Stroke 39, 2921–2922 (2008).

n Discussion about lacunes and their relevance to the wider picture of small vessel disease.

54. Potter GM, Doubal FN, Jackson CA et al.: Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke 41, 267–272 (2010).

55. Fisher CM: Lacunes: small, deep cerebral infarcts. Neurology 15, 774–784 (1965).

56. Jackson CA, Hutchison A, Dennis MS et al.: Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? Stroke 41, 624–629 (2010).

nn Systematic review and individual patient data meta-analysis of common vascular risk factors for small vessel and large artery ischemic stroke.

57. Adachi T, Kobayashi S, Yamaguchi S, Okada K: MRI findings of small subcortical ‘lacunarlike’ infarction resulting from large vessel disease. J. Neurol. 247, 280–285 (2002).

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61. Mead GE, Lewis SC, Wardlaw JM, Dennis MS, Warlow CP: Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischemic stroke: innocent bystanders? J. Neurol. 249(3), 266–271 (2002).

62. Ay H, OliveiraFilho J, Buonanno FS et al.: Diffusionweighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 30(12), 2644–2650 (1999).

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73. Chowdhury D, Wardlaw JM, Dennis MS: Are multiple acute small subcortical infarctions caused by embolic mechanisms? J. Neurol. Neurosurg. Psychiatry 75(10), 1416–1420 (2004).

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80. Wong KS, Li H: Longterm mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke 34(10), 2361–2366 (2003).


Review Wardlaw

81. Huang HW, Guo MH, Lin RJ et al.: Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerebrovasc. Dis. 24(1), 111–115 (2007).

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87. Mead GE, Wardlaw JM, Dennis MS, Lewis SC, Warlow CP: Relationship between pattern of intracranial artery abnormalities on transcranial Doppler and Oxfordshire Community Stroke Project clinical classification of ischemic stroke. Stroke 31(3), 714–719 (2000).

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98. Pico F, Labreuche J, Seilhean D, Duyckaerts C, Hauw JJ, Amarenco P: Association of smallvessel disease with dilatative arteriopathy of the brain: neuropathological evidence. Stroke 38, 1197–1202 (2007).

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101. Bailey EL, McCulloch J, Sudlow C, Wardlaw JM: Potential animal models of lacunar stroke. A systematic review. Stroke 40, E451–E458 (2009).

n Along with [165], presents a systematic review of potential models of lacunar stroke and what they tell us about potential mechanisms.

102. Wong TY: Is retinal photography useful in the measurement of stroke risk? Lancet Neurol. 3(3), 179–183 (2004).

103. Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ, Dhillon B: Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J. Anat. 206(4), 319–348 (2005).

104. Doubal FN, Hokke PE, Wardlaw JM: Retinal microvascular abnormalities and stroke: a systematic review. J. Neurol. Neurosurg. Psychiatry 80, 158–165 (2009).

n Along with [105], presents a systematic reviews of retinal vascular signs and stroke.

105. Baker ML, Hand PJ, Wang JJ, Wong TY: Retinal signs and stroke: revisiting the link between the eye and brain. Stroke 39(4), 1371–1379 (2008).

n Along with [104], presents a systematic reviews of retinal vascular signs and stroke.

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111. Doubal FN, Dhillon B, Dennis MS, Wardlaw JM: Retinopathy in ischemic stroke subtypes. Stroke 40, 389–393 (2009).

112. Doubal FN, MacGillivray TJ, Hokke PE, Dhillon B, Dennis MS, Wardlaw JM: Differences in retinal vessels support a distinct vasculopathy causing lacunar stroke. Neurology 72, 1773–1778 (2009).

n Along with [113], consists of two parallel but independent cohort studies of retinal vessels in lacunar and cortical stroke.

113. Lindley RI, Wang JJ, Wong MC et al.: Retinal microvasculature in acute lacunar stroke: a crosssectional study. Lancet Neurol. 8(7), 628–634 (2009).

n Along with [112], consists of two parallel but independent cohort studies of retinal vessels in lacunar and cortical stroke.

114. Doubal F, De Haan R, MacGillivray T et al.: Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on MRI. Int. J. Stroke 5(6), 434–439 (2010).



115. Baker ML, Wang JJ, Liew G et al.: Differential associations of cortical and subcortical cerebral atrophy with retinal vascular signs in patients with acute stroke. Stroke 41, 2143–2150 (2010).

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117. Black S, Gao F, Bilbao J: Understanding white matter disease. Imaging–pathological correlations in vascular cognitive impairment. Stroke 40(Suppl. 1), S48–S52 (2009).

nn Review of pathology, including venular disease, in cerebral small vessel disease.

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130. Calamante F, Gadian DG, Connelly A: Quantification of perfusion using bolus tracking magnetic resonance imaging in stroke: assumptions, limitations, and potential implications for clinical use. Stroke 33(4), 1146–1151 (2002).

131. Carpenter T, Armitage PA, Bastin ME, Wardlaw JM: DSC perfusion MRI – quantification and reduction of systematic errors arising in areas of reduced cerebral blood flow. Magn. Reson. Med. 55(6), 1342–1349 (2006).

132. Blamire A, Styles P: Does contrast based perfusion imaging give the right answer in pathological tissue? A Monte Carlo simulation study. Proc. Int. Soc. Magn. Reson. Med. 9, 1586 (2001).

133. Wardlaw JM, Doubal FN, Eadie E, Chappell F, Shuler K, Cvoro V: Little association between intracranial arterial stenosis and lacunar stroke. Cerebrovasc. Dis. 31, 12–18 (2011).

134. Knottnerus ILH, Ten Cate H, Lodder J, Kessels F, van Oostenbrugge RJ: Endothelial dysfunction in lacunar stroke: a systematic review. Cerebrovasc. Dis. 27, 519–526 (2009).

n Along with [135], consists of two systematic reviews of endothelial function in lacunar stroke.

135. Stevenson SF, Doubal FN, Shuler K, Wardlaw JM: A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke 41, E434–E442 (2010).

n Along with [134], consists of two systematic reviews of endothelial function in lacunar stroke.

136. Girouard H, Iadecola C: Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol. 100(1), 328–335 (2006).

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141. Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R: Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities. Longitudinal results of the Austrian Stroke Prevention Study. Stroke 36(7), 1410–1414 (2005).

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143. Smith FB, Lee AJ, Fowkes FGR, Price JF, Rumley A, Lowe GDO: Haemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler. Thromb. Vasc. Biol. 17, 3321–3325 (1997).

144. Woodward M, Lowe GD, Campbell DJ et al.: Associations of inflammatory and hemostatic variables with the risk of recurrent stroke. Stroke 36(10), 2143–2147 (2005).

145. Knottnerus ILH, GoversRiemslag JWP, Hamulyak K et al.: Endothelial activation in lacunar stroke subtypes. Stroke 41(8), 1617–1622 (2010).

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147. de Lau LM, Smith AD, Refsum H, Johnston C, Breteler MM: Plasma vitamin B

12 status and cerebral whitematter lesions.

J. Neurol. Neurosurg. Psychiatry 80(2), 149–157 (2009).

148. Laloux P, Gospodaru N, Cornil V, Ossemann M, Jamart J: Is hyperhomocysteinemia associated with a specific ischemic stroke subtype? Cerebrovasc. Dis. 21(Suppl. 4), 91 (2006).

149. de Jager J:, Kooy A, Lehert P et al.: Long term treatment with metformin in patients with Type 2 diabetes and risk of vitamin B12 deficiency: randomised placebo controlled trial. BMJ 340, C2181 (2010).


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150. Kooy A, de Jager J, Lehert P et al.: Longterm effects of metformin on metabolism and microvascular and macrovascular disease in patients with Type 2 diabetes mellitus. Arch. Intern. Med. 169(6), 616–625 (2009).

151. de Jager J:, Dekker JM, Kooy A et al.: Endothelial dysfunction and lowgrade inflammation explain much of the excess cardiovascular mortality in individuals with Type 2 diabetes: the Hoorn Study. Arterioscler. Thromb. Vasc. Biol. 26(5), 1086–1093 (2006).

152. Nomura E, Kohriyama T, Kozuka K, Kajikawa H, Nakamura S, Matsumoto M: Significance of serum soluable thrombomodulin level in acute cerebral infarction. Eur. J. Neurol. 11, 329–334 (2004).

153. Whiteley W, Jackson C, Lewis S et al.: Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin6. PLoS Med. 6(9), E1000145 (2009).

nn Cohort study of plasma biomarkers of inflammation and thrombosis and outcomes after stroke.

154. Bechmann I, Galea I, Perry VH: What is the blood–brain barrier (not)? Brain 29(1), 5–11 (2007).

155. 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. 50(2), 208–215 (2001).

nn Original description of imaging of abnormal perforating arterioles in lacunar stroke.

156. Lammie GA, Brannan F, Wardlaw JM: Incomplete lacunar infarction (type 1b lacunes). Acta Neuropathol. 96, 163–171 (1998).

157. Ma KC, Olsson Y: Structural and vascular permeability abnormalities associated with lacunes of the human brain. Acta Neurol. Scand. 88, 100–107 (1993).

158. Young VG, Halliday GM, Kril JJ: Neuropathologic correlates of white matter hyperintensities. Neurology 71(11), 804–811 (2008).

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160. Farrall AJ, Wardlaw JM: Blood brain barrier: ageing and microvascular disease – systemic review and metaanalysis. Neurobiol. Aging 30(3), 337–352 (2007).

nn Systematic review of changes in the BBB with aging and in dementia and white matter lesions.

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nn Observational study of BBB function in lacunar and cortical stroke.

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n Along with [101], presents a systematic review of potential models of lacunar stroke and what they tell us about potential mechanisms.

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n Discusses the importance of perivascular spaces to the circulation of interstitial fluid in the brain.

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nn Review of the role of inflammation in vascular dementia.

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Differing risk factors and outcomes in ischemic stroke subtypes: focus on lacunar stroke