pathology of small vessel stroke

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Pathology of small vessel strokeG Alistair LammieDepartment of Pathology, University of Wales College of Medicine, Cardiff, UK

Disease of small mtracerebral vessels is widely assumed to be responsible for themajority of small, deep-seated (lacunar) infarcts and primary intracerebralhaemorrhages. Our present, limited understanding of the pathogenesis of thesestroke subtypes, which togethe r constitute up to one-third of all strokes, isbased on a lim ited number of de tailed pathology studies, supported by clinical,risk factor and imaging data. Further progress using these traditionalapproaches has been prevented by a variety o f largely technical obstacles. It issuggested that advances in our understanding of the genetic basis ofestablished and new animal stroke models, in turn linked to more focusedhuman genetic stroke surveys, may hold the key to further insights.

An impasse appears to have been reached in our attempts to understandthe pathogenesis and, therefore, the preven tion, of strokes due to diseaseof small intracerebral vessels. Current dogma has it that small vesseldisease causes a significant proportion of small, deep-seated (lacunar)infarcts and primary (i.e. non-traumatic) intracerebral haemorrhage(PICH). This is a problem of clear socio-economic importance, forlacunar strokes constitute approximately 25% of first in-a-lifetimeischaemic stroke1, and PICH some 10% of all stroke, at least in theWest2. To this should be added the probable contribution of small vesseldisease to global, dementing b rain injury, further discussion of which liesoutside the scope of this article. I shall describe the central role ofpathology in achieving our current, if limited, understanding of smallvessel disease related stroke, in particular lacunar stroke, outline theobstacles that have prevented further progress, and suggest how themodern molecular pathologist may offer fresh insights.

Correspondence toDr G A Lammie,Department ofHistopathology,University Hospital ofWales. Heath Park,Cardiff CF4 4XW. UK

Lacunar infarction and the lacunar hypothesisThe original pathological descriptions of lacunar infarcts were made bythe beginning of this century by Durand Fardell and Marie in Paris3.Lacunar infarcts vary in maximal dimension from 3-20 mm, and are

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most commonly found in the putamen, caudate, thalamus, pons,internal capsule and cerebral white matter, in descending order offrequency. By the end of the century, Poiner and Derousne had p roposeda neuropathological classification of lacunes. They described old, smallinfarcts (type I lacunes), old, small haemorrhages (type II) and dilatedperivascular spaces (type III)4. Type I lacunes are by far the mostimportant clinically. Between times, Fisher had taken the descriptivepathological approach a stage further by his meticulous serial sectionautopsy reconstructions of the vascular supply of a limited number oflacunar infarcts5. His fundamental observation was that lacunar infarctsresult from occlusion of small perforating cerebral arteries, in somecases by a destructive process he termed 'segmental arterial disorgan-isation' or 'lipohyalinosis', and in others by atherosclerosis. In a smallminority, he found no occlusive lesion and assumed embolism. Thusarose what became known as the 'lacunar hypothesis', according towhich lacunar infarcts are caused by characteristic vascular lesionsinvolving single perforating brain arteries, often in combination withhypertension.

The nature of small vessel lesions causing lacunar infarcts -the legacy of Fisher

There are a large number of potential causes of small vessel occlusion,some autopsy-proven, others inferred (Table 1). These 'causes' may notnecessarily be mutually exclusive; for example, small vessel spasm maymediate destructive lesions or exacerbate atheroma 6. Despite this multi-plicity of possible causes, Fisher's work suggested, and there has been noconvincing contradictory data since, that there are two small vesselpathologies of major pathogenetic significance to stroke, the first'lipohyalinosis', the second atherosclerosis.Lipohyalinosis, as originally described, is a destructive vessel lesioncharacterised by a loss of normal arterial architecture, mural foam cellsand, in acute cases, evidence of fibnnoid vessel wall necrosis. Fishernoted that such vascular lesions involved small arteries of 40-200 |imdiameter, and caused correspondingly small (3-7 mm diameter), oftenasymptomatic, cerebral infarcts, particularly in the striatocapsule5. Bywhatever name, although perhaps less prevalent today in the era ofcontrolled hypertension5, such vessel lesions are still seen at post mortemin close proximity to lacunar infarcts (Fig. lb). The important, unresol-ved questions concerning this lesion are what proportion of lacunarinfarcts is it now responsible for and what is the underlying molecularmechanism?

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Table 1 Postulated causes of small deep cerebral infarctsC o m m o n (autopsy proven)

Destructive small vessel disease ('lipohyalinosis')Perforating/parent artery atherosclerosis

U ncommon/ ra re (may be autopsy proven but mechanism often assumed or inferred)EmbolismVasculitis

Collagen vascular diseaseInfectiveRecreational drugs (e g cocaine)Isolated CNS angntis

Infect ionHIVTuberculosisNeurosyphyhsCysteracosisLyme disease

HypoperfusionIn situ thrombosls/hypercoaguabi l rtyAnt iphosphol ip id ant ibod iesSLEDisseminated malignancyThrombocythaemiaPoh/cythaemia

Arterial dissectionCADASILCerebral amyloid angiopathy

Speculat ive (di f f icul t to prove)VasospasmOedemaPulsati le traumaDestructive ('lytic') agent

The term 'lipohyalinosis' has subsequently been misused to describealmost any cerebral small vessel pathology. It is distinct from, andshould not be confused with, the concen tric, hyaline wall thickening thatis a feature of most aged brains (Fig. la), particularly those from thehypertensive and diabetic elderly. Such poorly distensible collagen-rich' tubes', for which the term 'hyaline arteriosclerosis' is appropriate, areill-equipped to m atch cerebral blood supply with dem and, particularly ifsystemic blood pressure is abnormally high or low. They are an almostinvariant feature of brains with diffuse, presumed ischaemic, white matterdisease or leukoaraiosis. However, although such hyaline arteriosclerosisis often severe in brains harbouring lacunar infarcts, there is no directevidence that they are a cause of focal brain lesions and lacunar stroke.The other vascular lesion of pathologically-proven relevance to lacuneformation is intracranial atherosclerosis. This is pathologically similar tothe disease more familiar in the larger cervicocranial arteries, and affects

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J, a

Fig . 1 Photomicrographs i l lust rat ing tw o dis t in ct but of ten confused, types of int r ins iccerebral small vessel pathology, (a) Hyaline arteriosclerosis ('simple' small vessel disease) inthe putam en. Roughly concentr ic vessel wa l l th icke ning by hyal ine col lagenous mater ia l(asterix), with occasional surviving smooth muscle cell nuclei (arrow), (b) Healed'l ipohyalinosis' ( 'complex' small vessel disease) in the putamen of an elderly woman withmult iple basal ganglia lacunes. An asymmetrically thickened, disorganised vessel wall withfocal f ibrosis (asterix) and foam cell inf i l t rat ion (thick arrow). The vessel is cut in twoplanes. Haematoxylin and eosin: (a) x430; (b) x200.

somewhat larger perforating arteries than lipohyalinosis (200-800 umdiameter), causing correspondingly larger infarcts, 5 mm or more indiameter, which are more often symptomatic. According to Fisher, theculprit atheromatous plaques were seen in the proximal portion of theperforating artery (microatheroma), at its origin (junctional atheroma)or in the parent artery itself (mural atheroma)5. Infarcts were related tostenotic or occlusive plaques, some but not all of which were com-plicated by overlying thrombus.British Medical Bulletin 2000,56 (No 2) 299


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Progress in lacune research since FisherSince Fisher's land ma rk pathological observations, most lacune researchhas been in the clinical arena. Consistent with the lacunar hypothesis,lacunar stroke patients have been found to have a relatively lowfrequency of cardiac and large vessel atheromatous embolic sourcescompared to those with cortical infarcts7. That lacunar infarcts tend notto have a risk of early recurrence would also seem to mitigate againsttheir being caused by an active embolic source. The risk factor profilefor lacunar infarcts continues to be refined, but appears similar to thatfor ischaemic stroke in general, with the possible exception ofhypertension. Hypertension w as a m ore severe disease when Fisher firststudied lacunes and he perhaps overestimated its importance in lacunepathogenesis, but it may still be more prevalent in this stroke subtypetoday8. Thus, although not accepted by everyone9, the lacunarhypothesis has gained general support, not least because the distinctclinical lacunar syndromes have proved useful in patient management10.However, it could be argued that this large body of clinical andepidemiological work has not actually advanced our understanding ofwhat actually causes lacunar infarcts. As one eminent stroke physicianwrote of lacune research11, 'attem pts to infer the underlying disease by theanalysis of clinical risk factors...is at best an approximation of whatwould be learned by microscopy'. So what of recent pathology research?Perhaps unsurprisingly, there have been no further attempts at serialsection analysis, widely held to be the gold standard technique forvisualising small vessel anatomy, and there have been few novel technicalapproaches to visualising the small vessels supplying lacunes12. A fewlarge-scale autopsy surveys of lacune brains have been undertaken13-14, butthese have merely confirmed the epidemiological and risk factor trends . Anew pathological variant of lacune has been described which ischaracterised by partially or 'incompletely' infarcted brain tissue, thepotential significance of which lies in the fact that it suggests subtotal ortemporary stenosis/occlusion as likely causes of lacunar infarcts, forexample temporary embolic small vessel occlusion or vessel spasm 15.Clearly, pathology has contributed little to the debate m recent years,overshadowed perhaps by the promise of the new genetics.

The genetics of lacunar strokeIt is now clear from twin, family and population studies that there is asignificant familial or genetic com ponent underlying ischaemic stroke, andthere is now increasing effort to identify and characterise the susceptibilitygenes16-17. It is attractive, for example, to speculate that 'cortical' and

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' lacunar' stroke patients, who have similar risk factor profiles, sufferdifferent types of stroke because of different genetic predispositions. Ofthe rare inherited Mendehan disorders with an increased stroke risk,CADASIL and familial variants of cerebral amyloid angiopathy are bothassociated with specific cerebral small vessel pathologies and cortical/subcortical microinfarcts18 , but neither is likely to contribute significantlyto the overall prevalence of lacunar strokes. Gene polymorphism assoc-iation studies have, however, shown a weak but significant association ofthe DD genotype of the angiotensin converting enzyme (ACE) gene withischaemic stroke in general19 . Two studies have suggested an associationbetween I/D polymorphism status and lacunar stroke in particular20"21 , inone of which there was also suggested to be an association of the GGgenotype of the Glu298Asp endothelial nitric oxide synthase genepolymorphism with lacunes17 . Such genetic studies promise much, butthus far h ave yielded margina lly significant, n egative or conflicting re sults,for reasons which are discussed below.

Obstacles to progress in lacune research50 years after Fisher began his studies of lacunes, the bulk of clinical,radiological and epidemiological data would appear to support hisconclusion that lacunes are caused predominantly by some form ofintrinsic small vessel disease. However, we remain largely ignorant as tothe underlying cause of the small vessel lesions he described, and so havebeen powerless to prevent or treat them, apart from managing theirassociated risk factors. The reasons for this lack of progress are several,and most are intractable.

For the path ologist, the low case fatality1 means that only rarely does thepathogenetically informative acute small vessel lesion come to autopsy;when it does, it is usually late after the onset of stroke and so is organisedand at least partially healed, its appearance perhaps reflecting as much aresponse to injury as its cause. Even when the fresh lesion does presentitself, the technical difficulties inherent in tracing the lesion's vascularsupply are formidable. The current climate of research funding would seemto preclude further serial section analysis in a sufficiently large number ofinformative cases. As discussed, risk factor analysis is unlikely to providefurther insight and current methods of imaging small intracerebral vesselsduring life, lack the necessary resolution. To these problems should beadded the limitations inherent in a traditional descriptive pathologyapproach - the classical descriptions of lipohyalinosis, important thoughthey were, have not of themselves shed light on the underlying cellular ormolecular mechanisms. Further, our understanding of the potentialcontribution of intracranial atheroma is limited, is largely derived from

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somewhat crude radiological data, and lacks the detailed pathology studywhich has proved so informative in coronary artery and more recentlycarotid artery research22. A further problem is the clinical and patho-genetic heterogeneity of subcortical, as well as cortical, brain infarction23.For example, small infarcts in the centrum ovale may be manifestations ofcardiac or large artery disease more commonly than striatocapsularlesions24Faced with these problems, there has not been a satisfactory animalmodel of lacunar infarction to which the experimental pathologist canturn25 ; most animal stroke models have been used to study the patho-physiology and salvage of ischaemic brain tissue. The stroke-pronespontaneously hypertensive rat (SHRSP) does suffer microinfarcts andhaemorrhages, as well as fibrinoid small vessel lesions, and may yetprove to be a useful model of small vessel stroke. However, the SHRSPsuffers these lesions only in association with blood pressure levels notcomm only encountered in modern clinical practice25, and in this contextmay be regarded as a model of malignant hypertension.Finally, the early genetic studies of human lacunar and other types ofstroke have had major limitations which are becoming familiar in othercomplex or multifactorial diseases26. Many studies have had extremelysmall sample sizes, a lack of adequate numbers of genetically matchedcontrols, an absence of relevant biological data or even of a convincingbiological rationa le ('fishing'). They too of course have suffered from thedifficulties inherent in accurate clinical identification of pathologicalstroke subtypes.

Primary intracerebral haemorrhage - a related problemProblems have also beset researchers studying the pathogenesis of PICH .Some of these reflect the same inaccessibility of the culprit intracerebralvessels which has frustrated lacune research, although others are unique.Apart from those rare cases in which PICH is presumed to followrupture of structurally normal vessels, usually in association with acuterises in blood pressure or blood flow 27, it is reasonable to assume thatrupture of an intracerebral vessel is a consequence of focal vessel wallpathology. As Caplan has pointed out, the so-called Charcot-Bouchardnucroaneurysm has never been clearly identified as the definitive cause ofeven a single haematoma27, and its very existence has now beenquestioned by elegant histochemical studies suggesting it was an illusionof injection studies produced by complex arteriolar coils and perivascularclots28. The consensus view at present is perhaps that the same small vessellesion observed by Fisher in relation to lacunar infarcts is responsible forthe majority of PICH29-30 a lesion in its acute form characterised by



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fibrinoid vessel wall necrosis31 . PICH and lacunar infarction appear to co-localise, often co-exist in the same brain at autopsy, and show broadsimilarities in risk factor profile29 . However, why the same or a similarvessel lesion should in some cases lead to a small infarct and in others toan intracerebral haemorrhage is unclear. There is clearly potential for acomplex interplay of acute haemodynamic and acquired structural vesselwall changes in the pathogenesis of these stroke subtypes.

Study into the cause of PICH by traditional, observational clinical andautopsy studies have been beset by now familiar difficulties. Intracerebralhaemorrhages are a heterogenous stroke type, and it is often difficult todistinguish clinically those cases due, for example, to haemorrhagictransformation of infarcts, haemorrhagic venous infarction, crypticvascular malformations and cerebral amyloid angiopathy32. Clinical seriesof PICH are, therefore, likely to have mcluded a diversity of patho-genetically unrelated entities. Although a relatively high proportion ofsevere PICH cases have come to autopsy shortly after the ictus, theproblem of causal lesion localisation is the same as for lacunes, and isfurther complicated by the fact that the vessel lesion is destroyed or at leastmodified by the rupture itself and the consequent haemorrhage. Yet again,in vitro and in vivo models of PICH have been sought, but are used mainlyto examine the clinical properties of clots and their response to drugs, orthe effects of haemorrhage on surrounding brain33 . There ha s, to date, beenno satisfactory in vivo model tha t sheds light on the mechanism of hum anPICH.

Future prospectsIt is clear from the ab ove th at trad itional p athologica l lines of investigationhave been pivotal in formulating our current ideas as to how small vessel-strokes occur. There is still much that such an approach can offer, inparticular regarding the nature and consequences of cervicocranialatherosclerosis. Stroke researchers have been slow to apply the paradigmof plaque instability to the arteries supplying the brain. Thus, whilst itseems that thrombotic occlusion of the carotid artery usually occurs m amanner directly analogous to coronary artery thrombosis22 , very little isknown of the relations between plaque stability, stenosis, plaque pro-gression, thrombosis and embolism. This is particularly true of intracranialvessels, despite the obvious implications for lacunar infarct pathogenesis.

The prospects of such traditional approaches clarifying the role ofintracerebral small vessel disease in stroke are by comparison bleak.However, there should be some attempt to standardise pathologicalterminology in this field, particularly in relation to small vessel lesions.Thereafter, it is perhaps the emerging breed of experimental molecularBritish Medical Bu lletin 2000,56 (No 2) 30 3


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pathologist who has most to offer34 , ideally in the context of amultidisciplinary stroke research team. Questions which logically posethemselves are 'is there a specific intracerebral vessel lesion associated withlacunar infarction and PICH?' and then, ' is this lesion merely a stochasticevent caused by the unfortunate concurrence of multiple risk fartors or isit, to an extent at least, (genetically) predictable and hence maybepreventable?' Fisher's work, and the debate it provoked, have provided aprovisional answer to the first question - a characteristic destructivecerebral vessel lesion characterised in its acute form by nbrinoid necrosis,does appear to be specifically associated with lacunar infarction, and albeitless convincingly, PICH. The answer to the second question is at one levelstraightforward - small vessel stroke will, like the vast majority of multi-factorial diseases, prove to be a combination of genetic and environmentalrisk factors. Advances in our understanding of the genetics of establishedstroke risk factors, such as hypertension, will complement the search fornovel genes predisposing to stroke inde pend ent of such fartors. Also, smallvessel stroke researchers may now begin to take advantage of an improvedunderstanding of the genetic basis of established animal models, such asthe SHRSP, in which chromosomal regions have recently been identifiedcontaining blood pressure-independent genetic fartors predisposing tostroke 16 . In addition, a variety of newer transgenic and gene knock-outanimal models35 have the potential now to model the specific small vessellesions implicated by human autopsy research. Both approaches will beessential in focusing on biologically plausible candidate genes forassociation studies in human stroke, an increasingly important concerngiven the impending availability of the entire human genome sequence andits variability, as well as the development of comprehensive sets of singlenucleotide polymorphisms spanning the human genome36 . These humangenetic studies will, of course, continue to require valid stroke subtyping.Finally, more, and more informative, stroke intermediate phenotypes needto be developed. This is partly because such phenotypes are likely to beinfluenced by a smaller number of genes than stroke itself, therebyimproving the power of linkage and association studies, but also as theymay provide insights into the mechanisms underlying postulated geneticassociations16 . A well-defined small vessel lesion, modelled in a geneticallydefined animal, would be an obvious intermediate phenotype which wouldintegrate the fields of Virchowian pathology and molecular genetics insmall vessel-related stroke research.

AcknowledgementsThe author is grateful to Angela Penman for typing the manuscript, andto Charles Warlow for his consistent su ppo rt and constructive criticism.



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