Lacunar Syndromes, Lacunar Infarcts, and Cerebral Small-Vessel Disease

Historical Aspects

In 1838, Dechambre used the term lacune for the first time with pathologic criteria. The entity was confused with other cavity lesions in the brain such as état criblé (small bilateral, multiple lesions in the white matter described by Durand-Fardel in 1842; Fig. 27.1 ), residual necrotic tissue of small infarcts or hemorrhages, enlarged perivascular spaces ( Fig. 27.2 ), and porosis due to postmortem bacterial autolysis.

In 1901, Pierre Marie used lacune as his descriptive term for 50 cases of capsular infarction and clearly established the concept and classification of different small cavities in the brain, writing :

One could therefore picture the anatomo-pathological process of formation of lacunes in the following manner: the influence of the general causes of atherosclerosis, the vessels which irrigate the brain change, the nutrition of the brain diminishes, its parts become atrophied, which contributes to the dilatation of the ventricles of the perivascular spaces. As the vascular lesions progress, one or more small vessels break or are obliterated, hence the production of one or more lacunes. In effect, it is known that in the central areas of the brain the blood vessels are terminal, that is, there are no anastomoses, so that the whole territory is irrigated by the blood vessel which is obliterated is inevitably infarcted.

Marie emphasized a capsular and lenticular location for the syndrome.

Ferrand claimed the next year that the same syndrome occurred whether the lesion was capsular or pontine in location. During the first quarter of the 20th century, the German pathologists Cecil and Oscar Vogt firmly established the ischemic etiology.

Lacunes began their modern comeback almost entirely through the efforts of C. Miller Fisher. Fisher described pure motor hemiplegia, pure sensory stroke, homolateral ataxia and crural paresis (known mainly thereafter as ataxic hemiparesis), dysarthria-clumsy hand syndrome, sensorimotor stroke, basilar branch syndromes, and the vascular pathology underlying lacunes. The position was so thoroughly developed that it triggered companion studies, of which many corroborated and others enlarged on the clinical entities, vascular pathology, and clinico-radiologic correlations. Other researchers attacked the basic principles : some argued for other causes including embolism, and others recommended that the concepts be abandoned altogether. Numerous studies have claimed that the syndromes may have causes other than hypertensive arteriopathy. ^,

Lacunar infarcts in studies on lacunar infarcts causing acute stroke and transient ischemic attack (TIA) changed direction dramatically with the advent of modern imaging techniques. Problems with low resolution and low detection rates of lacunar infarcts with computed tomography (CT) were largely resolved by magnetic resonance imaging (MRI) techniques, in particular diffusion-weighted (DW) MRI, which permits identification of acute ischemic lesions in the vast majority of patients. Through DW MRI, much more precise clinic-imaging correlative studies became possible, changing the perspective of the precision of diagnosing lacunar stroke from clinical and CT features alone. A further important change in our concepts of cerebral small-vessel disease was the recognition that the majority of parenchymal manifestations of cerebral small-vessel disease (e.g., silent cerebral infarcts, microbleeds, white matter abnormalities) did not present with acute stroke but has been found to have other important consequences of brain function (see later).

The Spectrum Of Cerebral Small-Vessel Disease

For a long time, it was commonly thought that most arterial occlusions in the brain presented clinically with acute neurologic dysfunction and that the majority could be clinically diagnosed. Lacunar infarcts cause clinical symptoms when they affect the long motor and sensory tracts in the subcortical areas, linked to their clinical presentation. However, MRI studies of the general population, the reporting of which began in the 1990s, have shown that most lacunar infarcts do not produce acute stroke symptoms but are clinically unrecognized or “silent.” ^, Silent cerebral infarcts (95% of which are “lacunar”) are at least five times as common as symptomatic ones. Silent infarcts are not innocent; they have been shown to increase the risk of vascular events (including stroke), cognitive decline, and dementia. They are “silent” only in the aspect that they have not caused acute cerebral dysfunction. Silent cerebral infarcts have the same pathologic appearance as lacunar infarcts that cause acute stroke symptoms.

Diagnosing a visualized infarct as “silent” is challenging, and several potential sources of error should be recognized. A previous clinical symptom, and even hospital admissions resulting in a diagnosis of TIA or stroke, may not be adequately recalled in a patient’s self-report. Careful questioning may reveal that symptoms possibly related to the location of a silent cerebral infarct (SCI) were actually present but ignored due to a lack of awareness of stroke symptoms in the elderly and in the families. Furthermore, clinical symptoms may fail to be recognized as TIA or stroke even when brought to medical attention. There is a long list of “stroke chameleons” (i.e., uncommon presentations of stroke that may be missed).

Silent cerebral infarcts are closely linked to ischemic white matter lesions (WMLs). ^, WMLs are even more prevalent in the elderly population than SCIs, and the two conditions share most risk factors and show a high degree of covariance. The distinction between the two conditions may be less clear than previously thought. Not all symptomatic or silent infarcts cavitate but may be incorporated/merged in regions of WMLs.

A recent addition to the spectrum of silent brain infarcts is the cerebral microinfarct, very small (<1 mm) often a cortical infarct, that is not detected on conventional structural MRI. Despite the small size of these lesions, affected individuals can have hundreds to thousands of cerebral microinfarcts, which cause measurable disruption to structural brain connections, and are associated with dementia that is independent of Alzheimer disease pathology or larger infarcts (i.e., lacunar infarcts, and large cortical and nonlacunar subcortical infarcts). Substantial progress has been made with regard to understanding risk factors and functional consequences of cerebral microinfarcts, partly driven by new in vivo detection methods and the development of animal models that closely mimic multiple aspects of cerebral microinfarcts in human beings. Evidence from these advances suggests that cerebral microinfarcts can be manifestations of both small vessel and large vessel disease, that cerebral microinfarcts are independently associated with cognitive impairment, and that these lesions are likely to cause damage to brain structure and function that extends beyond their actual lesion boundaries. A recent review provided criteria for the identification of cerebral microinfarcts with in vivo MRI to support further studies of the association between these lesions and cerebrovascular disease and dementia.

Another component of the spectrum of cerebral small-vessel disease is the cerebral microbleed (CMB). CMBs are small (2–5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2∗-weighted gradient-echo (GRE) or susceptibility-weighted sequences. They are most often located in the cortico-subcortical junction, deep gray or white matter in the cerebral hemispheres, brainstem, and cerebellum. The common occurrence of CMB has been recognized only since the mid-1990s ^51,52 because CMBs are generally not visualized on CT or fluid-attenuated inversion recovery, T1- or T2-weighted MR sequences. There has been substantial progress made in the understanding of CMBs during recent years (recently summarized in a comprehensive monograph), but there are several areas in need of further study. CMBs localized to the deep hemispheric regions, brainstem, and cerebellum have been closely linked to traditional vascular risk factors similar to lacunar infarcts, whereas multiple, strictly lobar CMBs have been shown to be highly specific for severe cerebral amyloid angiopathy and are prerequisites in establishing a diagnosis of cerebral amyloid angiopathy. ^,

Definitions

Precise definitions of several terms related to cerebral small-vessel disease have been lacking. A large number of terms have been used, which has created confusion, in particular for the use of “lacune.” In a paper late in his career, C. Miller Fisher wrote: “Historically, the original small vessel disease feature was the lacune (hole), which derived from French for a small fluid-filled cavity that was thought to mark the healed stage of a small deep brain infarct. The term was adopted into English. By a process of medico-linguistic evolution, the precavitary phase became the lacunar infarct, the associated clinical entity became the lacunar stroke and the neurologic features became the lacunar syndrome.” Thus the term lacune is a neuropathologic term that refers to a finding of a cavitation ( Fig. 27.3 ).

Because of recent advances in the understanding of cerebral small vessel disease, the STandards for ReportIng Vascular changes on neuroimaging (STRIVE) consortium developed additional criteria that more accurately reflects neuroimaging findings of cerebral small vessel disease.

These criteria separate the imaging findings of lacunar stroke into recent small subcortical infarcts and lacunes of presumed vascular origin. The term recent small subcortical infarcts (which can be up to 20 mm in maximum diameter) describes infarcts that are seen on diffusion-weighted imaging (DWI) sequences in the acute setting. The chronic products of such infarctions include lacunes of presumed vascular origin and white matter hyperintensities. Chronic lacunes of presumed vascular origin are typically subcortical fluid-filled spaces (approximately 3–15 mm in diameter) and are best seen on T2-weighted MRI sequences (see later). Furthermore, WMHs have a diverse and heterogenous etiology of their own, in addition to resulting from cerebral small vessel disease.

Pathoanatomy

Most pathologic studies on lacunar infarcts were performed before or in the early CT era, whereas later reports are scarce. However, the paucity of autopsy reports overall in lacunar infarcts is not surprising: the early mortality rates after lacunar infarcts are very low, and if an autopsy examination is carried out, it is usually performed months or years after a stroke event, making inference of etiology very difficult. The pathologic reports on lacunes should be read with these limitations in mind.

Most autopsy-documented lacunar infarcts are small, ranging from 0.2 to 15 mm ³ in size. They vary according to the territory supplied by the occluded vessel feeding the infarct. In general, vessels are 100–400 μm ¹⁵ in size and serve territories varying from little more than a cylinder the size of the vessel itself to wedges as large as 15 mm on a side. Deep infarcts of larger size than 15 mm at autopsy were in some early reports labeled as “super lacunes” and found to be associated with occlusion (usually embolic) of the middle cerebral artery affecting multiple lenticulostriate branches; they are currently classified as striatocapsular infarcts and constitute a distinct stroke entity separate from lacunar infarct. However, it should be noted that partial striatocapsular infarcts occur and that they can shrink with time to less than 15 mm in diameter.

Lacunes predominate in the basal ganglia, especially the putamen, the thalamus, and the white matter of the internal capsule and pons; they also occur occasionally in the white matter of the cerebral gyri. They are rare in the gray matter of the cerebral surface, as well as in the corpus callosum, visual radiations, centrum semiovale of the cerebral hemispheres, medulla, cerebellum, and spinal cord. Most lacunes occur in the territories of the lenticulostriate branches of the anterior and middle cerebral arteries, the thalamoperforating branches of the posterior cerebral arteries, and the paramedian branches of the basilar artery. Their occurrence is rare in the territories of the cerebral surface branches.

The lenticulostriate vessels arise from the circle of Willis and the stems of the anterior and middle cerebral arteries to supply the putamen, globus pallidus, caudate nucleus, and internal capsule. They are composed of two main groups: those more medial, with diameters of 100–200 μm, and those more lateral, with diameters of 200–400 μm. The thalamoperforating vessels arise from the posterior half of the circle of Willis and the stems of the posterior cerebral arteries to supply the midbrain and thalamus. Their size varies from 100 to 400 μm. The paramedian branches of the basilar artery mainly supply the pons. Few branches have been measured, but sizes ranging from 40 to as large as 500 μm have been observed. ^, What these arteries have in common is a tendency to arise directly from much larger arteries and an unbranching end-artery anatomy. The penetrators are all less than 500 μm in size and arise directly from the larger, 6- to 8-mm, internal carotid or basilar artery. Their small size and their points of origin rather proximal in the arterial network are thought to expose these vessels to forces that scarcely reach other arteries of similar size in the cerebral cortex. These latter arteries are apparently protected by a gradual step-down in size from the 8-mm internal carotid, to the 3- to 4-mm middle cerebral, to the 1- to 2-mm surface branches, from which the intracortical vessels whose diameters are less than 500 μm arise. Perhaps this difference explains the low frequency of lacunes in the cerebral surface vessels. ^,

The lack of collateral circulation for the penetrators results in an infarct that spreads distally from the point of occlusion through the entire territory of the vessel affected. The exact volume of tissue supplied by each penetrating artery varies enormously. Some arteries supply little more than a territory of the same diameter as the vessels, whereas others arborize widely and leave an infarct shaped like a wedge or cone. Most capsular infarcts arise from arteries 200–400 μm in size and produce infarcts of approximately 2–3 mm ³ . These small infarcts are found regularly only on MRI with 1.5-Tesla strength, are commonly missed on CT scanning, and are easily overlooked at autopsy. The arterial occlusion usually occurs in the first half of the course of the penetrating vessel, which ensures that most such occlusions are quite small.

Several distinct but related arteriopathies cause lacunes. Microatheroma is believed to be the most common mechanism of arterial stenosis underlying symptomatic lacunes ( Fig. 27.4 ). ^{, ,} The artery is usually involved in the first half of its course. Microatheroma stenosing or occluding a penetrating artery was found in 6 of 11 capsular infarcts in the only published pathologic study on the cause of capsular infarcts, and it was the cause of the only published case of a thalamic lacune. The histologic characteristics of the microatheroma are identical to those affecting the larger arteries.

These tiny foci of atheromatous deposits are commonly encountered in chronic hypertension. In the usual nonhypertensive case, atheroma appears mostly in the extracranial internal carotid and basilar arteries but only rarely in the stems of the major cerebral arteries. ^, In hypertension, however, the lesions not only are more advanced for the patient’s age, but also are spread more distally in the arterial system, at times involving even some of the cerebral surface arteries. In patients with advanced hypertension, miniature foci of typical atherosclerotic plaques are found even in arteries as small as 100–400 μm in diameter, resulting in a stenosis or occlusion that sets the stage for a lacune. In a retrospective autopsy study of 70 brains with microscopic evidence of small-vessel disease, the morphology of the vessel disease, the arteriolosclerosis, was similar in normotensive and hypertensive subjects. Lacunes were as prevalent in normotensive subjects (36%) as in hypertensive patients (40%), which would suggest that the control of hypertension has modified the pathology of small-vessel disease.

Other arterial disorders seem less common. Lipohyalinosis, formerly considered the most frequent cause of lacunes, affects penetrating arteries in a segmental fashion in chronic hypertension. It was the cause attributed to 40 of 50 lacunes studied in serial section by Fisher in four cases of stroke. It seems to occur most often in the smaller penetrating arteries (i.e., in those less than 200 μm in diameter) and accounts for many of the smaller lacunes, especially those that are clinically asymptomatic. Lipohyalinosis has been thought to be an intermediate stage between the fibrinoid necrosis of severe hypertension and the microatheroma associated with more long-standing hypertension. ^{, ,}

Fibrinoid necrosis is a related condition found in arterioles and capillaries of the brain ( Fig. 27.5 ), retina, and kidneys in a setting of extremely high blood pressure. It appears histopathologically as a brightly eosinophilic, finely granular, or homogeneous deposit involving the connective tissue of blood vessels. The mechanism is believed to involve disordered cerebrovascular autoregulation ^, and has a necrotizing consequence. Fibrinoid necrosis shares someof the histochemical, electron microscopic, ^, and immuno-fluorescent characteristics of lipohyalinosis, another cause of lacunes.

Microembolism has been inferred in a few serially sectioned lacunes shown to have normal arteries leading to the infarct. However, such cases have been examined with autopsy years after the stroke, which makes inference on mechanisms of injury in the acute phase spurious.

Risk Factors

Lacunar infarctions share many risk factors with other types of ischemic stroke, of which the most common are hypertension and diabetes mellitus. These two risk factors for lacunar disease have been present with comparable frequencies in larger clinical series of lacunar infarcts: 75% and 29%, respectively, of lacunar cases diagnosed in the Harvard Cooperative Stroke Registry ; and 72% and 28%, respectively, of the Barcelona series reported by Arboix et al. There has been some debate in the past about whether these two risk factors are more prevalent, and characteristic, for lacunar infarcts compared with other subtypes. A problem with the TOAST classification, used in many of the risk factor studies, is that hypertension and diabetes have been included in the definition of the small-vessel disease (lacunar) subtype, creating a potential bias for risk factor analyses. In a systematic review of studies Jackson and Sudlow found only a marginal excess of hypertension in lacunar versus nonlacunar infarcts. In a later study pooling individual data on 2875 patients with first-ever ischemic stroke from five collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes, a lower prevalence of cardioembolic source (adjusted odds ratio [OR], 0.33; 95% confidence interval [CI], 0.24–0.46), ipsilateral carotid stenosis (OR, 0.21; 95% CI, 0.14–0.30), and ischemic heart disease (OR, 0.75; 95% CI, 0.58–0.97) were noticed in lacunar compared with nonlacunar patients, but no differences for hypertension, diabetes, or any other risk factors were searched for. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis. Thus hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes.

Atrial fibrillation, one of the hallmarks of embolism, has a low frequency of small, deep infarcts (5%), similar to the frequency in the general population older than 60 years. In very elderly patients (older than 85 years), there is a high frequency of atrial fibrillation (28%) as a consequence of age. Several other risk factors for vascular disease, such as smoking, obesity, and low physical activity, are also frequently present in patients with lacunar infarcts but appear as a general risk factor for stroke rather than being specific for lacunar infarction.

A population-based cohort study of TIA and ischemic stroke from the OXVASC study, with detailed records of premorbid blood pressure, showed that the associations of blood pressure and acute lacunar events differed by age. Patients with acute lacunar events at younger ages had significantly higher premorbid long-term average blood pressure than those with nonlacunar events, particularly in the 5 years before the index event, with further increases more immediately before the event. This group also had higher maximum premorbid blood pressure and a higher prevalence of uncontrolled blood pressure before the event than patients with nonlacunar etiology.

More advanced genetic studies on specific stroke subtypes have been reported only recently. A genetic risk of stroke may be mediated through already-known risk factors, such as cholesterol and blood pressure levels. In an earlier study on specific single nucleotide polymorphisms, the angiotensin-converting enzyme gene and the angiotensinogen gene were found to be associated with the presence of neurologic manifestations in lacunar infarctions. Homozygosity for the G allele of the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthetase gene was associated with brain infarction and, especially, with lacunar stroke. The TPA-7351C/T polymorphism appeared as an independent risk factor for lacunar stroke. AGT gene M235T polymorphism may represent a risk factor for lacunar infarction. An association between lacunar infarction and the genotype of the interleukin-6 polymorphism was also reported.

The latest and largest genome-wide association study of stroke has arisen from the MEGASTROKE collaboration, leveraging 67,162 stroke cases and 454,450 controls recruited from sites worldwide. This study has reinforced the idea that most associations between variants and stroke risk are restricted to a specific etiologic stroke subtype. In analyses restricted to small vessel disease stroke following standard subtyping criteria, MEGASTROKE reported associations with two loci at 16q24 and 2q33. The precise role of these loci for small vessel disease is unknown. Two other loci (14q22 and 12q24) were found to be associated both with large vessel ischemic stroke and small vessel disease. Genetics of small vessel disease remains complex and is related to monogenic causes (arteriolosclerosis related and amyloid related) and sporadic causes of small vessel disease.

Imaging Studies

Magnetic Resonance Imaging

MRI has greatly changed the frequency with which small infarcts are demonstrated. Although CT is still used in clinical practice as the first (and often only) imaging technique, MRI has currently surpassed it in sensitivity for the detection of lacunes. ^, In their study of 227 patients with lacunar infarcts, Arboix et al. found that CT findings were positive in 100 patients (44%), whereas MRI findings were positive in 35 of 45 (78%). MRI was significantly better ( P < .001) than CT for imaging lacunes, especially those located in either the pons ( P < .005) or the internal capsule ( P < .001). Motor stroke, pure or sensorimotor, has the highest positive rate on MRI, and pure sensory stroke has the lowest. This finding corresponds to the main volumes of the classic lacunar syndromes on MRI: sensorimotor, 1.7 mL; pure motor, 1.2 mL; ataxic hemiparesis, 0.6 mL; and pure sensory, 0.2 mL. Hommel et al. used MRI for 100 patients hospitalized with lacunar infarct syndrome and also found it more sensitive. MRI detected at least one lacune appropriate to the symptoms in 89 patients in whom 135 lacunes were found on imaging. MRI was more effective when it was performed a few days after the stroke. However, it should be recognized that MR-negative cases exist: in one study up to 30% of patients with symptomatic lacunar stroke syndromes no infarct was in the subcortex or elsewhere in the brain.

DW MRI is the most sensitive and specific imaging method for detection of acute subcortical ischemic lesions and can differentiate acute from nonacute lesions. Acute lacunar infarcts appear on DW MRI as a bright area of decreased apparent diffusion coefficient (ADC); a subacute lacunar infarct is seen as an area of decreased or normal ADC, and a chronic infarct is seen as with a normal or increased ADC. In several reports, almost all patients with clinical acute subcortical infarction had focal areas of high intensity appeared on DW MRI that correlated with all or part of the patient’s clinical syndromes. ^,

MRI criteria for cerebral small-vessel disease infarcts have been imprecise. The consensus STRIVE report on neuroimaging standards for research into small-vessel disease and its contribution to aging and neurodegeneration was published in 2013. Studies have shown that not all (symptomatic) acute small deep infarcts cavitate with time and appear as “lacunes”: some appear as white matter hyperintensities, whereas some are not visualized at all with time. As a consequence, the distinction between previous symptomatic cerebral infarcts, silent brain infarcts, and white matter hyperintensities of presumed vascular origin is less sharp than previously recognized, or reported in scientific studies, as interpreted from late neuroimaging findings alone. Estimates of the proportion of acute small deep infarcts that cavitate are variable and range from 28% to 94%. ^, Cavitation may be related to time and size of the lesion but also to neuroimaging methods such as MRI sequences. It should be recognized that a very small proportion of cavitated lesions appearing as a silent cerebral infarct may have been caused by a previous small bleed. The variable fates of small-vessel disease-related lesions and convergence of etiologically different lesions to result in similar late appearances on MRI are illustrated in Fig. 27.6 .

Presumed silent cerebral infarcts need to be carefully separated from prominent perivascular spaces (Virchow-Robin spaces), a distinction that may have been overseen in early reports. Perivascular spaces are fluid-filled spaces that follow a typical course of a vessel penetrating/transversing the brain through gray or white matter. They will appear linear when imaged parallel to the course of the vessel, and round or ovoid (with a diameter less than 2 mm) when imaged perpendicular to the course of the vessel.

Magnetic resonance angiography (MRA) can detect intracranial large-artery diseases, stenoses, or occlusions in 21% of patients meeting clinical and radiologic criteria for lacunar infarcts, but only in 10% is the artery disease related to the affected penetrating vessel. In one study, MRA disclosed a basilar artery stenosis in 4 of 11 patients with paramedian pontine infarction of lacunar type and a clinical lacunar syndrome (10 with pure motor hemiparesis and 1 with ataxic hemiparesis). Microvasculature of the brain as lenticulostriate arteries can be observed by 7.0-Tesla MRA.

Clinical Syndromes

When symptomatic, lacunar infarcts are associated with clinical “lacunar” syndromes, five of which are well recognized: pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, dysarthria-clumsy hand syndrome, and ataxic hemiparesis. Face, arm, and leg involvement are characteristic of the first three syndromes. The most important clinical feature for lacunar syndromes is the absence of cognitive symptoms or signs and visual field defects.