Lacunar infarcts

INTRODUCTION AND DEFINITION — Lacunar infarcts are small (2 to 15 mm in diameter) noncortical infarcts caused by occlusion of a single penetrating branch of a large cerebral artery [1,2]. These branches arise at acute angles from the large arteries of the circle of Willis, stem of the middle cerebral artery (MCA), or the basilar artery. Although this definition implies that pathological confirmation is necessary, diagnosis in vivo may be made in the setting of appropriate clinical syndromes and radiological tests. Not all small deep infarcts are lacunar, and the diagnosis of lacunar infarction also requires the exclusion of other etiologies of ischemic stroke.

Note that the pathology studies that defined lacunar infarcts were performed in the chronic phase of stroke [1]; some neuroimaging studies in the acute phase (<10 days from stroke onset) have used 20 mm as the upper size limit for lacunes, since some volume reduction is expected over time. (See 'Imaging confirmation' below.)

HISTORY — Dechambre first used the term "lacune" in 1838 to describe softenings in subcortical regions of the brain found on autopsy [3]. At the time, there was dispute regarding whether these lacunes were caused by encephalitis, a late phase of a small hemorrhage, or ischemic necrosis. Marie in 1901 first described a clinical syndrome associated with multiple lacunes, characterized by sudden hemiplegia with good recovery, a characteristic gait with small steps ("marche a petits pas de Dejerine"), pseudobulbar palsy, and dementia [4].

In the 1960s, careful clinicopathological correlations by Fisher generated the so-called "lacunar hypothesis," which suggested that lacunes are due to a chronic vasculopathy related to systemic hypertension, cause a variety of defined clinical syndromes, and imply a generally good prognosis [5].

The introduction of computed tomography (CT) and magnetic resonance imaging (MRI) has generated data that both supports and opposes the lacunar theory [6,7]. Some authors have suggested abandoning the concept altogether [8,9]. Detractors of the lacunar hypothesis note the lack of animal data or an animal model of lacunar infarction and the demonstration of embolic sources from the heart, aorta, or large arteries in a substantial percentage of lacunar strokes [10,11]. Proponents concede that some small number of lacunes may result from emboli, but they point out that the proportion of embolic sources found in association with lacunar syndromes is far lower than for other ischemic stroke types and that there are clear clinical and epidemiologic reasons to separate lacunes from other ischemic stroke subtypes [11,12].

One of the major difficulties in interpreting these data stems from the inability of imaging techniques to show that an infarct was due to occlusion of a single penetrating artery. Furthermore, various studies have used different sets of criteria to define "lacunar infarcts" and the many lacunar syndromes [13,14]. However, continuing publications on the subject have demonstrated that the term "lacune" is clinically useful and has gained wide acceptance in the literature.

VASCULAR ANATOMY — Most lacunes occur in the basal ganglia (putamen, globus pallidus, caudate), thalamus, subcortical white matter (internal capsule and corona radiata), and pons [5,15,16]. These locations correspond to vascular territories of the lenticulostriate branches from the anterior and middle cerebral arteries, the recurrent artery of Heubner from the anterior cerebral artery, the anterior choroidal artery from the distal internal carotid artery, thalamoperforant branches from the posterior cerebral artery, and paramedian branches from the basilar artery (figure 1) [17,18]. These small branches originate directly from large arteries, making them particularly vulnerable to the effects of hypertension, probably explaining this peculiar distribution.

A study using fluorescent and radiopaque dye injection techniques has demonstrated that penetrating vessels supply distinct microvascular territories of the basal ganglia, with minimal overlap and sparse anastomoses between the penetrating vessels [18]. The ultimately terminal rather than anastomotic nature of these vessels is another factor explaining the predisposition of this region to lacunar infarction.

ETIOLOGY — Several mechanisms for small vessel disease and lacunar infarction have been described, primarily hypertension-related microangiopathy, microatheroma of the origin of the penetrating arteries, embolism, and endothelial dysfunction with disruption of the associated blood-brain barrier [1,2,19-22]. The first two mechanisms are proven pathologically [1], and generally regarded as a consequence of systemic hypertension.

A systematic review of 19 cohort studies involving 5864 patients with ischemic stroke found that those who had a lacunar infarct as the index event were more likely to have lacunar than nonlacunar stroke recurrence, lending some support to the notion that lacunar strokes represent a different form of arteriopathy than other ischemic stroke subtypes [23]. Other mechanisms have been proposed to account for lacunar infarcts, but none are pathologically proven.

●Hypertensive microangiopathy – Hypertensive microangiopathy is considered the usual cause of lacunar infarcts. Uncontrolled hypertension leads to arteriolar wall thickening and narrowing of the lumen of the small penetrating arteries due to arteriolosclerosis and related pathologies including lipohyalinosis, fibrinoid necrosis, and segmental arterial disorganization, sometimes accompanied by microaneurysm formation [1,21,24].

The pathology of lacunar infarcts may be changing as the medical management of hypertension becomes more effective [25]. A decline in the number of lacunes per patient in comparable pathology series was attributed to the introduction of antihypertensive therapy [1]. A later neuropathology study in lacunar infarcts found only 69 percent of patients with evidence of systemic hypertension and rare cases of classic lipohyalinosis [25], further suggesting that modern antihypertensive therapy may have changed the natural history and/or pathophysiology of lacunes.

●Branch atheromatous disease – Microatheroma of the origin of the penetrating arteries coming off the middle cerebral artery stem, circle of Willis, or distal basilar or vertebral arteries is another mechanism of lacunar infarction, and has been termed branch atheromatous disease [19]. This mechanism has been proven pathologically by serial section for the basilar artery [26]. In a retrospective study, lacunar infarcts in the territory of a single perforating branch artery of the middle cerebral artery (MCA) were found significantly more often in association with atherosclerotic MCA occlusive disease than with internal carotid occlusive disease or cardiac embolism [27]. This observation supports the hypothesis that some lacunar strokes are caused by parent artery (eg, MCA or basilar artery) atheroma that occludes the origin of the penetrating artery [28].

●Embolism – The potential for embolism to cause lacunar infarcts is supported both experimentally [29] and by case reports of lacunes in patients with high-risk cardiac sources for emboli [30] and reports of lacunar infarcts following cardiac and arch angiography [31]. Studies investigating possible stroke mechanisms in lacunar infarcts have found carotid stenosis in 13 to 23 percent [32,33] and cardiac sources in 18 to 24 percent [33,34] of patients with a radiologically-demonstrated lacunes. These rates are much lower than those of patients with cortical infarcts [32,35] and may be similar to asymptomatic elderly populations, making the argument of a causal relationship between the verified sources and the lacunes difficult to prove. It also appears that patients with lacunar infarcts more often have milder degrees of carotid stenosis than those with cortical infarcts [36]. On the other hand, ipsilateral carotid stenosis appears to be more common than contralateral stenosis, which supports a possible causal relationship [37].

In some reports, multiple acute to subacute subcortical or small cortical infarcts have been detected by diffusion-weighted magnetic resonance imaging (DWI), suggesting an embolic source. One study using DWI in patients presenting with a lacunar syndrome found that 16 percent had multiple infarcts detected as DWI-hyperintense lesions, implying that all lesions were acute to subacute (image 1) [38]. This subgroup more frequently harbored a proximal embolic source than patients with single lesions (p <0.05).

●Endothelial dysfunction and disruption of the blood-brain barrier – One alternate explanation is that failure of the arteriolar and capillary endothelium and the blood-brain barrier leads to small vessel disease, lacunar stroke, and white matter lesions [20,39-42]. This failure allows extravasation of blood components into the vessel wall, which results in perivascular edema and damage to the vessel wall, perivascular neurons, and glia [43,44].

This theory remains unconfirmed. One neuropathologic study found no compelling evidence of a specific cerebral endothelial response in patients with small vessel disease [45]. However, a preliminary study using 3 Tesla MRI identified focal clusters, thought to be disorganized small vessels, in the white matter of patients with severe small vessel disease [46]. These clusters were visualized on susceptibility-weighted imaging (SWI), which can identify deoxygenated blood; they corresponded to white matter hyperintensities in various stages of cavity formation seen on fluid-attenuated inversion recovery (FLAIR) MRI. The clusters were associated with the number of lacunes and higher white matter hyperintensity volume. The investigators proposed that the vessel clusters represent dysfunctional and dilated small vessels.

EPIDEMIOLOGY — Lacunar infarcts account for 15 to 26 percent of ischemic stroke [32,47-50]. Like other stroke subtypes, the prevalence of lacunar stroke increases with age.

Limited data suggest that the incidence of lacunar strokes is higher in Black Americans compared with White Americans [49]. No significant differences by sex have been observed [51].

One group estimated that 18 percent of first ischemic strokes in the United States are lacunes [48]. This compares with 16 percent due to large vessel atherosclerosis with stenosis, 26 percent cardioembolic, 3 percent due to an uncommon mechanism, and 37 percent of unknown or no obvious cause.

A population-based study from Japan suggests that the incidence of lacunar stroke has been steadily declining since the 1960s [52]. This finding was attributed to improved control of hypertension and decreased prevalence of smoking during subsequent years.

RISK FACTORS AND ASSOCIATIONS — The main risk factor and mechanism for lacunar stroke is related to a chronic vasculopathy associated with systemic hypertension. (See 'Etiology' above.)

Other possible risk factors for lacunar infarction include diabetes mellitus, smoking, age, and low-density lipoprotein (LDL) cholesterol [53]. Hyperhomocysteinemia has been associated with an increased risk of ischemic stroke and lacunar infarction in several studies [54-56]. (See "Overview of homocysteine".)

Hypertension and diabetes — Hypertension and diabetes mellitus are associated with an increased risk of stroke in general. Whether they are more commonly associated with lacunar stroke and small vessel disease compared with other stroke subtypes (as many believe) is not clear, since the evidence is conflicting [48,57-61]. The answer may depend upon the population studied and the criteria used to define lacunar-type infarction.

One explanation for the difference in lacunar stroke incidence rates between White and Black Americans cited above (see 'Epidemiology' above) is a higher incidence of risk factors such as diabetes and hypertension among Black Americans [49]. In the community-based study of Black Americans in Cincinnati, Ohio, the odds ratios of first-ever lacunar infarct among patients with diabetes or hypertension were 4.4 and 5.0, respectively, compared with nondiabetic and normotensive individuals [49]. The attributable risk (proportion of cases that can be attributed to the risk factor) for these two diseases were 30 and 68 percent, respectively (hypertension has a greater impact than diabetes because of its higher overall prevalence in the population). The rates of hypertension and current smoking were found to be significantly increased in patients with lacunar infarcts compared with other stroke subtypes.

Other studies have also found a difference in the incidence of risk factors between patients with lacunar stroke and those with other stroke subtypes. In the Stroke Data Bank, patients with lacunar stroke had fewer previous transient ischemic attacks (TIAs) and strokes than those with large vessel atherosclerotic infarction and, compared with patients who had cardioembolic strokes, those with lacunar infarcts more frequently had hypertension and diabetes [32].

These findings contrast with some other community-based studies [48,60]. As an example, in the Oxfordshire Community Stroke Project, a study of first-ever stroke, comparison between the risk factor profiles of patients with lacunar infarction and carotid artery distribution infarct involving the cortex found that the two groups did not differ in the prevalence of prestroke hypertension or markers of sustained hypertension, or in the prevalence of other risk factors for ischemic stroke such as diabetes mellitus, previous TIA, cervical bruit, peripheral vascular disease, or cigarette smoking [60]. Similarly, the Rochester, Minnesota study found no greater incidence of diabetes and hypertension among patients with lacunar infarcts and those with other stroke subtypes [48].

Genetic factors — The heritability of small vessel ischemic stroke is estimated to be 16 to 25 percent [62,63]. A 2021 pooled analysis of individual patient data and genome-wide association studies reported 12 loci that were associated with lacunar stroke; five of these loci were directly associated with lacunar stroke, and seven were associated jointly with lacunar stroke and white matter hyperintensities, including two loci (COL4A2 and HTRA1) that are linked to monogenic small vessel stroke [64]. Further study is needed to identify and verify the genetic mechanisms related to lacunar stroke.

Several rare conditions are characterized by hereditary cerebral small vessel arteriopathy [65]:

●Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This is probably the most common monogenic cause of cerebral small vessel disease [51]. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".)

●Familial cerebral amyloid angiopathy (CAA), an important cause of primary lobar intracerebral hemorrhage in older adults, characterized by the deposition of congophilic material in small to medium-sized blood vessels of the brain and leptomeninges. (See "Cerebral amyloid angiopathy".)

●Autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), which is due to pathogenic variants in the TREX1 gene. The major clinical manifestations are retinopathy, focal neurological symptoms including ischemic events, and cognitive impairment. Other symptoms include liver disease, kidney disease, anemia, gastrointestinal bleeding, subclinical hypothyroidism, Raynaud phenomenon, migraine with and without aura, and hypertension. (See "Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)".)

●Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) due to HTRA1 pathogenic variants [66,67]. Several heterozygous HTRA1 pathogenic variants also cause symptomatic small vessel disease, with a milder clinical course compared with CARASIL [68,69].

●Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL), an autosomal dominant, adult-onset disorder caused by a pathogenic variant in the CTSA gene [70].

●Brain small vessel disease with hemorrhage [71-74].

While all of these conditions affect small vessels and may theoretically manifest as a classic lacunar syndrome, CADASIL is most likely to do so. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Ischemic stroke and transient ischemic attacks'.)

CLINICAL FEATURES

Lacunar syndromes — The five classic lacunar syndromes, which may present as transient ischemic attacks (TIAs) in addition to stroke, are named according to their clinical manifestations:

●Pure motor hemiparesis

●Pure sensory stroke

●Ataxic hemiparesis

●Sensorimotor stroke

●Dysarthria-clumsy hand syndrome

Other stroke syndromes that may be related to lacunar infarcts, sometimes referred to as atypical lacunar syndromes, are shown in the table (table 1), but these have not been studied in large clinical series [75].

●Absence of cortical signs – Due to their subcortical location in the brain, lacunar syndromes generally lack cortical symptoms and signs, such as aphasia, hemianopia, agnosia, neglect, or apraxia. Infarcts in several different subcortical locations can cause the clinical manifestations associated with each of these classic lacunar syndromes, as shown in the table (table 2).

●Time course – Penetrating artery occlusions usually cause symptoms that develop over a short period of time, typically minutes to hours (figure 2), in some cases preceded by TIAs with the same symptoms. With lacunar stroke, a stuttering course may ensue, as with large artery thrombosis, and symptoms sometimes evolve over several days. In fact, lacunar infarction is the main ischemic stroke subtype associated with worsening motor deficits after hospital admission [76].

The classic lacunar syndromes are reviewed in the sections that follow. The syndrome of multiple subcortical infarcts is also discussed since interest has arisen regarding whether this entity can cause dementia.

Pure motor hemiparesis — Pure motor hemiparesis is the most frequent syndrome in most clinical series, accounting for 45 to 57 percent of all lacunar syndromes [32,77-80]. It is characterized by weakness involving the face, arm, and leg on one side of the body in the absence of "cortical" signs (aphasia, agnosia, neglect, apraxia, or hemianopsia) or sensory deficit.

The motor deficit may develop as a single event or, less frequently, be preceded by hemiplegic TIAs [1]. A series of the latter cases has been described as the "capsular warning syndrome," which was found to be predictive of an acute internal capsule infarct on head CT [81]. Some of these cases may arise due to penetrating branch ischemia from a diseased parent vessel (middle cerebral artery [MCA] stem or basilar) causing intermittent and fluctuating symptoms.

Pure sensory stroke — Pure sensory stroke is defined as numbness of the face, arm, and leg on one side of the body in the absence of motor deficit or cortical signs [82]. It is found in 7 to 18 percent of lacunar syndromes in case series [32,77,79,80], but its prevalence is probably underestimated because many cases present as TIA and were not included in the series.

Ataxic hemiparesis — Ataxic hemiparesis is responsible for 3 to 18 percent of lacunar syndromes in case series [32,77,79,80,83]. Patients characteristically develop ipsilateral weakness and limb ataxia that is out of proportion to the motor deficit. Some patients may exhibit dysarthria, nystagmus, and gait deviation towards the affected side. As with other lacunar syndromes, the above-mentioned cortical signs are absent.

Sensorimotor stroke — Sensorimotor stroke is characterized by weakness and numbness of the face, arm, and leg on one side of the body in the absence of the aforementioned cortical signs [84]. It is responsible for 15 to 20 percent of lacunar syndromes [32,77,79,80].

Sensorimotor strokes arise from infarcts involving the posterolateral thalamus and posterior limb of the internal capsule. The exact vascular anatomy is debated. Theoretically, penetrating arteries from the posterior cerebral artery (PCA) supply the thalamus and the internal capsule is supplied from the lenticulostriate branches of the MCA. Occlusion of a single penetrating artery involving both arterial territories is difficult to implicate; the site of vascular occlusion was not identified in the original case description [84].

Dysarthria-clumsy hand syndrome — Dysarthria-clumsy hand syndrome is the least common of all lacunar syndromes in most case series, accounting for 2 to 6 percent of lacunar syndromes [32,77,79,80,85]. Facial weakness, dysarthria, dysphagia, and slight weakness and clumsiness of one hand are characteristic. There are no sensory deficits or cortical signs.

Multiple subcortical infarcts and dementia — Patients with arteriolosclerotic cerebral small vessel disease may develop multiple lacunes and/or extensive, confluent white matter lesions. leading to vascular dementia. Vascular dementia is reviewed in detail elsewhere. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

EVALUATION AND DIAGNOSIS — Acute identification of lacunar syndromes is important in choosing among treatment modalities and predicting clinical outcome.

Rapid evaluation — All adult patients with a suspected diagnosis of acute ischemic stroke should be screened for treatment with intravenous thrombolytic therapy. Simultaneously, patients with suspected acute ischemic stroke involving the anterior circulation should be rapidly screened for treatment with mechanical thrombectomy. Urgent neuroimaging is a critical component of the rapid evaluation for reperfusion thrombolysis and mechanical thrombectomy. Vascular imaging (with computed tomography angiography [CTA] or magnetic resonance angiography [MRA]) can be performed at the same time as brain imaging (with CT or MRI) to evaluate patients for these therapies, as discussed in detail separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Rapid evaluation'.)

By definition, patients with confirmed lacunar infarction are not candidates for mechanical thrombectomy since they do not have an amenable large artery occlusion as the cause of the stroke. However, small deep infarcts are not always lacunar infarctions and, therefore, vascular imaging is warranted in the acute setting. Notably, some patients presenting with a small deep infarct have concomitant large artery occlusive disease on imaging; this has been particularly true for patients of Asian origin [86].

Standard evaluation — We perform a standard evaluation of all patients with suspected acute stroke, since a minority of lacunar stroke cases will be associated with a potential cardiac or large artery source of embolism, which may require different management strategies. The standard evaluation (covering anything not already performed as part of a rapid evaluation) includes a complete history and physical examination, brain imaging with CT or MRI to determine the location and topography of the lesion, neurovascular imaging with CTA or MRA to evaluate for large artery source of stroke, and cardiac monitoring and echocardiography to look for potential cardiogenic source of embolism. More extensive investigation of potential embolic sources may be necessary in young patients with no cerebral risk factors.

The evaluation of acute stroke mechanisms is discussed in more detail separately. (See "Initial assessment and management of acute stroke" and "Overview of the evaluation of stroke".)

Clinical diagnosis — The diagnosis of lacunar infarction is suspected in patients who present with a recognized lacunar syndrome (eg, pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, dysarthria-clumsy hand syndrome) or other acute stroke symptoms without cortical involvement (table 2 and table 1). As a general rule, lacunar syndromes lack findings such as aphasia, agnosia, neglect, apraxia, or hemianopsia (so-called "cortical" signs). Monoplegia, stupor, coma, loss of consciousness, and seizures also are typically absent. (See 'Clinical features' above.)

Lacunar syndrome recognition in the hyperacute setting may not reflect a final diagnosis of lacunar infarction. A study of patients admitted within six hours of stroke symptom onset reported only a 30 percent positive predictive value for lacunar infarction by CT scan [87].

Unlike our ability to visualize large vessel occlusion by vascular imaging with conventional angiography and CTA or MRA, there is no clinically available imaging method to visualize small vessel occlusion, as the penetrating vessels responsible for lacunar infarction are not large enough to be seen on angiography. Thus, the radiologic diagnosis of lacunar infarction relies upon finding a small noncortical infarct on CT or MRI whose location is consistent with the clinical lacunar syndrome defined by history and examination. In some cases, neuroimaging may not identify the culprit lacunar infarction, and the diagnosis is made on purely clinical grounds. Confirmation with neuroimaging is desirable, but the sensitivity of CT for acute lacunar infarction is suboptimal, and follow-up imaging with MRI may be needed to determine the presence of lacunar infarction. (See 'Imaging confirmation' below.)

Imaging confirmation — We obtain brain MRI with diffusion-weighted imaging (DWI) and conventional MRI when head CT is nondiagnostic for clinically diagnosed lacunar infarction. For most situations, brain MRI with clinical correlation adequately defines the infarct location and excludes a cortically-based infarct.

Lacunar infarcts have traditionally been described as small (2 to 15 mm in diameter) noncortical lesions. However, some neuroimaging studies in the acute phase (<10 days from stroke onset) have defined the upper size limit for lacunes as 20 mm or even 25 mm on DWI [88,89], since some volume reduction is expected over time [90-92]. As already noted, not all small deep infarcts are lacunar, and the diagnosis of lacunar infarction requires the exclusion of other etiologies of ischemic stroke. (See 'Standard evaluation' above.)

●Computed tomography – Noncontrast head CT is the initial imaging modality for most patients presenting with an acute stroke syndrome. However, in prospective studies, CT has low sensitivity for detecting small acute infarcts such as lacunes (30 to 44 percent) [15,93]. The sensitivity of CT for lacunes in the hyperacute phase (<6 hours) is likely to be even lower [87]. Thus, a lacune seen on CT in this time window is more frequently chronic and not related to the clinical symptoms. CT also is limited in identifying posterior fossa infarcts and in defining the degree of cortical extension in subcortical infarcts.

●Magnetic resonance imaging – Standard brain MRI protocols that include conventional T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), and T2*-weighted gradient-recalled echo (GRE) sequences along with DWI can reliably diagnose both acute ischemic stroke and acute hemorrhagic stroke in emergency settings.

•Conventional MRI – On conventional MRI, lacunar infarcts typically are visualized as focal lesions characterized by decreased T1-weighted and increased T2-weighted signal intensity (image 1). Conventional MRI has a higher sensitivity and specificity than CT [93,94], and is better for defining the exact anatomical localization of acute infarcts. In one study, for example, MRI detected lacunar infarcts in 19 of 22 patients with compatible symptoms, compared with 11 found by CT [94]. A second report confirmed that MRI was superior to CT for detecting lacunes; the sensitivity of MRI was greatest for patients who presented with pure motor hemiparesis, detecting 85 percent of lesions [93]. MRI usually shows infarcts within eight hours of symptom onset.

•DWI – Diffusion-weighted imaging (DWI) is a fast MRI technique that demonstrates a hyperintense signal whenever there is an area of restricted water diffusion, as occurs during acute ischemia. DWI has the advantages of a higher sensitivity for acute lesions than T2-weighted MRI or FLAIR, ability to differentiate between acute and chronic lacunar infarcts, and ability to identify multiple acute infarcts potentially linked to embolic sources [38,95,96]. In one study, 25 percent of DWI-hyperintense lacunar infarcts were either not seen or mistakenly called "chronic" on T2 or FLAIR imaging [96]. This finding suggests that patients require DWI to define the clinically appropriate infarct when multiple subcortical infarcts of various ages are present (image 1). (See "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'.)

The size of acute lacunar infarction is overestimated on DWI by approximately 40 percent when compared with final infarct size at 30 days or more after stroke onset on conventional MRI (T2 or FLAIR sequences) and CT [90].

●Correlation of clinical lacunar syndromes with imaging findings – Of the 20 lacunar syndromes described, the five classic syndromes have been validated as being predictive for the presence of lacunar infarction on brain imaging:

•Pure motor hemiparesis (see 'Pure motor hemiparesis' above)

•Pure sensory stroke (see 'Pure sensory stroke' above)

•Ataxic hemiparesis (see 'Ataxic hemiparesis' above)

•Sensorimotor stroke (see 'Sensorimotor stroke' above)

•Dysarthria-clumsy hand syndrome (see 'Dysarthria-clumsy hand syndrome' above)

Predicted infarct locations in relation to clinical manifestations are shown in the table (table 2).

Earlier retrospective studies, mainly based on CT, found that the presence of these syndromes (as a group) had a positive predictive value as high as 87 to 90 percent for detecting a radiological lacune [77,97], although some clinical syndromes were more predictive than others [98-102]. Preceding TIAs and nonsudden onset increased the positive predictive value for these lacunar syndromes in another report [103].

●Clinical presentation does not always predict actual stroke type – Patients with lacunar syndromes identified clinically are sometimes found to have an acute nonlacunar infarct by imaging. In one report of 478 patients with lacunar syndromes nonlacunar infarcts were the cause in 21 percent [104]. Another study evaluated 73 patients presenting with lacunar syndromes; all underwent DWI as well as extensive neurovascular and cardiac evaluations for potential embolic sources [105]. DWI radiologic patterns suggestive of nonlacunar infarction (mainly embolism) were seen in a total of 30 patients (41 percent); of these, 16 had one large or multiple acute lesions within a single vascular territory, and another 14 had multiple infarcts in different vascular territories [105]. Patients with more than one infarct on DWI were significantly more likely to have a clinically proven embolic source, although no embolic source was found in nine patients with a DWI pattern suggestive of a nonlacunar/embolic stroke mechanism.

Conversely, brain imaging may identify acute lacunar infarcts that were not classified as lacunar syndromes on initial clinical evaluation [88]. In addition, the false negative rate with CT scan (ie, acute lacunar syndrome but no acute stroke on CT) ranges from 35 to 50 percent [87,106,107].

An inherent difficulty of both CT and conventional MRI, but not DWI, is the ability to differentiate between acute and chronic lesions. In one study, 16 percent of patients presenting with a lacunar syndrome had at least two lesions on conventional MRI that correlated with clinical symptoms [15]. Furthermore, in patients presenting with a lacunar syndrome, multiple chronic subcortical lesions are not rare, occurring in approximately 42 to 75 percent of cases [5,93]. For these reasons, knowledge of possible lesion locations based upon neurologic findings is necessary before implicating a particular lesion found on head CT or conventional MRI as responsible for the clinical symptoms (table 2).

Other studies — Genetic screening for pathogenic variants in NOTCH3 is appropriate if there is suspicion for CADASIL, as suggested by a family history of stroke and dementia, absence of hypertension or known vascular risk factors, and clinical features including TIA and ischemic stroke predominately involving small vessels, cognitive deficits with early executive dysfunction, migraine with aura, neuropsychiatric disturbances, and brain MRI with white matter hyperintensities on T2 imaging in the anterior temporal lobes and external capsule. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".)

ACUTE TREATMENT — All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. Screening patients with acute stroke for reperfusion therapies begins immediately upon presentation, even before the diagnosis is confirmed. (See 'Rapid evaluation' above.)

Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications, antiplatelet agents should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete.

●Reperfusion therapy – Randomized controlled trials have shown that intravenous alteplase (recombinant tissue-type plasminogen activator or tPA) improves functional outcome from ischemic stroke and that benefits outweigh the risks for eligible patients who receive treatment within 4.5 hours of symptom onset (or within 4.5 hours of when the patient was last seen normal in cases when onset time is unknown). Intravenous thrombolysis may also be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion MRI but no corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR) MRI. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.)

Most clinical trials investigating stroke treatment and prevention have failed to adequately study the lacunar infarct subpopulation. Nevertheless, subgroup analysis of trial data suggest that the benefit with thrombolysis is sustained in patients with lacunar stroke [108]. However, stroke subtype was classified mainly by clinical impression in the thrombolysis trials since vascular studies usually were not performed before treatment initiation. Thus, some patients with a large vessel or cardioembolic stroke mechanism (eg, those with proximal middle cerebral artery occlusion, good leptomeningeal collaterals, and recanalization after thrombolysis) may have been incorrectly classified as having a small vessel etiology. Nonetheless, until better data are available, we recommend that patients with lacunar syndromes be selected for thrombolysis according to current guidelines in the same way as patients with other subtypes of ischemic stroke (table 3). (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".)

Thrombolytic therapy is associated with a 6 percent risk of symptomatic brain hemorrhage. This treatment option should be discussed with the patient and family in each individual case.

●Antiplatelet therapy – Most patients with acute ischemic stroke should be treated with early antiplatelet therapy, and short-term dual antiplatelet therapy may be appropriate for select patients with high-risk TIA or minor ischemic stroke. This topic is discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

SECONDARY PREVENTION — Most patients with ischemic stroke or transient ischemic attack (TIA) should be treated with intensive medical intervention and risk factor management, including blood pressure control, antiplatelet and statin therapy, and lifestyle modification. These interventions for secondary prevention apply both to patients who present with stroke or TIA and to patients who have no history of symptomatic stroke but have imaging evidence of lacunar infarction (ie, silent stroke). However, the risk/benefit of antiplatelet therapy has not been adequately studied for patients with silent lacunar infarcts. (See "Overview of secondary prevention of ischemic stroke".)

●After the acute phase of stroke (when permissive hypertension is often employed) antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for prevention of recurrent stroke and other vascular events. In addition, antihypertensive therapy should be started in previously untreated, neurologically stable patients with any type of stroke or TIA who have an established blood pressure that is above goal. (See "Antihypertensive therapy for secondary stroke prevention".)

●Beyond the acute phase of TIA and ischemic stroke (ie, >21 days), and in the absence of an indication for oral anticoagulation, long-term single-agent antiplatelet therapy for secondary stroke prevention should be continued with aspirin, clopidogrel, or aspirin-extended-release dipyridamole. Long-term dual antiplatelet therapy with aspirin and clopidogrel is not recommended. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●Patients with ischemic stroke, all of whom are at high risk for recurrent cerebrovascular and cardiovascular events, should receive high-intensity statin therapy. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●Recommended lifestyle modifications to reduce the risk of stroke include smoking cessation, limited alcohol consumption, weight control, regular aerobic physical activity, salt restriction, and a Mediterranean diet. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.)

The efficacy of aspirin and other antiplatelet agents for preventing second strokes and mortality has been illustrated for patients with noncardioembolic ischemic stroke in general (see "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke"). A 2015 meta-analysis identified two trials that evaluated antiplatelets versus placebo and reported outcomes in the subgroup of patients with lacunar stroke; in the pooled analysis, treatment with any single antiplatelet agent was associated with a significant reduction in ischemic stroke recurrence (relative risk 0.48, 95% CI 0.30-0.78) [109].

Despite early enthusiasm, results from the SPS3 trial suggest that the long-term use of combined antiplatelet therapy with aspirin plus clopidogrel is harmful for patients with lacunar stroke because it leads to an increased risk of hemorrhage and death but does not reduce the risk of recurrent stroke [110]. Therefore, it should not be employed for secondary prevention in this population in the absence of proven indications. The use of aspirin plus clopidogrel for prevention of different subtypes of ischemic stroke is discussed separately in detail. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin plus clopidogrel'.)

PROGNOSIS

●Short-term outcomes – Lacunar infarcts have a better short-term prognosis than infarcts due to other stroke mechanisms, at least up to one year after onset. As examples, 91 percent of patients with lacunar stroke from the placebo arm of a controlled clinical trial had a favorable outcome at three months, as defined by moderate to good recovery on the Glasgow Outcome Scale [111]. This contrasts with strokes due to large vessel atherosclerosis; only 55 percent of these patients had a favorable outcome at three months. In a later prospective study of 1425 ischemic stroke survivors, patients with lacunar stroke (n = 234) were more likely to have further neurologic improvement between three months and one year compared with patients with nonlacunar stroke [112].

●Long-term outcomes – The long-term prognosis after lacunar stroke may not differ greatly from nonlacunar stroke. This observation comes from a systematic review of 19 cohort studies involving 2402 patients with lacunar and 3462 patients with nonlacunar ischemic stroke [23]. The odds of death were significantly greater following nonlacunar than lacunar infarction at one month, 1 to 12 months, and one to five years (odds ratio [OR] 3.81, 2.32 and 1.77, respectively), although the difference gradually decreased. However, the odds of recurrent stroke were significantly greater for nonlacunar infarction only at one month (OR 2.11), and the difference in stroke recurrence between nonlacunar and lacunar groups was nonsignificant at 1 to 12 months and one to five years.

Analogous findings were reported in a population-based study from Italy [47]. Patients with lacunar stroke (n = 491) had better five-year survival than patients with nonlacunar stroke (n = 2153), mainly due to lower mortality within the first year of follow-up for the lacunar stroke group. The lacunar group also had a lower average annual stroke recurrence rate within the first year. However, stroke recurrence and mortality rates were similar in the two groups from the second year through study completion at five years.

●Outcome predictors – Among patients with recent lacunar stroke, factors associated with an increased risk of ischemic stroke recurrence include a prior lacunar stroke or transient ischemic attack (TIA), diabetes, being from a Black population, and male sex [113]. In addition, the risk of stroke recurrence is increased in the presence of cerebral microbleeds [114].

Patients with lacunar infarction and more severe initial motor deficits have worse functional outcome [108,115]. What is not known is whether patients with a lacunar infarct due to embolism or large vessel atherosclerosis obstructing the ostium of a penetrator branch have a different prognosis and response to therapy. As long as this question remains, investigation of the operating stroke mechanism remains important. (See 'Etiology' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

SUMMARY AND RECOMMENDATIONS

●Description and location – Lacunar infarcts are small (0.2 to 15 mm in diameter) noncortical infarcts caused by occlusion of a single penetrating branch of a large cerebral artery. These branches arise at acute angles from the large arteries of the circle of Willis, stem of the middle cerebral artery, and the basilar artery (figure 1). Most lacunes occur in the basal ganglia (putamen, globus pallidus, caudate), thalamus, subcortical white matter (internal capsule and corona radiata), and pons. (See 'Introduction and definition' above and 'History' above and 'Vascular anatomy' above.)

●Etiology – Several mechanisms for occlusion of small penetrator branches have been described (see 'Etiology' above):

•Hypertensive microangiopathy

•Branch atheromatous disease

•Embolism from cardiac or large artery sources

•Endothelial dysfunction and associated blood-brain barrier disruption

●Epidemiology – Lacunes account for 15 to 26 percent of ischemic strokes. (See 'Epidemiology' above.)

●Risk factors – The main risk factor and mechanism for lacunar stroke is related to a chronic vasculopathy associated with systemic hypertension. Other likely risk factors include diabetes mellitus and possibly smoking. (See 'Risk factors and associations' above.)

●Clinical features

•Lacunar syndromes – More than 20 lacunar syndromes have been described. The five classic lacunar syndromes (table 2), which may present as transient ischemic attacks (TIAs) in addition to stroke, are named according to their clinical features:

-Pure motor hemiparesis (see 'Pure motor hemiparesis' above)

-Pure sensory stroke (see 'Pure sensory stroke' above)

-Ataxic hemiparesis (see 'Ataxic hemiparesis' above)

-Sensorimotor stroke (see 'Sensorimotor stroke' above)

-Dysarthria-clumsy hand syndrome (see 'Dysarthria-clumsy hand syndrome' above)

A large number of atypical lacunar syndromes are also recognized (table 1).

•Absence of cortical signs – As a general rule, lacunar syndromes lack findings such as aphasia, agnosia, neglect, apraxia, or hemianopsia (so-called "cortical" signs). Monoplegia, stupor, coma, loss of consciousness, and seizures also are typically absent. (See 'Clinical features' above.)

●Acute stroke evaluation – All patients presenting with acute ischemic stroke, including those with suspected lacunar stroke, should be screened for treatment with intravenous thrombolysis and mechanical thrombectomy and be evaluated with a standard stroke evaluation that includes brain and neurovascular imaging, cardiac monitoring, and echocardiography. (See 'Rapid evaluation' above and 'Standard evaluation' above.)

●Diagnosis – Lacunar infarction is suspected in patients who present with a recognized lacunar syndrome (eg, pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, dysarthria-clumsy hand syndrome) or other acute stroke symptoms without cortical involvement. The radiologic diagnosis of lacunar infarction relies upon finding a small noncortical infarct on CT or MRI whose location is consistent with the clinical lacunar syndrome defined by history and examination (image 1). We obtain brain MRI with diffusion-weighted imaging (DWI) and conventional MRI when head CT is nondiagnostic for clinically diagnosed lacunar infarction. (See 'Clinical diagnosis' above and 'Imaging confirmation' above.)

●Acute treatment – Intravenous thrombolysis improves outcomes for eligible patients with ischemic stroke. Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See 'Acute treatment' above.)

●Secondary prevention – For secondary prevention, most patients with ischemic stroke or TIA should be treated with intensive medical intervention and risk factor management, including blood pressure control, antiplatelet and statin therapy, and lifestyle modification. (See 'Secondary prevention' above.)

●Prognosis – Lacunar infarcts usually have a better short-term prognosis than infarcts due to other stroke mechanisms, at least up to one year after onset. However, the long-term prognosis after lacunar stroke may not differ greatly from nonlacunar stroke. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J Philip Kistler, MD, who contributed to an earlier version of this topic review.