Clinical manifestations

Presentation and course

Clinically, a lacunar infarct presents abruptly within 3 hours stepwise in one third of stroke patients; gradually over 2 to 3 (up to 6) days in one third; and is preceded by a transient ischemic attack within 24 hours in one third (24). Transient ischemic attacks preceding a lacunar infarct tend to be stereotypic and to occur in the days immediately prior to the stroke. Many lacunar infarcts are clinically silent (or covert), and more than 80% of silent or covert brain infarctions are lacunar infarcts (83).

Because of their small size, lacunar infarcts tend to cause restricted neurologic signs, which have been categorized into “lacunar” syndromes. There are five “classical” lacunar syndromes (See Table 1) and at least 70 other (miscellaneous) clinical lacunar syndromes (See Table 2) (58; 01). A small proportion of lacunar infarctions can present with an atypical lacunar syndrome, most frequently with isolated dysarthria or dysarthria facial paresis (05). Lacunar syndromes can be produced by nonlacunar infarctions (eg, from large artery disease or cardioembolism) or occasionally by nonvascular lesions (eg, secondary to a tumor or multiple sclerosis). In a patient presenting with a lacunar syndrome, one cannot assume the presence of a lacunar infarct, and it is important to establish the underlying pathogenesis by investigation.

Pure motor stroke is the most frequent lacunar syndrome. The hemiparesis may be complete with face, arm, and leg equally involved, or there may be a partial brachiocrural motor deficit, isolated central facial palsy, or isolated monoplegia. Twenty-eight percent of cases with pure motor stroke have an associated dysarthria. Eighty-five percent of pure motor strokes are caused by a lacunar infarct and by other stroke subtypes in 15% of cases. The second most frequent lacunar syndrome is sensorimotor stroke. This can be classified into four types according to the nature and the extent of the sensory loss: (1) all sensory modalities affected, (2) only nociceptive deficits present, (3) only proprioceptive deficits present, and (4) only one limb involved. Each of these types can be qualified into two groups: (A) submaximal motor or sensory deficit and (B) total paralysis or total sensory loss in at least one limb. Pure sensory stroke may involve nociceptive deficits, proprioceptive deficits, or both. The deficit may involve face, arm, and leg (83%) (cheiro-oral-pedal syndrome, 88% of which are caused by a lacunar infarct); face and arm (7%) (cheiro-oral syndrome, 35% caused by lacunar infarct); or arm and leg (8%). Partial pure sensory deficits include an isolated oral sensory loss and restricted acral sensory loss. Fractional anisotropy maps can make a more accurate diagnosis of lacunar infarction subtype. Sensorimotor syndromes are mostly caused by thalamic lacunes (50%), whereas pure motor hemiparesis is caused by lacunar infarctions in the internal capsule and corona radiata (91%) or basal ganglia (83%) (34). The clinical features and pathogenesis of pure midbrain infarctions was described showing isolated anterior internuclear ophthalmoplegia with paramedian area involvement (95). Of 4257 stroke registry patients between January 2000 and December 2015, 25 patients demonstrated pure midbrain infarctions. In those with lacunar stroke involving the paramedian area, 6 of 8 patients had diabetes mellitus, and five of these diabetic patients presented with internuclear ophthalmoplegia, demonstrating that internuclear ophthalmoplegia should be considered as a manifestation of lacunar stroke, especially in the setting of diabetes.

Due to associated cerebral small vessel disease, lacunar infarcts are no less likely to affect cognition than large cortical infarcts. A meta-analysis involving more than 7000 patients with different stroke subtypes comparing the prevalence of dementia and minimal cognitive impairment reported similar rates after lacunar (638/2222 [29%]) and nonlacunar infarcts (1001/4256 [24%]) (46). Cognitive impairment associated with lacunar infarcts is less selective than previously thought, affecting all major cognitive domains: executive function, memory, language, attention, visuospatial abilities, and global cognition (21). Lacunar infarcts may cause dementia in different ways. At one end of the spectrum is the classical lacunar state with multiple small deep infarcts and traditional clinical findings: (1) pseudobulbar syndrome (dysarthria, dysphagia, and emotional lability); (2) small stepped gait (marche á petit pas); (3) parkinsonian-like rigidity; (4) hyperreflexia; (5) Babinski sign; (6) dementia, gait imbalance, and urinary incontinence; (7) variable motor and sensory focal signs.

At the other end of the spectrum is a single strategically located lacunar infarct, causing persistent cognitive deficits. Lacunar infarcts in several locations can impair cognition: paramedian thalamic, anterior thalamic, and genu of the internal capsule. Lacunar infarcts in the internal capsule, corona radiata, putamen, or caudate nuclei can also cause subtle cognitive impairments or emotional disturbances. Secondary neurodegeneration, a focal cortical thinning in remote areas connected by fiber tracts to the lacunar infarction, has been demonstrated in a series of 32 patients that underwent multimodal brain MRI imaging (20). Dementia in patients with lacunar infarction often represents a combination of lacunes with diffuse cerebral small vessel disease. These patients tend to have frontal signs on clinical examination. Cerebral blood flow and cerebral vessel reactivity may be significantly decreased in patients with multiple lacunar infarctions and leukoaraiosis, causing cognitive impairment not related to the extent of tissue loss or anatomical location of lesions. With this mechanism in mind, the LACI-1 trial, a phase IIa dose-escalation trial, tested the tolerability, safety, and efficacy of isosorbide mononitrate and cilostazol in the secondary prevention of lacunar infarcts and cognitive decline related to small vessel disease (10). The drugs have been shown to have promising mechanisms of action to support their testing in the prevention of stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke, and this trial demonstrated their tolerability and safety with dose escalation. A larger follow-up trial is underway (87). The DISCOVERY (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY) study is currently ongoing to investigate the clinical factors, blood-based biomarkers, and neuroimaging markers that may predict the occurrence of cognitive impairment and dementia after stroke, including after lacunar infarction (64).

Table 1. Classical Lacunar Syndromes

Table 2. Miscellaneous Lacunar Syndromes

Prognosis and complications

Lacunes have some of the lowest mortality and recurrence rates as well as the best recovery and functional outcome of all strokes. However, the concept that lacunar strokes represent benign lesions is contradicted by studies of mortality, recurrent stroke, and functional outcomes. In a review of 24 studies involving 2863 patients, case fatality at 30 days was 2.5%, at 1 year was 2.8%, and at 5 years was up to 27.4% (51). The rate of loss of living independently was 42% at 3 years. A population-based study involving 442 patients showed that the recurrence rate of lacunes increases from 1.4% in the first month to 7% at 1 year and 25% after 5 years, whereas in atherothrombotic stroke the recurrence rate is 18.5% in the first month and goes as high as 40% after 5 years (56). Although in the first year the recurrence rate for lacunar infarctions is lower than in nonlacunar strokes, from the second year it becomes similar to the recurrence of other stroke subtypes (65). Similarly, differences between survival after lacunar versus non-lacunar stroke were attenuated after the first year in a hospital-based cohort study of 812 patients (57). In a contemporary clinical trial of secondary prevention after lacunar stroke (Secondary Prevention of Small Subcortical Stroke trial [SPS3]), overall mortality is much lower than previous population-based estimates, 1.78% per year, which is likely due to the younger age of trial participants, a population meeting trial inclusion criteria, and aggressive risk factor management (71). More than 80% of patients with lacunar infarction have minimal or no disability after stroke. A good premorbid functional status and lacunar stroke subtype are predictors for a good outcome (56; 31), whereas the severity of motor deficit is highly predictive of a poor outcome (68). Some authors consider that leukoaraiosis and nondipping nocturnal hypertension are independent predictors for subsequent dementia, whereas diabetes, multiple lacunes, and high 24 hour-systolic hypertension are independent predictors for recurrent strokes (92). Symptomatic lacunes accompanied by multiple silent lacunes, hypertension, and arteriolosclerosis confer a much poorer prognosis than solitary symptomatic lesions associated with microatheroma (18). A trial involving 1331 participants with prior lacunar stroke determined that those at higher baseline systolic blood pressure and systolic blood pressure variability were at a higher risk for adverse outcomes. Those with mildly elevated baseline systolic blood pressure and minimal visit-to-visit blood pressure variability were shown to have less risk of adverse outcomes (43). Overall, though lacunar infarction is thought to have a good prognosis compared to other stroke types, the risk factors that cause lacunar stroke are also associated with atherosclerotic disease in other organs. At 10 years after a lacunar infarction, less than a third of patients are free of recurrent stroke, cognitive impairment, or functional disability (52).

Biological basis

Etiology and pathogenesis

Lacunar infarction is caused by occlusion of individual small vessels that are, on average, 400 micrometers in size. Because these small vessels have no collateral circulation, the resulting infarct affects the entire territory of the occluded vessel (86).

There are a variety of etiologies for lacunar infarction, each with their own pathophysiology. There is overlap, however, in the risk factors that contribute to these different mechanisms. The primary mechanisms for lacunar infarction include lipohyalinosis, atherosclerotic disease, arterial stiffness/arteriosclerosis, and, rarely, embolism.

Lipohyalinosis

Pathophysiology. Lipohyalinosis was one of the first identified mechanisms of lacunar infarction (22). It is characterized by a focal, destructive angiopathy involving vessels smaller than 200 microns. The arterial wall is disorganized and replaced by connective tissue and fatty macrophages; this results in occlusion of the arterial lumen (23).

Risk factors. There are several risk factors for lipohyalinosis.

Hypertension. In Fisher’s original work, the majority of patients (111/114) examined at autopsy had a clinical history of hypertension, thereby identifying this risk factor as a primary etiology of lacunar infarcts (22). Besides the absolute level of blood pressure, important risk factors include persistent nighttime hypertension, high pulse pressure, and abnormal circadian variation, such as a higher magnitude of nocturnal systolic and diastolic blood pressure dip (14).

Diabetes mellitus. Diabetes mellitus is present in 2% to 37% of patients with lacunes, and lacunar infarctions are more common in diabetics than in nondiabetics (35.1% vs. 23.9%) (06). Excessive glycation and oxidation, endothelial dysfunction, increased platelet aggregation, and impaired fibrinolysis appear to underlie the pathogenesis of diabetes-related stroke. Insulin resistance was found to be an independent risk factor for cerebral small vessel disease (94). This can be estimated by the Homeostatic Model for Insulin Resistance (HOMA-IR) score, which has population-dependent cutoff values (26). In a post hoc analysis of the SPS3 trial, diabetes was found to independently double the risk of recurrent lacunar stroke, and diabetics tended to have higher rates of intracranial atherosclerosis (54).

Chronic kidney disease. Chronic kidney disease with poor glomerular filtration rate may associate glomerular and cerebral small vessel disease due to similarities of the two vascular beds (33). By causing endothelial dysfunction, chronic renal disease can independently increase the risk of lacunar infarcts, even in individuals without hypertension or diabetes (84). Kidney dysfunction was found to be an independent risk factor for the presence and number of silent lacunar infarctions in generally healthy adults (37).

Hyperlipidemia. Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of cerebrovascular disease. Increased apolipoprotein B and apolipoprotein A are considered risk factors for lacunes. A Chinese study showed that an increased plasma level of lipoprotein(a) causes a 2.05-fold increased risk for lacunar infarction (77). Serum saturated fatty acids may increase the risk for lacunes, whereas serum linoleic acid appears to be protective. In Japanese individuals, a linear and independent association between plasma levels of homocysteine and lacunes was observed. Homocysteine may be a stronger predictor for diffuse white matter disease than an isolated lacune, acting via endothelial dysfunction (32).

A Japan Public Health Center–based prospective study looking into the association of high-density lipoprotein cholesterol concentration with different types of stroke identified 1712 stroke events over a median 15-year follow-up (66). A low high-density lipoprotein cholesterol concentration slightly raised the risk for total strokes in men but not in women. An inverse relationship between high-density lipoprotein cholesterol concentration and the incidence of lacunar infarction was also demonstrated. Conclusions of the study brought forth likely associations of high-density lipoprotein cholesterol concentration with lacunar infarction as being related to different functional properties of high-density lipoprotein rather than to its protective function against lipid-rich atherosclerosis.

Other established risk factors. Other established risk factors for lipohyalinosis and lacunar infarction include age, excess body weight, ischemic heart disease, transient ischemic attacks, and cigarette smoking.

Arterial stiffness/arteriosclerosis

Pathophysiology. Another proposed mechanism for lacunar infarction is a loss of cerebrovascular reactivity in the setting of increased arterial rigidity. In lacunar stroke patients with neuropathology at autopsy, cases have shown thickening of the media and deposition of fibrinoid material in the vessel wall (12). These pathologic changes lead to alterations within the endothelium of the vessel to the point that cerebral autoregulation is impaired, and these small vessels are no longer able to appropriately dilate to maintain perfusion (62). Augmentation index measured by applanation tonometry at the radial artery has been found to be significantly increased in patients with lacunar infarcts when compared with patients with other stroke subtypes, suggesting that aortic arterial stiffness is increased in patients with lacunar stroke and may be related to the pathogenesis (11). Impaired cerebrovascular reactivity may reflect diffusely increased arteriosclerosis and rigidity of the vascular wall (48). Thus, cerebral blood flow is not maintained when a drop in systolic blood pressure occurs, which can contribute to the development of white matter disease (53).

Risk factors. Risk factors for arterial stiffness are similar to those for lipohyalinosis. Hypertension is an especially important risk factor for arterial stiffness and arteriosclerosis.

Atherosclerotic disease

Pathophysiology. Another known mechanism for lacunar infarction is intracranial branch occlusive (or atheromatous) disease. Instead of disease of the small penetrating arteries, this refers to atherosclerotic disease of the parent artery, which can obstruct the ostium of the small perforators, thus, leading to lacunar infarction (12). The degree of intracranial stenosis caused by atheromatous disease does not need to be severe in order to obstruct flow to small penetrating branches, particularly in the posterior circulation (91). Atheromatous disease of larger arteries can often be visualized with CT angiogram or MR angiogram and is an important part of the stroke work-up (12). Branch atheromatous disease has a poorer prognosis than lacunar infarcts and clinically presents more frequently as a progressive stroke (worsening of the NIHSS score with > 2 points within 48 hours of onset), even if the parent artery has less than 50% stenosis (93). The most common risk factors are poorly controlled diabetes and dyslipidemia (49).

Risk factors. Diabetics tend to have more intracranial atherosclerotic disease (54). Hyperlipidemia and smoking are also major contributors to intracranial atherosclerosis that can lead to lacunar infarction, in addition to the risk factors listed in the previous sections.

Embolic disease

Pathophysiology. Though less common, embolic sources should be considered in the differential for the etiology of lacunar stroke. This is particularly true when subcortical infarcts are larger than the typical 15 mm that defines a lacune. One study suggests that up to 25% of patients with lacunar disease have evidence of large artery occlusion and perfusion deficit. Many of these patients present clinically with lacunar syndromes and subcortical infarcts, though they may have had an embolic stroke mechanism (78). The location of the infarct can help to determine the mechanism: infarcts in the centrum semiovale, which is supplied by pial branches of the middle cerebral artery (called also medullary arteries), may be more susceptible to embolic pathology.

Risk factors. Cardioembolism, most commonly from atrial fibrillation, is a mechanism that should be considered. Atrial fibrillation is more frequent in patients older than 85 years of age with lacunar infarcts than in patients younger than 85 (28.2% vs. 8.7%). It is possible that in this age group, cardioembolic pathogenesis of lacunes is more important than originally thought. Large artery atheroembolism is another consideration, both from intracranial or extracranial sources, including carotid or vertebral disease as well as aortic arch atheroma. A higher prevalence of thoracic aorta atherosclerosis has been found in patients with lacunar infarction (67). Isolated carotid stenosis has also been more frequently associated with multiple, ipsilateral lacunar infarctions, particularly when the stenosis is greater than or equal to 75% (50).

Genetics

The pathogenesis of lacunar infarction, and of cerebrovascular disease in general, results from a combination of genetics and environmental and lifestyle risk factors. Family history of stroke is a moderate risk factor for stroke in cohort studies. In the Framingham Heart Study, parental history of stroke is associated with a category of stroke called atherosclerotic brain infarction, which includes the subtypes of lacunar infarction and large-artery atherosclerosis (70). Although lacunar stroke is typically the result of a complex pattern of inheritance, some rare, monogenic Mendelian disorders are associated with lacunar infarction, particularly disorders of the small arteries of the brain (Table 3). Lacunar infarction may be an expression of hereditary forms of cerebral small vessel disease, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or small vessel disease associated with mutations of the COL4A1 and COL4A2 genes. CADASIL is caused by a genetic mutation of the NOTCH3 gene, with inheritance linked to chromosome 19p13.1, and is the most common monogenic form of cerebral small vessel disease (1 per 20,000) (47). Additionally, NOTCH3 variants in the general population appear to be more common than expected, with 1 per 450 participants in the UK Biobank (N=200,632) carrying cysteine-altering variants of NOTCH3 (16). The COL4A2 gene was found to be associated with lacunar ischemic stroke in a meta-analysis among 21,500 cases and 40,600 controls (61). Other monogenic disorders causing stroke also develop small artery disease that may manifest as lacunar infarction, including sickle cell disease, Fabry disease, hyperhomocysteinemia, neurofibromatosis 1, and pseudoxanthoma elasticum. Research has only identified a small proportion of the genes associated with non-Mendelian inheritance that contributes to the risk of lacunar infarction. Genome-wide association studies (GWAS) have unraveled the genetic underpinnings of stroke (ischemic or hemorrhagic); however, only 56 loci have been associated with any stroke or specific subtypes of stroke to date (19). This contrasts with the estimate that up to 24% of brain imaging–defined small vessel stroke may be heritable (81). Genetic variants associated with vascular risk factors (eg, hypertension) may contribute to the genetic underpinnings of lacunar infarction, whereas other genes or proteins, such as APOE, may help to determine the resilience of the brain to vascular injury. Individual loci that have been identified to alter the risk of lacunar infarction have only small effects on risk.

Table 3. Mendelian Disorders Associated with Lacunar Infarction

Epidemiology

In the white population, lacunar infarction has an age- and sex-adjusted incidence comparable with the incidence of large vessel atherosclerotic stroke (ie, 25 out of 100,000 and 27 out of 100,000 persons respectively), with no significant sex-related differences (55). In patients older than 85 years the incidence is higher in women (56.4%) than in men (37.3%) (04). Lacunar infarctions are the most common type of stroke in the Japanese population, with an incidence almost double in men (3.8 out of 1000 persons-years) than in women (2.0 out of 1000 persons-years) (79). In Western countries, lacunes account for 15% to 20% of all strokes, whereas in Japan they represent 30% to 40% of all strokes (92). The Northern Manhattan Stroke Study reported that lacunar infarcts were the second most prevalent ischemic stroke subtype in their population (second to cardioembolic stroke), affecting non-Hispanic Black and Hispanic individuals more than non-Hispanic White individuals. This ethnic disparity was true in most stroke subtypes and thought to be due to an increased burden of vascular risk factors in the Black and Hispanic population (25). The African-American population of the metropolitan area of Cincinnati, Ohio, has a higher lacunar stroke incidence of 52 out of 100,000, compared to the White population with 29 out of 100,000 (90). The TOAST (Trial of Org 10172 in Acute Stroke Treatment) trial also reported a higher incidence of lacunar infarction in the African-American population, with poorer prognosis (31). A study of a multiethnic stroke population reported the highest prevalence of lacunar infarcts in Caribbean Blacks (44%), primarily associated with hypertension (41). Smoking and dyslipidemia were more frequent in African-American and Caribbean-Hispanic participants, resulting in a similar prevalence of lacunar infarcts (25% and 22%, respectively), whereas only 7% of non-Hispanic whites were found to have lacunar infarcts. In a large multiethnic cohort of patients with recent lacunar infarcts, MRI analysis demonstrated distinct imaging patterns associated with sex, vascular risk factors, race, and ethnicity. Multiple lacunar infarcts were associated with increased age (1.2 per 20 years, 95% CI 1.1, 1.5) and prior stroke (3.8 per 20 years; 95% CI 2.9, 5.0). Moderate-to-severe white matter hyperintensities were associated with increased age (4.3 per 20 years, 95% CI 3.4, 5.4), hypertension (1.8 per 20 mmHg, 95% CI 1.4, 2.3), and prior stroke (3.3 per 20 mmHg, 95% CI 2.3, 4.5). Black and Hispanic individuals had more infarcts in the brainstem/cerebellum (P < 0.001) than non-Hispanic white individuals, and women often had more thalamic lacunes than men (P < 0.001) (09).

Prevention

Although the management of hypertension is the single most important preventive strategy for lacunar infarctions, optimal primary prevention involves the management of all modifiable risk factors for atherosclerosis and ischemic stroke:

(1) Hypertension control. The SPRINT trial randomized patients with hypertension to intensive (goal systolic < 120) or to standard (goal systolic < 140) treatment (73). Primary outcome was a composite of myocardial infarction, stroke, heart failure, other acute coronary syndrome, or death from other cardiovascular disease. Intensive management was found to lower rates of cardiovascular events. Professional guidelines have endorsed a treatment target of less than 130/80 for the primary prevention of cardiovascular disease (07). Guidelines suggest the use of an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or thiazide diuretic to reach this goal (40).

(2) Smoking cessation. Cigarette smoking is associated with lacunar infarction more frequently than with other types of stroke (65). In a meta-analysis of smoking cessation trials, a multimodal approach including behavioral therapy and pharmacologic interventions was found to be most beneficial to patients (75). It is crucial to engage patients in methods for smoking cessation, both as part of primary prevention and secondary prevention after an infarct.

(3) Glycemic control is recommended to reduce microvascular complications and prevent the development of cerebral small vessel disease. The American Diabetes Association recommends a target HbA1c of less than 7% in most adult patients. Stroke prevention guidelines suggest a multidimensional approach to glycemic control, including diet and lifestyle counseling as well as medications. Specifically, in patients with cardiovascular risk factors, including prior stroke, the use of GLP-1 receptor agonists is recommended. In patients with renal dysfunction or heart failure, the use of sodium glucose cotransporter 2 (SGLT2) inhibitors is recommended (40).

(4) Patients with elevated cholesterol and elevated risk for heart disease should receive treatment with statins, in addition to lifestyle modification (07).

(5) Other modifiable risk factors: obesity, physical inactivity, alcohol abuse, hyperhomocysteinemia, and substance use disorders (28). Visceral adipose tissue has been associated with cerebral small vessel disease and lacunar infarcts. Visceral obesity is a potential therapeutic target for the prevention of cerebral small vessel disease (38). Other modifiable risk factors include vitamin deficiency. In 2015, the China Stroke Primary Prevention Trial (CSPPT) involved over 20,000 participants followed for 5 years and showed a significant reduction of stroke with folic acid administration in a setting where folate fortification was not previously implemented (72). In the setting of folate fortification, the main causes of elevated total homocysteine are renal failure and metabolic B12 deficiency.

Differential diagnosis

Lacunar syndromes may be caused by a variety of pathologies, such as neurocysticercosis, tumors, demyelinating lesions, and small hemorrhages. Large cerebral infarcts are differentiated from lacunar infarcts using the neurologic exam and neuroimaging. A pure motor monoparesis or a hemiparesis associated with “cortical” signs such as aphasia suggest a nonlacunar infarct. Restricted acral sensory syndromes or pseudothalamic sensory strokes can result from minor parietal strokes. A report details the case of a patient with ataxic hemiparesis resulting from acute infarction associated with localized lesions of the postcentral gyrus (39). A lacunar infarct must be differentiated from a deep cerebral watershed infarct. Deep watershed “low flow” infarcts tend to present with a combination of a lacunar syndrome and a “cortical” sign. Confluent low-flow white matter infarcts are larger than lacunar infarcts and have a worse prognosis (22). Symptomatic small centrum semiovale infarcts may be caused by large-vessel occlusive disease or cardioembolism and should be distinguished from lacunes and leukoaraiosis. The presence of retinal microangiopathy on retinography, white matter disease on MRI, and increased carotid pulsatility index on ultrasound is a marker of lacunar infarcts not secondary to macrovascular lesion (63). Diffusion-weighted MRI is more sensitive than other MRI sequences or CT in detecting them. Multiple diffusion-weighted imaging hyperintense lesions raise the possibility of an embolic mechanism rather than microvascular disease (08). A diffusion-weighted/perfusion-weighted imaging mismatch reliably distinguishes between a single perforating vessel occlusion and a large artery embolism for solitary small subcortical infarctions (27). Multiple acute ischemic lesions in different vascular territories might not always be of proximal cardiovascular embolic origin. Simultaneous small subcortical ischemic lesions may reflect remote ischemia due to small vessel disease reflecting simultaneous hemorheological dysfunction (89).

Diagnostic workup

CT or MRI of the brain, including ultrasound, CT angiography, or MR angiography imaging of the extracranial and intracranial large arteries, is necessary to rule out non-lacunar pathology. The diagnostic workup should be performed emergently in acute stroke, particularly if there is any sign of clinical progression or fluctuation. CT is less sensitive than MRI for smaller lacunes in the brainstem and thalamus. In acute settings, MRI-DWI sequence overestimates the final infarct size. One third of lacunar infarcts will not result in a cavity (42). The carotid arteries should be evaluated following a lacunar stroke with Doppler ultrasonography, CT angiogram, or MR angiogram. Cervical carotid arteries with moderate or greater stenosis ipsilateral to the side of infarct should be considered for carotid endarterectomy or stenting. Transcranial Doppler ultrasonography is an alternative, noninvasive method of detecting intracranial vascular stenoses. Clinical findings should be used to indicate the need for other tests. A review of 214 patients indicated that although transesophageal echocardiography has a well-established value in the investigation of the stroke mechanism, evidence suggests that the combination of a small subcortical infarction with a typical lacunar syndrome has a 100% negative predictive value for a cardioembolic source (60).

Management

Acute management

Acute lacunar infarcts seen within 4.5 hours of onset and presenting with disabling symptoms should be considered for intravenous thrombolysis (ie, tissue-type plasminogen activator [alteplase] or tenecteplase). Intravenous thrombolysis is the only treatment for lacunar infarction proven to improve clinical outcome. Lacunar strokes showed the most favorable outcome following intravenous thrombolysis (80), with the lowest rate of post-thrombolysis hemorrhagic transformation. Imaging identifies the lacunar infarct prior to thrombolysis better than the identification of a clinical lacunar syndrome (44). Between 24% and 37% of lacunar strokes progress and have a fluctuating course of motor deficit for the first 24 hours and up to 72 hours or 1 week. Multiple mechanisms have been considered responsible for progression: the inflammatory response, glutamate excitotoxicity, stepwise occlusion of the small penetrators (76), and severe hypoperfusion of the ischemic area with distal embolization (13). The only treatment proven to be effective in progressing lacunar stroke is augmentation of cerebral blood flow. Blood pressure should not be lowered, and volume expanders or pressor medication can be used, if necessary. Hyperglycemia has a detrimental effect on nonlacunar stroke outcome, but a moderate hyperglycemia (8-12 mmol/L) seems to be beneficial in lacunar infarct. A higher blood pressure during the first 24 hours after the occurrence of an acute lacunar infarct carries a better neurologic outcome (69). Although hyperglycemia is associated with worsened outcome in acute ischemic stroke, the impact may not be similar in lacunar versus non-lacunar infarct. Hyperglycemia has a detrimental effect on non-lacunar stroke outcome, but a moderate hyperglycemia (8-12 mmol/L) seems to be beneficial in lacunar infarct. This beneficial effect diminishes with severe hyperglycemia with more than 12 mmol/L (82).

Antiplatelets and neuroprotectants have limited utility as long as perfusion failure persists (13). Anticoagulation may not stop stroke progression, and, in addition, it may increase the already existing risk for cerebral hemorrhage. The T2-weighted gradient-echo MRI is sensitive in detecting hemosiderin resulting from cerebral microbleeds. One study showed an increased incidence of silent microbleeds in patients with Binswanger disease (77%) and multiple lacunar infarctions (51%), indicating an advanced bleeding-prone cerebral microangiopathy (30). This finding has important implications in clinical management. Rehabilitation, prevention, and treatment of medical complications are important measures.

Secondary prevention

A large part of secondary prevention in lacunar infarction is related to risk factor optimization. The section on Prevention includes more detail on overall risk factor management. An optimal blood pressure goal has been studied in various trials. In 2014, the SPS3 trial randomized patients with lacunar infarction to target blood pressure goals of less than 130 and 130 to 150 (74). There was a reduction in stroke recurrence in patients with a lower target blood pressure goal; however, the result was not statistically significant. The American Heart Association guideline as of 2017 defined stage 1 hypertension as less than 130/80, which should be the threshold for treatment in most stroke patients (88).

The Insulin Resistance Intervention after Stroke (IRIS) trial showed that pioglitazone could reduce the incidence of stroke recurrence among persons with insulin resistance, but the intervention was associated with a high frequency of weight gain, bone fractures, and edema (36). Thus, pioglitazone is not regularly used in clinical practice for secondary prevention.

A lipid panel should be checked as a part of the stroke work up. Patients with a target LDL cholesterol of less than 70 mg/dL were found to have a lower risk of subsequent cardiovascular events when compared to patients with a goal of less than 110 mg/dL (03). Independent of lipid-lowering properties, statins may have other vascular effects: improved endothelial function, plaque stabilization, and antithrombotic and neuroprotective properties. Antithrombotic therapy is another important aspect of secondary stroke prevention. Determining appropriate antithrombotic therapy for lacunar infarcts depends on the etiology. For lacunar infarcts thought to be due to lipohyalinosis, antithrombotic therapy typically includes a single antiplatelet agent.

Aspirin (160 or 325 mg) reduces the risk of early recurrent ischemic stroke (absolute risk reduction = 0.7%) (17). Aspirin in a dose as low as 30 mg daily, dipyridamole, and the combination of extended-release dipyridamole with aspirin are available measures for the secondary prevention of lacunar infarcts (02). Clopidogrel and ticlopidine are alternatives for patients who are intolerant to aspirin. In patients with minor stroke (NIHSS < 5) or classified as a high-risk transient ischemic attack (ABCD2 ≥4), there is a benefit of short-term dual antiplatelet therapy (DAPT) with aspirin and clopidogrel (or ticagrelor as an alternative) for 21 days followed by single antiplatelet therapy (85; 35). DAPT could also be considered for lacunar infarcts due to large artery atherosclerosis of a parent artery, occluding penetrator arteries. In this case, patients could be treated with DAPT for 90 days per the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Arterial Stenosis) trial, which compared DAPT to intracranial stenting in patients with intracranial atherosclerosis greater than 70% to 99% (15). It is important to note, however, that this trial did not compare DAPT to single antiplatelet therapy for stroke prevention in intracranial atherosclerotic disease, and more data are needed to answer this question.

Finally, for the smaller percentage of lacunar infarcts that are due to atrial fibrillation, patients should receive anticoagulation for secondary stroke prevention. Novel oral anticoagulants (NOACs) or warfarin can be used; however, data support the use of NOACs, especially apixaban, for stroke prevention with lower bleeding risk (29).

Special considerations

Pregnancy

Cerebrovascular disorders other than eclampsia include uncommon and unpredictable complications of pregnancy and puerperium associated with serious maternal morbidity and mortality. Venous infarctions, large arterial strokes (secondary to cardiac emboli, coagulopathies, and vascular dissection), and intracranial hemorrhages account for most cerebrovascular complications, but lacunar infarctions can occur. Experts recommend that pregnant women with acute ischemic stroke not be systematically denied the potential benefits of intravenous recombinant tissue plasminogen activator (45).