Lacunar Stroke

Etiology

Ischemic strokes are due to the occlusion of vascular supply to a specific part of the brain, leading to tissue hypoxia and damage. In lacunar infarction, the small penetrating cerebral vessels supplying the subcortical areas are occluded due to various vascular pathologies, including lipohyalinosis and microatheromas.[4] In some cases, small embolic fragments from a cardiac source or large vessel disease can cause deep penetrating artery occlusion. In other cases, large vessel disease causing blockage of the origin of the small perforating artery causes ischemia.[6][7][8] 

The development of small vessel disease, causing a lacunar stroke, is mainly due to underlying medical conditions such as hypertension and diabetes mellitus. Other risk factors include smoking, LDL levels, carotid artery atherosclerosis, peripheral artery disease, previous TIA, and hyperhomocysteinemia.[4] Genetic factors also increase the risk of developing small vessel disease, leading to lacunar infarcts. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare genetic disorder that can cause small vessel arteriopathy. Caused by mutations in the NOTCH3 gene on chromosome 19, CADASIL is the most common inherited cause of stroke and dementia in adults.[9] While clinical presentations vary, the most common symptoms and signs, starting around the third or fourth decade of life, include the following: recurrent ischemic strokes, transient ischemic attacks, progressive white matter degeneration, memory loss, migraine with aura, debilitating dementia, and multiple psychiatric symptoms.[10] A pathognomic feature of CADASIL is granular osmophilic material found near blood vessels and can be seen on skin biopsy under electron microscopy. The result is degeneration of blood vessels, and the disease is incurable and fatal. Characteristic magnetic resonance imaging features are white matter hyperintensities in the anterior temporal lobes, external capsules, and superior frontal gyri.[9] Other less common genes associated with cerebral small vessel disease are HTRA1, TREX1, GLA, COL4A1, COL4A2, FOXC1, and PITX2. The ApoE4 gene may also confer increased susceptibility to cerebral small vessel disease, in addition to being a risk factor for Alzheimer disease.[26]

Epidemiology

Globally, stroke accounts for about 12% of deaths, or 3.29 million individuals in 2019. Disability-adjusted life years are estimated at 63.49 million years. The lifetime risk of stroke for an individual older than 25 years is 25%, and for ischemic stroke, the risk is 18%.[11] In a community-based study, the incidence rate of lacunar infarct in a predominantly White community was 29 per 100,000 population, while in another community-based research with a mostly Black population, the incidence rate of lacunar infarct was 52 per 100,000 people.[12][13] The overall incidence of lacunar stroke is estimated at 25 to 50 per 100,000 people.[14] In a follow-up study, patients with lacunar infarcts are diagnosed with dementia 4 to 12 times more frequently than the average population.[15] Lacunar stroke at an older age is associated with worse long-term disability.[16]

Pathophysiology

Cerebral circulation is dependent on the internal carotid and vertebral arteries, which form the circle of Willis.[17] The main cerebral branches include the middle cerebral artery, anterior cerebral artery, posterior cerebral artery, and basilar artery, which supply the cerebrum, cerebellum, and brainstem. These arteries have deep branches that penetrate and feed deep gray and white matter of the cerebrum, cerebellum, and brainstem.[17]

Occlusion or blockage of the small penetrating arteries, which typically have a diameter of 40 to 900 μm, causes small lacunar strokes. Their size varies from 3 mm to 20 mm in dimension as acute infarcts may be slightly larger than the resulting lacunes due to edema.[4] Surprisingly, one large study found that infarct size and small vessel lesion characteristics did not impact whether a lesion was symptomatic or asymptomatic.[18] Small arterial occlusion is the fundamental pathogenesis for lacunar strokes. The primary underlying pathophysiological processes are lipohyalinosis and microatheroma formation.[19] In lipohyalinosis, the media of small vessels thickens, followed by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements. This results in the characteristic fibrinoid wall necrosis and segmental artery disorganization. This disorganization causes a significant reduction in the luminal diameter of small arteries and causes hypoperfusion to subcortical areas. They tend to be more distal towards the termination of the small penetrating arteries.[4]

Microatheromas are atheromatous arterial lesions within the brain parenchyma. They cause occlusion or stenosis of deep penetrating brain arteries. Histologically, a microatheroma is identical to a large-vessel atheroma. Microatheromas have the subintimal deposition of lipids and proliferation of fibroblasts, smooth muscle cells, and lipid-laden macrophages. Microatheromas are generally located in the proximal region near the origin of the parent artery in the wider part of the small arteries.[19]

More recent studies have elucidated the role of endothelial cell dysfunction and blood-brain barrier disruption. Aging, oxidative stress, underlying genetics, and hypertension can cause endothelial cell inflammation; this leads to connective tissue replacing normal blood vessel tissue, causing luminal narrowing, thrombosis, and occlusion.[4] Other studies have shown that increased blood-brain barrier permeability is associated with increased lacunar stroke risk and poor functional outcomes.[5] 

Deep penetrating branch occlusion via direct emboli or thrombus from a cardiac or large artery source can also cause a lacunar stroke. One prospective study found that 11% of patients diagnosed with a lacunar stroke had a potential embolic source.[20] Other rare postulated reasons for small cerebral infarcts include embolism, vasculitis, infections, and vasospasm, which are not proven by autopsy. Autopsy studies are often inconclusive as they are frequently performed many years after the ischemic event, during which the vasculature and anatomic findings may have changed. One study performed magnetic resonance imaging 1 year after minor strokes and found 37% of patients had regression of white matter hyperintensity, which could represent decreased small vessel disease. The decrease correlated with blood pressure decrease.[21]

Histopathology

A lacune is generally identified on autopsy as a fluid-filled cavity that marks the healed stage of small infarcted brain tissue. There are 3 types of lacunes, as described per histopathology. Type 1 is classified as an ischemic infarct, type 2 is an old hemorrhage, and type 3 includes dilated perivascular space.[18] In the 1960s, neurologist Charles Miller Fisher performed autopsy studies on patients and noted specific pathological changes associated with lacunar infarcts. It showed a characteristic histopathological finding of segmental arterial disorganization, fibrinoid degeneration, segmental arteriolar disorganization, and vessel enlargement with hemorrhage.[4][22] He termed this change "lipohyalinosis"; this results in the loss of normal arterial architecture accompanied by mural foam cells and fibrinoid necrotic changes in vessel walls.[23] The other characteristic pathological change in the small penetrating arteries causing lacunar infarcts is "microatheroma." Histologically, a microatheroma is like a large-vessel atheromatous plaque involving the subintimal deposition of lipids, the proliferation of fibroblasts and smooth muscles, and the presence of lipid-laden macrophages.[22]

History and Physical

As with ischemic strokes, lacunar infarcts usually present with sudden onset neurological deficits. However, a subset of lacunar infarctions may present in a stepwise pattern and worsen during admission. These are called stuttering lacunar infarcts. Lacunar infarcts are common in the subcortical deep brain structures, including the thalamus, basal ganglia, pons, and white matter of the internal capsule. Lacunar infarcts can be asymptomatic and are noted on imaging as incidental findings. 

Clinical presentation depends on the area of brain involvement. Lacunar infarcts in the centrum semiovale may present without symptoms and can be found incidentally on brain imaging for some other cause. However, certain lacunar infarcts, like in the posterior limb of the internal capsule or the pons, can present with severe hemiplegia. Cortical findings, including neglect, visual disturbances, aphasia, and behavioral changes, are typically and uniformly absent in the clinical presentation of lacunar stroke as they occur in subcortical areas of the brain.

Lacunar strokes seldom affect memory, language, and judgment. There are about 20 different types of lacunar syndromes described in the literature. The most common lacunar syndromes include:

• Pure motor hemiparesis: Pure motor hemiparesis involves the posterior limb of the internal capsule, corona radiate, or ventral pons. This type presents with contralateral hemiparesis of the face, arm, and leg. Mild dysarthria may be present with the absence of sensory symptoms. This is the most common presentation, accounting for 45% of cases of lacunar strokes. Cortical signs like aphasia, cognitive deficit, or visual symptoms are always absent. Pure motor stroke can be a combination of weakness in the arm, leg, or face on one side or any of these parts alone.
• Ataxic-hemiparesis: Ataxic-hemiparesis comprises 10% to 18% of cases and involves the internal capsule, pons, or corona radiata. This type of lacunar stroke causes hemiparesis of the contralateral face and leg and ataxia of the contralateral limb. Ataxia is the prominent feature of this stroke, in addition to milder hemiparesis.
• Pure sensory: Pure sensory stroke involves the thalamus; it presents with the impaired or abnormal sensation of the contralateral of the face, arm, and leg. It accounts for 7% of cases of lacunar strokes. The sensations affected are pain, temperature, touch, pressure, vision, hearing, and taste. A common form of thalamic lacunar stroke is known as poststroke thalamic pain (ie, Dejerine-Roussy syndrome). This is a syndrome of spontaneous neuropathic pain, often involving allodynia and hyperalgesia, after a thalamic lacunar infarct with pure sensory hemianesthesia.[24]
• Dysarthria-clumsy hand: This syndrome involves the pons or internal capsule. Dysarthria-clumsy hand syndrome presents with dysarthria and problems pronouncing words due to voice box muscle weakness, including tongue, larynx, and other facial muscle weakness. Contralateral clumsiness of the upper extremity is present with preserved motor strength. Difficulty with subtle fine movements (eg, writing or tying a shoelace) may be present.
• Sensory-motor: A sensory-motor stroke involves the thalamus, internal capsule, or putamen-capsule-caudate and presents clinically with a combination of contralateral sensory and motor loss. Sensory-motor lacunar strokes are the second most common type of lacunar strokes. They account for 20% of cases.[25][26][27]

Most penetrating branches arise from the middle cerebral artery; the intracranial non-stenotic atheroma in the large vessel may cause a lacunar stroke by blocking the penetrating branch artery at its takeoff point.[28] These infarcts are generally more extensive than the typical lacunar infarcts and are called striatocapsular infarcts. Neurological fluctuation and deterioration are common features of subcortical strokes. More than 40% with subcortical infarct deteriorate neurologically within the first week of onset of stroke symptoms. One-third of the deteriorated patients reverse spontaneously. The rest suffer a physical disability.[29] Lacunar strokes are a common cause of vascular dementia and mild cognitive impairment, often overlooked in clinical practice. Multiple silent lacunar strokes are documented on brain magnetic resonance imaging, with patients presenting with mild cognitive impairment and early dementia.[30]

Evaluation

The STRIVE criteria (Standards for Reporting Vascular Changes on Neuroimaging) is a consensus guideline for cerebral small vessel disease using criteria including recent small subcortical infarcts, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy based on imaging studies for disease classification.[31] 

Transcranial Doppler

This safe, noninvasive study can show important information about structural, functional, and hemodynamic characteristics, including blood flow velocity and pulsatility index of cerebral blood vessels. A higher pulsatility index is associated with increased vascular resistance, ie, increased small vessel disease and acute infarct size. Transcranial dopplers can also measure cerebral autoregulation, usually decreased in a stroke setting.[26]

Computed Tomography

The sudden onset of a neurological deficit requires emergent neuroimaging. An initial noncontrast head computed tomography (CT) scan is preferred in an acute setting as it is readily available, quick, and valuable to rule out life-threatening conditions such as intracerebral bleeding or herniation and to clear the patient for possible intervention. CT scans seldom identify lacunar ischemic infarcts within the first 24 hours due to their small size. If seen, lacunar strokes present as ill-defined hypodensities unless there is a hemorrhagic component to the acute stroke. A hyperdensity in a large artery on non-contrast head CT indicates the presence of a thrombus inside the arterial lumen or vessel calcification. Early infarct signs on non-contrast CT include loss of gray-white differentiation and focal hypoattenuation of brain parenchyma. These details are difficult to read in small subcortical strokes. Chronic lesions may appear as hypodense foci.[4]

A CT angiogram of the head and neck can also be performed. This may show a filling defect consistent with a thrombus blocking a specified vessel. A CT angiogram may also show arterial narrowing and extensive chronic vessel disease, like in the carotid arteries, which may be a source of an embolus, or it may show middle cerebral artery features consistent with an atheroma. Neurovascular imaging modalities are essential to locate the presence of large artery occlusion as they help determine the need for catheter-guided thrombolysis. In general, large-vessel strokes are more likely to benefit from thrombectomy than lacunar infarcts.[4] CT perfusion studies also can demonstrate an infarcted core indicating irreversible ischemia and penumbra or reversible ischemia. This modality can also be used to evaluate patients for possible thrombectomy, as lacunar strokes are usually not appropriate for thrombectomy.[32]

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is a superior imaging modality in acute and subacute settings to detect lacunar infarctions. In the acute stage, the MRI diffusion-weighted image (DWI) has the highest sensitivity, as it will be positive within half an hour of stroke onset and will remain positive for about 7 days. MRI-DWI helps to differentiate between acute and chronic infarctions.[33] In an acute setting, on T1-weighted images, lacunes appear as focal areas of decreased signal intensity and as focal areas of hyperintensity on T2-weighted images. Chronic lesions are isointense to cerebral spinal fluid on all sequences. MRI can detect lesions as small as 0.2 mm, which a CT scan cannot detect. Recent advances in high-resolution MRI can also image cerebral perforating arteries for the first time, as well as their velocity and pulsatility index.[33][34]

Additional Diagnostic Studies

A carotid ultrasound can help diagnose an atherosclerotic narrowing of the extracranial carotid artery when a neck angiogram is not performed. The risk of stroke is higher in patients with severe carotid artery stenosis. Depending on clinical symptoms, significant stenosis can be between 50% and 99%. See StatPearls' companion article "Carotid Stenosis" for further information on carotid imaging.[35] Extensive embolic workup, including echocardiography and vascular imaging evaluation, has a very low yield in cases of lacunar strokes.[36] However, this may be necessary in some cases, like in young patients with no apparent medical issues.

Other immediate tests to be performed include blood glucose levels, electrocardiogram, complete blood count including platelets, troponin, prothrombin time, international normalized ratio (INR), activated partial thromboplastin time, complete metabolic panel, lipid panel, hemoglobin A1c, and toxicology screen. These tests are helpful in the assessment of underlying stroke risk factors.

Treatment / Management

Lacunar Stroke Management

Treatment principles for acute lacunar stroke are similar to any acute ischemic stroke. The initial goal of acute-stage treatment is to ensure medical stability and determine candidacy for thrombolysis. Tissue plasminogen activator (tPA) improves outcomes for patients with ischemic stroke if administered within 4.5 hours of symptom onset. Once intracerebral bleeding is ruled out, intravenous thrombolysis is an important step in acute treatment.[34][37][38] The goal blood pressure before administering tPA is <185/110 mm Hg; after administering, the goal is <180/105 mm Hg.[39] Thrombectomy was previously restricted to patients presenting within 6 hours of neurologic deficit onset. However, more recent trials, including the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) and DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trials showed benefit when the treatment window was extended to 16 to 24 hours.[32][40] If symptom onset duration is >4.5 hours and there is suspicion of an intracranial arterial occlusion in the anterior circulation, computed tomography angiography and magnetic resonance angiography are useful for selecting candidates for mechanical thrombectomy between 6 to 24 hours from when they were last known to be unaffected. Heparin has been studied in acute lacunar stroke and was found to confer no benefit but increase the bleeding risk.(B2)

Management of a patient who presents with acute lacunar infarct out of the tPA window consistent with a noncardioembolic stroke includes dual antiplatelet therapy with aspirin and clopidogrel within 24 hours of symptom onset and continued for 21 days. Dual antiplatelet therapy in the acute phase effectively lowers recurrent ischemic stroke for 90 days from symptom onset. This is supported by the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trials. These studies were performed on patients with all types of ischemic stroke but supported for use in lacunar strokes in subgroup analysis. Antiplatelet therapy should be delayed for 24 hours in patients who received tPA.[34] Patients with stuttering lacunar infarcts may also benefit from intravenous tPA.

The Secondary Study of Small Subcortical Strokes studied over 3,000 patients with lacunar strokes demonstrated by MRI. This study evaluated blood pressure goals, finding that a systolic blood pressure goal of <130 mm Hg significantly reduced the incidence of hemorrhagic stroke.[41] This study also evaluated using clopidogrel and aspirin versus aspirin alone in the same population. Findings were adding clopidogrel to aspirin alone did not reduce recurrent stroke risk but did increase the risk of death and significant bleeding.[42](A1)

Management of hypertension includes allowing for permissive hypertension and cerebral autoregulation unless the blood pressure is markedly elevated to >220/120 mm Hg; in this case, blood pressure should be lowered by 15% during the first 24 hours, and outpatient antihypertensive medications should be held unless other comorbid conditions require the immediate lowering of blood pressure.[34] Blood sugar management is done to maintain euglycemia with recommended blood glucose levels at 60 to 180 mg/dL. Both hypoglycemia and hyperglycemia should be monitored and corrected. The recommended hemoglobin A1c goal is 6.5 to 7. The Insulin Resistance Intervention after Stroke Trial (IRIS) followed 3,000 patients with insulin-resistant diabetes who were treated with pioglitazone. After 5 years, patients in the treatment group had lower blood sugars, as well as decreased rates of stroke and myocardial infarction compared to placebo.[34] The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study investigated using high-dose statins to prevent stroke recurrence. Over 4,000 patients with a recent transient ischemic attack or stroke but without known coronary artery disease were randomized to high-dose atorvastatin or placebo. The risk of stroke or cardiovascular event was significantly decreased in the statin group but was associated with a slight increase in intracranial hemorrhage.[43] (A1)

Stroke Prevention

Primary and secondary stroke prevention remains an essential part of the treatment plan. Primary prevention includes the prevention of the first episode of stroke, and secondary prevention consists of the prevention of recurrence. Primary stroke prevention measures include risk factor management that uses antihypertensive medications, diabetes control, cholesterol-lowering agents, smoking cessation, dietary intervention, weight loss, and exercise. Secondary prevention comprises antithrombotic agents like aspirin, clopidogrel, extended-release dipyridamole, and ticlopidine and managing underlying risk factors. Antiplatelet agents reduce the risk of recurrence in patients with lacunar strokes.[44] Blood pressure control, diabetes control, lipid management, smoking cessation, weight loss, and regular exercise are included in secondary prevention strategies. Blood pressure reduction at a systolic blood pressure target of <130 mm Hg is beneficial.[41](A1)

Long-term dual antiplatelet therapy (ie, clopidogrel and aspirin) for secondary prevention has not shown a further reduction in the risk of recurrence in lacunar stroke.[42] Secondary stroke prevention is an essential strategy, preventing as many as 80% of all recurrent strokes.[45] Oral anticoagulants are not considered for small cerebral vessel disease-related stroke prevention, including recurrent lacunar infarcts, as they disproportionately increase intracranial cerebral hemorrhage risk.[46] Physical therapy and rehabilitation are essential steps for managing patients who suffer lacunar strokes that cause physical disability. These patients require rehabilitation. The goal of rehabilitation is to optimize functional recovery after a stroke, increase independence, and maintain quality of life.(A1)

Differential Diagnosis

Many physiologic states mimic the presentation of stroke. The differential diagnoses of lacunar infarcts include the following:

• Large vessel ischemic stroke in the middle cerebral artery territory is clinically differentiated from lacunar strokes by the presence of cortical signs, including altered mental status, aphasia, and hemineglect.
• Intracranial hemorrhages can usually be seen on neuroimaging modalities like brain CT scans.
• Seizures are caused by excess neuronal activity and can be differentiated clinically by their tonic-clonic activity, resolution of symptoms post-seizure, and postictal state.
• Complicated migraine symptoms are usually accompanied by headache and aura. A typical aura may involve visual disturbances, sensory symptoms, motor weakness, or speech disturbances.
• Brain tumors are distinguished by their characteristic appearance on MRI.
• Multiple sclerosis (MS) can cause paroxysmal attacks of ataxia and dysarthria. MRI helps distinguish the presence of plaques due to MS from a stroke. Further cerebral vasoreactivity measured by transcranial Doppler (TCD) sonography can be used for differentiating ischemic and demyelinating lesions. The presence of oligoclonal bands on lumbar puncture is characteristic of multiple sclerosis.
• Hypoglycemia can mimic stroke symptoms with decreased consciousness and even focal deficits. A blood sugar fingerstick should always be checked upon presentation.
• Transient global amnesia can present with selective amnesia without focal neurologic deficits. Symptoms usually resolve within 24 hours and are not associated with imaging abnormalities. Please see our companion StatPearls article, "Transient Global Amnesia."[47]

Prognosis

Earlier studies suggested that lacunar stroke has a better prognosis compared to other strokes. It has a high survival rate, a low recurrence rate, and a relatively good functional recovery. In general, lacunar infarcts have a relatively favorable prognosis.[48] Still, long-term prognosis with lacunar stroke constitutes an increased risk of death, mainly from cardiovascular causes. The risk of stroke recurrence is similar to any other type of stroke. Patients with recurrent small vessel disease are at increased risk of developing cognitive decline and dementia.[49][50]

Complications

Lacunar strokes are thought to be the leading cause of vascular dementia and cognitive impairment.[49] Accumulated lacunar infarcts can lead to other disease-related complications due to physical disability, including, but not limited to, aspiration pneumonia, deep vein thrombosis, pulmonary embolism, urinary tract infection, depression, and decubitus ulcers.