Stroke Snapshot: Cerebral Microinfarcts—Etiology and Clinical Implications of This Novel MRI Marker

Cerebral microinfarcts (CMIs) are, as the name implies, microscopic brain lesions of ischemic origin.¹ Because they are not visible to the naked eye, CMIs have been called “invisible lesions.” CMIs were initially only visible upon postmortem histopathologic examination, where they were found in abundance in the brains of individuals with vascular dementia or stroke. This fueled interest into the potential role of CMIs as a biomarker of stroke or vascular cognitive impairment. With the development of high-field-strength and diffusion-weighted MRI (DWI), characteristics of CMIs in vivo could be explored.² From these relatively recent studies, it emerged that CMIs are linked to multiple cerebrovascular disorders, including cerebral small vessel disease (cSVD) (arteriolosclerosis and cerebral amyloid angiopathy [CAA]), microemboli, and cerebral hypoperfusion. CMIs are of potential interest to the stroke neurologist, because several studies have confirmed an association of CMIs with cognitive decline and poor clinical outcome, including recurring ischemia.

Definition and Detection Modalities

CMIs can be detected by 3 modalities: postmortem histopathologic examination, structural high-field-strength (3T or 7T) MRI, or DWI. These modalities differ with regards to the proposed size (microscopic or larger), spatial resolution (whole brain coverage or selected brain regions), and temporal resolution (acute or chronic ischemic phase).^1,3 See the Table for a schematic overview and the Figure for examples of microinfarcts using these 3 modalities.

Histopathologic Evaluation

On histopathologic evaluation, CMIs as small as 50 µm can be detected in both the cortex and subcortical brain regions. Both acute CMIs (ie, displaying histopathologic characteristics of recent infarction, including tissue pallor with evidence of eosinophilic necrosis or “red” neurons) and chronic CMIs (ie, cell loss with cavitation or “puckering”) can be detected.⁴ This method does not indicate complete brain burden; it only provides an indication of CMI presence in a limited number of brain regions.

Structural High-Field-Strength MRI

Structural high-field-strength MRI allows for detection of CMIs between 0.5 and 4 mm. CMIs can also be found in the acute (within hours on T2-weighted images, within days on T1-weighted images) or chronic stage with structural high-field-strength MRI. CMIs are hypointense on T1-weighted images; hyperintense on T2-weighted images; and hyperintense, isointense, or cavitated on fluid-attenuated inversion recovery images.^1,3 Thus far, CMIs are defined to be strictly cortical, because it is otherwise difficult to distinguish them from subcortical lesions, such as white matter hyperintensities, lacunar infarcts, and enlarged perivascular spaces.^1,5

Diffusion-Weighted Imaging

DWI can detect CMIs up to 5 mm, but solely in the acute phase (ie, <2 weeks of onset).¹ CMIs appear as hyperintense small subcortical lesions with a corresponding hypointense or isointense signal on apparent diffusion coefficient maps. This technique allows for detection of both cortical and subcortical infarcts. In the recent Standards for Reporting Vascular Changes on Neuroimaging 2 (STRIVE-2) criteria, the recommended term for these infarcts is “incidental DWI-positive lesions”.³ Recently, serial DWI found that none of these “acute CMIs” were retraceable on follow-up imaging as chronic CMIs.⁶ CMIs differ between these modalities to such an extent that they cannot be readily compared, and whether they are to be classified as a single lesion type at all is uncertain. Each modality provides a different perspective on CMI etiology and prognosis.

Etiology and Risk Factors

Although CMIs have been frequently related to common vascular risk factors, studies across different populations (eg, individuals with different types of cerebrovascular disease or cognitive dysfunction) and different CMI detection modalities have yielded varying results. On the whole, hypertension, hypercholesterolemia, obesity, and diabetes seem to recur as significant risk factors for the development of CMIs.^7-9

Whereas CMIs were initially considered to be an exclusive manifestation of cSVD, a growing body of literature suggests that there are multiple etiologies of CMI. Neuropathologic studies have shown that CMIs are prevalent in individuals with cSVD (ie, arteriolosclerosis and CAA) and that more severe cSVD is associated with higher occurrence and higher number of CMI.^10-12 MRI studies found that CMIs frequently occur in individuals with CAA with or without lobar intracerebral hemorrhage, with proportions ranging from 40% to 60%.^13,14 In a small cohort of individuals with spontaneous intracerebral hemorrhage, CMIs were found in up to 75%.¹⁵ The ischemic tissue damage of CMIs might be caused by the direct lumen narrowing or cerebral blood flow regulation impairment caused by both CAA and arteriolosclerosis.¹⁴ Perforating end arteries likely involved in CMIs are presumably more vulnerable to ischemic injury due to decreased vascular reactivity.^16,17 Furthermore, both arteriolosclerosis and CAA can cause a cascade of pathologic changes, resulting in leakage of the blood–brain barrier, inflammation, oxidative stress, vascular remodeling, and a hypercoagulable state with CMIs.^4,12

As is the case with large vessel infarctions, CMIs can be caused by microemboli. Research across different populations suggests that emboli formation attributable to atherosclerosis can arise both from intracranial stenosis¹⁸ as well as extracranial carotid stenosis.⁷ Moreover, several studies are strongly suggestive of CMIs caused by cardiac embolic sources. For example, occurrence of CMIs in individuals with heart failure was more than twice as high as in a reference group (17% vs 7%).⁸ CMIs were also related to atrial fibrillation in people who had had a stroke¹⁹ or invasive cardiac procedures, such as percutaneous transluminal coronary angioplasty.⁸

Both neuropathologic and MRI studies suggested a predilection of CMIs for the cortical watershed areas, leading to the notion that hypoperfusion might play a role in the pathophysiology of CMIs. Using an MRI technique called arterial spin labeling, a noninvasive means of measuring cerebral perfusion, CMI occurrence was related to reduced global or whole-brain hypoperfusion rather than hypoperfusion directly surrounding the CMI or the watershed areas.²⁰ A remaining question is whether there is a causal relationship between global hypoperfusion and CMI formation or whether hypoperfusion and CMIs are linked by a shared etiology, such as cSVD.²¹ Additional evidence for a causal role of perfusion in CMI formation comes from clinical populations with compromised cerebral hemodynamics attributable to pathology proximal in the vascular tree, namely individuals with heart failure and individuals with carotid occlusive disease. In both these populations, CMI occurrence is related to severity of hemodynamic constraints, including more severe cardiac pump dysfunction in individuals with heart failure⁸ and higher number of occluded cervical arteries in individuals with carotid occlusive disease.⁷

Functional Effect on Cognition

The large majority of acute and chronic CMIs are asymptomatic, in the sense that they do not present themselves as acute stroke with acute neurologic disability. Rather, several cross-sectional studies found an association between CMIs and severity of cognitive dysfunction, especially in memory clinic populations with vascular cognitive impairment.^9,22 A few longitudinal studies in people attending a memory clinic established a relationship between presence of CMIs and accelerated cognitive decline²³ and an increase in neurobehavioral disturbances, such as apathy and hyperactivity, during follow-up.²⁴ In cohorts with acute ischemic stroke, the presence and number of CMIs on MRI at presentation was associated with a slower cognitive recovery after 1 year²⁵ and a higher rate of functional dependence or death at 90 days.²⁶

The relationship between CMIs and cognitive performance is not yet fully understood, because a single CMI is unlikely to cause sufficient damage to affect brain functioning measurably. One hypothesis is that a single CMI is a proxy for more extensive vascular brain damage. This damage consists of both small CMIs that escape the detection limit of current MRI together with the burden of other vascular lesions related to the underlying vascular pathology (eg, white matter hyperintensities in cSVD). CMI-related “perilesional” injury, whereby the CMI exerts a disruptive effect on its surrounding tissue, might also impact cognitive performance. One MRI study demonstrated cortical thinning of an adjacent cortical area many times larger than the CMI core, suggestive of perilesional injury.²⁷

Presence of acute CMI was also found to affect noncognitive clinical outcome, including an increased risk of stroke and other vascular events (such as cardiac morbidity and mortality) in both a population-based cohort²⁸ and a memory clinic cohort.²⁹ This raises the potential of CMIs as a biomarker of active cerebrovascular and vascular disease in general, signaling individuals with a high risk of recurrent stroke and adverse outcome.

Clinical Relevance

CMIs generate important insights that can impact the daily clinical practice of the neurologist. As highlighted in the aforementioned studies, CMIs carry prognostic value with regard to cognitive decline, future stroke, and poor clinical outcome. Detection of CMIs is not part of the everyday stroke or dementia workup, but CMIs are increasingly recognized on MRI. We recommend that the clinician place the occurrence of CMIs in their clinical context when they are encountered. CMIs should be treated with antithrombotics when considered symptomatic (eg, an acute CMI in the motor cortex on DWI in a patient with a transient ischemic attack or ischemic stroke). Furthermore, the individual’s vascular risk profile should be identified, including cardiac disease, and co-occurring vascular imaging markers should be noted. Particular effort should be made to identify those markers that could point to a specific underlying cerebrovascular pathology, such as microbleeds in cSVD, so that the underlying pathology can be optimally treated. Treatment with antithrombotics is not recommended for those individuals in which CMIs are an isolated finding, because the effect of treatment with antiplatelets or anticoagulants in instances of isolated CMIs has not been adequately researched. For these cases, we recommend optimizing control of vascular risk factors according to primary prevention guidelines in line with other presentations of silent cerebrovascular disease.³⁰

Conclusion

CMIs are small ischemic brain lesions that can be detected in both the acute and chronic phase on neuropathologic evaluation and in vivo on DWI and structural MRI. They are frequently encountered in people with a history of stroke and cognitive impairment. CMIs have multiple etiologies, including cSVD, microemboli, and hypoperfusion. Although they are not part of routine radiologic evaluation, CMIs are of potential clinical relevance as an important predictor of cognitive decline, recurring stroke, and poor clinical outcome.