Red meets white

Cerebral microbleeds have captured the fascination of neurologists and clinical stroke researchers in particular. In the past decade, research focused on microbleeds has risen exponentially, providing important insights into the risk factors, pathophysiology, and neurologic consequences of these lesions. Microbleeds (detected on gradient echo or T2*-weighted MRI sequences) consist of hemosiderin accumulations that occur adjacent to small vessels that are indicative of extravasation of blood from prior small bleeds.¹ Their significance for treatment decisions and patient management remains to be defined; nevertheless, it is clear that microbleeds have emerged as an important imaging marker of bleeding-prone microangiopathies and a possible contributor to vascular cognitive impairment.² As such, microbleeds are potential target biomarkers for treatment interventions and risk factor control.

Microbleeds are detected in 5% to 6% of the general elderly population, 30% of patients with ischemic stroke, and 60% of patients with primary intracerebral hemorrhage,³ numbers likely to grow with improving sensitivity of MRI.² Hypertensive small vessel disease and cerebral amyloid angiopathy are the 2 most common underlying angiopathies associated with microbleeds. Numerous studies have shown a strong correlation between microbleeds and leukoaraiosis, further pointing to the common denominator of a small vessel vasculopathy.

In this issue of Neurology®, Jeon et al.⁴ report an analysis of the frequency of new microbleeds appearing in the first 7 days after acute ischemic stroke. Of the 237 patients who underwent serial T2*-weighted MRI at presentation and a median of 4 days after stroke, 30 (12.7%) were found to have 1 or more new microbleeds outside of the acutely infarcted region. A total of 56 new microbleeds were detected, and 8 microbleeds “disappeared.” The presence of baseline microbleeds and severe small vessel disease were independent predictors of new microbleeds. Of note, the occurrence of new microbleeds was not associated with thrombolytic or antithrombotic therapy. The authors hypothesize that microbleeds may develop rapidly in response to certain critical events such as acute ischemic stroke.

Although the finding of rapid evolution of new microbleeds after an acute ischemic stroke is an intriguing addition to our knowledge of microbleeds, 2 potential limitations necessitating caution in interpreting the results should be noted. First, the baseline and follow-up images were not coregistered, leaving the possibility of misclassification due to different planes of section in image acquisition. In addition, the imaging interpretations were performed by readers not fully blinded to imaging time point or results of the initial scan, potentially introducing bias. However, the fact that far more microbleeds “appeared” on follow-up imaging compared with those that “disappeared” provides reassurance that the majority of the new microbleeds are truly recently formed. It is likely that the 8 that were not detected on follow-up imaging had not truly disappeared but rather were out of the plane of imaging.

Despite such potential confounds, this is the first report demonstrating the rapidly evolving nature of microbleeds in the acute phase of cerebral ischemic events. These findings, if confirmed, suggest a widespread active small vessel angiopathic process induced by an ischemic insult. The impact of specific mechanisms, such as endothelial dysfunction, blood-brain barrier disruption, and active inflammation, and their specific roles in this putative induced angiopathic process remains to be clarified, particularly in light of the association between new microbleed formation and increased body temperature.

In aggregate, these findings suggest the need to reframe our thinking about microbleeds from a relatively static to a more temporally dynamic process.

There are interesting parallels between the current finding of microbleeding in association with acute ischemic stroke and 2 recent reports of silent ischemic infarcts occurring in association with the hemorrhagic process of cerebral amyloid angiopathy.^5,6 The latter studies used diffusion-weighted MRI of patients with advanced cerebral amyloid angiopathy to identify a surprisingly high prevalence of acute or subacute microinfarcts, presumably reflecting small vessel dysfunction due to vascular amyloid. Together with the study by Jeon et al., these reports point to unexpected cross talk between hemorrhagic and ischemic mechanisms of small vessel injury—the “red” and the “white” strokes.

Further studies are needed to confirm the findings of Jeon et al. and to answer additional intriguing questions: whether the development of new microbleeds is associated with specific stroke subtypes, whether similar phenomena occur in association with primary intracerebral hemorrhage or other acute brain insults, and which pathophysiologic pathways are involved. Perhaps the most important question is whether this observation opens a new door of opportunity for vasculoprotective interventions to minimize ongoing damage occurring through this active angiopathic process.

DISCLOSURE

Dr. Kidwell serves on the editorial boards of Neurocritical Care, the Journal of Neuroimaging, and Stroke Research and Treatment; serves as a consultant to Embrella Cardiovascular™, Inc.; and receives research support from Baxter International Inc. and the NIH/NINDS [P50 NS044378 (Co-I) and U54 NS057405 (PI)]. Dr. Greenberg serves on scientific advisory boards for Hoffman-La Roche Inc.; serves on the editorial board of Neurology®; and receives research support from the NIH [5R01AG026484-05 (PI)] and the Alzheimer’s Association (PI).