Study shows ‘meaningful’ link between perivascular spaces, intracranial hemorrhage

Enlarged perivascular spaces within the basal ganglia represented a novel risk factor for intracranial hemorrhage among patients taking oral anticoagulants, according to a post hoc analysis of the CROMIS-2 (AF) study published in Neurology.

Ten or more enlarged perivascular spaces within the basal ganglia, as well as diabetes, remained significant risk factors for intracranial hemorrhages in a multivariable model, according to the study findings.

“Cross-sectional studies of intracerebral hemorrhage (ICH) survivors have associated enlarged basal ganglia perivascular spaces (BGPVS) with deep ICH, increased white matter hyperintensity volume, and deep cerebral microhemorrhages (CMBs), and enlarged centrum semiovale perivascular spaces (CSOPVS) with lobar ICH and cerebral amyloid angiopathy (CAA),” the researchers wrote. “In cognitively-impaired patients, BGPVS are associated with hypertension, deep CMBs and lacunes, and CSOPVS with lobar CMBS, cortical superficial siderosis and Alzheimer’s disease.”

These data suggest that BGPVS could indicate deep perforator arteriopathy and CSOPVS could represent amyloid-beta pathology, including CAA, according to the researchers. As a result, PVS could also represent increased ICH risk.

Jonathan G. Best, MRCP, of the department of brain repair and rehabilitation in the Stroke Research Center at the UCL Queen Square Institute of Neurology in London, and colleagues examined data from 1,386 patients with atrial fibrillation who had experienced a recent transient ischemic attack or ischemic stroke. All patients underwent MRI before starting oral anticoagulants.

The researchers rated BGPVS and CSOPVS, CMBs, white matter hyperintensities and lacunes. They dichotomized the PVS rating with a threshold of more than 10 PVS in the relevant region of either cerebral hemisphere. Best and colleagues also identified risk factors for symptomatic intracranial hemorrhage (sICH), which served as the primary outcome.

During 3,251 participant years of follow-up (mean follow-up period, 2.34 years), 14 sICHs occurred. Specifically, there were 11 intracerebral hemorrhages, two subdural hemorrhages and one subarachnoid hemorrhage. Median time from start of anticoagulation therapy to sICH was 272 days (interquartile range, 211-657 days).

In univariable analysis, diabetes, the presence of CMBs, the presence of lacunes and more than 10 BGPVS correlated with sICH, though CSOPVS did not. A multivariable model included all variables found to have significant associations on univariable analysis. In this model, more than 10 BGPVS (HR = 8.96; 95% CI, 2.41-33.4) and diabetes (HR = 3.91; 95% CI, 1.34-11.4) remained significant risk factors for sICH.

The primary finding from the study is the association between enlarged PVS within the basal ganglia and oral anticoagulant-related intracranial hemorrhages, “independent of major vascular risk factors and other markers of cerebral small vessel disease,” according to Best and colleagues. The statistics for this association are “consistent with a clinically meaningful association,” they continued, and point to the possibility that enlarged BGPVS represent a clinically relevant marker for oral anticoagulant-related ICH risk.

“The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts,” the researchers wrote.