Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy: A meta-analysis

Abstract

Objective: To assess the association of cortical superficial siderosis (cSS) presence and extent with future bleeding risk in cerebral amyloid angiopathy (CAA).

Methods: This was a meta-analysis of clinical cohorts of symptomatic patients with CAA who had T2*-MRI at baseline and clinical follow-up for future intracerebral hemorrhage (ICH). We pooled data in a 2-stage meta-analysis using random effects models. Covariate-adjusted hazard ratios (adjHR) from multivariable Cox proportional hazard models were used.

Results: We included data from 6 eligible studies (n = 1,239). cSS pooled prevalence was 34% (95% confidence interval [CI] 26%-41%; I ² 87.94%; p < 0.001): focal cSS prevalence was 14% (95% CI 12%-16%; I ² 6.75%; p = 0.37), and disseminated cSS prevalence was 20% (95% CI 13%-26%; I ² 90.39%; p < 0.001). During a mean follow-up of 3.1 years (range 1-4 years), 162/1,239 patients experienced a symptomatic ICH-pooled incidence rate 6.9% per year (95% CI 3.9%-9.8% per year; I ² 83%; p < 0.001). ICH incidence rates per year according to cSS status were 3.9% (95% CI 1.7%-6.1%; I ² 70%; p = 0.018) for patients without cSS, 11.1% (95% CI 7%-15.2%; I ² 56.8%; p = 0.074) for cSS presence, 9.1% (95% CI 5.5%-12.8%; I ² 0%; p = 0.994) for focal cSS, and 12.5% (95% CI 5.3%-19.7%; I ² 73.2%; p = 0.011) for disseminated cSS. In adjusted pooled analysis, any cSS presence was independently associated with increased future ICH risk (adjHR 2.14; 95% CI 1.19-3.85; p < 0.0001). Focal cSS was linked with ICH risk (adjHR 2.11; 95% CI 1.31-2.41; p = 0.002), while disseminated cSS conferred the strongest bleeding risk (adjHR 4.28; 95% CI 2.91-6.30; p < 0.0001).

Conclusion: In patients with CAA, cSS presence and extent are the most important MRI prognostic risk factors for future ICH, likely useful in treatment planning.

Classification of evidence: This study provides Class III evidence that in symptomatic CAA survivors with baseline T2*-MRI, cSS (particularly if disseminated, i.e., affecting >3 sulci) increases the risk of future ICH.

Figure 1. Representative examples of cortical superficial siderosis (cSS) on blood-sensitive MRI in patients with cerebral amyloid angiopathy (CAA)

(A) T2*-weighted gradient-recalled echo sequence shows focal cSS (i.e., affecting up to 3 sulci) on the left and disseminated cSS (i.e., affecting >3 sulci) on the right. (B) Susceptibility-weighted imaging sequences from 2 different patients with CAA with focal cSS (left) and disseminated cSS (right).

Figure 2. Flowchart of studies identification and selection

CAA = cerebral amyloid angiopathy.

Figure 3. Forest plot of the association between the presence of cortical superficial siderosis (cSS) and risk of future intracerebral hemorrhage (ICH) during follow-up

Meta-analysis was performed using a random effects model, pooling adjusted hazard ratios (HRs). The squares represent study-specific HRs, with their size proportional to their statistical weight (WGHT). LCL = lower confidence limit; UCL = upper confidence limit.

Figure 4. Forest plots of the association between focal cortical superficial siderosis (cSS) (A) and disseminated cSS (B) with risk of future lobar intracerebral hemorrhage (ICH) during follow-up

Meta-analyses were performed using a random effects model, pooling adjusted hazard ratios (HRs). The squares represent study-specific HRs, with their size proportional to their statistical weight (WGHT). LCL = lower confidence limit; UCL = upper confidence limit.