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<p>Cerebral cavernous malformations (CCMs) are slow-flow vascular lesions with a lifelong risk of intracerebral hemorrhage. Reliable markers that predict bleeding could improve clinical surveillance and guide treatment. This is the first systematic review compiling the current evidence on circulating and imaging biomarkers associated with hemorrhagic activity in CCMs.&#xa0;Following Cochrane and PRISMA guidelines, we systematically searched PubMed, Embase, and Web of Science through December 2025, for clinical studies reporting quantitative prognostic performance of circulating biomarkers or imaging markers for CCM hemorrhage. Two reviewers independently screened, extracted data, and assessed risk of bias using QUAPAS.&#xa0;Eleven studies (<i>n</i> = 945 patients) met eligibility. Most of the associations described in our review have been reported in single studies only, underscoring their preliminary nature. Circulating biomarkers linked to hemorrhagic presentation or recent bleed included: low 25-hydroxyvitamin D (&lt; 25.68 ng/mL), reduced non-HDL cholesterol (&lt; 138.5&#xa0;mg/dL), and elevated ROBO4 (<i>p</i> = 0.03), VEGF (<i>p</i> = 0.0003), and ENG. Composite plasma panels with sCD14, IL-6, VEGF, IL-1β and ROBO4 demonstrated high discriminatory performance (AUC ≈ 0.90; sensitivity 86%; specificity 88%). Imaging markers showed that increased iron content on quantitative susceptibility mapping (QSM) and higher permeability on dynamic contrast-enhanced quantitative perfusion (DCEQP) were associated with unstable lesions. Combined QSM + DCEQP analyses achieved a sensitivity of up to 88% and a specificity of 100%. A radiomics-based model using conventional MRI yielded an AUC of 0.83. However, small cohorts, heterogeneous methods, and inconsistent confounder adjustment limit generalizability. Emerging evidence supports integrating advanced imaging and molecular biomarkers to identify CCMs at higher risk of hemorrhage. Future multicenter prospective studies with standardized acquisition and validation protocols are essential before clinical application.</p>

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Imaging markers and circulating biomarkers for predicting hemorrhage from cerebral cavernous malformations: A systematic review

  • 期刊论文

  • 发表日期：

    2026年3月12日

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  • Lidia Cheidde,
  • Marcio Yuri Ferreira,
  • Gean Carlo Müller,
  • Alleh Nogueira,
  • Diego Alexandre Gomes Sousa,
  • Pedro Paulo Ladeira Junior,
  • Richard Daniel Ferreira Reis,
  • Luis F. Fabrini Paleare,
  • Rafael Martinez-Perez,
  • Jhon E. Bocanegra-Becerra,
  • Christian Ferreira,
  • Yafell Serulle,
  • Jason A. Ellis,
  • David Langer,
  • Netanel Ben-Shalom

摘要

Cerebral cavernous malformations (CCMs) are slow-flow vascular lesions with a lifelong risk of intracerebral hemorrhage. Reliable markers that predict bleeding could improve clinical surveillance and guide treatment. This is the first systematic review compiling the current evidence on circulating and imaging biomarkers associated with hemorrhagic activity in CCMs. Following Cochrane and PRISMA guidelines, we systematically searched PubMed, Embase, and Web of Science through December 2025, for clinical studies reporting quantitative prognostic performance of circulating biomarkers or imaging markers for CCM hemorrhage. Two reviewers independently screened, extracted data, and assessed risk of bias using QUAPAS. Eleven studies (n = 945 patients) met eligibility. Most of the associations described in our review have been reported in single studies only, underscoring their preliminary nature. Circulating biomarkers linked to hemorrhagic presentation or recent bleed included: low 25-hydroxyvitamin D (< 25.68 ng/mL), reduced non-HDL cholesterol (< 138.5 mg/dL), and elevated ROBO4 (p = 0.03), VEGF (p = 0.0003), and ENG. Composite plasma panels with sCD14, IL-6, VEGF, IL-1β and ROBO4 demonstrated high discriminatory performance (AUC ≈ 0.90; sensitivity 86%; specificity 88%). Imaging markers showed that increased iron content on quantitative susceptibility mapping (QSM) and higher permeability on dynamic contrast-enhanced quantitative perfusion (DCEQP) were associated with unstable lesions. Combined QSM + DCEQP analyses achieved a sensitivity of up to 88% and a specificity of 100%. A radiomics-based model using conventional MRI yielded an AUC of 0.83. However, small cohorts, heterogeneous methods, and inconsistent confounder adjustment limit generalizability. Emerging evidence supports integrating advanced imaging and molecular biomarkers to identify CCMs at higher risk of hemorrhage. Future multicenter prospective studies with standardized acquisition and validation protocols are essential before clinical application.