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Updated: May 11, 2026

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Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient

Philipp Dammann1,2, Alejandro N Santos1,2, Laven Mavarani3

  • 1Department of Neurosurgery and Spine Surgery, University Hospital Essen, Germany.

Neurology
|July 10, 2025
PubMed

Insights

Familial cavernous malformations (FCMs) carry a high lifelong risk of symptomatic hemorrhage (SH) and seizures, with approximately 80% experiencing SH. Genetic variations, particularly CCM3, are linked to a more aggressive disease course.

Area of Science:

  • Neuroscience
  • Genetics
  • Vascular Biology

Background:

  • Familial cavernous malformations (FCMs) are genetic vascular anomalies with unclear natural history.
  • These lesions present a lifelong risk of symptomatic hemorrhage (SH) and seizures.
  • Understanding the cumulative lifetime risk and genetic influences is crucial for patient management.

Purpose of the Study:

  • To determine the cumulative lifetime risk of a first symptomatic hemorrhage (SH) and/or seizure in patients with FCM.
  • To assess the influence of genetic variations on the risk of SH and seizures.
  • To evaluate the impact of SH and seizures on functional outcomes.

Main Methods:

  • International, multicenter retrospective cohort study of 1,592 patients with FCM.
  • Longitudinal follow-up data, including MRI, clinical features, and functional outcomes (mRS).
  • Survival analyses and mixed-effects regression models were used to estimate risks and associations.

Main Results:

  • High cumulative lifetime risks: ~80% for first SH and ~45% for first seizure.
  • The event rate for SH and seizures remained constant after age 20.
  • CCM3 variations were associated with a more aggressive hemorrhagic course compared to CCM1.
  • SH and seizures independently predicted worse modified Rankin Scale (mRS) outcomes.

Conclusions:

  • FCMs lead to substantial lifelong risks of SH and seizures with stable event rates over time.
  • Genetic variations, specifically CCM3, significantly impact disease aggressiveness.
  • This large international cohort provides robust estimates for FCM risk and progression, informing clinical strategies.
Abstract

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