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

Abstract

Background and objectives: Familial cavernous malformations (FCMs) are vascular lesions that pose a lifelong risk of symptomatic hemorrhage (SH) and seizures, yet their natural history remains unclear. This study aims to determine the cumulative lifetime risk of a first SH and/or seizure and assess whether genetic variations influence these risks.

Methods: This international, multicenter retrospective cohort study included data from 16 tertiary referral centers and 1 patient advocacy group. Eligible patients had confirmed or suspected FCM, available magnetic resonance imaging (MRI) data, documented baseline clinical features, and longitudinal follow-up (FU). Functional outcomes were assessed using the modified Rankin Scale (mRS) at last FU. Direct adjusted survival curves and mixed-effects Cox regression analyses were performed to estimate cumulative lifetime risk. The association between genetic variations and SH/seizure rates was evaluated, and mixed-effects logistic regression assessed the effect of SH/seizures on mRS outcomes.

Results: A total of 1,592 patients with FCM were included, with a mean age of 37.6 years (SD 17.1) and 55.7% female. The median FU was 42 years (IQR: 27-55), totaling 64,146 person-years. Of these, 869 (54.6%) had confirmed FCM, 775 (48.7%) experienced at least 1 hemorrhage, and 447 (28.1%) had at least 1 seizure. Genetic testing was performed in 47.7%, identifying CCM1 (31.0%), CCM2 (4.8%), and CCM3 (1.9%) variations. The lifetime risk of a first SH was ∼80%, with an event rate that remained constant beyond age 20. The lifetime risk of a first seizure was ∼45%. Patients with CCM3 variations exhibited a more aggressive hemorrhagic course than those with CCM1 (hazard ratio 1.799, 95% CI 1.008-3.208). SH and seizures were independently associated with worse mRS outcomes at last FU.

Discussion: The event rate of SH and seizures remained stable over time, leading to high cumulative lifetime risks. Patients with CCM3 variations exhibited a more aggressive disease course. Limitations include the non-population-based design, selection bias from tertiary centers, retrospective data collection, and variability in data extraction across centers. However, this study represents the largest international FCM cohort to date, improving the precision of risk estimates and providing valuable insights into disease progression.

Figure 1:

Flow chart of the Systematic review according to PRISMA Guidelines. FCM corresponds to Familial Cerebral cavernous malformation.

Figure 2:

(A) Bleeding events through Kaplan-Meier curves of the complete cohort, (B) stratified by center (associated center is marked on the right end of the figure with a personal color and form), and (C) stratified by genetic mutation (CCM1 shown in blue; CCM2 shown in green; CCM3 shown in red) The numbers of patients at risk are shown in a corner of each graph. HR of ICH between CCM1 VS CCM2 = 0.840/ HR of ICH between CCM3 VS CCM1 = 1.799

Figure 3:

(A) Seizure events through Kaplan-Meier curves of the complete cohort, (B) stratified by center (associated center is marked on the right end of the figure with a personal color and form), and (C) stratified by genetic mutation (CCM1 shown in blue; CCM2 shown in green; CCM3 shown in red) The numbers of patients at risk are shown in a corner of each graph. HR of ICH between CCM1 VS CCM2 = 0.764/ HR of ICH between CCM3 VS CCM1 = 1.373

Figure 4:

Box plot graphics showing the association between functional outcome through modified Rankin Scale (mRS) and siezure events (left graphic), as well as with ICH events (right graphic). mRS score schowed on the Y-axis, presence of seizure or ICH seen in the X-axis.