Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis.
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Dammann Philipp, Santos Alejandro N, Mavarani Laven, Guey Stéphanie, Chabriat Hugues, Herve Dominique, Croft Jacob, Renteria Mellisa, Jang David, Zhang Jun, Li Da, Wu Zhen, Weng Jian-Cong, Petracca Antonio, Fusco Carmela, D'Agruma Leonardo, Castori Marco, Rath Matthias, Pilz Robin A, Felbor Ute, Steinberg Gary K, Gu Jeanne, Bervini David, Goldberg Johannes, Raabe Andreas, Cervio Andrés, Villamil Facundo, Rosales Julieta, Rauschenbach Laurèl, Riess Christoph, Oppong Marvin Darkwah, Karadachi Hannah, Ahmadipour Yahya, Wrede Karsten H, Jabbarli Ramazan, Deuschl Cornelius, Li Yan, Santos Piedade Guilherme, Köhrmann Martin, Frank Benedikt, Wälchli Thomas, Schmidt Börge, Overstijns Manou, Beck Jürgen, Fung Christian, Al-Shahi Salman Rustam, Flemming Kelly D, Lanzino Giuseppe, Zafar Atif, Weinsheimer Shantel, Nelson Jeffrey, Zabramski Joseph M, Akers Amy, Morrison Leslie, McCulloch Charles E, Kim Helen, Sure Ulrich, Brain Vascular Malformation Consortium Cerebral Cavernous Malformation Investigator Group
Аннотация
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.