Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation
Authors: Weinsheimer Shantel , Nelson Jeffrey , Abla Adib A. , Ko Nerissa U. , Tsang Cynthia , Okoye Obiora , Zabramski Joseph M. , Akers Amy , Zafar Atif , Mabray Marc C. , Hart Blaine L. , Morrison Leslie , McCulloch Charles E. , Kim Helen , Abla Adib A. , Akers Amy , Awad Issam A. , Hart Blaine L. , Kim Helen , Ko Nerissa U. , Lawton Michael T. , Lee Cornelia , Mabray Marc C. , McCulloch Charles E. , Morrison Leslie , Pawlikowska Ludmila , Smith Edward R. , Torbey Michel , Vadivelu Sudhakar , Weinsheimer Shantel , Zabramski Joseph M. , Zafar Atif 
Published: January 2023

Background

Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in
KRIT1
,
CCM2
, or
PDCD10
. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long‐term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow‐up in a well‐characterized cohort of familial CCM cases.

Methods and Results

We studied 386 patients with familial CCM with follow‐up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow‐up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient‐years (95% CI, 1.9–4.1). Those with ICH before enrollment had a follow‐up ICH rate of 4.5 per 100 patient‐years (95% CI, 2.6–8.1) compared with 2.0 per 100 patient‐years (95% CI, 1.3–3.5) in those without (
P
=0.042). Total lesion count was associated with increased risk of ICH during follow‐up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10–1.71],
P
=0.006).

The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient‐years (95% CI, 1.9–4.1). Those with ICH before enrollment had a follow‐up ICH rate of 4.5 per 100 patient‐years (95% CI, 2.6–8.1) compared with 2.0 per 100 patient‐years (95% CI, 1.3–3.5) in those without (
P
=0.042). Total lesion count was associated with increased risk of ICH during follow‐up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10–1.71],
P
=0.006).

Conclusions
Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow‐up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.