Multiple cerebral cavernous malformations: Clinical course of confirmed, assumed and non‐familial disease

Abstract

Background and Purpose: Analyze and compare the natural course of confirmed familial cerebral cavernous malformation (FCCM), assumed FCCM and non-familial multiple cerebral cavernous malformation (CCM) disease over a 5-year period. Methods: Our institutional database was screened for patients with CCM admitted between 2003 and 2020. Patients with complete magnetic resonance imaging dataset, evidence of multiple CCM, clinical baseline characteristics, and follow-up examination were included. Patients were separated into confirmed familial cases, assumed familial cases or non-familial multiple cavernous malformations. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for hemorrhage and recurrent hemorrhage.Results: A total of 238 patients with multiple CCM were analyzed; 90 individuals had a confirmed FCCM disease, 115 an assumed FCCM, and 33 were allocated to the non-FCCM group. Univariate Cox regression analysis identified intracerebral hemorrhage (ICH) as mode of presentation (p = 0.001) as a predictor for occurrence of recurrent hemorrhage during the 5-year follow-up (FU). The cumulative 5-year risk of (re)bleeding was 21.6% for the entire cohort, 30.7% for patients with ICH at diagnosis, 22.1% for those patients with a confirmed diagnosis of FCCM, 23.5% for those with an assumed FCCM, and 21% for the non-FCCM cases.Conclusions: FCCM patients with ICH at diagnosis are prone to develop rebleeding.During untreated 5-year FU, FCCM patients and patients with sporadic multiple CCM reveal an almost equal susceptibility for (re)hemorrhage. Moreover, confirmed, assumed and non-FCCM patients showed an equal cumulative 5-year risk of symptomatic ICH. The probability of hemorrhage tends to increase over time, particularly in cases with ICH at presentation.

Natural history of familial cerebral cavernous malformation syndrome in children: a multicenter cohort study

“…Our results support similar 5-year annual and cumulative symptomatic hemorrhagic risks in pediatric FCCM subjects treated surgically based on clinical judgement in tertiary centers, compared to children and adults with all types of CCM. These findings are in line with the most recent studies on this topic [ 23 , 32 ]. However, the comparison of results between adult and pediatric cohorts should be made with caution.…”

“…The percentage of children in our cohort presenting with symptomatic hemorrhage is lower than reported in most previously published series including subjects with variable ages [ 15 , 16 , 20 , 22 , 23 , 32 ]. This is probably due to the high rate of known positive family history of CCM in our cohort, leading to a higher index of suspicion in cases of mild or non-specific complaints, such as headaches, and/or screening brain MRIs in asymptomatic subjects.…”

“…Another factor that may have influenced our results is the overall high rate of surgical treatment in our cohort (46%) when compared with other familial and/or pediatric CCM studies (up to 37.2%) [ 19 , 20 , 23 , 32 ]. There are currently no standard treatment guidelines specific for pediatric FCCM and indications for surgical treatment of accessible lesions remain personalized and dependent upon multiple factors, including the individual surgeon’s practice standards, patient’s insurance, family preference, presentation mode and type, and severity of clinical manifestations at follow-up.…”

Cerebral cavernous malformations do not fall in the spectrum of PIK3CA-related overgrowth

“…Therefore, these contradicting findings need to be investigated further with larger familial cohorts to decipher the existence of this relationship. Of note, evidence across the largest observational studies suggests that in both familial and sporadic cases the event of an initial CCM-related intracerebral haemorrhage (ICH) is the strongest validated clinical risk factor for (re-) haemorrhage (up to 40% cumulative risk within 5 years) while non-haemorrhagic, asymptomatic CCMs show a very low annual risk of a first ICH 46 71–74. This indicates that a certain ‘activation’ of the lesion leads to a phase of higher bleeding susceptibility.…”

“…The largest observational study on genotype/phenotype correlation revealed that PDCD10 (CCM3) carriers are at higher risk of CCM-related ICH, particularly during childhood, compared with CCM1 and CCM2 carriers 73. Regarding multiplicity of CCMs in sporadic and familial cases, a recent large observational study found that confirmed, assumed and non-familial cases show identical clinical course and susceptibility to (re)haemorrhage over 5 years 72…”