Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data

Abstract

SummaryBackgroundCerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.MethodsWe invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.FindingsAmong 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.InterpretationMode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

Rebleeding and Outcome in Patients with Symptomatic Brain Stem Cavernomas

“…We recognize that there are inherent biases in the annual hemorrhage recurrence rate calculation, since the rebleeding rate after a bleed are higher than in incidentally detected BCM [17,18]. In many surgical reports, the annual re-hemorrhage rates have been variable and generally high, ranging from 15 to 60%.…”

“…Therefore, only patients who were surgically treated were included. In a recent meta-analysis of the natural history of untreated cerebral cavernous malformations, 575 cases of BMC were included [18]. Brain stem location was independently associated with the occurrence of intracranial cerebral hemorrhage (30.8% 5-year risk bleed).…”

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

“…The haemorrhage rate per patient-year has been reported to be significantly lower in incidentally discovered groups when compared to symptomatic groups [Washington et al, 2010;Al-Holou et al, 2012;Al-Shahi Salman et al, 2012;Gross et al, 2016;Horne et al, 2016;Akers et al, 2017]. In a single-centre cohort of 107 individuals with CCM as an incidental finding, the only patient in whom a prospective haemorrhage was definitively related to the cavernous malformation was in fact diagnosed as having a familial form of CCM.…”

“…Seizures are the predominant first symptom of supratentorial lobar CCMs, while brainstem lesions are primarily associated with cranial nerve palsy, hemiparesis, and other focal neurological deficits. Prior haemorrhage and brainstem location appear to confer a higher risk for symptomatic haemorrhage, while the annual re-hemorrhage rate has been reported to decline over time [AlHolou et al, 2012;Al-Shahi Salman et al, 2012;Gross et al, 2016;Horne et al, 2016;Gross and Du, 2017].…”

Routinely Performed Serial Follow-Up Imaging in Asymptomatic Patients With Multiple Cerebral Cavernous Malformations Has No Influence on Surgical Decision Making

“…The principle danger inherent to CCM is the hemorrhage risk that has been estimated around 0.6–2% per lesion-year or 4.3–13% per patient-year in prospective studies with FCCM ( 3 – 5 ). While no definite evidence is suggested to correlate between hemorrhagic risk and size, age, sex, multiplicity or associated DVA, prior hemorrhage and brainstem CCM location were found to be the only significant risk factors for CCM hemorrhage ( 6 , 7 ). Whereas in other vascular malformations (i.e., aneurysms, arteriovenous malformations) grading systems have been established to estimate the risk of intracerebral hemorrhage (ICH), so far no grading system exists in the literature to serve as a valuable aid in the clinical decision as to whether perform conservative or surgical treatment in patients with CCM ( 8 – 10 ).…”