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.
Highlights
Cerebral cavernous malformations (CCMs) are the second commonest incidental vascular finding—after aneurysms1—on brain MRI, with a prevalence of one in 625 neurologically asymptomatic people.[2,3] Because brain MRI is needed for diagnosis of CCMs without pathological examination,[4] the number of people in whom CCM has been detected has risen since the advent of MRI.[5,6]CCMs can be asymptomatic or can cause epileptic seizures,[7] stroke due to symptomatic intracranial haemorrhage (ICH),[8] or new focal neurological deficit (FND) without evidence on brain imaging of recent haemorrhage.[8]
The estimated risk of first ICH within 5 years of diagnosis of CCM in the pooled dataset was higher for people presenting with ICH or FND versus other modes of presentation (26·4% [95% CI 23·1–29·7] vs 4·3% [2·5–6·1]; pooled unadjusted hazard ratios (HRs) 5·6 [95% CI 3·2–9·7]) and for people with a primary CCM location in the brainstem versus another location (27·7% [95% CI 23·6–31·8] vs 8·2% [6·2–10·2]; pooled unadjusted HR 4·4, [95% CI 2·3–8·6]); these findings were similar in individual cohorts
We found no evidence—even after multivariable adjustment for the two core predictors—that age, sex, or CCM multiplicity affected the risk of ICH, and these findings were generally consistent between cohorts
Summary
Cerebral cavernous malformations (CCMs) are the second commonest incidental vascular finding—after aneurysms1—on brain MRI, with a prevalence of one in 625 neurologically asymptomatic people.[2,3] Because brain MRI is needed for diagnosis of CCMs without pathological examination,[4] the number of people in whom CCM has been detected has risen since the advent of MRI.[5,6]CCMs can be asymptomatic or can cause epileptic seizures,[7] stroke due to symptomatic intracranial haemorrhage (ICH),[8] or new focal neurological deficit (FND) without evidence on brain imaging of recent haemorrhage.[8]. Some cohort studies have estimated the risk of ICH from untreated CCMs. findings from a recent systematic review[11] showed that these studies were mostly retrospective hospital-based series, with sample sizes not exceeding 139 people and short durations of follow-up, without clearly defined diagnostic criteria or outcome events,[8] and in which several different statistical methods were used to calculate the risk and predictors of ICH. Findings from a recent systematic review[11] showed that these studies were mostly retrospective hospital-based series, with sample sizes not exceeding 139 people and short durations of follow-up, without clearly defined diagnostic criteria or outcome events,[8] and in which several different statistical methods were used to calculate the risk and predictors of ICH Findings from these studies have left uncertainty about the magnitude of the risk of ICH and its predictors. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis
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