Hemorrhage from cerebral cavernous malformations: a systematic pooled analysis

Abstract

OBJECTIVE The aim of this paper is to define an overall cavernous malformation (CM) hemorrhage rate and risk factors for hemorrhage. METHODS The authors performed a systematic, pooled analysis via the PubMed database through October 2015 using the terms "cavernoma," "cavernous malformation," "natural history," "bleeding," and "hemorrhage." English-language studies providing annual rates and/or risk factors for CM hemorrhage were included. Data extraction, performed independently by the authors, included demographic data, hemorrhage rates, and hemorrhage risk factors. RESULTS Across 12 natural history studies with 1610 patients, the mean age at presentation was 42.7 years old and 52% of patients (95% CI 49%-55%) were female. Presentation modality was seizure in 30% (95% CI 25%-35%), hemorrhage in 26% (95% CI 17%-37%), incidental in 17% (95% CI 9%-31%), and focal deficits only in 16% of cases (95% CI 11%-23%). CM location was lobar in 66% (95% CI 61%-70%), brainstem in 18% (95% CI 13%-24%), deep supratentorial in 8% (95% CI 6%-10%), and cerebellar in 8% (95% CI 5%-11%). Pooling 7 studies that did not assume CM presence since birth, the annual hemorrhage rate was 2.5% per patient-year over 5081.2 patient-years of follow-up (95% CI 1.3%-5.1%). Pooling hazard ratios across 5 studies that evaluated hemorrhage risk factors, prior CM hemorrhage was a significant risk factor for hemorrhage (HR 3.73, 95% CI 1.26-11.1; p = 0.02) while younger age, female sex, deep location, size, multiplicity, and associated developmental venous anomalies (DVAs) were not. CONCLUSIONS Although limited by the heterogeneity of incorporated reports and selection bias, this study found prior hemorrhage to be a significant risk factor for CM bleeding, while age, sex, CM location, size, multiplicity, and associated DVAs were not. Future natural history studies should compound annual hemorrhage rate with prospective seizure and nonhemorrhagic neurological deficit rates.

Significant Hemorrhage Rate Reduction after Gamma Knife Radiosurgery in Symptomatic Cavernous Malformations: Long-Term Outcome in 95 Case Series and Literature Review

“…The hemorrhage rate from untreated CMs is described to be high initially (cluster effect), and it could decrease 2-3 years after the hemorrhage event without any treatment [23]. Comparing our results with the natural history series, the hemorrhage rate after treatment is remarkably lower in our series [24,25,26]. Thus, we can presume some radiosurgery effect.…”

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

“…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].…”

Rapidly Sequential and Fatal Hemorrhaging in a Case of Cerebral Amyloid Angiopathy

“…However, the size of the initial hemorrhage was magnitudes larger than the mean size of the hemorrhage (13.4±7.3 mm) described by Jeon et al [12] in 410 patients with cavernomas. The sequential hemorrhaging was also inconsistent with an etiology of cavernoma; and multiplicity of cavernomas has not been shown to be a risk for subsequent hemorrhage [13]. …”