Tag: Symptomatic hemorrhage

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Prospective untreated outcomes in patients with cerebral cavernous malformation

J Neurosurg 144:1344–1352, 2026

This prospective cohort study quantifies long-term functional outcomes in 332 untreated patients with cerebral cavernous malformation (CCM), using modified Rankin Scale (mRS) scores to evaluate disability over a mean 6.6-year follow-up. It reports incidence of symptomatic hemorrhage (SH), temporal patterns of recovery after a first SH, and external validation of published predictive nomograms.

Key findings identify brainstem location, a history of self-reported psychiatric disorder, and two or more SHs as independent predictors of long-term disability; most patients improved within one year after a first hemorrhage, and ten-year disability risk for nonbrainstem CCM was under 8%.

Objective Elucidate long-term morbidity and disability risk in adults with untreated cerebral cavernous malformation (CCM).

Methods Prospectively followed registry cohort; functional outcome tracked using mRS, with disability defined as mRS ≥ 3; time-to-disability analyzed via Kaplan–Meier and risk factors via Cox models; previously published morbidity nomograms were externally validated.

Cohort 332 patients (58.4% female; mean age 44.5); 19.8% familial CCM; 28.0% brainstem location; 38.3% presented with symptomatic hemorrhage (SH).

Recovery after first SH Among patients with SH who had no further SH and no surgery (n=48), disability (mRS ≥ 3) was 27.1% at diagnosis, improving to 6.2% at 1 year and 4.7% at 5 years, with most improvement in year 1.

Hemorrhage burden Over mean 6.6 years, 31.0% had ≥1 prospective SH and 14.5% had multiple prospective SHs; disability rose sharply with each SH (mRS ≥ 3: 2.3% with 0 SH up to 100% after 5 SHs in untreated follow-up).

Location risk Brainstem CCM carried substantially higher disability risk (18.8% at 5 years; 35.4% at 10 years) versus nonbrainstem locations (4.1% at 5 years; 7.5% at 10 years).

Predictors Multivariate predictors of disability included brainstem location, self-reported psychiatric disorder, and ≥2 SHs.

Nomogram validation Prior nomograms showed high specificity but limited sensitivity; AUC 0.687 for predicting mRS ≥ 2 and 0.783 for predicting mRS ≥ 3.

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Contemporary cohort of cerebral cavernous malformations: natural history and utility of follow-up MRI

J Neurosurg 141:1159–1167, 2024

This study reports the natural history of cerebral cavernous malformations (CCMs) in a contemporary cohort with prospectively collected data from multiple sources, access to follow-up imaging, integrated electronic medical records, and detailed imaging review by study investigators. The authors aimed to define the first prospective symptomatic hemorrhage (SH) and severe SH rates, determine the risk of a second prospective SH, and identify risk factors for SH.

METHODS From a prospectively maintained database of adult patients with radiologically defined CCM, those with radiation-induced CCM, those who underwent surgery within 3 months postdiagnosis, and those with < 1 year of followup were excluded. The patients’ medical history and radiological features of the CCM were recorded at the time of diagnosis. Follow-up annual written surveys were completed for 5 years after the initial diagnosis and then semiannually thereafter in addition to medical record and follow-up imaging review. Outcomes of interest included SH and severe SH.

RESULTS Of 315 patients, 58.7% were female and 19.7% had familial CCMs. At diagnosis, 37.1% of patients had ruptured CCMs and 28.9% of the CCMs were located in the brainstem. The 5-year cumulative rates of prospective SH and severe SH in those with ruptured CCMs at diagnosis were 41.2% and 12.8%, respectively, compared with 6.1% and 2.5% in patients with unruptured CCMs at diagnosis (p < 0.0001). Risk factors for prospective SH included a ruptured CCM at diagnosis and persistent or new hyperintensity on T1-weighted MRI performed > 3 months after baseline MRI. For those with a ruptured CCM at diagnosis, the risk of developing a second prospective SH was similar to that of developing a first SH.

CONCLUSIONS In a contemporary cohort of adult patients with CCM, the authors report 5-year SH and severe SH rates, rates of second prospective hemorrhage, and predictors of SH. Persistent or new hyperintensity on T1-weighted MRI may be a useful marker of disease activity.

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Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

Neurosurgery 2019 Dec 1;85(6):843-853

More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit.

OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCKactivity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups.

METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint.

EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug.

DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

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