Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations.

Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing. However, a loss of heterozygosity in CCM2 was observed on cDNA sequences in one of the two affected members, which strongly suggested that this locus might be involved. Whole genome sequencing (WGS) identified a balanced structural variant on chromosome 7 with a breakpoint interrupting the CCM2 gene, preventing normal mRNA synthesis. These data underline the importance of WGS in undiagnosed patients with typical multiple CCM.

Identifying potential (re)hemorrhage among sporadic cerebral cavernous malformations using machine learning.

The (re)hemorrhage in patients with sporadic cerebral cavernous malformations (CCM) was the primary aim for CCM management. However, accurately identifying the potential (re)hemorrhage among sporadic CCM patients in advance remains a challenge. This study aims to develop machine learning models to detect potential (re)hemorrhage in sporadic CCM patients. This study was based on a dataset of 731 sporadic CCM patients in open data platform Dryad. Sporadic CCM patients were followed up 5 years from January 2003 to December 2018. Support vector machine (SVM), stacked generalization, and extreme gradient boosting (XGBoost) were used to construct models. The performance of models was evaluated by area under receiver operating characteristic curves (AUROC), area under the precision-recall curve (PR-AUC) and other metrics. A total of 517 patients with sporadic CCM were included (330 female [63.8%], mean [SD] age at diagnosis, 42.1 [15.5] years). 76 (re)hemorrhage (14.7%) occurred during follow-up. Among 3 machine learning models, XGBoost model yielded the highest mean (SD) AUROC (0.87 [0.06]) in cross-validation. The top 4 features of XGBoost model were ranked with SHAP (SHapley Additive exPlanations). All-Elements XGBoost model achieved an AUROCs of 0.84 and PR-AUC of 0.49 in testing set, with a sensitivity of 0.86 and a specificity of 0.76. Importantly, 4-Elements XGBoost model developed using top 4 features got a AUROCs of 0.83 and PR-AUC of 0.40, a sensitivity of 0.79, and a specificity of 0.72 in testing set. Two machine learning-based models achieved accurate performance in identifying potential (re)hemorrhages within 5 years in sporadic CCM patients. These models may provide insights for clinical decision-making.

Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Diagnosis and treatment status of suprasellar optic pathway cavernous malformations.

Cerebral cavernous malformations constitute a subtype of cerebral vascular malformation typically located in the cerebral cortex. However, their occurrence in the suprasellar optic pathway is relatively rare. There is some uncertainty surrounding the clinical diagnostic methods and optimal treatment strategies specific to suprasellar optic pathway cavernous malformations. In this narrative review, we retrospectively analyzed relevant literature related to suprasellar visual pathway cavernous malformations. We conducted a study involving 90 patients who were postoperatively diagnosed with cavernous malformations, including the 16-year-old male patient mentioned in this article. We have summarized crucial clinical data, including the patient age distribution, sex ratio, lesion locations, primary symptoms, and surgical approaches. The comprehensive analysis of this clinical information underscores the critical importance of timely intervention in relieving symptoms and improving neurological deficits in affected patients. These findings provide valuable guidance and insight for clinical practitioners and researchers dealing with this specific medical condition.

Impact of Long-Term Antithrombotic and Statin Therapy on the Clinical Outcome in Patients with Cavernous Malformations of the Central Nervous System: A Single-Center Case Series of 428 Patients.

INTRODUCTION: Literature regarding the safety and efficacy of antithrombotic (antiplatelet or anticoagulant) therapy and statins in patients with cavernous malformations (CMs) of the central nervous system is sparse, resulting in uncertainty about its use in clinical practice. The aim of this study was to analyze the impact of antithrombotic therapy and statins on the risk of hemorrhage and focal neurological deficit in patients with CMs. METHODS: The authors' institutional database was screened for all patients with CMs of the central nervous system treated at their institution between 2006 and 2018. Patients with radiological and/or histological diagnosis of CMs, clinical baseline characteristics, available patient's medication history, and follow-up data were included in this study. Time-to-event probability (hemorrhage or focal neurological deficit) as well as the number of events (hemorrhage or focal neurological deficit) during follow-up were assessed in patients who were categorized according to their medical treatment (antithrombotic therapy, statins, combined therapy, or no treatment). RESULTS: Four hundred twenty-eight patients with CMs were eligible and included in the final analysis. Sixty-nine (16.1%) patients were on long-term antithrombotic therapy and 46 (10.6%) on long-term statins, of whom 31 patients were on a combination of both. The probability of experiencing first hemorrhage or focal neurological deficit was less likely in patients on antiplatelet therapy (HR 0.09, 95% CI 0.021-0.39, p = 0.001), anticoagulant therapy (HR 0.12, 95% CI 0.016-0.85, p = 0.034), or the combination thereof (HR 0.12, 95% CI 0.016-0.93, p = 0.043) compared to patients with no antithrombotic treatment. The number of hemorrhages and focal neurological deficits were significantly lower in patients on antithrombotic therapy compared to patients on no treatment during follow-up. In patients on statins alone, the time-to-event probability was comparable to that of patients on no treatment (HR 0.91, 95% CI 0.438-1.91, p = 0.812), and the number of events was similar to patients on no treatment. CONCLUSION: The results of our study provide further evidence that antithrombotic therapy alone or in combination with statins in patients with CMs of the central nervous system does not increase the risk of hemorrhage or focal neurological deficit but, on the contrary, may have some benefit.

Functional impact of multiple bleeding events in patients with conservatively treated spinal cavernous malformations.

OBJECTIVE: The aim of this study was to investigate the functional outcome in spinal cavernous malformation (SCM) patients with single or multiple intramedullary hemorrhagic events. METHODS: SCM patients who were conservatively treated between 2003 and 2021 and had complete clinical baseline characteristics, an MRI data set, at least one SCM-related intramedullary hemorrhage (IMH), and at least one follow-up examination were included in this study. Functional status was assessed using the modified McCormick Scale score at diagnosis, before and after each bleeding event, and at the last follow-up. RESULTS: A total of 45 patients were analyzed. Univariate analysis identified multiple bleeding events as the only statistically significant predictor for an unfavorable functional outcome at the last follow-up (OR 15.28, 95% CI 3.22-72.47; p < 0.001). Patients significantly deteriorated after the first hemorrhage (29.0%, p = 0.006) and even more so after the second hemorrhage (84.6%, p = 0.002). Multiple bleeding events were significantly associated with functional deterioration at the last follow-up (76.9%, p = 0.003). The time between the last IMH and the last follow-up did not influence this outcome. CONCLUSIONS: IMH due to SCM is linked to functional worsening. Such outcomes tend to improve after each hemorrhage, but the probability of full recovery declines with each bleeding event.