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.

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.

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.

Radiosurgery effects and adverse effects in symptomatic eloquent brain-located Cavernomas.

In this study, the dose schedule efficacy, safety and late adverse effects of stereotactic radiosurgery (SRS) were evaluated for patients with symptomatic cavernomas who were not eligible for surgery and treated with SRS. Between January 2013 and December 2018, 53 patients with cavernomas were treated using SRS with the CyberKnife® system. Patients' diseases were deeply located or were in subcortical functional brain regions. In addition to bleeding, 23 (43.4%) patients had epilepsy, 12 (22.6%) had neurologic symptoms and 16 patients (30.2%) had severe headaches. The median volume was 741 (range, 421-1351) mm3, and the median dose was 15 (range, 14-16) Gy in one fraction. After treatment, six (50%) of 12 patients with neurologic deficits still had deficits. Rebleeding after treatment developed in only two (3.8%) patients. The drug was completely stopped in 14 (60.9%) out of 23 patients who received epilepsy treatment, and the dose of levetiracetam decreased from 2000 mg to 1000 mg in four (17.3%) of nine patients. Radiologically, complete response (CR) was observed in 13 (24.5%) patients, and partial responses (PR) were observed in 32 (60.2%) patients. Clinical response of CR was observed in 30 (56.6%) patients, PR was observed in 16 (30.2%), stable disease (SD) was observed in three (5.7%) and four (7.5%) patients progressed. In conclusion, SRS applied in the appropriate dose schedule may be an effective and reliable method in terms of symptom control and prevention of rebleeding, especially in patients with inoperable cavernomas.

Cavernous Malformations: Updates in Surgical Management and Biology.

Cavernous malformations (CMs) are low-flow vascular lesions of the central nervous system prone to symptomatic hemorrhage. CMs are estimated to be present in approximately 0.5% of the population. Usually, they are characterized by a relatively benign clinical course, staying asymptomatic in many patients. However, depending on the anatomic location, CMs can cause significant morbidity due to symptoms such as seizures or focal neurologic deficits (most of the time caused by symptomatic hemorrhage). This nonsystematic review aims to summarize important recent clinical research focusing on the biology and surgical management of CMs published since 2017.

Natural History of Spinal Cord Cavernous Malformations: A Multicenter Cohort Study.

BACKGROUND: The natural history of spinal cord cavernous malformations (SCCMs) remains relatively unclear. OBJECTIVE: To investigate the natural history for hemorrhagic risks and neurological outcomes, as well as relevant predicting factors, of SCCMs. METHODS: All patients between 2002 and 2019 with diagnosis of SCCMs were identified retrospectively. An observational study of patients with conservative management was performed to reveal the natural history of SCCMs. RESULTS: We identified 305 patients in the full cohort, including 126 patients who were conservatively treated for at least 6 months (median observational period, 24.0 months). Forty-five hemorrhage events occurred during 527 person-years of follow-up, yielding an annual hemorrhage rate of 8.5% per person-year. The 1-, 2-, and 5-year cumulative risks of hemorrhage were 13.9%, 26.1%, and 35.1%, respectively. Prior hemorrhage (hazard ratio [HR] = 12.948, P = .012) and pediatric patients (HR = 2.841, P = .031) were independent predictors of hemorrhage in the long-term follow-up. Familial form (adjusted odds ratio [OR] = 30.695, P = .010) and subsequent hemorrhage events (adjusted OR = 16.333, P = .000) were independent risk factors for worsening of neurological function, and baseline neurological status (adjusted OR = 78.984, P = .000) and presence of subsequent hemorrhage (adjusted OR = 9.611, P = .001) were significantly associated with neurological outcomes. CONCLUSION: The natural history of SCCMs varies. Baseline characteristics, such as pediatric patients, familial form, and baseline neurological status, as well as prior and subsequent hemorrhagic events, significantly affect the natural history of the SCCMs, which prompts a differentiated treatment strategy.

Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.

BACKGROUND: To investigate whether common variants in EPHB4 and RASA1 are associated with cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. METHODS: Familial CCM cases enrolled in the Brain Vascular Malformation Consortium were included (n = 338). Total lesions and large lesions (≥5 mm) were counted on MRI; clinical history of ICH at enrollment was assessed by medical records. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We tested the association of seven common variants (three in EPHB4 and four in RASA1) using multivariable logistic regression for ICH (odds ratio, OR) and multivariable linear regression for total and large lesion counts (proportional increase, PI), adjusting for age, sex, and three principal components. Significance was based on Bonferroni adjustment for multiple comparisons (0.05/7 variants = 0.007). RESULTS: EPHB4 variants were not significantly associated with CCM severity phenotypes. One RASA1 intronic variant (rs72783711 A>C) was significantly associated with ICH (OR = 1.82, 95% CI = 1.21-2.37, p = 0.004) and nominally associated with large lesion count (PI = 1.17, 95% CI = 1.03-1.32, p = 0.02). CONCLUSION: A common RASA1 variant may be associated with ICH and large lesion count in familial CCM. EPHB4 variants were not associated with any of the three CCM severity phenotypes.

A novel insight into differential expression profiles of sporadic cerebral cavernous malformation patients with different symptoms.

Cerebral cavernous malformation (CCM) is a vascular lesion of the central nervous system that may lead to distinct symptoms among patients including cerebral hemorrhages, epileptic seizures, focal neurologic deficits, and/or headaches. Disease-related mutations were identified previously in one of the three CCM genes: CCM1, CCM2, and CCM3. However, the rate of these mutations in sporadic cases is relatively low, and new studies report that mutations in CCM genes may not be sufficient to initiate the lesions. Despite the growing body of research on CCM, the underlying molecular mechanism has remained largely elusive. In order to provide a novel insight considering the specific manifested symptoms, CCM patients were classified into two groups (as Epilepsy and Hemorrhage). Since the studied patients experience various symptoms, we hypothesized that the underlying cause for the disease may also differ between those groups. To this end, the respective transcriptomes were compared to the transcriptomes of the control brain tissues and among each other. This resulted into the identification of the differentially expressed coding genes and the delineation of the corresponding differential expression profile for each comparison. Notably, some of those differentially expressed genes were previously implicated in epilepsy, cell structure formation, and cell metabolism. However, no CCM1-3 gene deregulation was detected. Interestingly, we observed that when compared to the normal controls, the expression of some identified genes was only significantly altered either in Epilepsy (EGLN1, ELAVL4, and NFE2l2) or Hemorrhage (USP22, EYA1, SIX1, OAS3, SRMS) groups. To the best of our knowledge, this is the first such effort focusing on CCM patients with epileptic and hemorrhagic symptoms with the purpose of uncovering the potential CCM-related genes. It is also the first report that presents a gene expression dataset on Turkish CCM patients. The results suggest that the new candidate genes should be explored to further elucidate the CCM pathology. Overall, this work constitutes a step towards the identification of novel potential genetic targets for the development of possible future therapies.

Hemorrhage of a Cavernous Hemangioma of the Brainstem Presenting with Fever of Unknown Origin: A Case Report.

BACKGROUND Cavernous malformations (CMs) or hemangiomas are benign vascular hamartomas of the central nervous system (CNS) that constitute 5-15% of all CNS vascular malformations. Most patients with brainstem CMs present with a sudden onset of seizures, intracranial hemorrhage, cranial nerve deficits, headache, or ataxia. Up to 20% to 50% of patients are asymptomatic, and their CMs are diagnosed incidentally on brain magnetic resonance imaging. CASE REPORT We present a case of a 42-year-old man with a brainstem cavernous hemangioma presenting with fever of unknown origin and mild headache without meningismus. The patient underwent a midline suboccipital craniectomy and removal of a ruptured brainstem cavernous hemangioma and the surrounding thrombus. Postoperatively, the patient developed left facial nerve palsy, left abducens nerve palsy, and xerostomia. Abducens palsy and xerostomia resolved spontaneously days after the operation. At the 6-month follow-up, the patient showed stable improvement with resolution of his neurological deficits. CONCLUSIONS To our knowledge, there is no reported case of a patient with a ruptured brainstem cavernoma presenting with fever of unknown origin as the main symptom. We assume that the minimal intraventricular hemorrhage triggered the hypothalamic thermoregulating mechanism. Thus, it would be useful for physicians to raise the suspicion of a ruptured brainstem cavernous malformation with further imaging evaluation when investigating fever of unknown origin.

Towards precision nanomedicine for cerebrovascular diseases with emphasis on Cerebral Cavernous Malformation (CCM).

Introduction: Cerebrovascular diseases encompass various disorders of the brain vasculature, such as ischemic/hemorrhagic strokes, aneurysms, and vascular malformations, also affecting the central nervous system leading to a large variety of transient or permanent neurological disorders. They represent major causes of mortality and long-term disability worldwide, and some of them can be inherited, including Cerebral Cavernous Malformation (CCM), an autosomal dominant cerebrovascular disease linked to mutations in CCM1/KRIT1, CCM2, or CCM3/PDCD10 genes.Areas covered: Besides marked clinical and etiological heterogeneity, some commonalities are emerging among distinct cerebrovascular diseases, including key pathogenetic roles of oxidative stress and inflammation, which are increasingly recognized as major disease hallmarks and therapeutic targets. This review provides a comprehensive overview of the different clinical features and common pathogenetic determinants of cerebrovascular diseases, highlighting major challenges, including the pressing need for new diagnostic and therapeutic strategies, and focusing on emerging innovative features and promising benefits of nanomedicine strategies for early detection and targeted treatment of such diseases.Expert opinion: Specifically, we describe and discuss the multiple physico-chemical features and unique biological advantages of nanosystems, including nanodiagnostics, nanotherapeutics, and nanotheranostics, that may help improving diagnosis and treatment of cerebrovascular diseases and neurological comorbidities, with an emphasis on CCM disease.

Hemorrhagic Intracranial Cavernoma Presenting as a Homonymous Horizontal Sectoranopia.

ABSTRACT: Hemorrhagic lateral geniculate nucleus (LGN) insults are rare but have been reported in association with tumors, vascular malformations, and trauma. The localization of LGN lesions is facilitated by recognition of pathognomonic visual field defects. A 21-year old woman developed a sudden onset painless left homonymous horizontal sectoranopia. Magnetic resonance imaging revealed a hemorrhagic cavernous malformation of the right temporal lobe. Optical coherence tomography (OCT) and Humphrey perimetry findings localized the lesion to the right LGN. Specifically, OCT testing revealed a right homonymous sectoranopia pattern of hemi-retinal macular ganglion layer-inner plexiform layer (mGCIPL) thinning contralateral to the left sided visual field defect. The OCT pattern reflected retrograde neuroaxonal degeneration from the right LGN lesion. This case highlights a unique pattern of mGCIPL thinning characteristic for a posterior lateral choroidal artery injury, affecting the LGN. These findings illustrate how functional eloquence correlates with topographical elegance in the afferent visual pathway.

Cavernous malformation of the intracranial optic nerve with operative video and review of the literature.

Optic pathway cavernous malformations represent less than 1% of all central nervous system cavernomas. They can lead to visual loss with indeterminate speed, and therefore, the timing of intervention is controversial. We present a patient with an optic nerve cavernoma, which was discovered incidentally 3 years before the onset of visual symptoms. The evolution of her symptoms, visual function and radiographic findings are reported in detail. The cavernoma was eventually removed via a transciliary orbitocranial keyhole approach with the goal to protect the optic chiasm from progressive involvement. The function in the affected optic nerve was not salvageable. This is the second reported case of a cavernoma selectively involving the intracranial portion of the optic nerve. The debate on the timing of intervention is highlighted with reference to the natural history of these rare lesions.

Signalling through cerebral cavernous malformation protein networks.

Cerebral cavernous malformations (CCMs) are neurovascular abnormalities characterized by thin, leaky blood vessels resulting in lesions that predispose to haemorrhages, stroke, epilepsy and focal neurological deficits. CCMs arise due to loss-of-function mutations in genes encoding one of three CCM complex proteins, KRIT1, CCM2 or CCM3. These widely expressed, multi-functional adaptor proteins can assemble into a CCM protein complex and (either alone or in complex) modulate signalling pathways that influence cell adhesion, cell contractility, cytoskeletal reorganization and gene expression. Recent advances, including analysis of the structures and interactions of CCM proteins, have allowed substantial progress towards understanding the molecular bases for CCM protein function and how their disruption leads to disease. Here, we review current knowledge of CCM protein signalling with a focus on three pathways which have generated the most interest-the RhoA-ROCK, MEKK3-MEK5-ERK5-KLF2/4 and cell junctional signalling pathways-but also consider ICAP1-ß1 integrin and cdc42 signalling. We discuss emerging links between these pathways and the processes that drive disease pathology and highlight important open questions-key among them is the role of subcellular localization in the control of CCM protein activity.

DNA promoter methylation of CCM genes in human cerebral cavernous malformations: Importance of confirming MSP data through sequencing.

BACKGROUND: Cerebral cavernous malformations (CCMs) is the second most common cerebrovascular disease and is classified as familial (20%) and sporadic (80%) forms. Loss of function mutation of three CCM genes results in the familial CCM. Considering the similar clinic presentation of familial and sporadic CCMs, and based on enriched CpG islands in the DNA promoter region of three CCM genes, we hypothesized that DNA methylation of the CpG islands of the CCM genes is involved in human CCM, thereby leading to loss of CCM genes. MATERIAL AND METHODS: 69 human CCMs including sporadic (n = 40), multiple (n = 15) and familial (n = 14) cases. DNA was extracted from the surgical specimens of CCMs followed by bisulfite conversion. The methylation status of the promoter regions of three CCM genes was detected by methylation specific PCR (MSP). To confirm the results of MSP, four MSP-positive probes showing CCM3 methylation underwent deep bisulfite sequencing (DBS). RESULTS: MSP mostly excluded methylation of CCM1 and CCM2 promotor regions (data not shown). In the case of CCM3, 12 out of 55 sporadic cases showed positivity for MSP (21.8%). Deep bisulfite sequencing revealed that four CCM3 MSP positive cases were all negative for DNA methylation. CONCLUSION: The present study suggests that DNA promotor methylation of CCM1-3 genes is not involved in human family CCMs and that it is important to confirm MSP data with DBS. Further study with higher number of sporadic CCM patients is required for better understanding whether this epigenetic mechanism is involved in the pathology of CCM.