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Background: Surgical resection of the lesions remains the main treatment method for most symptomatic spinal cord cavernous malformations (SCCMs) to eliminate the occupation and associated subsequent lifelong haemorrhagic risk. However, the timing of surgical intervention remains controversial, especially for patients in the acute stage after severe haemorrhage., Methods: Patients diagnosed with SCCMs who were surgically treated between January 2002 and December 2021 were selected and retrospectively reviewed. The Modified McCormick Scale (MMS) was used to evaluate neurological and disability status. All medical information was reviewed, and all patients were followed up for at least 6 months., Results: A total of 279 patients were ultimately included. With regard to long-term outcomes, 110 (39.4%) patients improved, 159 (57.0%) remained unchanged and 10 (3.6%) worsened. For patients with an MMS score of 2-5 on admission, in univariate and multivariate analyses, a ≤6 weeks period between onset and surgery (adjusted OR 3.211, 95% CI 1.504 to 6.856, p=0.003) was a significant predictor of improved MMS. Among 69 patients who first presented with severe haemorrhage, undergoing surgery within 6 weeks of the onset of severe haemorrhage (adjusted OR 4.901, 95% CI 1.126 to 21.325, p=0.034) was significantly associated with improvement of MMS score., Conclusion: Surgical timing can influence the long-term outcome of SCCMs. For patients with symptomatic SCCMs, especially those with severe haemorrhage, early surgical intervention within 6 weeks can provide more benefit., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Cerebral vascular malformations (CVMs) may result in hemorrhage, seizure, neurologic dysfunction, and death. CVMs include capillary telangiectasias, venous malformations, cavernous malformations, and arteriovenous malformations. Cavernous and arteriovenous malformations carry the highest risk of complications. Retinal venous malformations (RVMs) have been proposed as an associated finding. Our objective was to determine the prevalence of RVMs in patients with high-risk CVMs., Methods: We retrospectively reviewed patients diagnosed with cerebral cavernous or arteriovenous malformations (high-risk CVMs) who were evaluated by the ophthalmology service at Northwestern University between 2017 and 2020. Patients were stratified into 3 cohorts based on level of certainty: dilated funduscopic examination (DFE), DFE with any form of ocular imaging, and DFE with complete imaging of the macula. We recorded ophthalmic examination abnormalities, ocular imaging findings, and major CVM complications., Results: We evaluated 156 patients with high-risk CVMs who had undergone DFE. Ocular imaging of any type was performed in 56 patients, of whom 46 had complete imaging of the macula. Zero RVMs were identified in any cohort (95% confidence interval: 0%-1.9% for the entire cohort, 0%-5.4% for any ocular imaging cohort, and 0%-6.5% for the complete macular imaging cohort). Cerebral hemorrhage or seizure occurred in 15%-33% of patients. Associated visual field defects or cranial nerve palsies were found in 14%-20% of patients., Conclusions: Zero RVMs were identified in patients with high-risk CVMs. However, neuro-ophthalmic findings were common. Therefore, we recommend neuroimaging for patients with RVMs and neuro-ophthalmic signs or symptoms. In asymptomatic patients with RVMs, a potential algorithm for neuroimaging is proposed., Competing Interests: J. A. Lavine is a consultant for Genentech for work unrelated to this study. All other authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

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., (© 2024. The Author(s).)

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.

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., Competing Interests: Declaration of conflicting interestsThe authors declare that there is no conflict of interest.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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.

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

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., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

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., (© 2021. The Author(s).)

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.

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by North American Neuro-Ophthalmology Society.)

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.

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., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this study we have optimized nanoelectrospray ionization (nanoESI) high resolution mass spectrometry (HR MS) performed on Orbitrap instrument in the negative ion mode for the determination of the composition and structure of gangliosides extracted from human brain cavernous hemangioma. The optimized HR MS platform, allowed the discrimination of 62 ions, corresponding to 52 different ganglioside species, which represents roughly twice the number of species existing in the current inventory of human brain hemangioma-associated gangliosides. The experiments revealed a ganglioside pattern dominated by GD-type of structures as well as an elevated incidence of species characterized by a low degree of sialylation and short glycan chains, including asialo GA1 (d18:1/18:0), which offer a new perspective upon the ganglioside composition in this benign tumor. Many of the structures are characteristic for this type of tumor only and are to be considered in further investigations for their potential use in early brain hemangioma diagnosis based on molecular markers. The detailed fragmentation analysis performed by collision-induced dissociation (CID) tandem MS provided information of structural elements related to the glycan core and ceramide moiety, which confirmed the molecular configuration of GD3 (d18:1/24:1) and GD3 (d18:1/24:2) species with potential biomarker role., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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-β1 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.

Cerebral cavernous malformations (CCM) are collections of enlarged capillaries with irregular structure, located in the brain or spinal cord, that can be life-threatening. We describe a neurologically asymptomatic 15-year-old boy who presented with cutaneous venous malformations (CVM) that developed in adolescence. Owing to his family history of CCM, genetic testing was obtained and confirmed a new mutation in the CCM3 (PDCD10) gene. Brain imaging showed multiple CCM. Although currently asymptomatic, he will continue to be monitored annually by neurology to assess for symptoms of intracranial hemorrhage (ICH) that would warrant investigation with MRI., (© 2020 Wiley Periodicals LLC.)

A 30-year-old woman presented with diplopia after resection of an intracranial cavernous malformation. Fundus examination showed an asymptomatic intraocular cavernous hemangioma of the retina. Clinicians should be aware of the potential coexistence of intraocular and intracranial cavernous malformations; the presence of both should suggest familial etiology. As with other intracranial and intraocular vascular lesions (e.g., arteriovenous malformation in Wyburn-Mason syndrome, retinal hemangioblastoma in von Hippel Lindau disease, and choroidal hemangioma in Sturge-Weber syndrome), the presence of a vascular lesion in either location should prompt evaluation for additional pathology.

Autosomal dominant cerebral cavernous malformations (CCM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family. We here asked the question whether further structural genomic rearrangements can be detected within NGS gene panel data of unsolved CCM cases. Hybrid capture NGS data of eight index patients without a pathogenic single nucleotide, indel or copy number variant were analyzed using two bioinformatics pipelines. In a 58-year-old male with multiple CCMs in his brain and spinal cord, we identified a 294 kb insertion within the coding sequence of CCM2. Fine mapping of the breakpoints, molecular cytogenetic studies, and multiplex ligation-dependent probe amplification verified that the structural variation was an inverted unbalanced insertion that originated from 1p12-p11.2. As this rearrangement disrupts exon 6 of CCM2 on 7p13, it was classified as pathogenic. Our study demonstrates that efforts to detect structural variations in known disease genes increase the diagnostic sensitivity of genetic analyses for well-defined Mendelian disorders.

Cavernous malformations (CM) are angiographically occult vascular malformations. CM appear as discrete, small lesions with mixed-signal characteristics on T2 reflecting the underlying pathology. However, the appearance is not pathognomonic. Distinguishing true CM from hemorrhagic tumors can be difficult. We report 5 cases of tumors mimicking CMs. We compared clinical, initial radiologic features, and MRI evolution between 5 tumor mimics and 51 true hemorrhagic, sporadic, brain CM. Compared to true CM, mimic patients were older (47.0 vs. 38.3 years; p = 0.076) and more likely to have a history of primary neoplasm (60% vs 12%; p = 0.0267). Radiologically, the CM mimics demonstrated a higher likelihood of lesion enhancement on the initial diagnostic MRI (60% vs. 16.7%%; p = 0.0609). On follow-up MRI (<1 year after baseline), CM mimics typically had persistent edema (100.0% vs. 6.25%, p = 0.0003) and demonstrated mixed density on ADC (100% vs. 32.1%; p = 0.0199) as well as increased likelihood of enhancement (100% vs 25.8, p = 0.0852). CM mimics were less likely to evolve to Type 2 or 3 lesions (25.0% vs. 84.4%, p = 0.0278). Clinical and radiologic factors may distinguish tumor metastases from true hemorrhagic CM. CM mimics should be suspected in older patients with a history of neoplasm and contrast enhancement on initial MRI. A repeat MRI within 90 days post-initial hemorrhage should be considered to confirm CM diagnosis. Persistent edema without rebleed, lesion enhancement, mixed signal on apparent diffusion co-efficient, and persistence of a Type 1 lesion should raise suspicion of a metastatic tumor., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Intraosseous cavernous malformations (ICMs) of the skull are relatively rare, benign, and slow-growing tumors. Knowledge of these lesions is poor. The goals of this study were to describe the clinical manifestations, radiological features, and long-term surgical outcomes of this disease. We performed a retrospective analysis of a series of 16 cranial ICM patients who underwent surgical treatment in our hospital between 2003 and 2016. The incidence of cranial ICM was 1.15% among the entire series of intracranial and intraspinal CMs. Our cohort included 6 male and 10 female patients; their mean age at operation was 38.7 years (range, 1.9 to 63 years). Slowly growing swelling was the commonest clinical manifestation of this disease. Complete lesion resection was achieved in all but one patient, and cranioplasty was performed using titanium mesh in 11 cases. Postoperative complication was found in one patient who developed diplopia, and this symptom resolved spontaneously before discharge. The mean follow-up period after operation was 76.2 months (range, 19 to 119 months). Only the patient with petroclival ICM had some occasional headaches (mRS = 1); others were all in stable neurological status (mRS = 0). No lesion recurrence was found during the follow-up period. Although cranial ICM is rare, it should always be considered as a differential diagnosis in the case of firm, gradually enlarging skull lesions. Surgical resection should be the treatment of choice for the symptomatic patients and their long-term outcomes were excellent after gross total removal.

Cavernous cerebral malformations (CCMs) can show typical and characteristic findings at neuroradiology, above all at magnetic resonance imaging, but differential diagnosis with other lesions of similar appearance can be challenging and should be taken into consideration. Management of CCMs can be conservative in most cases, and thus appropriate follow-up timing and modality is required. Growing input from neurologists, neurosurgeons, neuroradiologists, and patients recommend to offer a standard neuroradiological report, to enhance interpretation and comparability in daily clinical practice. The purpose of this chapter is to present differential diagnosis, follow-up, and reporting of CCMs by neuroradiology.

This is a review of imaging techniques used to evaluate cerebral cavernous malformations (CCMs) and imaging findings associated with CCMs. This chapter includes discussion of computed tomography and magnetic resonance imaging sequences, appearance of CCMs and associated hemorrhage and key features to evaluate on imaging studies.

The development of distinct cellular and animal models has allowed the identification and characterization of molecular mechanisms underlying the pathogenesis of cerebral cavernous malformation (CCM) disease. This is a major cerebrovascular disorder of proven genetic origin, affecting 0.5% of the population. Three disease genes have been identified: CCM1/KRIT1, CCM2, and CCM3. These genes encode for proteins implicated in the regulation of major cellular structures and mechanisms, such as cell-cell and cell-matrix adhesion, actin cytoskeleton dynamics, and endothelial-to-mesenchymal transition, suggesting that they may act as pleiotropic regulators of cellular homeostasis. Indeed, accumulated evidence in cellular and animal models demonstrates that emerged pleiotropic functions of CCM proteins are mainly due to their ability to modulate redox-sensitive pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, thus contributing to the preservation of cellular homeostasis and stress defenses. In particular, we demonstrated that KRIT1 loss-of-function affects master regulators of cellular redox homeostasis and responses to oxidative stress, including major redox-sensitive transcriptional factors and antioxidant proteins, and autophagy, suggesting that altered redox signaling and oxidative stress contribute to CCM pathogenesis, and opening novel preventive and therapeutic perspectives.In this chapter, we describe materials and methods for isolation of mouse embryonic fibroblast (MEF) cells from homozygous KRIT1-knockout mouse embryos, and their transduction with a lentiviral vector encoding KRIT1 to generate cellular models of CCM disease that contributed significantly to the identification of pathogenetic mechanisms.

Cerebral Cavernous Malformations (CCMs) are vascular lesions which can occur as a sporadic (80% of the cases) or a familial autosomal dominant disease (20%), the latter being characterized by the presence of multiple lesions. Three CCM genes have been identified in the last 10 years. More than 95% of familial cases and 60% of sporadic cases with multiple lesions harbor a germline heterozygous loss of function mutation in one of these 3 genes. Most mutations lead to a premature stop codon whatever the mechanism, including nonsense mutations, deletions, insertions and intronic mutations leading to abnormal splicing and frameshift. A combination of analyses, including sequencing and copy number analysis of germline DNA extracted from blood and cDNA analysis, are therefore required to ensure the best diagnostic sensitivity. Additional causative rare structural CCM gene anomalies have been identified in a research context, as well as rare causative missense mutations. These mutations are rarely searched for in a diagnostic context and explain part of the negative cases, in addition to germline mosaicism which occurs in some sporadic cases with multiple lesions. On top of germline mutations, somatic mutations occur on the wild-type allele in endothelial cells lining CCM lesions. These data established both the role of a double hit in the pathophysiology of CCM lesions and the heterogeneity of endothelial cells lining these lesions.

The incidence, prevalence, and mode of presentation of cavernous malformations is important to better understand the disease, educate patients and practitioners, aid in treatment decisions, and to design clinical trials. Prior to the advent of MRI, cavernous malformations were often diagnosed only when a catastrophic event occurred and/or the lesion was removed. With the more frequent diagnostic use of MRI, it has become clear that cavernous malformations are more prevalent than previously thought and many are identified incidentally. The remainder may present to clinical attention with intracerebral hemorrhage, seizure without hemorrhage, or focal neurologic deficit without overt hemorrhage. The precise reason why some cavernous malformations become symptomatic and others remain asymptomatic is not clear. However, evolving data suggests that brainstem location, estrogen use in women, and low vitamin D may play a role in hemorrhagic presentation.

Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by brain lesions that can cause hemorrhagic strokes, seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Genetic modifiers of CCM1 disease severity have been recently identified and included common genetic variants in inflammatory, immune response, and oxidative stress genes and pathways. Here, we describe the genotyping of CCM1 patients with the same gene mutation (Q455X) using a high-throughput genotyping array optimized for individuals of Hispanic/Latino ancestry. We then review the quality control steps following the genome-wide genotyping. Genome-wide genotyping of larger cohorts of CCM1 patients might reveal additional genetic variants contributing to the disease severity of CCM1.

The CRISPR/Cas9 system is a versatile tool that enables targeted genome editing in various cell types, including hard-to-transfect endothelial cells. The required crRNA, tracrRNA, and Cas9 protein have mostly been introduced into endothelial cells by viral transduction or plasmid transfection so far. We here describe an effective lipofection-based delivery of pre-complexed crRNA:tracrRNA:Cas9 ribonucleoproteins into human umbilical vein endothelial cells (HUVEC) and immortalized HUVEC (CI-huVEC). Complete inactivation of either CCM1, CCM2, or CCM3 in endothelial cells mimics the situation in cavernous lesions of CCM patients and thus represents a suitable model for future studies.

Surgical removal of accessible lesions is the only direct therapeutic approach for cerebral cavernous malformations (CCMs). The approach should be carefully evaluated according to clinical, anatomical, and neuroradiological assessment in order to both select the patient and avoid complications. In selected cases, a quantitative anatomical study with a preoperative simulation of surgery could be used to plan the operation. Neuronavigation, ultrasound, and neurophysiologic monitoring are generally required respectively to locate the CCMs and to avoid critical areas. The chapter describes all the possible surgical approaches for supratentorial, infratentorial, deep seated and brain stem CCMs. In any case before performing surgery, the physicians should always consider the benign nature of the lesions and the absolute necessity to avoid not only neurological deficits, but also a neuropsychological impairment that could affect the quality of life of the patients.

Linear scleroderma is a form of localized scleroderma that presents as band-like sclerotic lesions. When it occurs on the scalp or forehead, it is called "en coup de sabre scleroderma" (ECDS). Extracutaneous associations, mostly neurologic, have been described with ECDS. We report a patient with ECDS associated with multiple cerebral cavernomas. This serves to highlight the importance of neuroimaging and multidisciplinary team involvement in patients with ECDS., (© 2019 Wiley Periodicals, Inc.)

We describe Natural history, clinical and surgical management of cavernous malformation of the brain and spinal cord. Decision-making for treatment of cavernous malformations cannot ignore their natural history and risk of bleeding, which is different depending on the location. Surgical morbidity also depends on the position of the lesion. We performed a review of hemorrhage risk and clinical assessment of superficial and deep supratentorial, brainstem and intramedullary cavernous malformations.

The application of next generation sequencing (NGS) technique has a great impact on complex disease studies. Indeed, genetic heterogeneity, phenotypic variability, and disease rarity are all factors that make the traditional diagnostic approach to genetic disorders, whereby a specific gene is selected for sequencing based on the clinical phenotype, very challenging and obsolete.Exome sequencing, which sequences the protein-coding region of the genome, has been rapidly applied to variant discovery in research settings. Recent coverage and accuracy improvements have accelerated the development of clinical exome sequencing (CES) platforms targeting disease-related genes and enabling variant identification in patients with suspected genetic diseases. Nowadays, CES is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases, especially for those with heterogeneous etiology and clinical presentation. Reporting large CES series can improve guidelines on best practices for test utilization, and a better variant interpretation through clinically oriented data sharing.Herein, we suggest a feasible CES procedure for the genetic testing of Cerebral Cavernous Malformation (CCM) disease, including proband identification, library preparation, data analysis, and variant interpretation.

Cerebral cavernous malformation (CCM) is a rare cerebrovascular disorder of genetic origin consisting of closely clustered, abnormally dilated and leaky capillaries (CCM lesions), which occur predominantly in the central nervous system. CCM lesions can be single or multiple and may result in severe clinical symptoms, including focal neurological deficits, seizures, and intracerebral hemorrhage. Early human genetic studies demonstrated that CCM disease is linked to three chromosomal loci and can be inherited as autosomal dominant condition with incomplete penetrance and highly variable expressivity, eventually leading to the identification of three disease genes, CCM1/KRIT1, CCM2, and CCM3/PDCD10, which encode for structurally unrelated intracellular proteins that lack catalytic domains. Biochemical, molecular, and cellular studies then showed that these proteins are involved in endothelial cell-cell junction and blood-brain barrier stability maintenance through the regulation of major cellular structures and mechanisms, including endothelial cell-cell and cell-matrix adhesion, actin cytoskeleton dynamics, autophagy, and endothelial-to-mesenchymal transition, suggesting that they act as pleiotropic regulators of cellular homeostasis, and opening novel therapeutic perspectives. Indeed, accumulated evidence in cellular and animal models has eventually revealed that the emerged pleiotropic functions of CCM proteins are mainly due to their ability to modulate redox-sensitive pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, thus contributing to the preservation of cellular homeostasis and stress defenses.In this introductory review, we present a general overview of 20 years of amazing progress in the identification of genetic culprits and molecular mechanisms underlying CCM disease pathogenesis, and the development of targeted therapeutic strategies.

Cerebral cavernous malformations (CCMs) is a disorder of endothelial cells predominantly localized in the brain. Although a complete inactivation of each CCM protein has been found in the affected endothelium of diseased patients and a necessary and additional role of microenvironment has been demonstrated to determine in vivo the occurrence of vascular lesions, a microvascular endothelial model based on knockdown of a CCM gene represents today a convenient method to study some of critical signaling events regulating pathogenesis of CCM. For these reasons, in our laboratory we developed a microvascular cerebral endothelial model of Krit1 deficiency performing silencing experiments of CCM1 gene (Krit1) with siRNA procedure.

This chapter presents methods for exploiting the powerful tools available in the nematode worm Caenorhabditis elegans to understand the in vivo functions of cerebral cavernous malformation (CCM) genes and the organization of their associated signaling pathways. Included are methods for assessing phenotypes caused by loss-of-function mutations in the worm CCM genes kri-1 and ccm-3, CRISPR-based gene editing techniques, and protocols for conducting high-throughput forward genetic and small molecule screens.

Familial cerebral cavernous malformation (FCCM) is an autosomal dominant vascular disorder caused by heterozygous deleterious variants in KRIT1, CCM2 or PDCD10. In a previous study, we presented the clinical and molecular findings in 140 FCCM individuals. In the present work, we report supporting information on (a) applied diagnostic workflow; (b) clinical significance of molecular findings according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology recommendations; (c) standardization of molecular and clinical data according to the Human Phenotype Ontology; (d) preliminary genotype-phenotype correlations on a subgroup of patients by considering sex, age at diagnosis, neurological symptoms, and number and anatomical site(s) of vascular anomalies; (e) datasets submitted to the Leiden Open Variation Database. An overview of the changes of our diagnostic approach before and after the transition to next-generation sequencing is also reported. This work presents the full procedure that we apply for molecular testing, data interpretation and storing in public databases in FCCM., (© 2019 Wiley Periodicals, Inc.)