Concurrent multiple cerebral cavernous malformations and cauda equina paraganglioma: illustrative case.

BACKGROUND: Cauda equina neuroendocrine tumors (CENETs), previously known as cauda equina paragangliomas, and multiple cerebral cavernous malformations (CCMs) are uncommon conditions affecting the central nervous system. To the authors' knowledge, they have not been reported in the same patient. OBSERVATIONS: The authors present the case of a 45-year-old male with CENET and concurrent incidental MRI findings of multiple CCMs. Familial CCMs are associated with mutations in the KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) genes. Peripheral paragangliomas have been associated with mutations in succinate dehydrogenase (SDHx), RET (multiple endocrine neoplasia 2), VHL (von Hippel-Lindau syndrome), and NF1 (neurofibromatosis type 1) genes. Except for a single case, cauda equina paragangliomas have not been associated with any underlying genetic mutations. LESSONS: It is unclear whether the co-occurrence of these two rare conditions in the same patient is coincidental or suggests a possible shared pathogenesis. https://thejns.org/doi/10.3171/CASE24102.

Long-Term Outcomes of Gamma Knife Radiosurgery for Cerebral Cavernous Malformations: 10 Years and Beyond.

BACKGROUND: We aimed to evaluate long-term outcomes of gamma knife radiosurgery (GKS) for cerebral cavernous malformations (CCMs). METHODS: Among the 233 CCM patients who underwent GKS, 79 adult patients (96 lesions) followed for over 10 years were included and analyzed retrospectively. Annual hemorrhage rate (AHR) was analyzed the entire cohort of 233 patients and the subset of 79 enrolled patients by dividing lesions into overall CCM lesions and brainstem lesions. AHR, neurologic outcome, adverse radiation effect (ARE), and changes of lesions in magnetic resonance imaging (MRI) were compared before and after GKS. Cox-regression analysis was performed to identify risk factors for hemorrhage following GKS. RESULTS: Mean follow-up duration of 79 enrolled patients was 14 years (range, 10-23 years). The AHR of all CCMs for entire cohort at each time point was 17.8% (pre-GKS), 5.9% (≤ 2 years post-GKS), 1.8% (≤ 10 years post-GKS). The AHR of all CCM for 79 enrolled patients was 21.4% (pre-GKS), 3.8% (2 years post-GKS), 1.4% (10 years post-GKS), and 2.3% (> 10 years post-GKS). The AHR of brainstem cavernous malformation (CM) for entire cohort at each time point was 22.4% (pre-GKS), 10.1% (≤ 2 years post-GKS), 3.2% (≤ 10 years post-GKS). The AHR of brainstem CM for 79 enrolled patients was 27.2% (pre-GKS), 5.8% (2 years post-GKS), 3.4% (10 years post-GKS), and 3.5% (> 10 years post-GKS). Out of the 79 enrolled patients, 35 presented with focal neurologic deficits at the initial clinical visit. Among these patients, 74.3% showed recovery at the last follow-up. Symptomatic ARE occurred in five (6.4%) patients. No mortality occurred. Most lesions were decreased in size at the last follow-up MRI. Previous hemorrhage history (hazard ratio [HR], 8.38; 95% confidence interval [CI], 1.07-65.88; P = 0.043), and brainstem location (HR, 3.10; 95% CI, 1.26-7.64; P = 0.014) were significant risk factors for hemorrhage event. CONCLUSION: GKS for CCM showed favorable long-term outcomes. GKS should be considered for CCM, especially when it has a previous hemorrhage history and brainstem location.

Comprehensive analysis of Novel mutations in CCM1/KRIT1 and CCM2/MGC4607 and their clinical implications in Cerebral Cavernous malformations.

BACKGROUND: Cerebral Cavernous Malformations (CCM) is a genetic disease characterized by vascular abnormalities in the brain and spinal cord, affecting 0.4-0.5 % of the population. We identified two novel pathogenic mutations, CCM1/KRIT1 c.811delT (p.Trp271GlyfsTer5) and CCM2/MGC4607 c.613_614insGG p.Glu205GlyfsTer31), which disrupt crucial protein domains and potentially alter disease progression. OBJECTIVE: The study aims to comprehensively analyze a Brazilian cohort of CCM patients, integrating genetic, clinical, and structural aspects. Specifically, we sought to identify novel mutations within the CCM complex, and explore their potential impact on disease progression. METHODS: We conducted a detailed examination of neuroradiological and clinical features in both symptomatic and asymptomatic CCM patients, performing genetic analyses through sequencing of the CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes In silico structural predictions were carried out using PolyPhen-2, SIFT, and Human Genomics Community tools. Protein-protein interactions and docking analyses were explored using the STRING database. RESULTS: Genetic analysis identifies 6 pathogenic mutations, 4 likely pathogenic, 1 variants of uncertain significance, and 7 unclassified mutations, including the novel mutations in CCM1 c.811delT and CCM2 c.613_614insGG. In silico structural analysis revealed significant alterations in protein structure, supporting their pathogenicity. Protein-protein interaction analysis indicated nuanced impacts on cellular processes. Clinically, we observed a broad spectrum of symptoms, including seizures and focal neurological deficits. However, no statistically significant differences were found in lesion burden, age of first symptom onset, or sex between the identified CCM1/KRIT1 and CCM2/MGC4607 mutations among all patients studied. CONCLUSION: This study enhances the understanding of CCM by linking clinical variability, genetic mutations, and structural effects. The identification of these novel mutations opens new avenues for research and potential therapeutic strategies.

Outcomes after surgical and nonsurgical treatment of pediatric cerebral cavernous malformation.

Importance: Pediatric cerebral cavernous malformation (CCM) is a rarely encountered vascular entity. Comparative study on surgical excision and nonsurgical management outcomes of CCM in pediatrics is limited. Objective: To determine the demographic characteristics, hemorrhage rate, and long-term outcomes of pediatric patients with CCM. Methods: A retrospective study of pediatric patients with CCM in Chinese PLA General Hospital was conducted between January 2004 and January 2019. We compared the clinical characteristics, radiological features, and outcomes of the surgical and nonsurgical groups. Results: Seventy-nine children were included, with 69.6% being boys, and the average age was 11.8 ± 5.5 years. The annual retrospective hemorrhagic rate was 5.7% per patient per year. Fifty-six children (70.9%) underwent surgical excision, and they were more likely to present with seizure symptoms (P = 0.011), have a higher proportion of larger lesion size (P = 0.008), less likely to have durations ≤10 days (P = 0.048), and less likely to have supratentorial deep CCM (P = 0.014) compared to children who received nonsurgical management. Total resection was achieved in most surgical cases (55, 98.2%). During the 143.9 ± 50.8 months of follow-up, 44 patients (78.6%) achieved improvement, 12 patients (17.8%) remained the same, and two (3.6%) experienced worsening. In the nonsurgical management group, 14 children (60.9%) experienced symptom improvement, eight (34.8%) remained the same, and one (4.3%) worsened, with a re-hemorrhagic risk of 8.7%. Interpretation: Surgical removal of pediatric CCM can eliminate the risk of hemorrhage and lead to satisfactory outcomes. For children undergoing nonsurgical management, long-term close monitoring is essential due to the life-long risk of hemorrhage.

Intracranial Cavernous Malformation with Concomitant Isolated Cerebral Mucormycosis Infection: A Case Report.

Cerebral cavernous malformation is an angiographically occult, well-circumscribed, benign hamartoma consisting of thin-walled sinusoidal vascular channels. Intracranial mucormycosis represents one of the most severe manifestations of mucor infection. We, hereby, report a case of cavernous malformation made rarer with concomitant mucormycosis. A 22-year-old female presented with left-sided facial seizures since age of 7 years and headache for the past 3 years. Magnetic resonance imaging brain revealed a right posterior frontal lobe cavernous malformation. Right frontal craniotomy with excision of cavernoma was done. Gross examination showed a solid cystic mass with multiple mulberry protrusions. Histopathological examination revealed features of cavernous malformation with evidence of mucormycosis. A final diagnosis of cavernous malformation with mucormycosis was rendered and microbiological studies were advised. To the best of our knowledge, this is the first case report of a cerebral cavernous malformation with mucormycosis in an immunocompetent patient without any risk factor.

Management of intracranial cavernous malformations using conservative vs. surgical and/or radiosurgical treatment: A systematic review and meta­analysis.

Intracranial cavernous malformations (CMs) are vascular lesions with a high bleeding rate. At present, the debate regarding their treatment is still ongoing. The present systematic review and meta-analysis aimed to evaluate the safety of surgery or radiosurgery (SRS) for the management of CMs and to determine their potential outcomes compared with conservative treatment. The present systematic review and meta-analysis investigated the relative articles involving the management of intracranial CMs, namely their natural history (conservative treatment) vs. surgical/SRS treatment through electronic databases until June, 2023. The collected variables included the first author's name, the study period covered, the year of publication, the total number of patients examined and their age, and the number of males. In total, six articles met the eligibility criteria. The total number of patients was 399 (157 in the surgery/SRS group and 242 in the conservative treatment group). The results revealed that surgical or SRS management is a safe procedure for CMs compared with conservative treatment. Notably, the use of hemosiderin in the pre-MRI, the free of seizures parameter and the neurological deficit parameters were associated with improved outcomes in the surgical or SRS group of patients.

Giant cerebral cavernous malformation in a newborn: a rare case report and review of literature.

BACKGROUND: Cavernous malformations (CMs), also known as cavernomas or cavernous angiomas, are vascular malformations characterized by sinusoidal spaces lined by endothelial cells. Giant CMs (GCMs) are extremely rare, with limited understanding of their presentation and management. We present a case of symptomatic GCM in a newborn and review the literature on this rare entity. CASE DESCRIPTION: A 1-month-old newborn presented with focal seizures and signs of increased intracranial pressure. Imaging revealed a massive right frontal-parietal GCM, prompting surgical resection. Histopathological examination confirmed the diagnosis of cerebral cavernous malformation. The patient recovered well postoperatively with no neurological deficits. CONCLUSIONS: GCMs are exceedingly rare in children and have not been reported in newborns until now. Symptoms typically include seizures and mass effects. Gross total resection is the standard treatment, offering favorable outcomes. Further research is needed to understand the natural history and optimal management of GCMs, particularly in newborns, emphasizing the importance of heightened clinical awareness for timely diagnosis and appropriate management.

Clinical Features and Treatment of Pediatric Cerebral Cavernous Malformations.

Cerebral cavernous malformation (CCM) is a vascular anomaly commonly found in children and young adults. Common clinical presentations of pediatric patients with CCMs include headache, focal neurological deficits, and seizures. Approximately 40% of pediatric patients are asymptomatic. Understanding the natural history of CCM is crucial and hemorrhagic rates are higher in patients with an initial hemorrhagic presentation, whereas it is low in asymptomatic patients. There is a phenomenon known as temporal clustering in which a higher frequency of symptomatic hemorrhages occurs within a few years following the initial hemorrhagic event. Surgical resection remains the mainstay of treatment for pediatric CCMs. Excision of a hemosiderin-laden rim is controversial regarding its impact on epilepsy outcomes. Stereotactic radiosurgery is an alternative treatment, especially for deepseated CCMs, but its true efficacy needs to be verified in a clinical trial.

Infratentorial Cerebral Cavernous Malformation May be a Risk Factor for Symptomatic Bleeding and Precocity of Symptoms: A Multicenter, Propensity Score Matched, Case-Control Study.

BACKGROUND: Cerebral Cavernous Malformation (CCM) is one of the most common types of vascular malformation of the central nervous system. Intracerebral hemorrhage, seizures, and lesional growth are the main clinical manifestations. Natural history studies have tried to identify many risk factors; however, the clinical course remains highly unpredictable. OBJECTIVE: Here, we have analyzed a multicenter CCM cohort looking for the differential clinical data regarding the patients harboring supra and/or infratentorial cavernous malformations in order to better understand risk factors involved in the anatomical location of the unique neurosurgical disease. METHODS: We have presented a multicenter, Propensity Score Matched (PSM), case-control study including 149 consecutive CCM cases clinically evaluated from May 2017 to December 2022 from three different neurosurgical centers. Epidemiological data were defined at each clinical assessment. Logistic regression was used to identify the independent contribution of each possible risk factor to the bleeding risk. To balance baseline covariates between patients with and without symptoms, and specifically between those with and without symptomatic bleeding, we used a PSM strategy. The Kaplan-Meier curve was drawn to evaluate if patients with infratentorial lesions had a greater chance of bleeding earlier in their life. RESULTS: The presence of infratentorial lesions was a risk factor in the multivariate analysis comparing the bleeding risk with pure asymptomatic individuals (OR: 3.23, 95% CI 1.43 - 7.26, P = 0.005). Also, having an infratentorial CCM was a risk factor after PSM (OR: 4.56, 95% CI 1.47 - 14.10, P = 0.008). The presence of an infratentorial lesion was related to precocity of symptoms when the time to first bleed was compared to all other clinical presentations in the overall cohort (P = 0.0328) and in the PSM group (P = 0.03). CONCLUSION: Here, we have provided some evidence that infratentorial cerebral cavernous malformation may have a more aggressive clinical course, being a risk factor for symptomatic haemorrhage and precocity of bleeding.

Proteomics on human cerebral cavernous malformations reveals novel biomarkers in neurovascular dysfunction for the disease pathology.

BACKGROUND: Cerebral cavernous malformation (CCM) is a disease associated with an elevated risk of focal neurological deficits, seizures, and hemorrhagic stroke. The disease has an inflammatory profile and improved knowledge of CCM pathology mechanisms and exploration of candidate biomarkers will enable new non-invasive treatments. METHODS: We analyzed protein signatures in human CCM tissue samples by using a highly specific and sensitive multiplexing technique, proximity extension assay. FINDINGS: Data analysis revealed CCM specific proteins involved in endothelial dysfunction/inflammation/activation, leukocyte infiltration/chemotaxis, hemostasis, extracellular matrix dysfunction, astrocyte and microglial cell activation. Biomarker expression profiles matched bleeding status, especially with higher levels of inflammatory markers and activated astrocytes in ruptured than non-ruptured samples, some of these biomarkers are secreted into blood or urine. Furthermore, analysis was also done in a spatially resolving manner by separating the lesion area from the surrounding brain tissue. Our spatial studies revealed that although appearing histologically normal, the CCM border areas were pathological when compared to control brain tissues. Moreover, the functional relevance of CD93, ICAM-1 and MMP9, markers related to endothelial cell activation and extracellular matrix was validated by a murine pre-clinical CCM model. INTERPRETATION: Here we present a novel strategy for proteomics analysis on human CCMs, offering a possibility for high-throughput protein screening acquiring data on the local environment in the brain. Our data presented here describe CCM relevant brain proteins and specifically those which are secreted can serve the need of circulating CCM biomarkers to predict cavernoma's risk of bleeding.

Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

Large language models assisted multi-effect variants mining on cerebral cavernous malformation familial whole genome sequencing.

Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.

Cerebral cavernous malformation proteins, CCM1, CCM2 and CCM3, are decreased in metastatic lesions in a murine breast carcinoma model.

Three genes are associated with cerebral cavernous malformations (CCMs): CCM1, CCM2 and CCM3. These genes participate in microvascular angiogenesis, cell-to-cell junctions, migration and apoptosis. We evaluated the expression in vivo of CCM genes in primary tumors and metastastases in a murine model of metastatic breast carcinoma. We used cell lines obtained from metastasis of 4T1, 4TLM and 4THM breast cancer to liver and heart. These cells were injected into the mammary ridge of Balb/C female mice. After 27 days, the primary tumors, liver and lung were removed and CCM proteins were assessed using immunohistochemistry and western blot analysis. CCM proteins were expressed in primary tumor tissues of all tumor-injected animals; however, no CCM protein was expressed in metastatic tumor cells that migrated into other tissues. CCM proteins still were observed in the lung and liver tissue cells. Our findings suggest that CCM proteins are present during primary tumor formation, but when these cells develop metastatic potential, they lose CCM protein expression. CCM protein expression was lost or reduced in metastatic tissues compared to the primary tumor, which indicates that CCM proteins might participate in tumorigenesis and metastasis.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.

Pediatric cerebral cavernous malformations and stereotactic radiosurgery: an analysis of 50 cases from a multicentric study.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are the second most common vascular anomaly affecting the CNS in children. Although stereotactic radiosurgery (SRS) has been proposed as an alternative to microsurgery in the management of selected cases in adults, there is a paucity of studies focusing on pediatric patients. The aim of this study was to present the outcomes and associated risks of SRS in this subgroup of patients. METHODS: This retrospective multicenter study included pediatric patients treated with single-session SRS for CCMs. The annual hemorrhage rate (AHR) was calculated before and after SRS in hemorrhagic lesions. The Engel classification was used to describe post-SRS epileptic control. Adverse radiation effects (AREs) and the occurrence of new neurological deficits were recorded. RESULTS: The study included 50 patients (median age 15.1 [IQR 5.6] years) harboring 62 CCMs. Forty-two (84%) and 22 (44%) patients had a history of hemorrhage or epilepsy prior to SRS, respectively. The AHR from diagnosis to SRS excluding the first hemorrhage was 7.19 per 100 CCM-years, dropping to 3.15 per 100 CCM-years after treatment. The cumulative risk of first hemorrhage after SRS was 7.4% (95% CI 0%-14.3%) at 5 years and 23.6% (95% CI 0%-42.2%) at 10 years. Eight hemorrhagic events involving 6 CCMs in 6 patients were recorded in the post-SRS follow-up period; 4 patients presented with transient symptoms and 4 with permanent symptoms. Of the 22 patients with pre-SRS seizures, 11 were seizure free at the last follow-up (Engel class I), 6 experienced improvement (Engel class II or III), 5 had no improvement (Engel class IVA or IVB), and 1 experienced worsening (Engel class IVC). Radiographic AREs were documented in 14.5% (9/62) of CCMs, with 4 being symptomatic. CONCLUSIONS: Single-session SRS reduces the CCM hemorrhage rate in the pediatric population and provides adequate seizure control.

Keyhole Retrosigmoid Craniotomy for Lateral Pontine Cavernous Malformation.

With improvements in anesthesia, monitoring, and peroperative care, the surgical removal of intrinsic brainstem pathology has become a possibility.1 Although surgical removal of deep-seated lesions continues to have significant morbidity, at least temporarily, associated with it, removal of exophytic lesions can be accomplished with little disability for the patient. The key to a good outcome, when removing cerebral cavernous malformation, is preservation of adjacent neurovascular bundles, use of sharp dissection over blunt pulling, judicious use of cautery in and around the brainstem, and preservation of the developmental venous anomaly, when present. The authors present a case of a lateral pontine cerebral cavernous malformation that was exophytic at the lateral and peritrigeminal safe entry zones.2 Neuromonitoring was used an adjunct to ensure safety of the procedure. The lesion is accessed using a keyhole retrosigmoid craniotomy (Video 1). We do not routinely use lumbar drains for these procedures as careful arachnoid dissection can result in adequate cerebrospinal fluid release. The window of access to this area is between CN 5 and the CN 7/8 complex. The arachnoid over the nerves is preserved, but the layer between the nerves is exposed to gain access to the lateral pons. The lesion is sharply dissected from the lateral pons, taking care to save the developmental venous anomaly, from which this lesion arises.

Giant cerebellar cavernous malformation in children: A case report and literature review.

Giant cerebellar cavernomas in children are rare and must be differentiated from hemorrhagic cerebellar tumors. The diagnosis and treatment of giant cerebellar cavernomas is challenging, but complete surgical resection can lead to favorable outcomes and complete neurological recovery in most cases. We present a case of eight months old baby who was diagnosed with a giant cavernoma resulting in secondary obstructive hydrocephalus with neuropsychiatric presentations. The patient underwent a paramedian craniotomy surgery with a suboccipital approach and complete surgical resection of the cavernoma was done. Over nine months of observation, the child showed improvement in their ability to walk and fully recovered from a neurological perspective. We also conducted a literature review to identify eleven cases of giant cerebellar cavernomas in children, including our case. The data were analyzed to determine the clinical features, treatment, and outcomes of giant cerebellar cavernomas in children.

Imaging Features and Misdiagnosis of Giant Cerebral Cavernous Malformations.

BACKGROUND: While cerebral cavernous malformations (CCMs) have been extensively described, few reports have described the imaging appearance of giant CCMs (GCCMs). OBJECTIVE: To describe the imaging characteristics of GCCMs and study the reasons for preoperative misdiagnosis. METHODS: We retrospectively analyzed the data of 12 patients (5 men, 7 women; mean age, 35.23 ± 12.64 years) with histopathologically confirmed GCCMs. Two radiologists analyzed the CT (n = 12) and MRI (n = 10) features: location, number, size, shape, boundary, signal intensity, and enhancement. RESULTS: The sellar region, cerebral hemisphere, skull bone, and ventricle were involved in 5, 4, 2, and 1 patients, respectively. Three tumors were irregularly shaped, while nine were oval. Eleven lesions showed slightly high- and/or high-density on CT; 1 lesion appeared as a low-density cyst. Calcifications were found in 11 lesions. Four tumors showed uniform hypointensity on T1-weighted imaging (T1WI) and hyperintense signals on T2-weighted imaging (T2WI). Six tumors showed mixed low-, equal-, and high-intensity signals on T1WI and T2WI. Noticeable contrast enhancement and gradual strengthening were noted on T1WI. Ten lesions showed hemorrhage and hemosiderin deposition. The GCCMs were wrongly diagnosed as cartilage-derived tumors/ meningioma (3 patients); tumor and hematoma (2 patients each); and pituitary tumor/ meningioma, chondroma, chordoma, ependymoma, and macroadenoma (1 patient each). CONCLUSIONS: GCCMs present as an oval mass with slightly high- and/or high-density calcifications on CT and show hemorrhage and hemosiderin accumulation on MRI. Therefore, slightly high- and/or high-density calcification and hemosiderin accumulation are critical clinical characteristics of GCCMs.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation.

Cerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genes KRIT1(CCM1), MGC4607(CCM2), and PDCD10(CCM3). Patients affected by the PDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form of KRIT1 or CCM2 mutations and six patients with a sporadic form. In addition, we evaluated the PDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A > G. The mRNA expression was fourfold lower in both patients with PDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-type PDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the potential impact of mutations in clinical interpretation as well as support to better understand the mechanism and pathogenesis of CCM3.