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We describe the case of a 7-year-old girl referred to our diabetes unit for hyperglycemia associated with facial dysmorphic features, intellectual disability, and cerebral cavernomas. Based on presence of anti islet antigen-2 (IA2) antibodies and a human leukocyte antigen of DR3/DR4/DQ2, the patient was initially diagnosed to be a case of type 1 diabetes mellitus. At follow-up, the very good metabolic control on a low insulin dose and negative IA2 antibodies led to a suspicion of glucokinase (GCK)-related maturity-onset diabetes of the young (MODY 2). This suspicion was substantiated in multiplex ligation-dependent probe amplification (MLPA) which showed a heterozygous GCK deletion (exons 1 to 12). However, the patient's parents did not have such a deletion and were clinically euglycemic. Given the clinical picture and the MLPA findings, array based comparative genomic hybridization was performed showing a monoallelic deletion of 7.23 Mb in the short arm of chromosome 7 (7p13-p12.1). The deleted intervals contain 39 genes listed in the Online Mendelian Inheritance in Man list, including GCK associated with MODY 2, CCM2 associated with type 2 cerebral cavernous malformations, IGFBP-3 associated with decrease in postnatal growth, and OGD associated with alpha-ketoglutarate dehydrogenase deficiency, with cognitive impairment and movement abnormalities. This previously unreported deletion was considered to explain the clinical picture of the patient. Also, the findings suggest that 7p13-p12.1 contains genes involved in intellectual disability and craniofacial development. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Cerebral cavernous malformations (CCMs) are common vascular abnormalities often discovered on imaging as an incidental finding. The most common clinical presentations of CCMs include seizure, headache, focal neurological deficits, and intracranial hemorrhage. This article discusses the most recent guidelines including imaging diagnostic criteria and radiographic standards of CCMs and reviews the utility of currently available imaging techniques.Recent Findings: Gradient echo T2*-weighted imaging and susceptibility-weighted imaging are the recommended imaging protocols for evaluation of suspected CCMs. Diffusion tensor imaging-based tractography provides visualization of the eloquent white matter tracks in the brain. This imaging is increasingly used in clinical practice to assist in selecting the optimal surgical approach, especially for brainstem lesions. Quantitative susceptibility mapping and dynamic contrast-enhanced quantitative perfusion are presently considered experimental. Its proposed value might prove helpful in the future to monitor disease activity and response to treatments. The choice of imaging modality of CCMs depends on the goals the clinician expects to achieve, such as establishing the initial diagnosis, follow-up and monitoring disease activity, preoperative, intraoperative, and postoperative evaluation, or research and experimental work on patients with CCM. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects A majority (52.8%) of CCM patients evaluated had a high socioeconomic status (SES) (ADI 1-3), and only 11.5% were African American. Patients who had a symptomatic bleed were more likely to follow-up (p=0.01), and those with brainstem lesion were more likely to enroll/adhere in a clinical trial (p=0.02). Rates of clinical follow-up were similar across different ADI groups, insurance coverage and race. Patients who were uninsured/self-paying, and African Americans were more likely to decline/drop from clinical trials (OR 2.4, 95% CI 0.46-10.20 and OR 2.2, 95% CI 0.33-10.75, respectively), but differences were not statistically significant Access of disadvantaged patients to center of excellence care and research remains limited despite geographic proximity to their community. Patients with lower SES and African Americans are as likely to follow-up clinically, but there were trends of differences in enrollment/adherence in clinical trials. Mitigation efforts should target systemic causes of low access to specialized care among uninsured and African American patients. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1 , CCM2 and CCM3/PDCD10 . The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants. NGS detected all six CCM1/KRIT1 , two CCM2 and four CCM3/PDCD10 mutations that had previously been identified by Sanger sequencing. Two of the pathogenic variants presented here are novel. Additionally, 20 stringently selected CCM index cases that had remained mutation-negative after conventional sequencing and exclusion of copy number variations were screened for deep-intronic mutations. The combination of bioinformatics filtering and transcript analyses did not reveal any deep-intronic splice mutations in these cases. Our results demonstrate that target enrichment by LR-PCR combined with NGS can be used for a comprehensive analysis of the entire genomic regions of the CCM genes in a research context. However, its clinical utility is limited as deep-intronic splice mutations in CCM1/KRIT1 , CCM2 and CCM3/PDCD10 seem to be rather rare. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformation (CCM) is a congenital vascular abnormality that predominantly affects the central nervous system, but that sometimes encroaches other vital tissues, including the retina, skin, and even liver. The familial form of CCM (FCCM) is considered to be an autosomal dominant disease with incomplete penetrance and variable expression, which is often attributed to mutations in three genes: CCM1, CCM2, and CCM3. We screened a Chinese family diagnosed with FCCM by using Sanger sequencing. A 29-year-old male proband with cutaneous angiomas was pathologically diagnosed but presented with an atypical form of CCM as revealed by magnetic resonance imaging (MRI) findings, prompting further clinical evaluation and genetic analyses of him and his immediate family. We performed continuous observation over an 8-year period using MRI gradient echo imaging and susceptibility-weighted imaging of these individuals. Sanger sequencing of the CCM1, CCM2, and CCM3 genes identified a novel heterozygous nonsense nucleotide transition (c.1864C>T; p.Gln622X) in exon 17 of the CCM1/ KRIT1 gene; this mutation was predicted to cause a premature stop codon (TAG) at nucleotides 1864 to 1866 to generate a truncated Krev interaction trapped 1 (Krit1) protein of 621 amino acids. During this long-term observational study, one of the enrolled family members with neurological deficits progressed to a stage indicative of brain surgery. This study provides a new CCM gene mutation profile, which highlights the significance of genetic counseling for individuals suspected of having this condition. [ABSTRACT FROM AUTHOR]

Objective : Surgical resection of thalamic and brainstem cerebral cavernous malformations (CCMs) is associated with significant operative morbidity, but it may be outweighed, in some cases, by the neurological damage from recurrent hemorrhage in these eloquent areas. The goals of this retrospective cohort study are to describe the technical nuances of surgical approaches and determine the postoperative outcomes for CCMs of the thalamus and brainstem. Materials and Methods : We reviewed an institutional database of patients harboring thalamic or brainstem CCMs, who underwent surgical resection from 2010 to 2014. The baseline and follow-up neuroimaging and clinical findings of each patient and the operative details of each case were evaluated. Results : A total of eight patients, including two with thalamic and six with brainstem CCMs, were included in the study cohort. All patients had progressive neurological deterioration from recurrent CCM hemorrhage, and the median modified Rankin Scale (mRS) at presentation was 3. The median CCM maximum diameter and volume were 1.7 cm and 1.8 cm3, respectively. The thalamic CCMs were resected using the anterior transcallosal transchoroidal and supracerebellar infratentorial approaches each in one case (13%). The brainstem CCMs were resected using the retrosigmoid and suboccipital trans-cerebellomedullary fissure approaches each in three cases (38%). After a median follow-up of 11.5 months, all patients were neurologically stable or improved, with a median mRS of 2. The rate of functional independence (mRS 0-2) was 63%. Conclusion : Microneurosurgical techniques and approaches can be safely and effectively employed for the management of thalamic and brainstem CCMs in appropriately selected patients. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations are vascular anomalies of the central nervous system characterized by clusters of enlarged, leaky capillaries. They are caused by loss-of-function mutations in KRIT1, CCM2, or PDCD10. The proteins encoded by these genes are involved in four partially interconnected signaling pathways that control angiogenesis and endothelial permeability. Cerebral cavernous malformations can occur sporadically, or as a familial autosomal dominant disorder (FCCM) with incomplete clinical and neuroradiological penetrance and great inter-individual variability. Although the clinical course is unpredictable, symptoms typically present during adult life and include headaches, focal neurological deficits, seizures, and potentially fatal stroke. In addition to neural lesions, extraneural cavernous malformations have been described in familial disease in several tissues, in particular the skin. We here present seven novel FCCM families with neurologic and cutaneous lesions. We review histopathological and clinical features and provide an update on the pathophysiology of cerebral cavernous malformations and associated cutaneous vascular lesions. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Vascular malformations may arise in any of the vascular beds present in the human body. These lesions vary in location, type, and clinical severity of the phenotype. In recent years, the genetic basis of several vascular malformations has been elucidated. This review will consider how the identification of the genetic factors contributing to different vascular malformations, with subsequent functional studies in animal models, has provided a better understanding of these factors that maintain vascular integrity in vascular beds, as well as their role in the pathogenesis of vascular malformations. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Cerebral cavernous malformations ( CCM) are vascular lesions of the central nervous system that can be found in sporadic or autosomal dominantly inherited forms and manifest with headaches, seizures, and hemorrhagic stroke. The precise proportion of de novo mutations in the CCM1, CCM2, and CCM3 genes remains unknown. Methods We here present a series of six trios with de novo mutations that have been analyzed by amplicon deep sequencing to differentiate between constitutional and postzygotic mutations. Results In one case, allelic ratios clearly indicated mosaicism for a CCM3 splice site mutation found in blood and buccal mucosa of a 2-year-old boy with multiple CCMs. The remaining five de novo mutations proved to be constitutional. In addition to three CCM3, two CCM1, and one CCM2 de novo point mutations, a deletion of the entire CCM3 gene was identified in an index case that most likely originated from an early postzygotic event. These are the first high-level mosaic mutations reported in blood samples of isolated CCM cases. Conclusion Our data demonstrate that de novo mutations in CCM1-3 might be more frequent than previously thought. Furthermore, amplicon deep sequencing is useful to discriminate between patients with constitutional and postzygotic mutations, and thereby improves genetic counseling. [ABSTRACT FROM AUTHOR]

When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt-Hogg-Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595-597, , 2015) but it is not yet clear whether they represent a genuine part of that conditions' phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed. [ABSTRACT FROM AUTHOR]

Objective: Cerebral cavernous malformation (CCM) is a subtype of the vascular malformations found within the cerebral cortex. Although rare and usually discovered incidentally, these vascular abnormalities can predispose patients to spontaneous cerebral hemorrhage and subsequently lead to a myriad of neurological symptoms at presentation such as seizures and other focal neurological deficits. Although the symptoms and presentations of CCM have been adequately described in the adult population, disease characteristics and outcomes have not been extensively described in the pediatric population. Furthermore, the etiology of CCM-e.g., familial versus sporadic disease, as well as the risk factors for hemorrhage and neurological deficits and predictors of clinical and surgical outcomes-has not been adequately explored in the pediatric population. The current study attempts to classify and characterize differences in the clinical presentation, characteristics, and outcomes of CCMs between familial and sporadic cases within the pediatric population., Methods: A retrospective review identified 131 pediatric patients with radiographically confirmed diagnosis of CCM. All pertinent demographic and clinical variables were collected. CCM lesions were characterized using T2-weighted and susceptibility-weighted angiography (SWAN) MRI. Statistical analysis was conducted using the t-test for continuous variables, whereas categorical variables were analyzed with the Fisher exact test or chi-square test. Multivariate analysis was performed using a Cox proportional hazards model with R version 4.2.0., Results: This retrospective study identified 131 pediatric CCM patients with a mean age of 8.4 years, and 54% (n = 71) were male. Twenty-seven percent (n = 35) were identified as cases with familial CCM, with the remainder classified as sporadic. The most common symptoms at presentation included generalized symptoms (headaches, nausea, and vomiting) or seizures, with a large proportion of patients also presenting as asymptomatic. No significant differences were observed in severity of symptoms between patients harboring different forms of the disease. Patients with familial CCM were noted to have a larger lesion size on average (5.26 cm3 vs 1.6 cm3, p = 0.047). These patients also had a shorter progression-free follow-up interval, with 50% of patients showing progression by 888 days, compared with only 15% of sporadic CCM patients during the same period (p = 0.0019). Familial etiology of the disease and larger average lesion volume were independent, significant predictors of disease progression (p = 0.001, HR 3.29, 95% CI 1.65-6.54) and future hemorrhage (p = 0.023, HR 1.1, 95% CI 1.01-1.10), respectively., Conclusions: Familial and sporadic CCMs tend to present with similar characteristics within the pediatric population. Patients with the familial form of the disease have an increased risk of progressive disease in terms of further hemorrhagic events.

Directional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named FAM65A, which binds to activeRHOA, RHOB and RHOC. FAM65A links RHO proteins to Golgi-localising cerebral cavernous malformation-3 protein (CCM3; also known as PDCD10) and its interacting proteins mammalian STE20-like protein kinases 3 and 4 (MST3 and MST4; also known as STK24 and STK26, respectively). Binding of active RHO proteins to FAM65A does not affect the kinase activity of MSTs but results in their relocation from the Golgi in a CCM3-dependent manner. This relocation is crucial for reorientation of the Golgi towards the leading edge and subsequent directional cell migration. Our results reveal a previously unidentified pathway downstream of RHO that regulates the polarity of migrating cells through Golgi reorientation in a FAM65A-, CCM3- and MST3- and MST4-dependent manner. [ABSTRACT FROM AUTHOR]

Intraorbital and intracerebral cavernous malformation (CM) lesions are considered independent entities. Purely cerebral CMs have variable biology with recent evidence depicting inflammation as an important player and a risk factor for aggressiveness. We describe a case of concomitant left intraaxial and extraaxial CMs, linked by the ipsilateral basal vein, where the extraaxial component has developed an aggressive behavior. A 35-year-old female patient presented with a rapid and progressive exophthalmos and loss of vision on the left eye. Cranial magnetic resonance and angiography examinations demonstrated a left craniofacial CM and large intraorbital component. The lesion was connected through a large basal vein to a cerebral intraventricular CM. Transconjunctival resection showed typical findings of CM. A complete histopathology and immunostaining analysis was performed and revealed a clear acute lymphomononuclear reaction with a predominant immune cellular inflammation. A case of intraorbital and extracranial cavernomatous mass, connected to a cerebral intraventricular CM through a large basal vein, has presented with an aggressive course. A complete histopathologic and immunohistochemical analysis of the orbital mass has pictured a clear immune-cellular inflammatory reaction adding to the amounting evidence of association between inflammation and site aggressiveness in the setting of CMs. [ABSTRACT FROM AUTHOR]

Receptor-driven selective macroautophagy/autophagy delivers ubiquitinated targets for autophagosomal clearance to maintain metabolic homeostasis and orchestrate reparative inflammatory responses. Deregulated autophagy is linked to tumor progression, but the exact mechanisms of selective autophagy in the spatiotemporal control of cell polarity signaling components during cancer metastasis remain ill-defined. Our recent study has demonstrated that TRIM59, an E3 ligase upregulated in metastatic breast cancer, is required for cancer cell survival and metastasis. Genetic depletion of TRIM59 suppresses cancer metastasis by promoting RNFT1-induced K63 polyubiquitination and SQSTM1-directed autophagic degradation of PDCD10, thereby boosting ROCK (Rho associated coiled-coil containing protein kinase)-induced actomyosin contractility and enhancing CDH1-mediated adhesion formation. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCM) are vascular malformations in the brain and spinal cord. The familial form of cerebral cavernous malformation (FCCM) is uncommon. This autosomal dominant pathology mostly presents with seizures and focal neurological symptoms. Many persons affected by FCCM remain asymptomatic. However, acute hemorrhages may appear over time. MRI demonstrates multiple focal regions of susceptibility induced signal loss, well seen on gradient-echo sequences (GRE) or even better on susceptibility-weighted imaging (SWI). The presence of a single CCM – especially in young persons – without history of FCCM does not exclude this diagnosis. Some clinicians also advise an MRI of the spinal cord at the time of diagnosis to serve as a baseline and a control MRI of the brain every one to two years. MRI is certainly indicated in individuals with obvious new neurologic symptoms. Symptomatic siblings should also undergo an MRI of the brain to determine presence, size, and location of the lesions. Even in asymptomatic siblings, a screening MRI may be considered, as there may be an increased risk of hemorrhage, spontaneous or due to the use of certain medications; the knowledge of the presence and the type of these lesions are important. Surgical removal of a CCM may be justified to prevent a life-threatening hemorrhage. Control MRI may reveal the postoperative outcome.

• Seizure is the most common clinical presentation of CCM. • The most common seizure type of CRE was focal to bilateral tonic-clonic seizure. • Cerebral cavernous malformation (CCM) lesions of CRE patients were mostly located in the temporal lobe. • Patients with CCM diagnosis age ≤ 44 years had a higher risk of CRE. • Temporal lesion, cortical involvement, and hemosiderin rim around the lesion were risk factors of CRE. This study aimed to summarize the clinical characteristics and explore the risk factors for cerebral cavernous malformation (CCM)-related epilepsy (CRE). We retrospectively analyzed the clinical data of patients with CCM in our cerebral vascular malformations database. Descriptive statistics were used to present the clinical characteristics of CRE patients. Patients were divided into a CRE and a non-CRE group according to clinical presentation. Binary logistic regression analysis was used to analyze the risk factors of CRE. A total of 199 patients with CCM confirmed by postoperative pathological examination were enrolled, 93 of whom were diagnosed with CRE, and 34 patients had drug-resistant epilepsy. The most common seizure type of CRE patients was focal to bilateral tonic-clonic seizure (FBTCS), followed by focal impaired awareness motor seizure. All CCM lesions were supratentorial, 97.8% of which involved the cerebral cortex, 86.0% of lesions had hemosiderin rim, and 50.5% of lesions were located in the temporal lobe. Binary logistic regression analysis indicated that CCM diagnosis age ≤ 44 years (odds ratio [OR] 2.79, p = 0.010), temporal lobe lesion location (OR = 9.07, p = 0.042), medial temporal lobe lesion (OR = 14.09, p = 0.002), cortical involvement of the lesion (OR = 32.77, p = 0.010), and hemosiderin rim around the lesion (OR = 16.48, p = 0.001) significantly increased the risk of CRE. The most common seizure type of CRE was FBTCS. Those whose CCM diagnosis age was ≤ 44 years, having a temporal lobe lesion location, especially the medial temporal lobe lesion, cortical involvement, and hemosiderin rim around the lesion had a higher risk of developing CRE. [ABSTRACT FROM AUTHOR]

Objective We sought to analyze long-term outcome and quality of life after surgery of cerebral cavernomas (CCs) with special regard to localization (brainstem vs. nonbrainstem). Methods We conducted a retrospective study in a tertiary care center (2000–2010). Clinical charts were analyzed. Health-related quality of life (QoL) was evaluated with the Short Form−36 questionnaire. Results The study included 60 patients (21 male, 39 female, mean age 39.8 years). The distribution was 67% supratentorial, 7% cerebellar, and 26% brainstem (BS). In the BS group, 87.5% had a preoperative deficit versus 18.2% in the nonbrainstem group (NBS). Operative neurologic morbidity was 31.3% for BS versus 11.4% for NBS. After mean follow-up of 43 months, neurologic status was better or the same as compared with the preoperative status in 75% of BS and all of NBS. SF-36 showed no significant differences between all cavernoma patients compared with a normative healthy population except for a better “pain” score. Subgroup analysis found the same results when comparing NBS with the normative population. Comparison of BS versus norm and NBS, respectively, showed worse scores for BS in physical but not mental health ( P ≤ 0.01). Conclusion Clinical outcome was different depending on location: NBS recovered the same neurologic status as preoperatively and showed better QoL in physical health and lower working inability than BS. Surprisingly, there was no difference in mental health. Moreover, QoL of the operated cavernoma population after long-term follow-up did not differ from the norm. We conclude that surgery of cavernomas even in eloquent areas may result in favorable outcome and high patient satisfaction. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to assess the accuracy of susceptibility-weighted imaging (SWI), compared with T2*-weighted gradient echo (GRE) imaging in assessing cerebral cavernous malformations. Materials and methods We retrospectively evaluated 21 patients with a familial form of cavernous malformation. Magnetic resonance (MR) protocol included non-enhanced and contrast-enhanced fast-spin echo (FSE) T1-weighted sequences, FSE T2-weighted sequences, fluid-attenuated inversion-recovery (FLAIR), GRE T2*-weighted and SWI sequences. Images were reviewed in consensus by two expert neuroradiologists to assess the location, number, size and conspicuity of the lesions on T2*-weighted GRE and SWI sequences. Statistical differences in the number, size and conspicuity of the lesions seen on the SWI images and the T2*-weighted GRE images were assessed with the nonparametric Wilcoxon signed rank test. Results The number of cavernous malformations was significantly higher (p < .001) on the SWI images (n = 152) than on T2*-weighted GRE images (n = 56). Lesion size was significantly higher (p < .001) on SWI images (mean: 0.4 cm, SD ± 0.55) than on T2*-weighted GRE sequences (mean: 0.2 cm, SD ± 0.51) and the differences were statistically significant (p < .001). Lesion conspicuity was significant higher (p < .001) on SWI than on T2*-weighted GRE images. In one patient who underwent a 2-month follow-up for the onset of neurologic symptoms related to cerebral hemorrhage, a cerebral hematoma was identified at the site of a cerebral cavernous malformation that was demonstrated only on the SWI images in the previous MR examination. Conclusions The SWI sequence, being more sensitive to substances which distort the local magnetic field than the GRE T2*W sequence, showed a higher sensitivity in identifying cerebral cavernous malformations. Thus, routine clinical neuroimaging protocol should contain SWI sequences to evaluate patients with (or suspected) cerebral cavernous malformations. [ABSTRACT FROM AUTHOR]

Background Cerebral cavernous malformations (CCMs) are hemorrhagic brain lesions, where murine models allow major mechanistic discoveries, ushering genetic manipulations and preclinical assessment of therapies. Histology for lesion counting and morphometry is essential yet tedious and time consuming. We herein describe the application and validations of X-ray micro-computed tomography (micro-CT), a non-destructive technique allowing three-dimensional CCM lesion count and volumetric measurements, in transgenic murine brains. New method We hereby describe a new contrast soaking technique not previously applied to murine models of CCM disease. Volumetric segmentation and image processing paradigm allowed for histologic correlations and quantitative validations not previously reported with the micro-CT technique in brain vascular disease. Results Twenty-two hyper-dense areas on micro-CT images, identified as CCM lesions, were matched by histology. The inter-rater reliability analysis showed strong consistency in the CCM lesion identification and staging (K = 0.89, p < 0.0001) between the two techniques. Micro-CT revealed a 29% greater CCM lesion detection efficiency, and 80% improved time efficiency. Comparison with existing method Serial integrated lesional area by histology showed a strong positive correlation with micro-CT estimated volume (r 2 = 0.84, p < 0.0001). Conclusions Micro-CT allows high throughput assessment of lesion count and volume in pre-clinical murine models of CCM. This approach complements histology with improved accuracy and efficiency, and can be applied for lesion burden assessment in other brain diseases. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral cavernous malformation (CCM) is a vascular disorder characterized by the presence of central nervous system cavernomas. In familial forms, mutations in three genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) were identified. We describe a Portuguese family harboring a novel CCM1 mutation. Case Presentation: The proband is a woman who at the age of 55 years started to have complex partial seizures and episodic headache. Although nothing was found during her neurological examination, brain MRI showed bilateral, supra- and infratentorial cavernomas. She had a sister who, at the age 61 years, suffered a tonic-clonic seizure. Neurological examination was normal and imaging investigation demonstrated a right frontal intracerebral hemorrhage and multiple cavernomas. In the following years, she suffered several complex partial seizures and had a new intracerebral hemorrhage located in the right temporal lobe. Genetic analysis was performed and a novel nucleotide substitution, i.e. c.1927C>T (p.Gln643*) within the exon 17 of the CCM1 gene, was detected in both sisters. The substitution encodes a stop codon, with a consequent truncated KRIT1 protein, therefore supporting its pathogenic role. Further affected family members were detected, suggesting an autosomal dominant pattern of inheritance. Conclusion: We report a Portuguese family with a novel CCM1 (KRIT1) mutation - c.1927C>T (p.Gln643*). A better knowledge of the phenotype-genotype correlation is needed to improve the management of CCM patients. [ABSTRACT FROM AUTHOR]

Objective To quantify the risk of a first or recurrent hemorrhage and the associated functional impairment in patients with sporadic solitary cerebral cavernous malformations (CCMs) and to investigate the potential risk factors. Methods We undertook an observational study (n = 199) of consecutive patients with the diagnosis of a single, sporadic CCM using clinical and magnetic resonance imaging follow-up to identify prospective hemorrhage events and associated functional impairment. We calculated the annual hemorrhage risk rates, calculated cumulative risks, and performed uni- and multivariate analysis to assess outcome predictors. Results There were 199 adults identified, and 712.5 person years of follow-up were analyzed. Overall annual rates of hemorrhage were 6.03%, 11.95%, and 1.03% in the complete cohort, in those presenting with previous hemorrhage, and in those without, respectively. The 5-year risk of hemorrhage was higher in those presenting with previous hemorrhage than those without (40.9%; 95% confidence interval [CI], 31.78–50.73 vs. 8.6%; 95% CI, 3.97–16.95; P < 0.0001) and in those with a brainstem CCM compared with nonbrainstem CCM (51.6%; 95% CI, 37.61–65.46 vs. 17.1%; 95% CI, 4.55–32.04; P < 0.0001). In the multivariate analysis, previous hemorrhage (odds ratio, 7.18; 95% CI, 1.8–28.11; P = 0.005), age less than 45 years (odds ratio, 2.61; 95% CI, 1.03–6.61; P = 0.042), and brainstem location (odds ratio, 7.44; 95% CI, 2.09–26.50; P = 0.002) increased the risk of hemorrhage. Of the patients, 30% showed a moderate or severe disability associated with a CCM hemorrhage (5-year risk of severe hemorrhage, 8.9%; 95% CI, 5.50–13.99). Conclusions This study provides an estimate of symptomatic hemorrhage risk and the associated disability in patients with sporadic solitary CCM and an investigation of risk factors. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are relatively common vascular malformations, characterized by increased Rho kinase (ROCK) activity, vascular hyper-permeability and the presence of blood degradation products including non-heme iron. Previous studies revealed robust inflammatory cell infiltration, selective synthesis of IgG, in situ antigen driven B-cell clonal expansion, and deposition of immune complexes and complement proteins within CCM lesions. We aimed to evaluate the impact of suppressing the immune response on the formation and maturation of CCM lesions, as well as lesional iron deposition and ROCK activity. Two murine models of heterozygous Ccm3 (Pdcd10), which spontaneously develop CCM lesions with severe and milder phenotypes, were either untreated or received anti-mouse BR3 to deplete B cells. Brains from anti-mouse BR3-treated mice exhibited significantly fewer mature CCM lesions and smaller lesions compared to untreated mice. B cell depletion halted the progression of lesions into mature stage 2 lesions but did not prevent their genesis. Non-heme iron deposition and ROCK activity was decreased in lesions of B cell depleted mice. This represents the first report of the therapeutic benefit of B-cell depletion in the development and progression of CCMs, and provides a proof of principle that B cells play a critical role in CCM lesion genesis and maturation. These findings add biologics to the list of potential therapeutic agents for CCM disease. Future studies would characterize the putative antigenic trigger and further define the mechanism of immune response in the lesions. [ABSTRACT FROM AUTHOR]

Spontaneous intracerebral hemorrhage (ICH) is a morbid disease with a high case fatality rate. Prognosis, rehemorrhage rates, and acute, clinical decision making are greatly affected by the underlying etiology of hemorrhage. This review focuses on the evaluation, diagnosis, and management of structural, macrovascular lesions presenting with ICH, including ruptured aneurysms, brain arteriovenous malformations, cranial dural arteriovenous fistulas, and cerebral cavernous malformations. [ABSTRACT FROM AUTHOR]

Hyperintense perilesional edema in brain masses on T1-weighted images (T1WI) is an unusual radiological finding. We report three cases showing this particular type of edema, one representing cerebral hemorrhagic cavernous malformation (CCM, cavernoma) and the other two, metastases of melanoma. The association between this sign and cavernoma was recently recognized. On the other hand, in melanotic lesions, the relationship with T1WI-hyperintense perilesional edema has not yet been described. Despite being an infrequent sign, it can considerably narrow the differential diagnosis, which gives it a high value for clinical practice. Moreover, given the high prevalence of the entities that manifest this imaging feature, it can be occasionally noticed. [ABSTRACT FROM AUTHOR]

Background Cerebral cavernous malformations (CCMs) are present in up to 0.5% of the general population. Although CCMs have been considered congenital lesions, numerous reports have observed de novo formations in patients with the familial form of CCM and in patients after cranial radiotherapy. Outside of these circumstances, there is scant evidence as to the potential etiologies of CCM. Case Description We present a 48-year-old woman with a medical history of endometrial hyperplasia concomitant endometrial polyps demonstrating a large de novo CCM, which grew to a large size in a period of 20 months. A previous magnetic resonance imaging scan showed no abnormalities. This CCM exhibited aggressive biological behavior characterized by recurrent overt bleeding and seizure. Histopathologic analysis confirmed the diagnosis of CCM. Here, we discuss the growth mechanisms of these lesions. Conclusions Given the patient's medical history and imaging findings, we propose that de novo CCMs can arise directly from angiogenic proliferation, secondary to BCL-2 overexpression from underlying causes. We hypothesize that inappropriate secretion of estrogen could have set off a genetic cascade with attendant endothelial proliferation. Thus, female hormones may play an important role in influencing the biological behavior of CCMs. The relationship between estrogen and CCM needs further investigation. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are vascular malformations which may occur in familial forms which have autosomal dominant inheritance. Mutations have been identified in three genes: KRIT1, MGC4607 and PDCD10. We have documented a novel mutation on KRIT1 gene, and the second to be reported in a Portuguese family. This mutation consists in a two nucleotide insertion (c.947_948insAC) within the exon 10, resulting in premature protein termination (p.Leu317Argfs*2). These findings will hopefully contribute to a better clinical, imaging and genetic characterisation of this disease, particularly while trying to identify the factors that influence its treatment and prognosis. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformation (CCM) is a neurovascular disease that can lead to seizures and stroke-like symptoms. The familial form is caused by a heterozygous germline mutation in either the CCM1 , CCM2, or CCM3 gene. While the importance of a second-hit mechanism in CCM development is well established, it is still unclear whether it immediately triggers CCM development or whether additional external factors are required. We here used RNA sequencing to study differential gene expression in CCM1 knockout induced pluripotent stem cells ( CCM1 -/- iPSCs), early mesoderm progenitor cells (eMPCs), and endothelial-like cells (ECs). Notably, CRISPR/Cas9-mediated inactivation of CCM1 led to hardly any gene expression differences in iPSCs and eMPCs. However, after differentiation into ECs, we found the significant deregulation of signaling pathways well known to be involved in CCM pathogenesis. These data suggest that a microenvironment of proangiogenic cytokines and growth factors can trigger the establishment of a characteristic gene expression signature upon CCM1 inactivation. Consequently, CCM1 -/- precursor cells may exist that remain silent until entering the endothelial lineage. Collectively, not only downstream consequences of CCM1 ablation but also supporting factors must be addressed in CCM therapy development.

Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1 , CCM2 , or PDCD10 . Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long-term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow-up in a well-characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow-up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow-up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without ( P =0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P =0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without ( P =0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P =0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow-up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.