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Hereditary cerebral cavernous malformations (CCMs) are characterized by clustered dilated capillary-like vessels in the brain. Autosomal dominant polycystic kidney disease (PKD) is characterized by renal cysts and extra-renal abnormalities. We report a Taiwanese family in which the index case exhibited coexisting phenotypes of both CCMs and PKD. The index case was a 55-year-old woman with known PKD who developed an intracerebral hemorrhage (ICH) in the right medulla. Neuroimaging revealed numerous microbleeds in the bilateral cerebrum and cerebellum. Radiological CCMs were suspected given the absence of other imaging markers of small vessel disease. A comprehensive panel of 183 cerebral vascular malformation genes were investigated through genome sequencing. A novel CCM2 frameshift variant (c.607_608delCT, p.Leu203Valfs∗53) causing a pathogenic premature stop codon, and a known PKD2 nonsense variant (c.2407C > T, p.Arg803∗), were found. Segregation analysis revealed that four siblings were affected by either isolated aforementioned PKD2 or CCM2 variant. Notably, radiological CCMs were exclusively found in siblings who had this CCM2 variant, and bilateral internal carotid artery aneurysms were restricted to one sibling who had the PKD2 variant but not the CCM2 variant. Our study expands the genetic spectrum of CCM2 and demonstrates unambiguous cosegregation of CCM2 and PKD2 variants with their respective phenotypes. [ABSTRACT FROM AUTHOR]

• The expression of YKL-40 is upregulated in the sporadic CCM. • YKL-40 contributes to migration, proliferation and angiogenesis of endothelial cells. • A CCM mouse model was developed by injecting endothelial cells stereotaxically. The factors affecting the formation of sporadic CCMs remain unclear. A cDNA microarray was used to identify characteristic gene expression patterns in sporadic CCMs. Transcription level of YKL-40 was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). The location and expression were revealed by immunochemistry, immunofluorescence staining and level of YKL-40 was quantified by Western blotting. Alterations to endothelial function following the up or down regulation of gene expression was assessed by Transwell assays, cell counting kit-8 assays and capillary-like tube formation assays in human brain microvascular endothelial cells (HBMECs) in vitro. We generated a murine model by stereotaxically injecting HBMECs with expressing amounts of YKL-40 into the brain. cDNA microarray and RT-PCR results revealed that the transcription level of YKL-40 was ≥140-fold higher in sporadic CCMs in healthy controls. Histological staining revealed excessive YKL-40 expression in the CCM endothelium. Western blotting results analysis showed that YKL-40 protein expression was significantly higher in CCM endothelium (P < 0.05). YKL-40 over-expressing HBMECs showed increased cell proliferation, migration and tube formation ability compared with the control group, whereas downregulating of YKL-40 inhibited the proliferation, migration of HBMECs and capillary-like tube formation (P < 0.05). In animals, increased of YKL-40 was associated with abnormal vascular lesions that were similar to CCMs. YKL-40 is over-expressed in the CCM endothelium and acts as an angiogenic factor that promotes the pathogenesis of sporadic CCMs. YKL-40 may therefore represent a potential therapeutic target in the treatment of sporadic CCM. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are congenital abnormal clusters of capillaries that are prone to leaking and thought to result from a disorder of endothelial cells. The underlying pathology of CCM is not fully understood. We analyzed the expression of tissue factor (TF) and interleukin-6 (IL-6) in CCMs to determine the association of TF and IL-6 with clinical and pathological findings. Thirteen cases of operative specimens of sporadic CCMs were included in this study. The expression of messenger RNA of TF and IL-6 was assayed and the association with clinical factors was investigated. Then, the distribution of TF and IL-6 was examined with immunofluorescence. The mRNA expression of TF of CCMs was significantly higher than that of the control ( p = 0.017), and was correlated with the number of hemorrhage appearances ( p = 0.190, ρ = 0.62). The mRNA expression level of IL-6 was significantly correlated with the mRNA expression level of TF ( p = 0.034, ρ = 0.58). Examination of immunostained sections indicated that TF + cells were also positive for IL-6, and distributed around normal endothelial cells. Moreover, the TF + /IL-6 + cells expressed CD31 and VEGFR2. The expressions of IL-6 and TF were correlated, and both were present in the same immature endothelial cells. TF is elevated in CCM and might mediate progressive events. These factors may play a prognostic role in CCM. [ABSTRACT FROM AUTHOR]

The aim of this case series is to describe the surgical technique and postoperative outcomes for endoport-assisted microsurgical resection (EAMR) of cerebral cavernous malformations (CCM). Significant manipulation of subcortical white matter tracts may be necessary for the successful resection of CCM located in deep brain regions. Minimally invasive neurosurgical devices such as endoport systems can decrease disruption of the cortex and white matter tracts overlying deep-seated CCM through small cranial and dural openings. The role of endoport technology in modern CCM surgery is incompletely understood. Three patients with symptomatic CCM underwent EAMR at our institution using the BrainPath endoport system (NICO Corporation, Indianapolis, IN, USA). Complete resection was achieved in two patients. One patient with a large 4.5 cm callosal CCM was left with a small residual lesion. There were no postoperative complications and all patients were functionally independent (modified Rankin Scale score 2 or less) at follow-up. Based on our initial experience with EAMR for CCM we believe the endoport can be an effective alternative to traditional retractor systems. Due to the nature of the small craniotomy and durotomy performed for endoport placement EAMR has the potential to improve surgical outcomes by reducing postoperative pain, analgesic requirements and hospital stays. Therefore, EAMR may be considered for appropriately selected CCM patients, although additional experience is necessary to improve our understanding of its role in CCM management. [ABSTRACT FROM AUTHOR]

Abstract: Background and aim: In the diagnosis of cerebral cavernous malformations (CCMs) magnetic resonance imaging is established as the gold standard. Conventional MRI techniques have their drawbacks in the diagnosis of CCMs and associated venous malformations (DVAs). The aim of our study was to evaluate susceptibility weighted imaging SWI for the detection of CCM and associated DVAs at 7T in comparison with 3T. Patients and methods: 24 patients (14 female, 10 male; median age: 38.3y (21.1y–69.1y) were included in the study. Patients enrolled in the study received a 3T and a 7T MRI on the same day. The following sequences were applied on both field strengths: a T1 weighted 3D GRE sequence (MP-RAGE) and a SWI sequence. After obtaining the study MRIs, eleven patients underwent surgery and 13 patients were followed conservatively or were treated radio-surgically. Results: Patients initially presented with haemorrhage (n=4, 16.7%), seizures (n=2, 8.3%) or other neurology (n=18, 75.0%). For surgical resected lesions histopathological findings verified the diagnosis of CCMs. A significantly higher number of CCMs was diagnosed at 7T SWI sequences compared with 3T SWI (p<0.05). Additionally diagnosed lesions on 7T MRI were significantly smaller compared to the initial lesions on 3T MRIs (p<0.001). Further, more associated DVAs were diagnosed at 7T MRI compared to 3T MRI. Conclusion: SWI sequences at ultra-high-field MRI improve the diagnosis of CCMs and associated DVAs and therefore add important pre-operative information. [Copyright &y& Elsevier]

• Ctcfl overexpression is related with vascular abnormalities. • The presence of CCM1, CCM2 and CCM3 in Ctcfl transgenic mice are analyzed. • CTCFL expression in human CCM and AVM tissues is shown by IHC and Western Blot. • CTCFL might involve in pathogenesis of CCMs and AVMs. CTCFL is expressed in testis, oocytes and embryonic stem cells, and is aberrantly expressed in malignant cells, and is classified as a cancer-testis gene. We have previously shown by using a tetracycline-inducible Ctcfl transgene that inappropriate expression of Ctcfl negatively impacts fetal development and causes early postnatal lethality in the mouse. The affected pups displayed severe vascular abnormalities and localized hemorrhages in the brain evocative of cerebral cavernous malformations (CCM) and arteriovenous malformations (AVM) in humans. Thus, we aim to analyze; a) the presence of CCM-related proteins CCM1/KRIT1, CCM2/malcavernin and CCM3/PDCD10 in Ctcfl transgenic animals and, b) whether there is CTCFL expression in human CCM and AVM tissues. Ctcfl transgenic animals exhibited increased CD31 expression in vascular areas of the dermis and periadnexal regions but no difference was observed for vWF and α-SMA expressions. CCM-related proteins CCM1/KRIT1, CCM2/malcavernin and CCM3/PDCD10 were aberrantly expressed in coronal sections of the head in transgenic animals. We also observed CTCFL expression in human CCMs and AVMs. The induced expression of CTCFL resulting in vascular brain malformations in mice combined with the presence of CTCFL in human vascular malformations provide new insights into the role of this gene in vascular development in humans. [ABSTRACT FROM AUTHOR]