Gamma Knife Stereotactic Radiosurgery for Cerebral Cavernous Malformations: Meta-Analysis of Reconstructed Time-to-Event Data.

INTRODUCTION: Cavernomas are vascular lesions with a genetic heritage that can be spotted on the central nervous system. Whenever these lesions are localized in eloquent regions, surgical resection is not recommended. In this type of situation, Gamma Knife stereotactic radiosurgery (GKSRS) could be a feasible option for treating patients. Thus, we aimed to explore the outcomes associated with this procedure. METHODS: We performed a systematic review and meta-analysis of reconstructed time-to-event data based on Kaplan-Meier curves. A thorough search was conducted on PubMed, Cochrane, Web of Science, and Embase databases targeting papers that provided information regarding hemorrhagic outcomes associated with GKSRS through Kaplan-Meier curves. RESULTS: After a systematic search in the specific databases, seven studies were included in this review. Notably, a total of 1,071 patients had 1,104 cavernomas treated by GKSRS. Assessment of short-term and long-term post-procedure outcomes was performed, with the estimated overall events-free rate at 2 years being 89.8% (95% CI: 87.7-91.5), while, at 10 years, the estimated overall events-free rate was 71.3% (95% CI: 67.2-75.1). CONCLUSION: GKSRS seems to be a good alternative for the control of symptomatic events in early and long-term follow-up, despite the need for further investigation provided by future studies.

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.

Elevated proportion of TLR2- and TLR4-expressing Th17-like cells and activated memory B cells was associated with clinical activity of cerebral cavernous malformations.

BACKGROUND: Recent evidences have suggested the involvement of toll-like receptor (TLR)-4 in the pathogenesis of cerebral cavernous malformations (CCM). Elevated frequency of TLR+T-cells has been associated with neurological inflammatory disorders. As T-cells and B-cells are found in CCM lesions, the objective of the present study was to evaluate the cytokine profile of T-cells expressing TLR2 and TLR4, as well as B-cell subsets, in asymptomatic (CCMAsympt) and symptomatic (CCMSympt) patients. METHODS: For our study, the cytokine profile from TLR2+ and TLR4+ T-cell and B-cell subsets in CCMAsympt and CCMSympt patients was investigated using flow cytometry and ELISA. T-cells were stimulated in vitro with anti-CD3/anti-CD28 beads or TLR2 (Pam3C) and TLR4 (LPS) ligands. RESULTS: CCMSymptc patients presented a higher frequency of TLR4+(CD4+ and CD8+) T-cells and greater density of TLR4 expression on these cells. With regard to the cytokine profile, the percentage of TLR2+ and TLR4+ Th17 cells was higher in CCMSympt patients. In addition, an elevated proportion of TLR4+ Tc-1 cells, as well as Tc-17 and Th17.1 cells expressing TLR2 and TLR4, was observed in the symptomatic patients. By contrast, the percentage of TLR4+ IL-10+CD4+ T cells was higher in the CCMAsympt group. Both Pam3C and LPS were more able to elevate the frequency of IL-6+CD4+T cells and Th17.1 cells in CCMSympt cell cultures. Furthermore, in comparison with asymptomatic patients, purified T-cells from the CCMSympt group released higher levels of Th17-related cytokines in response to Pam3C and, mainly, LPS, as well as after activation via TCR/CD28. Concerning the B-cell subsets, a higher frequency of memory and memory activated B-cells was observed in CCMSympt patients. CONCLUSIONS: Our findings reveal an increase in circulating Th17/Tc-17 cell subsets expressing functional TLR2 and, mainly, TLR4 molecules, associated with an increase in memory B-cell subsets in CCM patients with clinical activity of the disease.

Association of Variants in FCGR2A, PTPN2, and GM-CSF with Cerebral Cavernous Malformation: Potential Biomarkers for a Symptomatic Disease.

BACKGROUND: Cerebral Cavernous Malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of people affected will develop clinical symptoms and the molecular mechanisms underlying lesional activity remain unclear. We analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients. We looked for plasmatic inflammatory cytokines, checking for a pattern of plasma expression heterogeneity and any correlation with genetic variations identified with different CCM clinical phenotypes. METHODS: This was a case-control study from a long-term follow-up cohort including 23 CCM patients, of which 16 were symptomatic, and 7 were asymptomatic. A 200-SNP panel was considered through next-generation sequencing and 18 different plasma molecules were assessed through a suspension array system. RESULTS: Fcγ receptor IIa rs1801274 (FCGR2A) and protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were statistically different between groups. Patients who had a combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in life. The combination of genetic polymorphisms and serum level of GM-CSF showed the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)]. CONCLUSION: We have shown that SNPs in inflammation genes might be related to a symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) is possibly capable of predicting a symptomatic phenotype during a patient's lifetime.

First Report of Concomitant Pathogenic Mutations Within MGC4607/CCM2 and KRIT1/CCM1 in a Familial Cerebral Cavernous Malformation Patient.

BACKGROUND: Familial cerebral cavernous malformations (CCM) are among the most common vascular malformations of the central nervous system (CNS) and are linked to mutations on the specific genes CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. We present the first report in the literature of a pharmaco-resistant epileptic patient harboring co-occurring pathogenic mutations within CCM2/MGC4607 and CCM1/KRIT1. CASE DESCRIPTION: A 51-year-old patient first presented at age of 33 years with episodes of seizures. Magnetic resonance imaging including a susceptibility-weighted imaging sequence had shown multiple cerebral cavernous malformation lesions. She had partial response of symptoms and remained in routine follow-up needing progressive pharmacological improvement. Direct sequencing allowed the detection of 1 nonsense pathogenic mutation in CCM2/MGC4607 (c.118C>T; p.Arg40Ter) and 1 unclassified frameshift insertion variant in CCM1/KRIT1 (c.1687_1688insT; p.Tyr563LeufsTer5). CONCLUSIONS: Although the CCM2/MGC460 variant seems to be the major contributor for the patient's CCM phenotype, the mutated CCM1/KRIT1 seems to act as a booster to CCM overall pathogenicity.

Novel CCM1 (KRIT1) Mutation Detection in Brazilian Familial Cerebral Cavernous Malformation: Different Genetic Variants in Inflammation, Oxidative Stress, and Drug Metabolism Genes Affect Disease Aggressiveness.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular capillary anomalies with a dysfunctional endothelial adherent junction profile, depicting hemorrhage and epilepsy as the main clinical features. With the advent of an increasingly personalized medicine, better comprehension of genetic mechanisms behind CCM represents an important key in the management of the patients and risk rating in relatives. In this context, genetic factors that might influence clinical expressiveness of CCM need to be identified. CASE DESCRIPTION: A 33-year-old woman harboring multiple CCM lesions with a CCM1 mutational profile already being treated conservatively for a right mesial temporal lobe CCM presented with refractory seizures. Magnetic resonance imaging showed no bleeding in the lesion, and the patient was submitted to complete resection of the CCM. Histopathology of the CCM samples depicted an extensive inflammatory reaction and colocalization of CD20+ and CD68+ cells. Genetic analyses of the patient and her mother demonstrated a novel CCM1 (KRIT1) frameshift mutation (c.1661_1662insT; p.Leu554PhefsTer14). Furthermore, variants in CD14 (rs778588), TLR-4 (rs10759930), SOD2 (rs4880), APEX1 (rs1130409), and OGG1 (rs1052133), known as polymorphisms related to disease aggressiveness, were detected in the patient and not in her oligosymptomatic mother harboring the same CCM1 mutation. CONCLUSIONS: Heterogeneity of clinical manifestations among individuals with familial CCM with the same genotype adds mechanistic involvement of modifier factors as phenotypic markers. We describe a novel CCM1/KRIT1 familial mutation in which the coexistence of genetic variants in inflammation and oxidative stress may be related to variable expressiveness of the disease.