ObjectiveTo define the pattern of long-term clinical outcomes and prognostic factors in patients with spinal dural arteriovenous fistulas (SDAVFs).DesginProspective cohort study based on constantly recruiting patients with SDAVFs in two medical centres in China.SettingPatients with SDAVFs were recruited consecutively between March 2013 and December 2014 in two referral centres.ParticipantsA prospective cohort of 94 patients with SDAVFs was included in this study, and 86 patients (mean age 53.0 years, 71 men) completed the study. Patients who had previously undergone endovascular or neurosurgical treatment or had neurological dysfunction caused by other diseases or refused treatment were excluded.InterventionsAll patients underwent neurosurgery or endovascular embolisation. These patients were evaluated with the modified Aminoff and Logue’s Scale (mALS) 1 day before and 3, 6, 12 and 72 months after treatments.ResultsThe duration of symptoms ranged from 0.5 to 66 months (average 12.8 months). The location of SDAVFs was as follows: 33.7% above T7, 50.0% between/include T7 and T12% and 16.3% below T12. 75 patients (87.2%) underwent neurosurgical treatment, and 9 patients (10.5%) underwent endovascular treatment. 58 patients (67.4%) exhibited an improvement in mALS of one point or greater at 72 months. Patients with less disability were more likely to improve at 72 months (p<0.05). 48 patients (55.8%) showed deterioration at 72 months compared with 12 months. 61% of the patients suffered numbness, and 22% had pain before treatment. However, 81% of patients had numbness, and 28% had pain after treatment. This deterioration was related to 1-year mALS and age.ConclusionNearly two-thirds of the patients experienced clinical improvement at 72 months, and preoperative (1 day before treatment) mALS was the strongest predictor of clinical improvement. However, 55.8% of patients showed deterioration after temporary recovery. All patients with SDAVFs should accept treatment as soon as possible.
Background and purpose A major challenge in spinal dural arteriovenous fistula (SDAVF) is timely diagnosis, but no specific predictive biomarkers are known. Methods In the discovery cohort (case, n = 8 vs. control, n = 8), we used cerebrospinal fluid (CSF) and paired plasma samples to identify differentially expressed proteins by label-free quantitative proteomics. Further bioinformatics enrichment analyses were performed to screen target proteins. Finally, it was validated by ELISA in two of the new cohorts (case, n = 17 vs. control, n = 9), and univariate analysis, simple linear regression, and receiver operator characteristic (ROC) curve analysis were performed to evaluate the diagnostic potential. Results In the discovery cohort, the most overexpressed proteins were APOB and C4BPA in CSF samples of patients. The GO/KEGG enrichment analysis indicated that the upregulated proteins were mainly involved in the acute inflammatory response and complement activation. Hub-gene analysis revealed that APP might be the key protein in the molecular interaction network. In the validation cohort, C4BPA and C1QA were significantly overexpressed in the CSF of patients, averaging 3046.9 ng/ml and 2167.2 ng/ml, respectively. Simple linear regression demonstrated that levels of C1QA and C4 were positively correlated with total protein in CSF (R2 = 0.8021, p = 0.0005; R2 = 0.7447, p = 0.0013). The areas under the ROC curves of C4BPA and C1QA were 0.86 and 1.00, respectively. Conclusions This study was the first to identify C4BPA and C1QA as potential biomarkers for the diagnosis of SDAVF and revealed that complement pathway activation might be one of the molecular mechanisms for venous hypertension myelopathy.
Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the central nervous system that can lead to seizure, hemorrhage, and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analyzed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation (c.1323C>G [p.Ile441Met]) but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the central nervous system. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labeling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.
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