Yuxiang Gu

Molecular Analysis of RNF213 Gene for Moyamoya Disease in the Chinese Han Population

Background Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cerebral ischemia and hemorrhage. Genetic factors in the etiology and pathogenesis of MMD are being increasingly recognized. Previous studies have shown that the RNF213 gene was related to MMD susceptibility in the Japanese population. However, there is no large scale study of the association between this gene and MMD in the Chinese Han population. Thus we designed this case-control study to validate the R4810K mutation and to define the further spectrum of RNF213 mutations in Han Chinese. Methodology/Principal Findings Genotyping of the R4810K mutation in the RNF213 gene was performed in 170 MMD cases and 507 controls from a Chinese Han population. The R4810K mutation was identified in 22 of 170 MMD cases (13%), including 21 heterozygotes and a single familial homozygote. Two of the 507 controls (0.4%) were heterozygous R4810K carriers. The R4810K mutation greatly increased the risk for MMD (OR = 36.7, 95% CI: 8.6∼156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.8∼16.1, P = 0.001). Genomic sequencing covering RNF213 exon 40 to exon 68 also identified eight other non-R4810K variants; P4007R, Q4367L, A4399T, T4586P, L4631V, E4950D, A5021V and M5136I. Among them A4399T polymorphism was found in 28/170 cases (16.5%) and 45/507 controls (8.9%) and was associated with MMD (OR = 2.0, 95% CI: 1.2∼3.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.2∼6.5, P = 0.014). Conclusions RNF213 mutations are associated with MMD susceptibility in Han Chinese. The ischemic type MMD is particularly related to the R4810K mutation. However, A4399T is also a susceptible variant for MMD, primarily associated with hemorrhage. Identification of novel variants in the RNF213 gene further highlights the genetic heterogeneity of MMD.

Whole-Brain CT Perfusion and CT Angiography Assessment of Moyamoya Disease before and after Surgical Revascularization: Preliminary Study with 256-Slice CT

Background/Aims The 256-slice CT enables the entire brain to be scanned in a single examination. We evaluated the application of 256-slice whole-brain CT perfusion (CTP) in determining graft patency as well as investigating cerebral hemodynamic changes in Moyamoya disease before and after surgical revascularization. Methods Thirty-nine cases of Moyamoya disease were evaluated before and after surgical revascularization with 256-slice CT. Whole-brain perfusion images and dynamic 3D CT angiographic images generated from perfusion source data were obtained in all patients. Cerebral blood flow (CBF), cerebral blood volume (CBV), time to peak (TTP) and mean transit time (MTT) of one hemisphere in the region of middle cerebral artery (MCA) distribution and contralateral mirroring areas were measured. Relative CTP values (rCBF, rCBV, rTTP, rMTT) were also obtained. Differences in pre- and post- operation perfusion CT values were assessed with paired t test or matched-pairs signed-ranks test. Results Preoperative CBF, MTT and TTP of potential surgical side were significantly different from those of contralateral side (P<0.01 for all). All graft patencies were displayed using the 3D-CTA images. Postoperative CBF, rCBF and rCBV values of surgical side in the region of MCA were significantly higher than those before operation (P<0.01 for all). Postoperative MTT, TTP, rMTT and rTTP values of the surgical side in the region of MCA were significantly lower than those before operation (P<0.05 for all). Conclusion The 256-slice whole-brain CTP can be used to evaluate cerebral hemodynamic changes in Moyamoya disease before and after surgery and the 3D-CTA is useful for assessing the abnormalities of intracranial arteries and graft patencies.

Clinical Analysis of 50 Cases of BAVM Embolization with Onyx, a Novel Liquid Embolic Agent.

To report the embolization technique of using Onyx, a new liquid embolic agent, to treat cerebral arteriovenous malformations (AVMs) as well as its efficacy. 38 cases of cerebral AVMs located in eloquent area (motor, speech, visual nerve center), 9 in deep cerebral area, and another 3 cases in cerebellar hemisphere. The diameter of AVMs was smaller than 3cm in 10 cases, 3–6cm in 30 cases, and larger than 6cm in 10 cases. A 6F sheath was placed into the femoral artery after Seldings puncture. After a 6F guiding catheter was introduced into the internal carotid artery or vertebral artery, Ultraflow or Marathon microcatheter could be navigated into the nidus of AVMs. A long-slow injection of Onyx under fluoroscopic control was performed to embolize cerebral AVMs by adopting the “plug and push” technique. 10 AVM cases (20.0%) were considered to be totally occluded with Onyx in this group, 3 cases of which were found no regrowth by a 6-month follow-up. 25 cases (50%) were subtotally occluded while another 15 cases (30%) were partially embolized. Complications include: (1) severe cerebral hemorrhage occurred in three cases, two of them left hemiplegia after hematoma resection. (2) mild hemiplegia occurred in one lager frontal AVM patient. (3) mild visual deficit was left in one larger occipital AVM case. There was no severe complication in other 45 patients. Onyx has unique and distinctive superiority in treating cerebral AVMs. Nonetheless, the correct embolization technique should be learned to achieve good clinical results and to avoid complications. The long-term efficacy of Onyx embolization needs to be followed up.

Motor evoked potential monitoring during surgery of middle cerebral artery aneurysms: a cohort study.

BACKGROUND Motor evoked potential (MEP) monitoring has been widely used in brain or spine surgery to recognize potential damage of the pyramidal motor system. However, its ability to detect ischemic injury during middle cerebral artery (MCA) aneurysm surgery remains unclear. A prospective cohort study was designed to evaluate MEP changes during MCA aneurysm surgery. METHODS From January 2009 to August 2011, 89 patients underwent MCA aneurysm surgery and were prospectively divided into 2 groups: MEP monitoring group and control group. Based on an amplitude decrement of >50% or loss, a 2-stage warning criterion of MEP changes was established. Concomitant somatosensory evoked potential changes were also recorded. MEP changes occurred in 15 patients, and various methods were used to avoid continued brain ischemia. Indocyanine green angiography and Doppler ultrasonography were performed if needed. A head computed tomography scan was performed immediately and the day after the operation. RESULTS At discharge, neither motor status nor Glasgow Coma Scale score was significantly different between the 2 groups. However, at the latest follow-up (mean, 31.9 months), motor status of the patients in the monitoring group was better (P = 0.037). MEP monitoring was identified as an independent prognostic factor for motor outcome in long-term results by multivariate analysis (P = 0.042). Both wave loss and >50% amplitude decrement of MEP monitoring showed good predictive value when used as part of a 2-stage warning criterion. CONCLUSIONS MEP monitoring is reliable for evaluation of the ischemic status of the pyramidal motor system during MCA aneurysm surgery and can improve surgical outcomes when used appropriately.

Disappearance of aneurysms associated with moyamoya disease after STA–MCA anastomosis with encephaloduro myosynangiosis

Moyamoya disease is a rare cerebrovascular disease characterized by steno-occlusive vasculopathy affecting the terminal internal carotid arteries. Although the effect of direct arterial bypass on the prevention of recurrent haemorrhage or ischemic events in patients with hemorrhagic moyamoya disease has been demonstrated, disappearance of aneurysms associated with moyamoya disease has rarely been reported. In this study, we present two patients with aneurysms associated with moyamoya disease. After superficial temporal artery to middle cerebral artery anastomosis combined with encephaloduro myosynangiosis, the aneurysms on the moyamoya vessels disappeared, which was confirmed by follow-up angiography.

Efficacy of extracranial–intracranial revascularization for non-moyamoya steno-occlusive cerebrovascular disease in a series of 66 patients

Although there is uncertainty about whether extracranial-intracranial arterial bypass is useful for the treatment of steno-occlusive cerebrovascular disease in general, there is some argument for its continued use in particular patients. In the present study, we evaluated the efficacy of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis combined with encephalo-duro-myo-synangiosis (EDMS) in the treatment of non-moyamoya steno-occlusive cerebrovascular disease by retrospectively reviewing clinical and radiological data from 66 patients treated between January 2006 and April 2011. Forty-six double STA-MCA anastomoses and 20 single anastomoses were completed, and all remained patent in the perioperative phase, as confirmed by CT angiography. Postoperative CT perfusion imaging demonstrated immediate improvement in perfusion in the revascularized hemisphere. On discharge, 50 of the 66 patients (75.8%) had an improved National Institutes of Health Stroke Scale (NIHSS) score relative to preoperative values. After at least 6 months of follow-up, 54 (88.5%) patients had improved NIHSS scores relative to discharge values. CT perfusion imaging showed significant improvement compared to post-operative images. Follow-up digital subtraction angiography confirmed that 95 of 96 (99%) anastomoses remained patent. There was no significant difference between the single and double bypasses in terms of either clinical or hemodynamic outcomes on the revascularized side. STA-MCA combined with EDMS was effective for the treatment of non-moyamoya steno-occlusive cerebrovascular disease with hemodynamic impairment. Hemodynamic evaluation before and after surgery may help identify patients in need of a bypass and may be useful for predicting outcome.

Clinicopathological analysis of rhabdoid meningiomas: report of 12 cases and a systematic review of the literature.

BACKGROUND Rhabdoid meningioma (RM) is a rare subtype of meningioma, classified as World Health Organization grade III with a poor prognosis. Here we present our experience on RM and review relevant literature in an attempt to investigate the clinical features, treatment, and prognosis of these tumors. METHODS Twelve patients underwent surgical treatment for intracranial RMs between 2003 and 2008 in our department. The clinical data, radiological manifestations, pathological findings, treatments, and prognoses of the patients were analyzed retrospectively; 58 other cases reported previously by other institutions also were summarized and reviewed. RESULTS These cases (6 men and 6 women, mean age 44.3 years old, ranging from 21 to 78 years old) constituted 0.28% of all meningioma patients admitted at our department during the same period. The mean duration of symptoms was relatively short at 1.6 months. There was no significant clinical manifestation noted, and the radiologic findings fell into 3 types of images. In the follow-up period of over 30 months, 7 patients died; 5 patients had recurrence and 2 patients died of unknown causes. CONCLUSIONS RM is a rare subtype of malignant meningioma featuring an increased tendency for recurrence and possible metastasis. It is still difficult to make a correct preoperative diagnosis. The overall prognosis for these patients is extremely poor, and the role of various adjuvant treatments needs to be further studied.

The rs522616 polymorphism in the matrix metalloproteinase-3 (MMP-3) gene is associated with sporadic brain arteriovenous malformation in a Chinese population

In this study, we investigated the association between common variants in the matrix metalloproteinase-3 (MMP-3) gene and the risk of developing sporadic brain arteriovenous malformation (BAVM). We performed genotyping analyses for five single nucleotide polymorphisms (SNPs) in MMP-3 in a case-control study involving 319 Chinese patients with BAVM and 333 Chinese controls. The association between MMP-3 genotypes and the risk of developing BAVM was evaluated using logistic regression analyses. We found that the genotype frequencies were significantly different between patients and controls for the rs522616 A > G variant of MMP-3 (p = 0.02). Logistic regression analysis revealed that the variant genotype of this polymorphism was associated with a significantly decreased risk of BAVM (adjusted odds ratio = 0.62, 95% confidence interval = 0.44-0.87, p = 0.006 for the AG compared with the AA genotype; adjusted odds ratio=0.68, 95% confidence interval = 0.49-0.94, p = 0.019 for the AG + GG compared with the AA genotype). These findings indicate for the first time that the MMP-3 rs522616 polymorphism may contribute to the etiology of sporadic BAVM in the Chinese population.

Polymorphisms of the vascular endothelial growth factor A gene and susceptibility to sporadic brain arteriovenous malformation in a Chinese population.

Human brain arteriovenous malformation (BAVM) tissue contains increased levels of vascular endothelial growth factor A (VEGFA). We carried out a case-control study to determine whether polymorphisms in the VEGFA gene are associated with sporadic BAVM. Nine selected VEGFA single-nucleotide polymorphisms (SNP) were genotyped in 319 patients with BAVM and 333 controls from a Chinese population using the MassARRAY genotyping system. We found four single variants in the VEGFA gene (rs1547651, rs2010963, rs833069 and rs3025010), with one haplotype, ACT, possibly associated with the risk of developing BAVM.

Spontaneous brain activity in adult patients with moyamoya disease: a resting-state fMRI study

Adult patients with moyamoya disease (MMD) are reported to suffer from vascular cognitive impairment (VCI), including considerable impairment of executive function/attention. The spatial pattern of functional brain activity in adult MMD patients with VCI has not been studied before and can be measured by examining the amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) during rest. Twenty-three adult patients with MMD were recruited to participate in this study, including 11 with VCI and 12 without VCI (NonVCI), as well as 22 healthy young adults (normal control, NC). Widespread differences in ALFF were observed between the VCI/NonVCI and NC groups in such regions as the frontal, parietal and temporal gyri, with parts of the frontal gyrus, such as the anterior cingulate cortex (ACC) and the right supplemental motor area (SMA), showing significant differences in ALFF. It is worth to note that regions such as the parietal gyrus, the right superior frontal gyrus (SFG), the right superior temporal gyrus (STG) and the left caudate nucleus (CN) exhibited significant changes in ALFF during the progressive cognitive decline of MMD. Taken together, our results demonstrate that MMD exhibits a specific intrinsic pattern of ALFF and that this pattern changes with the progression of cognitive decline, providing insight into the pathophysiological nature of this disease.