Donglei Song

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.

Onyx embolization for the treatment of brain arteriovenous malformations

BackgroundOnyx has emerged in recent years for the endovascular treatment of brain arteriovenous malformations (AVMs). However, the role of Onyx embolization is still under discussion. We report our initial experiences in the treatment of brain AVMs with Onyx embolization.MethodsBetween January 2004 and December 2007, 86 patients with brain AVMs were embolized with Onyx. Clinical presentation included intracerebral hemorrhage in 32 patients, seizures in 25 patients, headaches in 20 patients, neurologic deficits in 3 patients, and in 6 patients the AVM was an incidental finding. According to the Spetzler–Martin scale, three AVMs were grade I, 13 were grade II, 45 were grade III, 19 were grade IV, and 6 were grade V. Seventy-four AVMs were located in eloquent regions.ResultsInitial complete obliteration after final embolization was achieved in 16 patients (18.6%), with an average of 80.5% (range, 30–100%) volume reduction. Partial embolization was followed by surgery in 18 patients, whereas 17 AVMs were cured. In 48 patients treated by embolization and radiosurgery, four patients were lost to follow-up. Three-year follow-up angiography was performed on 30 patients and showed complete obliteration after radiosurgery in 23 patients. The remaining 14 patients are awaiting 3-year postradiosurgery results. Embolization-related permanent morbidity was 3.5%, whereas mortality was 1.2%.ConclusionsAlthough Onyx allows moderate obliteration rates, combined management, such as adjunctive embolization with microsurgery or radiosurgery, may be effective for selected large AVMs.

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.

Endovascular treatment of high-flow cervical direct vertebro-vertebral arteriovenous fistula with detachable coils and Onyx liquid embolic agent

We report the first experience in the treatment of high-flow cervical direct vertebro-vertebral arteriovenous fistula (VVAVF), which was successfully occluded with detachable coils and Onyx through transarterial approach. A 20-year-old female presented with 2-month history of paresis of bilateral extremities. Magnetic resonance imaging (MRI) showed that the dilated ventral epidural veins as well as the dilated left paraspinal veins compressed the spinal cord. Digital subtraction angiography demonstrated high-flow VVAVF between the left vertebral artery (VA) and the surrounding venous plexus at the C3 cervical level. The fistulas were also fed by backward flow from the right VA and left ascending cervical arteries. Transarterial endovascular treatment was performed by using detachable coils and Onyx; immediate angiographic obliteration was achieved. VVAVF-related symptoms resolved gradually, and there was complete neurologic recovery without clinical consequences on clinical follow-up. The fistulas remained closed, as ascertained by 2-month follow-up computed tomography angiography and MRI. No new neurological deficit related to the procedure was detected. The endovascular treatment of direct VVAVF with combination of detachable coils and Onyx is feasible, safe, and highly effective with low morbidity and mortality.

Treatment Strategies for Complex Internal Carotid Artery (ICA) Aneurysms: Direct ICA Sacrifice or Combined with Extracranial-to-Intracranial Bypass

OBJECTIVE Direct surgery for complex internal carotid artery (ICA) aneurysms can be difficult. In certain situations, sacrificing the parent artery is a unique way to obliterate the aneurysm and extracranial-to-intracranial (EC-IC) bypass is indispensable to prevent postoperative cerebral ischemia. This article discusses the indications for direct ICA occlusion, and the strategies, techniques, and outcomes in a series of patients treated for complex ICA aneurysms in a single institution. METHODS During a 7-year period, 49 patients with complex ICA aneurysms underwent direct ICA sacrifice, or ICA sacrifice combined with EC-IC bypass. The appropriate type of bypass was determined by the results of balloon occlusion test and computed tomographic perfusion. The technique of ICA sacrifice used was selected based on the evaluation of retrograde filling of the aneurysm during balloon occlusion test. RESULTS Ten patients underwent direct ICA sacrifice and no ischemia-related complications were evident during the 5-12 months of follow-up. A total of 39 patients were treated by ICA sacrifice combined with EC-IC bypass, including 21 cases of superficial temporal artery-radial artery-middle cerebral artery and 18 cases of external carotid artery-radial artery-middle cerebral artery. ICA sacrifice was achieved in 38 patients by using prolonged occlusion (25 cases) or acute occlusion (13 cases). Five patients presented with minor ischemia after surgery, but four patients recovered completely. Two patients developed brain swelling postoperatively and one developed intracranial hemorrhage, which required evacuation of the hematoma. CONCLUSION Balloon occlusion test combined with computed tomographic perfusion can be an efficient way to evaluate the compromised cerebrovascular reserve in patients with complex ICA aneurysms after ICA occlusion. In conjunction with EC-IC bypass, ICA proximal occlusion or trapping can be an effective treatment strategy.

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.

Dural arteriovenous fistula of the sphenobasilar sinus with concomitant meningioma: case report and review of the literature

Dural arteriovenous fistula of the sphenobasilar sinus is a true but rare lesion that connects the meningeal arteries from both the external and internal carotid arteries to the superficial middle cerebral vein (SMCV) and dural sinus. It must be distinguished from other dural arteriovenous fistulas (DAVFs) of the middle cranial fossa, such as cavernous DAVFs and sphenoparietal sinus DAVF, because of differences in the treatment and outcome between these DAVFs. Two patients with sphenobasilar sinus DAVFs reported in the literature have been identified, but they did not simultaneously harbor intracranial meningiomas. To the best of the authors’ knowledge, the patient described here is the first case that concomitantly harbors a sphenobasilar sinus DAVF and intracranial meningioma. A 42-year-old man presented with acute subarachnoid hemorrhage. Angiography demonstrated a DAVF of the sphenobasilar sinus with a giant venous aneurysm of the SMCV. After transarterial embolization, the fistula was successfully obliterated and the giant venous aneurysm was resected microsurgically. A fortuitous small meningioma at the anterior clinoid was found and removed during the operation. The patient recovered excellently and resumed his normal activities. The relevant literature is reviewed and discussed.

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.

Allelic variation of the MMP3 promoter affects transcription activity through the transcription factor C-MYB in human brain arteriovenous malformations.

MMPs comprise a family of proteolytic enzymes that degrade pericellular substances, which may result in the destabilization of vessels and related to the development of brain arteriovenous malformations (BAVM). MMP3 is a key member of this family, overexpressed in BAVM tissues, and a single nucleotide polymorphism within MMP3, −709A>G (rs522616), is significantly associated with the risk of BAVM. In this study, we aimed to investigate the mechanism through which the polymorphism rs522616 regulates the expression of MMP3. Our results showed that −709A led to a over 2-fold higher transcriptional activity compared with the G allele (P<0.05) and this transcriptional activity can be depressed by co-transfecting cells with competitive DNA fragments containing −709A but not −709G. Bioinformatics analyses suggested that the transcription factor C-MYB might bind to the area around rs522616. Overexpressed C-MYB significantly increased the transcriptional activity of −709A compared with −709G or controls that did not overexpress c-myb (P<0.01) in HEK293 and HUVEC cells. ChIP assays indicated that C-MYB bound to the SNP region in the two cell lines and three BAVM tissue samples. Together, these data indicated that C-MYB can bind to the −709A allele of the MMP3 promoter, activate its transcription and lead to a higher expression of this gene. This novel hypothesis, supported by molecular evidence, explains how this SNP affects MMP3 promoter function and results in a risk of BAVM development.