Expression of angiogenic factors in cerebral arteriovenous malformations

BACKGROUND: In the process of vascularization, vascular endothelial growth factor (VEGF), angiopoietin-2 and Tie2 are involved in the migration, differentiation and proliferation of vascular endothelial cells, and stimulate the rapid angiogenesis; Tie1 and angiopoietin-1 play important roles in facilitating the formation of vascular lumen and maintaining the integrity of vascular wall. Thus the distributions and expressions may be associated with the occurrence of cerebral arteriovenous malformation. OBJECTIVE: To observe the biological effects of angiogenic factors in the occurrence and development of cerebral arteriovenous malformation. DESIGN: An observational comparative experiment. SETTINGS: Department of Neurosurgery, General Hospital of Shenyang Military Area Command of Chinese PLA; Department of Neurosurgery, General Hospital of Tianjin Medical University. PARTICIPANTS: Fresh samples of complete cerebral arteriovenous malformations resected in 47 patients were collected from the Department of Neurosurgery, General Hospital of Tianjin Medical University from August 1999 to May 2001, including 22 males and 25 females, the mean age was 34.5 years. Informed consents were obtained from all the patients or their relatives. The initial symptom was hemorrhage in 28 cases. All the patients were classified according to the clinical imaging data and Spetzler-Martin grading standard, including 11 cases of gradeⅠ, 17 cases of grade Ⅱ, 11 cases of grade Ⅲ, and 8 cases of grade Ⅳ–Ⅴ. Normal brain tissues resected by decompression due to trauma were taken from 8 patients as controls, including 5 males and 3 females, aging 12–65 years. METHODS: ① The expressions of VEGF, Tie receptors, angiopoietin-1, angiopoietin-2, proto-oncogene c-myc and proliferating cell nuclear antigen(PCNA) in the samples of cerebral arteriovenous malformation were detected with immunohistochemical method. Under light microscope, the positively stained rat-anti-human factor VIII-related antigens (specific marker of vascular endothelial cells) were counted, then the immuno-positive cells of the other antibodies in the visual field of neighboring section which was in "mirror" relation were counted, and the percentage of the latter to the former was considered as the labeling index of positive cells. The immunostaining intensity was classified negative (–): no positive cells; positive (+): number of positive cells < 20%; moderately positive (++): number of positive cells 20%–50%; strongly positive (+++): number of positive cells > 50%. ② The differences of the enumeration data were compared with chi-square test, and the correlation were analyzed with the linear correlation analysis. MAIN OUTCOME MEASURES: Expressions and distributions of VEGF, Tie1 and Tie2 receptors, angiopoietin-1, angiopoietin-2, PCNA and c-myc in the samples of cerebral arteriovenous malformation and normal brain tissue. RESULTS: ① Expressions of angiogenic factors in the control group and cerebral arteriovenous malformation groups of each grade: The positive rates of VEGF, Tie2, angiopoietin-2, c-myc and PCNA expressions in the control group were significantly different from those in the cerebral arteriovenous malformation groups of each grade (χ2=21.09–34.23, P < 0.05), whereas the positive rates of Tie1 and angiopoietin-1 expressions were close (χ2=3.43–3.869, P > 0.05). ② Expressions of angiogenic factors in hemorrhage group and non-hemorrhage group: The expressions of VEGF, angiopoietin-2 and PCNA in the hemorrhage group were significantly lower than those in the non-hemorrhage group (χ2=16.22–26.56, P < 0.05). There ware no obvious differences in the expressions of Tie1 and angiopoietin-1 expressions between the hemorrhage group and non-hemorrhage group (χ2=3.22–3.78, P > 0.05). The VEGF was positively correlated with the expressions of c-myc and PCNA (r = 0.728, 0.916, P < 0.05). CONCLUSION: ① The expressions of angiogenic factors and related receptors may be involved in the process of cerebral arteriovenous malformation, and had important correlation the its clinical grading. ② Angiogenic factors may induce the expression of endothelial cell c-myc in cerebral arteriovenous malformation, and then interfere the cell proliferation and apoptosis.     

脑动静脉畸形栓塞治疗后的组织病理及免疫组化研究

目的研究脑动静脉畸形(CAVM)栓塞治疗后的组织病理变化。方法分析11例栓塞治疗后再行手术切除CAVM的病例资料,应用增殖细胞核抗原(PCNA)、α-平滑肌肌动蛋白(α-SMA)、骨桥蛋白(OPN)、血管内皮生长因子(VEGF)等抗体进行免疫组化研究。结果栓塞后,CAVM血管腔内出现不同程度的血管炎性反应,部分被栓塞的血管腔内可见再通。栓塞治疗后的新生内膜中OPN及α-SMA呈阳性染色;畸形血管团周围组织中发现异常微血管,其内皮细胞PCNA阳性染色率高,且VEGF呈阳性染色。畸形血管周围组织中的血管内皮细胞增殖指数(19.6%±8.4%)高于对照组(10.1%±6.2%),差异有统计学意义(P<0.05)。结论栓塞材料引起血管呈不同程度的炎性反应,适度的血管反应有助于管腔闭塞;栓塞治疗后畸形血管周边有微血管增生现象。     

儿童脑动静脉畸形的临床特点与治疗

目的总结分析儿童脑动静脉畸形（AVMs）的临床特点及治疗效果。方法回顾性分析34例儿童脑动静脉畸形患者的临床资料。结果本组病例平均年龄10．4岁,其中21例表现脑出血;按Spetzler—Martin分级,Ⅰ级8例,Ⅱ级13例,Ⅲ级9例,Ⅳ级4例;随访30例中,疗效优22例,良5例,差1例,死亡2例。结论儿童脑AVM最常见的临床表现是脑出血,综合治疗能获得良好临床效果。     

骨桥蛋白在人脑动静脉畸形的表达及意义

目的研究骨桥蛋白(OPN)在脑动静脉畸形(CAVM)的血管组织及其在放射、栓塞治疗后血管病理变化中的表达。方法采用免疫组化方法检测42例CAVM病理标本及对照组10例内减压手术所获脑组织血管中OPN的表达。结果26例无术前治疗史的畸形血管组织中22例有OPN的表达,主要见于CAVM的静脉部分,在粥样硬化样病变的动脉处也有表达。对照组脑组织的血管中未见OPN的表达;有伽玛刀治疗史的5例中,2例在早、中期放射反应的动脉中可见OPN的明显表达;在经历栓塞治疗的11例中,7例在新生内膜组织或异物巨细胞中有强阳性表达。结论人CAVM血管组织中多有OPN的表达,这可能是其适应于适应血流动力学状态而具有的血管重塑的表现,并可能在放射及栓塞治疗后的血管重塑中发挥重要作用。     

Onyx在颅内动静脉畸形栓塞治疗中的初步应用

目的总结Onyx在颅内动静脉畸形(AVM)栓塞治疗中的初步临床应用。方法应用Onyx对10例DSA确诊的颅内AVM进行栓塞治疗。AVM的直径在3~8cm,其中直径大于6cm的大型AVM6例。选用Ultraflow或Marathon微导管。每支供血动脉的注胶时间10~45min。结果栓塞结束时复查血管造影,畸形血管团闭塞30%~50%1例,50%~80%2例,80%~90%4例,90%以上3例。术毕1例患者将微导管留置体内。全部病例随访2~12月无再出血。结论应用Onyx栓塞AVM可以较长时间的注胶,娴熟掌握注胶技巧和控制返流能够提高AVM的栓塞疗效。     

Biology of cerebral arteriovenous malformations with a focus on inflammation

Cerebral arteriovenous malformations (AVMs) entail a significant risk ofintracerebral hemorrhage owing to the direct shunting of arterial blood into thevenous vasculature without the dissipation of the arterial blood pressure. Themechanisms involved in the growth, progression and rupture of AVMs are notclearly understood, but a number of studies point to inflammation as a majorcontributor to their pathogenesis. The upregulation of proinflammatory cytokinesinduces the overexpression of cell adhesion molecules in AVM endothelial cells,resulting in enhanced recruitment of leukocytes. The increased leukocyte-derivedrelease of metalloproteinase-9 is known to damage AVM walls and lead to rupture.Inflammation is also involved in altering the AVM angioarchitecture via theupregulation of angiogenic factors that affect endothelial cell proliferation,migration and apoptosis. The effects of inflammation on AVM pathogenesis arepotentiated by certain single-nucleotide polymorphisms in the genes ofproinflammatory cytokines, increasing their protein levels in the AVM tissue.Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement ofNotch signaling in AVMs provide promising data for a potential basis forpharmacological treatment of AVMs. Potential therapeutic targets and areasrequiring further investigation are highlighted.     

术前部分栓塞联合显微手术切除Ⅲ至V级脑动静脉畸形的疗效分析

目的回顾总结72例脑动静脉畸形（CAVM）的治疗经验,探讨术前部分栓塞病灶在显微手术切除Ⅲ-V级CAVM中的作用,为临床治疗提供参考。方法72例CAVM分为24例栓塞加手术组（Ⅲ一V级17例）和48例单纯手术组（Ⅲ-V级6例）。对术前资料包括：性别、年龄、Spetzler—Martin分级（S-M分级）,术后资料GOS评分进行相关性分忻,比较两组病例的治疗效果。结果24例行26次栓塞,平均每次栓塞2支,共52支供血动脉被栓塞,无栓塞相关并发症。全切69例,残留3例。恢复良好61例,轻残6例,重残3例,植物状态1例,术后死亡1例。术后无新增神经功能障碍,癫痫7例6例消失,1例改善。两组治疗效果无显著性差异。结论I-Ⅱ级CAVM显微手术切除是主要手段,Ⅲ-V级者术前栓塞能降低或改善S—M分级,减少手术风险。显微手术切除联合术前栓塞是对Ⅲ-V级CAVM最直接,最有效的治疗方法。     

97例脑动静脉畸形临床分析

目的:报道97例脑动静脉畸形临床分析。方法:外科手术、血管内栓塞治疗、伽玛刀(γ-刀)治疗和保守治疗。结果:手术治疗66例,优良率81.9％,病残率15.1％,手术死亡率3％。血管内栓塞治疗25例,其中栓塞100％4例,栓塞70％～95％12例,栓塞50％～70％5例,栓塞50％以下4例。3例行γ—刀治疗,3例保守治疗。有7例于手术后、4例于栓塞后行放射治疗。结论:作者认为提高脑动静脉畸形的治愈率,降低病残率及死亡率的关键在于不同部位、类型的脑动静脉畸形选择恰当的治疗方案,对各种治疗方法的适应证进行讨论。     

Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations

OBJECTIVES: To evaluate the therapeutic efficiency and adverse effects of stereotactic proton beam treatment of cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: Twenty-six patients treated in Uppsala during 1991-97 were included (men = 14, women = 12; mean age = 39, range = 23-64). The nidus volumes ranged from 0.3 to 102 ml (mean = 24, median = 13). The follow-up included clinical evaluation, magnetic resonance imaging (and/or computed tomography) every 6-12 months for 3 years and final angiography. RESULTS: The volume changes at final follow-up in AVMs >25 ml were -89, -85, -44, -29, -7, 0, 0, +5 and +18 (%); in AVMs 11-24 ml, -100, -100, -97, -92 and 0 (%); and in AVMs <10 ml, -100, -100, -100, -100, -100, -99, -98, -50, -0 and +40 (%). Two patients were lost to follow-up due to cerebral haemorrhage and myocardial infarction. Radiology displayed significant perifocal oedema in one patient and slight oedema in four patients. Of nine patients with epilepsy, seven became seizure-free after therapy while two continued to suffer from seizures. CONCLUSION: Proton beam irradiation is successful in a relatively high proportion of intermediate and large-sized cerebral AVMs. The adverse effects are acceptable. The advantage of proton treatment compared with gamma knife and LINAC stereotactic irradiation is that protons can irradiate even large volumes with a very sharp dose profile against normal surroundings. Thus, proton beam irradiation is a valuable option in the treatment of AVMs larger than 10 ml.     

脑动静脉畸形所致癫痫的治疗进展

脑动静脉畸形（AVMs）是一种复杂的血管病变,其特点是动脉血直接流入引流静脉,没有流经毛细血管床。通常缺乏小动脉和毛细血管产生的阻力,除了脑血管的解剖结构发生改变外,脑血流动力学也会出现显著改变。癫痫是该病的第二大临床表现,占诊治AVMs的20%～45%,癫痫会给患者带来一系列的问题,现将其新研究进展做一综述。     

脑动静脉畸形的血管造影诊断与栓塞治疗

目的加深对脑动静脉畸形(AVM)数字减影血管造影(DSA)表现特点的认识,并探讨其血管内栓塞治疗价值.方法回顾性分析98例脑动静脉畸形的血管内介入诊疗资料.结果DSA均可显示供血动脉、畸形血管团和引流静脉,获得明确的诊断.98例脑AVM中病灶最大直径4.0 cm以下者57例,位于深部46例,单支供血动脉17例,深部引流16例,单支引流静脉37例(P＜0.05).52例栓塞治疗的技术成功率为100%,单纯真丝线段栓塞36例,真丝线段和NBCA联合栓塞16例.栓塞程度:畸形血管团完全消失者12例,畸形血管团减少75%以上者21例,畸形血管团减少在50%～74%之间者11例,畸形血管团缩小不足50%者8例.结论DSA检查是脑动静脉畸形可靠的诊断方法,有利于估计其预后并制订治疗方案,血管内栓塞治疗是其安全有效的治疗手段.     

Onyx胶栓塞颅内动静脉畸形的临床分析

目的 探讨Onyx胶栓塞颅内动静脉畸形的临床效果。方法 回顾性分析2008年1月至2014年12月采用Onyx胶栓塞治疗的120例颅内动静脉畸形患者的临床资料。结果 栓塞范围≥80% 56例（畸形团完全闭塞14例）,<80% 64例。术中少量出血2例,术后无神经功能缺损。术后出血4例,其中2例死亡。术后一过性神经功能缺损2例。118例随访2~48个月,平均（25.1±5.6）个月,患者头痛、头晕及癫痫等均得到不同程度改善;其中45例DSA随访示,完全闭塞26例,与术前比较无变化19例。结论 Onyx胶血管内栓塞治疗脑动静脉畸形具有良好的效果,但是应掌握其适应症和使用方法。     

Relationships between hemorrhage, angioarchitectural factors and collagen of arteriovenous malformations

Objective While associations between the angioarchitecture of arteriovenous malformations (AVMs) in the brain and pathological features have been described, here we investigated the relationship between the angioarchitecture, the pathological features of the vessel wall, and hemorrhagic events. Methods The study was conducted on 43 patients: 16 with ruptured AVM (rAVM), 15 with non-ruptured AVM (nrAVM), 6 with craniocerebral trauma (control) and 6 with epilepsy (control). The diagnosis of AVM was confirmed by preoperative digital subtraction angiography. Tissues were stained with hematoxylin and eosin and Masson’s trichrome (for collagen fibers) to evaluate the vessel wall structure and endothelial integrity. The content and distribution of collagen types I and III in the vessel wall were assessed by immunohistochemical staining. Results In the nrAVM group, the nidus had more draining veins than the rAVM group (P <0.05). Severely damaged endothelial cells, significantly fewer smooth muscle cells in the media, and hyperplasic type-I and -III collagen fibers were found in the rAVM group. The content of collagen types I and III in rAVMs was higher than that in the nrAVM (P <0.05) and control groups (P <0.01). Conclusion There is an association between angioarchitectural features such as the number of draining veins and the pathological structure of the AVM wall. These abnormalities may contribute to AVM rupture.     

脑动静脉畸形破裂出血并血肿形成的手术治疗

目的探讨脑动静脉畸形(AVM)破裂出血并血肿形成手术治疗的临床疗效。方法回顾性分析40例该病患者的临床特点、影像学特征及手术治疗效果。结果本组病例死亡2例，其余38例获得随访，随访6～12月，恢复工作20例，自理生活12例，需要他人照顾6例；无再出血，14例出现癫痫发作，需服药控制。结论急诊开颅清除血肿的同时尽可能摘除畸形血管是治疗该病的首选方法。     

四维CT血管造影在脑动静脉畸形诊断中的应用

目的 从病灶检出及血管构筑显示方面探讨320排CT四维CT血管造影(4D-CTA)在脑动静脉畸形(CAVM)诊断中的临床应用价值.方法 对20例可疑CAVM患者行4D-CTA成像和数字减影血管造影(DSA)检查.比较两种成像方法所示畸形血管团位置、数目、大小及供血动脉来源、引流静脉深浅、数目方面的差异.结果 20例患者经4D-CTA诊断为CAVM,其中1例经DSA证实为脑动静脉瘘(CAVF);4D-CTA对畸形血管团位置、数目、大小,供血动脉及引流静脉的显示与DSA所示一致性良好,差异均无统计学意义(P＞0.05).结论 4D-CTA能实现颅内血流状态的无创性动态显示,在CAVM的诊断及治疗策略制定上具有重要价值.     

出血性脑动静脉畸形合并动脉瘤的栓塞治疗

目的 探讨出血性脑动静脉畸形合并动脉瘤的特点与血管内治疗的方法.方法 经CT或MRI确认脑出血的病例,经全脑血管造影证实为脑动静脉畸形(AVM)合并动脉瘤为36例患者,根据AVM病灶和动脉瘤的特点,采取不同的栓塞策略,经血管内超选择应用α氰基丙烯酸正丁酯、ONYX胶或弹簧圈栓塞畸形团和动脉瘤.结果 栓塞后35例动脉瘤完全栓塞,AVM病灶完全消除26例;1例残留AVM因引流静脉狭窄术后1年发生出血,行血肿清除并AVM病灶切除术治愈;另1例因残余病灶接受伽玛刀治疗3个月时发生出血,保守治疗后行2次栓塞治愈.结论 AVM病灶内或病灶旁存在动脉瘤是引起脑出血的重要原因,在栓塞前制定栓塞策略,优先处理动脉瘤样病变对防止脑出血有重要意义.     

Nongalenic cerebral arteriovenous malformations in neonates and infants Review of 26 consecutive cases (1982–1992)

We present 26 consecutive cases of nongalenic pial arteriovenous malformations (PAVMs) diagnosed in the neonatal period or in infancy. No diagnosis was made antenatally. Presenting symptoms in neonates were systemic cardiac manifestations (54%), seizures (31%), and hemorrhages (15%). In infants, hemorrhagic strokes and hydrodynamic disorders (external or internal hydrocephaly, macrocephaly, atrophy) both occurred in 38% of cases. Systemic cardiac manifestations and seizures were rare at that age (respectively 16% and 8%). Sixty-two percent of neonates and 31% of infants already had neurocognitive disorders (assessed by pediatric neurocognitive testing: Brunet-Leizine and Denver tests) when referred. The venous drainage and its anomalies (ectasias, stenoses, thromboses) were the main causes of symptoms. Atrophy and leukomalacic lesions occurred rapidly; they express local hydrovenous disorders and are specific to this population group. Untreated neonates and infants have a poor prognosis. Endovascular treatment, although partial and challenging in all instances, represents the treatment of choice in our series. Of the eight neonates treated, one improved to normal (12.5%), while four remained stable (50%): two neurologically normal, two with mild neurological deficit. Three (37%) died despite embolization (heart failure, multiorgan failure, postoperative death). Transient neurological complications occurred in two cases (25%): hemiparesis in one patient with a rolandic and in one with a thalamic AVM. Of the eight infants successfully embolized, one was significantly improved (12.5%) and is now neurologically normal, while five remained stable (62.5%): four neurologically normal, one with mild neurological deficit. One died between two sessions of embolization from intracerebral hemorrhage (12.5%). Hemianopsy occurred in one case (12.5%) after embolization of an occipital AVM. In one additional case in a normal child we failed to embolize the last small pial AVM of four after the three others had spontaneously thrombosed. With a minimal follow-up of 18 months and a maximum of 7 years, the review of our series shows 53% of the initial group of neonates and infants growing neurologically normal after therapeutic management in our institution; 23.5% died despite treatment, and the remaining 23.5% present minor neurological deficit. When targeted at the points of angioarchitectural weakness, embolization contributes to stabilizing a lesion. It should be undertaken rapidly to avoid loss of brain substance secondary to hemorrhage, atrophy, or leukomalacia, and to allow neurocognitive recovery and normal brain maturation. In our experience, theses lesions are the most aggressive ones for the maturating brain, and the most difficult to approach technically. They represent a new therapeutic field and have their own specific anatomy and physiology.     

复合手术在脑动静脉畸形治疗中的应用

目的 总结一站式复合手术在治疗脑动静脉畸形中的临床经验。方法 回顾性分析2014年4月至2017年11月采取复合手术治疗的24例脑动静脉畸形的临床资料,术前Spetzler-Martin分级Ⅲ级8 例,Ⅳ级14例,V级2例。14例术中先做治疗性供血动脉栓塞再进行手术切除,另10例直接行手术切除;全部病人均在切除病灶后行术中造影以评估切除程度。结果 24例畸形血管团全切除。20例术后恢复良好,4例术前昏迷病人术后意识障碍改善。没有死亡病人,未发生与介入相关的并发症。24例术后随访6个月至2年,16例行DSA、8例CTA检查;除1例存在部分病灶残留外,其余23例均无病灶残留或复发;日常生活能力分级Ⅰ级16例,Ⅱ级2例,Ⅲ级2例,Ⅳ级4例。结论 复合手术为脑动静脉畸形提供了一个新的外科治疗方案;该技术可简化多次介入以及显微手术的治疗过程,并且能够实时地对切除情况进行精准地评估,是一项安全有效的治疗方式。     

Spontaneous regression of brain arteriovenous malformations

Abstract Objective and importance Complete spontaneous obliteration of a brain arteriovenous malformation (AVM) is a rare event, with 67 angiographically proven cases in the world literature. We present a new case and a systematic literature review to determine possible mechanisms underlying this unusual phenomenon. Clinical presentation One patient with a brain AVM was referred for radiosurgical treatment. Shortly before treatment however, complete spontaneous regression occurred. This patient had experienced a hemorrhage in the months before referral. Results We found 38 articles in which 67 cases of complete and spontaneous regression of a brain AVM were presented. Male to female ratio was 1.2, with a mean age of 37 years (range 1–81). Regression occurred in 72% without new neurological events. Median size of the nidus was 2 cm (range 1–7). There was a single arterial feeder in 46 % and a single draining vein in 59%. Conclusion Spontaneous regression of a brain AVM is the result of multiple interacting factors. Intracranial hemorrhage and the presence of a single draining vein seem to play a major role in this process.     

大型脑动静脉畸形的伽玛刀体积分割治疗

目的 探讨伽玛刀体积分割治疗大型(体积＞10 cm3)脑动静脉畸形(AVM)的临床疗效.方法 回顾性分析2007～2017年收治的13例大小脑AVM的临床资料,均采用伽玛刀体积分割治疗,时间间隔3～18个月,治疗的AVM总体积平均为18.2 cm3(13.5～52 cm3),首次治疗的体积平均为14.1 cm3(8～2...