Expression of smooth muscle proteins in cavernous and arteriovenous malformations

Cavernous malformations (CVMs) and arteriovenous malformations (AVMs) were immunostained for three smooth muscle cell (SMC)-specific protein markers (smooth muscle alpha-actin, SM1 and SM2). Smooth muscle alpha-actin, a widely used marker of SMCs, is reportedly one of the earliest proteins expressed during differentiation of SMCs and expressed in some kinds of mesoderm-derived cells. In contrast, SM1, an isoform of myosin heavy chain (MHC), is detected only in SMCs. SM2 is another MHC isoform and expressed in the contractile phenotype of SMC. All 14 intraaxial CVMs were positive for smooth muscle alpha-actin, but SM1 was detected in only three of them and SM2 was not found. Their staining pattern resembled that of normal intraparenchymal and pial veins. All 15 cerebral AVMs and 5 out of 6 extraaxial CVMs from the cavernous sinus, orbit and scalp were positive for all three markers, as were the normal cerebral arteries. The venous components of AVMs, as well as the arterial components, expressed SM2, and were different from normal veins in the brain and intraaxial CVMs. This study shows that the histological analysis using the three markers for SMC is useful to differentiate intraaxial CVM from AVM and extraaxial CVMs.     

Afferent-inherent regulation of myosin heavy chain isoforms in rat muscle spindles

Whether afferents exert their morphogenetic influence on spindles through release of trophic factors at intrafusal fiber junctions or via participation in proprioceptive pathways which modulate the motor activity to muscles was investigated by comparing myosin heavy chain (MHC) expression in intrafusal fibers after ablation of afferents (deafferentation, or DA) to the extensor digitorum longus (EDL) of adult rats or after ablation of the corresponding central processes of afferents to the spinal cord (central-process ablation, or CPA). DA and CPA elicited an exaggerated pedal plantarflexion, and hypertrophy of the EDL concomitant with atrophy of the soleus in the affected hindlimb. Frequencies and patterns of expression of seven MHCs expressed by intrafusal fibers in CPA muscles were indistinguishable from normal rats. However, frequencies and patterns of expression of several MHCs were abnormal following DA. Thus factors transported anterogradely from afferents to intrafusal fibers may regulate MHC expression in intrafusal fibers. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1549–1560, 1997     

Expression of myosin heavy chain isoforms in stimulated fast and slow rat muscles

The expression of 4 myosin heavy chain (MHC) isoforms was analyzed in the rat soleus (SOL) and extensor digitorum longus (EDL) muscles after denervation and chronic electric stimulation. The stimulation frequencies used were 20 and 150 Hz and the amount of stimulation was either large (20 Hz), intermediate (150 Hz), or small (150 Hz). These patterns resemble some features of normal motor unit activity in SOL and EDL of freely moving rats (Hennig and L?mo, 1985). The relative expression of each MHC isoform depended strongly on the stimulation pattern. Furthermore, for any particular stimulation pattern, fibers in SOL and EDL expressed different MHCs. Coexistence of different MHC types in the same fiber was frequently observed in stimulated muscles. 20-Hz stimulation preserved normal expression of type 1-MHC in SOL but failed to induce type 1-MHC in type 2 fibers of the EDL, where type 2A- and 2X-MHC expression dominated and type 2B-MHC expression was completely suppressed. 150-Hz low-amount stimulation preserved nearly normal 2B-MHC expression in many type 2 fibers of the EDL but failed to induce type 2B-MHC expression in the SOL, where 2X-MHC became predominant. 150-Hz high-amount stimulation differed from 150-Hz small amount stimulation by suppressing almost all type 2B-MHC expression in EDL and by inducing considerable type 2A-MHC expression in the SOL. Scattered fibers in EDL that were probably the original type 1 fibers responded differently from both type 2 fibers in the EDL and from type 1 fibers in the SOL to stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of myosin heavy chain isoforms in Duchenne muscular dystrophy patients and carriers

The expression of MHC isoforms in the skeletal muscles of nine patients with Duchenne muscular dystrophy (DMD) (from 2.5 to 15 yr of age) and three DMD carriers was studied using different specific anti-MHC MAbs. We also analyzed muscle fiber size and fiber reactivity with acridine orange and/or with a surface antigen marker. One-quarter of all fibers of DMD patients, or less with age, were of normal size and contained only adult slow MHC. Half of the muscle fibers contained adult and developmental MHCs. Only half of these fibers were representative of an active regenerative process. MHC co-expression also altered the proportion of normal fast or slow fibers. Adult fast MHCs were expressed as unique MHC only in small and very small fibers in the oldest DMD patients. In DMD carrier muscles, the greatest alterations in MHC expression were observed in patients with the most reduced dystrophin expression. However, MHC changes in dystrophin-positive fibers were similar to those observed in dystrophin-free fibers. In conclusion, disruptions or delays in the switching of all genes coding for adult fast and slow MHC and developmental MHC coincided with dystrophin deletion and with perturbations in its expression.     

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; Tiel 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 grade Ⅰ, 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-squam test, and the correlation were analyzed with the linear correlation analysis. MAIN OUTCOME MEASURES： Expressions and distributions of VEGF, Tie 1 and Tie2 receptors, angiopoietin-1, angiopoietin-2, PCNA and c-myc in the samples of cerebral arteriovenons malformation and normal brain tissue. RESULTS： ① Expressions of angiogenic factors in the control group and cerebral arteriovenons 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 （ x^2=21.09 - 34.23, P 〈 0.05）, whereas the positive rates of Tiel and angiopoietin-1 expressions were close （ x^2=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 （ x^2= 16.22 - 26.56, P 〈 0.05）. There ware no obvious differences in the expressions of Tiel and angiopoietin-1 expressions between the hemorrhage group and non-hemorrhage group （ x^2=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： ①The 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.     

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.     

Expression of various NCAM isoforms in human embryonic muscles: correlation with myosin heavy chain phenotypes.

Neural cell adhesion molecules (NCAM) are known to play a pivotal role in regulating cell-cell interactions in various tissues. The diversity of NCAM is made by alternative splicing of a single gene and by post-translational modifications. The spatio-temporal expression of the various isoforms is developmentally regulated and may modulate cell interactions. We investigated the expression of NCAM isoforms, in particular polysialylated and phosphatidylinositol-anchored isoforms, in developing psoas and quadriceps human muscle from 15 weeks of gestation to term. In parallel, we examined the expression of the myosin heavy chain phenotype (another developmentally regulated system) to determine whether polysialylated-NCAM molecules (the so-called embryonic NCAM) and developmental myosin heavy chains are coexpressed. Our results showed an expression of polysialylated-NCAM and phosphatidylinositol-anchored isoforms during the early stages of myotube maturation. The expression of polysialylated-NCAM on developing myotube was always associated with the expression of developmental myosin heavy chains. However, the loss of polysialylated-NCAM from maturing myotubes was not correlated with the disappearance of the developmental myosin heavy chains, but rather with the appearance of an adult myosin heavy chain phenotype. The relationship between polysialylated-NCAM and myosin heavy chain phenotype was similar in psoas and in quadriceps muscles. We observed that maturation of quadriceps muscle takes place earlier than psoas. Biochemical analysis showed that phosphatidylinositol-anchored molecules were never polysialylated; this indicates different roles of these isoforms in muscle development.     

Immunocytochemical demonstration of myosin heavy chain expression in human muscle

Three new monoclonal antibodies are shown by immunocytochemical techniques to recognise the adult fast, slow and neonatal myosin heavy chain (MHC) isoforms in adult and fetal human muscle. In fetal muscle of 17-20 weeks of gestation, slow MHC was present only in primary myotubes. Secondary myotubes contained neonatal MHC with different levels of fast and some embryonic MHC. We confirmed the presence of tertiary myotubes in the fetal muscle (Draeger et al. (1987) J. Neurol. Sci., 81: 19-43) and show that these contained fast, neonatal and possibly some embryonic MHC. Fast MHC was therefore present in secondary and tertiary myotubes at least as early as 17 days of gestation.     

Increase in the degree of coexpression of myosin heavy chain isoforms in skeletal muscle fibers of the very old

Myosin heavy chain (MHC) isoform composition was determined in 2264 single skeletal muscle fibers from vastus lateralis muscle of a group (n = 12) of very old subjects (average age, 88 years). The number of fibers containing only MHC I, IIA, or IIX was 19.9%, 27.2%, and 0.3%, respectively. Surprisingly, 28.5% of the fibers displayed coexpression of both MHC I and IIA, a phenotype that is present in younger adults in very small percentages. Among these fibers coexpressing MHC I and IIA, the majority had a dominant expression of MHC I. Additionally, a small number of fibers coexpressing MHC I and IIX without any MHC IIA, and fibers co-expressing all three isoforms were observed. Altogether, 52.6% of all fibers examined in these very old subjects coexpressed two or three MHC isoforms. The present study provides evidence that advanced age leads to a significant elevation of skeletal muscle fibers displaying coexpression of two MHC isoforms and that a separation into slow and fast fibers in very old individuals may therefore be somewhat misleading. The clinical significance of the elevated number of fibers coexpressing MHC I and IIA is uncertain.     

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。     

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。     

Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle

Myostatin (Mstn) is a member of the transforming growth factor-beta family that negatively regulates skeletal muscle mass. Mstn knockout mice have greater skeletal muscle mass than wild-type littermates. We investigated the effect of Mstn on fiber type by comparing adult muscles from the murine Mstn knockout with wild-type controls. Based on myofibrillar ATPase staining, the soleus of Mstn knockout mice displays a larger proportion of fast type II fibers and a reduced proportion of slow type I fibers compared with wild-type animals. Based on staining for succinate dehydrogenase (SDH) activity, a larger proportion of glycolytic fibers and a reduced proportion of oxidative fibers occur in the extensor digitorum longus (EDL) of Mstn knockouts. These differences in distribution of fiber types are accompanied by differences in the expression of myosin heavy chain (MHC) isoforms. In both Mstn knockout soleus and EDL, larger numbers of faster MHC isoforms are expressed at the expense of slower isoforms when compared with wild-type littermates. Thus, the absence of Mstn in the knockout mouse leads to an overall faster and more glycolytic muscle phenotype. This muscle phenotype is likely a consequence of developmental processes, and inhibition of Mstn in adults does not cause a transformation to a more fast and glycolytic phenotype. Our findings suggest that myostatin has a critical role in regulating the formation, proliferation, or differentiation of fetal myoblasts and postnatal fibers.     

Embolization-induced angiogenesis in cerebral arteriovenous malformations

Endovascular occlusion of cerebral arteriovenous malformations (AVM) is often utilized as adjunctive therapy in combination with radiosurgery or microsurgery. Evidence supports that partial occlusion of AVM via endovascular embolization leads to increased angiogenesis. This phenomenon may be a contributing factor to the decreased efficacy of AVM radiosurgery following embolization. We review the literature for potential mechanisms of embolization-induced angiogenesis. A comprehensive literature search was performed using PubMed to identify studies that sought to elucidate the pathophysiology behind embolization-induced angiogenesis. The terms “arteriovenous malformation”, “embolization”, and “angiogenesis” were used to search for relevant publications individually and together. Three distinct mechanisms for embolization-induced angiogenesis were described in the literature: (1) hypoxia-mediated angiogenesis, (2) inflammatory-mediated angiogenesis, and (3) hemodynamic-mediated angiogenesis. Embolization-induced angiogenesis of cerebral AVM likely results from a combination of the three aforementioned mechanisms. However, future research is necessary to determine the relative contribution of each individual mechanism to overall post-embolization AVM neovascularization.     

Secondary epileptogenesis in cerebral arteriovenous malformations

There is debate as to whether secondary epileptogenesis occurs in humans. As part of a series of patients with cerebral arteriovenous malformations and epilepsy, we identified two patients with probable secondary epileptogenesis in the mesiotemporal regions, ipsilateral but anatomically distant from an arteriovenous malformation causing seizures. Both patients had arteriovenous malformations outside the mesiotemporal region and resection of the arteriovenous malformation and epileptogenic areas identified by electrocorticography produced initial freedom from seizures. Three to 6 months later both patients developed a different seizure pattern that proved to be mesiotemporal in origin by video/electroencephalogram (one with depth electrodes) and both patients are seizure free after a second resection of anterotemporal and mesiotemporal regions. Findings indicating a secondary epileptogenic focus include (1) different seizure type by patient history, (2) second seizure type by ictal video/electroencephalographic recordings, and (3) lack of pathologic abnormalities in the resected mesiotemporal specimens.     

Treatment-induced neoangiogenesis in cerebral arteriovenous malformations

We investigated the angiogenetic and proliferative activity of the endothelium of 30 consecutive surgical cases of AVM treated at our institution by immunohistochemical detection of the PCNA, MIB-1, Flk-1 and VEGF antibodies. Endothelial positive immunostaining was observed in 87% of the cases for PCNA, in 20% for MIB-1, and in 80% for Flk-1. Of 22 individuals treated with incomplete embolization prior to surgery, 17 showed an expression of VEGF (77%), but only two of the eight patients (25%) who were treated without prior embolization exhibited such an immunoreaction (P=0.0086). The proliferation and growth of cerebral AVMs is documented by endothelial expression of PCNA and MIB-1. The statistically significantly higher expression of VEGF in partially obliterated (embolized) AVMs is most likely caused by transient regional hypoxia within the AVM nidus that mediates neoangiogensis. It points out the clinical relevance of a complete occlusion in order to avoid neovascularization associated with subsequent morbidity and mortality.     

Lack of type 1 and type 2A myosin heavy chain isoforms in rat slow muscle regenerating during chronic nerve block

The degeneration regeneration process was induced by bupivacaine injection in innervated, denervated, and nerve-blocked rat soleus muscles. Nerve block was obtained by superfusion of the sciatic nerve with tetrodotoxin (TTX). Two weeks after bupivacaine injection, immunohistochemical and electrophoretical analyses showed the presence of type 1 myosin heavy chain (MHC) only in innervated regenerated muscles, type 2A in innervated and denervated, but not in TTX-paralyzed muscles, and type 2X under all experimental conditions. The presence of type 1 MHC in the innervated, and its absence in both denervated and TTX-paralyzed muscles were also verified immunohistochemically 1 week after bupivacaine injection. It is concluded that the nerve impulses play a determinant role in the expression of 1 and 2A MHC isoforms in the innervated regenerating muscle. The possible causes of the absence of the type 2A MHC isoform in the TTX-paralyzed muscles are discussed. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 226–232, 1998     

Treatment of unruptured cerebral arteriovenous malformations

The presence of a cerebral AVM is a potential risk to a patient's life or quality of life. Pharmacologic maneuvers or partial obliteration of an AVM by non-operative means will help most of its nonhemorrhagic manifestations but do not influence the threat of intracranial bleeding, which is the major cause of morbidity and mortality. This risk is eliminated if the AVM is removed. Surgical treatment, however, also carries a risk, and it is therefore important to determine how this risk compares to that of conservative management before surgery is recommended in patients with unruptured AVMs. The present analysis suggests that the surgical mortality and morbidity, although considerably reduced in recent years, still generally precludes surgery for unruptured AVMs. The most favorable figures for surgery are properly applicable to small, superficial AVMs located in clinically silent areas of the brain in young and otherwise well patients who are to be operated upon by surgeons especially experienced in treating AVMs. Even using these favorable figures, however, there is no clear advantage to surgical excision over conservative management over a 20-year period unless AVMs have ruptured once, following which the risks of further episodes of hemorrhage are increased.     

The neurology of cerebral arteriovenous malformations

INTRODUCTION: Brain arteriovenous malformations (AVMs) constitute a neurovascular disorder that comes to clinical attention mainly in young adults in their mid thirties. Associated symptoms often require neurological treatment for symptomatic seizures (focal or generalized), headaches (episodic or chronic), progressive neurological deficits, or spontaneous AVM rupture leading to intracerebral, intraventricular, and/or subarachnoid hemorrhage. STATE OF ART: Little data exist in the medical literature regarding the natural history risk of the disease and no controlled studies are available on the risk of invasive AVM treatment (endovascular, neurosurgery, radiotherapy). PERSPECTIVES: This review focuses on all aspects of neurological brain AVM management and discusses possible predictors of the natural history risk as well as the benefit and risk of invasive treatment. CONCLUSIONS: AVM patient management is ideally based on a trans-disciplinary approach via a neurovascular team of neurologists, neuroradiologists, neurosurgeons, and radiotherapists. A newly diagnosed AVM does not necessarily represent an a priori indication for interventional treatment. The decision in favor or against therapy mainly depends on clinical criteria (ruptured versus unruptured AVM, neurological exam, patient age and co-morbidity, etc.) and the angioarchitecture of the malformation. The ARUBA study is going to be the first randomized clinical trial comparing the risk of invasive treatment versus non-invasive management.     

Multimodal therapy of cerebral arteriovenous malformations

Over the last few decades two new modalities of treatment have been added to the therapy of cerebral arteriovenous malformations: stereotactic radiosurgery and angiographic embolisation. The aim of this review is to discuss surgery and the newer modalities of treatment with particular reference to an integrated multimodal approach to therapy.