Materiały źródłowe

• #1 Arteriovenous Malformation of the Brain – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430744/

  Arteriovenous malformations (AVMs) are a developmental anomaly of the vascular system, consisting of tangles of poorly formed blood vessels in which the feeding arteries are directly connected to a venous drainage network without any interposed capillary system. […] The cause of brain AVMs is yet unknown, however, it is possibly multifactorial; apparently both genetic mutation and angiogenic stimulation (the physiological process of formation of new blood vessels from pre-existing vessels) playing roles in AVM development. […] AVMs cause neurological dysfunction through the following three possible pathophysiological mechanisms. Firstly, the abnormal blood vessels have a propensity to bleed resulting in hemorrhage occurring in the subarachnoid space, the intraventricular space, or, more commonly in the brain parenchyma. Secondly, in the absence of hemorrhage, seizures may occur as a consequence of the mass effect of AVM or venous hypertension in draining veins. The third important cause of slowly progressive neurological deficits is attributed to the „steal phenomenon” which is thought to be related to normal brain parenchyma deprivation from nutrients and oxygen, as blood bypasses the normal capillary bed to the malformed arteriovenous channels.

• #2 Brain arteriovenous malformations – UpToDate

  https://www.uptodate.com/contents/brain-arteriovenous-malformations

  Brain arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. […] The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation. […] Genetic variation may influence brain AVM development and clinical course. […] The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. […] The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. […] Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis. […] Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs. […] Histopathologic studies demonstrate areas of chronic ischemia and gliosis in the region of the malformation.

• #3 Arteriovenous malformation – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/arteriovenous-malformation/symptoms-causes/syc-20350544

  In an arteriovenous malformation, also known as an AVM, blood passes quickly from an artery to a vein, disrupting the usual blood flow and depriving the surrounding tissues of oxygen. […] An arteriovenous malformation, also known as an AVM, is a tangle of blood vessels that creates irregular connections between arteries and veins. This disrupts blood flow and prevents tissues from receiving oxygen. An AVM can occur anywhere in the body, including in the brain. […] Because the tangled blood vessels in an AVM do not form properly, they can weaken and burst. If an AVM in the brain bursts, it can cause bleeding in the brain, which can lead to a stroke or brain damage. Bleeding in the brain is known as a hemorrhage. […] The cause of AVMs is not clear. Rarely, they are passed down in families.

• #4 Brain AVM (arteriovenous malformation) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/brain-avm/symptoms-causes/syc-20350260

  In a brain AVM, blood passes directly from the arteries to the veins via tangled vessels. This disrupts the typical process of how blood circulates through the brain. […] In a brain arteriovenous malformation, blood passes directly from arteries to veins through a tangle of blood vessels. […] A brain arteriovenous malformation (AVM) is a tangle of blood vessels that creates irregular connections between arteries and veins in the brain. […] A brain AVM disrupts this vital process. […] The cause of brain AVMs isn’t clear. Most people who have them are born with them, but they can form later in life. Rarely, AVM can be a trait passed down in families. […] The cause of brain arteriovenous malformations (AVMs) is not known. Researchers believe most brain AVMs are present at birth and form during a baby’s growth in the womb. But brain AVMs can happen later in life as well.

• #5 Brain arteriovenous malformations – UpToDate

  https://www.uptodate.com/contents/brain-arteriovenous-malformations/print

  Brain arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. […] The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation. […] However, genetic variation may influence brain AVM development and clinical course. […] The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. […] The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. […] Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis. […] Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs.

• #6 De Novo Cerebral Arteriovenous Malformation: Case Report and Literature Review | American Journal of Neuroradiology

  https://www.ajnr.org/content/30/1/111

  We describe a rare case of a de novo cerebral arteriovenous malformation (AVM) in a 9-year-old girl. […] The pathogenesis of AVMs is currently unknown. Although they are traditionally thought to be congenital in origin, with an initiating event occurring in early embryologic development, some have suggested a more dynamic developmental process. […] The pathogenesis of AVMs is not completely understood and has largely been theorized. It has been suggested that cerebral AVMs are primarily congenital, originating at or before the 40- to 80-mm embryo length stage and may be related to a primary abnormality of primordial capillary or venous formation. […] Other concepts of cerebral AVM pathogenesis focus on the potential temporal vulnerability of susceptible vascular cellular elements to a physiologic trigger.

• #7

  https://scite.ai/reports/brain-arteriovenous-malformation-pathogenesis-a-GOGglx

  The congenital nature of brain AVMs has been previously questioned by others, and as we have discussed, there is compelling evidence suggesting the postnatal development of many of these lesions. However, the exact mechanism of AVM formation has yet to be elucidated, and it may involve an interaction between genetic susceptibility and environmental (acquired) factors. […] In addition, a variety of candidate gene studies in patients with sporadic AVMs have identified single-nucleotide polymorphisms (SNPs) associated with a susceptibility to develop AVMs and with their progression to intracerebral hemorrhage. […] Studies of AVM tissue have shown increased endothelial cell proliferation and increased expression of angiopoietin-2 and vascular endothelial growth factor, which promote vascular destabilization and proliferation, respectively. However, the exact triggering event that leads to increased and disorganized angiogenesis ultimately leading to AVM formation has not been identified. […] The exact mechanism of AVM formation has yet to be elucidated, but most likely involves genetic susceptibility and environmental triggering factors.

• #8

  https://link.springer.com/article/10.1007/s10143-021-01526-0

  Considerable progress has been made over the past years to better understand the genetic nature and pathophysiology of brain AVM. […] Whole-genome sequencing clarified the genetic origin of sporadic and familial AVM to a large degree, although some open questions remain. […] Substantial progress has been made towards understanding the embryology of brain AVM. […] In contrast to arterial aneurysms, complete modeling of the intranidal flow and a thorough understanding of the mechanical properties of the AVM nidus are still lacking at the present time. […] There is little doubt that AVM are of dysembryological nature. […] Recent evidence suggests that germline and somatic mutations are crucial for AVM development and that aberrant angiogenesis might be the key mechanism. […] About 5% of brain AVMs are linked to a genetic disorder, Hereditary Hemorrhagic Telangiectasia (HHT, Rendu-Osler-Weber Syndrome), which is an autosomal dominant vascular disease that affects approximately 1 in 5000 people worldwide.

• #9

  https://link.springer.com/article/10.1007/s10143-021-01526-0

  HHT has been considered a disease caused by defects in the signaling of TGF- family members. […] Recent studies have shown that blockages for both Bone Morphogenic Protein BMP9 and BMP10 could induce AVM development in the retinal vasculature, but it is not entirely clear whether both BMP9 and BMP10 are needed for ENG-ALK1 signaling. […] The RAS/MAPK/ERK cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. […] It has been shown that alteration of the RAS-MAPK pathway triggers the development of tumors. […] Somatic activating KRAS mutations in AVM tissue samples from 45 of the 72 patients were identified; mutations were not identified in any of the 21 paired blood samples. […] Summarizing these genetic analyses, it can be concluded that sporadic AVM are consequences of local somatic mutations affecting the endothelium.

• #10 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Our understanding of these sporadic vascular anomalies changed dramatically in 2018 with the discovery from our own group that >50% of sporadic bAVM cases contain gain-of-function genetic variants within a gene encoding a small GTPase, KRAS. […] Given that HHT patients may feature bAVMs alongside arteriovenous malformations in other organs, and murine models of HHT phenocopy these multi-organ vascular anomalies, studies on this disease have yielded extensive insights into bAVM pathophysiology. […] The treatment of symptomatic bAVMs, whether as a part of a complex inherited genetic syndrome (such as HHT), or as an isolated sporadic lesion initiated by a somatic variant within the endothelium (e.g., KRAS gain of function), represents an incredible challenge for neurosurgical teams, due to the fragility of intracranial vessels and the associated risk of stroke and hemorrhage.

• #11 An updated review on the genetics of arteriovenous malformations

  https://accscience.com/journal/GPD/2/2/10.36922/gpd.0312

  Pathogenesis of brain arteriovenous malformations. […] Somatic activating KRAS mutations in arteriovenous malformations of the brain. […] Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. […] Activating KRAS mutations in arteriovenous malformations of the brain: Frequency and clinicopathologic correlation. […] High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. […] Recent progress understanding pathophysiology and genesis of brain AVM-a narrative review. […] The rs522616 polymorphism in the matrix metalloproteinase-3 (MMP-3) gene is associated with sporadic brain arteriovenous malformation in a Chinese population. […] Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation.

• #12 Understanding the role of miRNAs in the pathogenesis of brain arteriovenous malformations

  https://www.techscience.com/biocell/v46n1/44748/html

  Understanding the molecular basis of pathogenesis, timely diagnosis, and treatment of brain AVMs are some of the urgent problems in neurosurgery. […] Recent studies have shown that miRNAs can be involved in brain AVMs formation and rupture. […] According to some studies, heterozygous loss-of-function mutations in the RAS P21 protein activator 1 (RASA1) gene can cause a pathology such as capillary malformation, which is a recently discovered, familial disorder in which patients have cutaneous capillary malformations, but they can also be located in the brain. […] RASA1 mutations also link the pathogenesis of brain AVMs to extracellular signal-regulated kinase (ERK) signaling, as RAS is upstream of ERK and diminished RAS deactivation engenders increased ERK activity. […] The pathogenesis of JP-HHT might be due to different effects of lowered levels of mothers against decapentaplegic homolog 4 (SMAD4) within endothelial cells, leading to decreased transforming growth factor beta/bone morphogenetic proteins (TGF-/BMPs) signaling, which may produce vascular dysplasia.

• #13 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The scientific understanding of the nature of arteriovenous malformations (AVMs) in the brain is evolving. It is clear from current work that AVMs can undergo a variety of phenomena, including growth, remodeling, and/or regression and the responsible processes are both molecular and physiological. A review of these complex processes is critical to directing future therapeutic approaches. […] Understanding the complicated molecular milieu of developing AVMs is essential for defining their natural history. Growth factors, extracellular matrix proteins, and other molecular markers will be the key to unlocking novel targeted drug treatments for these brain malformations. […] The altered expression of up to 900 genes has been associated with AVMs. Perhaps 300 genes are upregulated and almost 560 are downregulated in cerebral vascular malformations. These genes encode growth factors, cell adhesion and ECM factors, inflammatory factors, MMPs, and endocrine hormones.

• #14 Pathogenesis of Brain Arteriovenous Malformations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4908075/

  In HHT, development of AVMs may require a copy of inherited mutated gene in particular cells, first. And then, a second hit by the focal somatic mutation in another copy of gene may result in AVM formation in that lesion, as occurred in cerebral cavernous malformation and venous malformation (second-hit model). […] From insights into these current bAVM models, it is suggested that both angiogenic stimulation (environmental factors) and regional conditional homozygous gene deletion (genetic predisposition) may promote the ideal bAVM development in the adult mouse brain. […] Although pathogenesis of bAVMs is not clearly understood, many researches are underway, especially using HHT animal models.

• #15 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation. […] Here, we review past and current observations from both clinicians and researchers that have led to emerging hypotheses for AVM formation. […] To develop novel effective therapeutic strategies for AVM treatment, a better understanding of the pathogenesis of AVM formation is paramount. Hypotheses on how AVMs form and evolve are still a matter of debate and are based on clinical observations employing different imaging modalities as well as on identification of molecular, genetic, and cellular key-player in affected tissues of humans and experimental animals. […] In summary, these studies suggested that a combination of a loss of one functional allele in an HHT-locus, a local loss of protein, and an angiogenic stimulus directed towards ECs might be required for AVM development in mice. […] Further research will be required to strengthen our understanding of AVM formation, and translate these insights from animal models to humans.

• #16 Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0248-8

  Vascular malformations are developmental congenital abnormalities of the vascular system which may involve any segment of the vascular tree such as capillaries, veins, arteries, or lymphatics. […] The causative factor and pathogenic mechanisms of AVMs are unknown. Importantly, no marker proteins have been identified for AVM. […] Altered local hemodynamics in the blood vessels can affect cellular metabolism and may trigger epigenetic factors of the endothelial cell. […] We propose that AVMs result from a series of changes in the DNA methylation and histone modifications in the genes connected to vascular development. […] This review focuses on the molecular pathways of arterial and venous development and discusses the role of hemodynamic forces in the development of AVM and possible link between hemodynamic forces and epigenetic mechanisms in the pathogenesis of AVM.

• #17 Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0248-8

  The causes for development of AVMs in the human brain are still elusive. It is widely speculated that altered hemodynamic forces at the junction of an artery and a vein might provoke the development of AVM and hemodynamic forces may be the critical epigenetic regulator in deciding the endothelial fate. […] All existing studies suggest that the abrupt changes in the hemodynamic flow in the junction of arteriovenous blood vessels might strongly influence the epigenetic mediators and eventually lead to the development of AVM. […] Thus, we speculate the presence of aberrant epigenetic landscape in AVM, particularly acquired mutations in epigenetic proteins and alterations of DNA methylations in the promoters of vascular developmental specific pathway genes.

• #18 Arteriovenous malformations of the brain | MedLink Neurology

  https://www.medlink.com/articles/arteriovenous-malformations-of-the-brain

  Arteriovenous malformations tend to grow slowly after initial formation. The feeding arteries and draining veins grow in caliber, recruiting adjacent vessels into its architecture. One theory as to why arteriovenous malformations grow is the inability of the abnormal vessel group to accommodate arterial pressure. […] Other important anatomic features associated with hemorrhagic presentation include the presence of drainage into the galenic system, venous outflow obstruction, and deep or infratentorial location. […] Cerebral arteriovenous malformations can also cause small recurrent intracerebral hemorrhages. These bleeds cause loss of adjacent brain parenchyma as hematoma and necrotic tissue are reabsorbed. The space created by this process may allow room for an arteriovenous malformation to abut and grow. Pulsation of the arteriovenous malformation is also thought to slowly damage surrounding tissue.

• #19 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  Integrins, immunoglobulins, cadherins, and selectins, along with the ECM milieu, may have significant effects on angiogenesis, vasculogenesis, and brain AVM growth. […] Matrix metalloproteinases, specifically MMP-9, may play a key role in brain AVM growth and spontaneous hemorrhage by affecting vascular stability and angiogenesis as they degrade pericellular substrates. […] The role of inflammatory cells in brain AVMs was considered as early as 1949, when Sorgo hypothesized that the combination of circulatory factors and perivascular leukocytes might stimulate the growth of vessels in these lesions. […] Apoptosis balances cell proliferation. Possible stimuli activating the proapoptotic pathways in brain AVMs include the following: 1) high local concentrations of oxidants such as oxygen free radicals, NO, and oxidized low-density lipoproteins; 2) inflammatory cytokines such as interleukin-1, tumor necrosis factor, and interferon-; 3) direct interaction with inflammatory cells, particularly T lymphocytes and macrophages; and 4) hemodynamic stress and changes in perinidal cerebral blood flow. […] Because 900 genes are thought to be involved in the pathogenesis of vascular malformations, elucidating the molecular characteristics of these lesions and their growth patterns has proven to be challenging.

• #20 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  An abnormally high numbers of inflammatory cells like macrophages, neutrophils, and T lymphocytes have been detected in human and mouse bAVMs, even in unruptured specimens. […] The roles of different cellular loci in bAVM initiation and progression have not been fully studied. In this review, we have summarized what we know based on studies conducted on animal models and surgical resected bAVM specimens. Understanding the roles of each cellular locus will help us to design targeted therapeutic strategies to treat bAVM or prevent bAVM hemorrhage.

• #21 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Recent scRNA-sequencing studies suggest that compromised BBB function, inferred from loss of mature CNS endothelial BBB markers and increased expression of peripheral endothelial genes, could lead to an influx of inflammatory cells that may drive bAVM rupture. […] The recruitment of monocyte-derived cell types, as well as the activation of resident CNS cells in the brain (e.g., microglia and astrocytes), combined with a flood of secreted proteolytic enzymes and barrier-disrupting cytokines and pro-angiogenic growth factors, together with the rise in reactive oxygen species, all act to promote vascular and basement membrane breakdown. […] The presence of macrophages in bAVMs may lead to unresolved inflammation, causing altered vessel remodeling and likely exacerbating the severity of the bAVM phenotype.

• #22 De Novo Cerebral Arteriovenous Malformation: Case Report and Literature Review | American Journal of Neuroradiology

  https://www.ajnr.org/content/30/1/111

  Vascular endothelial growth factor (VEGF) may be 1 link between insult and AVM formation. […] Thus, in theory, insults such as stroke, brain contusion, and encephalitis could all potentially promote the development of AVMs. […] This case and the few previous reports of de novo AVM challenge the concept that cerebral AVMs are purely congenital lesions. AVMs appear to be dynamic lesions that have the potential to develop and grow with time.

• #23 Arteriovenous Malformations – AANS

  http://www.aans.org/patients/conditions-treatments/arteriovenous-malformations/

  Arteriovenous malformations (AVMs) are defects in the vascular system, consisting of tangles of abnormal blood vessels (nidus) in which the feeding arteries are directly connected to a venous drainage network without interposition of a capillary bed. […] The presence of an AVM disrupts this vital cyclical process, causing a snarled tangle of arteries and veins that are connected to one another without the presence of any capillaries. […] Little is known about the etiology of brain AVMs. The cause of brain AVMs is debated, although it is likely multifactorial, with both genetic manipulation and angiogenic stimulation (the physiological process through which new blood vessels form from pre-existing vessels) appearing to play roles during AVM development. […] Some believe that AVMs develop in utero, while others advocate an angiopathic reaction, following either a cerebral ischemic or hemorrhagic event (sub-types of stroke) as a primary factor in their development.

• #24 Brain arteriovenous malformation | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/brain-arteriovenous-malformation?lang=us

  Brain arteriovenous malformations are a type of intracranial high-flow vascular malformation composed of enlarged feeding arteries, a nidus of vessels closely associated with the brain parenchyma through which arteriovenous shunting occurs and draining veins. […] The origin of arteriovenous malformations remains uncertain, although they are thought to be multifactorial and often attributed to being congenital. Their development may involve dysregulation of vascular endothelium growth factor (VEGF) receptor-mediated endothelial proliferation and cytokine-mediated vessel remodeling. […] The nidus is fed by one or more arteries and drained by one or more veins. The feeding arteries are enlarged due to the low resistance (as blood bypasses the capillary beds) and therefore increased flow, which may lead to flow-related arterial aneurysms.

• #25 Arteriovenous malformations of the brain | MedLink Neurology

  https://www.medlink.com/articles/arteriovenous-malformations-of-the-brain

  In cerebral arteriovenous malformations, although draining veins are large and easily recognizable on imaging, the arteries feeding them can be small, sometimes referred to as cryptic. These feeding arteries have medial hypertrophy and endothelial thickening, narrowing their lumen, which can then become stenotic and even occluded. […] The arteries within the cerebral arteriovenous malformations are usually deficient in the muscularis layer. Arteries within the lesion can also be large, but lined with thin walls, due to poorly developed internal elastic lamina and media. […] Examination of adjacent and intralesional parenchyma reveals abnormal gliosis. Angiographic findings indicate that the arterial portions of arteriovenous malformations shunt blood directly toward the venous components. This rapid shunting of blood into large, dilated, draining veins increases blood flow, promoting the formation of aneurysms.

• #26 Arteriovenous malformations of the brain | MedLink Neurology

  https://www.medlink.com/articles/arteriovenous-malformations-of-the-brain

  Cerebral arteriovenous malformations are congenital vascular malformations in the brain that result in direct connections between arteries and veins, without intervening capillary beds. […] Arteriovenous malformations have unique hemodynamics with direct connections between arteries and veins, without intervening capillary beds. These connections contain the nidus; a tangle of abnormal dilated channels that are neither arterial nor venous. Arterial blood is shunted through the nidus with elevated flow in both ends and pressure on the venous end, predisposing the vessel towards inflammation and thrombosis. […] The arterial supply or venous drainage may be composed of single or multiple vessels. Surrounding gliotic brain tissue is usually admixed with the vascular tangle, along with occasional micro or macrocalcifications.

• #27 Brain AVM (arteriovenous malformation) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/brain-avm/symptoms-causes/syc-20350260

  The arteries and veins in an AVM lack this supporting network of smaller blood vessels and capillaries. Instead, blood flows quickly and directly from the arteries to the veins. When this happens, surrounding brain tissue doesn’t receive the oxygen it needs. […] A brain AVM puts extreme pressure on the walls of the affected arteries and veins. The pressure causes the arteries and veins to become thin or weak. This may result in the AVM breaking open and bleeding into the brain, known as a hemorrhage. […] With a brain AVM, blood doesn’t flow through the network of small blood vessels called capillaries. Instead, it flows directly from arteries to veins. Blood rushes quickly because it isn’t slowed by the smaller blood vessels. […] Surrounding brain tissue can’t easily absorb oxygen from the fast-flowing blood. Without enough oxygen, brain tissues weaken or may die off completely. This results in stroke-like symptoms, such as trouble speaking, weakness, numbness, vision loss or trouble staying steady.

• #28 Brain Arteriovenous Malformation (AVM) – Diagnosis and TreatmentSecond Opinion IconGroup 49Group 49

  https://www.barrowneuro.org/condition/arteriovenous-malformation-avm/

  A brain arteriovenous malformation (AVM) is an abnormal tangle of blood vessels in the brain. This defect, which can occur anywhere in the central nervous system, causes blood to flow directly from arteries to veins through an abnormal passageway called a fistula instead of through capillaries. Generally speaking, there are three ways an AVM can damage the brain: […] An AVM can compress or displace parts of the brain. […] As mentioned above, arteriovenous malformations in the brain bypass this capillary network, causing oxygenated and deoxygenated blood to mix via fistulas that directly connect arteries and veins in an area of the AVM known as the nidus. […] In AVMs, blood flows directly from arteries to veins without the buffer of capillaries. Arterial pressure is too high for veins to accommodate due to their thinner walls, which can weaken the blood vessels and cause rupture. Researchers are studying other possible factors in AVM rupture.

• #29 Brain AVM (arteriovenous malformation) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/brain-avm/symptoms-causes/syc-20350260

  An AVM puts extreme pressure on the thin and weak walls of the blood vessels. A bulge in a blood vessel wall, known as an aneurysm, may form. The aneurysm may be at risk of bursting. […] The body may use more arteries to supply blood to the fast-flowing brain AVM. As a result, some AVMs may get bigger and displace or compress portions of the brain. This may prevent protective fluids from flowing freely around the brain.

• #30 Vascular Malformations of the Brain and Spine in Children | PM&R KnowledgeNow

  https://now.aapmr.org/vascular-malformations-of-the-brain-and-spine-in-children/

  Hemorrhage occurs in 0.5% of cases of cranial AVMs and is more common with the fistulous type. […] The natural history of AVMs in the pediatric population is not well understood. It is the most common cause of spontaneous intracranial hemorrhage in children, with 80-85% of pediatric patients suffering a hemorrhagic event as the initial presenting symptom. […] Risk factors for AVM hemorrhage include a previous history of hemorrhage (within 5 years), a deep-seated or infratentorial location, an exclusive deep venous drainage, nidal-type, association with an aneurysm, and diffuse morphology. […] AVM is the most unpredictable vascular malformation. It usually remains quiescent in childhood but tends to enlarge with time and cause local destruction. […] Acute hemorrhagic events in children have been associated with up to a 25% mortality rate.

• #31 Whole-Brain Perfusion CT Patterns of Brain Arteriovenous Malformations: A Pilot Study in 18 Patients | American Journal of Neuroradiology

  http://www.ajnr.org/content/32/11/2061

  BACKGROUND AND PURPOSE: Little is known about the pathological mechanism or the anatomic and functional imaging features related to the clinical manifestations in patients with brain AVM. […] Whole-brain PCT shows different patterns of perfusion abnormalities in patients with brain AVM. These perfusion patterns may discriminate the different pathologic mechanisms involved in these malformations. […] A congenital defect or a dysfunction of the embryonic capillary maturation process is expressed as the vascular malformation. It is believed that the reaction of the vascular tree to the defect and the hemodynamic alterations influence the different clinical presentations and the natural history. […] Decrease in CBF and CBV maps were the most common pattern of perfusion abnormality seen in 61.1% (11 of 18 patients). Such decrease of cerebral perfusion in the extranidal tissue of patients with brain AVMs has been referred to as arterial steal.

• #32 Whole-Brain Perfusion CT Patterns of Brain Arteriovenous Malformations: A Pilot Study in 18 Patients | American Journal of Neuroradiology

  http://www.ajnr.org/content/32/11/2061

  We believe that the decrease in the MTT (pattern 1) in these patients reflects a sump effect from the vascular pedicle supplying the shunt and the adjacent normal brain tissue; thus, we hypothesize this pattern to be a functional type of steal. […] On the other hand, areas of increased MTT with decreased CBF and CBV (pattern 2) may reflect the arterial steal due to indirect collateral connection or areas remote from the nidus where the blood flow is rerouted from the normal brain toward the AVM, resulting in delayed transit time; thus, we believe this to be an ischemic type of steal. […] Another distinct pattern of perfusion abnormality was increased CBV and MTT (pattern 3, n = 5). High-flow shunt in the brain (which may be associated with venous outflow restrictions) may overload the venous system and preclude normal venous drainage, causing venous congestion.

• #33 Arteriovenous Malformations: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1160167-overview

  Arteriovenous malformations (AVMs) are congenital lesions composed of a complex tangle of arteries and veins connected by one or more fistulae. The vascular conglomerate is called the nidus. The nidus has no capillary bed, and the feeding arteries drain directly to the draining veins. The arteries have a deficient muscularis layer. The draining veins often are dilated owing to the high velocity of blood flow through the fistulae. How the abnormal vessels appear or exactly when the process begins is unknown. Deranged production of vasoactive proteins is under investigation as the angiogenetic link to pathophysiology. […] AVMs produce neurological dysfunction through 3 main mechanisms. First, hemorrhage may occur in the subarachnoid space, the intraventricular space or, most commonly, the brain parenchyma. Second, in the absence of hemorrhage, seizures may occur as a consequence of AVM: approximately 15-40% of patients present with seizure disorder. Finally, but rarely, a progressive neurological deficit may occur in 6-12% of patients over a few months to several years. These slowly progressive neurological deficits are thought to relate to siphoning of blood flow away from adjacent brain tissue (the „steal phenomenon”), a concept that has been recently challenged. Neurological deficits may be explained alternatively by the mass effect of an enlarging AVM or venous hypertension in the draining veins.

• #34

  https://journals.lww.com/neurosurgery/fulltext/2025/04000/understanding_the_importance_of_blood_brain.14.aspx

  The major clinical implication of brain arteriovenous malformations (bAVMs) is spontaneous intracranial hemorrhage. There is a growing body of experimental evidence proving that inflammation and blood-brain barrier (BBB) dysfunction are involved in both the clinical course of the disease and the risk of bleeding. However, how bAVM treatment affects perilesional BBB disturbances is yet unclear. […] According to the inflammatory theory, damage to the endothelium, loss of pericytes, and blood-brain barrier (BBB) dysfunction play a primary role in bAVM instability. Therefore, a longitudinal assessment of BBB permeability might have prognostic implications in the management of bAVMs. […] In contrast to CCMs, BBB permeability in patients with bAVM is increased in the perilesional parenchyma, as assessed using DCE-MRI. However, bAVM surgical resection seems to reduce BBB permeability in the perilesional tissue.

• #35

  https://journals.lww.com/neurosurgery/fulltext/2025/04000/understanding_the_importance_of_blood_brain.14.aspx

  Our results suggest that bAVMs induce BBB alterations in the perilesional brain parenchyma, in both ruptured and unruptured conditions, and in contrast to the absence such alterations in cavernomas. Moreover, according to our data, bAVM surgical resection (with/without preoperative embolization) seems to decrease the BBB permeability alterations seen in the perilesional tissue. Overall, our data suggest that bAVM resection might be protective at a BBB level. […] Importantly, this decrease in BBB leakage seemed to surpass the relative increase in permeability because of surgical manipulation, as compared with controls (CCMs). In fact, in bAVMs, the Ktrans values decreased after treatment, whereas in CCMs, the Ktrans remained almost constant after surgery. […] A remarkable observation in our cohort was the significant decrease in BBB permeability of the perilesional brain after definitive treatment of bAVMs. This contrasts with the findings in CCMs, where BBB did not seem significantly altered at baseline; after the resection, only a slight and nonsignificant increase in BBB permeability was seen, probably accounting for surgical manipulation changes.

• #36 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  Brain arteriovenous malformations (bAVMs) are abnormal vessels that are prone to rupture, causing life-threatening intracranial bleeding. The mechanism of bAVM formation is poorly understood. Nevertheless, animal studies revealed that gene mutation in endothelial cells (ECs) and angiogenic stimulation are necessary for bAVM initiation. Evidence collected through analyzing bAVM specimens of human and mouse models indicate that cells other than ECs also are involved in bAVM pathogenesis. Both human and mouse bAVMs vessels showed lower mural cell-coverage, suggesting a role of pericytes and vascular smooth muscle cells (vSMCs) in bAVM pathogenesis. Perivascular astrocytes also are important in maintaining cerebral vascular function and take part in bAVM development. Furthermore, higher inflammatory cytokines in bAVM tissue and blood demonstrate the contribution of inflammatory cells in bAVM progression, and rupture. The goal of this paper is to provide our current understanding of the roles of different cellular loci in bAVM pathogenesis.

• #37 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  Mouse model studies identified several key factors that are crucial for bAVM initiation and progression. Angiogenesis and AVM causative gene mutation in endothelial cells (ECs) are necessary for AVM development. Arterial and venous specification of ECs is a crucial step for development of normal vascular bed, which is determined by genetic factors, although surrounding cells and hemodynamic forces may also contribute to vascular remodeling. Among those genes that are involved in EC arteriovenous specification, abnormal NOTCH signaling has been detected in human bAVMs and both gain or loss of function of Notch in mouse lead to bAVM formation. Although ECs have been identified as the primary cellular locus for AVM initiation, other cellular loci, such as pericytes and microglia/macrophages, have also been shown to play roles in bAVM pathogenesis.

• #38 Uncover the pathogenesis of brain arteriovenous malformation | Anesthesia

  https://anesthesia.ucsf.edu/research-projects/uncover-pathogenesis-brain-arteriovenous-malformation

  In this proposal, we will test our hypothesis that mutant ECs cause bAVM formation and progression through stimulating excessive angiogenesis, impairing pericyte function and induction of inflammation. […] We will also show that mutant EC impair pericyte function through reduction of PDGFB mediated ANG1, TGFb1 and PDGFRb expression in pericytes and that mutant EC drives microglia activation, macrophage, and lymphocyte infiltration through induction of EC-inflammation. […] The overarching goal of this project is to identify new therapeutic targets. […] Center for Cerebrovascular Research Cellular loci involved in the pathogenesis of brain arteriovenous malformations.

• #39 Cellular loci involved in the pathogenesis of brain arteriovenous malformations | Anesthesia

  https://anesthesia.ucsf.edu/research-projects/cellular-loci-involved-pathogenesis-brain-arteriovenous-malformations

  In this study, we will test our hypothesis that mutant endothelial cells impair mural function through a reduction of PDGFB expression, and activate microglia, astrocytes, and fibroblasts through endothelial inflammation; malfunction of other cells further enhances endothelial inflammation and bAVM severity. […] The goal of this study is to identify new targets for developing new therapies for bAVM patients. […] Center for Cerebrovascular Research Uncover the pathogenesis of brain arteriovenous malformation. […] Center for Cerebrovascular Research Reduction of brain AVM severity through inhibition of pathogenic angiogenesis.

• #40 Whole-Brain Perfusion CT Patterns of Brain Arteriovenous Malformations: A Pilot Study in 18 Patients | American Journal of Neuroradiology

  http://www.ajnr.org/content/32/11/2061

  Identification of the pathomechanism and scrutinizing of the imaging features that are directly related to the clinical presentation could allow targeted treatment and improved clinical outcome. […] The degree of arterial hypotension is related to the magnitude of flow through the fistula, thus a direct fistulous connection may be more prone to steal than a nidus type of connection. […] Whole-brain PCT shows different distinct patterns of perfusion abnormalities in patients with brain AVMs. These perfusion patterns may help to discriminate the different pathologic mechanisms involved in the disease with potential therapeutic implications.

• #41 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  The decision for intervention is patient-specific and depends on bAVM eloquence, size, location, vascular anatomy, and complexity, as well as hemorrhage history. […] With limited treatment option for these patients, there is an urgent need to identify novel therapeutic targets based on our current understanding of bAVM pathogenesis. Since the single greatest risk bAVM patients face is the possibility of lesion rupture and intracerebral hemorrhage, identifying factors that promote or prevent rupture is critical for understanding lesion progression and identifying novel potential therapies that may reduce the risk of intracranial hemorrhage. […] Thus, we must first examine inflammation and the cell signaling networks controlling this process, and how it impacts blood–brain barrier (BBB) integrity and the neurovascular unit (NVU) in the setting of bAVM.

• #42 Vascular compactness of unruptured brain arteriovenous malformation predicts risk of hemorrhage after stereotactic radiosurgery | Scientific Reports

  https://www.nature.com/articles/s41598-024-54369-2

  The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. […] Previous studies have reported various predictors for bAVM hemorrhage after SRS. […] Despite comprehensive studies on bAVM hemorrhage after SRS, the effect of bAVM morphology (compact or diffuse) is infrequently discussed. […] Using the compactness index, we classified the bAVMs into compact and diffuse types. We identified diffuse bAVM, larger bAVM volume and lower margin dose as independent predictors of post-SRS hemorrhage. […] The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (40 cm3) bAVMs and the diffuse Spetzler-Martin IVV bAVMs.

• #43 Vascular compactness of unruptured brain arteriovenous malformation predicts risk of hemorrhage after stereotactic radiosurgery | Scientific Reports

  https://www.nature.com/articles/s41598-024-54369-2

  The independent effect of the margin dose could be due to faster obliteration process with higher radiation dose level, which shortened the latency period of bAVMs receiving SRS; alternatively, it could reflect that the whole bAVMs were completely covered in a certain level of radiation dose. […] Our data showed that both volumetric and morphologic effects are decisive for post-SRS hemorrhage. Thus, the appropriate size limit for SRS management of unruptured bAVMs should be stratified by the compactness of the nidi. […] For compact bAVMs, the hemorrhage rate after SRS did not vary with bAVM volume (20 cm3 versus 2040 cm3 versus40 cm3) and was consistently below the natural hemorrhage risk. […] The finding of this study could help patient selection for the management of the unruptured bAVMs.

• #44

  https://scholars.duke.edu/individual/pub1646147

  Pediatric arteriovenous malformations (AVMs) are rare but carry a risk of devastating neurological morbidity and mortality. […] The complex etiology of pediatric AVMs persists as an impediment to a comprehensive understanding of pathogenesis and subsequent targeted gene therapies. […] A variety of gene mutations have been identified within sporadic AVM cases. The Ephrin B2/EphB4 (RASA-1, KRAS, and MEK) signaling axis, hemorrhagic telangiectasia, NOTCH, and TIE2 receptor complexes (PIK3CA and mTOR), in addition to other isolated gene variants, have been implicated in AVM pathogenesis. […] Furthering the understanding of the molecular mechanisms of AVM pathogenesis will lead to future novel therapies and treatment paradigms.

• #45 Arteriovenous malformation Map2k1 mutation affects vasculogenesis | Scientific Reports

  https://www.nature.com/articles/s41598-023-35301-6

  The transcriptome changes in MAP2K1 expressing ECs provides insights into the mechanisms that contribute to AVM formation. […] Our results showing that the Map2k1 mutation in ECs affects vasculogenesis genes and pathways contributes to our understanding of AVMs pathogenesis. […] The activating MAP2K1 EC mutation may cause AVM enlargement through abnormal blood vessel production that secondarily causes overgrowth of tissues. […] Drugs that inhibit EC migration, adhesion, and angiogenesis may prove beneficial to patients with AVMs.

• #46

  https://journals.lww.com/md-journal/fulltext/2019/05310/spontaneous_thrombosis_in_main_draining_veins_of.8.aspx

  Spontaneous obliteration of unruptured arteriovenous malformations (AVMs) is rare. It occurs in 1.5% of cerebral AVMs and only 7 cases have been reported so far. This phenomenon, together with the formation and outcome of cerebral AVMs, remains barely understood. […] Thrombosis of the draining veins may be due to venous stagnation. Spontaneous venous thrombosis in an unruptured AVM is rare. Spontaneous obliteration of an AVM can occur by 2 mechanisms: occlusion of the feeding arteries or of the draining veins. […] The mechanisms proposed to explain spontaneous thrombosis of the draining veins are venous stagnation due to stenosis of the veins, alteration of the endothelium, thrombophilia or acquired coagulation disorders, and mass effect from the nidus on the main draining veins. […] Spontaneous venous thrombosis in an unruptured AVM is rare; only 7 published cases were found during our survey. […] Some authors suggest that anticoagulation therapy would help the unruptured AVMs which are confirmed to have thrombosed draining veins to reach a satisfactory clinical resolution with a relatively low risk of bleeding due to the prevention of progressive venous hypertension.

• #47 Delayed versus immediate intervention of ruptured brain arteriovenous malformations: A case report

  https://www.wjgnet.com/2307-8960/full/v11/i9/1992.htm

  The case we presented is one of the many ruptured bAVM cases encountered in our center that was successfully managed using delayed definitive treatment. […] Despite the ongoing debate of early vs delayed definitive bAVM management, there remains a lack of studies comparing the two approaches and its outcome, especially those performed in a single cohort. […] In order to pave the way for more definitive recommendations on the management of AVM ruptures, we propose that several urgent matters need to be addressed. […] A clear consensus on the definition of immediate and delayed definitive treatment in bAVM management is urgently needed. […] Outcomes of treatment success also needs to be more strictly defined. […] A consensus on defined parameters, in addition to a pre-defined length of follow-up will greatly assist in the acquirement of homogenous data that is urgently needed to answer the current questions in regard to which time approach is more superior, with an end goal of a clear treatment paradigm for ruptured bAVM. […] An example is the recent discovery on the importance of TGF- signaling in bAVM pathogenesis.

• #48 A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-024-01774-7

  Multiple studies have noted the connection between occipital lobe AVMs and headache presentations similar to migraines, aligning with our research findings. […] This study offers critical insights into the effectiveness of different treatments in relieving headache symptoms. Compared to conservative treatment, microsurgery, stereotactic radiosurgery, and multimodal treatment demonstrate significant advantages in headache relief. […] This finding highlights the important role of active interventions in ameliorating headache symptoms.

• #49

  https://journals.lww.com/neurosurgery/fulltext/2025/04000/understanding_the_importance_of_blood_brain.14.aspx

  Ultimately, the comparison of these two cohorts casts out a net benefit for the resection of selected bAVMs in BBB normalization in the perilesional area. This might favor the strategy of treating unruptured bAVMs because restoring BBB may help prevent not only rupture but also other bAVM-related symptoms.

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