Materiały źródłowe

• #1 Intracranial venous malformations – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/intracranial-venous-malformations/symptoms-causes/syc-20353336

  Intracranial venous malformations are veins in the brain that are unusually large. […] Experts don’t understand what causes intracranial venous malformations. Certain genetic changes might play a role, and the malformations may happen during fetal development. However, some types may not be inherited and are acquired later in life, possibly after an injury to the central nervous system. […] Having a family history of intracranial venous malformations can increase your risk. But most types aren’t inherited. […] Certain hereditary conditions can increase your risk of intracranial venous malformations. These include hereditary hemorrhagic telangiectasia, Sturge-Weber syndrome and Klippel-Trenaunay syndrome.

• #1

  https://www.omim.org/entry/108010

  A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to intracranial hemorrhage in brain arteriovenous malformations. […] Somatic activating mutations in the KRAS gene (190070) have been identified as a cause of arteriovenous malformations of the brain. […] Chen et al. (2009) suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta (TGFB1; 190180) signaling and functional haploinsufficiency of ENG, as observed in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300). […] Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells.

• #1 Brain arteriovenous malformations – UpToDate

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

  PATHOPHYSIOLOGY […] – Pathogenesis – 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. Somatic variants in the mitogen-activated protein kinase signaling pathway have been identified in several patients with sporadic brain AVMs. […] – Genetic factors – The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. The presence of more than one brain AVM, otherwise uncommon, is highly predictive of HHT.

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

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

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). […] Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. […] 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. […] For the successful development of new therapies, identification of either one or multiple key pathways responsible for a change in EC behavior would be of high importance.

• #1 Vascular Brain Lesions (Congenital) | 5-Minute Pediatric Consult

  https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617025/all/Vascular_Brain_Lesions__Congenital_?q=Stroke

  VOGMs are embryonic AVMs consisting of choroidal arteries draining into the precursor of the vein of Galen. They develop between weeks 6 and 11 of fetal life. […] SWS occurs sporadically in 1/40,000 to 50,000 births and is associated with a somatic mosaic mutation in guanine nucleotidebinding protein G(q) subunit alpha. The pathophysiology is thought to be venous dysplasia, in which the primordial venous plexus that is normally present at 5 to 8 weeks of gestation fails to regress. The location of this plexus around the cephalic end of the neural tube and under the ectoderm destined to form the facial skin accounts for the clinical features. Venous stasis occurs due to the absence of normal cortical venous structures, and hypoperfusion of brain tissue occurs. These findings are unilateral in the majority but can be bilateral in up to 20% of cases.

• #1 Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2011155

  The underlying genetic mechanism in CCM is partially understood. Second-site genetic mutations have been proposed as one of the possible molecular mechanisms. […] Different explanations have been provided for the molecular pathogenesis of lesion formation in CCM. First, a Knudsonian two-hit mechanism might be involved. According to this mechanism, CCM formation would require a complete loss of the two alleles of a given CCM gene within affected cells. Loss of one of the alleles (first hit) would be the result of a germline mutation, whereas loss of the second allele (or second hit) will occur somatically. In this view, familial CCM exhibits an autosomal dominant mode of inheritance, but is likely recessive at the cellular level. […] On the basis of animal, as well as human studies, evidence grows for the two-hit mechanism.

• #1 Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2011155

  Second, haploinsufficiency may also be an explanation in CCM pathophysiology. In this case, the patient has only a single functional copy of one of the CCM genes, due to mutational inactivation of the other. The single functional copy of the gene, however, does not result in sufficient protein for, for example, an adequate functional junction formation between endothelial cells, which in turn leads to the development of abnormal vascular structures. […] Finally, trans-heterozygosity, in which a patient has synergistic mutations in different genes of the CCM pathway (for example, a germline mutation in the KRIT1 gene with an additional somatic mutation in the MGC4607 or PDCD10 gene), might also explain intrafamilial clinical variability. Indeed, it has been shown that a decrease in the KRIT1, MGC4607 or PDCD10 gene alone caused little or no effect independently, but when combined, resulted in very high incidence of intracranial haemorrhage.

• #1 Vascular Brain Lesions (Congenital) | 5-Minute Pediatric Consult

  https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617025/all/Vascular_Brain_Lesions__Congenital_?q=Stroke

  DVAs are an extreme variation of normal venous development. Typically, venous drainage in the brain occurs through a superficial system and a deep system. DVAs result when a deep venous territory drains toward the surface or when a superficial territory drains to the deep venous system instead of draining in the expected direction. Intervening brain tissue is normal. The mechanism responsible for DVA formation is unknown. […] The pathogenesis of CMs is unknown, although the report of cases of new cavernoma development adjacent to a DVA suggests that DVAs may lead to CM formation. Most CMs occur sporadically, although familial syndromes exist. Several genes have been associated with familial CMs. […] The cause of AVM formation is unknown. A failure of normal capillary development with dysplastic vessels forming between primordial arteriovenous connections has been suggested.

• #1 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. […] 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. […] 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.

• #1 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

  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. […] A detailed study of the epigenetic signals of genes associated with vascular development pathways could throw light on the genetic and epigenetic mechanisms in the development of AVMs.

• #1 Cervicofacial Venous Malformations Are Associated with Intracranial Developmental Venous Anomalies and Dural Venous Sinus Abnormalities | American Journal of Neuroradiology

  http://www.ajnr.org/content/41/7/1209

  Prior studies have suggested an association between the presence of cervicofacial venous malformations and intracranial developmental venous anomalies. […] Our case-control study demonstrated a significant association between cervicofacial venous malformations and cerebral developmental venous anomalies as well as between cervicofacial venous malformations and dural venous sinus abnormalities. […] Our findings suggest that venous malformations may be the result of a segmental in utero insult to cells involved in cerebrofacial venous development. […] Several recent studies have demonstrated an association between VMs and intracranial venous anomalies, specifically developmental venous anomalies (DVAs). […] This association makes sense from a pathophysiologic point of view because somatic mutations affecting venous endothelial progenitor cells could presumably affect the cerebral venous system if they occur before cell migration.

• #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. […] The main complications associated with AVMs include: Intracranial bleed, Mass effect, Seizures, Steal phenomenon, Neurological deficits.

• #1 Brain arteriovenous malformations – UpToDate

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

  – Pathology – 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.

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

  https://emedicine.medscape.com/article/252426-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.

• #1 Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-7091-0693-8_14

  Brain arteriovenous malformations (AVMs) are a rare but important cause of intracranial hemorrhage (ICH) in young adults. […] Based on the various lines of evidence reviewed in this paper, we propose a response-to-injury model of brain AVM pathogenesis.

• #1 Arteriovenous Malformations – AANS

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

  An AVM can occur anywhere in the body, but brain and spinal AVMs present substantial risks when they bleed. […] 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.

• #1 A “perfect storm” of genetic mutations is behind rare sporadic brain malformations that cause stroke, seizures – UChicago Medicine

  https://www.uchicagomedicine.org/forefront/neurosciences-articles/2022/march/genetic-mutations-behind-rare-brain-malformations

  A new study by researchers at the University of Chicago Medicine, Duke University and the University of Pennsylvania has identified a set of sporadic genetic mutations that make it more likely a person will develop these lesions, along with additional mutations in the same area that fuel the lesions growth. […] The new research has identified a unique combination of mutations that occurs during the development of the brain that results in a cavernous angioma. First, a mutation in the gene PIK3CA leads to an abnormal pattern of vessels in the brain, known as a developmental venous anomaly, or DVA. […] This is very novel, because we can now explain why the DVA forms in the first place, said Awad. Along with a second mutation, it is the genetic seed for the formation and growth of the cavernous angioma.

• #1 A “perfect storm” of genetic mutations is behind rare sporadic brain malformations that cause stroke, seizures – UChicago Medicine

  https://www.uchicagomedicine.org/forefront/neurosciences-articles/2022/march/genetic-mutations-behind-rare-brain-malformations

  Not only does this provide a genetic mechanism for the formation of the DVA, but the Chicago team also discovered molecules circulating in the blood that are associated with the key brain mutation. […] Now we can develop blood tests that can identify these mutations in the brain, and in the future, we can develop therapies that can inhibit the mechanisms that cause these lesions to form, Awad said. […] A mechanism is not just about scientific curiosity, he continued. It should motivate us to change patient care. If we dont know the mechanism, we cant have a truly rational therapy.

• #1 Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2011155

  Cerebral cavernous (or capillary-venous) malformations (CCM) have a prevalence of about 0.10.5% in the general population. Genes mutated in CCM encode proteins that modulate junction formation between vascular endothelial cells. Mutations lead to the development of abnormal vascular structures. […] At least three genes have been associated with CCM: k-rev interaction trapped protein 1 (KRIT1) (CCM1; OMIM no. 604214), MGC4607 (CCM2; OMIM no. 603284) and programmed cell death 10 (PDCD10) (CCM3; OMIM no. 603285). These genes encode proteins that are involved in junction formation between vascular endothelial cells. Mutations in the CCM genes, which are in general loss-of-function mutations, lead to the development of abnormal vascular structures characterized by thin-walled, dilated blood vessels with gaps between the endothelial cells.

• #2 Developmental venous anomaly | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/developmental-venous-anomaly?lang=us

  Developmental venous anomalies are usually incidental findings. However, patients can present with intracranial hemorrhage (1-5%). An association has also been described with ischemic stroke and epilepsy. […] The etiology of developmental venous anomalies remains uncertain but may relate to arrested development of venous structures. […] A study has demonstrated that in exceedingly rare cases, the DVA can become symptomatic by various vascular complications. The authors suggested identification of the underlying pathomechanism by MR and DSA for proper management. The importance of the preserved integrity of the DVA itself still holds true.

• #2 Intracranial venous malformations | Beacon Health System

  https://www.beaconhealthsystem.org/library/diseases-and-conditions/intracranial-venous-malformations?content_id=CON-20313605

  Experts don’t understand what causes intracranial venous malformations. Certain genetic changes might play a role, and the malformations may happen during fetal development. However, some types may not be inherited and are acquired later in life, possibly after an injury to the central nervous system. […] Having a family history of intracranial venous malformations can increase your risk. But most types aren’t inherited. […] Certain hereditary conditions can increase your risk of intracranial venous malformations. These include hereditary hemorrhagic telangiectasia, Sturge-Weber syndrome and Klippel-Trenaunay syndrome.

• #2 Pathogenesis of Brain Arteriovenous Malformations

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

  Brain arteriovenous malformations (bAVMs) represent a high risk of intracranial hemorrhages, which are substantial causes of morbidity and mortality of bAVMs, especially in children and young adults. […] Although pathogenesis of bAVMs is not yet well elucidated, genetic mutations and genetic risk factors are increasingly identified. […] The author reviewed pathogenesis of bAVMs using the current updated data, especially the new knowledge from clinical cases and animal experimental models of hereditary hemorrhagic telangiectasia (HHT), which is also known as Osler-Weber-Rendu disease. […] It is conceivable that sporadic bAVMs may have similar genetic backgrounds to HHT. In this context, HHT is a good clinical and experimental model for the investigation of pathogenesis of bAVMs. […] It is known that higher levels of angiogenic factors and inflammatory cytokines are observed in bAVMs than in the normal brain tissues.

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

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

  Over the last decades, it has become increasingly clear that causative mutations, either somatic or germline, in a single AVM are causing gene results in a complex interplay between multiple cellular pathways. […] 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. […] The three steps of AVM development identified above were also described in patients with pulmonary AVMs (PAVMs) in HHT using high resolution CT scanning.

• #2 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. […] 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. […] 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.

• #2 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

  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. […] A detailed study of the epigenetic signals of genes associated with vascular development pathways could throw light on the genetic and epigenetic mechanisms in the development of AVMs.

• #2 Cervicofacial Venous Malformations Are Associated with Intracranial Developmental Venous Anomalies and Dural Venous Sinus Abnormalities | American Journal of Neuroradiology

  http://www.ajnr.org/content/41/7/1209

  The pathogenesis of DVA is not clear. […] However, given the association between DVAs and VMs in our study, we believe that in at least some cases, they must be the result of errors in vasculogenesis of the venous system early in embryonic life. […] Another interesting finding from our study was the high prevalence of dural venous sinus abnormalities in patients with VMs. […] We hypothesize that the presence of VMs, DVAs, and dural venous sinus ectasia represents associations along a pathophysiologic spectrum similar to that of VM, DVA, and dural sinus malformations.

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

  https://emedicine.medscape.com/article/252426-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.

• #2 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.

• #2 A “perfect storm” of genetic mutations is behind rare sporadic brain malformations that cause stroke, seizures – UChicago Medicine

  https://www.uchicagomedicine.org/forefront/neurosciences-articles/2022/march/genetic-mutations-behind-rare-brain-malformations

  Not only does this provide a genetic mechanism for the formation of the DVA, but the Chicago team also discovered molecules circulating in the blood that are associated with the key brain mutation. […] Now we can develop blood tests that can identify these mutations in the brain, and in the future, we can develop therapies that can inhibit the mechanisms that cause these lesions to form, Awad said. […] A mechanism is not just about scientific curiosity, he continued. It should motivate us to change patient care. If we dont know the mechanism, we cant have a truly rational therapy.

• #3 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.

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