Brain arteriovenous malformation

Vascular Disease MONDO:0007154 Pathograph 36 Show in embeddings browser Arteriovenous malformation Cerebrovascular disease Vascular malformation

Brain arteriovenous malformation is a nidus of abnormal vessels connecting cerebral arteries to veins without an intervening capillary bed. Presentation includes intracranial hemorrhage, seizures, headache or focal neurological deficits; some lesions are detected incidentally. This entry focuses on sporadic brain AVM. Somatic activating KRAS variants, and less frequently activating BRAF variants, explain a substantial subset of sampled lesions, with endothelial enrichment and experimental evidence of MAPK-dependent vascular remodeling. A molecular cause is not established in every lesion. Altered endothelial metabolism, junctional integrity, mural-cell support and inflammatory interactions contribute to vascular instability, with different levels of human and model evidence. Germline syndromic AVMs are covered in the HHT and capillary-malformation–AVM syndrome entries.

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Classifications

Harrison's Part

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Inheritance

Somatic mosaicism (sporadic lesions, not inherited) HP:0001442

Sporadic brain arteriovenous malformation is not a heritable disorder. The causal activating KRAS (or BRAF) variant is a somatic event confined to the lesional endothelium and is absent from paired blood, so the lesion is a somatic mosaic clone within an otherwise normal vasculature. Familial AVM in hereditary hemorrhagic telangiectasia is a distinct germline entity and is not covered by this block.

Somatic mosaicism

Show evidence (1 reference)

PMID:29298116 SUPPORT Human Clinical

"We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples."

Lesion-restricted detection with absence from paired blood is the defining evidence of a somatic mosaic origin.

Discussions and Knowledge Gaps

Which patients with an unruptured brain AVM benefit from intervention when both hemorrhagic and nonhemorrhagic outcomes are considered?

KNOWLEDGE GAP OPEN bavm-unruptured-management-controversy

Attached to

pathophysiology#Nidus Rupture and Intracranial Haemorrhage pathophysiology#Nidus Formation with Direct Arteriovenous Shunting

ARUBA randomized adults and measured death or any symptomatic stroke, including ischemic stroke. MATCH emulated a target trial in an observational registry that included younger patients and measured AVM-related hemorrhage or death; its primary outcome excluded ischemic stroke, radiation injury, seizures and cognitive effects. Longer follow-up alone cannot explain the different estimates, and weighting cannot eliminate unmeasured confounding. MATCH high-grade subgroup estimates were imprecise. Diffuse lesions showed benefit at five years but no significant advantage at ten years, rather than uniform absence of benefit.

Proposed experiments

Long-term randomized assessment of net clinical benefit

bavm-long-horizon-randomisation

Compare intervention and observation with long-term randomized follow-up, prospectively stratified by clinically relevant lesion anatomy. Measure death, hemorrhagic and ischemic stroke, disability, cognition, seizures and treatment-related injury rather than assuming hemorrhage-free survival captures net benefit.

Readouts

Death, hemorrhagic and ischemic stroke, disability and treatment-related injury

pathophysiology#Nidus Rupture and Intracranial Haemorrhage

Would support

pathophysiology#Nidus Rupture and Intracranial Haemorrhage

Show evidence (2 references)

PMID:32562682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The incidence of death or symptomatic stroke was lower with medical management alone"

Final ARUBA randomized comparison at mean 50.4 months.

PMID:41231469 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the estimated 5-year hemorrhage-free survival was 96.23% (95% CI, 93.95%-97.65%) for the interventional treatment group and 89.00% (95% CI, 86.37%-91.24%) for the conservative management group"

Different population, endpoint and nonrandomized design; not a direct refutation of the ARUBA all-stroke result.

Can pathway-directed treatment provide durable clinical benefit in established human brain AVM, and which outcomes reflect that benefit?

HUMAN MODEL MISMATCH OPEN bavm-mek-inhibition-translation

Attached to

pathophysiology#Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells pathophysiology#Nidus Formation with Direct Arteriovenous Shunting

The evidence is no longer exclusively preventive: established-lesion mouse experiments report reduced bleeding and longer survival without clear loss of the nidus, and a preprint describes three uncontrolled human trametinib cases. One of those patients hemorrhaged during treatment. Conversely, a two-patient bevacizumab trial showed no volume reduction. Genotype, mature vascular architecture, dose, treatment duration, rebound after withdrawal and systemic toxicity remain unresolved. NCT06098872 was withdrawn without enrollment; active studies should not be counted as positive efficacy results.

Proposed experiments

MEK inhibition in established, genotyped brain AVM

bavm-mek-established-lesion-trial

A controlled study in established brain AVM should assess bleeding, disability, nidus volume and shunt flow, with systematic toxicity monitoring and follow-up after treatment withdrawal. Genotyping through clinically obtained tissue or validated liquid biopsy could test differential response without requiring research biopsy as routine care.

Readouts

Nidus volume and shunt flow

pathophysiology#Nidus Formation with Direct Arteriovenous Shunting

Hemorrhage and neurological function

pathophysiology#Nidus Rupture and Intracranial Haemorrhage

Would support

pathophysiology#Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells

Show evidence (3 references)

PMID:41410028 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the size and number of bAVMs were not noticeably changed in trametinib-treated mice based on our MRA imaging"

Distinguishes bleeding reduction from anatomical regression.

url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient 3 had a hemorrhagic stroke, but was still deemed ineligible for surgical or endovascular intervention"

Preprint uncontrolled human observation; no demonstrated hemorrhage prevention.

PMID:34189463 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment."

Small clinical pilot limits a broad assumption that pathway inhibition shrinks established lesions.

Do candidate inherited variants improve prediction of sporadic AVM hemorrhage beyond clinical and anatomical factors?

KNOWLEDGE GAP OPEN bavm-candidate-genetic-modifiers

Attached to

pathophysiology#Nidus Rupture and Intracranial Haemorrhage

A natural-history review describes candidate IL6, TNF and APOE associations and notes that most awaited independent replication. These associations concern hemorrhage susceptibility, not proven initiating mutations or clinically validated tests. A small familial report proposing PTPN13 also does not establish an alternative cause for unselected sporadic lesions.

Show evidence (2 references)

PMID:24930128 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"the majority of these genetic association results await replication in independent AVM cohorts."

Limitation stated by the 2014 review; candidate associations are not treated as validated clinical predictors.

PMID:41418676 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"PTPN13 was identified as a possible causative gene for non-syndromic inherited bAVM."

Candidate proposed from two related affected individuals; not an established sporadic AVM driver.

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Pathophysiology

Somatic Activating KRAS or BRAF Mutation in Brain Endothelium

Somatic activating KRAS variants, and a smaller set of activating BRAF variants, occur in sampled sporadic brain AVMs. KRAS variants are enriched in lesional endothelial cells. Brain endothelial expression of mutant KRAS or BRAF can induce AVM-like lesions in animals. The timing and cell of origin of individual human mutations remain unresolved, and variant-negative lesions are not assumed to share an identified driver.

brain microvascular endothelial cell CL:2000044

Downstream

Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells Activating RAS/RAF variants increase downstream ERK activity.

Increased Endothelial GLUT1 Membrane Localization KRAS G12V changes GLUT1 trafficking in cultured endothelial cells; this response is not reversed by MEK inhibition.

Endothelial Inflammatory Mediator Production KRAS-mutant endothelial cells develop an inflammatory secretory phenotype.

Show evidence (2 references)

PMID:29298116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples."

Human tissue and paired-blood results support somatic mosaicism in the assayed subset.

PMID:29298116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations"

Endothelial enrichment; not proof of a universal clonal boundary.

Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells

Activating KRAS increases ERK phosphorylation in patient-derived AVM endothelial cultures and engineered endothelial cells. MEK inhibition reverses several mutant-cell phenotypes. This establishes a causal pathway in the tested models without showing that MAPK is the sole or rate-limiting process in every human lesion. Some KRAS-dependent changes, including GLUT1 membrane trafficking, persist under MEK inhibition.

brain microvascular endothelial cell CL:2000044

ERK1 and ERK2 cascade GO:0070371 ⇑ GAIN OF FUNCTION MAPK cascade GO:0000165 ↑ INCREASED

Animal models

Postnatal AAV-PHP.V1 KRAS G12D endothelial mouse Mouse perturbs Mutant-transcript suppression tests dependence on the initiating KRAS perturbation.

Downstream

Increased Endothelial Hexokinase-2 Expression MEK inhibition lowers HK2 in mutant endothelial cells, although ERK stimulation alone is insufficient to induce HK2.

Aberrant Endothelial Angiogenic Sprouting MAPK-dependent angiogenic transcription and migration promote abnormal sprouting.

Endothelial-to-Mesenchymal Transition KRAS-dependent mesenchymal-marker changes are reduced by trametinib in mouse and cultured-cell models.

Endothelial Junction Disruption MEK inhibition restores VE-cadherin organization in engineered endothelial cells.

Show evidence (2 references)

PMID:29298116 SUPPORT In Vitro

"expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity"

Directly demonstrates that the mutation raises ERK activity in endothelial cells, the molecular content of this node.

PMID:29298116 SUPPORT INDIRECT Other

"We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells."

Author mechanistic interpretation integrating human and experimental findings; not a direct clinical measurement of pathway dependence.

Increased Endothelial GLUT1 Membrane Localization

KRAS G12V increases GLUT1 localization at the plasma membrane in immortalized HUVECs and primary human brain microvascular endothelial cells, without increasing total GLUT1 expression. SL327 does not reverse trafficking, distinguishing it from MEK-dependent HK2 induction.

Downstream

Increased Endothelial Glycolytic Flux Increased surface glucose transport supports greater glucose uptake.

Show evidence (3 references)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"an increase in GLUT1 plasma membrane localization in KRASG12V ECs"

Positive trafficking measurement in the mutant endothelial model.

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"GLUT1 levels were unchanged in the total membrane fraction"

Membrane redistribution, not a general increase in GLUT1 abundance.

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"BAY876 and SL327 treatments did not significantly alter GLUT1 trafficking to the plasma membrane."

Primary human brain endothelial-cell transfection experiment; trafficking persists with MEK inhibition.

Increased Endothelial Hexokinase-2 Expression

HK2 expression increases in engineered KRAS-mutant endothelial cells and in examined mouse and human AVM vessels. In the cultured-cell proteome, HK2 was the only detected glycolytic protein significantly elevated; that result does not imply that every glycolytic component is unchanged in human lesions, where PFKFB3 RNA was also elevated.

Downstream

Increased Endothelial Glycolytic Flux Increased hexokinase activity supports glucose phosphorylation and glycolytic flux.

Show evidence (2 references)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Among these, HK2 was again the only glycolysis protein upregulated with KRASG12V expression"

Cultured-cell proteomics, not a universal statement about human AVM metabolism.

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"endothelial HK2 expression was elevated in the endothelium of bAVM vessels compared to temporal lobe vessels"

Direct immunostaining of human tissue; the study examined two AVM and two control tissue samples.

Increased Endothelial Glycolytic Flux

Mutant endothelial cells show increased glucose uptake, extracellular acidification and lactate secretion. HK2 knockdown and glycolytic inhibitors suppress selected angiogenic behaviors. Most mechanistic experiments used immortalized HUVECs; primary brain cells and human lesion-derived cultures provide additional validation.

Experimental models

KRAS-engineered endothelial cultures CELL LINE Models mutant-cell metabolism and its perturbation by HK2 knockdown.

Animal models

Embryonic KRAS G12V zebrafish arteriovenous-shunt model Zebrafish perturbs Glycolytic blockade perturbs shunt maintenance in an early developmental model.

Downstream

Aberrant Endothelial Angiogenic Sprouting HK2 knockdown reduces excessive sprouting and migration in mutant-cell assays.

Show evidence (2 references)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Quantification of the extracellular acidification rate (ECAR) showed that KRASG12V ECs featured a notable elevation of glycolysis in comparison with KRASWT ECs, without changes in mitochondrial respiration as measured by the oxygen consumption rate (OCR)"

Direct functional metabolic measurements in engineered endothelial cells substantiate the flux claim.

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"siRNA knockdown of HK2 resulted in a dose-dependent reduction of both average sprout length and number per EC spheroid"

Perturbation of HK2 supports a contribution of glycolysis to the cultured-cell sprouting phenotype.

Aberrant Endothelial Angiogenic Sprouting

Mutant KRAS promotes angiogenic gene expression, migration and sprouting in endothelial assays. Notch-associated transcripts increase in the 2018 HUVEC experiments, but arterial and venous identity markers did not change there. Human AVM single-cell data instead show loss of capillary and venular signatures in nidus endothelial populations. These are distinct observations rather than proof that Notch activation abolishes all arterial–venous identity. Increased proliferation is model-dependent.

Experimental models

Patient-derived brain AVM endothelial spheroids PRIMARY CELL CULTURE Patient-derived cells provide an assay of sprouting under metabolic and MEK inhibition.

Downstream

Nidus Formation with Direct Arteriovenous Shunting Dysregulated endothelial remodeling contributes to abnormal arteriovenous architecture; endothelial KRAS/BRAF animal models support sufficiency at the pathway level.

Show evidence (2 references)

PMID:29298116 SUPPORT DIRECT PRIMARY RESULT In Vitro

"expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior."

Engineered endothelial-cell experiments establish several cellular responses; they do not by themselves establish a human identity-switch mechanism.

PMID:35084939 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"endothelial subsets were enriched for arterial and venous, but not venular or capillary transcriptional identity scores in AVMs"

Human single-cell comparison identifies the specific zonation disturbance.

Endothelial-to-Mesenchymal Transition

KRAS G12V induces mesenchymal markers in cultured mouse brain endothelial cells and engineered mouse AVMs. Trametinib reduces these changes alongside improved barrier measurements. EndMT as the mediator of hemorrhage reduction remains a hypothesis because the treatment affects multiple processes.

Downstream

Endothelial Junction Disruption A shift toward mesenchymal characteristics accompanies reduced endothelial junction organization; independent mediation has not been established.

Show evidence (1 reference)

PMID:41410028 SUPPORT DIRECT PRIMARY RESULT In Vitro

"N-Cad, Slug, and CD44 were significantly increased, but VE-Cad was decreased, in ECG12V compared to control"

Cultured mouse brain endothelial cells expressing KRAS G12V.

Nidus Formation with Direct Arteriovenous Shunting

The nidus contains tortuous vessels connecting feeding arteries to draining veins without a normal intervening capillary network. The resulting low-resistance shunt alters local flow and venous loading. Vessel architecture and drainage differ between lesions.

endothelial cell of artery CL:1000413 vein endothelial cell CL:0002543

Animal models

Endothelial BrafV600E mouse model of sporadic brain AVM Mouse partially recapitulates Reproduces selected vascular architectural features, but not a spontaneous human somatic event.

Postnatal AAV-PHP.V1 KRAS G12D endothelial mouse Mouse partially recapitulates Engineered postnatal arteriovenous connections reproduce aspects of nidus architecture.

Downstream

High-Flow Shunt Haemodynamics and Venous Hypertension Direct arteriovenous connections alter flow and expose venous structures to abnormal hemodynamic loading.

Cerebral arteriovenous malformation The nidus and direct shunt define the structural phenotype.

Show evidence (1 reference)

PMID:41999461 SUPPORT Other

"Brain arteriovenous malformations (bAVMs) are high-flow vascular lesions characterized by direct arteriovenous shunting without an intervening capillary bed."

Defines the nidus lesion in exactly the terms of this node - high flow, direct shunting, absent capillary bed. Evidence source is OTHER as this is a review article.

High-Flow Shunt Haemodynamics and Venous Hypertension

High-flow shunting changes venous pressure and mechanical loading, while the degree of venous hypertension depends on drainage anatomy and outflow resistance. Deep venous drainage is an epidemiological risk marker and is not synonymous with venous stenosis or a direct measurement of outflow pressure. Hemodynamic and structural mechanisms may interact in rupture.

Downstream

Nidus Rupture and Intracranial Haemorrhage Abnormal loading may contribute to failure of vulnerable vascular walls.

Perinidal Cortical Irritation and Seizure Generation Altered perinidal perfusion and venous congestion may contribute to cortical dysfunction.

Show evidence (1 reference)

PMID:25015366 SUPPORT Human Clinical

"Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p = 0.02 in imputed dataset) may be additional predictors."

The complete-case estimate for exclusively deep drainage is imprecise and crosses 1; the imputed analysis reaches significance. Neither directly measures venous pressure or proves outflow obstruction.

Endothelial Inflammatory Mediator Production

Cultured KRAS G12V mouse endothelial cells increase IL1B, IL6 and CCL2/MCP1 expression and release inflammatory mediators. Mouse AVM tissue also shows endothelial and myeloid cytokine expression. The specific mediators necessary for each downstream effect have not all been isolated experimentally.

Downstream

Perivascular Myeloid Cell Activation Mutant endothelial conditioned medium activates BV2 microglia and promotes migration in vitro.

Show evidence (1 reference)

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT In Vitro

"KRASG12V increased the mRNA expression of the pro-inflammatory cytokines (IL-1β and IL-6), as well as monocyte chemoattractant protein-1 (MCP-1)"

Cultured mutant mouse endothelial cells.

Perivascular Myeloid Cell Activation

Human AVMs contain activated and infiltrating myeloid populations. In murine co-cultures, mutant endothelial conditioned medium activates BV2 microglia, and macrophages amplify endothelial barrier dysfunction. BV2 is an immortalized mouse line and does not capture all primary microglial states. GPNMB-positive monocytes are enriched in ruptured human lesions, but cross-sectional enrichment does not establish whether recruitment preceded rupture.

Downstream

Endothelial Junction Disruption Primed microglial conditioned medium reduces selected endothelial junction transcripts.

Myeloid-associated Vascular Smooth Muscle Cell Apoptosis Patient-derived GPNMB-positive monocytes increase smooth-muscle-cell apoptosis in co-culture.

Show evidence (2 references)

PMID:35084939 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"GPNMB+ Mo3 monocytes, was over-represented in ruptured AVMs"

Human bulk-RNA deconvolution supported by cellular assays; association with rupture does not establish temporal direction.

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Normal ECs treated with BV2-MG-CM had decreased mRNA expression of cell adhesion molecules (CDH5 and TJP1) after 48 h of incubation"

Conditioned medium from primed BV2 cells affected wild-type mouse endothelial cells.

Endothelial Junction Disruption

VE-cadherin organization is disrupted in engineered KRAS-mutant endothelial cells and examined human AVM tissue. Murine endothelial and microglial experiments show context-dependent changes in CDH5, TJP1, OCLN and CLDN5; conditioned-medium effects should not be described as degradation of every junction protein.

Downstream

Increased Blood-Brain Barrier Permeability Disrupted endothelial junctions reduce barrier resistance and can permit leakage.

Show evidence (2 references)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"VE-cadherin expression was weak and diffuse in bAVM tissue compared to temporal lobe tissue"

Human lesion tissue staining, with preserved CD31 and ZO-1 staining in the same comparison.

PMID:41696778 NO_EVIDENCE DIRECT PRIMARY RESULT In Vitro

"normal ECs treated with KRAS-G12V-EC-CM had no changes in the mRNA expression of cell junction molecules"

Direct mutant endothelial conditioned medium did not reproduce the effect of primed microglial conditioned medium.

Increased Blood-Brain Barrier Permeability

Barrier dysfunction is demonstrated by reduced electrical resistance in murine endothelial–astrocyte cultures. At the tested early time point, KRAS-mutant endothelium alone did not increase dextran passage; added macrophages did. Mouse tracer leakage is reduced by minocycline. Permeability measurements and microscopic leakage do not by themselves establish prevention or causation of clinical hemorrhage.

Experimental models

Murine endothelial–astrocyte–macrophage barrier co-culture CO CULTURE Tests cellular interactions that amplify barrier leakage.

Animal models

Adult AAV-BR1 KRAS G12V brain endothelial mouse Mouse partially recapitulates Tracer leakage and endothelial junction changes respond to minocycline in the related KRAS G12V model.

Downstream

Nidus Rupture and Intracranial Haemorrhage Loss of endothelial barrier integrity may contribute to vessel vulnerability, together with wall support and hemodynamic stress.

Show evidence (1 reference)

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the presence of Mφ significantly enhanced FITC-dextran permeability in a 3D BBB coculture system"

Functional permeability assay separates macrophage-dependent dextran leakage from the earlier fall in electrical resistance.

Myeloid-associated Vascular Smooth Muscle Cell Apoptosis

GPNMB-positive monocytes isolated from patients with ruptured AVMs increase apoptosis of primary brain vascular smooth muscle cells in co-culture. Soluble osteopontin also increases apoptosis, attenuated by CD44 or integrin blockade. These assays support a possible inflammatory route to mural-cell loss without proving that it initiated rupture in the donor lesions.

Experimental models

Patient-monocyte vascular smooth-muscle co-culture CO CULTURE Models an inflammatory mechanism of smooth-muscle injury.

Downstream

Deficient Mural Cell Coverage and Vessel Wall Instability Apoptosis can reduce smooth-muscle support; the degree of in-vivo contribution is unresolved.

Show evidence (1 reference)

PMID:35084939 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Co-culture of isolated GPNMB+ monocytes from ruptured AVM patients with primary brain vascular smooth muscle cells (VSMCs) increased apoptotic cleaved caspase-3+ VSMCs"

Patient-derived monocytes with primary vascular smooth muscle cells; an in-vitro functional result.

Deficient Mural Cell Coverage and Vessel Wall Instability

Altered mural-cell number or coverage can weaken vascular support. Human bulk transcriptomics show reduced extracellular-matrix and angiopoietin–TIE gene programs, but do not directly establish a specific recruitment defect. Patient-derived monocyte co-culture supplies a separate functional mechanism for smooth-muscle apoptosis. Pericyte depletion findings from hereditary AVM models require caution when applied to sporadic KRAS-associated disease.

pericyte CL:0000669 smooth muscle cell CL:0000192

Downstream

Nidus Rupture and Intracranial Haemorrhage Deficient vascular support may contribute to wall instability; individual human rupture events are multifactorial.

Show evidence (2 references)

PMID:34541474 SUPPORT Other

"The vessel walls in bAVMs have structural defects, which impair vascular integrity. Mural cells are essential structural and functional components of blood vessels and play a critical role in maintaining vascular integrity. Changes in mural cell number and coverage have been implicated in bAVMs."

Establishes deficient mural cell coverage as a structural defect of bAVM vessels impairing vascular integrity. Evidence source is OTHER as this is a review article.

PMID:31795902 SUPPORT Human Clinical

"we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-beta signaling"

Human bAVM tissue RNA-seq showing downregulation of extracellular-matrix and angiopoietin-TIE programmes, the signalling system that governs mural cell recruitment.

Perinidal Cortical Irritation and Seizure Generation

Perinidal cortical dysfunction can produce seizures. Proposed contributors include altered perfusion, venous congestion, gliosis and iron deposition after bleeding; their relative contributions vary and are not measured directly by surgical outcome cohorts.

Downstream

Seizure Epileptogenic cortical activity produces clinical seizures.

Show evidence (1 reference)

PMID:40428814 SUPPORT Human Clinical

"Seizures are a common clinical manifestation in patients with brain AVMs, ranking as the second most frequent presentation."

Establishes seizure as the second commonest presentation of brain AVM, the clinical content of this node.

Nidus Rupture and Intracranial Haemorrhage

Rupture of malformed nidus or draining vessels produces intracerebral, intraventricular or subarachnoid haemorrhage - the presentation that makes brain AVM a leading cause of haemorrhagic stroke in the young. In an individual-patient meta-analysis of four untreated cohorts spanning 6,074 patient-years, the annual haemorrhage rate was 2.3% overall, and this figure is strongly conditioned on presentation: 4.8% per year in lesions that had already ruptured versus 1.3% per year in those that had not. Prior haemorrhage and increasing age were the independent predictors.

Animal models

Endothelial BrafV600E mouse model of sporadic brain AVM Mouse partially recapitulates Spontaneous bleeding occurs in the engineered model.

Adult AAV-BR1 KRAS G12V brain endothelial mouse Mouse partially recapitulates Models hemorrhage and the distinction between reduced bleeding and anatomical cure.

Downstream

Intracranial haemorrhage Rupture releases blood into intracranial compartments.

Stroke Clinically symptomatic hemorrhage can produce hemorrhagic stroke.

Focal neurological deficit Intracranial bleeding can injure or compress neural tissue and produce a focal deficit.

Headache A sufficiently large hemorrhage can increase intracranial pressure and cause headache.

Show evidence (3 references)

PMID:25015366 SUPPORT Human Clinical

"A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation."

Quantifies the natural-history haemorrhage rate and the ruptured-versus-unruptured split that governs management decisions.

PMID:25015366 SUPPORT Human Clinical

"This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up."

Identifies the independent predictors of subsequent haemorrhage in untreated disease.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4141996/?report=xml SUPPORT DIRECT PRIMARY RESULT Human Clinical

"these hemorrhage risk estimates cannot be extrapolated to the entire lifetime of a patient."

Full text of PMID:25015366: natural-history follow-up is limited by censoring at intervention and selection; annual estimates are not lifetime constants.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 1

Intracranial haemorrhage Intracranial hemorrhage HP:0002170

Temporal: ACUTE

Show evidence (2 references)

PMID:29298116 SUPPORT Human Clinical

"are a leading cause of hemorrhagic stroke in young adults and children"

Establishes haemorrhagic stroke as the defining clinical danger of brain AVM.

PMID:25015366 SUPPORT Human Clinical

Supplies the annual haemorrhage rate in untreated disease, stratified by whether the lesion had previously ruptured.

Cardiovascular 2

Cerebral arteriovenous malformation HP:0002408

Show evidence (1 reference)

PMID:41999461 SUPPORT Other

"Brain arteriovenous malformations (bAVMs) are high-flow vascular lesions characterized by direct arteriovenous shunting without an intervening capillary bed."

Defines the structural lesion. Evidence source is OTHER as this is a review article.

Stroke HP:0001297

Temporal: ACUTE

Show evidence (1 reference)

PMID:24268105 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Haemorrhagic | 25 (21·9%) | 6 (5·5%) |"

ARUBA Table 2: first hemorrhagic strokes in the randomized intervention and medical-management groups, respectively. These are observed events rather than only an endpoint definition.

Nervous System 5

Seizure HP:0001250

Show evidence (2 references)

PMID:40428814 SUPPORT Human Clinical

"Seizures are a common clinical manifestation in patients with brain AVMs, ranking as the second most frequent presentation."

Establishes seizure as the second commonest presentation of brain AVM.

PMID:41303829 SUPPORT Human Clinical

"Epileptic seizure was the most common presenting symptom (80.4%)."

Quantifies seizure as the dominant presentation in a surgical series of unruptured lesions. Not mapped to a frequency band because the cohort is restricted to unruptured, surgically treated AVMs.

Focal neurological deficit Abnormal nervous system physiology HP:0012638

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:41303829 SUPPORT Human Clinical

"In our cohort, epileptic seizures were the most frequent initial clinical manifestation, whereas headaches and focal neurological deficits were less commonly observed."

Names focal neurological deficits as a presenting manifestation and places their frequency below seizure in an unruptured surgical cohort. No frequency band is asserted because the source gives an ordering, not a proportion, and the cohort is surgically selected.

Headache HP:0002315

Show evidence (1 reference)

PMID:41303829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"whereas headaches and focal neurological deficits were less commonly observed."

Primary clinical series of unruptured lesions.

Hemiparesis HP:0001269

Show evidence (1 reference)

PMID:34189463 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Since diagnosis, the patient experienced progressive weakness of the right arm and leg."

Patient 1 before bevacizumab treatment; no prior AVM hemorrhage was reported.

Paresthesia HP:0003401

Show evidence (1 reference)

PMID:34189463 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"occasional left arm numbness that lasted a few minutes per episode"

Patient 2 before investigational treatment.

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Genetic Associations

KRAS (Somatic activating mutation in lesional endothelium)

Gene: KRAS hgnc:6407 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:29298116 SUPPORT Human Clinical

"We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples."

Somatic variants were detected in a subset of resected lesions and not in the 21 paired blood samples assayed; this is not a universal statement about all blood-based methods.

PMID:29298116 SUPPORT Human Clinical

"We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed."

Activating KRAS variants occurred in a majority of the sampled lesions; animal and cellular perturbations provide additional causal evidence.

BRAF (Somatic activating mutation in lesional endothelium)

Gene: BRAF hgnc:1097 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:31891627 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Eight specimens contained KRAS mutations, which included p.G12D (n = 5) and p.G12V (n = 3). Two specimens contained BRAF mutations: p.V600E and p.Q636X."

Primary surgical cohort; includes one V600E and one functionally unresolved Q636X BRAF variant.

PMID:38700584 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions."

Engineered activating BRAF model supports causal potential of this allele; does not validate every detected BRAF variant.

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Medical Actions

Microsurgical resection

Action: Neurosurgical Procedure NCIT:C15656

Platform: Surgery

Microsurgery aims at complete nidus removal and can provide immediate obliteration, with outcome dependent on lesion anatomy and surgical risk. A selected 52-patient retrospective series found better outcomes for supplementary Spetzler-Martin scores ≤6. MATCH sensitivity analyses favored microsurgery for AVM hemorrhage or death, but this observational result does not establish superiority for all patients or all neurological outcomes.

Mechanism Target:

INHIBITS Nidus Formation with Direct Arteriovenous Shunting — Resection physically removes the shunting nidus, eliminating both the haemodynamic and the inflammatory arms of the lesion at once.

Show evidence (2 references)

PMID:41303829 SUPPORT Human Clinical

"In the low-risk group, there were no deaths, and poor outcomes were rare (6.8% at discharge; 2.3% at 9 months). Conversely, the high-risk group demonstrated significantly worse outcomes (62.5% poor outcome at discharge, 28.6% at 9 months)."

Selected surgical cohort shows an association between anatomical grade and outcome; it is not a randomized comparison against observation.

PMID:41231469 SUPPORT Human Clinical

"Only microsurgical resection was consistently associated with reduced hemorrhage risk in sensitivity analyses."

Observational MATCH analysis of AVM hemorrhage or death; it does not directly compare the all-stroke endpoint of ARUBA or establish randomized modality superiority.

Stereotactic radiosurgery

Action: Stereotactic Radiosurgery NCIT:C15358

Platform: Radiotherapy

Focused radiation produces progressive vascular injury and eventual nidus obliteration over a latency period. Hemorrhage remains possible before obliteration, and radiation-related injury is an additional risk. A 101-patient retrospective pediatric cohort reported 64% estimated obliteration at five years and 82% at ten years, with permanent symptomatic radiation changes in 8%. A separate prospective TOBAS SRS registry reported three-year occlusion in 51/79 patients with imaging, or 54% of all 94 analyzed patients.

Mechanism Target:

INHIBITS Nidus Formation with Direct Arteriovenous Shunting — Radiation-induced obliteration progressively closes nidus vessels, abolishing the shunt over a period of years rather than immediately.

Show evidence (3 references)

PMID:31942635 SUPPORT Human Clinical

"Estimated probabilities of AVM obliteration at 5 and 10 yr were 64% and 82%, respectively."

Estimated obliteration rises over time but remains incomplete in this selected pediatric cohort.

PMID:31942635 SUPPORT Human Clinical

"The primary endpoint occurred in 14%, comprising hemorrhagic stroke, death, and permanent radiation-induced changes in 6%, 3%, and 8%, respectively."

Quantifies the harm profile, including radiation-induced change, that has to be set against the obliteration benefit.

PMID:42140314 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Three-year imaging follow-up, available in 79/94 (84%) confirmed AVM occlusion in 51/79 (65%"

TOBAS prospective SRS registry, predominantly ruptured small lesions; 54% when all enrolled analyzed patients are the denominator.

Conservative medical management

Action: Supportive Care NCIT:C15747

Platform: Other

Observation with treatment of symptoms and coexisting vascular risk factors is an option for selected unruptured AVMs. In the ARUBA randomized trial, medical management reduced death or any symptomatic stroke compared with the pooled intervention strategy over a mean 50.4 months in the final analysis. This is not a comparison of each procedure individually or evidence about ruptured lesions, and longer-term net benefit remains uncertain.

Show evidence (3 references)

PMID:24268105 SUPPORT Human Clinical

"The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months."

The randomised trial's conclusion supporting conservative management for unruptured lesions, with its follow-up duration stated.

PMID:24268105 SUPPORT Human Clinical

"The primary endpoint had been reached by 11 (10.1%) patients in the medical management group compared with 35 (30.7%) in the interventional therapy group."

Quantifies the difference in death or symptomatic stroke that led the data and safety monitoring board to halt randomisation.

PMID:32562682 SUPPORT Human Clinical

"After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation."

The final follow-up analysis, which supersedes the 2014 interim horizon and shows the effect did not decay with longer observation.

Endovascular embolization

Action: Embolization Therapy NCIT:C15230

Platform: Device

Catheter-delivered embolic material can occlude components of the shunt. Embolization may be used before resection or radiosurgery, or with curative intent in selected anatomy. Obliteration and procedural risk require individual assessment; partial angiographic occlusion is not equivalent to demonstrated long-term prevention of hemorrhage.

Mechanism Target:

INHIBITS Nidus Formation with Direct Arteriovenous Shunting — Embolic occlusion of nidus compartments and feeding arteries removes shunting channels, either as definitive treatment or to reduce flow before resection or radiosurgery.

Show evidence (2 references)

PMID:24268105 SUPPORT Human Clinical

"medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination)"

Establishes embolization as one of the three standard interventional modalities, as randomised in ARUBA.

PMID:41231469 NO_EVIDENCE Human Clinical

"Only microsurgical resection was consistently associated with reduced hemorrhage risk in sensitivity analyses."

The observational sensitivity finding concerns microsurgical resection and does not establish a hemorrhage-prevention benefit for embolization.

Antiseizure medication

Action: Pharmacotherapy NCIT:C15986

Agent: Phenytoin NCIT:C741 Phenobarbital NCIT:C739 Levetiracetam NCIT:C47581

Platform: Small molecule

Treat established seizures according to seizure type, response and tolerability. In the bevacizumab pilot, one participant had controlled seizures with phenytoin plus phenobarbital, while another remained symptomatic on levetiracetam. These observations do not rank the drugs or support universal prophylaxis.

Mechanism Target:

INHIBITS Perinidal Cortical Irritation and Seizure Generation — Antiseizure drugs suppress seizures generated by perinidal cortex without treating the arteriovenous shunt.

Show evidence (2 references)

PMID:34189463 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures were controlled with phenytoin extended-release 400 mg daily and phenobarbitol 100 mg daily."

Patient 1 baseline care; the source misspells phenobarbital.

PMID:34189463 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Seizures reported to occur one to two times per month, refractory to levetiracetam 500 mg two times per day."

Persistent seizures despite levetiracetam in one patient; this does not establish comparative efficacy among antiseizure drugs.

Investigational MEK inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: Trametinib NCIT:C77908

Platform: Small molecule

Trametinib is being explored for brain AVM but clinical efficacy is unestablished. A 2024 preprint describes three uncontrolled compassionate-use cases with relative imaging stability; one patient had a hemorrhagic stroke during treatment, and lesion genotypes were unknown. A separate male-mouse study found prolonged survival and reduced hemorrhagic burden without significant MRA lesion-number reduction. The planned presurgical trial NCT06098872 was withdrawn with zero enrollment.

Mechanism Target:

INHIBITS Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells — MEK inhibition suppresses downstream ERK activation; clinical benefit for brain AVM remains unestablished.

Show evidence (4 references)

url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full SUPPORT DIRECT PRIMARY RESULT Human Clinical

"have shown stable disease with little to no progression since beginning treatment, although this follow-up timeframe is truncated and further follow-up is needed."

Preprint, three uncontrolled cases; imaging stability cannot establish efficacy or prevention of hemorrhage.

url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical

"Patient 3 had a hemorrhagic stroke, but was still deemed ineligible for surgical or endovascular intervention"

Hemorrhage during an uncontrolled course is a safety/outcome observation, not evidence of efficacy or proof of drug causation.

PMID:41410028 REFUTE DIRECT PRIMARY RESULT Model Organism

"the size and number of bAVMs were not noticeably changed in trametinib-treated mice based on our MRA imaging"

Counterevidence to anatomical lesion regression in this mouse experiment; it does not negate the separate hemorrhage-volume benefit.

+ 1 more reference

Investigational bevacizumab

Action: Pharmacotherapy NCIT:C15986

Agent: Bevacizumab NCIT:C2039

Platform: Monoclonal antibody

A completed single-arm pilot treated two adults with large unresectable unruptured AVMs. Neither had a measurable reduction in nidus volume at 26 or 52 weeks. No clinically important adverse events were identified in this small sample, which is insufficient to establish safety or hemorrhage prevention. NCT06264531 is evaluating symptomatic benefit. Improvement of post-radiosurgery edema in separate reports must not be equated with efficacy against the untreated nidus.

Show evidence (2 references)

PMID:34189463 REFUTE DIRECT PRIMARY RESULT Human Clinical

"No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment."

Two-patient pilot did not demonstrate radiographic volume reduction; the null finding is limited by sample size.

PMID:34189463 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical

"our study is underpowered to detect the hypothesised change in bAVM volume."

Explicit limitation of the clinical pilot.

🔬

Diagnosis

Digital subtraction angiography

Catheter DSA is the reference standard for defining feeding arteries, nidus and venous drainage, and for confirming obliteration. Its findings inform treatment planning alongside symptoms, functional anatomy, patient factors and procedural risk.

digital subtraction angiography NCIT:C190556

Results: Demonstration of a nidus with arteriovenous shunting, with feeding-artery and draining-vein anatomy sufficient to assign a Spetzler-Martin grade.

Show evidence (1 reference)

PMID:39125532 SUPPORT Human Clinical

"using digital subtraction angiography (DSA) as the reference standard"

Confirms DSA as the reference standard against which other modalities are measured.

Non-contrast-enhanced time-resolved MR angiography

Non-contrast 4D MRA can detect and characterize shunting while avoiding gadolinium. In a retrospective study of 54 imaging pairs from 43 patients, reported sensitivity was 75% and specificity 95% against DSA. The mixture of treated and untreated lesions and widely varying intervals between MRA and DSA limit inference; it does not establish that MRA can replace DSA in every setting.

magnetic resonance angiography NCIT:C190557

Results: Detection of arteriovenous shunting and grading concordant with DSA, without gadolinium-based contrast.

Show evidence (3 references)

PMID:39125532 SUPPORT Human Clinical

"Our results demonstrated that NCE-4D-MRA had a higher accuracy and specificity compared to CE-4D-MRA (0.85 vs. 0.83 and 95% vs. 85%, respectively) and similar agreement, with DSA detecting shunts in bAVMs or residuals."

Quantifies non-contrast 4D-MRA accuracy against the contrast-enhanced comparator and DSA.

PMID:39125532 SUPPORT Human Clinical

"The safety profile of imaging techniques is a significant concern in the long-term follow up of bAVMs"

States the contrast-avoidance rationale that makes this modality specifically valuable in a lifelong lesion requiring repeated imaging.

PMID:39125532 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the 75% sensitivity observed for NCE-4D-MRA"

Results section: sensitivity is lower than specificity; the discussion reverses these two percentages.

Somatic genotyping from lesion tissue or cell-free DNA

Sensitive sequencing or droplet digital PCR of resected lesion tissue can detect low-level somatic KRAS/BRAF variants. Negative peripheral-blood testing does not exclude a lesional somatic variant. Circulating-DNA and local arterial sampling are investigational, with diagnostic performance under study; routine diagnosis relies on imaging and does not require a tissue biopsy solely to establish a molecular cause.

molecular genetic testing NCIT:C15709

Results: Detection of a somatic activating KRAS or BRAF variant in lesional tissue; a negative blood test does not exclude the diagnosis.

Show evidence (3 references)

PMID:29298116 SUPPORT Human Clinical

"We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples."

Negative paired-blood results in this cohort do not exclude a lesional somatic mutation or establish the sensitivity of future liquid-biopsy methods.

PMID:41999461 SUPPORT Other

"Future approaches combining minimally invasive sampling methods, such as endovascular biopsy and peripheral blood cell-free DNA analysis, with ultra-sensitive detection technologies are expected to help overcome these limitations."

Names the emerging sampling routes that address the tissue-access problem. Evidence source is OTHER as this is a review article.

clinicaltrials:NCT06494358 SUPPORT DIRECT Other

"This research aims to evaluate the diagnostic performances of liquid biopsies"

Registry of an observational diagnostic study, not established sensitivity or clinical utility.

VALE hemorrhage-risk assessment

VALE estimates rupture risk from ventricular involvement (+2), venous aneurysm (−4), deep location (+1), and exclusively deep venous drainage (+2). The derivation and validation cohorts were predominantly Chinese; the conservative cohort included 235 prospectively followed and 793 retrospectively selected patients. Only 36 hemorrhages occurred, and the authors warn that hemorrhage-free survival may be overestimated. Venous aneurysm was protective in the fitted score, not a uniform risk-increasing feature. VALE is a prognostic adjunct, not a diagnostic test or proof of treatment benefit.

Show evidence (2 references)

PMID:36857052 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Venous aneurysm was a protective factor for AVM rupture in the study cohort"

Primary score derivation; the direction must not be conflated with arterial aneurysms.

PMID:36857052 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Thirty-six hemorrhages occurred over a median (IQR) follow-up of 4.2 (0.3-6.0) years among 1028 patients"

Validation cohort event count and follow-up constrain precision.

📊

Prevalence

New York islands, United States (prospective population-based surveillance)

Annual Incidence 1.34 per 100,000 (1.18–1.49) person-years

Average annual detection rate in a defined population, based on 284 diagnoses over 21,216,467 person-years. Detection does not date formation of the malformation.

Show evidence (1 reference)

PMID:12690217 SUPPORT Human Clinical

"leading to an average annual AVM detection rate of 1.34 per 100,000 person-years (95% CI, 1.18 to 1.49)"

Prospective population-based detection rate, the basis for the normalised rate recorded here.

Scotland, adults aged 16 and over (prospective population-based study)

Annual Incidence 1.12 per 100,000 (0.9–1.37) person-years

Crude first-ever-diagnosis detection rate per 100,000 adult person-years in the Scottish population-based study; not a cross-sectional prevalence estimate.

Show evidence (1 reference)

PMID:12702837 SUPPORT Human Clinical

"1.12 (95% CI, 0.90 to 1.37) for brain AVMs"

Crude annual detection rate per 100,000 adults for brain AVM in a prospective population-based study.

🔬

Clinical Trials

NCT00389181 PHASE_III COMPLETED

ARUBA randomized adults with unruptured brain AVM to medical management alone or management plus intervention. Enrollment stopped early; completed follow-up provides randomized evidence on death or symptomatic stroke.

Target Phenotypes: Stroke HP:0001297 Intracranial hemorrhage HP:0002170

Show evidence (2 references)

PMID:24268105 SUPPORT Human Clinical

"This trial is registered with ClinicalTrials.gov, number NCT00389181."

Ties the published trial report to its ClinicalTrials.gov registration, which is the identifier this record is keyed on.

clinicaltrials:NCT00389181 SUPPORT DIRECT Other

"The purpose of this study is to determine if medical management is better than invasive therapy for improving the long-term outcome"

Registry describes the randomized comparison; clinical outcomes are supplied by the published reports.

NCT02098252 NOT_APPLICABLE RECRUITING

TOBAS combines randomized comparisons and prospective registries for ruptured and unruptured AVMs. It studies conservative versus interventional management and the contribution of embolization. Registry publications should be distinguished from randomized trial results.

Target Phenotypes: Stroke HP:0001297 Intracranial hemorrhage HP:0002170

Show evidence (1 reference)

clinicaltrials:NCT02098252 SUPPORT Human Clinical

"The trial has been designed to test a) whether medical management or interventional therapy will reduce the risk of death or debilitating stroke"

States the trial's primary question, which is the unresolved comparison this entry's management-controversy discussion records.

NCT04572568 NOT_APPLICABLE RECRUITING

MATCH is a prospective multicenter observational registry of multidisciplinary AVM management; it supplied data for the 2025 target-trial emulation.

Show evidence (1 reference)

clinicaltrials:NCT04572568 SUPPORT DIRECT Other

"This study is a multi-center, prospective, registry study."

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT06098872 PHASE_II WITHDRAWN

Presurgical trametinib pilot for adult unruptured AVMs, including intracranial lesions. Withdrawn with zero actual enrollment and the stated reason that no patients enrolled; it supplies no treatment outcome evidence.

Show evidence (1 reference)

clinicaltrials:NCT06098872 SUPPORT DIRECT Other

"The purpose of this pilot study is to see whether taking an oral medication called Trametinib can improve upon the AVM structure"

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT06913725 PHASE_II RECRUITING

Open-label exploratory FCN-159 study in brain AVM, with an estimated ten participants and an MRA response endpoint.

Show evidence (1 reference)

clinicaltrials:NCT06913725 SUPPORT DIRECT Other

"A single-center, open-label, non-randomized controlled exploratory study is conducted in the Xuanwu Hospital Capital Medical University"

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT02314377 PHASE_I COMPLETED

Completed two-participant bevacizumab pilot for AVMs unsuitable for surgery; published results found no change in nidus volume.

Show evidence (1 reference)

clinicaltrials:NCT02314377 SUPPORT DIRECT Other

"Bevacizumab Therapy for brain arteriovenous malformation that is not amenable to surgical intervention."

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT06264531 RECRUITING

Bevacizumab study in symptomatic cerebral AVM; the primary endpoint evaluates improvement in cognition, neurological symptoms, epilepsy or headache rather than proven nidus eradication.

Show evidence (1 reference)

clinicaltrials:NCT06264531 SUPPORT DIRECT Other

"The aim of our study is to assess the efficacy of IV Bevacizumab on the disabling symptoms associated with symptomatic brain AVMs."

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT06494358 NOT_APPLICABLE RECRUITING

Observational evaluation of local arterial and peripheral venous liquid biopsies against surgical-tissue genotyping.

Show evidence (1 reference)

clinicaltrials:NCT06494358 SUPPORT DIRECT Other

"This research aims to evaluate the diagnostic performances of liquid biopsies"

Registry describes study intent; enrollment status and design do not establish efficacy.

NCT07314047 NOT_APPLICABLE RECRUITING

PARTNER randomized noninferiority device study comparing a liquid embolic agent with Onyx. Its primary endpoint is effective embolization, defined as at least 50% reduction after the last procedure, which is not complete cure.

Show evidence (1 reference)

clinicaltrials:NCT07314047 SUPPORT DIRECT Other

"This study is designed as a prospective, multi-center, open-label, non-inferiority, randomized controlled clinical trial."

Registry describes study intent; enrollment status and design do not establish efficacy.

🧫

Experimental Models

KRAS-engineered endothelial cultures CELL_LINE

Doxycycline-inducible immortalized HUVECs provide glycolysis, sprouting and junction assays. Selected results were validated by transfection of primary human brain microvascular endothelial cells. The principal cell line is not brain endothelium, lacks flow and mural support, and showed no increase in proliferation in the reported comparison.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Immortalized HUVEC line; selected primary human brain endothelial validation

Publication

PMID:41708990

Pathograph links

Increased Endothelial Glycolytic Flux perturbs fidelity: moderate Models mutant-cell metabolism and its perturbation by HK2 knockdown.

Show evidence (1 reference)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"siRNA knockdown of HK2 resulted in a dose-dependent reduction of both average sprout length and number per EC spheroid"

Functional perturbation in immortalized HUVECs.

Show evidence (1 reference)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The primary mechanistic insights in our study were made using an immortalized HUVEC cellular system, with validation in primary brain ECs."

Explicit model identity and scope.

Patient-derived brain AVM endothelial spheroids PRIMARY_CELL_CULTURE

Endothelial cultures from four resected AVMs show increased sprouting. Two samples with detected KRAS mutations responded more strongly to trametinib; combined BAY876 and trametinib reduced sprout length in all four samples. Small sample size, culture selection and lack of intact vascular anatomy preclude clinical-response prediction.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Primary endothelium from surgically resected human lesions

Publication

PMID:41708990

Pathograph links

Aberrant Endothelial Angiogenic Sprouting partially recapitulates fidelity: moderate Patient-derived cells provide an assay of sprouting under metabolic and MEK inhibition.

Show evidence (1 reference)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"human bAVM ECs showed enhanced angiogenic potential with increased average sprout length and number per spheroid"

Primary lesion-derived culture compared with purchased brain endothelial cells.

Show evidence (1 reference)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT In Vitro

"combination treatment with BAY876 and trametinib reduced sprout length in all patient-derived EC samples"

Four patient-derived cultures; a culture response is not a patient treatment response.

Murine endothelial–astrocyte–macrophage barrier co-culture CO_CULTURE

Transwell cultures combine KRAS G12V mouse endothelial cells, astrocytes and macrophages. Macrophages amplify loss of barrier resistance and dextran leakage. Separate conditioned-medium experiments use immortalized BV2 microglia; mural cells and physiological flow are absent.

Organism

Mus musculus NCBITaxon:10090

Cell source

Cultured mouse endothelial cells, astrocytes and macrophages; separate BV2 conditioned-medium assays

Publication

PMID:41696778

Pathograph links

Increased Blood-Brain Barrier Permeability perturbs fidelity: moderate Tests cellular interactions that amplify barrier leakage.

Show evidence (1 reference)

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT In Vitro

"minocycline treatment in the KRAS-G12V-EC on day 1 post-transfection markedly reduced the increased BBB permeability"

In-vitro intervention, not a clinical efficacy result.

Show evidence (1 reference)

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the presence of Mφ significantly enhanced FITC-dextran permeability in a 3D BBB coculture system"

Direct permeability result in the multicellular in-vitro model.

Patient-monocyte vascular smooth-muscle co-culture CO_CULTURE

GPNMB-positive monocytes isolated from ruptured AVMs are co-cultured with primary brain vascular smooth muscle cells. Increased apoptosis and responses to osteopontin/CD44/integrin perturbation support a candidate route to mural-cell injury, without resolving the timing of recruitment relative to rupture.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived GPNMB-positive monocytes and primary brain vascular smooth muscle cells

Publication

PMID:35084939

Pathograph links

Myeloid-associated Vascular Smooth Muscle Cell Apoptosis partially recapitulates fidelity: moderate Models an inflammatory mechanism of smooth-muscle injury.

Show evidence (1 reference)

PMID:35084939 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Co-culture of isolated GPNMB+ monocytes from ruptured AVM patients with primary brain vascular smooth muscle cells (VSMCs) increased apoptotic cleaved caspase-3+ VSMCs"

Direct co-culture evidence.

Show evidence (1 reference)

PMID:35084939 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Soluble OPN induced a 2.7-fold increase in VSMC apoptosis"

Osteopontin challenge in culture; not a direct patient hemorrhage readout.

🐁

Animal Models

Endothelial BrafV600E mouse model of sporadic brain AVM

Engineered activating BRAF expression produces dilated AVM-like vessels with reduced wall stability, spontaneous hemorrhage and inflammation. Early dabrafenib slows progression; efficacy against established lesions was unresolved. Available evidence is the published abstract, not a complete assessment of model fidelity.

Species

Mouse

Genotype

Brain endothelial-cell-specific BrafV600E expression

Publication

PMID:38700584

Pathograph links

Nidus Formation with Direct Arteriovenous Shunting partially recapitulates fidelity: moderate Reproduces selected vascular architectural features, but not a spontaneous human somatic event.

Show evidence (1 reference)

PMID:38700584 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions."

Engineered mouse phenotype; abstract-only retrieval limits assessment.

Nidus Rupture and Intracranial Haemorrhage partially recapitulates fidelity: moderate Spontaneous bleeding occurs in the engineered model.

Show evidence (1 reference)

PMID:38700584 SUPPORT DIRECT PRIMARY RESULT Model Organism

"accompanied by spontaneous hemorrhage and neuroinflammation."

Reported mouse outcome; no human treatment efficacy.

Adult AAV-BR1 KRAS G12V brain endothelial mouse

Adult mice develop multiple cerebral AVM-like lesions and hemorrhage. Trametinib begun ten weeks after induction prolongs survival and reduces some measures of bleeding without significant MRA lesion-number change. The treatment study used males and widespread transgene expression, exceeding the usual focal human lesion burden. Related experiments test inflammatory interactions and minocycline.

Species

Mouse

Genotype

AAV-BR1-mediated brain endothelial KRAS G12V overexpression

Publication

PMID:41410028

Pathograph links

Nidus Rupture and Intracranial Haemorrhage partially recapitulates fidelity: moderate Models hemorrhage and the distinction between reduced bleeding and anatomical cure.

Show evidence (1 reference)

PMID:41410028 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the mice treated with 1 mg/kg of trametinib demonstrated significantly lower hemorrhagic volumes than the vehicle treated mice"

Eight-week treatment measurement in mice with established lesions; the higher-dose result was not significant.

Increased Blood-Brain Barrier Permeability partially recapitulates fidelity: moderate Tracer leakage and endothelial junction changes respond to minocycline in the related KRAS G12V model.

Show evidence (1 reference)

PMID:41696778 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the leaking of BSA-647, a BBB tracer, in the KRASG12V/bEC mouse was significantly attenuated by minocycline treatment"

Preclinical barrier readout, not proof of clinical hemorrhage prevention.

Postnatal AAV-PHP.V1 KRAS G12D endothelial mouse

Postnatal endothelial KRAS G12D induction produces vascular tangles and hemorrhage, with lesion burden dependent on viral dose. CRISPR/CasRx targets mutant RNA rather than editing genomic DNA. Concurrent delivery strongly suppresses formation; treatment fourteen days after induction reduces lesion size while lesion-number reduction is not significant. Overexpression, spinal lesions, occasional splenic bleeding and repeated-AAV immunity limit translation.

Species

Mouse

Genotype

AAV-PHP.V1 conditional KRAS G12D in Cdh5-CreERT2 mice

Publication

PMID:39576014

Pathograph links

Nidus Formation with Direct Arteriovenous Shunting partially recapitulates fidelity: moderate Engineered postnatal arteriovenous connections reproduce aspects of nidus architecture.

Show evidence (1 reference)

PMID:39576014 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Tortuous and enlarged vascular tangles connected with feeding arteries and draining veins were observed in the cleared brains"

Direct three-dimensional anatomical observation in mice.

Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells perturbs fidelity: moderate Mutant-transcript suppression tests dependence on the initiating KRAS perturbation.

Show evidence (1 reference)

PMID:39576014 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The lesion number showed a tendency to decrease, and the size significantly decreased"

Delayed CasRx treatment after lesion development had a clearer effect on size than number.

Embryonic KRAS G12V zebrafish arteriovenous-shunt model

Embryonic shunts can improve after glycolytic or MEK inhibition. BAY876 plus reduced-dose SL327 improved reversal compared with SL327 alone. This early arteriovenous-shunt model does not establish regression of a mature, complex human brain nidus; the MEK inhibitor was SL327 rather than trametinib.

Species

Zebrafish

Genotype

Mosaic endothelial expression of fluorescently tagged KRAS G12V

Publication

PMID:41708990

Pathograph links

Increased Endothelial Glycolytic Flux perturbs fidelity: low Glycolytic blockade perturbs shunt maintenance in an early developmental model.

Show evidence (1 reference)

PMID:41708990 SUPPORT DIRECT PRIMARY RESULT Model Organism

"combined BAY876 + SL327 significantly improved shunt reversal compared to SL327 alone in our zebrafish model"

Combination result; the 2-DG plus SL327 comparison showed a nonsignificant trend.

{ }

Source YAML

click to show

name: Brain arteriovenous malformation
creation_date: '2026-08-19T23:20:00Z'
category: Vascular Disease
description: >-
  Brain arteriovenous malformation is a nidus of abnormal vessels connecting cerebral arteries to veins without
  an intervening capillary bed. Presentation includes intracranial hemorrhage, seizures, headache or focal
  neurological deficits; some lesions are detected incidentally. This entry focuses on sporadic brain AVM.
  Somatic activating KRAS variants, and less frequently activating BRAF variants, explain a substantial subset
  of sampled lesions, with endothelial enrichment and experimental evidence of MAPK-dependent vascular remodeling.
  A molecular cause is not established in every lesion. Altered endothelial metabolism, junctional integrity,
  mural-cell support and inflammatory interactions contribute to vascular instability, with different levels
  of human and model evidence. Germline syndromic AVMs are covered in the HHT and capillary-malformation–AVM
  syndrome entries.
disease_term:
  preferred_term: arteriovenous malformations of the brain
  term:
    id: MONDO:0007154
    label: arteriovenous malformations of the brain
synonyms:
- Cerebral arteriovenous malformation
- Intracranial arteriovenous malformation
- bAVM
- Brain AVM
- Arteriovenous malformation of the brain, somatic
parents:
- Arteriovenous malformation
- Cerebrovascular disease
- Vascular malformation
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:29298116
      reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sporadic arteriovenous malformations of the brain, which are morphologically
        abnormal connections between arteries and veins in the brain vasculature, are a
        leading cause of hemorrhagic stroke in young adults and children.
      explanation: >-
        Brain AVM is a cerebrovascular lesion presenting as haemorrhagic stroke and
        seizure, placing it in Harrison's Neurologic Disorders Part.
inheritance:
- name: Somatic mosaicism (sporadic lesions, not inherited)
  inheritance_term:
    preferred_term: Somatic mosaicism
    term:
      id: HP:0001442
      label: Typified by somatic mosaicism
  description: >-
    Sporadic brain arteriovenous malformation is not a heritable disorder. The causal activating KRAS
    (or BRAF) variant is a somatic event confined to the lesional endothelium and is absent from
    paired blood, so the lesion is a somatic mosaic clone within an otherwise normal vasculature.
    Familial AVM in hereditary hemorrhagic telangiectasia is a distinct germline entity and is not
    covered by this block.
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples."
    explanation: Lesion-restricted detection with absence from paired blood is the defining evidence of a somatic mosaic origin.
genetic:
- name: KRAS
  notes: >-
    Somatic activating KRAS variants are recurrent drivers in lesional endothelium. The founding study detected
    variants in 45/72 resected lesions and none of 21 paired blood samples. Endothelial enrichment increases
    detection, while assay sensitivity, tissue composition and low variant allele fractions affect yield. These
    findings support mosaicism but do not establish the developmental timing or a sharply bounded clone in
    every patient, or imply that all sporadic lesions are genetically explained.
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Somatic activating mutation in lesional endothelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected somatic activating KRAS mutations in tissue samples from 45 of the 72
      patients and in none of the 21 paired blood samples.
    explanation: >-
      Somatic variants were detected in a subset of resected lesions and not in the 21 paired blood samples
      assayed; this is not a universal statement about all blood-based methods.
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified activating KRAS mutations in the majority of tissue samples of
      arteriovenous malformations of the brain that we analyzed.
    explanation: >-
      Activating KRAS variants occurred in a majority of the sampled lesions; animal and cellular perturbations
      provide additional causal evidence.

- name: BRAF
  notes: >-
    Activating BRAF variants are less common than KRAS variants. A 2019 surgical series found KRAS variants
    in 8/16 and BRAF variants in 2/16 lesions. Its BRAF V600E variant is an established activating allele,
    whereas the functional consequence of Q636X was not resolved. Detection of a BRAF sequence variant alone
    does not establish gain of function.
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Somatic activating mutation in lesional endothelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:31891627
    reference_title: Somatic mutations in intracranial arteriovenous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: 'Eight specimens contained KRAS mutations, which included p.G12D (n = 5) and p.G12V (n = 3). Two specimens contained BRAF mutations: p.V600E and p.Q636X.'
    explanation: Primary surgical cohort; includes one V600E and one functionally unresolved Q636X BRAF variant.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38700584
    reference_title: Somatic Braf(V600E) mutation in the cerebral endothelium induces brain arteriovenous malformations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions.
    explanation: Engineered activating BRAF model supports causal potential of this allele; does not validate every detected BRAF variant.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Somatic Activating KRAS or BRAF Mutation in Brain Endothelium
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Somatic activating KRAS variants, and a smaller set of activating BRAF variants, occur in sampled sporadic
    brain AVMs. KRAS variants are enriched in lesional endothelial cells. Brain endothelial expression of mutant
    KRAS or BRAF can induce AVM-like lesions in animals. The timing and cell of origin of individual human
    mutations remain unresolved, and variant-negative lesions are not assumed to share an identified driver.
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  downstream:
  - target: Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
    description: Activating RAS/RAF variants increase downstream ERK activity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Increased Endothelial GLUT1 Membrane Localization
    description: KRAS G12V changes GLUT1 trafficking in cultured endothelial cells; this response is not reversed by MEK inhibition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Endothelial Inflammatory Mediator Production
    description: KRAS-mutant endothelial cells develop an inflammatory secretory phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples.
    explanation: Human tissue and paired-blood results support somatic mosaicism in the assayed subset.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations
    explanation: Endothelial enrichment; not proof of a universal clonal boundary.
    quote_role: PRIMARY_RESULT
- name: Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    Activating KRAS increases ERK phosphorylation in patient-derived AVM endothelial cultures and engineered
    endothelial cells. MEK inhibition reverses several mutant-cell phenotypes. This establishes a causal pathway
    in the tested models without showing that MAPK is the sole or rate-limiting process in every human lesion.
    Some KRAS-dependent changes, including GLUT1 membrane trafficking, persist under MEK inhibition.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  downstream:
  - target: Increased Endothelial Hexokinase-2 Expression
    description: MEK inhibition lowers HK2 in mutant endothelial cells, although ERK stimulation alone is insufficient to induce HK2.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Aberrant Endothelial Angiogenic Sprouting
    description: MAPK-dependent angiogenic transcription and migration promote abnormal sprouting.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Endothelial-to-Mesenchymal Transition
    description: KRAS-dependent mesenchymal-marker changes are reduced by trametinib in mouse and cultured-cell models.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Endothelial Junction Disruption
    description: MEK inhibition restores VE-cadherin organization in engineered endothelial cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased
      ERK (extracellular signal-regulated kinase) activity
    explanation: >-
      Directly demonstrates that the mutation raises ERK activity in endothelial cells,
      the molecular content of this node.
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We propose that these malformations develop as a result of KRAS-induced activation
      of the MAPK-ERK signaling pathway in brain endothelial cells.
    explanation: >-
      Author mechanistic interpretation integrating human and experimental findings; not a direct clinical
      measurement of pathway dependence.

    directness: INDIRECT
- name: Increased Endothelial GLUT1 Membrane Localization
  biological_scale: CELLULAR
  description: KRAS G12V increases GLUT1 localization at the plasma membrane in immortalized HUVECs and primary human brain microvascular endothelial cells, without increasing total GLUT1 expression. SL327 does not reverse trafficking, distinguishing it from MEK-dependent HK2 induction.
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: an increase in GLUT1 plasma membrane localization in KRASG12V ECs
    explanation: Positive trafficking measurement in the mutant endothelial model.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: GLUT1 levels were unchanged in the total membrane fraction
    explanation: Membrane redistribution, not a general increase in GLUT1 abundance.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: BAY876 and SL327 treatments did not significantly alter GLUT1 trafficking to the plasma membrane.
    explanation: Primary human brain endothelial-cell transfection experiment; trafficking persists with MEK inhibition.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Increased Endothelial Glycolytic Flux
    description: Increased surface glucose transport supports greater glucose uptake.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Increased Endothelial Hexokinase-2 Expression
  biological_scale: MOLECULAR
  description: HK2 expression increases in engineered KRAS-mutant endothelial cells and in examined mouse and human AVM vessels. In the cultured-cell proteome, HK2 was the only detected glycolytic protein significantly elevated; that result does not imply that every glycolytic component is unchanged in human lesions, where PFKFB3 RNA was also elevated.
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Among these, HK2 was again the only glycolysis protein upregulated with KRASG12V expression
    explanation: Cultured-cell proteomics, not a universal statement about human AVM metabolism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: endothelial HK2 expression was elevated in the endothelium of bAVM vessels compared to temporal lobe vessels
    explanation: Direct immunostaining of human tissue; the study examined two AVM and two control tissue samples.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Increased Endothelial Glycolytic Flux
    description: Increased hexokinase activity supports glucose phosphorylation and glycolytic flux.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Increased Endothelial Glycolytic Flux
  biological_scale: CELLULAR
  description: Mutant endothelial cells show increased glucose uptake, extracellular acidification and lactate secretion. HK2 knockdown and glycolytic inhibitors suppress selected angiogenic behaviors. Most mechanistic experiments used immortalized HUVECs; primary brain cells and human lesion-derived cultures provide additional validation.
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Quantification of the extracellular acidification rate (ECAR) showed that KRASG12V ECs featured a notable elevation of glycolysis in comparison with KRASWT ECs, without changes in mitochondrial respiration as measured by the oxygen consumption rate (OCR)
    explanation: Direct functional metabolic measurements in engineered endothelial cells substantiate the flux claim.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: siRNA knockdown of HK2 resulted in a dose-dependent reduction of both average sprout length and number per EC spheroid
    explanation: Perturbation of HK2 supports a contribution of glycolysis to the cultured-cell sprouting phenotype.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Aberrant Endothelial Angiogenic Sprouting
    description: HK2 knockdown reduces excessive sprouting and migration in mutant-cell assays.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Aberrant Endothelial Angiogenic Sprouting
  biological_scale: CELLULAR
  description: Mutant KRAS promotes angiogenic gene expression, migration and sprouting in endothelial assays. Notch-associated transcripts increase in the 2018 HUVEC experiments, but arterial and venous identity markers did not change there. Human AVM single-cell data instead show loss of capillary and venular signatures in nidus endothelial populations. These are distinct observations rather than proof that Notch activation abolishes all arterial–venous identity. Increased proliferation is model-dependent.
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior.
    explanation: Engineered endothelial-cell experiments establish several cellular responses; they do not by themselves establish a human identity-switch mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35084939
    reference_title: A single-cell atlas of the normal and malformed human brain vasculature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: endothelial subsets were enriched for arterial and venous, but not venular or capillary transcriptional identity scores in AVMs
    explanation: Human single-cell comparison identifies the specific zonation disturbance.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    description: Dysregulated endothelial remodeling contributes to abnormal arteriovenous architecture; endothelial KRAS/BRAF animal models support sufficiency at the pathway level.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Endothelial-to-Mesenchymal Transition
  biological_scale: CELLULAR
  description: KRAS G12V induces mesenchymal markers in cultured mouse brain endothelial cells and engineered mouse AVMs. Trametinib reduces these changes alongside improved barrier measurements. EndMT as the mediator of hemorrhage reduction remains a hypothesis because the treatment affects multiple processes.
  evidence:
  - reference: PMID:41410028
    reference_title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: N-Cad, Slug, and CD44 were significantly increased, but VE-Cad was decreased, in ECG12V compared to control
    explanation: Cultured mouse brain endothelial cells expressing KRAS G12V.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Endothelial Junction Disruption
    description: A shift toward mesenchymal characteristics accompanies reduced endothelial junction organization; independent mediation has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Nidus Formation with Direct Arteriovenous Shunting
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The nidus contains tortuous vessels connecting feeding arteries to draining veins without a normal intervening
    capillary network. The resulting low-resistance shunt alters local flow and venous loading. Vessel architecture
    and drainage differ between lesions.
  cell_types:
  - preferred_term: endothelial cell of artery
    term:
      id: CL:1000413
      label: endothelial cell of artery
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
  downstream:
  - target: High-Flow Shunt Haemodynamics and Venous Hypertension
    description: Direct arteriovenous connections alter flow and expose venous structures to abnormal hemodynamic loading.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cerebral arteriovenous malformation
    description: The nidus and direct shunt define the structural phenotype.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41999461
    reference_title: Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Brain arteriovenous malformations (bAVMs) are high-flow vascular lesions
      characterized by direct arteriovenous shunting without an intervening capillary bed.
    explanation: >-
      Defines the nidus lesion in exactly the terms of this node - high flow, direct
      shunting, absent capillary bed. Evidence source is OTHER as this is a review article.

- name: High-Flow Shunt Haemodynamics and Venous Hypertension
  biological_scale: TISSUE
  role: consequence
  description: >-
    High-flow shunting changes venous pressure and mechanical loading, while the degree of venous hypertension
    depends on drainage anatomy and outflow resistance. Deep venous drainage is an epidemiological risk marker
    and is not synonymous with venous stenosis or a direct measurement of outflow pressure. Hemodynamic and
    structural mechanisms may interact in rupture.
  downstream:
  - target: Nidus Rupture and Intracranial Haemorrhage
    description: Abnormal loading may contribute to failure of vulnerable vascular walls.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Perinidal Cortical Irritation and Seizure Generation
    description: Altered perinidal perfusion and venous congestion may contribute to cortical dysfunction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:25015366
    reference_title: >-
      Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage
      predictors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60,
      0.95-2.68, p = 0.02 in imputed dataset) may be additional predictors.
    explanation: >-
      The complete-case estimate for exclusively deep drainage is imprecise and crosses 1; the imputed analysis
      reaches significance. Neither directly measures venous pressure or proves outflow obstruction.

- name: Endothelial Inflammatory Mediator Production
  biological_scale: CELLULAR
  description: Cultured KRAS G12V mouse endothelial cells increase IL1B, IL6 and CCL2/MCP1 expression and release inflammatory mediators. Mouse AVM tissue also shows endothelial and myeloid cytokine expression. The specific mediators necessary for each downstream effect have not all been isolated experimentally.
  evidence:
  - reference: PMID:41696778
    reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: KRASG12V increased the mRNA expression of the pro-inflammatory cytokines (IL-1β and IL-6), as well as monocyte chemoattractant protein-1 (MCP-1)
    explanation: Cultured mutant mouse endothelial cells.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Perivascular Myeloid Cell Activation
    description: Mutant endothelial conditioned medium activates BV2 microglia and promotes migration in vitro.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Perivascular Myeloid Cell Activation
  biological_scale: CELLULAR
  description: Human AVMs contain activated and infiltrating myeloid populations. In murine co-cultures, mutant endothelial conditioned medium activates BV2 microglia, and macrophages amplify endothelial barrier dysfunction. BV2 is an immortalized mouse line and does not capture all primary microglial states. GPNMB-positive monocytes are enriched in ruptured human lesions, but cross-sectional enrichment does not establish whether recruitment preceded rupture.
  evidence:
  - reference: PMID:35084939
    reference_title: A single-cell atlas of the normal and malformed human brain vasculature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: GPNMB+ Mo3 monocytes, was over-represented in ruptured AVMs
    explanation: Human bulk-RNA deconvolution supported by cellular assays; association with rupture does not establish temporal direction.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41696778
    reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Normal ECs treated with BV2-MG-CM had decreased mRNA expression of cell adhesion molecules (CDH5 and TJP1) after 48 h of incubation
    explanation: Conditioned medium from primed BV2 cells affected wild-type mouse endothelial cells.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Endothelial Junction Disruption
    description: Primed microglial conditioned medium reduces selected endothelial junction transcripts.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Myeloid-associated Vascular Smooth Muscle Cell Apoptosis
    description: Patient-derived GPNMB-positive monocytes increase smooth-muscle-cell apoptosis in co-culture.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Endothelial Junction Disruption
  biological_scale: CELLULAR
  description: VE-cadherin organization is disrupted in engineered KRAS-mutant endothelial cells and examined human AVM tissue. Murine endothelial and microglial experiments show context-dependent changes in CDH5, TJP1, OCLN and CLDN5; conditioned-medium effects should not be described as degradation of every junction protein.
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: VE-cadherin expression was weak and diffuse in bAVM tissue compared to temporal lobe tissue
    explanation: Human lesion tissue staining, with preserved CD31 and ZO-1 staining in the same comparison.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41696778
    reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: normal ECs treated with KRAS-G12V-EC-CM had no changes in the mRNA expression of cell junction molecules
    explanation: Direct mutant endothelial conditioned medium did not reproduce the effect of primed microglial conditioned medium.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Increased Blood-Brain Barrier Permeability
    description: Disrupted endothelial junctions reduce barrier resistance and can permit leakage.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Increased Blood-Brain Barrier Permeability
  biological_scale: TISSUE
  description: Barrier dysfunction is demonstrated by reduced electrical resistance in murine endothelial–astrocyte cultures. At the tested early time point, KRAS-mutant endothelium alone did not increase dextran passage; added macrophages did. Mouse tracer leakage is reduced by minocycline. Permeability measurements and microscopic leakage do not by themselves establish prevention or causation of clinical hemorrhage.
  evidence:
  - reference: PMID:41696778
    reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: the presence of Mφ significantly enhanced FITC-dextran permeability in a 3D BBB coculture system
    explanation: Functional permeability assay separates macrophage-dependent dextran leakage from the earlier fall in electrical resistance.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Nidus Rupture and Intracranial Haemorrhage
    description: Loss of endothelial barrier integrity may contribute to vessel vulnerability, together with wall support and hemodynamic stress.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Myeloid-associated Vascular Smooth Muscle Cell Apoptosis
  biological_scale: CELLULAR
  description: GPNMB-positive monocytes isolated from patients with ruptured AVMs increase apoptosis of primary brain vascular smooth muscle cells in co-culture. Soluble osteopontin also increases apoptosis, attenuated by CD44 or integrin blockade. These assays support a possible inflammatory route to mural-cell loss without proving that it initiated rupture in the donor lesions.
  evidence:
  - reference: PMID:35084939
    reference_title: A single-cell atlas of the normal and malformed human brain vasculature.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Co-culture of isolated GPNMB+ monocytes from ruptured AVM patients with primary brain vascular smooth muscle cells (VSMCs) increased apoptotic cleaved caspase-3+ VSMCs
    explanation: Patient-derived monocytes with primary vascular smooth muscle cells; an in-vitro functional result.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Deficient Mural Cell Coverage and Vessel Wall Instability
    description: Apoptosis can reduce smooth-muscle support; the degree of in-vivo contribution is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Deficient Mural Cell Coverage and Vessel Wall Instability
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Altered mural-cell number or coverage can weaken vascular support. Human bulk transcriptomics show reduced
    extracellular-matrix and angiopoietin–TIE gene programs, but do not directly establish a specific recruitment
    defect. Patient-derived monocyte co-culture supplies a separate functional mechanism for smooth-muscle
    apoptosis. Pericyte depletion findings from hereditary AVM models require caution when applied to sporadic
    KRAS-associated disease.
  cell_types:
  - preferred_term: pericyte
    term:
      id: CL:0000669
      label: pericyte
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  downstream:
  - target: Nidus Rupture and Intracranial Haemorrhage
    description: Deficient vascular support may contribute to wall instability; individual human rupture events are multifactorial.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:34541474
    reference_title: The role of mural cells in hemorrhage of brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The vessel walls in bAVMs have structural defects, which impair vascular integrity. Mural
      cells are essential structural and functional components of blood vessels and play a
      critical role in maintaining vascular integrity. Changes in mural cell number and
      coverage have been implicated in bAVMs.
    explanation: >-
      Establishes deficient mural cell coverage as a structural defect of bAVM vessels
      impairing vascular integrity. Evidence source is OTHER as this is a review article.
  - reference: PMID:31795902
    reference_title: >-
      RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in
      Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found 498 genes downregulated including genes implicated in extracellular matrix
      composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-beta
      signaling
    explanation: >-
      Human bAVM tissue RNA-seq showing downregulation of extracellular-matrix and
      angiopoietin-TIE programmes, the signalling system that governs mural cell recruitment.

- name: Perinidal Cortical Irritation and Seizure Generation
  biological_scale: TISSUE
  role: consequence
  description: >-
    Perinidal cortical dysfunction can produce seizures. Proposed contributors include altered perfusion, venous
    congestion, gliosis and iron deposition after bleeding; their relative contributions vary and are not measured
    directly by surgical outcome cohorts.
  evidence:
  - reference: PMID:40428814
    reference_title: >-
      The Dynamics of Seizures After Microsurgical Treatment of Brain AVMs in Patients with
      Symptomatic Epilepsy: A Single-Center Experience over 10 Years.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures are a common clinical manifestation in patients with brain AVMs, ranking as
      the second most frequent presentation.
    explanation: >-
      Establishes seizure as the second commonest presentation of brain AVM, the clinical
      content of this node.

  downstream:
  - target: Seizure
    description: Epileptogenic cortical activity produces clinical seizures.
    causal_link_type: DIRECT
- name: Nidus Rupture and Intracranial Haemorrhage
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Rupture of malformed nidus or draining vessels produces intracerebral, intraventricular
    or subarachnoid haemorrhage - the presentation that makes brain AVM a leading cause of
    haemorrhagic stroke in the young. In an individual-patient meta-analysis of four
    untreated cohorts spanning 6,074 patient-years, the annual haemorrhage rate was 2.3%
    overall, and this figure is strongly conditioned on presentation: 4.8% per year in
    lesions that had already ruptured versus 1.3% per year in those that had not. Prior
    haemorrhage and increasing age were the independent predictors.
  evidence:
  - reference: PMID:25015366
    reference_title: >-
      Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage
      predictors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up
      (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured
      (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation.
    explanation: >-
      Quantifies the natural-history haemorrhage rate and the ruptured-versus-unruptured
      split that governs management decisions.
  - reference: PMID:25015366
    reference_title: >-
      Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage
      predictors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This large, individual patient data meta-analysis identified hemorrhagic presentation
      and increasing age as independent predictors of hemorrhage during follow-up.
    explanation: >-
      Identifies the independent predictors of subsequent haemorrhage in untreated disease.

  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4141996/?report=xml
    reference_title: "Untreated brain arteriovenous malformation: Patient-level meta-analysis of hemorrhage predictors - PMC"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: these hemorrhage risk estimates cannot be extrapolated to the entire lifetime of a patient.
    explanation: 'Full text of PMID:25015366: natural-history follow-up is limited by censoring at intervention and selection; annual estimates are not lifetime constants.'
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Intracranial haemorrhage
    description: Rupture releases blood into intracranial compartments.
    causal_link_type: DIRECT
  - target: Stroke
    description: Clinically symptomatic hemorrhage can produce hemorrhagic stroke.
    causal_link_type: DIRECT
  - target: Focal neurological deficit
    description: Intracranial bleeding can injure or compress neural tissue and produce a focal deficit.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Local neural injury or compression after bleeding
    evidence:
    - reference: PMID:30285374
      reference_title: Intracranial Arteriovenous Malformations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: When ruptured, intracranial AVMs usually present with focal neurological deficits, seizures, and sequelae of increased intracranial pressure.
      explanation: Clinical synthesis supports focal neurological deficits following rupture; it does not establish a mechanism for every unruptured presentation.
  - target: Headache
    description: A sufficiently large hemorrhage can increase intracranial pressure and cause headache.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased intracranial pressure
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK531479/
      reference_title: Intracranial Arteriovenous Malformations - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: If the hemorrhage is large enough to cause a significant increase in intracranial pressure, patients will often present with headache, nausea and vomiting, and a decreased level of consciousness.
      explanation: The chapter links headache to pressure elevation after a sufficiently large hemorrhage; this does not explain all headaches in AVM.
      quote_role: REVIEW_SYNTHESIS
phenotypes:
- category: Structural
  name: Cerebral arteriovenous malformation
  description: >-
    The defining structural lesion: a nidus of dilated vessels shunting arterial blood
    directly into veins without an intervening capillary bed, demonstrated on catheter
    angiography, CT angiography or MR angiography.
  phenotype_term:
    preferred_term: Cerebral arteriovenous malformation
    term:
      id: HP:0002408
      label: Cerebral arteriovenous malformation
  evidence:
  - reference: PMID:41999461
    reference_title: Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Brain arteriovenous malformations (bAVMs) are high-flow vascular lesions
      characterized by direct arteriovenous shunting without an intervening capillary bed.
    explanation: >-
      Defines the structural lesion. Evidence source is OTHER as this is a review article.

- category: Clinical
  name: Intracranial haemorrhage
  description: >-
    Rupture can cause intracerebral, intraventricular or subarachnoid hemorrhage. Untreated hemorrhage rates
    depend strongly on prior rupture; the four-cohort meta-analysis estimated 1.3% annually after an unruptured
    presentation and 4.8% after a ruptured presentation.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
    temporality: ACUTE
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      are a leading cause of hemorrhagic stroke in young adults and children
    explanation: >-
      Establishes haemorrhagic stroke as the defining clinical danger of brain AVM.
  - reference: PMID:25015366
    reference_title: >-
      Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage
      predictors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up
      (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured
      (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation.
    explanation: >-
      Supplies the annual haemorrhage rate in untreated disease, stratified by whether the
      lesion had previously ruptured.

- category: Clinical
  name: Seizure
  description: >-
    Seizures are a common presentation. A retrospective surgical series restricted to 52 unruptured lesions
    reported epilepsy at presentation in 80.4%; this selected proportion is not a disease-wide frequency.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40428814
    reference_title: >-
      The Dynamics of Seizures After Microsurgical Treatment of Brain AVMs in Patients with
      Symptomatic Epilepsy: A Single-Center Experience over 10 Years.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures are a common clinical manifestation in patients with brain AVMs, ranking as
      the second most frequent presentation.
    explanation: >-
      Establishes seizure as the second commonest presentation of brain AVM.
  - reference: PMID:41303829
    reference_title: >-
      Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year
      Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epileptic seizure was the most common presenting symptom (80.4%).
    explanation: >-
      Quantifies seizure as the dominant presentation in a surgical series of unruptured
      lesions. Not mapped to a frequency band because the cohort is restricted to
      unruptured, surgically treated AVMs.

- category: Clinical
  name: Stroke
  description: >-
    Hemorrhagic stroke is a major clinical consequence. Ischemic stroke also occurred in ARUBA, especially
    in the intervention arm; treatment-associated events should not be treated as the natural-history frequency
    of ischemia.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
    temporality: ACUTE
  evidence:
  - reference: PMID:24268105
    reference_title: "Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: '| Haemorrhagic | 25 (21·9%) | 6 (5·5%) |'
    explanation: 'ARUBA Table 2: first hemorrhagic strokes in the randomized intervention and medical-management groups, respectively. These are observed events rather than only an endpoint definition.'
    quote_role: PRIMARY_RESULT
- category: Clinical
  name: Focal neurological deficit
  description: >-
    Some clinical series report focal neurological deficits without specifying the affected functions. More
    specific motor and sensory findings are represented separately where primary patient descriptions permit.
  phenotype_term:
    preferred_term: Focal neurological deficit
    term:
      id: HP:0012638
      label: Abnormal nervous system physiology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:41303829
    reference_title: >-
      Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year
      Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort, epileptic seizures were the most frequent initial clinical manifestation,
      whereas headaches and focal neurological deficits were less commonly observed.
    explanation: >-
      Names focal neurological deficits as a presenting manifestation and places their
      frequency below seizure in an unruptured surgical cohort. No frequency band is asserted
      because the source gives an ordering, not a proportion, and the cohort is
      surgically selected.
- name: Headache
  category: Neurologic
  description: Headache, including migraine-like presentations, occurs in patients with brain AVM. The observational cohorts do not establish that every headache is caused by the lesion.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:41303829
    reference_title: "Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year Single-Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: whereas headaches and focal neurological deficits were less commonly observed.
    explanation: Primary clinical series of unruptured lesions.
    quote_role: PRIMARY_RESULT
- name: Hemiparesis
  category: Neurologic
  description: Progressive unilateral limb weakness was reported in an adult with a large unruptured left frontoparietal lesion.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Since diagnosis, the patient experienced progressive weakness of the right arm and leg.
    explanation: Patient 1 before bevacizumab treatment; no prior AVM hemorrhage was reported.
    quote_role: PRIMARY_RESULT
- name: Paresthesia
  category: Neurologic
  description: Intermittent unilateral arm numbness was reported in an adult with a right temporal AVM and seizures; the individual symptom mechanism was not resolved.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: occasional left arm numbness that lasted a few minutes per episode
    explanation: Patient 2 before investigational treatment.
    quote_role: PRIMARY_RESULT
prevalence:
- population: New York islands, United States (prospective population-based surveillance)
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 1.34
  rate_low: 1.18
  rate_high: 1.49
  notes: >-
    Average annual detection rate in a defined population, based on 284 diagnoses over 21,216,467 person-years.
    Detection does not date formation of the malformation.
  evidence:
  - reference: PMID:12690217
    reference_title: 'The New York Islands AVM Study: design, study progress, and initial results.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leading to an average annual AVM detection rate of 1.34 per 100,000 person-years (95%
      CI, 1.18 to 1.49)
    explanation: >-
      Prospective population-based detection rate, the basis for the normalised rate
      recorded here.
  rate_denominator: PERSON_YEARS
- population: Scotland, adults aged 16 and over (prospective population-based study)
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 1.12
  rate_low: 0.90
  rate_high: 1.37
  notes: >-
    Crude first-ever-diagnosis detection rate per 100,000 adult person-years in the Scottish population-based
    study; not a cross-sectional prevalence estimate.
  evidence:
  - reference: PMID:12702837
    reference_title: >-
      Prospective, population-based detection of intracranial vascular malformations in
      adults: the Scottish Intracranial Vascular Malformation Study (SIVMS).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      1.12 (95% CI, 0.90 to 1.37) for brain AVMs
    explanation: >-
      Crude annual detection rate per 100,000 adults for brain AVM in a prospective
      population-based study.

  rate_denominator: PERSON_YEARS
diagnosis:
- name: Digital subtraction angiography
  description: >-
    Catheter DSA is the reference standard for defining feeding arteries, nidus and venous drainage, and for
    confirming obliteration. Its findings inform treatment planning alongside symptoms, functional anatomy,
    patient factors and procedural risk.
  diagnosis_term:
    preferred_term: digital subtraction angiography
    term:
      id: NCIT:C190556
      label: Angiography
  results: >-
    Demonstration of a nidus with arteriovenous shunting, with feeding-artery and
    draining-vein anatomy sufficient to assign a Spetzler-Martin grade.
  evidence:
  - reference: PMID:39125532
    reference_title: >-
      Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess
      Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      using digital subtraction angiography (DSA) as the reference standard
    explanation: >-
      Confirms DSA as the reference standard against which other modalities are measured.

- name: Non-contrast-enhanced time-resolved MR angiography
  description: >-
    Non-contrast 4D MRA can detect and characterize shunting while avoiding gadolinium. In a retrospective
    study of 54 imaging pairs from 43 patients, reported sensitivity was 75% and specificity 95% against DSA.
    The mixture of treated and untreated lesions and widely varying intervals between MRA and DSA limit inference;
    it does not establish that MRA can replace DSA in every setting.
  diagnosis_term:
    preferred_term: magnetic resonance angiography
    term:
      id: NCIT:C190557
      label: Magnetic Resonance Angiography
  results: >-
    Detection of arteriovenous shunting and grading concordant with DSA, without
    gadolinium-based contrast.
  evidence:
  - reference: PMID:39125532
    reference_title: >-
      Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess
      Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results demonstrated that NCE-4D-MRA had a higher accuracy and specificity compared to
      CE-4D-MRA (0.85 vs. 0.83 and 95% vs. 85%, respectively) and similar agreement, with DSA
      detecting shunts in bAVMs or residuals.
    explanation: >-
      Quantifies non-contrast 4D-MRA accuracy against the contrast-enhanced comparator and DSA.
  - reference: PMID:39125532
    reference_title: >-
      Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess
      Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The safety profile of imaging techniques is a significant concern in the long-term follow
      up of bAVMs
    explanation: >-
      States the contrast-avoidance rationale that makes this modality specifically valuable in
      a lifelong lesion requiring repeated imaging.

  - reference: PMID:39125532
    reference_title: Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: the 75% sensitivity observed for NCE-4D-MRA
    explanation: 'Results section: sensitivity is lower than specificity; the discussion reverses these two percentages.'
    quote_role: PRIMARY_RESULT
- name: Angioarchitectural grading (Spetzler-Martin and related scales)
  description: >-
    Spetzler-Martin grading uses nidus size, eloquence and deep venous drainage to estimate microsurgical risk.
    Supplementary grading adds patient age, hemorrhagic presentation and nidus diffuseness. Grading informs
    rather than determines treatment selection and is distinct from predicting untreated rupture risk.
  diagnosis_term:
    preferred_term: disease grading
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    A Spetzler-Martin or supplementary Spetzler-Martin grade that stratifies operative risk.
  evidence:
  - reference: PMID:41303829
    reference_title: >-
      Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year
      Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were classified according to the supplementary Spetzler-Martin (suppl-SM) grading system
    explanation: >-
      Documents the grading system in operational use to stratify surgical risk.
  - reference: PMID:39125532
    reference_title: >-
      Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess
      Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concordance in grading bAVMs was substantial between NCE-4D-MRA and DSA, particularly for
      the Spetzler-Martin and Buffalo scales
    explanation: >-
      Shows the grading scales can be applied on non-invasive imaging with substantial
      concordance against DSA.

- name: Somatic genotyping from lesion tissue or cell-free DNA
  description: >-
    Sensitive sequencing or droplet digital PCR of resected lesion tissue can detect low-level somatic KRAS/BRAF
    variants. Negative peripheral-blood testing does not exclude a lesional somatic variant. Circulating-DNA
    and local arterial sampling are investigational, with diagnostic performance under study; routine diagnosis
    relies on imaging and does not require a tissue biopsy solely to establish a molecular cause.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Detection of a somatic activating KRAS or BRAF variant in lesional tissue; a negative blood
    test does not exclude the diagnosis.
  evidence:
  - reference: PMID:29298116
    reference_title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients
      and in none of the 21 paired blood samples.
    explanation: >-
      Negative paired-blood results in this cohort do not exclude a lesional somatic mutation or establish
      the sensitivity of future liquid-biopsy methods.
  - reference: PMID:41999461
    reference_title: Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Future approaches combining minimally invasive sampling methods, such as endovascular
      biopsy and peripheral blood cell-free DNA analysis, with ultra-sensitive detection
      technologies are expected to help overcome these limitations.
    explanation: >-
      Names the emerging sampling routes that address the tissue-access problem. Evidence source
      is OTHER as this is a review article.

  - reference: clinicaltrials:NCT06494358
    reference_title: Liquid Biopsies for the Detection of Somatic Mutations in Brain Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: This research aims to evaluate the diagnostic performances of liquid biopsies
    explanation: Registry of an observational diagnostic study, not established sensitivity or clinical utility.
- name: VALE hemorrhage-risk assessment
  description: VALE estimates rupture risk from ventricular involvement (+2), venous aneurysm (−4), deep location (+1), and exclusively deep venous drainage (+2). The derivation and validation cohorts were predominantly Chinese; the conservative cohort included 235 prospectively followed and 793 retrospectively selected patients. Only 36 hemorrhages occurred, and the authors warn that hemorrhage-free survival may be overestimated. Venous aneurysm was protective in the fitted score, not a uniform risk-increasing feature. VALE is a prognostic adjunct, not a diagnostic test or proof of treatment benefit.
  evidence:
  - reference: PMID:36857052
    reference_title: Development and Validation of a Scoring System for Hemorrhage Risk in Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Venous aneurysm was a protective factor for AVM rupture in the study cohort
    explanation: Primary score derivation; the direction must not be conflated with arterial aneurysms.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36857052
    reference_title: Development and Validation of a Scoring System for Hemorrhage Risk in Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Thirty-six hemorrhages occurred over a median (IQR) follow-up of 4.2 (0.3-6.0) years among 1028 patients
    explanation: Validation cohort event count and follow-up constrain precision.
    quote_role: PRIMARY_RESULT
treatments:
- name: Microsurgical resection
  description: >-
    Microsurgery aims at complete nidus removal and can provide immediate obliteration, with outcome dependent
    on lesion anatomy and surgical risk. A selected 52-patient retrospective series found better outcomes for
    supplementary Spetzler-Martin scores ≤6. MATCH sensitivity analyses favored microsurgery for AVM hemorrhage
    or death, but this observational result does not establish superiority for all patients or all neurological
    outcomes.
  treatment_term:
    preferred_term: Neurosurgical Procedure
    term:
      id: NCIT:C15656
      label: Neurosurgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    treatment_effect: INHIBITS
    description: >-
      Resection physically removes the shunting nidus, eliminating both the haemodynamic
      and the inflammatory arms of the lesion at once.
  evidence:
  - reference: PMID:41303829
    reference_title: >-
      Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year
      Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the low-risk group, there were no deaths, and poor outcomes were rare (6.8% at
      discharge; 2.3% at 9 months). Conversely, the high-risk group demonstrated
      significantly worse outcomes (62.5% poor outcome at discharge, 28.6% at 9 months).
    explanation: >-
      Selected surgical cohort shows an association between anatomical grade and outcome; it is not a randomized
      comparison against observation.
  - reference: PMID:41231469
    reference_title: >-
      Interventional Treatment vs Conservative Management of Unruptured Brain Arteriovenous
      Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only microsurgical resection was consistently associated with reduced hemorrhage risk
      in sensitivity analyses.
    explanation: >-
      Observational MATCH analysis of AVM hemorrhage or death; it does not directly compare the all-stroke
      endpoint of ARUBA or establish randomized modality superiority.

- name: Stereotactic radiosurgery
  description: >-
    Focused radiation produces progressive vascular injury and eventual nidus obliteration over a latency period.
    Hemorrhage remains possible before obliteration, and radiation-related injury is an additional risk. A
    101-patient retrospective pediatric cohort reported 64% estimated obliteration at five years and 82% at
    ten years, with permanent symptomatic radiation changes in 8%. A separate prospective TOBAS SRS registry
    reported three-year occlusion in 51/79 patients with imaging, or 54% of all 94 analyzed patients.
  treatment_term:
    preferred_term: Stereotactic Radiosurgery
    term:
      id: NCIT:C15358
      label: Stereotactic Radiosurgery
  therapeutic_modality: RADIOTHERAPY
  target_mechanisms:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    treatment_effect: INHIBITS
    description: >-
      Radiation-induced obliteration progressively closes nidus vessels, abolishing the
      shunt over a period of years rather than immediately.
  evidence:
  - reference: PMID:31942635
    reference_title: "Radiosurgery for Unruptured Intervention-Naïve Pediatric Brain Arteriovenous Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Estimated probabilities of AVM obliteration at 5 and 10 yr were 64% and 82%,
      respectively.
    explanation: >-
      Estimated obliteration rises over time but remains incomplete in this selected pediatric cohort.
  - reference: PMID:31942635
    reference_title: "Radiosurgery for Unruptured Intervention-Naïve Pediatric Brain Arteriovenous Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary endpoint occurred in 14%, comprising hemorrhagic stroke, death, and
      permanent radiation-induced changes in 6%, 3%, and 8%, respectively.
    explanation: >-
      Quantifies the harm profile, including radiation-induced change, that has to be set
      against the obliteration benefit.

  - reference: PMID:42140314
    reference_title: "Stereotactic Radiosurgery for Brain Arteriovenous Malformations as Expected Curative Treatment: Outcomes of Patients Included in the Prospective Registry of a Pragmatic Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Three-year imaging follow-up, available in 79/94 (84%) confirmed AVM occlusion in 51/79 (65%
    explanation: TOBAS prospective SRS registry, predominantly ruptured small lesions; 54% when all enrolled analyzed patients are the denominator.
    quote_role: PRIMARY_RESULT
- name: Conservative medical management
  description: >-
    Observation with treatment of symptoms and coexisting vascular risk factors is an option for selected unruptured
    AVMs. In the ARUBA randomized trial, medical management reduced death or any symptomatic stroke compared
    with the pooled intervention strategy over a mean 50.4 months in the final analysis. This is not a comparison
    of each procedure individually or evidence about ruptured lesions, and longer-term net benefit remains
    uncertain.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:24268105
    reference_title: >-
      Medical management with or without interventional therapy for unruptured brain
      arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ARUBA trial showed that medical management alone is superior to medical management
      with interventional therapy for the prevention of death or stroke in patients with
      unruptured brain arteriovenous malformations followed up for 33 months.
    explanation: >-
      The randomised trial's conclusion supporting conservative management for unruptured
      lesions, with its follow-up duration stated.
  - reference: PMID:24268105
    reference_title: >-
      Medical management with or without interventional therapy for unruptured brain
      arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary endpoint had been reached by 11 (10.1%) patients in the medical management
      group compared with 35 (30.7%) in the interventional therapy group.
    explanation: >-
      Quantifies the difference in death or symptomatic stroke that led the data and safety
      monitoring board to halt randomisation.
  - reference: PMID:32562682
    reference_title: >-
      Medical management with interventional therapy versus medical management alone for
      unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre,
      non-blinded, randomised controlled trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After extended follow-up, ARUBA showed that medical management alone remained superior to
      interventional therapy for the prevention of death or symptomatic stroke in patients with
      an unruptured brain arteriovenous malformation.
    explanation: >-
      The final follow-up analysis, which supersedes the 2014 interim horizon and shows the
      effect did not decay with longer observation.

- name: Endovascular embolization
  description: >-
    Catheter-delivered embolic material can occlude components of the shunt. Embolization may be used before
    resection or radiosurgery, or with curative intent in selected anatomy. Obliteration and procedural risk
    require individual assessment; partial angiographic occlusion is not equivalent to demonstrated long-term
    prevention of hemorrhage.
  treatment_term:
    preferred_term: Embolization Therapy
    term:
      id: NCIT:C15230
      label: Embolization Therapy
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    treatment_effect: INHIBITS
    description: >-
      Embolic occlusion of nidus compartments and feeding arteries removes shunting channels,
      either as definitive treatment or to reduce flow before resection or radiosurgery.
  evidence:
  - reference: PMID:24268105
    reference_title: >-
      Medical management with or without interventional therapy for unruptured brain
      arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      medical management with interventional therapy (ie, neurosurgery, embolisation, or
      stereotactic radiotherapy, alone or in combination)
    explanation: >-
      Establishes embolization as one of the three standard interventional modalities, as
      randomised in ARUBA.
  - reference: PMID:41231469
    reference_title: >-
      Interventional Treatment vs Conservative Management of Unruptured Brain Arteriovenous
      Malformations.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only microsurgical resection was consistently associated with reduced hemorrhage risk in
      sensitivity analyses.
    explanation: >-
      The observational sensitivity finding concerns microsurgical resection and does not establish a hemorrhage-prevention
      benefit for embolization.

- name: Antiseizure medication
  description: Treat established seizures according to seizure type, response and tolerability. In the bevacizumab pilot, one participant had controlled seizures with phenytoin plus phenobarbital, while another remained symptomatic on levetiracetam. These observations do not rank the drugs or support universal prophylaxis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Phenytoin
      term:
        id: NCIT:C741
        label: Phenytoin
    - preferred_term: Phenobarbital
      term:
        id: NCIT:C739
        label: Phenobarbital
    - preferred_term: Levetiracetam
      term:
        id: NCIT:C47581
        label: Levetiracetam
  evidence:
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Seizures were controlled with phenytoin extended-release 400 mg daily and phenobarbitol 100 mg daily.
    explanation: Patient 1 baseline care; the source misspells phenobarbital.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Seizures reported to occur one to two times per month, refractory to levetiracetam 500 mg two times per day.
    explanation: Persistent seizures despite levetiracetam in one patient; this does not establish comparative efficacy among antiseizure drugs.
    quote_role: PRIMARY_RESULT
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Perinidal Cortical Irritation and Seizure Generation
    treatment_effect: INHIBITS
    description: >-
      Antiseizure drugs suppress seizures generated by perinidal cortex without treating the arteriovenous
      shunt.
- name: Investigational MEK inhibition
  description: Trametinib is being explored for brain AVM but clinical efficacy is unestablished. A 2024 preprint describes three uncontrolled compassionate-use cases with relative imaging stability; one patient had a hemorrhagic stroke during treatment, and lesion genotypes were unknown. A separate male-mouse study found prolonged survival and reduced hemorrhagic burden without significant MRA lesion-number reduction. The planned presurgical trial NCT06098872 was withdrawn with zero enrollment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Trametinib
      term:
        id: NCIT:C77908
        label: Trametinib
  evidence:
  - reference: url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full
    reference_title: "MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations | bioRxiv"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: have shown stable disease with little to no progression since beginning treatment, although this follow-up timeframe is truncated and further follow-up is needed.
    explanation: Preprint, three uncontrolled cases; imaging stability cannot establish efficacy or prevention of hemorrhage.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full
    reference_title: "MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations | bioRxiv"
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Patient 3 had a hemorrhagic stroke, but was still deemed ineligible for surgical or endovascular intervention
    explanation: Hemorrhage during an uncontrolled course is a safety/outcome observation, not evidence of efficacy or proof of drug causation.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41410028
    reference_title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: the size and number of bAVMs were not noticeably changed in trametinib-treated mice based on our MRA imaging
    explanation: Counterevidence to anatomical lesion regression in this mouse experiment; it does not negate the separate hemorrhage-volume benefit.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41410028
    reference_title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: at 8 weeks of treatment, the mice treated with 1 mg/kg of trametinib demonstrated significantly lower hemorrhagic volumes than the vehicle treated mice
    explanation: The positive hemorrhage endpoint is distinct from unchanged lesion size/number; this preclinical benefit does not establish clinical efficacy.
    quote_role: PRIMARY_RESULT
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
    treatment_effect: INHIBITS
    description: MEK inhibition suppresses downstream ERK activation; clinical benefit for brain AVM remains unestablished.
- name: Investigational bevacizumab
  description: A completed single-arm pilot treated two adults with large unresectable unruptured AVMs. Neither had a measurable reduction in nidus volume at 26 or 52 weeks. No clinically important adverse events were identified in this small sample, which is insufficient to establish safety or hemorrhage prevention. NCT06264531 is evaluating symptomatic benefit. Improvement of post-radiosurgery edema in separate reports must not be equated with efficacy against the untreated nidus.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Bevacizumab
      term:
        id: NCIT:C2039
        label: Bevacizumab
  evidence:
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment.
    explanation: Two-patient pilot did not demonstrate radiographic volume reduction; the null finding is limited by sample size.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: our study is underpowered to detect the hypothesised change in bAVM volume.
    explanation: Explicit limitation of the clinical pilot.
    quote_role: PRIMARY_RESULT
  therapeutic_modality: MONOCLONAL_ANTIBODY
- name: Acute management of AVM-related hemorrhage
  description: Acute hemorrhage requires cardiorespiratory stabilization, management of intracranial pressure and reversal of coagulopathy when present. Ventricular drainage may be required for intraventricular blood with hydrocephalus; a large hematoma with mass effect may require emergency decompression. Stabilization and hematoma management are distinct from the timing and method of definitive nidus treatment.
  treatment_term:
    preferred_term: Acute hemorrhage management
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK531479/
    reference_title: Intracranial Arteriovenous Malformations - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: coagulopathies should be reversed, and patients should be treated for fever, hyperglycemia, and intracranial hypertension.
    explanation: Current 2026 StatPearls clinical-management chapter; acute supportive care, not trial evidence for elective AVM intervention.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK531479/
    reference_title: Intracranial Arteriovenous Malformations - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: External ventricular drainage may be indicated if there is intraventricular hemorrhage extension and hydrocephalus is present.
    explanation: Specific acute neurosurgical indication, conditional on hemorrhage anatomy.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
clinical_trials:
- name: NCT00389181
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ARUBA randomized adults with unruptured brain AVM to medical management alone or management plus intervention.
    Enrollment stopped early; completed follow-up provides randomized evidence on death or symptomatic stroke.
  target_phenotypes:
  - preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  - preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:24268105
    reference_title: >-
      Medical management with or without interventional therapy for unruptured brain
      arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial is registered with ClinicalTrials.gov, number NCT00389181.
    explanation: >-
      Ties the published trial report to its ClinicalTrials.gov registration, which is the
      identifier this record is keyed on.

  - reference: clinicaltrials:NCT00389181
    reference_title: A Randomized Trial of Unruptured Brain Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: The purpose of this study is to determine if medical management is better than invasive therapy for improving the long-term outcome
    explanation: Registry describes the randomized comparison; clinical outcomes are supplied by the published reports.
  notes: Registry status verified on 2026-10-01.
- name: NCT02098252
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    TOBAS combines randomized comparisons and prospective registries for ruptured and unruptured AVMs. It studies
    conservative versus interventional management and the contribution of embolization. Registry publications
    should be distinguished from randomized trial results.
  target_phenotypes:
  - preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  - preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: clinicaltrials:NCT02098252
    reference_title: "Treatment of Brain AVMs (TOBAS) Study: A Randomized Controlled Trial and Registry"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The trial has been designed to test a) whether medical management or interventional
      therapy will reduce the risk of death or debilitating stroke
    explanation: >-
      States the trial's primary question, which is the unresolved comparison this entry's
      management-controversy discussion records.

  notes: Registry status verified on 2026-10-01.
- name: NCT04572568
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: MATCH is a prospective multicenter observational registry of multidisciplinary AVM management; it supplied data for the 2025 target-trial emulation.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT04572568
    reference_title: Registry of Multimodality Treatment for Brain Arteriovenous Malformation in Mainland China
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: This study is a multi-center, prospective, registry study.
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT06098872
  phase: PHASE_II
  status: WITHDRAWN
  description: Presurgical trametinib pilot for adult unruptured AVMs, including intracranial lesions. Withdrawn with zero actual enrollment and the stated reason that no patients enrolled; it supplies no treatment outcome evidence.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT06098872
    reference_title: Pilot Study on the Efficacy of MEK1/MEK2 Inhibitor Trametinib in Patients With Surgical Unruptured Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: The purpose of this pilot study is to see whether taking an oral medication called Trametinib can improve upon the AVM structure
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT06913725
  phase: PHASE_II
  status: RECRUITING
  description: Open-label exploratory FCN-159 study in brain AVM, with an estimated ten participants and an MRA response endpoint.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT06913725
    reference_title: An Exploratory Study to Evaluate the Efficacy and Safety of FCN-159 in Patients With Brain Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: A single-center, open-label, non-randomized controlled exploratory study is conducted in the Xuanwu Hospital Capital Medical University
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT02314377
  phase: PHASE_I
  status: COMPLETED
  description: Completed two-participant bevacizumab pilot for AVMs unsuitable for surgery; published results found no change in nidus volume.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT02314377
    reference_title: Bevacizumab Therapy for Brain Arteriovenous Malformation
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: Bevacizumab Therapy for brain arteriovenous malformation that is not amenable to surgical intervention.
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT06264531
  status: RECRUITING
  description: Bevacizumab study in symptomatic cerebral AVM; the primary endpoint evaluates improvement in cognition, neurological symptoms, epilepsy or headache rather than proven nidus eradication.
  notes: Registry status verified on 2026-10-01; registered as phase 2/phase 3.
  evidence:
  - reference: clinicaltrials:NCT06264531
    reference_title: Evaluation of the Efficacy and Safety of Anti-angiogenic Therapy With Intravenous Bevacizumab in Patients With Symptomatic Cerebral Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: The aim of our study is to assess the efficacy of IV Bevacizumab on the disabling symptoms associated with symptomatic brain AVMs.
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT06494358
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Observational evaluation of local arterial and peripheral venous liquid biopsies against surgical-tissue genotyping.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT06494358
    reference_title: Liquid Biopsies for the Detection of Somatic Mutations in Brain Arteriovenous Malformations
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: This research aims to evaluate the diagnostic performances of liquid biopsies
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
- name: NCT07314047
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: PARTNER randomized noninferiority device study comparing a liquid embolic agent with Onyx. Its primary endpoint is effective embolization, defined as at least 50% reduction after the last procedure, which is not complete cure.
  notes: Registry status verified on 2026-10-01.
  evidence:
  - reference: clinicaltrials:NCT07314047
    reference_title: "a Prospective, Multi-center, Open-label, Non-inferiority, Randomized, Controlled Registration Trial of the Liquid Embolic Agent for the Treatment of Brain Arteriovenous Malformation"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: This study is designed as a prospective, multi-center, open-label, non-inferiority, randomized controlled clinical trial.
    explanation: Registry describes study intent; enrollment status and design do not establish efficacy.
animal_models:
- name: Endothelial BrafV600E mouse model of sporadic brain AVM
  species: Mouse
  genotype: Brain endothelial-cell-specific BrafV600E expression
  publication: PMID:38700584
  description: Engineered activating BRAF expression produces dilated AVM-like vessels with reduced wall stability, spontaneous hemorrhage and inflammation. Early dabrafenib slows progression; efficacy against established lesions was unresolved. Available evidence is the published abstract, not a complete assessment of model fidelity.
  modeled_mechanisms:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Reproduces selected vascular architectural features, but not a spontaneous human somatic event.
    evidence:
    - reference: PMID:38700584
      reference_title: Somatic Braf(V600E) mutation in the cerebral endothelium induces brain arteriovenous malformations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions.
      explanation: Engineered mouse phenotype; abstract-only retrieval limits assessment.
      quote_role: PRIMARY_RESULT
  - target: Nidus Rupture and Intracranial Haemorrhage
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Spontaneous bleeding occurs in the engineered model.
    evidence:
    - reference: PMID:38700584
      reference_title: Somatic Braf(V600E) mutation in the cerebral endothelium induces brain arteriovenous malformations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: accompanied by spontaneous hemorrhage and neuroinflammation.
      explanation: Reported mouse outcome; no human treatment efficacy.
      quote_role: PRIMARY_RESULT
- name: Adult AAV-BR1 KRAS G12V brain endothelial mouse
  species: Mouse
  genotype: AAV-BR1-mediated brain endothelial KRAS G12V overexpression
  publication: PMID:41410028
  description: Adult mice develop multiple cerebral AVM-like lesions and hemorrhage. Trametinib begun ten weeks after induction prolongs survival and reduces some measures of bleeding without significant MRA lesion-number change. The treatment study used males and widespread transgene expression, exceeding the usual focal human lesion burden. Related experiments test inflammatory interactions and minocycline.
  modeled_mechanisms:
  - target: Nidus Rupture and Intracranial Haemorrhage
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Models hemorrhage and the distinction between reduced bleeding and anatomical cure.
    evidence:
    - reference: PMID:41410028
      reference_title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: the mice treated with 1 mg/kg of trametinib demonstrated significantly lower hemorrhagic volumes than the vehicle treated mice
      explanation: Eight-week treatment measurement in mice with established lesions; the higher-dose result was not significant.
      quote_role: PRIMARY_RESULT
  - target: Increased Blood-Brain Barrier Permeability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Tracer leakage and endothelial junction changes respond to minocycline in the related KRAS G12V model.
    evidence:
    - reference: PMID:41696778
      reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: the leaking of BSA-647, a BBB tracer, in the KRASG12V/bEC mouse was significantly attenuated by minocycline treatment
      explanation: Preclinical barrier readout, not proof of clinical hemorrhage prevention.
      quote_role: PRIMARY_RESULT
- name: Postnatal AAV-PHP.V1 KRAS G12D endothelial mouse
  species: Mouse
  genotype: AAV-PHP.V1 conditional KRAS G12D in Cdh5-CreERT2 mice
  publication: PMID:39576014
  description: Postnatal endothelial KRAS G12D induction produces vascular tangles and hemorrhage, with lesion burden dependent on viral dose. CRISPR/CasRx targets mutant RNA rather than editing genomic DNA. Concurrent delivery strongly suppresses formation; treatment fourteen days after induction reduces lesion size while lesion-number reduction is not significant. Overexpression, spinal lesions, occasional splenic bleeding and repeated-AAV immunity limit translation.
  modeled_mechanisms:
  - target: Nidus Formation with Direct Arteriovenous Shunting
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Engineered postnatal arteriovenous connections reproduce aspects of nidus architecture.
    evidence:
    - reference: PMID:39576014
      reference_title: CRISPR/CasRx suppresses KRAS-induced brain arteriovenous malformation developed in postnatal brain endothelial cells in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Tortuous and enlarged vascular tangles connected with feeding arteries and draining veins were observed in the cleared brains
      explanation: Direct three-dimensional anatomical observation in mice.
      quote_role: PRIMARY_RESULT
  - target: Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
    relationship: PERTURBS
    fidelity: MODERATE
    description: Mutant-transcript suppression tests dependence on the initiating KRAS perturbation.
    evidence:
    - reference: PMID:39576014
      reference_title: CRISPR/CasRx suppresses KRAS-induced brain arteriovenous malformation developed in postnatal brain endothelial cells in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: The lesion number showed a tendency to decrease, and the size significantly decreased
      explanation: Delayed CasRx treatment after lesion development had a clearer effect on size than number.
      quote_role: PRIMARY_RESULT
- name: Embryonic KRAS G12V zebrafish arteriovenous-shunt model
  species: Zebrafish
  genotype: Mosaic endothelial expression of fluorescently tagged KRAS G12V
  publication: PMID:41708990
  description: Embryonic shunts can improve after glycolytic or MEK inhibition. BAY876 plus reduced-dose SL327 improved reversal compared with SL327 alone. This early arteriovenous-shunt model does not establish regression of a mature, complex human brain nidus; the MEK inhibitor was SL327 rather than trametinib.
  modeled_mechanisms:
  - target: Increased Endothelial Glycolytic Flux
    relationship: PERTURBS
    fidelity: LOW
    description: Glycolytic blockade perturbs shunt maintenance in an early developmental model.
    evidence:
    - reference: PMID:41708990
      reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: combined BAY876 + SL327 significantly improved shunt reversal compared to SL327 alone in our zebrafish model
      explanation: Combination result; the 2-DG plus SL327 comparison showed a nonsignificant trend.
      quote_role: PRIMARY_RESULT
discussions:
- discussion_id: bavm-unruptured-management-controversy
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Nidus Rupture and Intracranial Haemorrhage
  - pathophysiology#Nidus Formation with Direct Arteriovenous Shunting
  prompt: >-
    Which patients with an unruptured brain AVM benefit from intervention when both hemorrhagic and nonhemorrhagic
    outcomes are considered?
  rationale: >-
    ARUBA randomized adults and measured death or any symptomatic stroke, including ischemic stroke. MATCH
    emulated a target trial in an observational registry that included younger patients and measured AVM-related
    hemorrhage or death; its primary outcome excluded ischemic stroke, radiation injury, seizures and cognitive
    effects. Longer follow-up alone cannot explain the different estimates, and weighting cannot eliminate
    unmeasured confounding. MATCH high-grade subgroup estimates were imprecise. Diffuse lesions showed benefit
    at five years but no significant advantage at ten years, rather than uniform absence of benefit.
  evidence:
  - reference: PMID:32562682
    reference_title: "Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The incidence of death or symptomatic stroke was lower with medical management alone
    explanation: Final ARUBA randomized comparison at mean 50.4 months.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41231469
    reference_title: Interventional Treatment vs Conservative Management of Unruptured Brain Arteriovenous Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: the estimated 5-year hemorrhage-free survival was 96.23% (95% CI, 93.95%-97.65%) for the interventional treatment group and 89.00% (95% CI, 86.37%-91.24%) for the conservative management group
    explanation: Different population, endpoint and nonrandomized design; not a direct refutation of the ARUBA all-stroke result.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: bavm-long-horizon-randomisation
    name: Long-term randomized assessment of net clinical benefit
    description: >-
      Compare intervention and observation with long-term randomized follow-up, prospectively stratified by
      clinically relevant lesion anatomy. Measure death, hemorrhagic and ischemic stroke, disability, cognition,
      seizures and treatment-related injury rather than assuming hemorrhage-free survival captures net benefit.
    readouts:
    - name: Death, hemorrhagic and ischemic stroke, disability and treatment-related injury
      target: pathophysiology#Nidus Rupture and Intracranial Haemorrhage
    would_support:
    - pathophysiology#Nidus Rupture and Intracranial Haemorrhage

- discussion_id: bavm-mek-inhibition-translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
  - pathophysiology#Nidus Formation with Direct Arteriovenous Shunting
  prompt: >-
    Can pathway-directed treatment provide durable clinical benefit in established human brain AVM, and which
    outcomes reflect that benefit?
  rationale: >-
    The evidence is no longer exclusively preventive: established-lesion mouse experiments report reduced bleeding
    and longer survival without clear loss of the nidus, and a preprint describes three uncontrolled human
    trametinib cases. One of those patients hemorrhaged during treatment. Conversely, a two-patient bevacizumab
    trial showed no volume reduction. Genotype, mature vascular architecture, dose, treatment duration, rebound
    after withdrawal and systemic toxicity remain unresolved. NCT06098872 was withdrawn without enrollment;
    active studies should not be counted as positive efficacy results.
  evidence:
  - reference: PMID:41410028
    reference_title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: the size and number of bAVMs were not noticeably changed in trametinib-treated mice based on our MRA imaging
    explanation: Distinguishes bleeding reduction from anatomical regression.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full
    reference_title: "MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations | bioRxiv"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Patient 3 had a hemorrhagic stroke, but was still deemed ineligible for surgical or endovascular intervention
    explanation: Preprint uncontrolled human observation; no demonstrated hemorrhage prevention.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34189463
    reference_title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment.
    explanation: Small clinical pilot limits a broad assumption that pathway inhibition shrinks established lesions.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: bavm-mek-established-lesion-trial
    name: MEK inhibition in established, genotyped brain AVM
    description: >-
      A controlled study in established brain AVM should assess bleeding, disability, nidus volume and shunt
      flow, with systematic toxicity monitoring and follow-up after treatment withdrawal. Genotyping through
      clinically obtained tissue or validated liquid biopsy could test differential response without requiring
      research biopsy as routine care.
    readouts:
    - name: Nidus volume and shunt flow
      target: pathophysiology#Nidus Formation with Direct Arteriovenous Shunting
    - name: Hemorrhage and neurological function
      target: pathophysiology#Nidus Rupture and Intracranial Haemorrhage
    would_support:
    - pathophysiology#Constitutive RAS-MAPK-ERK Signalling in Brain Endothelial Cells
- discussion_id: bavm-candidate-genetic-modifiers
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Nidus Rupture and Intracranial Haemorrhage
  prompt: Do candidate inherited variants improve prediction of sporadic AVM hemorrhage beyond clinical and anatomical factors?
  rationale: A natural-history review describes candidate IL6, TNF and APOE associations and notes that most awaited independent replication. These associations concern hemorrhage susceptibility, not proven initiating mutations or clinically validated tests. A small familial report proposing PTPN13 also does not establish an alternative cause for unselected sporadic lesions.
  evidence:
  - reference: PMID:24930128
    reference_title: Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: the majority of these genetic association results await replication in independent AVM cohorts.
    explanation: Limitation stated by the 2014 review; candidate associations are not treated as validated clinical predictors.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41418676
    reference_title: Combined exome and RNA-seq analysis in patients with rare non-syndromic inherited brain arteriovenous malformation suggests a novel function for PTPN13 in arterial specification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: PTPN13 was identified as a possible causative gene for non-syndromic inherited bAVM.
    explanation: Candidate proposed from two related affected individuals; not an established sporadic AVM driver.
    quote_role: PRIMARY_RESULT
notes: >-
  The MONDO binding denotes brain arteriovenous malformations broadly; this entry emphasizes the sporadic phenotype
  and does not imply that the ontology term itself excludes hereditary disease. Syndromic HHT and capillary-malformation–AVM,
  and cerebral proliferative angiopathy, require distinct diagnostic consideration. Brain AVM is a non-neoplastic
  vascular malformation even though some experimental endothelial contexts show increased proliferation.
experimental_models:
- name: KRAS-engineered endothelial cultures
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: Doxycycline-inducible immortalized HUVECs provide glycolysis, sprouting and junction assays. Selected results were validated by transfection of primary human brain microvascular endothelial cells. The principal cell line is not brain endothelium, lacks flow and mural support, and showed no increase in proliferation in the reported comparison.
  cell_source: Immortalized HUVEC line; selected primary human brain endothelial validation
  publication: PMID:41708990
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: The primary mechanistic insights in our study were made using an immortalized HUVEC cellular system, with validation in primary brain ECs.
    explanation: Explicit model identity and scope.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Increased Endothelial Glycolytic Flux
    relationship: PERTURBS
    fidelity: MODERATE
    description: Models mutant-cell metabolism and its perturbation by HK2 knockdown.
    evidence:
    - reference: PMID:41708990
      reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: siRNA knockdown of HK2 resulted in a dose-dependent reduction of both average sprout length and number per EC spheroid
      explanation: Functional perturbation in immortalized HUVECs.
      quote_role: PRIMARY_RESULT
- name: Patient-derived brain AVM endothelial spheroids
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: Endothelial cultures from four resected AVMs show increased sprouting. Two samples with detected KRAS mutations responded more strongly to trametinib; combined BAY876 and trametinib reduced sprout length in all four samples. Small sample size, culture selection and lack of intact vascular anatomy preclude clinical-response prediction.
  cell_source: Primary endothelium from surgically resected human lesions
  publication: PMID:41708990
  evidence:
  - reference: PMID:41708990
    reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: combination treatment with BAY876 and trametinib reduced sprout length in all patient-derived EC samples
    explanation: Four patient-derived cultures; a culture response is not a patient treatment response.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Aberrant Endothelial Angiogenic Sprouting
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Patient-derived cells provide an assay of sprouting under metabolic and MEK inhibition.
    evidence:
    - reference: PMID:41708990
      reference_title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: human bAVM ECs showed enhanced angiogenic potential with increased average sprout length and number per spheroid
      explanation: Primary lesion-derived culture compared with purchased brain endothelial cells.
      quote_role: PRIMARY_RESULT
- name: Murine endothelial–astrocyte–macrophage barrier co-culture
  experimental_model_type: CO_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  description: Transwell cultures combine KRAS G12V mouse endothelial cells, astrocytes and macrophages. Macrophages amplify loss of barrier resistance and dextran leakage. Separate conditioned-medium experiments use immortalized BV2 microglia; mural cells and physiological flow are absent.
  cell_source: Cultured mouse endothelial cells, astrocytes and macrophages; separate BV2 conditioned-medium assays
  publication: PMID:41696778
  evidence:
  - reference: PMID:41696778
    reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: the presence of Mφ significantly enhanced FITC-dextran permeability in a 3D BBB coculture system
    explanation: Direct permeability result in the multicellular in-vitro model.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Increased Blood-Brain Barrier Permeability
    relationship: PERTURBS
    fidelity: MODERATE
    description: Tests cellular interactions that amplify barrier leakage.
    evidence:
    - reference: PMID:41696778
      reference_title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: minocycline treatment in the KRAS-G12V-EC on day 1 post-transfection markedly reduced the increased BBB permeability
      explanation: In-vitro intervention, not a clinical efficacy result.
      quote_role: PRIMARY_RESULT
- name: Patient-monocyte vascular smooth-muscle co-culture
  experimental_model_type: CO_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: GPNMB-positive monocytes isolated from ruptured AVMs are co-cultured with primary brain vascular smooth muscle cells. Increased apoptosis and responses to osteopontin/CD44/integrin perturbation support a candidate route to mural-cell injury, without resolving the timing of recruitment relative to rupture.
  cell_source: Patient-derived GPNMB-positive monocytes and primary brain vascular smooth muscle cells
  publication: PMID:35084939
  evidence:
  - reference: PMID:35084939
    reference_title: A single-cell atlas of the normal and malformed human brain vasculature.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Soluble OPN induced a 2.7-fold increase in VSMC apoptosis
    explanation: Osteopontin challenge in culture; not a direct patient hemorrhage readout.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Myeloid-associated Vascular Smooth Muscle Cell Apoptosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Models an inflammatory mechanism of smooth-muscle injury.
    evidence:
    - reference: PMID:35084939
      reference_title: A single-cell atlas of the normal and malformed human brain vasculature.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: Co-culture of isolated GPNMB+ monocytes from ruptured AVM patients with primary brain vascular smooth muscle cells (VSMCs) increased apoptotic cleaved caspase-3+ VSMCs
      explanation: Direct co-culture evidence.
      quote_role: PRIMARY_RESULT
references:
- reference: PMID:12690217
  title: "The New York Islands AVM Study: design, study progress, and initial results."
- reference: PMID:12702837
  title: "Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS)."
- reference: PMID:24268105
  title: "Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial."
- reference: PMID:24930128
  title: Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations.
- reference: PMID:25015366
  title: "Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors."
- reference: PMID:29298116
  title: Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.
- reference: PMID:31795902
  title: RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations.
- reference: PMID:31891627
  title: Somatic mutations in intracranial arteriovenous malformations.
- reference: PMID:31942635
  title: Radiosurgery for Unruptured Intervention-Naïve Pediatric Brain Arteriovenous Malformations.
- reference: PMID:32562682
  title: "Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial."
- reference: PMID:34189463
  title: Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.
- reference: PMID:34541474
  title: The role of mural cells in hemorrhage of brain arteriovenous malformation.
- reference: PMID:35084939
  title: A single-cell atlas of the normal and malformed human brain vasculature.
- reference: PMID:36857052
  title: Development and Validation of a Scoring System for Hemorrhage Risk in Brain Arteriovenous Malformations.
- reference: PMID:38700584
  title: Somatic Braf(V600E) mutation in the cerebral endothelium induces brain arteriovenous malformations.
- reference: PMID:39125532
  title: Diagnostic Accuracy of Non-Contrast-Enhanced Time-Resolved MR Angiography to Assess Angioarchitectural Classification Features of Brain Arteriovenous Malformations.
- reference: PMID:39576014
  title: CRISPR/CasRx suppresses KRAS-induced brain arteriovenous malformation developed in postnatal brain endothelial cells in mice.
- reference: PMID:40428814
  title: "The Dynamics of Seizures After Microsurgical Treatment of Brain AVMs in Patients with Symptomatic Epilepsy: A Single-Center Experience over 10 Years."
- reference: PMID:41231469
  title: Interventional Treatment vs Conservative Management of Unruptured Brain Arteriovenous Malformations.
- reference: PMID:41303829
  title: "Microsurgical Resection of Unruptured Brain Arteriovenous Malformations: A 12-Year Single-Center Experience."
- reference: PMID:41410028
  title: Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS(G12V)-Induced Brain Arteriovenous Malformations in Mice.
- reference: PMID:41418676
  title: Combined exome and RNA-seq analysis in patients with rare non-syndromic inherited brain arteriovenous malformation suggests a novel function for PTPN13 in arterial specification.
- reference: PMID:41696778
  title: Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.
- reference: PMID:41708990
  title: KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
- reference: PMID:41999461
  title: Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.
- reference: PMID:42140314
  title: "Stereotactic Radiosurgery for Brain Arteriovenous Malformations as Expected Curative Treatment: Outcomes of Patients Included in the Prospective Registry of a Pragmatic Trial."
- reference: clinicaltrials:NCT00389181
  title: A Randomized Trial of Unruptured Brain Arteriovenous Malformations
- reference: clinicaltrials:NCT02098252
  title: "Treatment of Brain AVMs (TOBAS) Study: A Randomized Controlled Trial and Registry"
- reference: clinicaltrials:NCT02314377
  title: Bevacizumab Therapy for Brain Arteriovenous Malformation
- reference: clinicaltrials:NCT04572568
  title: Registry of Multimodality Treatment for Brain Arteriovenous Malformation in Mainland China
- reference: clinicaltrials:NCT06098872
  title: Pilot Study on the Efficacy of MEK1/MEK2 Inhibitor Trametinib in Patients With Surgical Unruptured Arteriovenous Malformations
- reference: clinicaltrials:NCT06264531
  title: Evaluation of the Efficacy and Safety of Anti-angiogenic Therapy With Intravenous Bevacizumab in Patients With Symptomatic Cerebral Arteriovenous Malformations
- reference: clinicaltrials:NCT06494358
  title: Liquid Biopsies for the Detection of Somatic Mutations in Brain Arteriovenous Malformations
- reference: clinicaltrials:NCT06913725
  title: An Exploratory Study to Evaluate the Efficacy and Safety of FCN-159 in Patients With Brain Arteriovenous Malformations
- reference: clinicaltrials:NCT07314047
  title: "a Prospective, Multi-center, Open-label, Non-inferiority, Randomized, Controlled Registration Trial of the Liquid Embolic Agent for the Treatment of Brain Arteriovenous Malformation"
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4141996/?report=xml
  title: "Untreated brain arteriovenous malformation: Patient-level meta-analysis of hemorrhage predictors - PMC"
- reference: url:https://www.biorxiv.org/content/10.1101/2024.05.15.594335v1.full
  title: "MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations | bioRxiv"
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK531479/
  title: Intracranial Arteriovenous Malformations - StatPearls - NCBI Bookshelf
- reference: PMID:30285374
  title: Intracranial Arteriovenous Malformations.
  tags:
  - StatPearls
  findings: []

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