Retinal Arteriovenous Malformations Research Articles

Congenital Retinal Vascular Anomalies- 2 (Coloboma, Retinal Cavernous Hemangioma, Arterio-Venous Malformation, Retinal Capillary Hemangioblastoma, Von Hippel-Lindau Syndrome)

Retinal vascular anomalies are a heterogeneous group consisting of congenital and acquired lesions. The visual prognosis varies in a wide range from asymptomatic to advanced vision loss according to the location of the lesion. Diagnosis is made by fundus examination, fluorescein angiography, and optical coherence tomography. It may be associated with systemic diseases and may require detailed systemic examination. This review includes coloboma, retinal cavernous hemangioma, arterio-venous malformation, and retinal capillary hemangioblastoma. The important clinical and diagnostic features, systemic relationships, and current treatment strategies of these anomalies are emphasized in the light of current literature.

RWC Update: Vitrectomy Surgery in a Pre-Phthisical Eye; Update on the Surgical Management of Macular Holes: The Inverted ILM Flap Technique and How It Revolutionized Macular Hole Surgery; Retinal Arteriovenous Malformation.

RWC Update: Vitrectomy Surgery in a Pre-Phthisical Eye; Update on the Surgical Management of Macular Holes: The Inverted ILM Flap Technique and How It Revolutionized Macular Hole Surgery; Retinal Arteriovenous Malformation.

Retinal and intracranial arteriovenous malformations in Wyburn–Mason syndrome

A 12-year-old female presented with left exotropia for 1 year. The left eye fundus revealed dilation and tortuosity of the retinal arteries and veins consistent with group 3 retinal arteriovenous malformation (AVM; Fig. 1A). Fundus fluorescein angiography showed AVM filling without leakage but with a temporal nonperfusion area (Fig. 1B). Magnetic resonance angiogram of the head and cerebral angiography showed left orbital and suprasellar AVMs (Fig. 1C, D). The patient was diagnosed with Wyburn–Mason syndrome. No treatment was recommended for the intracranial AVMs because of the associated surgical risk to the perforators and the visual pathway.

Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas.

Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Education: Retinal racemose hemangioma arteriovenous malformation investigations, clinical course and management.

The authors report no financial or nonfinancial conflicts of interest that are directly or indirectly related to this manuscript.

CONGENITAL ARTERIO-VENOUS MALFORMATION OF OPTIC NERVE HEAD- A RARE CASE

Introduction: Retinal arterio-venous malformations (AVMs) are rare, congenital, high-flow congenital developmental vascular anomalies without intervening capillary bed also known as racemose angioma, They are unilateral, nonhereditary lesions located anywhere in retina and may involve optic nerve.
 Case report: A 55 year old male was found to have abnormal congenital arterio-venous malformation over optic nerve head in his left eye, as an incidental clinical finding. He had reported for his routine fundus examination due to diabetes. He had no other relevant systemic findings. Further follow up was advised to see the progression of the lesion and structural damage to optic nerve.
 Discussion: The typical clinical picture, fluorescein angiogram findings, normal MRI brain and orbits, and normal base line blood investigations all points in favour of a congenital arterio-venous malformation. 
 Conclusion: Arterio- venous malformations of Optic nerve head are very rare to find as compared to retinal malformations. This is the first such case report from India.

Ultra-Widefield Imaging of a Patient with Extensive Retinal Arteriovenous Malformation

Ultra-Widefield Imaging of a Patient with Extensive Retinal Arteriovenous Malformation

Paediatric Ophthalmology: Raised superior bilateral conjunctival lesions in 7-year-old child

Periocular steroids for macular edema associated with retinal arterio-venous malformation Romana Fazal Aravind Eye Hospital and Post graduate Institute of Ophthalmology, India Abstract Retinal racemose hemangiomas are vascular malformations comprising of direct arteriovenous communications in the retina which may sometimes present with defective vision. Exudation and neurosensory detachment are some of the complications which may be responsible for decreased visual acuity. We describe a case of a 38-year-old male presenting with unilateral group II retinal racemose hemangioma complicated with macular edema. Intravitreal bevacizumab was injected after which an increase in edema was noted at one month follow up. He was subsequently treated with posterior sub tenon injection of triamcinolone following which there was a prompt decrease in the intra retinal and subretinal fluid with simultaneous improvement in vision. The visual acuity was maintained and no recurrence was seen till six months after successful treatment. Biography: Romana Fazal has completed her MBBS from West Bengal university at the age of 24 years and DNB from Aravind Eye Hospital, Pondicherry. She is currently pursuing her fellowship in Vitreo retinal diseases at Aravind Eye Hospital, Pondicherry. She has 3 publications in reputed national and international journals and number of presentations in national level conferences. 29th International Conference on Insights in Ophthalmology; Webinars- June 17-18, 2020 Abstract Citation: Romana Fazal, Periocular steroids for macular edema associated with retinal arterio-venous malformation, 29th International Conference on Insights in Ophthalmology; Webinars- June 17-18, 2020 (https://ophthalmology.insightconferences.com/abstract/2020/periocular-steroids-for-macular-edema-associated-with-retinal-arterio-venous-malformation )

Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG, ALK1, or SMAD4. Since proteins from all 3 HHT genes are components of signal transduction of TGF-β (transforming growth factor β) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. We generated a novel mouse allele (ROSA26Alk1) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1- and Eng-inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng-iKO as well as Alk1-iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1-iKO models. These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.

Bilateral Wyburn–Mason Syndrome Presenting with Macular Edema

The Wyburn-Mason or Bonnet-Dechaume-Blanc syndrome is a sporadic illness which is a type of phakomatosis, usually present as unilateral arteriovenous malformations(AVM), for the first defined by Magnus in 1874 as retinal AVM later in 1932 another description gave by Yates and Payne; as an AVMs of the retina and cerebral vasculature, while in 1937 Bonnet, Dechaume and Blanc defined as AVM involving facial, retinal and brain blood vessels, then in 1943 all literature revised by Wyburn-Mason to put together to his case reports, therefore, the name of Bonnet-Dechaume-Blanc syndrome given in France, but in English articles entitled as Wyburn-Mason syndrome. At that time, due to a deficiency in diagnostic imaging techniques, all the diagnosis were performed by clinical findings, operation, or autopsy. Usually, it is a unilateral disorder comprising of three distinct components: orbit, brain (ipsilateral to the retina) and face, in the face; the sensory region of the trigeminal nerve distribution involved, that takes the shape of naevi which might be wholly formed and illness, is complete, or the naevi might be faint or absent, the latter regarded as an incomplete disease but rarely a bilateral involvement encountered with an asymmetrical grade of malformation. The pathology starts in the early embryonic period, and if vascular dysgenesis encountered can lead to a wide range of neurocutaneous vascular defects in the cerebrum or ocular or both. When the disorder reaches the last stage, the AVM can compress the optic nerve causing impaired perfusion, ischemia eventually optic atrophy. Another explanation for visual loss is glaucoma as a result of elevated vascular pressure, neovascularization resulting from ischemia, which might lead to vitreous hemorrhage(5). Archer et al. staged the disease into three groups: Group 1 (AVM cannot be detected clinically). Group 2 (Clinically seen as edema and hemorrhage due to direct AVM, i.e., no capillary network between them). Group 3 (Clinically, it is impossible to distinguish arteries from veins due to severely dilated blood vessels all over retina). We present a 41-year-old male presented with a gradual decrease in his visual acuity in both eyes.

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models.

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.

Wyburn Mason Syndrome: Novel presentation with Bilateral Retinal Arteriovenous malformation

A five-year-old girl with poor vision on examination and left eye esotropia was found to have bilateral intraorbital and unilateral intracranial arteriovenous malformation (AVM) and unilateral optic neuropathy. Magnetic Resonance Imaging with contrast revealed a small AVM involving the left ophthalmic artery and a large AVM involving the junction of anterior cerebral artery and anterior communicating artery. The simultaneous presence of retinal and intracranial AVM constitutes the Wyburn- Mason Syndrome (Retinoencephaloangiomatosis). Wyburn mason syndrome is associated with unilateral retinal racemose hemangioma with few cases with bilateral symmetrical involvement been reported in the literature. The present case has asymmetric bilateral retinal AVM and optic neuropathy, rare presentation of rare disease.

Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model.

Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFβ) pathway members, including the central transcriptional mediator of the TGFβ pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFβ downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown. To identify potential biological targets of the TGFβ pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFβ downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.

A Conjunctival Vascular Malformation as a Rare Presenting Sign of Wyburn–Mason Syndrome

AbstractWyburn–Mason syndrome is a rare condition that is characterized by ipsilateral arteriovenous malformations affecting the eye, brain, and facial skin. A conjunctival vascular dilation can be a rare ocular presenting sign. We report a 6-year-old boy who attended the hospital because of the sudden appearance of a conjunctival vascular lesion in his right eye. Inspection of his facial skin showed a subtle discoloration along the right trigeminal nerve and a vascular structure of the conjunctiva. Fundoscopy showed dilated and tortuous retinal vessels. Brain magnetic resonance imaging (MRI) revealed a large arteriovenous malformation involving the thalamus and perimesencephalic area. Ophthalmologic and neuroradiologic findings were consistent with the diagnosis of Wyburn–Mason syndrome. The sudden emergence of a vascular malformation in the conjunctiva should alert the clinician to perform an ophthalmoscopy, and in our patient, this finding was the clue to diagnosis of Wyburn–Mason syndrome. Because of the association between retinal and intracranial arteriovenous malformations, an MRI of the brain is strongly recommended in all patients with ocular arteriovenous malformations.

Hemiretinal Vein Occlusion Secondary to Arteriovenous Malformation

Purpose: To describe an hemiretinal vein obstruction secondary to a congenital arteriovenous malformation. Methods: Case report of a young patient with retinal arteriovenous malformation and hemiretinal vein obstruction. Results: A 9-year-old girl had a grade II retinal arteriovenous communication in her left eye. She presented with sudden loss of vision in her left eye, and a diagnosis of a hemiretinal vein obstruction secondary to a congenital arteriovenous malformation complicated with macular edema, capillary nonperfusion and neovascularization of the retina was made. She received intravitreal bevacizumab and multiple sessions of laser photocoagulation. Magnetic resonance imaging of the brain was normal and disclosed no signs of Wyburn-Mason syndrome. During follow up the patient remained with stable visual acuity, involuted disease, and persistent macular edema. Conclusions: Awareness of retinal vascular obstruction associated with arteriovenous communication may aid early recognition, and prompt treatment of potential complications, such as retinal and iris neovascularization.

RETINAL ARTERIOVENOUS MALFORMATION

To describe a case of an isolated Group 3 retinal arteriovenous malformation (AVM). Observational case report. A 15-year-old girl with no significant medical history presented with no light perception vision in her right eye and gradually decreasing vision in her left eye over several years. She was found to have a large AVM in the posterior pole of the right eye with associated perivascular sheathing in the periphery. Her left eye seemed totally unremarkable. Neuroimaging revealed no intracranial or intraorbital abnormalities. A diagnosis of isolated Group 3 retinal AVM was made. Retinal AVMs are congenital, nonhereditary, and sporadic vascular anomalies that develop in the posterior pole. A number of patients with this finding can have coexisting AVMs in the brain, mandible, skin, or orbit, which comprises the Wyburn-Mason syndrome. Because of these systemic associations, neuroimaging should always be considered when a retinal AVM is seen. Severe vision loss can occur from these AVMs secondary to a number of ocular complications, including central retinal vein occlusions.

A Case of Wyburn-Mason Syndrome with Facial Nevus Flammeus and the Associated Optical Coherence Tomography Findings

Purpose: To describe a case of Wyburn-Mason Syndrome, which is a rare phakomatosis, and its associated optical coherence tomography findings. Case summary: A 5-year-old boy was referred to our clinic for decreased vision in his right eye. He had nevus flammeus on his right forehead, upper eyelid, and cheek. His best corrected visual acuity was hand motion in the right eye, in which a relative afferent pupillary defect was noted. Fundus examination of the right eye showed marked dilation and tortuosity of retinal vessels, which could not be discriminated between arteries and veins on the posterior pole. Optical coherence tomography showed multiple large intraretinal vessels without involvement of the internal limiting membrane. Cerebral angiography revealed arteriovenous malformations (AVMs) and feeder vessels from the internal carotid artery to the ophthalmic artery, extending to the ethmoidal artery in the nasal cavity. Conclusions: Wyburn-Mason syndrome is a rare phakomatoses and shows unique retinal AVM. Misdiagnosis or undertreatment of Wyburn-Mason syndrome can lead to serious complications. Patients with facial nevus flammeus should undergo thorough ocular examinations to rule out this disorder. Optical coherence tomography is a useful method for understanding structural features of retinal vascular malformations in Wyburn-Mason syndrome. J Korean Ophthalmol Soc 2016;57(8):1333-1338

English

Hereditary hemorrhagic telangeiectasia (HHT) is an autosomal dominant genetic disorder that leads to vascular malformations. It was first recognized in the 19th century as a familial disorder with abnormal vascular structures causing bleeding from the nose and gastrointestinal tract. HHT is characterized by telangiectatic lesions of the nose, lips, lungs, brain, and spinal cord. The reported incidence in Europe and Japan is between 1:5000 and 1:8000; but is widely variable in other regions. It is seen more frequently in whites. Ocular involvement has been reported in patients with HHT. Although conjunctival telangiectasia is the most common manifestation, rarely intraocular vascular lesions such as retinal telangiectasia and arteriovenous malformations in the retina, are seen. We describe a patient with HHT who had an abnormal unilateral retinal vascular abnormality along with tortuous conjunctival vasculature in the other eye, which has not been reported till date.

Mature vessel occlusion after anti-VEGF treatment in a retinal arteriovenous malformation

BackgroundTo report engorged vessel occlusion after repeated intravitreal injections of bevacizumab to treat the macular oedema in a case of arteriovenous malformation.Case presentationA 37-year-old woman presented with a sudden, painless loss of vision in her left eye. Her visual acuity was 20/200 in the left eye, and 20/20 in the right eye. Ophthalmoscopic examination revealed an abnormal tangle of vessels and enlarged draining veins. A fluorescence angiogram revealed fluorescence leakage at a turn near the fovea. Horizontally oriented optical coherence tomography revealed an increased macular thickness and an accumulation of intraretinal fluid, indicating macular oedema. After three intravitreal injections of 1.25 mg bevacizumab, her vision improved to 20/20. Ophthalmoscopic examination revealed a decreased calibre of the previously engorged draining veins and ghost vessels. Repeated horizontally oriented optical coherence tomography revealed a decreased macular thickness and the absence of an intraretinal cyst. At the 2-year follow-up visit, the vision of the patient was stable.ConclusionThis finding implies that certain middle-size vessels can become occluded during anti- vascular endothelium growth factor (anti-VEGF) therapy, which could induce fatal complications if it occurred in the heart or brain. Clinicians should be cautious of the potential thrombotic effects on systemic blood vessels when administering anti-VEGF treatment.