Ocular Manifestations of Hereditary Hemorrhagic Telangiectasia

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Disease

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber Disease is an autosomal-dominant inherited disease characterized by extensive vascular malformations manifesting throughout multiple organ systems. Arteriovenous malformations (AVM) commonly manifest as connections between the arteriole and venule system, bypassing the capillaries that normally connect the two. Telangiectasias are physiologically similar, but present only on the skin and mucosal tissues, whereas AVM are confined to the internal organs.

Pathogenesis

HHT is inherited in an autosomal-dominant pattern, and therefore often presents in many members of a family. However, it is not to be excluded in families without documented history, as the variable presentation often makes the initial diagnosis elusive. Mutations in the endoglin and activin A receptor kinase type 1 are typical in most cases of HHT.[1]

Affected patients have been found to have increased serum levels of angiogenic factors (vascular endothelial growth factor, transforming growth-factor beta).[2][3]

Diagnosis is typically made using the Curacao’s criteria: recurrent epistaxis, systemic telangiectasias, skin/mucosal telangiectasias, and a first-degree relative with HHT4. Only three of these four criteria are required to make a clinical diagnosis.[4] Genetic testing can be used to make a formal diagnosis and identify the mutated gene.

Systemic Presentation

Epistaxis is the most common symptom at presentation for patients with HHT; up to 95% of patients will develop recurrent epistaxis in their lives.[5][6]

Pulmonary AVMs may present with a right-to-left cardiovascular shunt, which may cause brain abscess, stroke and peripheral emboli.[7] Shunting itself may cause hemoptysis, pulmonary hypertension, and signs of hypoxemia (clubbing, peripheral cyanosis, polycythemia).[8][9][10][11]

Liver AVMs are typically asymptomatic, but cases of cirrhosis, portal hypertension, and encephalopathy have been documented.[8][12][13] High-output cardiac failure presents as a consequence of the chronic shunting of blood back to the heart, causing a decrease in blood pressure. Reflexive sympathetic response triggers tachycardia and increased cardiac output, leading to heart failure over time.[8] Gastrointestinal bleeding may occur due to intestine and stomach involvement8.[8][9][14] Central nervous system involvement is common, and complications of cerebral AVMs include aneurysm, transient ischemic attack, embolic and hemorrhagic stroke, and epilepsy. Spinal cord involvement is much rarer, but can cause hemorrhage and paralysis.[8][9][15]

Ophthalmic Presentation

Telangiectasias of the eye are common findings in patients with HHT. Conjunctival telangiectasias are frequently observed as the main ophthalmic presentation in up to half of patients, while retinal telangiectasias observed less frequently in approximately 2-10% of patients.[16][17] Neovascularization of the retina, retinal vascular aneurysm, and parafoveal telangiectasias may be visualized on dilated fundoscopy.[18] When present, retinal telangiectasias may mimic hypertensive retinopathy. True retinal AVMs may present as engorged vessels on angiography.[19] Close examination is important in identifying and monitoring these vessels, as retinal hemorrhage may occur.[17][20] Visualization of retinal vessels with fluorescein angiography for identification of dilated vessels and telangiectasias may be beneficial to monitor progression of retinal involvement.[17][21]

Although not reported in association with HHT, patients may present with orbital AVMs. These patients are at increased risk of proptosis, chemosis, and double vision.[21] If orbital involvement is present, management may include embolization of the vascular structure, which induces regression and reduces symptoms.[4] Patients are also at an increased risk of thrombosis of the venous structures of the orbit. Thrombosis of both the superior ophthalmic vein and orbital AVMs with subsequent proptosis has been documented, and can be managed with anticoagulation.[22][23]

Diagnosis

Clinical diagnosis of HHT is based on the Curacao criteria: recurrent epistaxis, systemic telangiectasias, skin/mucosal telangiectasias, and a first-degree relative with HHT.[8] Probable HHT is diagnosed in those meeting two of the four criteria. Definitive HHT is diagnosed in those meeting three or four of the criteria.[8] Molecular diagnosis can be made by identification of a known mutated gene. This also differentiates the disease into a specific type of HHT, depending on the gene that is identified. It should be noted that the type of HHT and its corresponding mutation does not change the presentation or management of the disease. Family members of those diagnosed with HHT may undergo genetic testing to determine if they are affected.

Management

Overall management of the disease is symptomatic in nature, accompanied with periodic screening for AVMs. At the time of diagnosis, even asymptomatic patients should receive screening as described below:[24][25][26][27][28][29][30]

  • MRI/MRA screening of the brain for AVMs concerning for stroke or aneurysm
  • Transthoracic echocardiogram
  • Colonoscopy and endoscopy
  • Doppler ultrasound of the liver
  • ENT evaluation for evaluation of epistaxis
  • Dermatologic evaluation

Management is dependent on the clinical presentation. Involvement of a multidisciplinary team of physicians is crucial in determining what approach is appropriate for each patient. Upon diagnosis, referrals to specialists should be considered to allow for appropriate screening, treatment and anticipatory guidance. As for systemic treatment options, estrogen and progestin analogues may be considered for potential bleeding complications associated with HHT. More recently, anti-VEGF antibodies (i.e. bevacizumab), systemic beta-blockers and thalidomide have been used to treat this patient population, especially in patients with refractory or progressive nature of disease.[24][25][26][27][28][29][30]

As an ophthalmologist presented with a HHT patient, it is crucial to obtain a thorough history regarding any ophthalmic concerns. Close follow-up and screening in these patients should be encouraged, as changes in vision and symptomology of the eye and orbit can become vision-threatening if hemorrhage should occur. While the ocular manifestations of HHT vary widely, frequent dilated examinations can catch concerning vascular changes may guide the ophthalmologist in how to best guide treatment and testing. Intraocular lesions are rare and often stable; however, any retinal neovascularization can be treated with anti-VEGF agents, pan retinal photocoagulation, and in one case, photo dynamic therapy.[31]

References

  1. Bossler AD, Richards J, George C, Godmilow L, Ganguly A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): Correlation of genotype with phenotype. Human Mutation. 2006;27(7):667-675. doi:10.1002/humu.20342.
  2. Sadick H, Riedel F, Naim R, Goessler U, Hörmann K, Hafner M, Lux A. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression. Haematologica. 2005 Jun;90(6):818-28. PMID: 15951295.
  3. Letarte M, McDonald ML, Li C, et al. Reduced endothelial secretion and plasma levels of transforming growth factor-β1 in patients with hereditary hemorrhagic telangiectasia type 1. Cardiovascular Research. 2005;68(1):155-164. doi:10.1016/j.cardiores.2005.04.028.
  4. 4.0 4.1 Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for Hereditary Hemorrhagic Telangiectasia (Rendu- Osler-Weber Syndrome). American Journal of Medical Genetics. 2000;91(1):66-67. doi:10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P.
  5. Aassar OS, Friedman CM. The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 1991;101(9):977-980. doi:10.1288/00005537-199109000-00008.
  6. Sautter NB, Smith TL. Hereditary hemorrhagic telangiectasia-related epistaxis: Innovations in understanding and management. International Forum of Allergy and Rhinology. 2012;2(5):422-431. doi:10.1002/alr.21046.
  7. Press OW, Ramsey PG. Central nervous system infections associated with hereditary hemorrhagic telangiectasia. The American Journal of Medicine. 1984;77(1):86-92. doi:10.1016/0002-9343(84)90441-8.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: Diagnosis and management from the hematologist’s perspective. Haematologica. 2018;103(9):1433-1443. doi:10.3324/haematol.2018.193003.
  9. 9.0 9.1 9.2 Garg N, Khunger M, Gupta A, Kumar N. Optimal management of hereditary hemorrhagic telangiectasia. Journal of Blood Medicine. 2014;5:191-206. doi:10.2147/JBM.S45295.
  10. Brydon HL, Akinwunmi J, Selway R, Ul-Haq I. Brain abscesses associated with pulmonary arteriovenous malformations. British Journal of Neurosurgery. 1999;13(3):265-269. doi:10.1080/02688699943664.
  11. Circo S, Gossage JR. Pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Current Opinion in Pulmonary Medicine. 2014;20(5):421-428. doi:10.1097/MCP.0000000000000076.
  12. Harwin J, Sugi MD, Hetts SW, Conrad MB, Ohliger MA. The Role of Liver Imaging in Hereditary Hemorrhagic Telangiectasia. Journal of Clinical Medicine. 2020;9(11):3750. doi:10.3390/jcm9113750.
  13. Memeo M, Stabile Ianora AA, Scardapane A, Buonamico P, Sabbà C, Angelelli G. Hepatic involvement in hereditary hemorrhagic telangiectasia: CT findings. Abdominal Imaging. 2004;29(2):211-220. doi:10.1007/s00261-003-0101-3.
  14. Tortora A, Riccioni ME, Gaetani E, Ojetti V, Holleran G, Gasbarrini A. Rendu-Osler-Weber disease: A gastroenterologist’s perspective. Orphanet Journal of Rare Diseases. 2019;14(1). doi:10.1186/s13023-019-1107-4.
  15. Brinjikji W, Iyer VN, Sorenson T, Lanzino G. Cerebrovascular Manifestations of Hereditary Hemorrhagic Telangiectasia. Stroke. 2015;46(11):3329-3337. doi:10.1161/STROKEAHA.115.010984.
  16. Gomez-Acebo I, Prado SR, de La Mora Á, et al. Ocular lesions in hereditary hemorrhagic telangiectasia: Genetics and clinical characteristics. Orphanet Journal of Rare Diseases. 2020;15(1). doi:10.1186/s13023-020-01433-5.
  17. 17.0 17.1 17.2 Sindhar S, O’Bryhim BE, Licata J, Piccirillo JF, Apte RS. Identification of Retinal Vascular Lesions Using Ultra-Widefield Angiography in Hereditary Hemorrhagic Telangiectasia Patients. Ophthalmology Retina. 2019;3(6):510-515. doi:10.1016/j.oret.2019.02.004.
  18. Ugurlu N, Emre S, Yülek F, Akcay EK, Sengun A. Hereditary hemorrhagic telangiectasia with multiple fusiform retinal aneurysms. Journal of Ocular Biology, Diseases, and Informatics. 2012;5(2):48-50. doi:10.1007/s12177-013-9100-y.
  19. Brant AM, Schachat AP, White RI. Ocular manifestations in hereditary hemorrhagic telangiectasia (rendu-osler-weber disease). American Journal of Ophthalmology. 1989;107(6):642-646. doi:10.1016/0002-9394(89)90261-4.
  20. Peery WH. Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). The American Journal of Medicine. 1987;82(5):989-997. doi:10.1016/0002-9343(87)90162-8.
  21. 21.0 21.1 Tsutsumi S, Oishi H, Nonaka S, et al. Orbital Arteriovenous Fistula Coexistent with an Arteriovenous Hemangioma: A Rare Occurrence and Review of Literature. World Neurosurgery. 2019;122:287-292. doi:10.1016/j.wneu.2018.11.003.
  22. Lim LH, Scawn RL, Whipple KM, et al. Spontaneous superior ophthalmic vein thrombosis: A rare entity with potentially devastating consequences. Eye (Basingstoke). 2014;28(3):348-351. doi:10.1038/eye.2013.273.
  23. van Went C, Ozanne A, Saliou G, et al. Spontaneous thrombosis of an orbital arteriovenous malformation revealing hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease): A case report. Interventional Neuroradiology. 2011;17(4):466-471. doi:10.1177/159101991101700411.
  24. 24.0 24.1 Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nature Medicine. 2010;16(4):420-428. doi:10.1038/nm.2131.
  25. 25.0 25.1 Peng HL, Yi YF, Zhou SK, Xie SS, Zhang G sen. Thalidomide effects in patients with hereditary hemorrhagic telangiectasia during therapeutic treatment and in Fli-EGFP transgenic zebrafish model. Chinese Medical Journal. 2015;128(22):3050-3054. doi:10.4103/0366-6999.169068.
  26. 26.0 26.1 Dupuis-Girod S, Ginon I, Saurin JC, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA - Journal of the American Medical Association. 2012;307(9):948-955. doi:10.1001/jama.2012.250.
  27. 27.0 27.1 Iyer VN, Apala DR, Pannu BS, et al. Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia–Related Epistaxis and Gastrointestinal Bleeding. Mayo Clinic Proceedings. 2018;93(2):155-166. doi:10.1016/j.mayocp.2017.11.013.
  28. 28.0 28.1 Robert F, Desroches-Castan A, Bailly S, Dupuis-Girod S, Feige JJ. Future treatments for hereditary hemorrhagic telangiectasia. Orphanet Journal of Rare Diseases. 2020;15(1). doi:10.1186/s13023-019-1281-4.
  29. 29.0 29.1 Albinana V, Cuesta AM, de Rojas-P I, et al. Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding. Journal of Clinical Medicine. 2020;9(6):1766. doi:10.3390/jcm9061766.
  30. 30.0 30.1 Jameson JJ, Cave DR. Hormonal and Antihormonal Therapy for Epistaxis in Hereditary Hemorrhagic Telangiectasia. Laryngoscope. 2004;114(4):705-709. doi:10.1097/00005537-200404000-00021.
  31. Mennel S, Hoerle S, Meyer CH. Photodynamic therapy in symptomatic parafoveal telangiectasia secondary to Osler-Rendu-Weber disease. Acta Ophthalmol Scand. 2006 Apr;84(2):273-5. doi: 10.1111/j.1600-0420.2005.00519.x. PMID: 16637855.