Ocular Manifestations of Hereditary Hemorrhagic Telangiectasia
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.
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.
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. Genetic testing can be used to make a formal diagnosis and identify the mutated gene.
Pulmonary AVMs may present with a right-to-left cardiovascular shunt, which may cause brain abscess, stroke and peripheral emboli. Shunting itself may cause hemoptysis, pulmonary hypertension, and signs of hypoxemia (clubbing, peripheral cyanosis, polycythemia).
Liver AVMs are typically asymptomatic, but cases of cirrhosis, portal hypertension, and encephalopathy have been documented. 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. Gastrointestinal bleeding may occur due to intestine and stomach involvement8. 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.
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. Neovascularization of the retina, retinal vascular aneurysm, and parafoveal telangiectasias may be visualized on dilated fundoscopy. When present, retinal telangiectasias may mimic hypertensive retinopathy. True retinal AVMs may present as engorged vessels on angiography. Close examination is important in identifying and monitoring these vessels, as retinal hemorrhage may occur. Visualization of retinal vessels with fluorescein angiography for identification of dilated vessels and telangiectasias may be beneficial to monitor progression of retinal involvement.
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. If orbital involvement is present, management may include embolization of the vascular structure, which induces regression and reduces symptoms. 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.
Clinical diagnosis of HHT is based on the Curacao criteria: recurrent epistaxis, systemic telangiectasias, skin/mucosal telangiectasias, and a first-degree relative with HHT. 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. 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.
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:
- 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.
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.
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