Takayasu’s arteritis: a unique ophthalmic presentation with CRAO and BRVO

Abstract

A unique case of sequential occurrence of central retinal artery occlusion (CRAO) and superotemporal branch retinal vein occlusion (ST-BRVO) in a patient of Takayasu’s arteritis is described. An 18-year-old man was diagnosed as left eye CRAO on his initial presentation and was subjected to a complete cardiovascular evaluation revealing findings diagnostic of Takayasu’s arteritis. Patient was however lost to follow-up and presented 16 months later with ST-BRVO in the right eye. Multidisciplinary intervention and an appropriate ocular intervention led to complete recovery of vision in the right eye that was maintained until his last ophthalmic evaluation (2.5 years after the initial presentation). Though uncommon, small retinal vessel involvement can occur in Takayasu’s arteritis as the inaugural feature. Hence, CRAO or branch retinal vein occlusion in a young patient, especially a male, mandates a thorough systemic evaluation and a high index of suspicion of Takayasu’s arteritis to prevent vision threatening complications.

Background

Takayasu’s arteritis (TA) is a rare granulomatous large vessel vasculitis with a poorly understood pathogenesis and variable course leading to multiple organ damage because of tissue hypoperfusion and secondary chronic ischaemia.¹ The disease has a worldwide prevalence, predominantly affects women (90%) and typically presents during the second to third decade of life.^2–4 However, most cases are seen in Asia and Africa.

Diagnosis of TA is a challenge because of its non-specific presentation, multisystem involvement and lack of diagnostic serological tests. Ocular manifestations are described in 8.1%–68% of patients with TA,^{1 2 5} especially in the late course of the disease. These are usually due to carotid artery involvement leading to ischaemic lesions of the retina, choroid and anterior segment. These include retinal microaneurysms, microhaemorrhages, proliferative retinopathy, cataract, neovascular glaucoma and vitreous haemorrhage.^6–8 Other manifestations like anterior ischaemic optic neuropathy, central retinal artery occlusion (CRAO), branch retinal vein occlusion (BRVO), ocular ischaemic syndrome, uveitis and scleritis have been reported infrequently.^6–12

We report an unusual case of TA presenting with rare ophthalmic features of arterial occlusion in one eye and venous involvement in the other eye (left eye CRAO and right eye superotemporal BRVO (ST-BRVO)).

Case presentation

An 18-year-old man presented to us with chief complaints of sudden painless diminution of vision in the left eye for 2 days associated with headache. His medical history was unremarkable. There was no history of significant fever, syncope, breathlessness, neck pain or any claudicant pain. There was no family history of any cardiovascular disease or any autoimmune vasculitis. On ocular examination, his BCVA was 6/6 in the right eye and no light perception in the left eye with left relative afferent pupillary defect. Intraocular pressure was normal in both eyes and anterior segment appeared unremarkable.

Dilated fundus examination of the right eye revealed marked vascular tortuosity and copper wiring of the arterioles. Left eye had retinal whitening, boxcarring of the retinal arterioles, with a few flame-shaped haemorrhages and a cherry-red spot at the macula (figure 1). With the diagnosis of late presentation of left CRAO, patient was given oral acetazolamide (250 mg thrice daily) and referred to a cardiologist for a detailed systemic review.

Figure 1.

Fundus photographs (both eyes) on 23 December 2010. Right eye: normal optic disc, marked vascular tortuosity and copper wiring of arterioles. Left eye: cherry-red spot at macula, retinal whitening and boxcarring of retinal arterioles with a few flame-shaped haemorrhages.

Systemic examination revealed a blood pressure of 170/100 mm Hg, weakened left superior temporal and carotid pulses and weak bilateral brachial pulses, with absence of distal pulses in the upper limb. Among the lower limb pulses, femoral of the right side was weak. Laboratory results revealed hypertriglyceridaemia with significant rise in serum homocysteine levels (40.59 µmol/L). Anticardiolipin antibodies, lupus anticoagulant, pANCA, cANCA and anti-GBM antibodies were negative. The Erythrocyte Sedimentation Rate (ESR) was 40 mm/hour. CRP was 1.8 mg/L. The patient was started on oral antihypertensive (amlodipine 10 mg) and evaluated further. On imaging, carotid Doppler study showed a thrombus almost completely involving proximal and middle thirds of the left-sided common carotid artery, with marked reduction of flow distal to the occlusion. Magnetic resonance angiography (MRA; figure 2) revealed occlusion of the right vertebral artery, the left common carotid artery, the left internal carotid artery (with collateral filling) and also of the subclavian arteries bilaterally. Circle of Willis and bilateral main ophthalmic arteries appeared normal. The right external iliac artery was also found to be occluded at its origin, with distal filling by collaterals and normal bilateral lower limb arterial signals. Patient was started on anticoagulants (heparin 1.5 mg subcutaneously), antiplatelet drugs (clopidogrel 75 mg and aspirin 75 mg), lipid-lowering agents (atorvastatin 10 mg and fenofibrate 160 mg) and a second antihypertensive drug atenolol (50 mg) was added for his hypertension.

Figure 2.

MR angiogram. (A) Head and neck, revealing blockade in left common carotid and bilateral subclavian arteries; (B) pelvis and lower limbs, showing blockade in right external iliac artery at its origin, distal filling by collaterals and normal bilateral lower limb arterial signals.

Based on the clinical presentation, physical findings and angiographic features, the patient was diagnosed as TA according to American College of Rheumatology criteria. He was asked to consult a rheumatologist for anti-inflammatory therapy and to review with us in 3 weeks. However, he was lost to follow-up. He returned 16 months later with distortion of vision in the right eye for the past 3 days. On examination, his best corrected visual acuity (BCVA) in the right eye had reduced from 6/6 to 6/24. Fundus examination of the right eye revealed multiple flame-shaped and dot haemorrhages in the superotemporal quadrant, along with cotton wool spots and a macular star suggestive of right eye ST-BRVO. There were associated features of vitritis and peripheral vasculitis. Left eye showed optic atrophy with sclerosis of vessels (figure 3).

Figure 3.

Fundus photographs (both eyes). Right eye (pre-anti-VEGF injection, 5 May 2012): flame-shaped haemorrhages and soft exudates in superotemporal quadrant (superotemporal branch retinal vein occlusion) with macular oedema. Left eye: central retinal artery occlusion with optic atrophy. Right eye (2 weeks post-anti-VEGF injection, 23 May 2012): resolving macular oedema with macular star configuration. Left eye: total optic atrophy.

Investigations

Optical coherence tomography (OCT) revealed neurosensory detachment with macular oedema (464 µm) in the right eye and retinal atrophy (113 µm) in the left eye (figure 4) corroborating the diagnosis of right eye superotemporal BRVO with macular oedema and left eye burnt-out CRAO.

Figure 4.

OCT (both eyes) on 5 May 2012. Right eye: cystoid macular oedema (central macular thickness 464 µm) due to branch retinal vein occlusion and neurosensory detachment. Left eye: gross macular thinning (central macular thickness 113 µm) secondary to chronic central retinal artery occlusion. OD, ocular dextra; OS, ocular sinistra.

Cardiac evaluation at this time revealed high blood pressure (162/100) with ECG showing left ventricular hypertrophy (LVH) with strain. Echocardiography showed severe concentric LVH with a normal left ventricular ejection fraction. Conventional angiography of the cardiac, carotid and peripheral arteries revealed complete occlusion of the left common carotid artery and bilateral subclavian arteries. There was 99% stenosis in both renal arteries along with complete stenosis of the right iliac artery.

Differential diagnosis

Differential diagnosis for our 18-year-old patient were other causes of large vessel vasculitis such as inflammatory aortitis due to tuberculosis and syphilis, spondyloarthropathies and Behcet’s disease, which were all excluded based on the systemic angiographic features and lack of specific features of these diseases. Fibromuscular dysplasia was a close differential as well, as it is characterised by resistant hypertension and large vessel vasculitis involving even the retinal vessels. However, angiography did not reveal the classic ‘beads-on-string’ appearance as seen in fibromuscular dysplasia.

Treatment

To induce remission of active vasculitis in our patient of TA, he was started on immunosuppressants in the form of oral prednisolone (50 mg) daily with weekly methotrexate (15 mg). Oral antihypertensives were continued for his renovascular hypertension (amlodipine 10 mg+atenolol 50 mg). Lipid-lowering drugs (rosuvastatin 10 mg and fenofibrate 67 mg), anticoagulants and antiplatelet drugs (clopidogrel 75 mg and aspirin 75 mg) were given to prevent further thrombotic complications of the disease. Cilostazol (50 mg) was added to prevent intermittent claudication of the lower limbs. Folic acid (10 mg) with multivitamins (including high doses of pyridoxine and methylcobalamin) were given to reduce plasma homocysteine levels and prevent further ischaemic events. On review examinations, because of uncontrolled hypertension on medications (250/130 mm Hg), the patient also underwent bilateral renal angioplasty with stenting.

Patient was given intravitreal injection of anti-VEGF (ranibizumab 0.5 mg) in the right eye for superotemporal BRVO with macular oedema, while in the left eye, no active ocular intervention was done since the acute phase of CRAO had passed, and there was no evidence of neovascularisation.

Outcome and follow-up

Ophthalmic review at 3 weeks after the intravitreal ranibizumab in the right eye showed decrease in macular oedema with improvement of visual acuity to 6/6 (figure 5). Sequential OCTs of the same eye done over the next 3 months showed a complete resolution of neurosensory detachment and macular oedema (figure 5). Also, there was maintenance of the visual acuity at 6/6 in his right eye. Both eyes also did not show any evidence of neovascularisation until his last follow-up (2.5 years after the initial presentation). His systemic hypertension was also well controlled following renal artery stenting, and there were no further vascular events until his last follow-up visit.

Figure 5.

Sequential OCT images (right eye on 5 May 2012, 23 May 2012, 6 June 2012 and 7 June 2012). Showing resolution of cystoid macular oedema and neurosensory detachment with restoration of normal architecture in right eye. OCT, optical coherence tomography.

Discussion

Takayasu’s disease is an uncommon inflammatory arteritis predominantly affecting the aorta, its branches and pulmonary and coronary arteries. Major systemic features include reduced or absent pulses, hypertension, vascular bruits, congestive cardiac failure and transient ischaemic attacks.

Retinal manifestations are the most frequently reported ocular lesions in TA (up to 35% patients).² There are two classical patterns of retinal involvement in TA: Takayasu’s retinopathy, a specific manifestation secondary to carotid involvement with hypoperfusion of the eye, and hypertensive retinopathy, secondary to chronic systemic hypertension occurring as a sequelae to renal artery stenosis. It is characterised by dilatation of small vessels, capillary microaneurysms, arteriovenous anastomosis and other ocular complications.⁷ Hypertensive retinopathy, like Takayasu’s retinopathy, occurs in chronic state, when systemic damage has already occurred.⁸

Besides these two patterns of retinal involvement in TA, small retinal vessel occlusion can occur and may be the inaugural presentation of the disease. The observation that the granulomatous inflammatory pan-arteritis seen in TA affects regions of the arterial walls nourished by the vasa vasorum, which have a similar diameter to small vessels like those in the cutaneous, myocardial and retinal vessel systems, supports the involvement of the microcirculation in this large vessel vasculitis.^{10 13} Although systemic small vessel involvement has been described as presenting feature in TA,^{10 13} however, its prevalence as regards retinal vessel involvement is unknown and seems to be very rare.¹⁰ Conrath et al ¹⁴ were the first to report a case of unilateral BRVO in a patient of TA in 2004 as an atypical ophthalmic presentation of TA. They reported that shrinkage of the venous branch at the level of arteriovenous crossing could play a role in the emergence of occlusion of the retinal vein. Occlusion of retinal venous branch is favoured by raised blood pressure, arteriosclerosis and diabetes, with fibrosis of adventitious tissue around the crossing. Noel et al ¹⁰ in their literature review have described seven cases of BRAO and two cases of BRVO indicative of small vessel retinal involvement in TA. However, no case has been reported to date with both arterial and venous involvement occurring in eyes of the same patient. The pathogenesis of BRVO in our case can be explained on the basis of the hardened retinal arteriole impinging on the branch vein as a rare process associated with TA where there is primary involvement of small vessels including both retinal arteries and veins. This primary occlusion may be further accentuated because of retinal arteriolar sclerosis and arteriovenous nipping as part of hypertensive retinopathy changes seen in our patient due to renovascular hypertension. Also, our patient had increased plasma homocysteine levels. It has been reported by De Souza et al ¹⁵ that plasma homocysteine levels are higher in patients with TA in comparison with normal subjects. This increase is multifactorial and is associated with an increased risk of arterial ischaemic events that may be independent of the disease entity. It has also been mentioned that addition of folate to methotrexate therapy apparently prevents further increase in homocysteine levels in these patients.^{15 16}

From the management perspective, the new imaging modalities—MRA and 18-fluorodeoxyglucose positron emission tomography besides the gold standard conventional angiography—are the tools being used for disease activity assessment in patients with TA.¹⁷ Medical treatment in the form of disease-modifying agents for the small vessel ocular manifestations in TA is not codified. Usually, systemic immunosuppressants are the mainstay of therapy and glucocorticoids are often the first-line immunosuppressants used. Second-line agents, including cyclophosphamide, azathioprine and methotrexate, can be added if the patient is unresponsive to glucocorticoids alone. Role of antitumour necrosis factor-alpha agents and newer immunosuppressives like sirolimus and everolimus is considered when other therapies fail.¹⁸ We gave corticosteroids and methotrexate as immunomodulators, along with antihypertensives, anticoagulants, antiplatelets, arterials vasodilators, statins, multivitamins with high doses of pyridoxine, folic acid and vitamin B12 to our patient for preventing further ischaemic and vascular events. Intravitreal injection of anti-VEGF was given for macular oedema associated with BRVO.

In conclusion, our case shows that besides classical retinal findings, small vessel involvement as sequential CRAO in one eye and BRVO with macular oedema in the other eye in a patient of TA is a very rare presentation of this disease. Hence, CRAO or BRVO in a young patient, especially a male, mandates a thorough clinical and paraclinical exploration to prevent blinding consequences.

Learning points.

• Most retinal findings in Takayasu’s arteritis result from hypoperfusion and resemble those seen in the ocular ischaemic syndrome caused by atheromatous carotid artery occlusion.

• Small retinal vessel involvement in Takayasu’s arteritis is rare and can be the presenting manifestation.

• Retinal arterial occlusions are frequently found in patients of Takayasu’s arteritis; however, retinal venous occlusions have only been described in two case reports.

• This case shows involvement of both retinal arterial and venous systems in the two eyes of the same patient.