Combined central retinal artery and vein occlusion associated with antiphospholipid syndrome

Abstract

A female patient in early 50s presented to us several months after developing severe visual loss in her right eye. The patient was diagnosed with resolved central retinal vein occlusion (CRVO) based on the clinical picture at the time of presentation, however, retroactive evaluation of fundus imaging and further multi-disciplinary workup led to the rare diagnosis of combined central retinal artery and vein occlusion associated with antiphospholipid syndrome (APS). Only a few cases reporting retinal arterial and venous occlusions in patients with APS are found in the literature. To the best of our knowledge, no case of simultaneous CRAO and CRVO has been reported with APS. The patient was started on lifelong warfarin therapy to prevent a similar episode in the left eye. It is important to properly evaluate patients presenting with retinal vascular occlusions, as a missed diagnosis of APS can lead to recurrent and more devastating vascular events.

Background

Combined central retinal artery and vein occlusion (CCRAVO) causing sudden and severe visual loss is a rare entity. For most ophthalmologists a case of CCRAVO would be the first they would see. Several aetiologies such as cardiovascular diseases and coagulation abnormalities have been reported in these cases.¹ However, antiphospholipid syndrome (APS) has not been reported with CCRAVO causing permanent visual damage. In this article, we report the case of a middle-aged woman presenting to us with CCRAVO with a unique diagnostic dilemma.

Case presentation

A female patient in her 50s presented to us for a second opinion with a history of sudden loss of vision in her right eye, around 10 months ago, on waking up after a nap in the afternoon. She noticed feeling a little dizzy before this but denied any other associated symptoms such as headache or jaw claudication. She was diagnosed with central retinal vein occlusion (CRVO) by her primary ophthalmologist. The patient was under the care of a rheumatologist for polyarthralgia, morning stiffness, itchy rash on hands, blue discolouration of digits and digital ulcers among other complaints. She was diagnosed with mixed connective tissue disorder (MCTD). She had taken corticosteroids, methotrexate, hydroxychloroquine, azathioprine, sildenafil for varying durations over the last seven years. She also had hypertension (HTN) for which she was taking amlodipine 10 mg but had no history of diabetes mellitus (DM). The patient reported no self or family history of recurrent fetal loss or thrombosis. She regularly saw her rheumatologist and her condition was well managed on methotrexate. There was a gap in her visits starting from a year, up until a month before the episode of vision loss in her right eye. At her most recent visit before the event, she presented with uncontrolled HTN and severe pancytopenia due to which she was taken off methotrexate and switched to corticosteroids. She was seen for a few months by her rheumatologist after developing visual loss but then she was lost to follow-up for around 10 months. At the time of the patient’s visit to our clinic, her best-corrected visual acuity (BCVA) in the right eye was ‘counting fingers’ with sluggishly reactive mid-dilated pupil and relative afferent pupillary defect. Fundus examination revealed a pale optic disc in the right eye with a featureless macula, diminished foveal reflex and attenuated retinal arteries (figure 1). She had no visual complaint in the left eye and on examination, BCVA in the left eye was 20/25, optic disc, foveal reflex and retinal blood vessels all appeared normal.

Figure 1.

Fundus photograph of the right eye taken at the time of presentation to our clinic, showing pale optic disc, featureless macula, diminished foveal reflex and attenuated retinal vessels.

We requested her to bring fundus photographs and investigations done 10 months back. Fundus photographs of the right eye at the onset of visual loss showed multiple retinal haemorrhages in all quadrants with oedematous disc, Roth spots and vascular sheathing (figure 2). Additionally, on close observation, a pale macula with a cherry red spot was also noted. We were also able to review fundus photographs from 2 months after the initial complaint. These showed a pale disc in the right eye, multiple resolving retinal haemorrhages, thinned arteries and the central ischaemic area was still noticeable.

Figure 2.

Fundus photograph of the right eye at the time of initial visual complaint; showing oedematous disc with blurred margins, multiple retinal haemorrhages at the macula along with a cherry red spot (arrow). Roth spots and vascular sheathing is also visible as well as multiple haemorrhages in the periphery.

Investigations

Immediately prior to the patient’s visual complaints, her routine blood labs showed pancytopenia (Haemoglobin: 9.7, Haematocrit: 31.1, White cell count: 3.3, platelets: 136) which resolved after methotrexate was discontinued. Additionally, a persistently elevated erythrocyte sedimentation rate was also seen, ranging from the values of 64–70 mm/first hour, reaching a maximum of 90 mm/first hour. On presentation to our clinic around 10 months after the event, she underwent several investigations. A protein electrophoresis test showed raised total protein level of 9.0 g/dL (normal range: 6.4–8.3 g/dL), slightly decreased albumin of 3.07 g/dL (normal range: 3.2–5.5 g/dL) and markedly raised gamma globulin fraction of 4.09 g/dL (normal range: 0.5–1.6 g/dL) which was persistent with her primary diagnosis of MCTD. Antinuclear antibody (ANA) test was reported positive with a coarse speckled pattern. She had a positive ribonucleoprotein test and had a negative anti-Ro, anti-La, anti-Sm and anti-Sc7 antibodies. A lupus anticoagulant (LA) screen showed a positive result of 49.4 s (31–44 s) along with a raised LA ratio of 1.5 (0.8–1.2) whereas anticardiolipin IgG (6.93 GPL/mL) and IgM (4.20 GPL/mL) both were negative. Repeat LA screen after around 7 months was also raised with the value of 51.8 s and LA ratio of 1.7. Thrombophilia screening test showed normal protein C and Anti-thrombin III values, raised factor V percentage of 160% (normal range: 62%–150%) and slightly raised homocysteine level of 12.70 umol/L (5–12 umol/L). Protein S which was performed around 19 months after the acute event was below the lower normal limit with levels of 42% (normal range: 56%–121%). Extractable nuclear antigen antibodies panel was negative.

Optical coherence tomography (OCT) scan performed around 1 month after the initial episode showed hyper-reflective inner retina which slowly fades away on subsequent OCTs and is indicative of inner retinal ischaemia (figure 3). The inner retina is supplied by the central retinal artery which was occluded in our patient’s case and is confirmed by the OCT findings. MRI brain with MRA contrast showed non-specific changes.

Figure 3.

Optical coherence tomography scan done around 1 month after the initial episode showing hyper-reflective inner retina; suggestive of ischaemia.

Differential diagnosis

She was initially seen by her primary ophthalmologist right after the event and was given a diagnosis of CRVO. After reviewing fundus photographs from the time of the acute event, we revised our diagnosis to resolved CCRAVO, evident by the retinal features described earlier. Common aetiologies usually seen with a similar clinical picture include atherosclerosis, collagen-vascular diseases, inflammatory conditions such as giant cell arteritis (GCA) and hypercoagulable states. Retinal arterial occlusions are often caused by conditions resulting in arterial atheroma or inflammation. These can cause primary thrombus formation or lead to acute obstruction of the central retinal artery by emboli arising elsewhere.² HTN is a common systemic disease associated with both CRVO and CRAO. In a case series of 23 patients diagnosed with CCRAVO, Brown et al found that 13 (57%) of the 23 patients had a positive history of HTN.³ Pacella et al in their prospective study of patients presenting with CRVO reported presence of HTN in 62.8%, which was the highest of all the included cardiovascular risk factors.⁴

Our patient did not have a history consistent with GCA and had no evidence of atherosclerotic disease apart from HTN. She had a long-standing history of MCTD but her clinical findings warranted additional investigations to pinpoint the exact pathology. Further blood workup revealed a positive ANA (with a coarse speckled pattern) and two raised values of antiphospholipid screening tests (first value: 49.4 s, second value: 51.8 s) performed more than 3 months apart. According to the revised Sapporo classification criteria (2006), the clinical and laboratory picture confirmed APS as the most likely diagnosis.⁵ It is therefore essential that patients presenting with atypical retinal vascular occlusions like CCRAVO, have a comprehensive workup along with fundus examination, to reach an early and conclusive diagnosis. A detailed history to look for any underlying predisposing conditions, clinical examination including blood pressure measurement, laboratory workup for hypercoagulable conditions (LA, ACA, protein C and S, etc) and imaging to look for source of emboli (carotid Doppler ultrasound, echocardiogram) should be done.

Treatment

After further workup, the patient was referred to haematology to consider long-term anticoagulation. The multidisciplinary team involved in the patient’s care reached a consensus to start anticoagulation therapy to prevent similar episode in her left eye. She was started on life-long warfarin with starting dose of 5 mg once daily with the aim to reach the target INR between 2 and 3. Losartan potassium 50 mg once daily was added along with her routine HTN medication, amlodipine. After review of serial blood pressure monitoring, this was switched to a combination tablet of amlodipine 5 mg and valsartan 80 mg two times per day, which brought her blood pressure under control.

Outcome and follow-up

The patient reported no further improvement in visual acuity on subsequent visits and is being monitored for complications such as neovascular glaucoma in the affected right eye as well as early signs of retinal occlusive disease in the left eye. She is being seen by a haematologist for adjustment of warfarin’s dosage to reach the target therapeutic INR.

Discussion

APS is an autoimmune condition which can occur on its own or secondary to an underlying condition. It is usually divided into three broad categories depending on the clinical presentation, namely, thrombotic, obstetric and catastrophic APS. The pathophysiology of the disease involves antiphospholipid antibodies (APA) binding to and activating cell antigens, leading to thrombus formation.⁶ For diagnosis of APS, revised Sapporo classification criteria (2006) requires at least one clinical and laboratory criteria to be met.⁵ Clinical criteria include a confirmed vascular thrombotic event or pregnancy related adverse event such as fetal death or three or more successive abortions before 10 weeks of gestation, or premature delivery before 34 weeks. In laboratory investigations, either one of LA, anticardiolipin antibody or anti-beta-2 glycoprotein-I antibody needs to be detected twice, at least 12 weeks apart. A few studies have explored the relationship between APS and retinal vascular disease. Maaroufi et al did a prospective study of 33 patients to assess the relationship between APA and retinal vascular occlusions.⁷ They reported that all of the patients with positive APA had retinal vein occlusions only and no simultaneous arterial occlusions were seen. Palmowski-Wolfe et al looked at the data of 368 patients with retinal vascular disease. They reported that after excluding patients with other significant risk factors for thromboembolism, 15.3% of 85 patients had a positive APA test, with an OR of 3.42.⁸ This reinforces the significant relationship between APS and retinal vascular occlusions.

CCRAVO presents as acute, painless loss of vision with typical fundus findings of retinal haemorrhages, disc swelling and cherry red spot with retinal pallor. After several weeks, ischaemia leads to atrophy and narrowed retinal vessels.⁹ Aetiology behind CCRAVO vary with age as certain systemic diseases such as HTN, atherosclerosis, carotid artery disease and DM are more common in the older age group. Other associations include conditions such as Protein S deficiency, systemic lupus erythematosus (SLE), and cancer.¹ In most cases, visual outcome and prognosis is poor, partly due to the severity of the underlying disease mechanism and partly due to subsequent complications of CCRAVO (such as neovascular glaucoma and rubeosis iridis).¹⁰

Our case differs from the literature in terms of the nature of the disease, its severity and the visual outcome. We came across two cases describing consecutive central retinal vein and ophthalmic artery occlusion associated with primary APS. These contrast from our patient as they did not develop arterial and venous occlusions simultaneously and there was involvement of ophthalmic artery rather than central retinal artery. Ang et al described a case who first presented with CRVO and was started on warfarin after primary APS was diagnosed.¹¹ After 1 month, she developed further deterioration of vision in the same eye as a result of ophthalmic artery occlusion. She also had raised IOP and iris neovascularisation. Treatment with pan-retinal photocoagulation, oral acetazolamide, topical timolol, atropine and a higher INR target only led to improvement in visual acuity from perception of light to hand movements. Gelman and Tsang presented a case of a 15-year-old patient who developed CRVO and was then diagnosed with primary APS after extensive workup.¹² After 1 week, the vision in the same eye deteriorated from 20/200 to perception of light. OCT and fundus imaging revealed a subsequent development of ophthalmic artery occlusion which was treated with anticoagulation and immunosuppression. He later on developed neovascular glaucoma for which intravitreal bevacizumab and pan-retinal photocoagulation was done but no further improvement in vision was recorded.

Two cases with simultaneous CCRAVO found during our search, had history of SLE along with APS. Chang et al’s patient presented with sudden vision loss and was started on IV methylprednisolone (3 days) and subcutaneous low molecular weight heparin (7 days).¹³ Over the course of the next few weeks her fundus appearance showed significant resolution of oedema and haemorrhages and after 1 month her visual acuity was noted to be 6/6. This is different from our patient as recovery in vision was seen in this case. The second case is reported by Durukan et al, in which the patient had given birth 5 days ago and developed sudden visual loss.¹⁴ BCVA in the affected eye was no light perception and had characteristic fundus findings of CCRAVO as described earlier. She was put on heparin, prednisolone, pentoxifylline and aspirin but did not show any improvement in visual acuity even after several months.

Management of vascular occlusive events is by anti-coagulation agents such as direct-acting oral anticoagulants (DOAC) or warfarin. Lifelong anticoagulation is given if the patient has an unprovoked event and is deemed high-risk for further episodes or complications. Patients with positive LA are candidates for vitamin K antagonist therapy as a clinical trial with DOACs failed to prevent recurrence of thromboembolism. Trial of rivaroxaban in APS was a multicentre prospective randomised controlled trial which compared the use of rivaroxaban to warfarin in patients with high-risk APS. The trial was terminated prematurely because of an increased rate of thromboembolism seen with DOAC (19%) compared with warfarin (3%).¹⁵ Therefore, our patient was advised lifelong warfarin therapy since she only had vision in one eye now and any similar event in her left eye would be seriously incapacitating.

Our case highlights a rare disease presentation with poor visual outcome for the patient and shows the importance of an early diagnosis and multidisciplinary treatment approach. It can help physicians to deal with similar challenging cases and establish systemic correlations with unusual ocular signs and symptoms.

Patient’s perspective.

I have this problem with my vision in the right eye for the last 2 years now. I woke up 1 day and I couldn’t see from my right eye completely, suddenly. I had noticed dizziness 2–3 days prior to this episode, and then 1 day I took a nap during the afternoon and when I woke up, I couldn’t see from my right eye. I got treatment as suggested by the doctor and I visited another doctor before coming to my current physician, as I was not satisfied with them. Currently, I am undergoing treatment and a haematologist is also looking after my eye problem.

Before this eye problem, I have had arthritis for 6–7 years for which I was being treated with steroids by my rheumatologist. The pain and discomfort get better during summers and worse during colder months. I also develop sores/ulcers on my fingers and the arthritis affects my small joints. Currently my symptoms are under control, and I am satisfied with how it is being managed.

I am a stay-at-home mother and have two sons. I can do household chores normally without trouble on most days. I do have domestic help available because some days I feel a greater strain on my vision and some days I am able to manage everything without help. Since I have started treatment, I am able to cook but I do have some issue with reading and writing. I can write down my signature but have trouble writing more than that. As far as reading is concerned; I can read with the help of my spectacles, and I read as much as I can until I notice a strain on my eyes. I notice some difficulty going out and about and I feel I am hesitant because of the fear of falling. I do manage very well, and I am able to live my life comfortably, but I do wish that I get my vision back and things go back to normal as they were before. Eyesight is a huge blessing and I have hope that with this current treatment I might regain my vision back. Sometimes I feel that I might get my vision back the same way I lost it; all of a sudden.

I am happy with my treatment so far and I come regularly for my routine check-ups. I hope that with my story being published in an international publication, someone might be able to help.

Learning points.

• Combined central retinal artery and vein occlusion is a rare phenomenon and often presents with profound and sudden visual loss with fundus features including retinal haemorrhages, cherry red spot, disc oedema and retinal pallor due to ischaemia.

• It is important to perform basic ocular imaging at the time of presentation. As the disease may evolve over time, the final clinical appearance may not depict the actual clinical diagnosis.

• Antiphospholipid syndrome has a link with development of retinal vascular occlusions. In patients with unusual retinal occlusions, workup should be done to rule out predisposing hypercoagulable conditions.

• In patients with several comorbidities, it is important to have a multidisciplinary approach in all aspects of care from diagnosis to management. This reduces the chances of incorrect or inconclusive diagnosis and treatment.

• Vitamin K antagonists are the anticoagulant therapy of choice for patients with positive lupus anticoagulant as direct-acting oral anticoagulants have shown to not prevent recurrent thromboembolism.

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