The Holistic Spectrum of Thrombotic Ocular Complications: Recent Advances with Diagnosis, Prevention, and Management Guidelines

Abstract

Thromboembolic manifestations of the eye can vary from a trivial tributary retinal vein occlusion to a catastrophic cerebral venous sinus thrombosis. These conditions can be classified as pathologies directly affecting the eye or those causing secondary lesions due to systemic issues and can be managed accordingly. Also, recently the incidence of thrombotic phenomenon affecting multiple organs (with the eye being no exception) is estimated to be around 25% among patients hospitalized in the intensive care unit for COVID-19, even though anticoagulant treatment was administered prophylactically. In this chapter, the various pathophysiologies of the ocular thrombotic events are highlighted with a special focus on the COVID-19 induced thrombotic ocular complications. Ophthalmologists, sometimes being the first responder, have a vigilant role to play with a heightened awareness of these atypical extrapulmonary thrombotic ocular manifestations, which are not only vision-threatening; in certain instances, life-threatening too. This chapter summarizes the recent advances in ocular thrombotic diseases with focal points on the current recommendations in COVID-19 induced ocular thrombotic complications. The potential diagnostic and preventive actions such as the prophylactic role of anti-thrombotic therapy, baseline non-contrast chest computed tomography, as well as recommendations for patients with COVID-19 infection are discussed in detail.

1. Introduction

Thromboembolic manifestations of the eye can vary from a trivial tributary retinal vein occlusion to a catastrophic cerebral venous sinus thrombosis, leading to ocular associations. These conditions can be classified as pathologies directly affecting the eye or those causing secondary lesions due to systemic issues. It is important to have an understanding and knowledge regarding the ophthalmic signs and symptoms of thromboembolic manifestations considering its systemic implications, to identify patients at risk of developing such diseases and reduce the risk of developing systemic involvement. In this chapter, the thromboembolic phenomenon and its management ranging from medical to surgical (thrombectomy) are described in detail both from an ophthalmologist and a non-ophthalmic (intensivist, emergency physician, neurologist & anesthesiologist) point of view, in managing not only the vision-threatening aspect, but also the life-threatening part of these pathologies effectively.

2. Disease spectrum

The various artery and venous thromboembolic phenomena affecting the eye are shown in Figure 1.

Figure 1.

Various artery and venous thromboembolic phenomena affecting the eye.

2.1 Retinal vein occlusions

2.1.1 Disease entity

Retinal vein occlusions (RVO) are a group of disorders that have an impaired venous return in common [1]. It is the second leading cause of retinal vascular blindness after diabetic retinopathy. Classification of RVO depends on the site of obstruction. If the occlusion occurs within or posterior to the optic nerve head, it is termed as central retinal vein occlusion (CRVO), occlusion at the level of major bifurcation is termed as hemiretinal vein occlusion (HRVO), and occlusion within a tributary is termed as branch retinal vein occlusion (BRVO). CRVO can further be classified into ischemic CRVO and non-ischemic CRVO [2].

2.1.2 Etiopathogenesis

Majority of the RVOs are commonly associated with typical atherosclerosis, but it can be secondary to other conditions such as inflammation, vasospasm, or compressions [3]. The atherosclerotic causes include systemic arterial hypertension, arteriosclerosis, diabetes, and thrombophilia [4, 5]. BRVO commonly occurs due to venous compression at the arteriovenous crossing, whereas CRVO is most likely linked to glaucoma and sleep apnea [6, 7]. In young individuals we need to look out for uncommon associations like thrombophilia and homocystinuria [8, 9]. So RVOs is caused by three mechanisms (Videos 1, https://www.youtube.com/watch?v=JSC_E9vPnG0 and 2, https://www.youtube.com/watch?v=-wT5biKVxtE):

• Occlusion of the vein externally

• Occlusion of the vein due to degenerative inflammation of the vessel wall

• Hemodynamic disturbances [10]

According to Eye Disease Case–Control Study, CRVO is associated with the following risk factors:

• Systemic arterial hypertension

• Open-angle glaucoma

• Diabetes mellitus

• Hyperlipidemia [11]

According to Eye Disease Case–Control Study, BRVO is associated with the following risk factors:

• Increasing age

• Systemic arterial hypertension

• Smoking

• Glaucoma [4]

2.1.3 Clinical features

Symptoms are varied depending on the region involved. Sometimes symptoms of RVO can be subtle, especially if the severity is mild or the area affected does not involve the macula [12]. In cases of non-ischemic CRVO, the patient is usually asymptomatic and may be detected as an incidental finding on routine examination, revealing mild retinal hemorrhages and retinal venous stasis. The patient might have experienced amaurosis fugax before developing a constant blur in certain cases.

2.1.3.1 Clinical features of ischemic CRVO

In ischemic CRVO, patient complaints unilateral loss of vision and experiences marked loss of visual acuity, frequently noted on waking up in the morning. Visual acuity is usually counting fingers or worse, with a poor visual prognosis considering the macular ischemia. Relative afferent pupillary defect (RAPD) is typically seen here [13]. Sometimes patients would have ignored or not noticed a prior reduction in vision and might present with a painful eye, following the development of neovascular glaucoma (NVG) (Figure 2a). This is also known as hundred-day glaucoma [14, 15]. Such cases would present with raised intraocular pressure, corneal edema, and neovascularization of the iris (Figure 3). Routine gonioscopy is mandatory to check for angle neovascularization. Fundus evaluation (Figure 4a and b) will show severe tortuosity and dilatation of all the branches of the central retinal vein with extensive dot-blot and flame-shaped hemorrhages. Early signs include severe optic disc hyperemia, optic disc edema and retinal edema, especially macular edema. Cotton wool spots are typically seen here, more than in non-ischemic type. Here the acute signs start to resolve over 9–12 months. The macula develops chronic cystoid macular edema (CME), atrophic changes, epiretinal membrane, and retinal pigment epithelium changes in later stages. Retinal neovascularization is seen in about 5% of the eyes, leading to severe vitreous hemorrhages (Figure 2b) in most of the eyes. Optic disc collaterals are common and can reduce the risk of anterior and posterior segment neovascularization.

Figure 2.

(a) Fundus photograph showing total glaucomatous cupping secondary to NVG with panretinal photocoagulation LASER marks. (b) Fundus photograph showing CRVO with neovascularization elsewhere and vitreous hemorrhage.

Figure 3.

Anterior segment slit lamp photograph showing neovascularization of iris (red arrows) and ectropion uveae with mid-dilated pupil.

Figure 4.

(a) Fundus photograph showing ischemic CRVO with dilated and tortuous veins, several flame-shaped hemorrhages, and cotton-wool spots with disc edema. (b) Fundus photograph showing resolution of hemorrhages. (c) Optical coherence tomography (OCT) of the macula of the same case showing cystoid macular edema (CME). (d) OCT macula post anti-vascular endothelial growth factor injection showing resolution of CME. (e) Fluorescein angiography (FA) showing extensive areas of capillary nonperfusion with vessel wall staining. (f) FA showing ischemia in the peripheral zones.

2.1.3.2 Clinical features of non-ischemic CRVO

Non-ischemic CRVO is also called venous stasis retinopathy. It is more common than the ischemic type, but one-third of these patients will progress towards ischemic CRVO. Visual acuity is better than 6/60 in majority of the cases and vision returns to near normal in about 50% of the cases. Poor vision would be seen in cases with chronic macular edema leading to secondary atrophy. The clinical features of non-ischemic CRVO are shown in Figure 5.

Figure 5.

Clinical features of non-ischemic CRVO.

2.1.3.3 Clinical features of BRVO

In BRVO, there is sudden unilateral painless visual loss, asymptomatic if there is no macular edema. The superotemporal quadrant (Figure 6) is the most commonly affected at the arteriovenous crossing point. There is dilatation and tortuosity of the affected venous segment with associated retinal hemorrhages and macular edema. Following the acute phase, resolution starts within 6–12 months with associated venous sheathing and sclerosis. Collateral vessels (Figure 7a) may form near the region of decreased capillary perfusion. In BRVO, it is seen between the inferior and superior vascular arcades, crossing the horizontal raphe. The presence of collaterals indicates better prognosis and care should be taken during laser to avoid hitting it. Retinal neovascularizations are more common than CRVO and are seen in about 8% of eyes.

Figure 6.

Fundus photograph showing superotemporal BRVO with retinal hemorrhage, and cotton wool spots. Retinal pigment changes in the macula, with collaterals and ghost vessels in the inferotemporal quadrant.

Figure 7.

(a) An old BRVO showing multiple optociliary shunts with an epiretinal membrane in the macula. (b) Fundus photo showing the same fundus after treatment with sectoral laser photocoagulation.

2.1.3.4 Clinical features of macular BRVO (tributary vein occlusion)

Macular BRVO (Figure 8) is another variant where only the venule within the macula is occluded. Occlusion of a small macular tributary branch vein, not involving a major arcade, can be extremely subtle with minimal hemorrhage, telangiectasia or macular edema, and the correct diagnosis is frequently missed [16].

Figure 8.

Tributary vein occlusion. A venule within the macula is occluded showing few retinal hemorrhages in the involved area.

2.1.3.5 Clinical features of HRVO

HRVO (Figure 9) is a variant of CRVO. The site of occlusion is within the optic nerve which is associated with corresponding disc edema [17]. It is less common than CRVO and BRVO. It either involves the superior or inferior branch of the central retinal vein. Signs are similar to that of CRVO, but involves only a single hemisphere.

Figure 9.

Hemiretinal vein occlusion (HRVO). HRVO of the inferior branch of the central retinal vein with moderate flame-shaped hemorrhages in the inferior quadrants with associated disc edema.

2.1.4 Ocular investigations

Fluorescein angiography (FA) (Figure 10) is important to differentiate between ischemic and non-ischemic CRVO. FA will show delayed arteriovenous transit time, with good capillary perfusion and some late leakage in non-ischemic CRVO. In ischemic CRVO there will be extensive areas of capillary nonperfusion accompanied with vessel wall staining and leaking (Figure 4e and f). More than 10 disc areas of capillary nonperfusion are associated with an increased risk of neovascularization. As retinal hemorrhages cause blocked fluorescence, extensive hemorrhages will fail to provide us with adequate information on capillary nonperfusion areas [1, 18]. FA will also help exclude substantial macular ischemia prior to grid laser therapy. Similarly, in BRVO more than 5 disc areas of capillary nonperfusion is associated with an increased risk of neovascularization.

Figure 10.

Fundus fluorescein angiographic findings in various artery, and vein occlusions.

OCT macula (Figure 4c) is used to confirm the presence of CME and quantify it, which is often mild in a non-ischemic case.

2.1.5 Systemic investigations

RVOs are multifactorial in origin and a whole host of factors acting in different combinations are the cause for an occlusion [17]. So considering this it is mandatory to do a thorough workup as shown in Figure 11a.

Figure 11.

(a) Systemic investigations done in retinal vein occlusion cases. (b) Systemic investigations done in special cases of retinal vein occlusion.

2.1.5.1 Systemic investigations in special cases of RVO

A selective series of tests need to be done in patients under the age of 50, in bilateral RVO, patients with previous thrombosis or a family history of thrombosis, and some patients in whom the above investigations are negative. The battery of investigations suggested is shown in Figure 11b.

2.1.6 Treatment

2.1.6.1 CRVO management

2.1.6.1.1 Intravitreal anti-vascular endothelial growth factor (VEGF) therapy

Study of Efficacy and Safety of Ranibizumab Injection in Patients with Macular Edema Secondary to Central Retinal Vein Occlusion (CRUISE) shows that 0.5 mg or 0.3 mg of monthly injections of ranibizumab were found effective in the treatment of CME [19].

Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Central Retinal Vein Occlusion (GALILEO and COPERNICUS) studies shows that monthly injections of aflibercept can be utilized for the treatment of macular edema secondary to CRVO (Figure 4c and d) [20].

2.1.6.1.2 Intravitreal corticosteroids

The CRVO arm of Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) study has shown that intravitreal triamcinolone acetonide (IVTA) injections of either 1 mg or 4 mg triamcinolone are effective in treating macular edema, though it is associated with the risk of raised IOP and cataract formation [21].

Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema due to Retinal Vein Occlusion (GENEVA) study showed that 0.7 mg dexamethasone implant (Ozurdex®) can be used successfully for the treatment of macular edema. Side effects might include glaucoma and cataract [22].

2.1.6.1.3 Laser therapy

The Central Vein Occlusion Study (CVOS) states that grid photocoagulation of macula does not improve visual acuity in macular edema secondary to CRVO [23].

Delivery of panretinal photocoagulation (PRP) (Figure 12) is indicated at the first sign of neovascularization in CRVO [24]. But the delivery of PRP can be difficult in the eyes with NVG. So, in such scenarios anti-VEGF is used to temporarily resolve the neovascularization until PRP laser is given [25].

Figure 12.

Fundus photograph showing a case of CRVO treated with panretinal photocoagulation therapy.

2.1.6.2 BRVO management

2.1.6.2.1 Intravitreal anti-VEGF therapy

Study of the Efficacy and Safety of Ranibizumab Injections in Patients with Macular Edema Secondary to Branch Retinal Vein Occlusion (BRAVO) shows the monthly injections of 0.5 mg or 0.3 mg of ranibizumab causes improvement in macular edema and gain in visual acuity [19].

Study to Assess the Clinical Efficacy of VEGF Trap-Eye in Patients with Branch Retinal Vein Occlusion (VIBRANT) shows that aflibercept injection is useful for the treatment of CME in BRVO [26].

Comparison of Anti-VEGF Agents in the Treatment of Macular Edema from Retinal Vein Occlusion (CRAVE) shows that monthly injections of ranibizumab and bevacizumab both can be successfully used for the treatment of CME [27].

2.1.6.2.2 Intravitreal corticosteroids

The BRVO arm of the SCORE study states that macular grid laser is the benchmark for the treatment of CME when compared with IVTA injection. Grid laser is utilized with a duration of 0.1 seconds and 100 microns spot size with medium white burns [21]. IVTA was associated with elevated IOP and cataract formation [28]. Micro-pulse laser therapy is an alternative method that can be used as it causes less retinal damage, but its onset of action is slower. Though laser has been a success in macular edema secondary to BRVO, it is not effective in cases of CRVO [1].

The GENEVA study shows significant improvement of macular oedema with ozurdex implant [29].

2.1.6.2.3 Laser therapy

The Branch Vein Occlusion Study (BVOS) states that macular laser shows significant improvement in visual acuity. Scatter photocoagulation is done to treat neovascularization as it reduces the risk of vitreous hemorrhage. Laser duration of 0.1–0.2 seconds with 200–500 micron spot size of medium white burn setting is utilized [30].

Neovascularization elsewhere (NVE) or neovascularization of the disc (NVD) is considered as an indicator for sectoral photocoagulation (Figure 7a and b) in cases of BRVO [17].

2.1.7 Surgical management

Pars plana vitrectomy might prove to be beneficial in eyes with non-clearing vitreous hemorrhage in both CRVO and BRVO eyes.

2.1.8 Management of retinal vein occlusions from an emergency physician’s perspective

Patients usually present to the emergency room with complaints of unilateral loss of vision, which is frequently noted on waking up in the morning. Visual acuity is usually counting fingers or worse in severe cases. RAPD elicitation is mandatory [13]. Fundus evaluation (Figure 4a and b) will show extensive dot-blot and flame-shaped hemorrhages in any one or all the quadrants depending on the level of vein occlusion. Apart from elective ophthalmic management, systemic therapy can also be initiated. Since there is no convincing evidence of systemic medical treatment in treating this condition, pilot studies have suggested the usage of oral inhibitors of platelet and erythrocyte aggregation, and hemodilution treatment to lower blood viscosity (thrombolysis) may be of some benefit. Intravenous administration of streptokinase can reduce morbidity. Unfortunately, it never gained favor because of the risk of intravitreal hemorrhage. Surgical thrombectomy is not warranted as a management option.

2.2 Ocular artery occlusions

2.2.1 Disease entity

Arterial occlusions of the eye can involve various branches. The ophthalmic artery is a branch of the internal carotid artery, which in turn gives rise to the central retinal artery and the ciliary arteries. It can either be an ophthalmic artery occlusion (OAO), a central retinal artery occlusion (CRAO), or a branch retinal artery occlusion (BRAO) (Figure 13) [29]. Obstruction can occur due to an embolus or a thrombus formation (Videos 3, https://www.youtube.com/watch?v=t6CwwBUl6yY and 4, https://www.youtube.com/watch?v=UnC8jo4sQgE). It can be secondary to an inflammation of a retinal vessel wall, known as vasculitis [31, 32]. Any arterial occlusion warrants a careful systemic evaluation. Several studies have reported a strong association between retinal artery occlusions and stroke [33, 34].

Figure 13.

(a) Fundus photograph showing BRVO with branch retinal artery occlusion (BRAO). Pale retina is seen in superotemporal aspect with tortuosity and dilatation of retinal veins, with few retinal hemorrhages and cotton-wool spots in that region. (b) OCT macula showing thickening of inner retinal layers in the superior quadrant.

Cilioretinal artery is derived from the short posterior ciliary arteries and is seen in about 15–50% of eyes. They provide blood supply to the central macula [16]. Sometimes cilioretinal artery occlusions may accompany a CRVO.

2.2.2 Central retinal artery occlusion

2.2.2.1 Etiopathogenesis

CRAO is commonly due to vascular embolic obstruction. There are several risk factors associated with retinal emboli such as shown in Figure 14 [35, 36]. The incidence of retinal artery occlusions (RAO) increases with age and is seen more frequently in men [37, 38]. In younger patients with no atherosclerotic risk factors, conditions like vasculitis, myeloproliferative disorders, sickle cell disease, hyper-coagulable states, use of intravenous drugs or oral contraceptive pills should be explored [39]. The arteritic cause for CRAO is always due to giant cell arteritis (GCA), which has been reported in 4.5% of CRAO cases [40].

Figure 14.

Risk factors of CRAO associated with retinal emboli.

Pathophysiologies of the embolic phenomenon due to atherosclerosis is shown in Figure 15.

Figure 15.

Pathophysiology of an embolic phenomenon due to atherosclerosis in CRAO.

2.2.2.2 Clinical features

Patients with CRAO present with sudden, painless loss of visual acuity or a decrease in field of vision that occurs over a few seconds [41]. In 74% of the patients, visual acuity was found to be finger counting or worse with associated relative afferent pupillary defect (RAPD) [42]. If a cilioretinal artery is preserved central vision will be spared [43]. Bilateral occurrence has been noted in 1 to 2% of cases [41]. An ocular examination (Figure 16a) can reveal the following findings: retinal opacity of the posterior pole (58%), cherry-red spot in the macula (90%), retinal arterial attenuation (32%), cattle trucking or boxcarring (19%) associated with optic disc edema (22%) and pallor (39%) [44]. An intra-arterial embolus was found in 20% of the patients, which can either be small, yellow, and refractile plaques also known as ‘Hollenhorst plaque’ or non-scintillating, white plaques situated in the proximal retinal vasculature due to calcific emboli, or a small pale bodies of fibrin-platelet embolus [43].

Figure 16.

Central retinal artery occlusion (CRAO). (a) Recent CRAO with the cherry-red spot in the macula with surrounding pale retina and associated disc edema. (b) OCT macula showing thickening of inner retinal layers, with thickening of the macula.

In some cases, BRAO might go unnoticed if central vision is spared.

2.2.2.3 Ocular investigations

FA shows delay in arterial filling with reduced arterial caliber, associated with masking of background choroidal fluorescence due to retinal edema. If a patent cilioretinal artery is present, it will fill during the early phase [45]. Amlaric’s triangle or triangular areas of ischemia are seen in the periphery region which indicates choroidal ischemia [46].

OCT (Figure 16b) demonstrates an increased thickness of the inner retinal layer at the acute phase of the disease with optic disc swelling [47].

2.2.2.4 Classification

CRAO can be divided into 4 different subclasses is shown in Figure 17.

Figure 17.

Classification of CRAO.

2.2.2.5 Systemic investigations

The battery of investigations is shown in Figure 18.

Figure 18.

Systemic investigations done in CRAO.

2.2.2.6 Acute management of CRAO

Significant improvement of vision is seen in only 10% of cases with spontaneous reperfusion. There are barriers involved in effective treatment because of delayed reporting of patients to the hospital and due to no consensus for guideline-based therapy [48]. The acute phase of management involves an attempt to restore the central retinal artery perfusion. It involves several non-invasive therapies and the use of intravenous or intra-arterial thrombolytics [48].

The non-invasive therapies include

• Sublingual isosorbide dinitrate, inhalation of carbogen, systemic pentoxifylline, and hyperbaric oxygen are used to dilate the retinal artery [49, 50].

• Dislodging the emboli via ocular massage [51].

• Intravenous administration of mannitol and acetazolamide along with anterior chamber paracentesis, followed by withdrawal of a small quantity of aqueous to reduce the intraocular pressure, hence increasing retinal artery perfusion [49, 52].

Although intervention has shown improved retinal perfusion, this did not necessarily lead to improved visual acuity, and therapies do not much alter the outcome than the natural course of the disease [53]. Thrombolysis is targeted to dissolve the fibrinoplatelet occlusion in cases of non-arteritic CRAO. Several studies have shown that local intra-arterial thrombolysis has been used to re-canalize the central retinal artery, with 60–70% of the subjects responding with an improvement in visual acuity [54]. Alternatively, intravenous thrombolysis is also being administered as per standard ischemic stroke protocol. It is said to have easier access and reduced risk as compared to the intra-arterial route [55].

2.2.2.7 Sub-acute phase management of CRAO

This includes the prevention of secondary neovascular complications of the eye. Neovascularization in eyes post CRAO tends to occur between the 2nd and 16th week. Therefore, it is important to review the patient with acute CRAO at regular intervals during the first 2 weeks, followed by monthly visits for the next 4 months [56].

2.2.2.8 Long term management

The ultimate goal is to prevent other ocular ischemic events of the eye or other end organs. It is noted that 64% of patients with CRAO had at least one new vascular risk factor following the retinal occlusive event [57]. Hyperlipidemia which has been reported as the common undiagnosed vascular risk factor at the time of sentinel CRAO event should be treated chronically.

2.2.3 Cilioretinal artery occlusion

2.2.3.1 Etiopathogenesis

Cilioretinal artery occlusion (CLRAO) is the acute obstruction or blockage of blood flow within a cilioretinal artery. It typically occurs in patients aged 65 years and older but can be seen at any age. The incidence of CLRAO is approximately 1:100,000 patients [58]. It is seen unilaterally in over 99% of the cases and has no recognized hereditary pattern.

The various pathophysiological mechanisms are:

• Embolic

• Hypertensive arterial necrosis

• Inflammatory

• Hemorrhage under an atherosclerotic plaque

• Associated with concurrent central retinal vein obstruction[59]

2.2.3.2 Clinical features

2.2.3.2.1 Visual acuity

There is acute, unilateral, painless visual field loss occurring over several seconds with approximately 10% of those having a history of transient visual loss (amaurosis fugax) in the affected eye before the current episode.

2.2.3.2.2 Pupillary changes

An afferent pupillary defect may or may not be present. It entirely depends on the area of distribution of the obstruction.

2.2.3.2.3 Fundus changes

Three variants

• Cilioretinal artery obstruction (Figure 19a)

• Cilioretinal artery obstruction associated with central retinal vein obstruction

• Cilioretinal artery obstruction associated with acute anterior ischemic optic neuropathy [59].

Figure 19.

(a) Fundus photograph showing cilioretinal artery obstruction with vitreous hemorrhage. (b) OCT macula image of the same showing vitreous hemorrhage and increased macular thickness with thickening of the inner retinal layers.

2.2.3.2.4 Retinal intra-arterial emboli

Prevalence is uncertain.

2.2.3.2.5 Cholesterol

It is termed as Hollenhorst plaque named after Robert Hollenhorst at the Mayo Clinic. It typically arises from the carotid arteries, which appear glistening yellow [60].

2.2.3.2.6 Differential diagnosis

• Infectious retinitis or inflammatory retinitis

• Toxoplasmosis

• Cytomegalovirus

2.2.3.3 Ocular investigations

2.2.3.3.1 Intravenous fluorescein angiography

Cilioretinal arteries normally fill with fluorescein dye during the early choroidal phase of a fluorescein angiogram. A cilioretinal artery obstruction typically shows nonperfusion of dye in the affected area throughout the retinal arteriovenous phase.

OCT macula shows increased macular thickness with thickening of the inner retinal layers (Figure 19b) [61].

2.2.3.4 Systemic investigations

Rule out the following:

• Causes for emboli with Carotid Doppler & Cardiac Echocardiogram

• Inflammatory causes such as Giant cell arteritis, Wegener granulomatosis, Polyarteritis Nodosa, Systemic lupus erythematous, Toxoplasmosis retinitis, Orbital Mucormycosis.

• Coagulopathies such as Lupus anticoagulant syndrome, Protein S deficiency, Protein C deficiency, Antithrombin III deficiency, Sickle cell disease, Homocystinuria.

• Miscellaneous: Fabry disease, Migraine, Lyme disease, Hypotension, Fibromuscular hyperplasia, Sydenham chorea.

2.2.3.5 Treatment

There is no consistent proven treatment to ameliorate the visual acuity. In isolated cases, even without treatment, 90% of the eyes return to 20/40 vision or better [59, 62]. With concurrent central retinal vein occlusion, 70% of eyes often return to 20/40 vision or better [63]. With anterior ischemic optic neuropathy, the vision often remains counting fingers to hand movements (HM+) despite therapy [64]. Most importantly, though uncommon, giant cell arteritis should be ruled out because, in that scenario, the fellow eye can be involved by retinal arterial obstruction within hours to days, hence hastening the need for diagnosis and treatment with high dose corticosteroids. It is essential to reduce the risk of involvement of the fellow eye [59].

2.2.4 Acute ophthalmic artery obstruction (occlusion)

2.2.4.1 Etiopathogenesis

Acute ophthalmic artery obstruction is the acute blockage of the ophthalmic artery. OAO may lead to severe ischemia of the affected globe and associated ocular structures [46]. The occlusions are usually located proximal to the branch point of the general posterior ciliary arteries and central retinal artery. Acute ophthalmic artery obstruction occurs in approximately 1:100,000 outpatient ophthalmologic visits. The mean age of onset is approximately 60 years and there is no hereditary pattern. The pathophysiological mechanism is as follows:

• Embolic

• Trauma

• Infections (Mucormycosis)

• Inflammatory (Collagen vascular disease, Giant cell arteritis)

• Dissecting Aneurysm within the ophthalmic artery

• Hemorrhage under an atherosclerotic plaque

• Vasospasm

2.2.4.2 Clinical features

2.2.4.2.1 Visual acuity

Vision loss is acute, unilateral and painless, and occurs over a period ranging from seconds to minutes. The visual acuity is no light perception in 90% of the cases.

2.2.4.2.2 Pupillary changes

An afferent pupillary defect occurs immediately.

2.2.4.2.3 Fundus changes

Superficial retinal whitening occurring in the posterior pole in acute ophthalmic artery obstruction is more pronounced than with acute retinal artery obstruction. This is because the retinal pigment epithelium may be opacified as well as with acute obstruction to the ophthalmic artery. The cherry-red spot sign may or may not be present. One-third of the patients have none, one-third of the patients have a mild cherry-red spot and another one-third of the patients have a prominent cherry-red spot.

The presence of a retinal artery embolus is variable. “Salt and Pepper” retinal pigment epithelial change can occur in the posterior pole within weeks after the acute obstruction. The pigmentary epithelial change does not occur due to central retinal artery obstruction alone.

2.2.4.2.4 Differential diagnosis

Central Retinal Artery Obstruction.

2.2.4.3 Ocular investigations

2.2.4.3.1 Intravenous fluorescein angiography

The choroid should be completely filled within 5 seconds after the injection of dye. In this condition, there will be a delay in choroidal filling. There is delayed retinal arterial and venous filling observed as well, along with late focal or diffuse staining of the retinal pigment epithelium caused by choroid ischemia.

2.2.4.3.2 Electroretinography

The a-wave is decreased or absent suggestive of outer layer retinal ischemia. The b-wave is decreased or absent suggestive of inner layer retinal ischemia.

2.2.4.4 Systemic investigations

The most common etiology is iatrogenic; occurring after retrobulbar injection. Other systemic investigations are the same as CRAO.

2.2.4.5 Treatment

Spontaneous reversal of the condition is rare. The long-term vision in most cases is usually only perception of light. There is no proven treatment yet [46]. Vigilant systemic workup is mandatory due to the lack of an effective ocular treatment. The patient should be observed closely for neovascularization for the first several months. Laser PRP should be considered if and when neovascularization develops [65].

2.2.5 Management of retinal artery occlusions from an emergency physician’s perspective

The patient will present to the emergency room with acute, unilateral, painless, and severe loss of vision in the worst-case scenario. The vision loss occurs quickly within a period ranging from seconds to minutes. The visual acuity is no light perception in 90% of the cases. An afferent pupillary defect should be elicited. Fundus examination will reveal superficial retinal whitening occurring in the posterior pole in patients presenting with acute ophthalmic artery obstruction which is more pronounced than seen in patients presenting with acute retinal artery obstruction. The presence of a retinal artery embolus is variable.

Intravenous thrombolysis reduces the morbidity from acute arterial ischemic stroke pertaining to the eye, when given within 4.5 hours of the time a person was last free of symptoms [66, 67]. Intra-arterial thrombolysis is given via cannulation of the femoral artery. The introduction of a catheter is then done into the internal carotid artery, followed by the proximal ophthalmic artery at which point thrombolysis is administered. Thus, a precise dose of thrombolytic can be tailored to the individual patient in real-time. The role of surgical thrombectomy/ mechanics thrombectomy is not advocated.

2.3 Ocular ischemic syndrome

2.3.1 Disease entity

Ocular ischemic syndrome (OIS) is a result of chronic hypoperfusion, which is caused by severe ipsilateral atherosclerotic carotid stenosis, which accounts for about more than 90% of the cases. It is a rare condition [68]. It was noted that signs of ischemia were seen in both the anterior and posterior segments of the eye [69].

2.3.2 Etiopathogenesis

OIS is mostly seen in the elderly (>65 years) and men are affected twice as often as women, which is in correlation with the higher incidence of cardiovascular disease and underlying morbidity in males. Bilateral involvement is seen in 20% of the cases [70]. OIS has a five-year mortality rate of 40% mainly due to cardiac disease.

2.3.3 Clinical features

The clinical features of ocular ischemic syndrome are shown in Figure 20 [68, 69, 71, 72, 73].

Figure 20.

Clinical features of ocular ischemic syndrome.

2.3.4 Investigations

FA shows prolonged arteriovenous transit time, with delayed and patchy choroidal filling, retinal vessel wall staining is present. Leakage from the disc capillaries can be present.

The most essential diagnostic tool is carotid artery imaging. Non-invasive tests like Doppler ultrasound and ocular plethysmography allow detection of stenosis in about 75% of cases. An invasive technique used is carotid arteriography, which is utilized especially before planning for surgery. In cases where Doppler ultrasound is normal, ophthalmic artery Doppler imaging should be done. Other methods such as computed tomographic angiography and magnetic resonance angiography are also used.

2.3.5 Treatment

OIS needs a multidisciplinary approach and not just an ophthalmologist. It would also require a vascular surgeon, cardiologist, neurologist, and general physician if mandated. The inflammatory component is treated with topical steroids, non-steroidal anti-inflammatory agents, and cycloplegics. In the early stages of NVG, medical management utilizing topical beta-blockers or alpha-agonists along with oral carbonic anhydrase inhibitors might be used. In cases of refractory NVG, surgical management will be required. Macular edema is either treated by IVTA or intravitreal anti-VEGF injections, but not much data regarding this treatment is available [69]. PRP is used for treatment when there is NVE, NVD and NVI in OIS.

Systemic management will include carotid endarterectomy or stenting to decrease the risk of stroke. It may even help stabilize vision by aiding in controlling NVG. In cases of total obstruction, extracranial or intracranial arterial bypass surgery will be needed [74]. Care should be taken as there is an increase in intraocular pressure (IOP) after surgery, which should be managed accordingly. Proper systemic management of cardiovascular risk factors is also mandatory.

2.3.6 Management of ocular ischemic syndrome from an emergency physician’s/intensivist’s perspective

OIS needs a multidisciplinary approach. It would also require a battery of ophthalmologists, vascular surgeons, cardiologists, neurologists, and general physicians. The patient may present with complaints of transient loss of vision or gradual loss of vision with the above-mentioned fundus findings. The inflammatory component is treated with medical therapy such as topical steroids, non-steroidal anti-inflammatory agents, and cycloplegics. The surgical management includes carotid endarterectomy with no role for mechanical thrombectomy.

2.4 Cerebral venous and dural sinus thrombosis

2.4.1 Disease entity

Cerebral venous sinus thrombosis (CVST) is a clot in the venous drainage system of the brain (Video 5, https://www.youtube.com/watch?v=Y5EftYAGab0) which can result either in vision-threatening or life-threatening. Ribes MF was the first to report a case of CVST in 1825 in a 45-year-old man. The patient presented with headaches, seizures, and delirium. The autopsy confirmed cerebral venous thrombosis in the form of superior sagittal and lateral sinus thrombosis. The first postpartum autopsy confirming CVST was performed in 1828 by Abercrombie on a 25-year-old woman who died 2 weeks after an uncomplicated delivery due to CVST. Currently, the largest study exploring CVST is an Italian multi-centric study. This study involves 706 patients with CVST. The second largest study is the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVDST) which included 624 patients with CVST [75].

2.4.2 Etiopathogenesis

CVST is an atypical stroke accounting for 0.5–1% of all strokes and affects approximately 5 per one million people annually. Cerebral Venous and Sinus Thrombosis are most commonly seen in women and children [76]. A patient presenting with CVST is more likely to be younger (less than 50 years old) when compared to typical ischemic strokes [77].

Females are at increased risk for hormone-specific risk factors such as oral contraceptives, pregnancy, and hormone replacement therapy [78]. The risk factors for CVST can be classified into genetic causes and acquired causes.

The more commonly reported etiologies of CVST are shown in Figure 21 [79]. Virchow’s triad (Figure 22) is the main reason behind the pathophysiology of CVST.

Figure 21.

Etiology of cerebral venous sinus thrombosis (CVST).

Figure 22.

Virchow’s triad.

The thrombosis of cerebral veins occurs, most commonly in the junction between the cerebral veins and larger sinuses. The dural sinuses contain arachnoid granulations, which drain the cerebrospinal fluid (CSF) from the subarachnoid space into the systemic venous system, along with its function as venous channels. A thrombosis to the dural sinuses causes an increase in the impedance to CSF drainage resulting in increased intracranial pressure (ICP) (e.g., headache, nausea, vomiting, papilledema, and visual problems) [80].

Due to the variability in the cortical venous system, the clinical findings of a cortical vein thrombosis depend on the size of the thrombus, extent of the thrombus, location of thrombus, and nature of collateral supply. During unfavorable conditions, a CVST may lead to increased venous and capillary pressure and a breakdown in the blood–brain barrier which results in vasogenic edema, cytotoxic edema, and hemorrhage [81].

The proposed pathogenesis is explicitly shown in Figure 23. Commonly, both dural sinus and cortical venous thrombosis occur simultaneously, with isolation of either being very rare due to the effect of one over the other [81, 82].

Figure 23.

Pathogenesis of CVST.

The pathophysiology causing visual impairments in CVST (Figure 24) is as follows:

Figure 24.

Pathophysiology causing visual impairments in CVST.

2.4.2.1 Raised ICP without infarction

Whenever ICP increases there is a compensatory increase in CSF absorption by the arachnoid granulations. These arachnoid granulations are disrupted in dural sinus thrombosis. This leads to axoplasmic flow stasis with swelling of the optic nerve fiber and optic disc. The subsequent venous stasis and extracellular fluid accumulation manifest as papilledema. Patients presenting with signs and symptoms of raised ICP may be indistinguishable from idiopathic intracranial hypertension (IIH). Hence, it is mandatory that any patient with papilledema should undergo magnetic resonance imaging (MRI) of the head and a magnetic resonance venogram (MRV). Transient visual obscurations (lasting seconds at a time) or visual field defects develop due to papilledema. Diplopia may occur due to a false localizing finding of a sixth nerve palsy (Figure 25) due to increased ICP. Headache and pulsatile tinnitus may also occur as false localizing symptoms of increased ICP and can mimic the presentation of IIH.

Figure 25.

(a to i) Evaluation of extraocular movements in all nine gazes showing bilateral abduction deficit (false localizing sign).

2.4.2.2 Venous infarcts

Venous infarcts involve the geniculocalcarine tract especially the primary visual cortex. The involvement of occipital infarcts produces homonymous hemianopia.

2.4.2.3 Raised ICP following the development of secondary dural arteriovenous (AV) fistula

A late complication of CVST is dural AV fistula. Dural AV fistulas can cause an increase in dural sinus pressure with a subsequent decrease in CSF absorption and an increase in ICP.

2.4.2.4 Occipital arterial infarcts

Occipital arterial infarcts secondary to mass effect from the herniated large venous infarcts [83].

2.4.3 Clinical features

• Headache: In the ISCVDST, headache was the most common symptom (88.8%) in CVST. Headaches may be the only presenting sign, which can further complicate the diagnosis [84]. CVST in the absence of a headache is more common in older patients and men, when compared to CVST with a headache [85]. There is also a higher incidence of seizures and paresis, and a lower incidence of papilledema in CVST without a headache.

• Visual problems: Another common presenting sign/symptom in CVST according to the ISCVST is problems related to vision. Visual loss (13.2%), diplopia (13.5%), and papilledema (28.3%) were all noted. Migraine-like visual phenomena (colored photopsia, dark spots, and visual blurring associated with vertical wavy lines), have also been reported. A common finding seen in CVST is papilledema (Figure 26) and it is directly associated with elevated ICP. However, in eyes that have progressed to optic atrophy secondary to papilledema, the absence of papilledema cannot be used as a marker for raised ICP. Facial or craniofacial pains could be present as well.

• Seizures (39.3%): Seizures due to CVST compared to seizures due to arterial stroke (40% vs. 6%)

• Paresis (37.2%)

• Mental status changes (22%)

• Aphasia (19.1%)

• Stupor/Coma (13.9%)

• Sensory deficits (5.4%)

Figure 26.

(a and b) Fundus photograph showing papilledema of right (OD) and left eye (OS) respectively. (c and d) OCT optic nerve head showing disc edema of OD and OS respectively.

2.4.3.1 Clinical diagnosis

CVST has a variable clinical presentation. The diagnosis should be suspected in patients with new-onset focal neurological deficits, signs of increased ICP, seizures, or mental status changes. A thorough ocular exam comprising of dilated fundus examination, optic nerve photographs, and visual field examinations are mandatory in patients with CVST.

2.4.4 Investigations

2.4.4.1 Diagnostic imaging

The most sensitive test for identifying CVST is MRI T2 weighted imaging along with MRV. The appearance on MRI is dependent on the timeline of the thrombus. In the acute setting (days 1–5), the thrombus is typically hypointense on T2 and isointense on T1 weighted MRI. The subacute thrombosis (days 6–15) is usually strongly hyperintense on both T1 and T2 weighted images. After 3 weeks, the signal becomes irregular and either flow was restored or a persistent thrombus was seen [86].

In view of recent onset neurological deficits, a non-contrast head CT is usually the first test ordered. This test is not very specific for CVST and is abnormal in only approximately 30% of cases. In the roughly 30% of cases where CT reveals a CVST, an empty delta sign may be seen represented as a dense triangle in the posterior portion of the superior sagittal sinus (Figure 27). In areas where MRI/MRV are not as readily available, computed tomography venography may be added to CT to aid in the suspected diagnosis [87].

Figure 27.

Plain CT of axial section of the brain showing (a) left transverse sinus thrombosis (green arrow), (b) straight sinus thrombosis (red arrow) and superior sagittal sinus thrombosis (green arrow).

2.4.4.2 Laboratory tests

There is no laboratory study able to help rule out a CVST in the acute state [75]. However, complete blood count, chemistry panel, prothrombin time, aPTT, and a hypercoagulable state evaluation are mandatory. Testing for infectious or inflammatory states is also recommended in CVST.

2.4.4.3 Differential diagnosis

Due to the varying presentation of CVST, the differential diagnosis list (Figure 28) may vary according to the presenting symptom.

Figure 28.

Differential diagnosis of CVST.

2.4.5 Management

2.4.5.1 Medical therapy

Anticoagulation in the acute phase is preferred if there are no contraindications. Body weight adjusted subcutaneous low-molecular-weight heparin (LMWH) or dose-adjusted intravenous heparin is the drug of choice. If the patient has a concomitant intracranial hemorrhage related to the CVST, then still it is not an absolute contraindication for heparin therapy. In uncomplicated cases, LMWH is preferred over intravenous heparin due to fewer major bleeding problems. There is no evidence in the literature available for the duration of anticoagulation after the acute phase has subsided [75, 88, 89].

In cases of intracranial hypertension with secondary papilledema, progressive headache, or third or sixth nerve palsies management consists of a collection of strategies to reduce the pressure and preserve vision. The first measure is listed above; anticoagulation to reduce thrombotic occlusion of venous outflow. Other measures resemble the treatment of IIH. Serial lumbar punctures to reduce CSF volume can be considered with the caveat of needing to hold anticoagulation while it is performed. Other alternatives include treatment with acetazolamide to decrease CSF production [86]. Because blindness can be the long-term complication of elevated pressures on the optic nerve, close monitoring of visual acuity and visual fields is mandatory in patients with elevated ICP.

2.4.5.2 Surgery

Optic Nerve Sheath Fenestration (ONSF) can be planned for patients with CVST with raised ICP in situations where medical management has failed and visual function is failing. In patients where intracranial hypertension remains persistent despite adequate medical management and a lumbar drain, a CSF diversion procedure (ventriculoperitoneal or lumboperitoneal shunt) may be considered [90].

Endovascular thrombolysis and mechanical thrombectomy have not played a prominent role in the treatment of CVST but may be considered in cases of severe neurological deterioration despite the use of anticoagulation, venous infarcts causing mass effect, or intracerebral hemorrhage causing treatment-resistant intracranial hypertension [91].

2.4.5.3 Prognosis

The various prognosis of CVST is shown in Figure 29 [92].

Figure 29.

Prognosis of CVST.

2.4.6 Management of CVST from an emergency physician’s/intensivist’s perspective

CVST has a variable clinical presentation ranging from new-onset focal neurological deficits to features suggestive of raised ICP and seizures as mentioned in the clinical features section. A thorough ocular fundus exam is mandatory in patients with CVST. It would also require a battery of vascular surgeons, neurologists, and general physicians apart from ophthalmologists.

Though the prognosis is relatively poor, coma patients in particular have been noted as a predictor of even poorer outcomes. The gold standard treatment for CVST in adults is systemic anticoagulation. The aim of anticoagulation therapy is to establish recanalization of the thrombus vessel. Emergent endovascular mechanical thrombectomy (EMT) with balloon percutaneous transmural angioplasty and catheter aspiration is indicated, in the event of failure to respond to anticoagulation or in comatose state patients. However, the role of endovascular therapy in the management of pediatric and young adult CVST is unclear [93].

2.5 Cavernous sinus thrombosis

2.5.1 Disease entity

Cavernous sinus thrombosis (CST) is a condition caused by any thrombosis involving the cavernous sinus which may present as a combination of bilateral ophthalmoplegia (cranial nerves (CN) III, IV, VI), sensory trigeminal (V1-V2) loss, or autonomic dysfunction (Horner syndrome).

2.5.2 Etiopathogenesis

Patients with CST may present with ophthalmic symptoms initially to an ophthalmologist and will require urgent management considering its life-threatening prognosis. CST is typically seen as a sequela of facial infections, such as sinusitis or cellulitis. The valveless nature of the facial dural sinuses makes them vulnerable to stagnation. Poor drainage of the sinus in the setting of severe infection causes a thrombus formation. Then thrombus can cause damage to the local tissues or travel to the brain, causing stroke-like symptoms, encephalitis, or meningitis (Video 6, https://www.youtube.com/watch?v=lsSXM5SfnXE) [94].

2.5.3 Clinical features

The common clinical findings of CST are as shown in Figure 30 [94, 95, 96].

Figure 30.

Clinical features of cavernous sinus thrombosis.

2.5.4 Investigations

2.5.4.1 Diagnostic procedures

The diagnosis of cavernous sinus thrombosis is initially suspected on clinical grounds. However, further workup is needed to determine the underlying pathology. Due to the wide array of potential causes, an extensive workup is warranted and called for. To confirm the diagnosis, imaging of the head and orbit, and laboratory tests play an important role.

Clinical correlation of patients’ history should be done with the physical examination findings. This should be followed by appropriate diagnostic tests. Blood tests, such as complete blood count (CBC) and blood cultures are used to evaluate underlying infection. Serum studies, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), angiotensin-converting enzyme (ACE), and anti-neutrophil cytoplasmic antibodies (ANCA) are recommended to evaluate for an underlying inflammatory process. MRI of the brain and orbits with contrast and MRV are preferred investigations of choice to determine the presence of CST. Imaging with computed tomography (CT) of the brain and orbits or CT venography can be done as an adjunct to help adjudicate the presence of CVT [95].

2.5.5 Management

As such, treatment is not standardized but for CST recognition and timely emergency management is foremost. Intravenous antibiotics are started immediately for the treatment of any underlying infection. Though controversial, anticoagulation is recommended. Otolaryngology should be consulted to evaluate the need for surgical drainage of the primary infection [97].

2.5.6 Management of CST from an emergency physician’s/intensivist’s perspective

Patients with CST may initially present to an ophthalmologist but will require urgent management considering its life-threatening prognosis. Once diagnosed, this condition would warrant a battery of vascular surgeons, neurologists, and general physicians apart from ophthalmologists. CST leading to ocular hypertension and acute visual loss should be treated urgently with thrombectomy and thrombolysis of the cavernous sinuses and superior ophthalmic veins. Successful recanalization of the bilateral cavernous sinuses and superior ophthalmic veins can be achieved with transfemoral thrombectomy. Given the poor visual prognosis, if not treated urgently, recanalization with mechanical thrombectomy to immediately decrease the IOP and thus to spare the eyesight is mandatory. Anticoagulation therapy alone may not be adequate in cases of CST where vision is acutely threatened by ocular hypertension [98].

2.6 COVID-19 related/induced thrombotic ocular complications

2.6.1 Disease entity

There is a recent surge in the reporting of the various thrombotic complications related to coronavirus disease 2019 (COVID-19) in the literature, among which ophthalmology is no exception. The thromboembolic events occurring as sequela due to COVID-19 are defined as COVID-19 related/induced thrombotic ocular complication. Ophthalmologists being the first responders, have a vigilant role to play with a heightened awareness of these atypical thrombotic phenomena due to COVID-19. The incidence of a thrombotic phenomenon affecting multiple organs (with the eye being no exception) is estimated to be around 25% among patients hospitalized in the intensive care unit for COVID-19; even though anticoagulant treatment was administered prophylactically [99].

2.6.2 Etiopathogenesis

The pathophysiology of the ocular thrombotic events due to COVID-19 is linked to the complement-mediated thrombotic microangiopathy (TMA) and D-dimer levels. A potential link between mortality, D-dimer values, and the pro-thrombotic syndrome; and how it affects the end artery ocular system has been reported. Extrapulmonary thrombotic ocular manifestations are not only vision-threatening, but life-threatening too in certain instances, and are potentially treatable complications of the COVID-19.

The possible pathophysiology of the thromboembolic event is as follows: the COVID-19 virus initiates dysfunction of the endothelial cells, which in turn leads to excess thrombin generation and inhibition of fibrinolysis. This manifests with raised prothrombin levels as the end result [100]. In addition, hypoxemia is associated with an elevation of blood viscosity and activation of hypoxia-related genes that can mediate coagulation and fibrinolysis, thus favoring the fatal thrombotic events. When the plasma coagulation starts to take place, soluble fibrins are generated. This leads to the release of D-dimers which are characteristic degeneration products of cross-linked fibrin. Increased D-dimer levels trigger the activation of the coagulation cascade followed by the fibrinolytic processes.

International Federation of Clinical Chemistry Guidelines on COVID-19 strongly recommends D-dimer testing in patients with COVID-19. SARS-CoV-2 revealed a high correlation between the severity of illness and increased D-dimer levels [101, 102]. Additionally, fibrin, fibrinogen degradation products and fibrinogen are also significantly higher among patients with COVID-19.

2.6.2.1 Risk factors

2.6.2.1.1 COVID-19: the novel RNA beta-coronavirus

The novel RNA beta-coronavirus is identified as the causative pathogen for COVID-19 related/induced thrombotic ocular complications. The first infected people were exposed to live bats being sold in a wet market in Wuhan. The phylogenetic analysis revealed that bats are the potential original host of the virus.

2.6.2.2 COVID-19: the microvascular retinal circulation equation

Many different studies have shown a strong association between elevated D-dimer levels and severity of the thrombotic disease complications of COVID-19. The various thrombotic complications reported with COVID-19 are pulmonary embolism, stroke, disseminated intravascular coagulation limb infarcts, and digit infarcts [101, 102]. The involvement of the microvasculature system has created a whole new spectrum of eye diseases due to COVID-19; and the fact that retinal circulation is an end arterial system does not help. The end arterial system of the retinal vasculature is of clinical significance, because of the potential vision-threatening nature of retinal vascular diseases. Ocular manifestations have been reported to be the first sign of COVID-19 in many studies [102]. The reported ocular manifestations of COVID-19 are conjunctivitis, granulomatous anterior uveitis, choroiditis with retinal detachment, and retinal vasculitis [103].

2.6.2.3 Diabetic retinopathy-complement mediated thrombotic microangiopathy (TMA)

Zhang et al. suggested that complement-mediated thrombotic microangiopathy (TMA) is the leading factor of microvascular damage pathogenesis after COVID-19 in diabetic patients [104]. Complement system activation may be directly responsible for ocular vascular damage in accentuating diabetic retinopathy; with rare cases of atypical hemolytic uremic syndrome, leading to retinal artery, and vein occlusions [105]. High serum levels of C3 complement factor can cause an increased risk of developing diabetic retinopathy, nephropathy, and neuropathy; via endothelial dysfunction and thrombosis [106].

Immunohistochemical analysis conducted on the human eye has also revealed in favor of the ‘COVID-19 induced thrombotic event’ hypothesis. The ciliary body, choroid, retina, and retinal pigment epithelium (RPE) express significant levels of ACE receptors [107]. Since COVID-19 has a good affinity for vascular pericytes and expresses ACE-2, viral infection leads to complement-mediated endothelial cell dysfunction. Endothelial cell dysfunction leads to microvascular damage finally resulting in an ocular circulation infarct [108].

2.6.3 Clinical features

2.6.3.1 Retinal features

COVID-19-associated coagulopathy predisposes to a spectrum of thromboembolic events such as deep venous thrombosis, pulmonary embolism, and large-vessel ischemic strokes in patients with COVID-19. CRVO has also been described in a mechanism similar to the other thromboembolic manifestations of COVID-19. There are also cases of CRVO and CRAO being reported. The role of thrombophilic risk factors in the etiopathogenesis of retinal vein occlusions is controversial, and many authors suggest that cardiovascular risk factors for artery diseases play a more important role than coagulation disorders. The various studies reporting retinal signs and sequela post COVID-19 are shown in Table 1.

Study	Study sample	Inference
Marinho et al. [109]	12 adults (six males and six females, aged 25–69 years) were examined 11–33 days after the onset of COVID-19 symptoms	Hyperreflective lesion at the level of ganglion cell and inner plexiform layers at the level of papillomacular bundle
Bikdeli et al. [110]	Comprehensive Review Article	COVID-19 may predispose patients to arterial and venous thrombosis and that initial series suggest that the occurrence of venous thromboembolic disease in patients with severe COVID-19 is common

Table 1.

Retinal signs and sequelae post COVID 19 infection.

2.6.3.2 Optic nerve head features due to cerebral venous thrombosis

The various studies reporting optic nerve head changes and sequelae post COVID-19 are shown in Table 2. The optic nerve head involvement is predominantly indirect, manifesting as papilledema post cerebral venous thrombosis after COVID -19.

Study	Study sample	Inference
Cavalcanti et al. [111]	Three young patients, less than 41 years of age with COVID-19 had features of bilateral disc edema	COVID-19 associated cerebral venous thrombosis
Ramesh et al. [112]	A 22-year-old female patient without comorbidities presented with fever, headache, diplopia, and recurrent episodes of transient loss of vision which lasted for a few seconds in both eyes (OU) for two days. On examination, the best visual acuity was 20/20 in OU with the false localizing sign. The anterior segments were normal with bilateral disc edema, and disc hemorrhage in the right eye (OD) after the onset of COVID-19 symptoms	An unusual presentation with catastrophic cerebral venous thrombosis in previously healthy young patients infected with SARS-CoV-2 was demonstrated

Table 2.

Optic nerve signs and sequela post COVID-19 infection due to cerebral venous thrombosis.

2.6.4 Diagnostic and preventive actions

2.6.4.1 Diagnosis

The diagnosis is clinically based with laboratory investigations strengthening the association with COVID-19. The laboratory abnormalities found in COVID-19 patients include lymphopenia and elevation in lactate dehydrogenase. C-reactive protein, D-dimer, ferritin, and interleukin-6 (IL-6) have a strong correlation with disease severity and are mandatory tests in the procoagulant profile.

2.6.4.2 Role of anti-thrombotic therapy

A Chinese single-center retrospective cohort study (Tonghi hospital) of 449 consecutive patients recently concluded that severe COVID-19 patients will need prophylactic doses of heparins for improved survival (20%) especially if there is any evidence of sepsis-induced coagulopathy (SIC / DIC) [113, 114]. Severe COVID-19 was defined as either a respiratory rate ≥ 30/min, arterial oxygen saturation ≤ 93% at rest, and/or PaO2/FiO2 ≤ 300 mmHg. Exclusion criteria included patients with bleeding and clotting disorders, hospital stay <7 days, and lack of information on coagulation parameters and medications. Heparin was associated with lower 28-day mortality in patients with SIC/DIC.

2.6.4.3 Chest CT

To enable standardized reporting, CO-RADS were coined by the Dutch Radiological Society reporting the typical CT pattern of COVID-19 pneumonia; characterized by the consistent presence of peripheral ground-glass opacities associated with multilobar, and posterior involvement, bilateral distribution, and sub-segmental vessel enlargement [114]. Vessel enlargement described in the vicinity of ground-glass opacity areas was compatible with the thrombo-inflammatory processes [115, 116, 117, 118, 119, 120]. Sub-segmental vascular enlargement (more than 3 mm diameter) in areas of lung opacity was observed in 89% of patients with confirmed COVID-19 pneumonia. All the CTs were done without contrast. Although in situ thrombosis is certainly a possibility, these findings could also represent hyperemia or increased blood flow. Anticoagulant therapy demonstrated partial or complete resolution at follow-up CT pulmonary angiography and significantly decreased mortality rates. Careful attention needs to be paid to the initial diagnosis, prevention, and treatment of the pro-thrombotic and thrombotic ophthalmic state, which can occur in a minimal but significant percentage of COVID-19 patients.

2.6.4.4 Recommendations

1. Prophylactic-dose low-molecular-weight heparin should be initiated in all patients with (suspected) COVID-19 admitted to the hospital, irrespective of risk scores especially if associated with severe vision-threatening or life-threatening ophthalmic thromboembolic conditions.

2. A baseline (non-contrast) chest CT should be considered in all patients with suspected COVID-19 with severe vision-threatening or life-threatening ophthalmic thromboembolic conditions.

3. In patients with suspected COVID-19 with severe vision-threatening or life-threatening ophthalmic thromboembolic conditions, CT pulmonary angiography should be considered, if the D-dimer level is elevated.

4. In patients with COVID-19 and severe vision-threatening or life-threatening ophthalmic thromboembolic conditions, routine serial D-dimer testing should be considered during the hospital stay for prognostic stratification.

5. COVID-induced CVST and CST should be treated urgently with thrombectomy and thrombolysis of the cavernous sinuses and superior ophthalmic veins, if they are causing ocular hypertension.

6. The role of mechanical thrombectomy is not warranted in COVID-induced retinal artery and vein occlusions.

3. Conclusions

Ocular thromboembolic complications may be the first manifestations of a life-threatening system disease or COVID-19. Ophthalmologist being the first responder needs to be vigilant and keep this possibility in mind. Heightened awareness of these atypical but life-threatening extrapulmonary treatable complications of the COVID-19 disease spectrum is encouraged and called for, especially during the time of the pandemic.

Acknowledgments

We sincerely thank Dr. Veena Shankari Padmanaban, Radiology Consultant - Anderson Diagnostics, Chennai, Tamil Nadu, India for her constant support in the interpretation of the radiological features pertaining to ocular thrombotic events. We are grateful for Mr. Pragash Michael Raj - Department of Multimedia, Mahathma Eye Hospital Private Limited, Trichy, Tamil Nadu, India for his technical support throughout the making of this chapter and its illustrations.

Conflict of interest

The authors declare no conflict of interest.

INTERNATIONAL STATISTICAL CLASSIFICATION OF DISEASES AND RELATED HEALTH PROBLEMS (ICD) CODES, PERTAINING TO OCULAR THROMBOTIC PHENOMENA

ICD-10-CM Diagnosis CodeH34 Retinal vascular occlusions

ICD-10-CM Diagnosis Code H34.0 Transient retinal artery occlusion

    H34.00—unspecified eye

    H34.01—right eye

    H34.02—left eye

    H34.03—bilateral

ICD-10-CM Diagnosis Code H34.1 Central retinal artery occlusion

    H34.10—unspecified eye

    H34.11—right eye

    H34.12—left eye

    H34.13—bilateral

ICD-10-CM Diagnosis Code H34.2 other retinal artery occlusions

    H34.21 Partial retinal artery occlusion

       H34.211—right eye

       H34.212—left eye

       H34.213—bilateral

       H34.219—unspecified eye

H34.23 Retinal artery branch occlusion

       H34.231—right eye

       H34.232—left eye

       H34.233—bilateral

       H34.239—unspecified eye

ICD-10-CM Diagnosis Code H34.8 other retinal vascular occlusions

    H34.81 Central retinal vein occlusion

       H34.811 Central retinal vein occlusion, right eye

           H34.8110—with macular edema

           H34.8111—with retinal neovascularization

           H34.8112—stable

    H34.812 Central retinal vein occlusion, left eye

        H34.8120—with macular edema

        H34.8121—with retinal neovascularization

        H34.8122—stable

    H34.813 Central retinal vein occlusion, bilateral

        H34.8130—with macular edema

        H34.8131—with retinal neovascularization

        H34.8132—stable

    H34.819 Central retinal vein occlusion, unspecified eye

        H34.8190—with macular edema

        H34.8191—with retinal neovascularization

        H34.8192—stable

H34.82 Tributary (branch) retinal vein occlusion

    H34.821 Tributary (branch) retinal vein occlusion, right eye

        H34.8210—with macular edema

        H34.8211—with retinal neovascularization

        H34.8212—stable

    H34.822 Tributary (branch) retinal vein occlusion, left eye

        H34.8220—with macular edema

        H34.8221—with retinal neovascularization

        H34.8222—stable

    H34.823 Tributary (branch) retinal vein occlusion, bilateral

        H34.8230—with macular edema

        H34.8231—with retinal neovascularization

        H34.8232—stable

    H34.829 Tributary (branch) retinal vein occlusion, unspecified eye

        H34.8290—with macular edema

        H34.8291—with retinal neovascularization

        H34.8292—stable

ICD-10-CM Diagnosis Code H34.9 Unspecified retinal vascular occlusion

ICD-10-CM Diagnosis Code H35.82 Ocular Ischemic Syndrome

ICD-10-CM Diagnosis Code I67.6 Cerebral Venous Thrombosis

Notes/thanks/other declarations

I (Dr. Prasanna Venkatesh Ramesh) owe a deep sense of gratitude to my daughters (Pranu and Hasanna) and family (in-laws) for all their prayers, support, and encouragement. Above all, I extend my heartfelt gratitude to all the patients who consented for images which are utilized for this chapter.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the chapter. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Nomenclature

ACE	Angiotensin-Converting Enzyme
ANA	Anti-Nuclear Antibody
AV	Arteriovenous
BBB	Blood-Brain Barrier
BP	Blood Pressure
BRAO	Branch Retinal Artery Occlusion
BRAVO	Study of the Efficacy and Safety of Ranibizumab Injections in Patients with Macular Edema Secondary to Branch Retinal Vein Occlusion
BRVO	Branch Retinal Vein Occlusion
BVOS	Branch Vein Occlusion Study
CBC	Complete Blood Count
CLRAO	Cilioretinal Artery Occlusion
COPERNICUS	Vascular Endothelial Growth Factor Trap-Eye
COVID-19	Corona Virus Disease-2019
CRAO	Central Retinal Artery Occlusion
CRAVE	Comparison of Anti-VEGF Agents in the Treatment of Macular Edema from Retinal Vein Occlusion
C-RP	C-Reactive Protein
CRUISE	Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion
CRVO	Central Retinal Vein Occlusion
CSF	Cerebrospinal Fluid
CST	Cavernous Sinus Thrombosis
CT	Computed Tomography
CVST	Cerebral Venous Sinus Thrombosis
DIC	Disseminated Intravascular Coagulation
ECG	Electrocardiography
ESR	Erythrocyte Sedimentation Rate
FA	Fluorescein Angiography
GALILEO	Vascular Endothelial Growth Factor Trap-Eye for Macular Edema Secondary to Central Retinal Vein Occlusion Study (Conducted outside North America)
GCA	Giant Cell Arteritis
GENEVA	Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion with Macular Edema
HM	Hand Movements
HRVO	Hemiretinal Vein Occlusion
IBD	Inflammatory Bowel Disease
ICP	Intracranial Pressure
IIH	Idiopathic Intracranial Hypertension
IOP	Intraocular Pressure
ISCVDST	International Study on Cerebral Vein and Dural Sinus Thrombosis
IVTA	Intravitreal Triamcinolone Acetonide
LMWH	Low Molecular Weight Heparin
MRI	Magnetic Resonance Imaging
MRV	Magnetic Resonance Venogram
NVD	Neovascularization of Disc
NVE	Neovascularization Elsewhere
NVG	Neovascular Glaucoma
OAO	Ophthalmic Artery
OIS	Ocular Ischemic Syndrome
ONFS	Optic Nerve Sheet Fenestration
PIRW	Peri-Venular Ischemic Retinal Whitening
PRP	Panretinal Photocoagulation
PV	Plasma Viscosity
RAO	Retinal Artery Occlusion
RAPD	Relative Afferent Pupillary Defect
RPE	Retinal Pigment Epithelium
RVO	Retinal Vein Occlusion
SCORE	The SCORE Study will compare the effectiveness and safety of standard care to intravitreal injection(s) of triamcinolone for treating macular edema (swelling of the central part of the retina) associated with central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO)
SIC	Sepsis Induced Coagulopathy
SLE	Systemic Lupus Erythematosus
TMA	Thrombotic Microangiopathy
VEGF	Vascular Endothelial Growth Factor
VIBRANT	Intravitreal Aflibercept for Macular Edema following Branch Retinal Vein Occlusion study