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.

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Chapter
The Holistic Spectrum of
Thrombotic Ocular Complications:
Recent Advances with Diagnosis,
Prevention, and Management
Guidelines
Prasanna Venkatesh Ramesh, Shruthy Vaishali Ramesh,
Prajnya Ray, Aji Kunnath Devadas,Tensingh Joshua,
Anugraha Balamurugan, Meena Kumari Ramesh
and Ramesh Rajasekaran
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 hospi-
talized in the intensive care unit for COVID-19, even though anticoagulant treat-
ment 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. Ophthalmolo-
gists, sometimes being the first responder, have a vigilant role to play with a
heightened awareness of these atypical extrapulmonary thrombotic ocular mani-
festations, 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.
Keywords: Thrombotic Ocular Complications, Central Retinal Vein Occlusion,
Central Retinal Artery Occlusion, COVID-19 Induced Thrombotic Complications,
Cerebral Venous Thrombosis, Dural Sinus Thrombosis
1

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 affect-
ing 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 phenome-
non 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.
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
Figure 1.
Various artery and venous thromboembolic phenomena affecting the eye.
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Thrombectomy - Recent Advances in Ischaemic Damage Treatment

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 compres-
sions [3]. The atherosclerotic causes include systemic arterial hypertension, arterio-
sclerosis, 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 uncom-
mon 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.
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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.
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 ische-
mic 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 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.
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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.
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 involv-
ing a major arcade, can be extremely subtle with minimal hemorrhage, telangiecta-
sia or macular edema, and the correct diagnosis is frequently missed [16].
Figure 3.
Anterior segment slit lamp photograph showing neovascularization of iris (red arrows) and ectropion uveae
with mid-dilated pupil.
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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 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.
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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,
Figure 5.
Clinical features of non-ischemic CRVO.
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.
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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.
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.
Figure 8.
Tributary vein occlusion. A venule within the macula is occluded showing few retinal hemorrhages in the
involved area.
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Thrombectomy - Recent Advances in Ischaemic Damage Treatment

Similarly, in BRVO more than 5 disc areas of capillary nonperfusion is associated
with an increased risk of neovascularization.
OCT macula (Figure 4c) is used to confirm the presence of CME and quantify it,
which is often mild in a non-ischemic case.
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.
Figure 10.
Fundus fluorescein angiographic findings in various artery, and vein occlusions.
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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.
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].
Figure 11.
(a) Systemic investigations done in retinal vein occlusion cases. (b) Systemic investigations done in special cases
of retinal vein occlusion.
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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
macularedema,thoughitisassociatedwiththeriskofraisedIOPandcataract
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 tempo-
rarily resolve the neovascularization until PRP laser is given [25].
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
Figure 12.
Fundus photograph showing a case of CRVO treated with panretinal photocoagulation therapy.
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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 effec-
tive 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 sig-
nificant 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
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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
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.
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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].
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].
Pathophysiologies of the embolic phenomenon due to atherosclerosis is shown in
Figure 15.
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
Figure 14.
Risk factors of CRAO associated with retinal emboli.
14
Thrombectomy - Recent Advances in Ischaemic Damage Treatment

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 situ-
ated in the proximal retinal vasculature due to calcific emboli, or a small pale bodies
of fibrin-platelet embolus [43].
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.
2.2.2.5 Systemic investigations
The battery of investigations is shown in Figure 18.
Figure 15.
Pathophysiology of an embolic phenomenon due to atherosclerosis in CRAO.
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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].
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.
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Although intervention has shown improved retinal perfusion, this did not nec-
essarily 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
Figure 18.
Systemic investigations done in CRAO.
Figure 17.
Classification of CRAO.
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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 (amauro-
sis 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.
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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].
2.2.3.2.4 Retinal intra-arterial emboli
Prevalence is uncertain.
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.
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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 obstruc-
tion 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].
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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.
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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 pos-
terior 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 throm-
bolysis 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.
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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, 71–73].
2.3.4 Investigations
FA shows prolonged arteriovenous transit time, with delayed and patchy cho-
roidal 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
Figure 20.
Clinical features of ocular ischemic syndrome.
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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 physi-
cian 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 treat-
ment 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 sur-
gery 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 sys-
temic 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 oph-
thalmologists, vascular surgeons, cardiologists, neurologists, and general physi-
cians. The patient may present with complaints of transient loss of vision or gradual
loss of vision with the above-mentioned fundus findings. The inflammatory com-
ponent 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 sys-
tem 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].
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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.
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 throm-
bus, 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 21.
Etiology of cerebral venous sinus thrombosis (CVST).
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The pathophysiology causing visual impairments in CVST (Figure 24)isas
follows:
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
Figure 22.
Virchow’s triad.
Figure 23.
Pathogenesis of CVST.
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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 symp-
toms of raised ICP may be indistinguishable from idiopathic intracranial hyperten-
sion (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.
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].
Figure 24.
Pathophysiology causing visual impairments in CVST.
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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%)
Figure 25.
(a to i) Evaluation of extraocular movements in all nine gazes showing bilateral abduction deficit (false
localizing sign).
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•Aphasia (19.1%)
•Stupor/Coma (13.9%)
•Sensory deficits (5.4%)
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
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.
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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].
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 inflam-
matory 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 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).
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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 con-
comitant 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 evi-
dence 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
Figure 28.
Differential diagnosis of CVST.
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despite adequate medical management and a lumbar drain, a CSF diversion proce-
dure (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].
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 neuro-
logical 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 cath-
eter 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].
Figure 29.
Prognosis of CVST.
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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 oph-
thalmologist 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 [94–96].
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
Figure 30.
Clinical features of cavernous sinus thrombosis.
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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 immedi-
ately 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].
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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 complica-
tions 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 associ-
ated 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 gener-
ated. 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 phylo-
genetic 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 uve-
itis, 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
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pathogenesis after COVID-19 in diabetic patients [104]. Complement system
activation may be directly responsible for ocular vascular damage in accen-
tuating diabetic retinopathy; with rare cases of atypical hemolytic uremic syn-
drome, leading to retinal artery, and vein occlusions [105]. High serum levels of
C3 complement factor can cause an increased risk of developing diabetic reti-
nopathy, 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.
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 predomi-
nantly indirect, manifesting as papilledema post cerebral venous thrombosis after
COVID -19.
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.
36
Thrombectomy - Recent Advances in Ischaemic Damage Treatment

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 satu-
ration ≤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 Radio-
logical Society reporting the typical CT pattern of COVID-19 pneumonia; charac-
terized 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 pro-
cesses [115–120]. 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
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.
37
The Holistic Spectrum of Thrombotic Ocular Complications: Recent Advances with Diagnosis…
DOI: http://dx.doi.org/10.5772/intechopen.100265

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.
Acknowledgements
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.
38
Thrombectomy - Recent Advances in Ischaemic Damage Treatment

Notes/thanks/other declarations
I (Dr. Prasanna Venkatesh Ramesh) owe a deep sense of gratitude to my daugh-
ters (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.
Appendices and Nomenclature
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
39
The Holistic Spectrum of Thrombotic Ocular Complications: Recent Advances with Diagnosis…
DOI: http://dx.doi.org/10.5772/intechopen.100265

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
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-EyeInvestigation of
Efficacy and Safety in Central Retinal Vein Occlusion Study
(Conducted within North America)
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
40
Thrombectomy - Recent Advances in Ischaemic Damage Treatment

CRUISE Ranibizumab for the Treatment of Macular Edema after Central
Retinal Vein OcclusionEvaluation of Efficacy and Safety study
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 Throm-
bosis
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 ret-
ina) 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
41
The Holistic Spectrum of Thrombotic Ocular Complications: Recent Advances with Diagnosis…
DOI: http://dx.doi.org/10.5772/intechopen.100265

Author details
Prasanna Venkatesh Ramesh
1
*, Shruthy Vaishali Ramesh
2
, Prajnya Ray
3
,
Aji Kunnath Devadas
3
, Tensingh Joshua
4
, Anugraha Balamurugan
5
,
Meena Kumari Ramesh
2
and Ramesh Rajasekaran
6
1 Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited,
Trichy, Tamil Nadu, India
2 Department of Cataract and Refractive Surgery, Mahathma Eye Hospital Private
Limited, Trichy, Tamil Nadu, India
3 Department of Optometry and Visual Science, Mahathma Eye Hospital Private
Limited, Trichy, Tamil Nadu, India
4 Mahathma Centre of Moving Images, Mahathma Eye Hospital Private Limited,
Trichy, Tamil Nadu, India
5 Department of Vitreo-Retinal Surgery, Mahathma Eye Hospital Private Limited,
Trichy, Tamil Nadu, India
6 Department of Paediatric Ophthalmology and Strabismus, Mahathma Eye
Hospital Private Limited, Trichy, Tamil Nadu, India
*Address all correspondence to: email2prajann@gmail.com
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
42
Thrombectomy - Recent Advances in Ischaemic Damage Treatment

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