Retinal Artery Occlusions: Clinical Guidelines

List of Abbreviations

IOP — intraocular pressure

HIV — human immunodeficiency virus

ICA — internal carotid artery

OA — ophthalmic artery

GCA — giant cell arteritis

OD — optic disc

SPCA — short posterior ciliary artery

ON — optic nerve

CT — computed tomography

BCVA — best corrected visual acuity

MRI — magnetic resonance imaging

ECA — external carotid artery

RAPD — relative afferent pupillary defect

BRAO — branch retinal artery occlusion

OAI — ophthalmic artery occlusion

OCT — optical coherence tomography

OCT-A — optical coherence tomography angiography

CVA — cerebrovascular accident

CRAO — central retinal artery occlusion

CRVO — central retinal vein occlusion

ClRAO — cilioretinal artery occlusion

PAMM — paracentral acute middle maculopathy

PRLP — panretinal laser photocoagulation

RAO — retinal artery occlusion

RCT — randomized controlled trial

EMS — emergency medical services

ESR — erythrocyte sedimentation rate

CRP — C-reactive protein

TBVL — transient binocular vision loss

TIA — transient ischemic attack

TMVL — transient monocular vision loss (amaurosis fugax)

TVL — transient vision loss

US — ultrasound

FA — fluorescein angiography of the ocular fundus

CRA — central retinal artery

CRA — cilioretinal artery

ERG — electroretinography

Terms and Definitions

Central retinal artery occlusion (CRAO) is an acute circulatory disorder in the main trunk of the central retinal artery, with or without retinal ischemia.

Arteritic CRAO: CRAO associated with systemic vasculitis.

Non-arteritic CRAO: CRAO not associated with systemic vasculitis (most commonly due to embolism).

Branch retinal artery occlusion (BRAO) is an acute blood flow disorder in a second- or third-order branch of the central retinal artery due to thromboembolism or vasospasm, with or without retinal ischemia.

Ophthalmic artery occlusion (OAO) is an acute blood flow disorder in the ophthalmic artery, with or without retinal and/or choroidal ischemia.

Paracentral acute middle maculopathy (PAMM) is a condition associated with impaired arterial blood supply to the retina. It may present as an independent disease or in combination with other retinal vascular disorders, where local microcirculatory disturbances occur exclusively at the level of the inner nuclear layer, causing temporary vision reduction and limited alterations in the paracentral visual field.

Reperfused (transient) CRAO is a variant of CRAO resulting from a short-term blood flow disruption and manifesting as a combination of severe sudden vision loss and the classic ophthalmoscopic picture of CRAO.

Transient monocular vision loss (TMVL – amaurosis fugax) is a temporary, painless, monocular loss of vision followed by its recovery.

CRAO with preserved cilioretinal artery blood flow is CRAO occurring in the presence of a functioning cilioretinal artery.

Ocular biomicroscopy is a method of intravital visual examination of the optical media and tissues of the eye based on creating contrast between illuminated and non-illuminated areas, performed using a slit lamp and additional diagnostic lenses (in particular, for fundus biomicroscopy).

Optical coherence tomography (OCT) is a diagnostic non-invasive non-contact method of intravital visualization, qualitative and quantitative analysis of the morphological features of fundus structures, based on the principle of light interferometry.

Optical coherence tomography angiography (OCT-A) is a diagnostic non-invasive non-contact method of intravital visualization, qualitative and quantitative analysis of microcirculation in fundus structures, taking into account the segmentation of retinal layers.

Cherry-red spot sign is a clinically significant ophthalmoscopic sign of a number of pathological conditions accompanied by retinal ischemia: a reddish area in the center of the macula, surrounded by a pale retina (clouded due to thickening and loss of transparency).

Relative afferent pupillary defect (RAPD, Marcus Gunn pupil) is an asymmetry of afferent pupillary impulses, which serves as a sensitive indicator of unilateral or asymmetric damage to the afferent limb of the light pupillary reflex.

Fluorescein angiography of the ocular fundus (FA, sodium fluorescein angiography) is a diagnostic method used to detect vascular bed disorders in the ocular fundus and assess the state of the outer and inner blood-retinal barriers by recording the passage of a dye (intravenously administered sodium fluorescein) through the vessels of the eye in photo and video monitoring modes.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Retinal artery occlusion (RAO) is an urgent ophthalmological condition associated with impaired blood flow in the arterial vessels (the ophthalmic artery, central retinal artery or its branches, cilioretinal artery) due to various causes (spasm, thrombosis, embolism, or inflammation), characterized by temporary or persistent vision loss with or without the clinical picture of inner retinal layer ischemia.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The pathogenetic mechanism uniting all forms of RAO, which can be subdivided into inflammatory and non-inflammatory, is hypoperfusion (impaired blood supply) of the retina, and less commonly of the choroid or optic nerve (ON). RAO can occur in any of the vessels supplying blood to the eye.

1.2.1 Features of the blood supply to the retina and optic nerve.

The main artery supplying the eye, including the retina and surrounding structures (including partially the ON), is the ophthalmic artery (arteria ophthalmica). The OA is a vessel with a diameter of about 2 mm; in the vast majority of people, it is a branch of the internal carotid artery (ICA). After the origin of the OA, the diameter of the ICA decreases from 5.4 mm to 3.8 mm. It is believed that such a narrowing of the ICA caliber leads to an increase in blood pressure in the OA, thereby providing a more intensive blood flow. The OA most commonly passes through the optic canal into the orbit, located inferior to the optic nerve. In the orbit, at a distance of approximately 15–18 mm from the posterior pole of the eyeball, it passes from the lateral side of the nerve to the superior surface, looping around it to form an arch. Further, the OA passes inferior to the superior rectus muscle, heads toward the medial wall of the orbit, and along the way gives off a number of branches distributed in the following sequence: 1) lacrimal artery; 2) central retinal artery (CRA); 3) posterior ciliary arteries; 4) muscular arteries; 5) posterior ethmoidal artery; 6) anterior ethmoidal artery; 7) supraorbital artery; 8) medial palpebral arteries; 9) supratrochlear artery; 10) dorsal nasal artery [1].

The CRA, which passes to the eyeball within the thickness of the ON, divides at the optic disc (OD) into superior and inferior branches, each of which in turn divides into nasal and temporal arterioles that lack anastomoses between them. The CRA is the main source of blood for the inner layers of the retina. In addition, in the blood supply to the inner layers of the retina in the central zone, inconstant additional vessels—cilioretinal arteries (identified in 6.9%–49.5% of people in amounts of 1 to 3)— may take part as branches of the short posterior ciliary arteries (SPCA), emerging directly on the optic disc from its temporal side or in the peripapillary zone [2]. The cilioretinal artery (CRA) supplies the temporal part of the macula with complete or partial involvement of the perifoveolar zone. The SPCA are also branches of the OA; they supply the choroid and outer layers of the retina (via choriocapillaris).

There are variants of the OA originating from other cerebral arteries and a developmental variant of the CRA with division into superior and inferior branches directly within the thickness of the ON. A number of individuals have well-developed collateral circulation between the OA and the external carotid artery (ECA). This has a significant positive effect on the blood supply to the eye even under conditions of complete ICA occlusion.

Branches of the CRA give off separate precapillary arterioles, which together with precapillary venules form a perifoveal capillary ring around the macula, consisting only of capillaries of the superficial capillary plexus (SCP). Through "diving" capillaries, the intermediate and deep capillary plexuses are formed, from which blood drains directly into the precapillary venules of the SCP.

1.2.2. Main forms and mechanisms of circulatory disorders in RAO

Circulatory disturbances in the OA and its branches can be acute or chronic.

Acute forms include: OA occlusion, CRA occlusion and its branches, occlusion of paraoptic SPCAs (clinically manifesting as the development of anterior ischemic optic neuropathy) and CRA occlusions, as well as the development of paracentral acute middle maculopathy (PAMM). Chronic forms: venous stasis retinopathy as a manifestation of ocular ischemic syndrome, and episodes of transient monocular vision loss (TMVL) [3-5].

The main mechanisms of retinal and optic nerve circulatory disorders are:

• hypoperfusion associated with diseases of the external and internal carotid arteries (vascular developmental anomalies in the brachiocephalic artery (BCA) system, as well as stenosis due to atherosclerotic lesions). According to BCA duplex scanning, ipsilateral ICA stenosis narrowing the vessel lumen by 50% or more is detected in 34–40% of patients with CRAO and in 30% of patients with BRAO [6]. Hypoperfusion can also be triggered by acute angiospasm associated with a sharp drop in blood pressure (due to an excessive hypotensive effect of medications, massive blood loss, or the use of vasoconstrictors in ENT, oral cavity, and periorbital surgeries) [7, 8].

• embolism: the source of platelet and fibrin emboli can be the cardiac chambers, heart valve disease, myxoma, an unstable surface of an atherosclerotic plaque in the brachiocephalic arteries, thrombosis of an internal carotid artery (ICA) aneurysm in the ophthalmic segment, ICA dissection, etc. [9]. Echocardiography performed in patients with central retinal artery occlusion (CRAO) revealed a cardiac embolic source in 52% of patients; most frequently, the source was the aortic valve or combined aortic and mitral valve disease associated with calcification. The source of cholesterol emboli (Hollenhorst plaques) is atherosclerotic plaques of the carotid arteries, detected in 71% of cases with CRAO and in 66% with branch retinal artery occlusion (BRAO) [6]. In 74% of cases, the emboli represent cholesterol aggregates, in 10.5% they contain calcium, and in 15.5%, fibrin and platelets. The presence of an embolus within the arterial lumen is an inconsistent finding. The embolus may be located in the proximal segment of the central retinal artery (CRA) and be inaccessible to visualization, or it may disintegrate or migrate [6]. Embolism may also be iatrogenic in nature: the entry into the retinal artery via collateral circulation of certain agents used in cosmetology (fillers, platelet-rich plasma, etc.) [10].

• inflammation associated with conditions such as giant cell arteritis, Susac syndrome, systemic lupus erythematosus, polyarteritis nodosa, antiphospholipid syndrome, granulomatosis with polyangiitis, and Takayasu arteritis [11]. Immune-mediated inflammation is likely the cause of local retinal vasculitis associated with the intravitreal administration of certain medications (including vancomycin, pegcetacoplan, several anti-angiogenic drugs, and some others) [12]. Autoimmune inflammation is considered one of the most likely causes of Purtscher-like retinopathy, which is classified as an occlusive microvasculopathy developing in the setting of pancreatitis, renal failure, and autoimmune diseases [13].

• vasospasm caused by nervous system disorders (migraine, occipital epilepsy, posterior reversible encephalopathy syndrome, hysteria) [14].

• thrombosis in situ, arising due to various disorders, including atherosclerotic disease, collagenoses, inflammation, and hypercoagulability [15, 16].

Risk factors for retinal artery occlusion (RAO).

Risk factors and demographic characteristics typical for RAO are similar to those for ischemic stroke and myocardial infarction.

• Major: arterial hypertension (73%), arterial hypotension, hyperglycemia (14%), hyperlipidemia (49%), obesity (82%), smoking (49%) [17-19].

• Additional: hypercoagulable states (antiphospholipid syndrome, other forms of inherited and acquired thrombophilia, malignancies, including myeloproliferative disorders) [6, 20], and ophthalmological causes that indirectly affect perfusion pressure and impede blood flow (optic disc edema, optic disc drusen, intermittent angle-closure glaucoma) [14].

In approximately 25–30% of cases, the etiology of RAO cannot be established [21].

Brief retinal hypoperfusion usually does not cause structural changes. It has been experimentally proven that complete cessation of blood flow in the CRA for 97 minutes does not lead to irreversible changes in primates; however, a total occlusion period exceeding 240 minutes causes extensive and irreversible changes in all retinal layers (primarily affecting the ganglion cell and inner nuclear layers). The experimental CRA model cannot provide a reliable representation of the survival time of retinal ganglion cells, which are essentially central nervous system cells. Brain neuron death during blood flow arrest in cerebral arteries during surgery occurs after 5 minutes. This is because the rate of oxygen consumption by the brain is one of the highest in the body, at about 3.5 ml/100 g/min. An even higher rate of oxygen consumption is observed only in the inner layers of the human retina, ranging from 8 to 13 ml/100 g/min. Therefore, it is believed that irreversible changes under conditions of complete occlusion of the retinal artery or CRA occur within 5–15 minutes, and potential visual function improvement in a later period may be explained by the preservation of residual blood flow [22]. Meanwhile, the outer layers of the retina, supplied by the choroidal vessels, remain intact, and the inner layers may partially preserve their functional activity.

In the last decade, owing to in vivo imaging of retinal structures using optical coherence tomography (OCT), another condition associated with impaired retinal arterial blood supply has been described—paracentral acute middle maculopathy (PAMM). The pathogenesis of this condition is still being studied. It is known that PAMM can occur as an independent disease or in combination with other retinal vascular disorders. Specifically, PAMM is detected in 50% of patients with RAO, in 63.5% of cases with a diagnosis of CRAO, and in 36.5% of cases with branch retinal artery occlusion (BRAO). In PAMM, local microcirculatory disturbances occur only at the level of the inner nuclear layer, causing temporary vision reduction and limited changes in the paracentral visual field [23, 24].

From a pathophysiological standpoint, transient monocular vision loss (TMVL) is not considered an independent nosological entity, as it is one of the manifestations of a transient ischemic attack in atherosclerotic disease of the brachiocephalic arteries.

The development of RAO is one of the manifestations of cardiovascular disease, increasing the risk of stroke by 2–3% and reducing life expectancy by 5.5 years [25, 26].

1.3 Epidemiology of the Disease or Condition

The overall incidence of CRAO ranges from 1 to 2.7 per 100,000 population, and the disease is more common in men. Bilateral CRAO is observed in less than 2% of cases [27-30]. The disease is age-dependent: every decade of population aging leads to a twofold increase in prevalence; at age 80 and older, the incidence of CRAO is about 10 per 100,000 population per year [31].

The incidence of BRVO is somewhat higher at 4.99/100,000 person-years [32].

Data on the prevalence of transient monocular vision loss correlate with the prevalence of cardiovascular diseases. In individuals who have experienced an episode of transient monocular vision loss, a hemodynamically significant ICA stenosis is detected in 18.9% of cases, requiring urgent surgical treatment in 14.2% of cases. The prevalence of ICA stenosis in individuals with transient monocular vision loss is significantly higher than in individuals who have suffered a stroke, in whom these figures range from 5% to 12% [33].

Transient monocular vision loss most often indicates chronic hypoperfusion of the optic nerve, retina, and the eyeball as a whole, and typically occurs in patients over 50 years of age with vascular risk factors, including hypertension, hypercholesterolemia, smoking, previous episodes of transient ischemic attacks (TIAs), and intermittent claudication. The risk of acute cerebrovascular accident (stroke) in patients with transient monocular vision loss is estimated at 2% per year and increases to 3% per year in those with a history of retinal embolism [7]. According to S.S. Hayreh and M.B. Zimmerman, transient monocular vision loss occurred in various ocular vascular occlusions with the following frequencies: CRAO in 12.18% of cases, BRVO in 14.20%, CRVO in 4.86%, CRVO + cilioretinal artery occlusion in 37.84%, hemi-central retinal vein occlusion in 13.43%, branch retinal vein occlusion in 0.35%, ocular ischemic syndrome in 15.38%, non-arteritic anterior ischemic optic neuropathy (AION) in 2.54%, and giant cell arteritis (GCA) in 26.53% [34].

1.4 Features of Coding the Disease or Condition

H34.0 — Transient retinal artery occlusion

H34.1 — Central retinal artery occlusion

H34.2 — Other retinal artery occlusions

1.5 Classification of the disease or condition

Classically, the following forms of retinal arterial occlusions are distinguished:

• Transient monocular vision loss — TMVL (amaurosis fugax);

• Central retinal artery occlusion (CRAO);

• Branch retinal artery occlusion (BRAO);

• Cilioretinal artery occlusion [35].

Previously, terms such as «thromboembolism of the central retinal artery and its branches» and «acute circulatory disorder in the retinal arteries» were also used.

Relatively recently, our understanding has undergone certain changes. This is due to the fact that previously CRAO was considered a single disease, but studies by S.S. Hayreh et al. [36, 37] made it possible to identify four of its variants with different clinical manifestations:

1. Non-arteritic CRAO (estimated frequency of 66% of all CRAO cases): cases with the classic clinical picture of CRAO (ophthalmoscopic "cherry-red spot" sign, absent or weak residual retinal circulation) in the absence of signs of GCA.

2. Non-arteritic CRAO with sparing of the cilioretinal artery (13%): the presence of a functioning cilioretinal artery in CRAO can contribute to the preservation of blood flow in its basin and higher visual functions, which makes it important to distinguish this category of the disease.

3. Arteritic CRAO (5%): most commonly develops against the background of temporal arteritis, which is a manifestation of GCA. Less common vasculitis forms leading to this condition include polyarteritis nodosa, granulomatosis with polyangiitis, Churg-Strauss syndrome, and Behçet's disease.

   In most cases, arteritic CRAO is combined with various forms of arteritic anterior ischemic optic neuropathy [38, 39]. Consequently, vision loss is the result of acute ischemia affecting not only the retina but also the optic nerve.

4. Reperfused non-arteritic CRAO. It presents as a short-term decrease or loss of vision. This variant may be associated with two mechanisms: a short-term sudden drop in the perfusion pressure of the retinal vascular bed below a critical level, or the migration of an embolus that caused the CRA occlusion. The visual function outcome in this type of CRAO depends on the duration of blood flow impairment in the CRA [40].

The current version of the CRAO classification, taking into account anatomical and pathophysiological data, is as follows [41]:

Other classifications of CRAO also exist. Thus, D.P. Schmidt et al. proposed dividing CRAO according to the severity of certain criteria, the main one being blood flow impairment assessed by fundus fluorescein angiography (FFA) [42]. It has also been proposed to classify CRAO depending on changes in retinal thickness and reflectivity, which correlate with the severity of retinal ischemia [43].

In 2013, the American Heart Association and the American Stroke Association published an updated classification of cerebrovascular disorders, in which CRAO and BRAO are classified as central nervous system infarctions, and amaurosis fugax as transient ischemic attacks [44, 45].

1.6 Clinical presentation of the disease or condition

Retinal artery occlusion (RAO) is an acute circulatory disorder in the retina associated with spasm, embolism, thrombosis, or inflammation of the arteries supplying the retina. The diagnosis of RAO can be established based on:

- patient complaints of sudden, painless, monocular vision loss;

- decreased visual acuity down to light perception;

- impaired pupillary reactions;

- presence of a relative afferent pupillary defect (RAPD);

- characteristic fundus changes: the optic disc is pale and edematous, the retina is milky-white, while the central part of the macula appears bright pink (“cherry-red spot sign”), retinal arteries are markedly narrowed, and blood flow within them is segmental [35].

The most severe complication of RAO is the development of posterior and/or anterior segment neovascularization of the eye, caused by chronic retinal ischemia that occurs when reperfusion of the affected vessel fails to happen. The prevalence of neovascular complications following CRAO ranges from 2.5% to 31.6%, and the mean time to their development is 8.5 weeks (ranging from 2 to 16 weeks) [46, 47].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostics of RAO should be aimed at identifying pathological changes in the fundus, major systemic risk factors for the onset and progression of the disease, as well as the presence of contraindications to various treatment methods. The goals and scope of diagnostic procedures for RAO directly depend on the disease duration.

2.1 Complaints and Anamnesis

Comments: RAO is typically characterized by patient complaints of sudden, complete, or partial vision loss in one eye, which occurs within a few seconds. Patients may report preceding transient vision loss and a history of cardiovascular disease. RAO presents with decreased vision (down to the absence of light perception), as well as possible impairment of color vision and binocular vision [7, 35, 40].

2.2 Physical Examination

Comments: thickening of the temporal artery and pulselessness of the temporal artery are indicators associated with the diagnosis of GCA [48].

2.3 Laboratory Diagnostics

Comments. The decision to hospitalize a patient in an ophthalmology department for inpatient examination and treatment in cases of non-arteritic RAO is made on an individual basis, taking into account the patient's general condition. For the arteritic form of the disease, further examination and treatment are carried out in an inpatient setting, preferably in a neurological department, with a comprehensive evaluation prior to initiating glucocorticoid therapy [50, 51]. Upon hospitalization, it is necessary to perform enzyme-linked immunosorbent assay (ELISA) for antibodies to Treponema pallidum in the blood (A26.06.082.002), determination of hepatitis B virus surface antigen (HbsAg) in the blood (A26.06.036), determination of total antibodies of classes M and G (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus in the blood (A26.06.041.002), and qualitative determination of human immunodeficiency virus (HIV) RNA by polymerase chain reaction (PCR) (A26.05.021.002) [50].

2.4 Instrumental Diagnostics

Comments: the standard method is the assessment of visual acuity using charts or a visual acuity projector. The degree of visual acuity reduction in RAO can vary. In CRAO, depending on the severity of the process, visual acuity usually (in about 80% of cases) ranges from light perception to hundredths of a decimal (decimal visual acuity values are used here and hereafter). The absence of light perception (absolute blindness) generally indicates ciliary artery occlusion (while ruling out optic nerve pathology and cilioretinal artery occlusion). In the presence of a spared cilioretinal artery, vision can be high (up to 0.8–1.0). In BRAO, visual acuity depends on the location and area of the ischemic zone and is usually 0.02–0.1 [16, 51, 52].

Comments: autorefractometry has several advantages over subjective refractometry with trial lenses. First, it is an objective method for assessing refraction; second, in the emergency department setting of a medical facility, it allows the examination to be performed not only by an ophthalmologist or optometrist, but also by a general practitioner (family doctor) [53].

Comments: visual field changes in retinal artery occlusion (RAO) depend on the severity of blood flow impairment. In 8% of patients, only constriction of the peripheral visual field boundaries is present; in 3%, a paracentral scotoma is detected; in 19%, central and centrocecal scotomas are found. With significant ischemia, a small "island" of the visual field is usually preserved on the temporal side (59%) or the visual field is entirely absent (10%). The severity of visual field changes correlates with best-corrected visual acuity (BCVA). Positive dynamics of the visual field are observed in incomplete RAO in 39% of cases, most frequently involving its peripheral boundaries [40]. The necessity and implementation of perimetric studies are determined by the ophthalmologist based on the patient's characteristics and pathology, taking into account available testing methods and potential limitations from the specific perimeter's user manual.

Comments: biomicroscopy of the anterior segment of the eyeball must initially be performed without mydriasis, as pupil dilation can hinder the detection of "early" (mild) iris neovascularization [47].

Comments: in complete central retinal artery occlusion (CRAO), the direct pupillary light reflex is sharply reduced or absent; in partial occlusion, a relative afferent pupillary defect (RAPD, Marcus Gunn pupil) may be present.

Diagnosis of RAPD involves examining the pupil, measuring its size and shape under ambient light, observing pupillary constriction when the eye is illuminated with a bright light, and then observing the return of the pupil to its previous size when the light is removed. During all examinations, each eye is tested separately. Both pupils should constrict equally to light and maintain this constriction during a smooth yet rapid transition of the light source from one eye to the other (swinging flashlight test). An asymmetric reaction of one pupil when light falls upon it (ranging from less constriction and greater subsequent redilation to a complete absence of light reaction) indicates a relative afferent pupillary defect in that eye [35, 55].

Comments: gonioscopy reveals angle-closure or iridocorneal angle neovascularization in 10.9% of cases. The average time for detecting anterior segment neovascularization following CRAO is 3 months (ranging from 2 to 16 weeks). For early detection of iris and iridocorneal angle neovascularization, gonioscopy should be performed 2 weeks after disease onset and repeated at least once a month for the first 4 months, after which examinations may be performed as clinically indicated [47, 56].

Comments: fundus biomicroscopy with aspheric lenses using a slit lamp (or indirect and/or direct ophthalmoscopy) must be performed only with a dilated pupil (under medical mydriasis). It is important to remember that the state of the anterior chamber must be assessed prior to pharmacological pupil dilation.

Comments: the necessity and frequency of OCT are determined by the ophthalmologist depending on the clinical course of the disease. The examination is recommended to be performed under pharmacological mydriasis, as this significantly improves scan quality.

OCT reveals hyperreflectivity and edema of the inner retinal layers in acute stages. The degree of retinal edema correlates with the visual prognosis [51, 58]. Over approximately 1 month, the inner retinal layers undergo atrophy and thinning.

Comments the necessity and frequency of ultrasound are determined by the ophthalmologist based on the clinical course of the disease. Ultrasound may offer advantages over other imaging modalities for identifying orbital pathology (e.g., vascular anomalies, optic nerve pathology, and pathologically enlarged extraocular muscles) [39].

2.5 Other Procedures

Comments: according to modern concepts, RAO is a condition largely similar to cerebral ischemic stroke (and, according to some researchers, one of its forms) [35, 40, 60]. It should be noted that the prevalence of concomitant ischemic stroke—often asymptomatic—in RAO is approximately 24% according to several studies [60, 61]. It is also known that among patients with transient ischemic attack (TIA), of which transient monocular vision loss (TMVL) is a form, 10–15% experience a stroke within 90 days, with approximately half of these cerebrovascular events developing within 48 hours [62, 63]. For this reason, following diagnosis and initial examination by an ophthalmologist, given the high risk of stroke, the situation must be evaluated by a neurologist [35].

The evaluation and treatment of patients with TMVL should be carried out in accordance with the Clinical Guidelines on "Ischemic Stroke and Transient Ischemic Attack" [64].

Thus, prompt referral of a patient presenting with painless monocular vision loss to an ophthalmologist is advisable. If the symptom duration of RAO is less than 6 hours (the therapeutic window for thrombolytic therapy in a potentially concurrent cerebrovascular event), the ophthalmologist must immediately perform a concise examination including visometry, ophthalmoscopy (preferably under medical mydriasis), and, upon confirming the diagnosis of RAO, urgently refer the patient for a neurological consultation (to rule out cerebral stroke) [60].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

It is impossible to establish the exact time of development of irreversible changes during arterial blood supply impairment in the retina with absolute certainty (see Section 1.2.). The probability of partial recovery of visual functions depends on the severity of the initial condition (determined by the degree of visual acuity reduction) [54, 66-69]. A meta-analysis published in 2015 showed that first-aid measures previously used for RAO (eyeball massage, anterior chamber paracentesis, and/or hemodilution) did not lead to improved vision, even compared to patients receiving no treatment (natural course of the disease) [69].

Conservative treatment

Comments: a sharp and significant decrease in blood pressure leads to a drop in perfusion pressure and exacerbates capillary dysfunction. Therefore, it is crucial that therapeutic interventions do not worsen the pathological process through additional blood pressure reduction [54].

Comments: carbogen inhalations should be initiated within the first hours after the onset of vision loss, although evidence of their benefit is limited [52]. To dilate retinal blood vessels, the patient can also be advised to breathe ("inhale-exhale") into a plastic bag for 10 minutes (elevated carbon dioxide levels and respiratory acidosis promote vasodilation) [68].

Comments: high-dose systemic glucocorticoids are the therapy of choice for the arteritic form of RAO caused by giant cell arteritis and should be prescribed to patients immediately after the diagnosis is established [54, 70-73]. Early initiation of treatment is critical to prevent irreversible ischemic complications, such as acute vision loss in the contralateral eye.

High-dose glucocorticoid pulse therapy is prescribed: 500–1000 mg/day (depending on body weight) of #methylprednisolone** intravenously for three days, followed by oral administration of 40–60 mg of #prednisolone** daily for at least 3–4 weeks to prevent disease development in the contralateral eye [70]. For further treatment and monitoring, the patient is immediately referred to a rheumatologist.

Reduction of the glucocorticoid dose is possible only in the absence of clinical manifestations of the disease and in the absence of laboratory markers indicating active disease process. Typically, the dose of #prednisolone** is decreased by 10 mg every 2 weeks down to 20 mg, then by 2.5 mg every 2–4 weeks down to 10 mg, and thereafter by 1 mg every 1–2 months in the absence of relapse. Glucocorticoid therapy should preferably be combined with antiplatelet agents other than heparin [70-72]. Before initiating hormonal therapy, it is necessary to determine whether the patient has a history of gastrointestinal diseases (erosive gastritis, peptic ulcer disease, etc.); from the first day of therapy, proton pump inhibitors, calcium supplements, and vitamin D and its analogs are indicated to prevent potential complications [73].

The management of patients with the arteritic form of RAO should be carried out by ophthalmologists in cooperation with rheumatologists (exceptionally by a general family practitioner, but with consultative support from a rheumatologist) and with the involvement of specialists in other medical fields (nephrologists, dermatologists, hematologists, cardiologists, neurologists, etc.), based on close interaction between the physician and the patient. It must be remembered that, first and foremost, treatment is aimed at preventing vision loss in the contralateral eye, as recovery of vision in the affected eye is unlikely, even with immediate therapy [71, 73].

3.1 Laser treatment

Comments: standard panretinal photocoagulation (PRPC) is usually performed over several sessions. PRPC sessions can be carried out in both inpatient and outpatient settings under maximum drug-induced mydriasis.

PRPC is typically initiated in the inferior areas of the mid-periphery, as these zones may become inaccessible in the event of vitreous hemorrhage. Laser treatment is then continued by applying burns across the entire surface of the mid-peripheral fundus from the temporal vascular arcades. In cases of iris and/or anterior chamber angle neovascularization, it is also necessary to coagulate the far peripheral regions of the retina [74].

3.2 Surgical Treatment

Surgical treatment is not indicated for patients with RAO.

3.3 Dietary therapy

Nutrition should be part of the therapeutic plan and contribute to achieving metabolic goals. Dietary recommendations are formulated by a physician in therapeutic practice (a general practitioner or general family practitioner) as part of the management of the underlying disease [75].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Comments: the frequency and required scope of examination are determined by the physician based on a comprehensive assessment of the clinical picture of the disease, visual functions, condition of the fellow eye, concomitant pathology of the patient, and other factors. Ophthalmological follow-up is important for optimizing residual vision, monitoring neovascularization-related complications, and preserving the functions of the fellow eye [56].

Comments: the frequency, duration, and scope of examinations are determined by specialist physicians based on the patient's underlying systemic pathology that caused the development of RAO, in accordance with relevant clinical guidelines.

Secondary prevention is necessary to optimize atherosclerosis control and prevent future cardiovascular complications [77]. Patients with central retinal artery occlusion (CRAO) are at significant risk for ischemic events. A retrospective analysis showed that 64% of patients had at least one undiagnosed vascular risk factor, with 36% of these patients having hyperlipidemia at the time of RAO onset [77]. Treatment aimed at eliminating modifiable RAO risk factors (e.g., management of arterial hypertension, restoration of normal heart rhythm, normalization of blood lipid levels, medical correction of hypercoagulation and hyperaggregation states) as well as controlling systemic risk factors for atherosclerosis (including hypertension, hyperlipidemia, diabetes, obesity, and obstructive sleep apnea) is a mandatory component. Smoking cessation, diet, and regular physical activity are also important for secondary prevention of RAO [77].

6. Organization of Medical Care

Medical evacuation is carried out by ambulance teams. Primary specialized health care is provided by an ophthalmologist in an outpatient clinic or in a medical organization's inpatient facility.

Treatment (medical, laser, or surgical) is performed by an ophthalmologist on an outpatient basis, in a day hospital, or in a 24-hour inpatient setting.

Indication for emergency hospitalization in a medical organization (ophthalmic inpatient facility operating 24/7): RAO with a prospect of visual function improvement, as determined by an ophthalmologist based on clinical and instrumental examination data (in the absence of indications for hospitalization in a specialized department of another profile).

Indications for patient discharge from a medical organization:

1. completion of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment-related complications requiring medical correction and/or inpatient medical interventions;

2. refusal of the patient or their legal representative to receive specialized, including high-tech, medical care in a 24-hour or day hospital setting;

3. the need to transfer the patient to another medical organization.

7. Additional Information

The patient must be informed about the need to normalize blood pressure, glycemia, and lipid metabolism parameters. It is also necessary to encourage the patient to strictly comply with all specialist appointments and prescriptions (ophthalmologist, neurologist, cardiologist, general practitioner/family physician, etc.).

The patient must be informed that in most cases, the goal of examination and treatment is not to improve visual functions, but to prevent complications and potential cardiovascular events.

In cases of irreversible blindness or low vision, the patient must be fully informed about the opportunities for vocational, social, and psychological rehabilitation.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Neroev V.V., Head of the Working Group, Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, Director of the National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Head of the Department of Eye Diseases at the Faculty of Postgraduate Education of the Moscow State University of Medicine and Dentistry named after A.I. Evdokimov of the Ministry of Health of the Russian Federation, Chief freelance ophthalmologist of the Ministry of Health of the Russian Federation, Honored Doctor of the Russian Federation, Honored Worker of Science of the Russian Federation, President of the Association of Ophthalmologists.

2. Bobykin E.V., Doctor of Medical Sciences, Associate Professor, Department of Ophthalmology, Ural State Medical University of the Ministry of Health of the Russian Federation, member of the Association of Ophthalmologists.

3. Zaitseva O.V., Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Associate Professor of the Department of Eye Diseases at the Faculty of Postgraduate Education, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov, Executive Director of the Association of Ophthalmologists.

4. Lisochkina A.B., Candidate of Medical Sciences, Associate Professor of the Department of Ophthalmology with the Clinic named after Professor Yu.S. Astakhov, First Saint Petersburg State Medical University named after Acad. I.P. Pavlov, member of the Association of Ophthalmologists.

5. Neroeva N.V., Candidate of Medical Sciences, Head of the Department of Retinal and Optic Nerve Pathology, National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, member of the Association of Ophthalmologists.

6. Tultseva S.N., Doctor of Medical Sciences, Professor of the Department of Ophthalmology with the Clinic named after Professor Yu.S. Astakhov, First Saint Petersburg State Medical University named after Acad. I.P. Pavlov, member of the Association of Ophthalmologists.

7. Shadrichev F.E., Candidate of Medical Sciences, Head of the Ophthalmological Consultative and Diagnostic Department of the Regional Endocrinological Center of the City Clinical and Diagnostic Center No. 1, Assistant at the Department of Ophthalmology with the Clinic named after Professor Yu.S. Astakhov, Pavlov First Saint Petersburg State Medical University, member of the Association of Ophthalmologists.

8. Shklyarov E.B., Candidate of Medical Sciences, Ophthalmologist at the Ophthalmological Consultative and Diagnostic Department of the Regional Endocrinological Center of the City Clinical and Diagnostic Center No. 1, member of the Association of Ophthalmologists.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Ophthalmologists

• General practitioners (family physicians)

• Neurologists

• Rheumatologists

Methods used for collecting/selecting evidence: search in electronic databases; analysis of modern scientific developments on the issue of retinal arterial occlusion in Russia and abroad; generalization of practical experience of Russian and foreign specialists. Description of methods used for collecting/selecting evidence: the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on this topic. Methods used to assess the quality and strength of evidence: expert consensus, significance assessment in accordance with the rating scheme.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the levels of evidence for recommendations (LER) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new data from the perspective of evidence-based medicine regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, in the presence of justified additions/comments to previously approved clinical guidelines, but no more than once every 6 months.

Appendix A3. Reference Materials

1. State Register of Medicines (http://grls.rosminzdrav.ru).

2. International Statistical Classification of Diseases and Related Health Problems (10th Revision).

3. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

4. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

5. Order of the Ministry of Health of the Russian Federation No. 902n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, Its Adnexa, and Orbit."

6. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

7. Order of the Ministry of Health and Social Development of the Russian Federation No. 786n dated December 29, 2008, "On the Procedure for Formulating and Approving the State Assignment for the Provision of High-Tech Medical Care to Citizens of the Russian Federation at the Expense of Federal Budget Allocations in 2009" (with amendments and additions).

8. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'."

9. Order of the Ministry of Health of the Russian Federation No. 1129n dated October 20, 2020, "On Approval of the Rules for Conducting Mandatory Medical Examination to Detect Human Immunodeficiency Virus (HIV Infection)" (Registered with the Ministry of Justice of Russia on November 11, 2020, No. 60847).

10. Management of Planned Hospitalization in a Multidisciplinary Hospital. Methodological Recommendations No. 2001/144 (approved by the Ministry of Health of the Russian Federation on November 9, 2001).

Appendix B. Physician Action Algorithms

Treatment regimen for a patient with sudden vision loss [78].

# Emergency referral is strongly recommended if the patient presents within 1 week of vision loss. If the initial evaluation takes longer than 1 week and the patient has no additional symptoms, an urgent outpatient evaluation is recommended.

* Standard blood tests that should be evaluated include complete blood count (including platelet count), comprehensive metabolic panel, hemoglobin A1C, prothrombin time and partial thromboplastin time, as well as a fasting lipid profile.

** Hypercoagulable tests that require evaluation: antiphospholipid antibodies, Factor V Leiden mutation, prothrombin gene G20210A mutation, elevated Factor VIII, and hyperhomocysteinemia.

Appendix C. Patient Information

Patients with risk factors for retinal artery occlusion should be informed that sudden painless vision loss is a dangerous condition that can threaten not only vision but also life. The necessity of seeking immediate medical attention in the event of sudden vision loss should be emphasized, and patients should be advised to regularly check their vision by covering each eye alternately to detect any sudden vision deterioration. For patients with risk factors for retinal artery occlusion, the following may be useful: information on available self-administered pre-hospital emergency care methods (eyeball massage, vasodilators, carbogen inhalation), information on the importance of avoiding trigger factors (smoking, heavy physical exertion, stressful situations, hot baths, visiting saunas and bathhouses, long-haul flights, scuba diving, etc.), and addresses of emergency eye care clinics.

Timely consultation with an ophthalmologist can be crucial for preserving vision, and delay can lead to irreversible damage. Retinal artery occlusion is a medical emergency and, although there are currently no highly effective treatments, early diagnosis and prompt initiation of available treatment may improve vision in some cases, as well as prevent the development of other serious conditions (e.g., stroke or myocardial infarction).

Common risk factors for retinal artery occlusion, such as hypertension, diabetes, cardiovascular disease, and hyperlipidemia, should be discussed. Patients should be encouraged to control these risk factors through lifestyle modifications, including smoking cessation and medication adherence. Patients should be informed of the need for a thorough evaluation by medical professionals, including neurologists, general practitioners, and ophthalmologists, to determine the underlying cause and make appropriate treatment decisions.

The uncertain prognosis for visual recovery in retinal artery occlusion should be discussed. Although some individuals may experience partial or complete recovery, the majority of patients (about 80%) may experience persistent visual impairment. The outcome of retinal artery occlusion depends on factors such as the degree of ischemia and the effectiveness of interventions. The need for follow-up with an ophthalmologist and other specialists (based on individual clinical features) should be emphasized. Regular monitoring is essential to assess the patient's visual function, manage risk factors, and address potential complications.

It is necessary to account for the emotional impact of sudden vision loss and provide information on available support services, including counseling or support groups, to help patients cope with the psychological aspects of this condition. To reduce the risk of vascular events, patients should be educated on lifestyle modifications such as maintaining a healthy diet, regular exercise, blood pressure and cholesterol control, and smoking cessation [17, 22, 95].

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

These clinical guidelines do not use rating scales, questionnaires, etc.