Update on central retinal artery occlusion

Abstract

The medical condition referred to as “central retinal artery occlusion” (CRAO) was first documented by Albrecht von Graefe in 1859. Subsequently, CRAO has consistently been identified as a serious medical condition that leads to substantial visual impairment. Furthermore, it is correlated with vascular complications that have the potential to affect crucial organs such as the brain and heart. A considerable amount of research has been extensively published on the various aspects of this topic, which is marked by notable debates and misconceptions, especially regarding its management and outcomes. The primary aim of this review article is to analyze the latest developments in the understanding of CRAO, which includes its causes, techniques for retinal imaging, systemic evaluation, and therapeutic strategies, such as vitrectomy. This review article offers readers a comprehensive learning experience to gain knowledge on the fundamental principles and recent advancements in CRAO.

In 1859, Von Graefe was the first to identify central retinal artery occlusion (CRAO) as an embolic disease caused by endocarditis.[1] In 1864, Schweigger described the ophthalmoscopic observations made during CRAO.[2] CRAO affects about one in every 100,000 people, mostly in their early 60s with less than 2% presenting with bilateral involvement. Men are slightly more likely to be affected than women. Hypertension, smoking, hyperlipidemia, diabetes, hypercoagulable states, and male gender are risk factors for thromboembolic disease.[3] CRAO can be caused by an embolus suddenly obstructing the lumen of the central retinal artery (CRA) or by spasmodic contractions within a compromised ocular arterial circulation, resulting in retinal infarction or hypoperfusion.[4] Patients with CRAO have a 5.5-year life expectancy compared to 15.4 years for age-matched non-CRAO patients.[3] When compared to a matched control population diagnosed with cataracts, patients with CRAO have an increased risk of death, stroke, and myocardial infarction at both short-term and long-term intervals after CRAO. These findings suggest that patients who had CRAO may benefit from multidisciplinary evaluation and long-term systemic follow-up.[5] In cases of CRAO, the primary objective is to reduce the risk of irreversible retinal tissue damage and restore baseline visual acuity. To displace or dissolve the obstructive embolus or thrombus, prompt diagnosis and intervention are essential.[6] A considerable amount of research has been extensively published regarding the various aspects of this disease, which is characterized by notable controversies and misunderstandings, particularly in regard to its treatment and prognosis.[7]

This article’s primary objective is to examine the most recent advancements in the understanding of CRAO. This covers a review of its etiology, systemic evaluation, retinal imaging findings and therapeutic approaches, including the utilization of pars plana vitrectomy (PPV).

Etiopathogenesis of CRAO

The CRA is the first branch of the ophthalmic artery, has a relatively long and narrow course within the optic nerve, and has poor collateral circulation with no anastomoses with other ophthalmic artery branches (unlike the ciliary arteries for example). These facts make this artery especially vulnerable to infarctions. CRAO is typically considered an embolic condition, with the embolus frequently originating from an atheromatous plaque in the carotid arteries or cardiac valves.[8] As observed in Leriche’s syndrome, atheroma present in the peripheral vascular system can occasionally contribute to the occurrence of CRAO.[9] When the ipsilateral internal carotid artery, ophthalmic artery, or CRA are already compromised due to the presence of an in-situ thrombus, spasmodic contractions in the ocular arterial circulation can result in a sudden decrease in ocular blood flow and retinal perfusion. This reduction in blood flow may manifest as a clinical presentation similar to CRAO.[10,11] Thrombi can be caused by atherosclerosis, collagen-vascular disease, inflammation, and hypercoagulability. Polycythemia vera, sickle cell anemia, multiple myeloma, SLE, factor V Leiden, prothrombin III mutation, hyperhomocysteinemia, polyarteritis nodosa, giant cell (temporal) arteritis, antiphospholipid syndrome, activated protein C resistance, Behcet disease, and syphilis are common predisposing conditions for CRAO.[3] Also, patent foramen ovale may be linked to CRAO. This applies especially to young patients without other risk factors. The mechanism is unknown. Hypothesis suggests that a patent foramen ovale may help emboli pass from right to left circulation.[12]

Types of CRAO

Hayreh and Zimmerman classified CRAO in 2005, identifying two distinct types: A) non-arteritic CRAO and B) arteritic CRAO.[13] The non-arteritic type of CRAO is characterized by retinal opacification and a cherry red spot; however, it is not associated with anterior ischemic optic neuropathy [Fig. 1a]. Arteritic CRAO, in contrast, exhibits optic disc edema and pallor in addition to the typical characteristics of CRAO and is associated with anterior ischemic optic neuropathy [Fig. 1b]. The most common cause of an arteritic CRAO is giant cell arteritis. Other clinical variations of CRAO described in the literature include CRAO with cilioretinal artery sparing (CLRA) and transient CRAO. In up to 30% of eyes, the CLRA, also known as cilioretinal rescue in CRAO, supplies blood to the macular area. It is a branch of the posterior ciliary artery that is perfused by the choroidal circulation. CLRA sparing has been shown to improve both visual outcomes and retinal circulation [Fig. 1c]. The transient form of CRAO can last from a few minutes to several hours, depending on the cause of obstruction. The duration of transient CRAO may have a greater impact on its visual outcome than other types.[13] Hayreh and Zimmermann discovered that 67% of 260 eyes with CRAO had non-arteritic CRAO and 4% had arteritic CRAO.[13] Furthermore, CRAO with CLRA sparing was observed in 14% of the cases, whereas the transient form of CRAO was observed in 16% of the cases.

Figure 1.

Types of CRAO. (a) Non-arteritic variety of CRAO. (b) Arteritic variety of CRAO with ophthalmic artery occlusion due to giant cell arteritis. (c) Non-arteritic variety of CRAO with sparing of the cilioretinal artery

Interactions with paracentral acute middle maculopathy

PAMM is a retinal vascular phenomenon, mostly arterial, caused by the hypoperfusion of the deep capillary plexus and secondary postischemic loss of the inner nuclear layer. CRAO can develop in PAMM patients. Therefore, PAMM cases with other risk factors for CRAO, such as age, atherosclerosis, or giant cell arteritis, may require additional attention. Deteriorating hypoperfusions may cause CRAO a few days after the PAMM presentation.[14] In contrast, PAMM can be considered a biomarker in the context of CRAO outcomes. Particularly, PAMM is associated with good visual acuity improvement during follow-up in patients with RAO. Therefore, patients with PAMM in the setting of CRAO should be treated more actively to maximize functional outcomes.[15,16] Interestingly, PAMM may represent persisting ischemic lesions in partial improvement of retinal circulation (particularly in superficial capillary plexus) in CRAO eyes under the treatment, this possibly explains its positive prognostic meaning in CRAO.[17]

Clinical features in CRAO

• Presenting visual symptoms:

  The majority of people with CRAO report a sudden, unilateral, significant, and painless loss of vision. Amaurosis fugax is the term used to describe visual symptoms in a case of transient CRAO.[18] Amaurosis fugax is a transient ischemic attack caused by acute retinal ischemia without retinal infarction that causes <24-h period of blindness. Normal vision often gets restored following amaurosis fugax.[19]

• Presenting visual acuity:

  The majority of people with CRAO have a severe visual impairment, which can range from hand motions to light perception.[13] A person’s visual acuity below light perception suggests an ophthalmic artery occlusion. In CRAO, visual acuity depends on several factors. The severity of artery occlusion, retinal opacification, CLRA length and area supplied, papillomacular bundle perfusion, optic disc condition, and any other retinal and ocular findings should be considered.[13,20,21,22,23]

• Ocular examination:

  In general, intraocular pressures (IOP), anterior chamber exams, and extraocular eye movements are usually within normal limits. If a CRAO complicates an ocular ischemic syndrome, the affected eye may develop iris and angle neovascularization; otherwise, CRAO eyes rarely develop ocular neovascularization.[24] The prevalence of ONV in eyes with CRAO ranges from 3.0% to 18.8%.[25,26] Furthermore, the detection of ONV after CRAO has ranged from as early as the day of presentation to 2 years later. Rudkin et al.[26] concluded that because ONV can occur early, regular follow-up appointments, particularly within the first 4 months, should be required. A thorough fundoscopic examination is required for an accurate diagnosis of CRAO, and a dilated exam should be performed on any patient who presents with visual symptoms suggestive of CRAO and has no contraindications to mydriatic medications. The fundoscopic findings of CRAO differ depending on how long it has been since the event and the degree of CRAO. The retina in an acute CRAO will typically appear diffusely pale, white, and opaque, with a cherry-red spot in the fovea [Fig. 2a]. Because it lacks inner retinal layers, the fovea is not involved in CRAO. Choroidal circulation is preserved at the fovea in CRAO. In addition, the center of the macula is surrounded by retinal opacification, which is typically caused by the thickening and loss of transparency of the retina’s posterior pole.[27] These factors contribute to the visibility of the cherry-red spot at the fovea.[28] Atherosclerotic constriction, “box-caring,” or segmentation are also other fundus findings documented in CRAO [Fig. 2b].[28] In 20% of CRAO patients, fundus examination revealed the presence of intra-arterial emboli [Fig. 2c]. This is important because the morphology of the emboli can help determine the cause of CRAO. Small, yellow, refractile plaques, also known as “Hollenhorst plaques,” indicate the presence of cholesterol emboli, whereas single, white, non-scintillating plaques in the proximal retinal vasculature indicate the presence of calcific emboli, and fibrin-platelet emboli appear as small pale bodies.[28] The presence of associated optic disc edema due to arteritic anterior ischemic optic neuropathy distinguishes arteritic CRAO (giant cell arteritis) from non-arteritic CRAO. The area supplied by the patent temporal CLRA appears as an island of normal-appearing retina in the papillomacular bundle region in CRAO with CLRA sparing clinical variety, surrounded by retinal whitening and opacification due to acute CRAO. The normal retinal region, as well as the preservation of perfusion in the papillomacular bundle region, can influence the visual outcome. The fundus findings in transient CRAO differ greatly depending on the duration of the condition. Examining the fellow contralateral eye may reveal underlying pathology such as hypertensive retinopathy. At chronic stages, fundoscopic findings revealed optic atrophy (91%), retinal arterial attenuation (58%), cilioretinal collaterals (18%), and macular retinal pigment epithelial (RPE) alterations (11%) [Fig. 2d].[28]

• Medical history and systemic examination:

  Once CRAO has been clinically diagnosed, any condition that could predispose to embolus formation (e.g., atrial fibrillation, endocarditis, atherosclerotic disease, hypercoagulable state) should be included in the past medical history.[3] To determine potential causes, a physical examination with a focus on the cardiovascular system should be performed. The radial pulse rate and cardiac rhythm are important because irregular rhythms indicate atrial fibrillation, which increases the risk of embolic events.[3] Given the link between CRAO and hypertension, it is critical to keep blood pressure under control. In older patients, the clinician should inquire about temporal arteritis symptoms (e.g., headache, jaw claudication, scalp tenderness, proximal muscle and joint aches, anorexia, weight loss, and fever). To rule out temporal arteritis, scale tenderness and a nodular temporal artery examination should be performed.[29] Young patients should be thoroughly examined to rule out any autoimmune connective tissue diseases that may put them at risk for vasculitis.[30] Long-term direct pressure to the globe during a drug-induced coma and incorrect face-down surgery positioning are risk factors. The doctor should also inquire about illegal drug use. Cosmic facial filler injections of autologous fat, hyaluronic acid, and collagen in the glabellar and nasolabial folds have caused retinal artery occlusions.[31,32,33]

Figure 2.

Clinical findings in a typical case of CRAO. (a) Retinal opacification with cherry-red spot. (b) “Box-carring” of the retinal arteries (black arrow). (c) Intra-arterial emboli (black arrow). (d) Pale optic disc with retinal vessel attenuation and posterior pole atrophic changes seen in a case of chronic CRAO

Differential diagnoses

Purtscher’s or Purtscher-like retinopathy is characterized by precapillary arteriole occlusion due to head or thoracic compressive trauma or non-traumatic factors such as acute pancreatitis, renal failure, disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, and autoimmune diseases.[34,35] Purtscher’s flecken, cotton wool spots, and a few retinal hemorrhages are found. Commotio retinae, Tay-Sachs, and Niemann–Pick diseases can cause cherry red spots on fundus examination.[27] However, distinguishing them from one another can be facilitated by considering their distinct clinical presentations. Combined CRAO and CRVO, which include ischemic retinal whitening, a cherry-red macula spot, retinal hemorrhage, and dilated or tortuous retinal veins, can be difficult. This condition has systemic, potentially life-threatening risk factors but may also cause unusually high neovascularization rates.[36]

Investigations in CRAO

The investigations in the case of CRAO are broadly divided into two categories: 1) systemic investigations to primarily identify the source and cause of emboli or reduced retinal perfusion and 2) ocular investigations to document the clinical findings related to CRAO.

Systemic investigations

A CRAO is comparable to a cerebrovascular accident or a myocardial infarction. Patients with CRAO are more likely to suffer a stroke. According to some studies, the risk of having a stroke during the first 3.5 years after a CRAO is up to 10 times higher than in the general population.[37,38,39] The highest risk for stroke occurs in the days following a CRAO.[39] This risk could persist for a decade after the CRAO event. Hence, the evaluation of a CRAO is comparable to that of a case of stroke or heart attack [Table 1].

Table 1.

Systemic investigations to be considered in a case of CRAO

Investigation		Rationale
Carotid doppler		To rule out atheromatous plaques causing narrowing in the ipsilateral carotid arteries
2D (transoesophageal) echocardiography		For diagnosis of valvular heart disease and the presence of vegetation at the cardiac valves, which can act as a source of emboli
Complete blood counts including peripheral blood smear		To rule out blood dyscrasias and hyperviscosity states
Erythrocyte sedimentation rate and C-reactive protein		To rule out temporal or giant cell arteritis in patients >50 years with CRAO and abnormal optic disc
Coagulation profile (bleeding time and clotting time)		To rule out coagulation disorders
Blood sugar levels and lipid profile including triglycerides and cholesterol levels		To rule out atherosclerotic diseases
Blood cultures		To rule out bacterial endocarditis or septic emboli
Serum homocysteine levels		To rule out hypercoagulable states, especially in young patients with CRAO
Vasculitis profile (including Mantoux or QuantiFERON Test and Chest X-ray)		To rule out hypercoagulable states especially in young patients with CRAO and associated signs of retinal vasculitis
Factor V Leiden, prothrombin mutation, homocysteine levels, fibrinogen, antiphospholipid antibodies, prothrombin time/activated partial thromboplastin time [PT/aPTT], serum protein electrophoresis		To rule out coagulation disorders
Magnetic resonance imaging angiography or computed tomography angiography of the brain and neck		To rule out vascular occlusive disease
Computed tomography and calcium score test		Useful in screening and risk stratification of asymptomatic patients for developing CRAO

Ocular imaging

Optical coherence tomography (OCT)

OCT has proven to be a highly valuable imaging modality for the non-invasive identification of various structural characteristics of the inner and outer retina in cases of CRAO.[21,22,40,41,42] It is observed that eyes affected by acute and chronic CRAO exhibit distinct OCT findings. The primary goals of conducting OCT in an eye affected by CRAO are to assess the stage (acute versus chronic) and severity of the occlusion, as well as to identify potential pathogenetic mechanisms contributing to retinal tissue damage.[43] The most important OCT diagnostic criteria for acute CRAO are inner retinal layer hyperreflectivity and outer retinal layer shadowing. In contrast, the chronic phase of the disease reduces inner retina thickness while maintaining stratification. The classification of an acute CRAO can be determined by evaluating OCT results, which allows for the categorization of occlusions as mild, moderate, or severe [Table 2 and Fig. 3].[43] In unclear cases, OCT findings can appear earlier than fundus findings, making it useful. In contrast to acute inner retinal layer hyperreflectivity, mild and moderate cases may show middle retinal layer hyperreflectivity and a prominent middle limiting membrane.[43]

Table 2.

Severity of acute CRAO based on OCT features

		Middle±inner retinal layer opacification		Inner retinal layer thickening		Absent inner retinal layer stratification
Mild		Yes		No		No
Moderate		Yes		Yes		No
Severe		Yes		Yes		Yes

Figure 3.

Severity of CRAO on OCT. (a) Mild CRAO–Prominent middle retinal layer ± inner retinal layer hyperreflectivity with no inner retinal thickening with no loss of inner retina layer stratification. (b) Moderate CRAO–Prominent inner retinal layer hyperreflectivity with inner retinal thickening with no loss of inner retina layer stratification. (c) Severe CRAO–Prominent inner retinal layer hyperreflectivity with inner retinal thickening with loss of inner retina layer stratification

A number of OCT features are noted in the case of CRAO. In this review article, we shall describe those features in congruence with the pathogenesis of CRAO.

A sudden CRA blockage stops blood flow and leaves the CRA branches and retinal arterioles without blood. OCT shows the empty blood vessel as a vertically oval cavity in the inner retina with hyperreflective upper and lower borders, minimal back shadowing, and a hyporeflective lumen. This finding is called the “empty vessel sign” [Fig. 4a].[42]

Figure 4.

Important OCT features in CRAO. (a) Empty vessel sign (white arrow). (b) Prominent middle retinal layer hyperreflectivity (red arrow) with prominent middle limiting membrane (white arrow) and retinal pigment epithelium hyperreflectivity at the fovea (yellow arrow). (c) Internal limiting membrane separation in CRAO. (d) Inner retinal cystoid spaces with shallow neurosensory detachment in CRAO. (e) Inner retinal layer necrosis in CRAO. (f) Inner retinal layer thinning and atrophy seen in chronic CRAO

The deep and superficial capillary plexuses are most affected by CRA flow interruption, causing bipolar, horizontal, and amacrine cell edema in the middle retinal layers and opacification. Thus, milder CRAO only opacifies middle retinal layers. The superficial capillary plexus becomes involved as the occlusion worsens, causing total inner retinal layer opacification and outer retinal layer shadowing. The inner boundary of the outer plexiform layer has a middle limiting membrane with bipolar cell synapses. Mild and moderate acute CRAO causes bipolar cell synaptic swelling and a prominent OCT hyperreflective line, suggesting p-MLM. Mild acute CRAO eyes develop middle retinal layer opacification and p-MLM sign. [Fig. 4b].[43,44] These findings are usually absent in higher grades of acute CRAO.

The inner retinal layer thickens and loses stratification as cellular edema spills into the extracellular spaces as retinal hypoperfusion worsens. CRAO does not affect fovea. Fovea RPE reflectivity is higher than surrounding RPE reflectivity when dense opacification occurs in the inner retinal layer and shadowing affects the outer retinal layer. [Fig. 4b].[43] This finding is consistent with the observation of a foveal cherry-red spot.

The retina can tolerate varying degrees of ischemia without showing any functional deficits or injury. When ischemia lasts longer than 97 min for retinal tissue, cell death occurs.[45] The severity and duration of ischemia affect cell dysfunction, injury, and death. During prolonged ischemia, intracellular biochemical and metabolic changes cause cell swelling, rupture, necroptotic, apoptotic, and autophagic death.[46] Although prompt reperfusion restores oxygen and substrate delivery, it can also increase reactive oxygen species generation and proinflammatory neutrophilic infiltration of ischemic tissues. This is reperfusion injury.[47,48] OCT findings such as ILM separation, inner retinal fluid-filled hyporeflective cavities, neurosensory detachment, inner retinal hyperreflective foci, and posterior vitreous hyperreflective dot opacities, can be explained by the concept of secondary inflammation as a result of severe ischemia or reperfusion injury [Fig. 4c-f].[41,49,50,51]

As the disease progresses to the chronic stage, cellular atrophy and death occur, resulting in thinning and atrophy of the inner retinal layers while the inner retinal layer stratification is preserved.[43] The outer retina including the RPE, the photoreceptors, and the outer nuclear layer are perfused by the choroidal circulation and remain unaffected.

Color coded enface OCTs (either full retinal thickness or including only the inner retinal layers) present as “blue retina” in the affected areas and exhibit potential macular sparing in case of a cilioretinal artery.[52]

Fundus fluorescein angiography (FFA)

FFA is not commonly used in cases of CRAO due to the invasive nature of retinal imaging, the emergency nature of this disease, and the absence of neovascularization. According to Hayreh et al.,[7] FFA is required to help distinguish between different types of CRAO and determine the extent of fundus circulatory abnormalities. Eyes with non-arteritic CRAO almost always have sluggish retinal vasculature filling and variable amounts of residual retinal circulation; the complete absence of retinal vascular filling is uncommon in these eyes.[53,54] The majority of ophthalmologists incorrectly believe that the CRA is not completely occluded in CRAO due to the variable amount of residual retinal circulation. The retinal circulation is normal or nearly normal in eyes with transient non-arteritic CRAO. In the eyes with CRAO and CLRA sparing, FFA is the only way to definitively outline the region supplied by the patent CLRA.[7] This is critical in determining the visual outcome. The presence of associated posterior ciliary artery occlusion, as observed in giant cell arteritis, is the key diagnostic feature of an arteritic CRAO. Failure to diagnose arteritic CRAO and, as a result, giant cell arteritis can result in catastrophic vision loss in both eyes; thus, FFA is critical. As a result, it must be performed on all CRAO patients over the age of 50.[55] In their study, Gong et al.[54] investigated the correlation between central visual impairment and FFA characteristics in patients diagnosed with CRAO. By analyzing arm-retina time, retinal vessel leakage, and optic disc leakage, the authors identified three angiographic patterns: poor perfusion, exudative, and mixed. Exudative CRAO caused less vision impairment than poor perfusion and mixed types.

During the acute phase of CRAO, the macular region experiences predominant manifestations of retinal opacification and swelling. In the event of re-established circulation within the CRA, the capillaries located in the central and most substantial region of the macula fail to replenish their contents. This lack of refilling is attributed to the compression exerted by the swollen superficial retinal tissue in the vicinity, thereby giving rise to the observed “no re-flow phenomenon” [Fig. 5].[16] The extent of retinal capillary non-perfusion in the central region is subject to variations among individuals and is influenced by the degree of macular retinal thickening.

Figure 5.

No “re-flow-phenomenon”. In this figure, the fundus fluorescein angiography demonstrates that the capillaries in the macula’s central region fail to fill with fluorescein dye. The “no re-flow phenomenon” is caused by the compression exerted by the swollen superficial retinal tissue in the vicinity

The presence of one or more hyperfluorescent pinpoint spots during the middle phase of the FFA was observed as a distinguishing feature of acute CRAO, as reported in a recent publication authored by Mangla et al.[56] These entities are commonly referred to as mid-phase hyperfluorescent spots (MPHS) [Fig. 6]. These entities are prominent in the posterior pole, more common in moderate to severe acute CRAO, and manifest during the intermediate stage of FFA with delayed staining and minimal perivascular leakage. The MPHS persisted until significant blockage and then disappeared during CRAO resolution. Red blood cell aggregates or rouleaux are the most likely cause of MPHS.[56] MPHS is common in severe CRAO patients and affects the posterior pole of the eye. It has the most retinal capillaries and the smallest capillary vessels. Less severe acute CRAO does not appear to block blood flow, causing rouleaux formation. In advanced acute CRAO, retinal whitening and thickening can obscure the MPHS beneath the retinal layer when observed through FFA. Thus, MPHS on FFA was more common in moderate occlusion severity patients than in milder and more severe cases. MPHS resolution follows CRAO resolution. Indocyanine green angiography (ICGA):

Figure 6.

Mid-phase pinpoint hyperfluorescent spots. This figure shows multiple hyperfluorescent pinpoint spots at the posterior pole during the middle phase of the angiogram. These spots are referred to as mid-phase hyperfluorescent spots (MPHS)

The utilization of ICGA is not a routine practice in cases of CRAO. In a recent publication, we conducted an analysis of eight ICGA studies of five patients diagnosed with acute retinal artery occlusions.[57] We noted that the utilization of ICGA yields significant and practical insights into the assessment of choroidal perfusion in individuals afflicted with acute retinal artery occlusions. The occlusion leads to the manifestation of rouleaux formation as hypercyanescent spots in the retinal circulation during the late phase of ICGA.[57]

OCT angiography (OCTA)

OCTA is an innovative non-invasive technique that eliminates the necessity of dye injection during the evaluation of the retinal microvasculature. In cases of CRAO, OCTA demonstrates a reduction in vascular perfusion within the superficial and deep retinal capillary plexuses.[58] This reduction in perfusion is consistent with the poor perfusion observed during FFA. The deep capillary plexus remains perfused in patients who possess the variant of CLRA-sparing CRAO.[58] In a case report authored by Bhanushali et al.,[59] the authors presented evidence showcasing the successful restoration of retinal perfusion through the use of OCTA subsequent to anterior chamber paracentesis on a patient diagnosed with acute CRAO. In contrast to the FFA, the OCTA lacks the ability to provide evidence of a delay in transit time. Nevertheless, it is crucial to exercise great caution when interpreting OCTA results in cases of acute CRAOs that exhibit pronounced retinal hyperreflectivity, thickening, and absence of retinal layer stratification. The aforementioned statement holds true for individuals with chronic CRAOs characterized by significant thinning of the inner retinal layer. The erroneous automated segmentation performed by the machine is the cause of this problem.[60] The OCTA retinal vascular metrics of the non-affected fellow eyes are also impaired when compared to age-matched controls highlighting again the acute nature of a CRAO in a general systemic underlying cardiovascular condition.[61]

Fundus autofluorescence (FAF)

During the acute phase of CRAO, the reduction in FAF signal observed in the less perfused areas can be attributed to retinal edema obstructing the normal RPE.[62,63] Over time, it is possible for the situation to revert to its original state, or it may be accompanied by heightened autofluorescence due to a window defect caused by the thinning of the inner retinal layers. Depending on the composition of the plaque, a hyper-FAF lesion corresponding to the emboli may be seen within the occluded artery. A hypo FAF emboli may correspond to a calcific/fibrin-platelet emboli.[64,65]

Electroretinography (ERG)

Numerous studies have been conducted to investigate the correlation between different ERG components, visual acuity, and the degree of retinal artery occlusion.[66,67] Three parameters of the ERG, specifically the amplitude of the B-wave in scotopic 3.0, the B/A ratio, and the amplitude of the photopic negative response (PhNR), have been identified as dependable indicators of visual prognosis. In cases of mild to severe ischemia, the amplitudes of the PhNR, which serve as an indicator of ganglion cell function, exhibited a more significant reduction compared to the amplitudes of the B-wave. Regarding visual function and outcome, there was a significant correlation between baseline visual acuity and visual field defects with the B/A ratio (both P < .001). Additionally, improvements in visual acuity and visual field were correlated with the B-wave amplitude in dark-adapted 3.0 (P = 0.004 and 0.006), B/A ratio (P = 0.023 and 0.008), and PhNR amplitude (P < 0.001 and 0.004).[66]

Management of CRAO - time is retina

CRAO is a medical emergency, requiring immediate diagnosis and treatment. The faster a patient is treated, the higher the possibility to prevent damage. The primary goal of treating CRAO is to quickly restore blood flow to the retina and achieve optimal retinal cell function. The exact perfusion window (which is the time period in which the retinal tissue may be still rescued in case the blood flow is restored) is not well defined and may vary, but is estimated to range from 4-6 h from the onset of symptoms. This can be accomplished by either displacing the embolus from the obstruction site, removing the embolus, or increasing retinal oxygenation to meet the metabolic demands of the retinal cells.[6,68] Based on the time elapsed (thus within or outside the perfusion window) different approaches can be chosen. It has to be highlighted though that there are no definite guidelines of how to treat an acute CRAO and the management and approaches differ from country to country. The following techniques are usually practiced in the management of CRAO with the aim of achieving the following objectives: a) achieving vasodilatation of the CRA and subsequently dislodge the embolus and improve the tissue ischemia by ocular massage, sudden reduction in the IOP by performing anterior chamber paracentesis, IOP lowering drugs such as acetazolamide, inhalation of 95% oxygen and 5% carbon dioxide, rebreathing of expired carbon dioxide in a bag, retrobulbar vasodilators, pars plana vitrectomy (PPV); b) removal of the embolus from the CRA by intra-arterial thrombolysis (IAT), neodymium: yttrium-aluminium-garnet (Nd:YAG) laser arteriotomy and embolectomy or PPV with endovascular surgery, or cannulation of the supraorbital artery and retrograde injection of antispasmodic papaverine, c) improving the retinal oxygenation by hyperbaric oxygen therapy (HBOT), and d) additional measures such as use of pentoxifylline and isovolumic haemodilution to reduce the red blood cell rigidity and administration of systemic steroids to reduce vascular endothelial edema after CRAO.

• Conservative treatment options:

  Many conservative methods have been used to restore vision. Possible treatments include anterior chamber paracentesis, ocular massage, intraocular pressure-lowering agents, sublingual isosorbide dinitrate, systemic β-blockade, carbogen therapy (95% O_2/5% CO₂), and paper bag breathing. Most conservative treatments aim to dislodge the obstruction and allow the embolus to migrate peripherally by modulating intraocular pressure or retinal vasculature. Combining ≥ 2 modalities (e.g., hemodilution, timolol, intravenous acetazolamide, and ocular massage) makes it challenging to distinguish their effects.[69] According to a meta-analysis, patients treated with various combinations of such strategies had a visual recovery rate of 7.4% compared to 17.7% in the natural history.[70] Small, retrospective, uncontrolled, and selection and reporting bias-limited studies often examine such strategies. Two retrospective analyses, one of anterior chamber paracentesis and carbogen and the other of anterior chamber paracentesis alone, found no benefit regardless of timing.[71,72] The goal of ocular massage is to cause significant changes in intraocular pressure, embolus migration, and reperfusion. A three-mirror contact lens is applied to the eye for 10 s to induce retinal artery pulsation or flow cessation, followed by a 5-s release.[73] It has also been proposed that increasing the concentration of carbon dioxide causes vasodilation. To increase carbon dioxide concentration, the patient is instructed to breathe into a bag.[74] A patient may also be given an oxygen mask to try to increase oxygen perfusion via the choroidal circulation. A 95% oxygen/5% carbon dioxide mixture has also been proposed to increase blood flow. Pentoxifylline and isovolumic haemodilution were previously used to reduce erythrocyte viscosity. The literature suggests these treatments may be harmful; so, professional guidelines for CRAO management do not recommend them.[75]

• Local intra-arterial thrombolysis (IAT)

  Selective administration of a thrombolytic agent, such as tissue plasminogen activator (tpA), is used in this technique to achieve intra-arterial fibrinolysis of the occluding thrombus.[76] Biousse et al.[77] reported that in a case series of 249 IAT-treated patients with CRAO, 87 (34.9%) showed four Snellen lines of improvement in visual acuity. Another non-randomized study found that IAT may be effective in improving visual acuity; however, there was significant heterogeneity in treatment duration (3.4 ± 2 h in the IAT group and 25.8 ± 20 h in the conservative treatment group).[78] Schumacher et al.[69] conducted the only prospective randomized trial to date comparing the efficacy of IAT to conservative therapy. The study was halted early due to patient safety concerns and the lack of a statistically significant difference in visual acuity. Notably, one patient in the IAT group suffered from cerebral hemorrhage, whereas another suffered from cerebellar hemorrhage. Because of the increased risk of arterial dissection and the low likelihood of visual benefit, temporary microcatheterization of the ophthalmic artery is generally not recommended.

• Hyperbaric oxygen therapy (HBOT):

  HBOT has been reported to be used in the treatment of retinal vascular occlusions.[79] HBOT is used to treat retinal vascular disorders because hyperoxia-dependent oxygenation improves retinal and macular oxygenation, especially in areas with deficient perfusion and interstitial edema, and vasoconstriction prevents fluid leakage that causes retinopathy. CRAO treated with HBOT may meet retinal cell metabolic needs with increased collateral and choroidal blood flow, whereas the CRA re-cannulates naturally.[80,81,82] For the initial treatment of CRAO, hyperbaric oxygen is compressed to 2-atmosphere absolutes (ATA). If vision improves significantly at 2 ATA, the treatment is continued for 90 min at this depth. If vision does not improve after 30 min at 2 ATA, the oxygen is compressed to 2.4 ATA, and the treatment is repeated for another 90 min if vision improves at this depth. If no improvement is observed at 2.4 ATA, the oxygen is compressed to 2.8 ATA. If no improvement is observed at 2.8ATA, the treatment is stopped.[79]

• Nd: YAG laser arterial embolysis:

  The main focus of Nd: YAG laser embolysis is visible emboli in CRAO. This represents only 17% of all emboli. This proportion is so low that Nd: YAG laser embolysis cannot be considered a routine treatment modality for CRAO. Nd: YAG laser embolysis employs infrared laser energy to fragment emboli using a fundus contact lens. Man et al.[83] performed a meta-analysis on 61 patients who had received Nd: YAG laser embolysis for various types of retinal artery occlusion. This study also included 14 CRAO patients. They discovered that 87% of the patients had some degree of visual improvement. These findings suggest that Nd: YAG laser embolysis may improve visual acuity in CRAO patients.

• Pars plana vitrectomy (PPV):

  PPV under low infusion pressure helps to lower the IOP, which leads to an increase in the perfusion pressure within the CRA. This helps in dislodging the embolus. Two recent studies have demonstrated improvements in visual acuity; notably, one patient recovered from no light perception to 20/20 within 1 month after surgery. Okonkwo et al.[84] performed PPV surgery under general anesthesia, with IOP controlled by a compensatory infusion system. After PPV, IOP was set to < 3 mm hg for 3 min, infusion stopped for 6 min and patient’s blood pressure raised to a maximum of 165/100 mg for 6 min. Reperfusion of the CRA and central retina vein was observed. Altun described an alternative approach to control IOP during surgery.[85] Conventional vitrectomy caused cyclical IOP changes near the optic nerve head. The active suction pressure was 35 mmHg for 5 s and the continuing infusion pressure was 15 mm Hg for 15 s. No complications were reported during or after surgery with PPV plus intraoperative IOP management by Okonkwo et al.[84] or Altun,[85] possibly due to the small number of cases or the lack of arterial wall penetration. Direct central retinal artery massage with PPV was found to be an effective and relatively safe treatment option in CRAO cases by Lu et al.[86]

• PPV plus endovascular surgery:

  A new approach combining PPV and endovascular surgery has attracted the interest of a growing number of vitreoretinal surgeons. Takata et al.[87] reported significant visual improvement in two CRAO patients treated with PPV plus endovascular surgery more than 8 h after onset. A custom-designed microneedle was inserted into the retinal artery at the optic disc following the PPV procedure, and 0.1 to 0.2 mL of tPA was injected into the artery. This method differs from IAT in that the simultaneous presence of white arteries and veins was considered a successful injection, resulting in higher pressure in the artery wall than IAT. A similar study was carried out by Kadonosono et al.[88] They performed the surgery under hypotensive local anesthsia to reduce intraoperative bleeding. Following the PPV procedures, 0.4 mL of tPA was injected into the CRA using a 47-gauge microneedle at a pressure of 30 pounds per square inch. Visual acuity improved in all patients with incomplete and subtotal CRAO (mean onset time of 37.8 [range, 26–48] h), but not in those with total CRAO. These findings are consistent with the Tobalem et al. theory.[89] Both studies’ authors emphasize the importance of utilizing experienced vitreoretinal surgeons to perform this procedure.[87,88]

• Management of arteritic CRAO:

  When arteritic CRAO is confirmed or suspected, immediate and urgent action is required to preserve the affected and fellow eyes. Routine therapy should consist of 3 days of high-dose (500–1000 mg) methylprednisolone followed by 3 days of high-dose prednisone.[90] The British Society of Rheumatology recommends 75 mg of aspirin orally every day.[91] Longer time treatment with systemic tocilizumab for the underlying condition of giant cell arteritis has been shown to induce sustained glucocorticoid-free remissions in respective patients and is nowadays recommended as first-line therapy.[92,93]

Conclusion

CRAO, as an ophthalmic emergency, presents a clinical management challenge. However, advancements in technology and diagnostic modalities, particularly the introduction of PPV surgery, have increased the number of possible treatments for CRAO. To evaluate current treatment options and improve CRAO management, large-scale, multicentre randomized controlled trials with clear inclusion criteria in terms of onset of symptoms are warranted.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.