The National Stroke Association and the American Heart Association define central nervous system (CNS) stroke as brain, spinal cord, or retina cell death.¹ Accordingly, patients with acute retinal ischemia (branch retinal artery occlusion [BRAO] or central retinal artery occlusion [CRAO]) need an urgent stroke workup similar to that in patients with acute cerebral ischemia to identify and, prospectively, ameliorate related risk factors that could lead to future cardiovascular events. This approach is also endorsed by the American Academy of Ophthalmology (AAO).²

Importantly, current guidelines recommend that if carotid endarterectomy is indicated (ie, NASCET criteria: when a CNS stroke is associated with internal carotid artery stenosis of 70% or greater³), it should be performed within 2 weeks to reduce risk of further CNS stroke events, which tend to occur early after the initial event.⁴ As such, urgent referral (after blood pressure evaluation) for appropriate systemic and imaging workup is important. Therefore, an acute symptomatic CRAO, or BRAO (which represent 38% of all retinal artery occlusions⁵), is a stroke equivalent. This ischemic event is associated with sudden, significant vision loss; the incidence is 1 to 2 cases per 100,000 per year.⁶

No Level I data exist to support any specific therapy for nonarteritic RAO. Therapies often attempted include digital massage, anterior-chamber paracentesis, vasodilation, breathing into a paper bag, carbogen inhalation therapy, topical pressure-lowering therapies, hyperbaric chambers, and transluminal neodymium yttrium-aluminum-garnet (Nd:YAG) laser embolysis. However, a meta-analysis suggested that systemic fibrinolysis with alteplase administered within 4.5 hours of the retinal artery occlusion (the “therapeutic window”) may achieve a favorable vision outcome in CRAO patients⁷; a randomized, placebo-controlled clinical trial is necessary to validate this observation. Unfortunately, nearly all patients with RAO present for evaluation well after the 4.5-hour window.

A commonly cited historic longitudinal series of 37 patients found a mean survival of 5.5 years after CRAO compared to a calculated mean life expectancy of 15.4 years.⁸ The reported incidence of coincident ischemic stroke (symptomatic or asymptomatic, often documented with diffusion-weighted MRI) with RAO ranges from 13% to 37.3%, with symptomatic strokes in 2.2% to 15%.^8-11 The relative incidence rate ratio for stroke is highest in the first 7 days (it is 44 during this window) and elevated for 30 days after presentation.¹² After CRAO, critical carotid and structural cardiac disease is found in 36.7% and 20.0% and the risk of subsequent stroke, myocardial infarction (MI), and death is the same as in patients with high-risk transient ischemic attack (TIA).¹⁰ Retinal emboli are seen in 20% to 40% of eyes with CRAO.¹³ Patients with either category of retinal artery occlusion are at higher risk of stroke or cardiovascular disease¹⁴ than age-matched controls; the prognosis for ischemic stroke, MI, and all-cause mortality is similar after either CRAO or BRAO.¹⁵

Therefore, most significantly, a nonarteritic RAO is an important prognostic event, and the results of the workup can fashion life prognosis going forward. Below, we will consider whether the practitioner needs to refer the BRAO/CRAO patient to a stroke center or emergency department (often by ambulance transport) for workup or if the workup can be done in an outpatient setting.¹⁶ We are fortunate to have the perspectives of Timothy Olsen, MD, and Kamal Kishore, MD.

The Ophthalmology Role in Management of RAO

Timothy W. Olsen, MD

In 2015, while I was serving as chair of the AAO Preferred Practice Pattern (PPP) Committee, our group was assigned to construct the first PPP to address retinal vascular disease. We quickly realized that retinal vein and retinal arterial disease had dramatically differing outcomes, treatment recommendations, and overall health implications. Therefore, we wrote 2 evidence-based PPP documents to address the differences and specific requirements for venous and arterial occlusions. We were struck by the evolving literature examining management of patients with RAOs, including ophthalmic, central, and branch RAOs. Our recommendations have led to a meaningful modification in care for those with RAO.¹⁷ The RAO PPP document was updated again in 2020.¹⁸

The incidence of CRAO in the general population is estimated at 1.3 in 100,000.¹⁹ In 2013, the American Heart Association/American Stroke Association updated the definition of stroke: a central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence of permanent injury.¹ Therefore, an RAO is a stroke.

THE OPHTHALMOLOGIST’S ROLE

First, an accurate diagnose of sudden, painless, usually unilateral loss of vision is important. Emergency department (ED) physicians are simply not expected to diagnose specific retinal disorders, for example, differentiating RAOs from a retinal detachment. When an RAO is the suspected diagnosis, the next step is to rule out arteritic forms of arterial occlusion, such as giant cell arteritis (GCA).²⁰ An immediate erythrocyte sedimentation rate, c-reactive protein, and complete blood count with platelets is important to help determine if the patient needs urgent systemic corticosteroids. A thorough history is important, and the ophthalmologist should inquire, especially for those over age 50, if there are headache, jaw claudication, scalp tenderness, neck pain, neurologic symptoms, fever, or generalized malaise. Caution is advised for managing patients with diabetes because corticosteroid therapy can destabilize diabetic control quickly. Younger patients (<50 years) should be suspected of autoimmune disorders, hypercoagulation, or carotid dissections.

Once an embolic RAO has been determined to be the etiology for vision loss, immediate ocular interventions or conservative therapies (eg, aracentesis, rebreathing bags, ocular massage, laser embolysis) have been shown to be ineffective.²¹ In fact, such therapies should not delay further management.²² If the RAO can be diagnosed and confirmed within 4.5 hours of onset of symptoms, often referred to as the “therapeutic window,” intravenous alteplase thrombolysis, delivered by experienced personnel, should be discussed as a treatment option.²¹ Cases of RAO that can be properly diagnosed within 4.5 hours of symptom onset are very rare.

At the Mayo Clinic, our current practice is for nonarteritic RAO cases that are detected after the 4.5-hour timeframe but before 24 hours from onset of symptoms to be sent directly to the emergency department (ED) because RAO is a stroke. The stroke literature is extensive, changes regularly, and most practicing ophthalmologists are not familiar with current, evidence-based stroke protocols, especially for the management of acute stroke. The ophthalmologist should certainly be involved in diagnostic and therapeutic decisions, raising awareness and testing for GCA, Susac syndrome in younger individuals,²³ and determining visible embolus type (cholesterol or calcific). This information is helpful to the medical team managing the patient.

THE EMERGENCY DEPARTMENT IS WARRANTED

While some may consider an ED visit expensive and unwarranted, acute RAO patients are experiencing a stroke. The ED is the appropriate place for acute stroke patients. ED teams are trained to manage the complex and acute issues that may arise. These patients should not be managed in an outpatient setting because the relative risk of either an MI or central nervous system stroke (cerebral) approaches the highest incidence (as high as 10% risk) within 7 days.¹² Acute RAO patients are considered unstable from a vascular perspective. Also, RAO and a stroke have nearly identical risks for cerebral ischemia, MI, and cardiovascular death.²⁴ Patients with RAO should be managed urgently, by neurologists and cardiologists who are familiar with acute stroke and acute MI management as well as anticoagulation and antiplatelet protocols.

In the ED, the neurology service initiates prompt carotid imaging and other relevant studies. If stable, patients are discharged to the outpatient setting. Patients then are referred to the TIA clinic in neurology, and an MRI-brain and MRI head and neck with a clinical carotid plaque protocol are obtained within 1 to 2 weeks. An echocardiogram (ideally transesophageal) and a 48-hour Holter monitor are also completed within 1 to 2 weeks.

If patients present with symptom onset from 24 hours to 2 weeks, they are referred to the stroke clinic at our neurology service. If they cannot be seen within 48 hours, they are sent to the ED and evaluated by the neurology department with carotid imaging, completed prior to discharge. Full-dose aspirin therapy is started, and an MRI-brain, MRI head and neck with a clinical carotid plaque protocol, echocardiogram (ideally transesophageal), and a 48-hour Holter monitor are obtained within 1 to 2 weeks.

When patients present with symptom onset of more than 2 weeks, we refer to the TIA attack clinic in neurology, start full-dose aspirin, and order MRI-brain, MRI head and neck with a clinical carotid plaque protocol, echocardiogram (ideally transesophageal), and 48-hour Holter monitor. If patients have a contraindication to MRI scanning (metal, pacemaker, other implantable device), then computed tomography of the head and computed tomography angiography of the head and neck are ordered along with a carotid ultrasound. When an asymptomatic embolus is detected on routine ophthalmologic exam, this is usually managed in an outpatient setting with scheduled carotid studies and an internal medicine referral.

An RAO is a stroke and represents an urgent medical condition that warrants immediate action. Neurology colleagues are critical to the process because they are trained to manage strokes and are aware of the importance of preventing potential impending stroke or MI. An acute RAO patient is at high risk for cerebral stroke or MI. Ophthalmologists are uniquely positioned to ensure that the patient does not have an arteritic vasculopathy, can help the team determine the source of the embolus (cholesterol vs calcific emboli), and are aware of conditions with ophthalmic findings and stroke (eg, Susac syndrome). Importantly, long-term follow-up of RAO requires monitoring for iris or angle neovascularization from ocular ischemia that has been reported in up to 17% of CRAO cases.²⁵ However, urgent management of acute stroke belongs in an ED with neurologists trained in stroke management protocols and cardiologists available to assess for MI risk and overall vascular stabililty.²⁶ Delay in referral of acute RAO should be avoided. Trying to schedule outpatient imaging studies, commonly fraught with delays, may miss treatment options to prevent stroke, MI, or death.

Outpatient Workup and Management of Patients With RAO

Kamal Kishore, MD, FASRS

Retinal artery occlusions are acute ischemic strokes, and their management ought to be guided by the 2019 update to the 2018 guidelines for the early management of acute ischemic stroke (AIS).²⁷ For patients who are outside the 4.5-hour therapeutic window for thrombolysis for RAO, a controversial topic by itself,²⁸ the only therapeutic goal is secondary prevention of serious systemic adverse events (heart attack, stroke, or death). Patients with TIA, AIS, and RAO may have a 5% to 10% risk of developing another stroke or heart attack within the next 90 days. The risk of systemic adverse events (SAE) follows a biphasic course, with a particularly high risk in the first 7 days following the index event followed by relative stability. Approximately 60% to 70% of SAEs occur within the first week, most likely due to plaque instability soon after ulceration increasing the risk of embolism and thrombosis, followed by plaque maturation over the next several weeks to months.²⁹ Hence, the emerging concept of “acute” secondary prevention of SAE following the index event is gaining momentum.²⁹

WHAT IS NOT RECOMMENDED?

One may be tempted to think that immediate administration of a potent blood thinner, such as intravenous heparin might reduce the risk of SAE in the setting of RAO, TIA, AIS, or even evolving stroke. It doesn’t, and it is even harmful.²⁷ Intravenous administration of antiplatelet agents is not recommended. Emergency mechanical thrombectomy is recommended only for severe strokes (NIH stroke scale ≥6) and causative occlusion of a large vessel, such as the internal carotid artery or M1 segment of the middle cerebral artery. Stenting of the intracranial carotid artery or its branches offers no benefit over medical therapy and is not recommended.^27,30 Routine workup for thrombophilic disorders has uncertain value and is not recommended.^27,28

CLASSIFICATION OF RETINAL ARTERY OCCLUSION

For workup and management, it is useful to classify RAO into 1 of the following 4 categories.

Arteritic RAO. Giant cell arteritis is a very important though rare (<5%) cause of RAO. These eyes will also demonstrate disc edema due to concurrent anterior ischemic optic neuropathy in addition to the usual findings of RAO.²⁸ Giant cell arteritis can be excluded by appropriate history and blood tests.³¹

Cardioembolic causes. The most important conditions in this group are atrial fibrillation, seen in 2% of patients with RAO in a Danish registry,³² and valvular heart disease (most commonly calcific aortic valve followed by mitral valve disease). The EAGLE study showed 17% prevalence of valvular heart disease in patients with CRAO.³³ Atrial fibrillation and flutter can be ruled out by an EKG in most patients. The role of prolonged rhythm monitoring is currently uncertain. Routine echocardiogram received only a “reasonable” recommendation, because “intracardiac thrombus occurs almost exclusively in patients with clinical evidence of heart disease but is rare even in them” and false positive results are common.^27,34 Moreover, patients with calcific aortic valves and mitral valve prolapse do not need emergency management. I clearly remember a case of CRAO where I found a systolic murmur by auscultation of the heart only to be told by a cardiologist, “Good job finding an asymptomatic aortic stenosis! This patient needs no treatment other than aspirin.” According to the American Heart Association, “transesophageal echocardiography should be reserved for those patients in whom there is a high suspicion for an occult structural cardiac lesion and an otherwise negative diagnostic workup.”³⁵

Atypical cases. These include RAO associated with sickle cell anemia³⁶; infective endocarditis³⁷; leukemia³⁸; migraine-associated RAO³⁹; carotid dissection secondary to chiropractic manipulation⁴⁰; cardiac or neurovascular interventions⁴¹; cosmetic hyaluronic acid fillers⁴²; fall in perfusion pressure due to a variety of causes such as orbital hemorrhage⁴³; systemic vasculitides, the most important of them being ANCA-associated vasculitis particularly eosninophic granulomatosis with polyangitis (formerly known as Wegener granulomatosis)⁴⁴; and thrombophilic disorders.⁴⁵ They all are rare, have characteristic history and/or systemic features and will need to be managed based on the clinical situation, including referral to an ED for conditions such as infective endocarditis or systemic vasculitis.

Atherosclerotic cardiovascular disease. The largest (70% to 90%) and the most important group is RAO as a manifestation of atherosclerotic cardiovascular disease. Although thrombosis of the central retinal artery at or posterior to lamina cribrosa is possible and accounts for some cases, most (>90%) cases are embolic. The most important source of embolus is a plaque in the ipsilateral carotid artery. Severe carotid stenosis, defined as 70% or greater according to the NASCET criteria is seen in 20% to 40% of patients with RAO.^28,33

ROLE OF THE EMERGENCY DEPARTMENT

Emergency departments exist for emergent or immediate care in life-threatening or organ-threatening situations. In the setting of RAO or AIS, the role of an ED is to perform immediate evaluation and provide thrombolysis (and mechanical thrombectomy in selected patients) as soon as possible within the therapeutic window. Usually, this workup consists of a noncontrast CT scan to rule out intracranial hemorrhage, EKG, and routine bloodwork. Diffusion-weighted MRI, an expensive and time-consuming study that may show ischemic lesions in the brain in 25% of patients with RAO (silent infarcts), is typically not performed in the ED, nor are MR angiography and carotid doppler. Instead, patients are typically admitted to the floor for “stroke” workup, as shown in a recent publication.⁴⁶ Results of such workups were not disclosed but were likely nonproductive in most patients. The effectiveness of routine brain MRI in guiding treatment selection for secondary prevention of stroke is not known.²⁷ There is no difference in the medical management of RAO patients with an asymptomatic lesion on diffusion-weighted MRI and those without.

WHAT IS URGENTLY NEEDED?

For patients with isolated nonarteritic RAO, 2 conditions need urgent attention. For atrial fibrillation, therapy with an oral anticoagulant, such as warfarin or preferably a direct-acting oral anticoagulant (DOAC), should be initiated between 4 and 14 days of symptom onset.²⁷ It is reasonable to get an urgent EKG, which can be done at the patient’s primary care office or at an urgent care center. The role of prolonged rhythm monitoring is currently uncertain,³⁵ but can be done by outpatient Holter monitoring if desired. The screening for significant ipsilateral carotid disease, the other condition, is best done with a carotid duplex ultrasound, which can be performed as outpatient within 1 to 3 days in most circumstances.⁴⁷

Those who have significant (≥70%) extracranial carotid stenosis (15% according to Rudkin et al)⁴⁸ should have carotid revascularization procedure by endarterectomy or carotid stenting between 3 and 14 days after symptom onset. Generally, carotid revascularization procedures are not recommended in the first 2 days from the index event.²⁷

The most important therapeutic measure for secondary prevention for patients who are not anticoagulated is dual antiplatelet therapy with aspirin and clopidogrel or ticagrelor for 21 days followed by aspirin monotherapy and should be started within 24 hours from symptoms onset.²⁷ Several years ago, we established a policy of giving the patients with RAO a tablet of aspirin while they are still in our office. A single 81 mg aspirin plus 300 mg clopidogrel loading dose followed by 81 mg aspirin plus 75 mg clopidogrel daily will be the most beneficial intervention that can be done by any physician in the setting of RAO. Switching to warfarin is not indicated for secondary stroke prevention in patients who have a noncardioembolic AIS while taking antiplatelet therapy.²⁷

Other measures for secondary prevention include high-intensity statin therapy in most patients with a goal to bring ≥50% reduction in low-density lipoprotein cholesterol levels.²⁷ Control of hypertension and diabetes, weight control, smoking cessation, plant-based diet, and exercise are also important and should be instituted.⁴⁹ Statins are useful not only for lowering of low-density lipoprotein cholesterol, but also for their plaque-stabilizing effect.⁵⁰

WHY NOT REFER THEM TO ED?

Care in the ED in the United States is very expensive and is discouraged by insurance companies. It is also complicated by long delays for a patient with an “eye” condition who didn’t qualify for intravenous alteplase; large copay, deductible, and coinsurance amounts; and nuances like bills from out-of-network providers. Most of the urgently needed tests can be done outside the ED, saving the patient and health-care system a significant amount of money. Many tests performed in the ED as part of stroke workup in an RAO patient and from the floor are low-value investigations that can be performed as outpatient only if indicated, and not as a shotgun approach. Only 5.3% and 7.1% of patients presenting to the ED with a diagnosis of RAO received echocardiogram and carotid imaging, respectively, according to a recently published nationwide study.⁵¹

SUMMARY

For a patient with RAO outside the therapeutic window for thrombolysis, do the following 4 things. First, take a detailed history for symptoms of GCA, systemic conditions, other neurological symptoms, and any possible contraindications to antiplatelet therapy (bleeding disorder, recent major bleed, allergies, etc.). Second, order an EKG, complete blood count, erythrocyte sedimentation rate, and c-reactive protein to rule out GCA, and, preferably, a fasting lipid profile and blood glucose. Third, order an urgent carotid doppler either yourself or in collaboration with the patient’s medical doctor. Tell the patient and their family members that the patient suffered a stroke in the eye; there is a high risk of another stroke, heart attack, or death particularly in the first week; there are things that can be done urgently to minimize that risk; and there is no proof that any treatment benefits the eye, but some patients improve on their own.

Finally, start antiplatelet therapy, preferably dual with aspirin and clopidogrel, but at least start aspirin. Have the patient evaluated urgently by an internist or neurologist, as outpatient to discuss high-intensity statin therapy and other therapeutic measures as indicated. RP

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