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23.Are there any other uses for anti-vascular endothelial growth factor agents in diabetic retinopathy?
Intravitreal anti-vascular endothelial growth factor drugs will produce a dramatic reduction in the activity of neovascularization in PDR. They are often used, off-label, for treatment of vitreous hemorrhage in PDR, sometimes in conjunction with PRP or in anticipation of vitrectomy. They can be very helpful in inducing regression of NVI for treatment or prevention of neovascular glaucoma (NVG).
Bibliography
Benson WE, Brown GC, Tasman W: Diabetes and its ocular complications, Philadelphia, 1988, W.B. Saunders.
Diabetic Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus, Arch Ophthalmol 113:36–51, 1995.
Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report number 8, Ophthalmology 88:583–600, 1981.
Diabetic Retinopathy Vitrectomy Study Research Group: Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2, Arch Ophthalmol 103:1644–1652, 1985.
Early Treatment for Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema: Early Treatment for Diabetic Retinopathy Study report number 1, Arch Ophthalmol 103:1796–1806, 1985.
Martidis A, Duker JS, Greenberg PB, et al.: Intravitreal triamcinolone for refractory diabetic macular edema, Ophthalmology 109:920–927, 2002.
Pendergast SD, Hassan TS, Williams GA: Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid, Am J Ophthalmol 130:178–186, 2000.
Diabetic Retinopathy Clinical Research Network: Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema, Ophthalmology 118:609–614, 2011.
RETINAL ARTERIAL OBSTRUCTION
Rebecca Droms and Jay S. Duker
1.What types of retinal arterial obstructions can occur?
Retinal arterial obstructions are generally divided into branch retinal arterial obstructions and central retinal arterial obstructions, depending on the precise site of obstruction:
•A branch retinal arterial obstruction (BRAO) occurs when the blockage is distal to the lamina cribrosa of the optic nerve; in other words, within the visible vasculature of the retina. A BRAO can involve as large an area as three-quarters of the retina or as small an area as just a few micrometers.
•A central retinal arterial obstruction (CRAO) occurs when the blockage is within the optic nerve substance itself. The site of obstruction is therefore not generally visible on ophthalmoscopy. In a CRAO most, if not all, of the retina is affected.
Obstructions more proximal to the central retinal artery, in the ophthalmic artery, or even in the
internal carotid artery can cause visual loss as well. Ophthalmic arterial obstructions can be difficult to differentiate from CRAO on a clinical basis.
2.What causes a retinal artery to become blocked?
The typical causes differ for CRAO and BRAO. Because the site of obstruction is not visible on clinical examination and, in general, the central retinal artery is too small to image with most techniques, the precise cause of most CRAOs cannot be definitely determined. It is currently believed that most CRAOs are caused by thrombus formation. Localized intimal damage from atherosclerosis probably incites the thrombus in most cases. In approximately 20% of cases an embolus is visible in the central retinal artery or one of its branches, suggesting an embolic cause (Fig. 46-1). Rarely, extrinsic mechanical compression is caused by an orbital or an optic nerve tumor, hemorrhage, or inflammation. Inflammation due to vasculitis, optic neuritis, or even orbital disease (e.g., mucormycosis) can cause a CRAO as well. Trauma with direct damage to the optic nerve or blood vessels can lead to CRAO. In addition, systemic coagulopathies can also be associated with both CRAO and BRAO.
Emboli are the cause of more than 90% of BRAOs. Cholesterol, calcium, fibrin, and platelets have all been implicated individually or together. Emboli are usually visible in the retinal arterial tree. In an older individual the most common source of emboli is the ipsilateral carotid artery. In a younger
Figure 46-1. A central retinal arterial obstruction caused emboli in this patient. Note the refractile particles in the central retinal artery in the center of the optic disc, as well as in two branch retinal arteries superior to the optic disc.
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person it is more likely to be cardiac in origin. Rarely, retinal vasculitis or intraocular inflammation such as toxoplasmosis or herpes retinitis (acute retinal necrosis) can lead to BRAO.
3.Describe the typical symptoms of a retinal arterial obstruction.
The hallmark symptom of an acute retinal arterial obstruction is abrupt, painless loss of sight in the visual field that corresponds to the territory of the obstructed artery. In a CRAO this would be most, if not all, of the visual field. In some patients an artery derived from the choroidal circulation, called a cilioretinal artery, may perfuse a small amount of the central retina. The cilioretinal artery, which is present in up to 20% of individuals, remains patent when the site of obstruction is the central retinal artery. Some of the visual field corresponding to the territory of the patent cilioretinal vessel can be spared in select individuals. Cilioretinal artery sparing can rarely leave a patient with 20/20 (normal) central vision, albeit with a very constricted visual field (Fig. 46-2).
Occasionally, patients report stuttering visual loss or episodes of amaurosis fugax before arterial obstruction. Pain is not generally a part of retinal arterial obstruction unless some other underlying disease is present (e.g., giant cell arteritis, ocular ischemia).
In a BRAO the visual field loss can vary from up to three-quarters of the visual field to as little as a few degrees, depending on the territory of the obstructed vessel. Often, the central vision will be 20/20, therefore sparing the macular area.
4.What do you see on examination when a retinal arterial obstruction has occurred?
The decreased blood flow results in ischemic whitening of the retina in the territory of the obstructed artery. Because the retinal vasculature supplies circulation only to the inner retina (the outer retina gets its circulation from the choroid), the ischemia is limited to the inner retina. The retinal whitening is most pronounced in the posterior pole where the nerve fiber layer (NFL) is thickest.
In an arterial obstruction the retinal arteries distal to the blockage appear thin and attenuated. The blood column may be interrupted in both the distal arteries and the corresponding draining veins. This phenomenon has been labeled “boxcarring.” Splinter retinal hemorrhages on the disc are common. Embolic material may be visible in the central retinal artery, where it exits the disc, or in one of the branches of the central retinal artery. In most instances a cherry-red spot will be visible in the macular area.
The most common sites of obstruction in a BRAO are the retinal arterial bifurcations. Because there are more bifurcations and more retinal vessels in the temporal retina, temporal BRAOs are more common than nasal BRAOs.
In a CRAO the visual acuity is usually quite poor. The patient typically can only discern motion or, perhaps, count fingers from a distance of several feet. Many episodes of BRAO result in only peripheral visual loss with intact central acuity.
5.What is a cherry-red spot?
A cherry-red spot represents a pathologic appearance of the macula, the center of the retina. There are two main causes: ischemia and abnormal NFL deposits. A cherry-red spot occurs in CRAO because of the retinal whitening of the surrounding nerve fiber layer. The fovea itself has no nerve
Figure 46-2. Typical inferior hemispheric branch retinal arterial obstruction. The visual acuity was 20/20, but there was a marked superior visual field defect.
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fibers, so its appearance does not change significantly from normal. The retinal whitening surrounding the normal reddish tint of the macular area produces the cherry-red spot.
6.What other conditions result in a cherry-red spot of the retina? How can you differentiate these from an arterial obstruction?
In addition to CRAO, a cherry-red spot may be seen in conditions in which abnormal deposits accumulate in cells of the retinal nerve fiber layer. The classic example is Tay-Sachs disease, which is a sphingolipidosis. A cherry-red spot has been reported in other sphingolipidoses, such as Farber syndrome, Sandhoff’s disease, Niemann-Pick disease, Goldberg’s syndrome, Gaucher’s disease, and
gangliosidase GM1, type 2. A cherry-red spot has also been described in Hurler’s syndrome (MPS I-H), β-galactosidase deficiency (MPS VII), Hallervorden-Spatz disease, and Batten-Mayou (VogtSpielmeyer) disease.
An ischemic cherry-red spot can be differentiated from these other entities by a history of visual loss, concurrent systemic disease, the age of the patient, and the appearance of the surrounding retinal blood vessels and retina.
7.Is there any ancillary testing that can be done to confirm the diagnosis?
In most cases an experienced observer can accurately diagnose CRAO and BRAO. In cases in which the diagnosis is in doubt, an intravenous fluorescein angiogram can be performed. This will show a significant diminution in dye flow through the obstructed vessels. A color Doppler ultrasound evaluation of the orbital circulation can also be used to determine the degree of obstruction and to differentiate an ophthalmic artery obstruction from CRAO.
8.Which systemic diseases are associated with retinal arterial obstruction?
Although many systemic diseases are associated with retinal arterial obstruction, more than 50% of all affected patients will manifest no apparent systemic or local cause for their retinal disease. The most common association is ipsilateral carotid artery disease, which is present in approximately one-third of affected patients. Approximately 10% of arterial obstructions in patients over 50 years of age are associated with giant cell arteritis. This is a critical association because visual loss can occur rapidly in the fellow eye in these patients. Prompt administration of high doses of corticosteroids may prevent the contralateral visual loss.
In both CRAO and BRAO, all patients should be evaluated for embolic sources from the carotid artery system and the heart with carotid noninvasive testing and echocardiogram. In some instances, esophageal echocardiography is necessary to detect embolic sources. Holter monitoring to detect a cardiac arrhythmia may be appropriate in select patients.
9.Do you always have to test for giant cell arteritis?
It is of paramount importance that giant cell arteritis be ruled out in all patients older than age 50 with a CRAO. A stat erythrocyte sedimentation rate, C-reactive protein, and platelet count should be ordered and, if the results are high, or if there is a strong clinical suspicion of giant cell arteritis, a biopsy should be considered along with high-dose corticosteroids until definitive biopsy results are known. BRAO associated with giant cell arteritis is exceedingly uncommon.
KEY POINTS: GIANT CELL ARTERITIS
1. Must be considered in all patients over age 50 with amaurosis.
2. Order a stat erythrocyte sedimentation rate, C-reactive protein, and platelet count.
3. Temporal arteritis may occur in patients with normal blood tests. Clinical suspicion is important. 4. High-dose steroids must be started immediately. A biopsy should be done within a week, but may
be positive up to a month after steroids are initiated.
10.Which patients are at risk to get a retinal arterial obstruction?
Patients who have suffered an arterial obstruction in one eye are at a higher risk for developing an obstruction in the contralateral eye. Ten percent of patients have bilateral retinal arterial obstructions. Patients with known carotid artery disease, diseased heart valves, or cardiac arrhythmias are also at increased risk. In addition, conditions that result in abnormal rheologic parameters such as pancreatitis, lupus, pregnancy, and amniotic fluid emboli can result in artery obstructions.
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11.Can any prophylactic treatment be given?
With the exception of corticosteroid treatment for giant cell arteritis, prophylaxis against arterial obstructions is not generally given. The utility of anticoagulation to prevent retinal arterial obstructions in the setting of known carotid disease is not definitively proven. Extrapolation from studies showing a benefit of lowering the risk of subsequent stroke in this situation suggests that anticoagulation is useful to lower the risk of arterial obstruction as well. The same conclusion may be extrapolated from the studies proving a benefit for carotid endarterectomy for appropriate patients with carotid arterial disease.
12.What is the incidence of bilateral retinal arterial obstructions?
Ten percent.
13.Is there any proven treatment for retinal arterial obstruction?
There is no proven treatment for either CRAO or BRAO. Some investigators feel that none of the currently recommended treatments have any value. Because the inner retina is highly sensitive to loss of perfusion, intervention is rarely, if ever, attempted in anyone with an obstruction more than 72 hours old. Proposed therapies for retinal arterial obstructions are as follows:
•Dislodging emboli to a more distal location
•Dissolving thrombi
•Increasing oxygenation to the retina
•Protecting surviving retinal cells from ischemic damage
The traditional approach to CRAO includes paracentesis, ocular massage, and medications to lower the intraocular pressure. All three of these interventions are an attempt to dislodge any embolus that may be present. A paracentesis is the removal of a small amount of aqueous humor via a small needle (30 or 27 gauge). This can be done in an office setting. Although generally simple and safe, it has rarely been reported to cause endophthalmitis.
Increasing oxygenation to the retina is attempted by having patients inhale a mixture of 95% oxygen and 5% carbon dioxide (carbogen) for 10 minutes every 2 hours for 24 to 48 hours after the blockage. Carbon dioxide counteracts the normal retinal arterial vasoconstriction that occurs when pure oxygen is inhaled. However, there is no clinical evidence of any beneficial effect. Carbogen should not be used to treat any patient suffering from chronic obstructive pulmonary disease. Hyperbaric oxygen therapy is another approach intended to increase oxygenation to the ischemic inner retina. This may be considered for patients seeking treatment within 24 hours of onset.
More recently, both systemic (via intravenous infusion) and local (directly into the ophthalmic artery via an arterial catheter) infusions of clot-dissolving medications (streptokinase, tissue plasminogen activator, urokinase, heparin) have been tried for retinal arterial obstruction. However, a random-
ized clinical trial found no difference in visual outcome between intra-arterial thrombolysis (IAT) via local infusion of tissue plasminogen activator and traditional CRAO treatments at 1 month follow-up, although IAT was associated with more adverse reactions. The long-term procedural results and potential favorable anatomic outcomes of IAT, such as central retinal artery reperfusion, have not yet been determined. IAT is not without risk and should be contemplated only for obstructions less than 48 hours old. Because branch retinal arterial obstructions do not usually affect central vision, such invasive procedures probably should not be attempted in these cases.
At present, there are no means to “rescue” ischemic retinal tissue. This is an area of active research and it may be possible in the future.
KEY POINTS: RETINAL ARTERIAL OBSTR UCTION
1. Systemic disease must be ruled out in any retinal artery obstruction.
2. Giant cell arteritis should be considered and ruled out in any patient older than age 60 with a central retinal artery obstruction.
3. No proven treatment exists for retinal artery obstruction.
14.Why is the retina so sensitive to arterial inflow problems?
The retina is a highly metabolic organ and is therefore sensitive to ischemia. The central retinal artery is an end artery with no true normal anastomosis. As part of the central nervous system, the retina is unable to regenerate if damaged.
