Retina and Vitreous
Peter Reed Pavan
Andrew F. Burrows
Deborah Pavan-Langston
I. Normal anatomy and physiology
(see frontispiece)
The retina is the innermost layer of the eye and is derived from neuroectoderm. It is composed of two layers: the outer retinal pigment epithelium (RPE) and the inner neural retina, with a potential space between the two layers. The RPE, a single layer of hexagonal cells, is continuous with the pigment epithelium of the pars plana and ciliary body at the ora serrata. The inner sensory retina is a delicate sheet of transparent tissue varying in thickness from 0.4 mm near the optic nerve to approximately 0.15 mm anteriorly at the ora serrata. The center of the macula contains the thin sloping fovea that lies 3 mm temporal to the temporal margin of the optic nerve. The macula is close to the insertion of the inferior oblique muscle and is made almost entirely of cones. It is the site of detailed fine central vision (20/20 normal). Visual acuity decreases rapidly in the paramacular areas and is only 20/400 at a distance of 2 or 3 mm from the fovea. The ora serrata is located 6 mm posterior to the corneoscleral limbus nasally and 7 mm temporally. The scleral insertions of the medial rectus and the lateral rectus serve as landmarks for the location of the ora serrata nasally and temporally.
Nutritional support for the sensory retina comes largely from the Müller cell, which spans almost the entire thickness of the retina. The inner two-thirds of the retina is nourished by the retinal vessels to the level of the outer plexiform layer. The outer one-third, consisting of the outer part of the outer plexiform layer, the photoreceptors and the RPE, is nourished by the choriocapillaris of the choroid.
Histology. The retina consists of 10 parts. Proceeding from the outside in, they are:
RPE.
Photoreceptor cells (rods and cones).
External limiting membrane.
Outer nuclear layer.
Outer plexiform layer.
Inner nuclear layer.
Inner plexiform layer.
Ganglion cell layer.
Nerve fiber layer.
Inner limiting membrane.
Physiology. The neuronal component of the retina consists of rods and cones that transduce light signals into electric impulses, which are amplified and integrated through circuitry involving bipolar, horizontal, amacrine, and ganglion cells and transmitted through the nerve fiber layer to the optic nerve.
Vitreous. The vitreous body, which makes up the largest volume of the eye, provides support for the delicate inner structures of the eye. It is limited by the lens anteriorly and by the ciliary body, pars plana, and the retina posteriorly. The vitreous is a clear jellylike substance consisting of a delicate framework of collagen interspersed with a hydrophilic mucopolysaccharide, hyaluronic acid. Delicate collagen fibrils attach the vitreous to the internal limiting membrane of the retina, the attachment being strongest around the ora serrata and at the optic disk and fovea.
II. Tests of retinal function
Visual function is classified under the terms light sense, form sense, and color sense. Scientifically, these characteristics of incident light striking the eye are analyzed in terms of spatial, luminous, spectral, and temporal functions.
Visual acuity. In clinical practice, form sense is assessed by use of tests such as the Snellen chart test (see Chapter 1, Section II.B.). This test is primarily of macular function. It is subjective and depends on patient cooperation. Objective tests are of value in assessing visual acuity of infants, mentally disturbed patients, and malingerers. The amplitude of the visual evoked response (VER) or the optokinetic nystagmus response can be correlated with visual acuity. Thus, it is estimated that the visual acuity at birth is approximately 20/600 and improves by the age of 5 months to 20/60 and to adult levels by the age of 2 years.
Visual fields. Light sense is assessed by visual field examination, which reflects any damage to the visual pathway from the retina to the visual cortex. The conventional method of testing the visual field is called kinetic perimetry and consists of moving a target to identify points of equal retinal sensitivity. The normal visual field extends at least 90 degrees on the temporal side, 70 degrees nasally and inferiorly, and 60 degrees superiorly. Static perimetry involves the determination of the differential light threshold in chosen areas of the retina. This method is more sensitive and reproducible than kinetic perimetry (see Chapter 1, Section II.F. and Chapter 13, Section I.A–F.).
Color vision. The retinal cones mediate color vision. Many abnormalities of visual function are characterized by defects in color vision. The simplest and best-known method of testing color vision is by the use of Ishihara pseudoisochromatic plates. The Ishihara plates can only identify defects in red-green discrimination, whereas the American Optical Hardy-Rand-Ritter plates are useful in detecting red-green and blue-yellow defects. The Farnsworth-Munsell 100-hue test and anomaloscopes are more sophisticated devices used in clinical research on color vision testing (see Chapter 1, Section II.E.).
Dark adaptation. This test depends on the increase in visual sensitivity occurring in the eye when it goes from the light-adapted state to the dark-adapted state. The Goldmann-Weekers machine is used to plot the dark-adaptation curve. The eye to be tested is exposed to a bright light for 10 minutes and then all lights are extinguished. At intervals of 30 seconds, a measurement of light threshold is made in one area of the visual field by presenting a gradually increasing light stimulus until it is barely visible to the patient. The graph of decreasing retinal threshold against time shows an initial steep slope denoting cone adaptation and a subsequent gradual slope due to rod adaptation. Depression of the dark-adaptation curve occurs in conditions affecting the outer retina and RPE, such as retinitis pigmentosa.
Fluorescein angiography is the study of retinal and choroidal vasculature using fluorescein (see Chapter 1, Section III.G.).
Technique. Fluorescence is a physical property of certain substances that, on exposure to light of short wavelength, emit light of longer wavelength in a characteristic spectral range. Sodium fluorescein, a yellow-red substance, absorbs light between 485 and 500 nm in aqueous solution and exhibits a maximum emission between 525 and 530 nm. A 5-mL bolus of dye is rapidly injected via the antecubital vein, and rapid retinal photographs are taken with a fundus camera containing an excitatory filter with maximum transmission between 485 and 500 nm and a barrier filter peaking close to the maximum of the fluorescein emission curve (between 525 and 530 nm). The value of fluorescein angiography is based on the fact that fluorescein dye does not penetrate healthy RPE and normal retinal capillaries because of the tight endothelial junction. Fluorescein does leak freely from the normal choriocapillaris. Under optimum conditions, the smallest retinal capillaries (5 to 10 μm in diameter) can be seen with this technique, a feat impossible by ophthalmoscopy or by color photography.
Use in retinal and choroidal disease. Fluorescein angiography is of particular value in elucidating small vessel disease such as diabetic retinopathy, outlining clearly such changes as microaneurysms, shunt vessels, and sites of early neovascularization. Vascular abnormalities within the retina commonly leak fluorescein because of damage to the endothelium. New vessels, both those anterior to the retina and those arising from the choroid under the retina, characteristically leak fluorescein because of the absence of tight endothelial junctions. Angiography provides a valuable means of identifying such vessels in macular degeneration, diabetes, sickle cell disease, and retinal vein obstruction. It also provides a means of assessing the efficacy of treatment, particularly photocoagulation, in eliminating these vessels and in sealing leaks from vascular abnormalities within the retina, as in clinically significant diabetic macular edema (ME).
Use in RPE and optic nerve evaluation. Although angiography does not provide any clue regarding the function of RPE, it anatomically delineates the true extent of RPE atrophy in diseases affecting RPE, such as rubella, retinitis pigmentosa, and age-related macular degeneration. Angiography is also helpful in distinguishing early papilledema, in which both the superficial and deep vascular networks become dilated and leak fluorescein, from “full” disks or disks with buried drusen. Papillitis shows many of the fluorescein characteristics of early papilledema. In optic atrophy, a loss of vessels occurs in both the superficial and the deep networks.
Optical coherence tomography (OCT) measures tissue variation in light interference patterns to construct a 2-D cross-sectional image of the retina. The relative position of features such as hyaloid face, internal limiting membrane, RPE, and intraretinal and subretinal fluid collections are well defined.
Electrophysiology. There are three major electrophysiologic tests used in the investigation of the visual system (see also Chapter 1).
Electro-oculography (EOG) measures slow changes in the standing potential of the retina caused by the interaction of the RPE with the photoreceptors. Electrodes are attached to the skin over the orbital margin opposite the medial and lateral canthi, and the potential difference between the electrodes is amplified and recorded after both light and dark adaptation as the patient is asked to look back and forth at targets to the right and left. The maximum height of the potential in light divided by the minimum height of the potential in dark gives the Arden ratio, which is normally 1.85 or greater. Its principal diagnostic usefulness is in distinguishing Best vitelliform degeneration (in which the ratio is abnormal but the electroretinography [ERG] is normal) from other macular diseases such as Stargardt disease or pattern dystrophies.
ERG reflects the chain of graded electric responses from each layer of the retina. The human response, for clinically useful purposes, is a biphasic wave, an early negative a wave, generated by the rods and cones, followed by a larger positive b wave, generated in the Müller and the bipolar cell layer. The recording is done with a corneal contact lens electrode and a reference electrode on the forehead. Cone responses predominate under photoptic testing conditions when a bright flash stimulates the retina. Rod responses predominate in a scotopic environment when a dim flash is used. A bright flash under scotopic conditions elicits a combined response. In addition, the ERG can distinguish the differences in response between the rods and cones to flickering flash; only the cones respond at 30 Hz because they have a much higher temporal resolution than the rods. The ERG is very useful in evaluating early retinal function loss before ophthalmoscopic changes are evident. The ERG is normal in diseases involving only the ganglion cells and the higher visual pathway, such as optic atrophy.
Visual evoked response (VER). The VER is the response of the electroencephalogram recorded at the occipital pole and is a macula-dominated response due to the disproportionately large projection of the macular retina in the occipital cortex. The VER can be recorded using an intense flash
stimulation or a pattern stimulation. The VER is the only clinically objective technique available to assess the functional state of the visual system beyond the retinal ganglion cells. The flash VER can assess retinocortical function in infants and demented or aphasic patients, and it can distinguish patients with psychological blindness from those who have an organic basis for poor vision.
III. Retinal vascular disease
Retinal vascular anomalies cause loss of visual function primarily through incompetence of the endothelial lining of the anomalous vessels, permitting transudation of serum and, less often, blood into the retinal tissues and the subretinal space. The serous component of the exudate is resorbed, leaving behind clinically visible bright yellow deposits with sharp borders called hard exudates, often in the macular area. The presence of such deposits in the absence of leakage in the posterior pole on fluorescein angiography should lead to a search of the peripheral retina for a vascular anomaly. Effective methods of treatment of these lesions include photocoagulation and cryotherapy, with repeated freezing and slow thawing. Photocoagulation can be effective even after serous detachment of the retina has occurred. Once the lesion is destroyed, the subretinal fluid will absorb. Retinal vascular anomalies may be classified as follows:
Retinal telangiectasia or Coats disease. The basic lesion in Coats disease is a congenital anomaly of the vasculature of the retina, manifested ophthalmoscopically as telangiectasias. There is a marked male predominance (85%) and more rapid progression in children under 4 years of age, simulating retinoblastoma. Fluorescein angiography shows an abnormally coarse net of dilated capillaries, often with irregular aneurysmal dilations, which leak fluorescein. The telangiectasis may involve superficial or deep retinal vessels and can be associated with hemorrhages and hard exudates. Even advanced cases may regress spontaneously. Retinal telangiectasia is usually unilateral. Patients with loss of central vision from subretinal or intraretinal exudation are ideal candidates for photocoagulation. There is a high incidence of recurrence after treatment; therefore, these patients should be followed indefinitely.
Retinal angiomatosis or von Hippel-Lindau disease. The basic lesion in the phakomatosis, von Hippel-Lindau disease, is a vascular hamartoma consisting of capillaries with proliferating endothelial cells, a feeding artery, and draining veins. This disease is bilateral in 50% of patients. It can occur spontaneously or be dominantly inherited. Partly through abnormal hemodynamics and partly through hypertrophy and hyperplasia of the constituent elements, these lesions may enlarge over a period of time. However peripheral the lesion may be, abnormal permeability can result in changes at the macular region, including development of hard exudates, retinal edema, and serous detachment. Repeated photocoagulation of the tumor will usually eliminate the exudation. Long-term follow-up is needed to detect new lesions. Treatment of angiomas on or near the temporal margin of the optic nerve head is difficult without destroying central vision. Appropriate systemic evaluation is necessary to detect associated central nervous system vascular abnormalities (hemangioblastomas), renal cell carcinoma, and pheochromocytoma.
Retinal cavernous hemangioma may arise in the retina or optic nerve head. The lesion is composed of clusters of saccular aneurysms filled with dark venous blood. Fluorescein angiography shows that these lesions do not leak and that they have a sluggish blood flow. Dermal vascular lesions and intracranial lesions may be associated with this condition. Photocoagulation may be used when spontaneous hemorrhage occurs.
Arteriovenous (AV) malformations, a rare condition, have been called “racemose” or “cirsoid” angioma. There is a direct communication between the artery and vein with no intervening capillary bed. The retinal vessels appear dilated and tortuous. Smaller caliber malformations are well compensated, stationary, and usually do not require any treatment. Large-caliber AV malformations can have
a breakdown of the blood-retinal barrier with development of ME. Photocoagulation may be of benefit in these cases. Severe cases of widespread AV malformations, often with face, orbit, and intracranial associations, are not amenable to therapy because of widespread retinal disorganization (i.e., Wyburn-Mason syndrome).
Retinal macroaneurysms occur in the retinal arterioles of arteriosclerotic and often hypertensive elderly patients. The aneurysms appear as outpouchings of the arteriolar wall that leak on fluorescein angiography. They can bleed into the vitreal, retinal, subretinal, or subretinal pigment epithelial spaces. The blood will often resorb, and there will be no further hemorrhaging. The artery beyond the aneurysm may become sclerosed and occluded. If ME or exudate formation is present, gentle photocoagulation of the aneurysm without occluding the associated arteriole may help.
Vascular retinopathies
Mechanisms of visual loss. These diseases reduce vision through either abnormal vascular permeability or retinal ischemia. The former decreases vision principally through exudation of fluid into the macula. Clinically, exudation is seen as thickening of the retina, cystic changes in the retina, and/or as hard exudates. On fluorescein angiography, the leakage can be diffuse or specific, such as that coming from a microaneurysm.
Areas of retinal ischemia often show no changes on ophthalmoscopy. On fluorescein angiography, ischemia appears as focal or diffuse areas of capillary disappearance, often called capillary dropout. Sometimes an area of apparent capillary dropout on fluorescein angiography may correlate with areas of retinal whitening about one-quarter of a disk diameter in size. Because of their fuzzy or ill-defined edges, these lesions are sometimes called soft exudates. This feature plus their bright white appearance has also earned them the eponym cotton-wool spots (CWS) (see Section III.B.8.a). Retinal ischemia may also correlate with widespread retinal whitening as seen in acute central retinal artery occlusion.
Ischemia can cause visual loss in a variety of ways. Ischemic areas can contribute to leakage in the macula. The perifoveal capillary network may be partially or totally destroyed. Vascular endothelial growth factor (VEGF) released by partially ischemic tissue may induce the proliferation of new vessels on the disk or surface of the retina. These new vessels become tightly bound to the posterior vitreous. They leak fluid into it, and this fluid induces contraction of the vitreous gel, resulting in traction on the new vessels, which can then bleed into the vitreous cavity. Depending on the size of the hemorrhage, only a few floaters might be seen, or there can be a sudden and severe decrease in vision. The blood components can cause further contraction of the vitreous and further bleeding, setting up a vicious cycle of recurrent hemorrhaging. In addition to, or instead of, inducing vitreous hemorrhaging, the traction can lead to pulling and detachment of the retina under and around the new vessels (traction retinal detachment). If the fovea is involved, vision will decrease. Retinal ischemia may also induce new vessel formation on the iris and trabecular meshwork blocking Schlemm’s canal, leading to severe pressure elevations (neovascular glaucoma). In diabetic retinopathy, posterior proliferative changes predominate with vitreous hemorrhaging and traction retinal detachments, whereas in central retinal vein occlusion, neovascular glaucoma is more common. In artery occlusions, total ischemia with destruction of the perifoveal capillary network is the mechanism of visual loss. New vessel formation either anteriorly or posteriorly is rare, presumably because little VEGF is produced by totally ischemic tissue.
Management of the vascular retinopathies consists of treatment of the underlying medical condition. Depending on the underlying cause, laser photocoagulation has been shown in controlled clinical trials to be of visual benefit in treating the exudation of fluid into the macula and the retinal complications of the partial ischemia by reducing or eliminating new vessel growth. Intravitreal triamcinolone acetonide (Kenalog) (4 mg in 0.1 mL) or bevacizumab (Avastin (1.25 mg
in 0.05 mL) have shown promise in uncontrolled case series in the treatment of macula edema. Intravitreal bevacizumab has anecdotally been shown to cause regression of new vessels, both on the disc and retina and anteriorly on the iris and trabecular meshwork. Pars plana vitrectomy is useful in managing vitreous hemorrhages and traction retinal detachments.
Hypertensive retinopathy. The retinal changes in hypertension are essentially the same as in the retinopathies seen in the collagen diseases and are secondary to local ischemia.
Pathology. Essential hypertension is associated with thickening of the arteriolar wall caused by intimal hyalinization and hypertrophy of muscle fibers in the media. Sustained elevations of blood pressure cause necrosis of vascular smooth muscle and seepage of plasma into the unsupported wall through a damaged endothelium. Angiography at this stage will demonstrate a focal leak of fluorescein. Progressive plasma exudation into the vessel wall with further muscle necrosis results in secondary occlusion and the typical picture of advanced fibrinoid necrosis.
Clinical findings
Retinal. In its milder forms, hypertension causes increased arteriolar light reflexes called “copper and silver wiring.” Thickening of the common adventitial sheath compresses venules where they pass under the arterioles and causes arteriovenous (AV) nicking. In its extreme form, this compression can cause a branch retinal vein occlusion (BRVO) (see Section III.B.4.a). With higher levels of blood pressure, intraretinal hemorrhages (typically flame shaped, indicating they are in the nerve fiber layer), CWS, and/or retinal edema are seen. Malignant hypertension is characterized by papilledema, and with time, a macular star figure.
Choroidal. Young patients with acute, severe elevations in blood pressure from pheochromocytoma, preeclampsia, eclampsia, or accelerated hypertension can develop hypertensive choroidopathy. Pale or reddish areas of RPE (Elschnig spots) indicate poor choroidal perfusion. Focal serous or large exudative retinal detachments occur in more severe disease.
Prognosis. Serious impairment of vision does not usually occur as a direct result of the hypertensive process unless there is local arteriolar or venous occlusion. Patients with hemorrhages, CWSs, and edema without papilledema have a mean life expectancy of 27.6 months. With papilledema, life expectancy is 10.5 months.
Venous retinopathy. Retinal vein occlusion can manifest itself as a central retinal vein occlusion (CRVO), in which the site of occlusion is behind the cribriform plate, or as a branch retinal vein occlusion (BRVO), in which the occlusion is anterior to the cribriform plate. Obstruction of outflow occurs in retinal vein occlusion, resulting in an increase of intravascular pressure and stagnation of flow. The increase in intravascular pressure is responsible for abnormal leakage, edema, and hemorrhage. Collaterals often form over several weeks to months. In CRVO, the collaterals are on the disc between the retinal and choroidal circulations. In BRVO, the collaterals are within the retina between areas affected and those unaffected by the BRVO. Stagnation of flow can also lead to ischemia of endothelial cells resulting in varying degrees of capillary nonperfusion and CWS formation. The development of large areas of capillary closure stimulates the growth of new vessels. In BRVO, these new vessels are usually at the junction of the normal and ischemic retina. They can lead to vitreous hemorrhage. In CRVO, the new vessels commonly occur on the iris and trabecular meshwork and cause neovascular glaucoma. They also occur on the disc or retina.
BRVO
The site of occlusion in BRVO is usually at AV crossings. Thickening of the arteriolar wall within the common adventitial sheath around the two vessels compresses the venule and induces thrombosis. When a BRVO is not at an AV crossing, vasculitis should be suspected.
Conditions predisposing to BRVO are systemic arterial hypertension, cardiovascular disease, increased body mass index at age 20 years, and glaucoma. The superotemporal quadrant is affected more than 60% of the time. The clinical picture consists of superficial and deep intraretinal hemorrhages with a variable number of CWSs. Subhyaloid and vitreous hemorrhages occur rarely.
The natural history of BRVO varies from complete resolution with no long-term visual difficulties to severe visual loss. Patients presenting acutely should be followed for at least 3 months to allow for the development of collaterals and spontaneous improvement. In general, about 55% of patients retain vision of 20/40 or more after 1 year. In those who do not, the most common causes are ME and preretinal neovascularization. ME occurs in 57% of cases with temporal branch occlusion. The Branch Vein Occlusion Study showed that photocoagulation was effective treatment of ME in patients who had had a BRVO for at least 3 months, acuity 20/40 or worse, and an intact perifoveal capillary network. This same study showed that panretinal photocoagulation in the distribution of the occluded vein significantly lessened the chance of a vitreous hemorrhage in eyes that developed retinal or disc neovascularization. For macular disease, a light grid pattern of 100- to 200-μm spots is given to areas of leakage identified by fluorescein in the macular region extending no closer to the fovea than the edge of the foveal avascular zone and not extending peripheral to the major vascular arcade. Areas of dense intraretinal hemorrhage are avoided. There is no effective treatment for visual loss secondary to macular ischemia.
CRVO
Clinical course. CRVO presents a wide spectrum of clinical appearances. The variations depend on the severity of obstruction of venous outflow. In the mildest cases, minimum dilation of veins and hemorrhages are present with little ME and little decrease in vision. In the severe cases, vision may deteriorate to hand motions, with extensive deep and superficial hemorrhages with stagnant blood columns in grossly dilated veins and numerous CWSs throughout the fundus. Mild to severe disk edema may be present. As in BRVO, the principal vascular response in CRVO consists of dilation of retinal capillaries, abnormal vascular permeability, and retinal capillary closure. Macular edema is often present in the nonischemic CRVO with dilated, leaking capillaries. Ischemic CRVO is characterized by widespread capillary closure as demonstrated on fluorescein angiography. Serious neovascular complications are common, such as rubeosis iridis and neovascular glaucoma. If it is going to occur, rubeosis iridis and/or neovascularization of the angle is usually visible within 6 months of the occlusion. The incidence of the latter complication depends upon the amount of retinal ischemia. In eyes with less than 10 disk areas of nonperfusion, less than 10% will develop rubeosis or angle neovascularization. In eyes with more than 80 disk areas of nonperfusion, approximately 50% will have rubeosis or angle neovascularization on follow-up.
Diseases predisposing to CRVO include cardiovascular disease, systemic hypertension, diabetes, and open-angle glaucoma. Increased physical activity lowers the chance of a CRVO, as does the use of estrogen in postmenopausal women.
Differential diagnosis. There are four conditions from which CRVO must be differentiated.
Venous stasis retinopathy or retinopathy of carotid occlusive disease has been described in patients with internal carotid stenosis or occlusion. Venous stasis retinopathy is characterized by micro-aneurysms in close proximity to the retinal veins and small blossom-shaped hemorrhages in the midperiphery, as well as dilation of the
retinal veins. Other signs of unilateral carotid occlusive disease include a larger appearance to the arterioles on the affected side.
Systemic hypertension often coexists with CRVO. Severe hypertensive retinopathy, however, is usually bilateral and often symmetric with superficial hemorrhages and a macular star of hard exudates present. Retinal hemorrhages do not extend to the periphery as in CRVO. Severe ME and visual loss are rare in hypertensive retinopathy.
Hyperviscosity syndromes, such as macroglobulinemia, leukemias, polycythemias, and some hyperlipemias, show a clinical picture similar to CRVO. These conditions are usually bilateral with few hemorrhages and little ME.
Diabetic retinopathy is usually bilateral. Beading and reduplication of the vein is rare in CRVO.
Treatment. Underlying medical conditions such as hypertension, elevated blood sugar, or congestive heart failure should be corrected. Increased intraocular pressure (IOP) in either the involved or uninvolved eye should be corrected. Focal photocoagulation for ME does not improve acuity. A careful undilated slitlamp examination and gonioscopy should be done every month for 6 months. If neovascularization is detected, give panretinal photocoagulation promptly to prevent neovascular glaucoma. Eyes presenting with good vision (>20/40) have a fair chance of retaining good vision. Eyes with poor vision are more likely to have widespread ischemia, are not likely to recover their vision, and have an increased incidence of rubeosis and angle neovascularization.
Diabetic retinopathy is the leading cause of new cases of blindness in the United States in patients between the ages of 20 and 74. In the developed Western countries, at least 12% of all blindness is due to diabetes. In the United States, a diabetic patient has more than a 20-fold chance of becoming blind compared to a nondiabetic counterpart.
Risk factors. The duration of insulin-dependent diabetes is the main factor in the appearance of diabetic retinopathy. When diabetes is diagnosed before age 30 years, the risk of developing retinopathy is about 2% per year. After 7 years and 25 years, 50% and 90% of diabetic patients, respectively, will have some form of retinopathy. After 25 to 50 years of diabetes, 26% will have the proliferative form. Puberty and pregnancy both stimulate development of retinopathy. The 10-year rate of vision loss to less than 20/40 bilaterally is about 10% in juvenile diabetics, 38% in adult-onset, insulin-dependent disease, and 24% in adult-onset, non-insulin-dependent diabetes. The Diabetes Control and Complications Trial (DCCT) showed that intensive insulin treatment to control blood sugar levels tightly decreased the risk of developing severe nonproliferative or proliferative retinopathy and reduced the need for laser surgery by about 50%.
Types of diabetes
Type I (juvenile onset) diabetes cases are autoimmune (pancreatic destruction) and have a high risk for developing severe proliferative retinopathy.
Type II (adult onset) cases have normal to high insulin production but insulin-resistant receptor cells. There are more type II patients with blinding sequelae because of the greater number of type II diabetic patients.
Medical evaluation. Every diabetic patient deserves the benefit of a comprehensive evaluation, with careful attention paid to determine the presence of symptoms of diabetic retinopathy, such as decreased vision, distortion of vision, loss of color vision, and the presence of floaters. The duration of diabetes and the method of control of diabetes should be assessed. The presence of associated systemic disease should be noted. Hypertension is present in 20% of insulin-dependent diabetics and in 58% of non-insulin-dependent
diabetics. Optimal medical control is key to minimizing ocular and systemic complications.
Clinical appearance. Diabetic retinopathy is classified into four groups.
Background retinopathy (nonproliferative retinopathy). The diabetic lesions of background retinopathy are dilated veins, intraretinal hemorrhages, microaneurysms, hard exudates, edema, and CWS. Dot-blot hemorrhages, retinal edema, and hard exudates result from increased vascular permeability. Microaneurysms cluster around areas of capillary nonperfusion.
Preproliferative diabetic retinopathy represents the most severe stage of background retinopathy (nonproliferative retinopathy). Preproliferative retinopathy is categorized by the presence of many intraretinal hemorrhages and microaneurysms, intraretinal microvascular abnormalities (dilated vessels within the retina), and venous beading. There is widespread capillary closure. Approximately 10% to 50% of patients with preproliferative retinopathy develop proliferative retinopathy within a year.
Proliferative diabetic retinopathy occurs in 5% of patients with diabetic retinopathy. In the proliferative stage, vascular abnormalities appear on the surface of the retina or within the vitreous cavity, starting postequatorially. Visual loss can be severe. New blood vessels grow on the surface of the retina and the optic nerve and are usually attached to the posterior hyaloid surface of the vitreous body. In the cicatricial stage, contraction of the vitreous body causes traction on the retinal neovascularization, resulting in vitreous hemorrhage and/or traction retinal detachment.
Diabetic maculopathy may result from increased vascular permeability with or without intraretinal lipoprotein deposits (hard exudates) or, less commonly, from ischemia due to closure of foveal capillaries. Diabetic maculopathy may be seen in any phase of retinopathy except for very early background disease.
Pathology. Histology of eyes with diabetic retinopathy shows loss of intramural pericytes and extensive capillary closure in trypsin-digest flat preparations of the retina. The blood-retinal barrier is compromised mainly by defects in the junctions between abnormal vascular endothelial cells. The most widely accepted working hypothesis for the pathogenesis of proliferative retinopathies such as diabetes, retinopathy of prematurity (ROP), and CRVO is that a retina rendered ischemic by widespread capillary closure elaborates VEGF, which stimulates retinal neovascularization and/or rubeosis of the iris and trabecular meshwork.
Management. Diabetic eyes should be inspected for rubeosis with a slitlamp before the pupil is dilated because fine vessels on the iris are almost impossible to see once mydriasis is induced. Gonioscopy is necessary if new vessels are seen on the surface of the iris with the slitlamp. To properly inspect the retina, wide pupillary dilation is needed. Diabetic retinas are best examined using a binocular viewing system that provides moderate magnification, such as a slitlamp at 10× in conjunction with a 90-D lens to allow the detection of retinal thickening and tractional retinal detachments with stereoscopic vision. It is important to have the patient look in various fields of gaze so the more peripheral retina to the equator can be inspected, because approximately 27% of retinal abnormalities are found outside the central 45-degree area. Indirect ophthalmoscopy provides a view of the retina at and anterior to the equator. Color photography is used to document the progress or regression of retinopathy following treatment. Fluorescein angiography defines areas of leakage and ischemia and confirms the presence of neovascularization of the retina or disc. OCT shows areas of retinal edema.
Three major clinical trials have been carried out by the National Eye Institute to determine the retinal history of nonproliferative and proliferative diabetic retinopathy, as well as guidelines for treatment.
The Diabetic Retinopathy Study (DRS) showed that scatter argon laser photocoagulation (panretinal photocoagulation [PRP]) reduced the incidence of severe visual loss (vision less than or equal to 5/200) by half or more in eyes with neovascularization on the disc or within one disc diameter of the disk (new vessels disc, or NVD). A similar reduction in the rate of severe visual loss was obtained in eyes with neovascularization elsewhere (new vessels elsewhere or NVE) associated with vitreous hemorrhage.
The Early Treatment Diabetic Retinopathy Study showed that eyes with clinically significant macular edema benefited from focal argon laser to discrete areas of leakage and grid photocoagulation to areas of nonperfusion or diffuse leakage. Moderate visual loss was defined as a doubling of the visual angle (e.g., going from 20/20 to 20/40). Laser treatment reduced the risk of such visual loss by 50% or more, increased the chance of improved vision, and had only minor visual field effect. Focal photocoagulation for vision-threatening ME should be given before scatter photocoagulation (PRP) for approaching high-risk proliferative retinopathy. Aspirin had no clinical effect. Observation only was indicated for eyes with mild to moderate nonproliferative retinopathy.
The Diabetic Retinopathy Vitrectomy Study showed that type I diabetic patients with recent, severe vitreous hemorrhage associated with vision equal to or less than 5/200 undergoing early vitrectomy (within 6 months) had a notably better chance of attaining 20/40 or better vision than those whose vitrectomy was deferred a year. Type II or mixed diabetic patients did not benefit from early vitrectomy for severe vitreous hemorrhage. Patients with severe proliferative retinopathy with vision equal to or greater than 10/200 had a better chance of attaining 20/40 or better vision if they had early vitrectomy than those managed with conventional therapy.
Follow-up and management guidelines for diabetic retinopathy, as recommended by the American Academy of Ophthalmology, are as follows:
Normal or rare microaneurysms: annual examination, good diabetic control.
Mild nonproliferative diabetic retinopathy (NPDR) (few hemorrhages and microaneurysms in one field or several fields, but no ME or exudates): examination every 9 months, good diabetic control.
Moderate NPDR (hemorrhages and/or exudates in all fields, intraretinal microvascular abnormalities [IRMAs] or CWS): examination every 6 months, good diabetic control.
Severe NPDR (one or more of the following: severe number of retinal hemorrhages and microaneurysms, moderate IRMAs, venous beading): examination every 4 months.
ME at any time: examination every 3 to 4 months, focal laser if clinically significant edema develops.
Clinically significant ME includes any of the following features:
Thickening of the retina at or within 500 μm of the center of the macula.
Hard exudates at or within 500 μm of the center of the macula.
Zones of retinal thickening one disk area or larger, any part of which is within one disk diameter of the center of the macula.
Appropriate argon laser photocoagulation reduces the risk of visual loss substantially.
Non-high-risk proliferative diabetic retinopathy occurs when there are any new vessels but the eye does not yet have high-risk characteristics (HRC) as defined by the DRS. These eyes should be followed
every 2 to 3 months. In patients with bilateral non-high-risk proliferative retinopathy, PRP should be considered in one eye.
Proliferative retinopathy with HRC. Panretinal laser photocoagulation is the treatment of choice for this stage, which is characterized by one or more of the following:
NVD greater than one fourth to one third of the disk area.
Vitreous or preretinal hemorrhage associated with less extensive NVD or NVE one-half disk area or more in size.
Laser applications. The risk of severe visual loss in patients with HRC is substantially reduced by means of panretinal laser photocoagulation. The goal is to achieve regression of existing vessels and inhibition of new vessel growth. Treatment is commonly done in two to four stages separated by 1 or more weeks. Typically, 400 to 600 burns of 500-μm diameter are placed in the retinal periphery in one session. They come to within 500 μm of the disk on the nasal side. To preserve central vision, none are placed within two disk diameters of the center of the macula. To preserve peripheral field, burns are placed one to one-half burn width apart. The duration of each burn is 0.1 to 0.2 seconds and the power is adjusted to achieve definite retinal whitening. Flat new vessels away from the disk receive confluent burns. Areas of significant fibrosis, traction retinal detachment, and vitreous or preretinal hemorrhage are avoided. If proliferative diabetic retinopathy continues to be active despite panretinal laser photocoagulation in all quadrants, additional laser spots may be added between, or anterior to, the old laser scars. Panretinal cryoablation is useful in selected patients. If a blinding vitreous hemorrhage occurs despite these measures or before laser can be given, pars plana vitrectomy should be performed within 6 months in type I diabetics. Intraoperative laser photocoagulation is often performed when these patients undergo pars plana vitrectomy. If B-scan ultrasonography suggests an underlying traction retinal detachment of the macula, vitrectomy should be done in all patients. Of course, when a recent traction macular detachment or a combination traction and rhegmatogenous retinal detachment is present even when there is no vitreous hemorrhage, vitreous surgery is indicated.
PRP is not necessary in phakic eyes if there is peripupillary rubeosis but no abnormal new vessels on the trabecular meshwork. Such eyes should be followed every 3 months. If there are new vessels in the angle, the eye is aphakic, or the eye is pseudophakic with a broken posterior capsule, prompt PRP is needed to prevent neovascular glaucoma even when proliferative diabetic retinopathy with HRCs is absent.
Focal macular laser therapy for clinically significant macular edema commonly uses 100- to 200-μm spot sizes and 0.1-second duration. The goal is to change the color of leaking microaneurysms through direct treatment; grid treatment is given to areas of diffuse leakage and ischemia. Leaks within 500 μm of the center of the macula are usually not treated with the laser unless previous treatment has failed, vision is less than 20/40, and treatment will not damage the perifoveal capillary network on the edge of the foveal avascular zone.
Sickle cell retinopathy
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