The human retina is the most complex of the ocular tissues with a highly organized structure. It receives the visual image, produced by the optical system of the eye, and converts the light energy into an electrical signal, which undergoes initial processing and is then transmitted through the optic nerve to the visual cortex, where the structural (form, color, and contrast) and spatial (position, depth, and motion) attributes are perceived. The anatomy of the retina is described in Chapter 1, Figure 1–17 showing its layers. Function and functional disturbance in the retina often can be localized to a single layer or a single cell type.
Rod and cone cells in the photoreceptor layer are responsible for the initial transformation, by the process of phototransduction, of light stimuli into the nerve impulses that are conducted through the visual pathways to the visual cortex. These photoreceptors are arranged such that there is an increased density of cones in the center of the macula (fovea), decreasing to the periphery, and a higher density of rods in the periphery. In the foveola, there is a nearly 1:1 relationship between each cone photoreceptor, its ganglion cell, and the emerging nerve fiber, whereas in the peripheral retina, many photoreceptors connect to the same ganglion cell. The fovea is responsible for good spatial resolution (visual acuity) and color vision, both requiring high ambient light (photopic vision) and being best at the foveola, while the remaining retina is utilized primarily for motion, contrast, and night (scotopic) vision.
The rod and cone photoreceptors are located in the avascular outermost layer of the sensory retina. Each rod photoreceptor cell contains rhodopsin, a photosensitive visual pigment embedded in the double-membrane disks of the photoreceptor outer segment. It is made up of two components, an opsin protein combined with a chromophore. The opsin in rhodopsin is scotopsin, which is formed of seven transmembrane helices. It surrounds the chromophore, retinal, which is derived from vitamin A. When rhodopsin absorbs a photon of light, 11-cis retinal is isomerized to all-trans retinal and eventually to all-trans retinol. The resulting configurational change initiates a secondary messenger cascade. Peak light absorption by rhodopsin occurs at approximately 500 nm, which is the blue-green region of the light spectrum. Spectral sensitivity studies of cone photopigments have shown peak wavelength absorption at 430, 540, and 575 nm for blue-, green-, and red-sensitive cones, respectively. The cone photopigments are composed of 11-cis retinal bound to other opsin proteins than scotopsin.
Night (scotopic) vision is mediated entirely by rod photoreceptors. With this dark-adapted form of vision, varying shades of gray are seen, but colors cannot be distinguished. As the retina becomes fully light-adapted, the spectral sensitivity of the retina shifts from a rhodopsin-dominated peak of 500 nm to approximately 560 nm, and color sensation becomes evident. An object takes on color when it selectively reflects or transmits certain wavelengths of light within the visible spectrum (400–700 nm). Daylight (photopic) vision is mediated primarily by cone photoreceptors, and twilight (mesopic) vision by a combination of cones and rods.
The photoreceptors are maintained by the retinal pigment epithelium, which plays an important role in the visual process. It is responsible for phagocytosis of the outer segments of the photoreceptors, transport of vitamins, and reduction of light scatter, as well as providing a selective barrier between the choroid and retina. The basement membrane of the retinal pigment epithelial cells forms the inner layer of Bruch's membrane, which is otherwise composed of a specialized extracellular matrix and the basement membrane of the choriocapillaris as its outer layer. Retinal pigment epithelial cells have little capacity for regeneration.
Examination of the retina is described in Chapter 2 and depicted in Figures 2–11, 2–12, 2–13, 2–14, 2–15, 2–16 and 2–17. The retina can be examined with a direct or indirect ophthalmoscope or with a slitlamp (biomicroscope) and handheld or contact biomicroscopy lens. This allows identification of the type, level, and extent of retinal disease. Retinal imaging techniques (Figures 2–26, 2–27, 2–28, 2–29 and 2–30) are useful adjuncts to clinical examination, enabling identification of anatomical, vascular (both retinal and choroidal), and functional abnormalities. They include fundus photography, fluorescein angiography, optical coherence tomography (OCT), indocyanine green angiography, and autofluorescence. The clinical application of visual electrophysiologic and psychophysical tests is described in Chapter 2.
Age-Related Macular Degeneration
Age-related macular degeneration (AMD) affects people aged over 55 and is the leading cause of irreversible blindness in the developed world. It is a complex multifactorial progressive disease. Current evidence suggests genetic susceptibility involving the complement pathway and environmental risk factors, including increasing age, white race, and smoking. Among whites aged over 55, the 10-year risk of developing AMD is approximately 11.5% for early and 1.5% for late disease.
The pathogenesis is still poorly understood; however, degeneration of the retinal pigment epithelium, linked to oxidative stress, seems to be a crucial component. Changes in the adjacent extracellular matrix of Bruch's membrane and the formation of subretinal deposits are central to disease progression. Progressive diffuse thickening of Bruch's membrane reduces the ability of oxygen to diffuse through to the retinal pigment epithelium and photoreceptors. The resulting hypoxia results in release of growth factors and cytokines, which stimulate growth of choroidal new vessels. Development of single or multiple areas of weakness in Bruch's membrane allows the new vessels to grow through into the subretinal space, between the retinal pigment epithelium and the retina, to form a choroidal neovascular membrane. The new vessels leak serous fluid and/or blood, resulting in distortion and reduction of clarity of central vision. Alternatively, visual loss results from progression of the degenerative process to cell death and atrophy of the retinal pigment epithelium.
Twin studies and linkage analysis have identified multiple loci for genes related to AMD. The two most important loci are at 1q25–31 (complement factor H–CFH) and 10q26 (age-related maculopathy susceptibility 2-ARMS2/HTRA serine peptidase 1-HTRA1). The genes can be divided into those which have an influence on structural (HTRA1), inflammatory (CFH, C3, C2, and Factor B), and lipid (APOE) pathways. HTRA1 is a heat shock protein that is involved in the degradation of extracellular proteins such as that found in Bruch's membrane. Polymorphisms in its promoter gene have been found to be associated with a 10-fold increased risk of AMD. CFH is involved in the alternative complement pathway, thereby identifying an inflammatory component to the pathogenesis of AMD. Its Y402H polymorphism is associated with an increased risk of AMD. C3 mutations confer a 3-fold increased risk, whereas C2 and Factor B appear to have a protective effect. The function of the LOC387715 gene, which is found within the ARMS2 locus next to HTRA1, is unknown but a polymorphism is associated with a 2–3-fold increased risk of AMD, with an additive effect from the CFH polymorphism.
Individuals with genetic predisposition are even more likely to develop the disease if they smoke or have a low intake of antioxidants.
AMD can be classified simply into early and late, the latter being subdivided into geographic atrophy and neovascular disease. The Age-Related Eye Disease Study (AREDS) devised a grading system based on fundal features, of which a simplified form is also useful clinically.
Early AMD is characterized by limited drusen, pigmentary change, or retinal pigment epithelial atrophy. The level of associated visual impairment is variable and may be minimal. Fluorescein angiography demonstrates irregular patterns of retinal pigment epithelial hyperplasia and atrophy.
Drusen are visualized clinically as yellow deposits, which are situated within Bruch's membrane. They vary in size and shape. They may be discrete or confluent (Figure 10–1). Histopathologically, drusen may also be detected as diffuse subretinal deposits, either basal laminar deposits, formed mainly of collagen-based material and situated between the plasma and basement membranes of the retinal pigment epithelium, or basal linear deposits, consisting of granular lipid-rich material located within Bruch's membrane.
AMD with discrete (small arrow) and large confluent (large arrow) macular drusen.
Pigmentary change may be due to focal clumps of pigmented cells in the subretinal space and outer retina, or attenuated areas of hypopigmented retinal pigment epithelium progressing to atrophy.
Geographic atrophy (“dry AMD”) is responsible for up to 20% of legal blindness attributable to AMD. It manifests as well-demarcated areas, larger than two disk diameters, of atrophy of the retinal pigment epithelium and photoreceptor cells, allowing direct visualization of the underlying choroidal vessels. Accumulation of lipofuscin in the retinal pigment epithelium is thought to contribute to the atrophic changes. Visual loss occurs once the fovea is affected. Geographic atrophy is best monitored with autofluorescence imaging, different patterns of abnormality possibly providing clarification of disease progression.
Neovascular (“wet”) AMD is characterized by the development of choroidal neovascularization or serous retinal pigment epithelial detachment. Choroidal new vessels may grow in a flat cartwheel or sea-fan configuration away from their site of entry into the subretinal space to form a choroidal neovascular membrane. Hemorrhagic detachment of the retina may undergo fibrous metaplasia, resulting in an elevated subretinal mass called a disciform scar. Permanent loss of central vision ensues. OCT imaging identifies both subretinal and intraretinal fluid, along with the choroidal neovascular membrane. Fluorescein angiography should be performed on all patients with AMD with new onset of reduced vision or distortion, as the most sensitive method for detection of choroidal neovascularization. It can also guide treatment options. Choroidal neovascularization can be classified angiographically into either classic or occult, depending on the pattern of new vessel growth. Classic is characterized by early hyperfluorescence, which is usually well circumscribed and may have a lacy pattern (Figure 10–2). Occult is characterized by ill-defined and late hyperfluorescence. For research studies, choroidal neovascularization has been subdivided into predominantly classic, in which more than 50% of the lesion has the characteristics of classic choroidal neovascularization; minimally classic, in which less than 50% of the lesion has the characteristics of classic choroidal neovascularization; and pure occult, in which no classic component can be identified.
Flourescein angiogram of classic choroidal neovascularization showing well-circumscribed, lacy pattern.
Retinal pigment epithelial detachment is included in the category of neovascular AMD because of its strong, although not absolute, association with choroidal neovascularization, to the extent that choroidal neovascularization should be assumed to be present until investigations or natural history has excluded it. Serous retinal pigment epithelial detachment may develop from influx of proteinaceous material through a plane of cleavage at the site of drusen. Focal retinal pigment epithelial detachment may also develop from leak of serous fluid from the choroid through small defects in Bruch's membrane. Retinal pigment epithelial detachments may spontaneously flatten, with variable visual results, but usually leaving an area of geographic atrophy.
It is uncertain whether retinal angiomatous proliferation (RAP) is a manifestation of AMD, but it usually presents in the same clinical setting. The cause is unknown. It manifests as superficial (inner retinal) hemorrhage with retinal pigment epithelial detachment and extensive exudation (Figure 10–3) and is characterized by anastomosis between the retinal and choroidal circulations (Figure 10–4).
RAP with superficial hemorrhage, retinal pigment epithelial detachment, and extensive exudation.
Mid-venous phase of fluorescein angiogram of RAP showing the retino-choroidal anastomosis and early filling of the pigment epithelial detachment.
Risk of Progression to Late AMD
The AREDS, which includes an interventional longitudinal study of progression of AMD, has identified pigmentary changes and large drusen (>250 microns) to be the most important fundal features predictive of progression to late AMD, from which a simple clinical scoring system to predict risk of progression has been devised. Points are assigned according to whether pigmentary changes or large drusen can be identified on fundoscopy. For patients with no late disease, 1 point is assigned for each eye with large drusen, for each eye with pigmentary abnormalities, and if neither eye has large drusen for intermediate-size drusen present in both eyes. For patients with late disease in one eye, 2 points are assigned for the eye with late disease and 1 point for each of large drusen or pigmentary abnormalities in the fellow eye. The 5-year risk of progression to late AMD is 0.5%, 3.0%, 12.0%, 25%, and 50%, respectively, as the cumulative score rises from 0 to 4.
Treatment with oral vitamins and antioxidants, comprising vitamin C (500 g), vitamin E (400 IU), betacarotene (15 mg), and zinc (80 mg) and copper (2 mg) daily, was found in the AREDS to reduce the 5-year risk of progression to late AMD from 28% to 20% in patients with cumulative scores of 3 or 4 on the risk prediction score (see above) but did not show any benefit for those with lower cumulative scores. In a separate study, smokers taking betacarotene have been shown to have an increased risk of development of lung cancer. Therefore, smokers and ex-smokers are advised to omit the betacarotene.
Smoking is a proven risk factor for development of all forms of macular degeneration. Cessation of smoking is thought to reduce the rate of progression, although further trials are required to establish the extent of its effect. It is recommended that smoking be discontinued, together with change in lifestyle to incorporate gentle daily exercise, which lowers the risk of AMD. It takes about 20 years of smoking cessation to reduce the level of risk of development of AMD to that of a non smoker.
Retinal laser photocoagulation reduces the extent of drusen but increases the rate of choroidal neovascularization and is not recommended outside a clinical trial.
Treatment of Neovascular AMD
Vascular endothelial growth factor (VEGF) plays a crucial role in the expansion of choroidal neovascular membranes. It induces both angiogenesis and increased permeability. Blocking VEGF (anti-VEGF therapy) has become the preferred treatment for neovascular AMD.
Ranibizumab (Lucentis, Genentech) is a humanized Fab fragment of a murine monoclonal anti-VEGF antibody, which is able to bind all isoforms of VEGF. It is able to penetrate through all layers of the retina and is administered by intravitreal injection. The MARINA trial showed stabilization of vision in 94% of eyes with minimally classic or occult lesions and improvement in 34%. The ANCHOR trial showed similar results, with significant benefit over photodynamic therapy (PDT) (see later in the chapter) for predominantly classic lesions.
Currently, ranibizumab is the treatment of choice for all forms of neovascular AMD. Repeated intravitreal injections are well tolerated with minimal side effects, but the ideal treatment regimen is still under investigation. Long-term monthly injections, which are a significant burden to patients and health care systems, may not be needed, but a loading phase of three injections at monthly intervals followed by a maintenance phase of injection frequency being determined by disease activity is probably required. The small PrONTO trial suggested that monthly monitoring with treatment according to results of OCT provides near-equivalent visual outcome to monthly dosing, but this was not confirmed in a larger study using the original retreatment criteria. More rigorous treatment criteria are being investigated to optimize outcome without having to rely upon monthly injections.
The oligonucleotide aptamer (chemically synthesized single-stranded nucleic acid), pegaptanib (Macugen, Eyetech), binds the major pathogenic isoform of VEGF, VEGF165. It is administered by intravitreal injection. Stabilization of vision has been demonstrated in 71% of patients, with improvement occurring in 6% (VISION trial).
Bevacizumab (Avastin, Genentech) is a humanized full-length monoclonal antibody to VEGF. Initially it was thought not to be able to pass through the retina, but it has been widely used with good results. Several (CATT, IVAN, VIBERA and GEFAL) trials are currently being undertaken in the United States and Europe to evaluate its efficacy and safety compared to ranibizumab.
Conventional retinal laser photocoagulation can achieve direct destruction of a choroidal neovascular membrane. It requires confluent high-energy burns over and around the whole membrane. The overlying retina is also destroyed, the laser scar may expand, leading to visual loss, and the rate of recurrence of the neovascular membrane is high. Laser photocoagulation is only used for choroidal neovascular membranes that are more than 200 microns from the center of the foveal avascular zone (extrafoveal).
Photodynamic therapy (PDT) requires an intravenous infusion of a photosensitive dye, verteporfin (Visudyne, Novartis), which is activated by a low-energy visible laser (689 nm). However, this treatment has now largely been replaced by anti-VEGF treatments.
Combining anti-VEGF therapy with PDT steroids, or other agents continues to be investigated. The Mont Blanc study showed that PDT with ranibizumab is no better than ranibizumab alone. Other agents being investigated include the VEGF trap, a designer molecule that binds to VEGF to prevent it binding to its receptor, and RNA interference (RNAi) technology to prevent transcription of VEGF or its receptors.
Surgery for late AMD continues to be studied with mixed results. Options include surgical removal of the choroidal neovascular membrane, macular translocation, and retinal pigment epithelial transplantation. Surgery is recommended only as part of a clinical trial.
Myopic Macular Degeneration
Pathologic myopia is one of the leading causes of blindness in the United States and is much more common in the Far East and Japan. It is characterized by progressive elongation of the eye with subsequent thinning and atrophy of the choroid and retinal pigment epithelium in the macula. Usually there is at least 6 diopters myopia. Peripapillary chorioretinal atrophy and linear breaks in Bruch's membrane (“lacquer cracks”) are characteristic findings on fundoscopy (Figure 10–5). Degenerative changes of the macular pigment epithelium resemble those found in older patients with AMD. A characteristic lesion of pathologic myopia is a raised, circular, pigmented macular lesion called a Fuchs spot. Most patients are in the fifth decade when the degenerative macular changes cause a slowly progressive loss of vision; rapid loss of visual acuity is usually caused by serous and hemorrhagic macular detachment overlying a choroidal neovascular membrane, which occurs in 5%–10% of patients.
Myopic macular degeneration with choroidal vessels visible through atrophic retinal pigment epithelium and peripapillary atrophy.
Fluorescein angiography shows delayed filling of choroidal and retinal blood vessel and is helpful in identifying and locating the site of choroidal neovascularization in eyes with serous or hemorrhagic detachment of the macula. Anti-VEGF therapy has become the treatment of choice for sub- or juxta-foveal choroidal neovascularization.
The chorioretinal changes of pathologic myopia predispose to retinal breaks and thus to retinal detachment. Peripheral retinal findings may include paving-stone degeneration, pigmentary degeneration, and lattice degeneration. Retinal breaks usually occur in areas involved with chorioretinal lesions, but they also arise in areas of apparently normal retina. Some of these breaks, particularly those of the “horseshoe” and round retinal tear type, will progress to rhegmatogenous retinal detachment.
Retinal Vascular Diseases
Diabetic retinopathy is one of the leading causes of blindness in the Western world, particularly among individuals of working age. Chronic hyperglycemia, hypertension, hypercholesterolemia, and smoking are all risk factors for development and progression of retinopathy. Young people with type I (insulin-dependent) diabetes do not develop retinopathy for at least 3–5 years after the onset of the systemic disease. Type II (non-insulin-dependent) diabetics may have retinopathy at the time of diagnosis, and it may be the presenting manifestation.
Early detection and treatment of diabetic retinopathy is essential. Readily detectable changes occur before vision is affected. Their identification and appropriate treatment will usually prevent permanent visual loss. Screening for diabetic retinopathy should be performed within 3 years from diagnosis in type I diabetes, on diagnosis in type II diabetes, and annually thereafter in both types. Digital fundal photography has been proven to be an effective and sensitive method for screening. Seven-field photography is the gold standard, but two 45° fields, one centered on the macula and the other centered on the disk, are becoming the method of choice in most screening programs. Mydriasis is necessary for best quality photographs, especially if there is cataract.
Diabetic retinopathy can progress rapidly during pregnancy. Every pregnant diabetic woman should be examined by an ophthalmologist or digital fundal photography in the first trimester and at least every 3 months until delivery.
Diabetic retinopathy can be classified into nonproliferative retinopathy, maculopathy, and proliferative retinopathy.
Diabetic retinopathy is a progressive microangiopathy characterized by small-vessel damage and occlusion. The earliest pathologic changes are thickening of the capillary endothelial basement membrane and reduction of the number of pericytes. The capillaries develop tiny dot-like outpouchings called microaneurysms. Flame-shaped hemorrhages are so shaped because of their location within the horizontally oriented nerve fiber layer.
Mild nonproliferative retinopathy is characterized by at least one microaneurysm. In moderate nonproliferative retinopathy, there are extensive microaneurysms, intraretinal hemorrhages, venous beading, and/or cotton wool spots (Figure 10–6). Severe nonproliferative retinopathy is characterized by cotton-wool spots, venous beading, and intraretinal microvascular abnormalities (IRMA). It can be diagnosed when there are intraretinal hemorrhages in four quadrants, venous beading in two quadrants, or severe IRMA in one quadrant.
Moderate nonproliferative diabetic retinopathy showing microaneurysms, deep hemorrhages, flame-shaped hemorrhage, exudates, and cotton wool spots.
Diabetic maculopathy manifests as focal or diffuse retinal thickening or edema, caused primarily by a breakdown of the inner blood–retinal barrier at the level of the retinal capillary endothelium, which allows leakage of fluid and plasma constituents into the surrounding retina. It is more common in type II diabetes and requires treatment once it becomes clinically significant (Figure 10–7), which is defined as any retinal thickening within 500 microns of the fovea, hard exudates within 500 microns of the fovea associated with retinal thickening, or retinal thickening greater than one disc diameter in size, of which any part lies within one disc diameter of the fovea.
Clinically significant macular edema with two circinate rings of exudates.
Maculopathy can also be due to ischemia, which is characterized by macular edema, deep hemorrhages, and little exudation. Fluorescein angiography shows loss of retinal capillaries with enlargement of the foveal avascular zone (Figure 10–8).
Fluorescein angiogram shows hypofluorescence from capillary nonperfusion (arrows), with enlargement of the foveal avascular zone, typical of ischemic diabetic maculopathy.
The most severe ocular complications of diabetes mellitus are due to proliferative diabetic retinopathy. Progressive retinal ischemia eventually stimulates the formation of delicate new vessels that leak serum proteins (and fluorescein) profusely (Figures 10–9 and 10–10). Early proliferative diabetic retinopathy is characterized by the presence of any new vessels on the optic disk (NVD) or elsewhere in the retina (NVE). High-risk characteristics are defined as new vessels on the optic disk extending more than one-third disk diameter, any new vessels on the optic disk with associated vitreous hemorrhage, or new vessels elsewhere in the retina extending more than one-half disk diameter with associated vitreous hemorrhage.
Frond of neovascular tissue (arrows) arising from the superotemporal vascular arcade in proliferative diabetic retinopathy.
Fluorescein angiogram of proliferative diabetic retinopathy shows leakage from the neovascular tissue. The pinpoint areas of hyperfluorescence are microaneurysms.
The fragile new vessels proliferate onto the posterior face of the vitreous and become elevated once the vitreous starts to contract away from the retina. If the vessels bleed, massive vitreous hemorrhage may cause sudden visual loss (Figure 10–11). There is a risk of developing neovascularization and vitreous hemorrhage once a complete posterior vitreous detachment has developed. In eyes with proliferative diabetic retinopathy and persistent vitreoretinal adhesions, elevated neovascular fronds may undergo fibrous change and form tight fibrovascular bands, which cause vitreoretinal traction. This can lead to either progressive traction retinal detachment or, if a retinal tear is produced, rhegmatogenous retinal detachment. The retinal detachment may be heralded or concealed by vitreous hemorrhage. When vitreous contraction is complete in these eyes, proliferative retinopathy tends to enter the burned-out or “involutional” stage. Advanced diabetic eye disease may also be complicated by iris neovascularization (rubeosis iridis) and neovascular glaucoma.
Proliferative diabetic retinopathy with preretinal hemorrhage obscuring the inferior macula. Macular exudates, microaneurysms, and intraretinal hemorrhages are also present.
Proliferative retinopathy develops in 50% of type I diabetics within 15 years of onset of their systemic disease. It is less prevalent in type II diabetics, but as there are more patients with type II diabetes, more patients with proliferative retinopathy have type II than type I diabetes.
OCT is invaluable in the identification and monitoring of macular edema as well as identification of structural changes within the retina. The development of spectral domain OCT, with increased scan speed and resolution and eye tracking with improved reproducibility, has further enhanced disease assessment and monitoring.
Fluorescein angiography is useful for identifying microvascular abnormalities in diabetic retinopathy (Figure 10–12). Large filling defects of capillary beds—“capillary nonperfusion”—show the extent of retinal ischemia (Figure 10–8) and are usually most prominent in the midperiphery. The fluorescein leakage associated with retinal edema may assume the petaloid configuration of cystoid macular edema (CME) or may be diffuse (Figure 10–13). This can help determine prognosis as well as extent and placement of laser treatment. Eyes with macular edema and significant ischemia have a poorer visual prognosis, with or without laser treatment, than eyes with edema and relatively good perfusion.
Fluorescein angiogram in nonproliferative diabetic retinopathy shows microaneurysms (arrow) and perifoveal retinal vascular changes.
Late-phase fluorescein angiogram shows hyperfluorescence typical of diffuse (noncystoid) diabetic macular edema.
The mainstay of prevention of progression of retinopathy is good control of hyperglycemia, systemic hypertension, and hypercholesterolemia.
Ocular treatment depends on the location and severity of the retinopathy. Eyes with diabetic macular edema that is not clinically significant should usually be monitored closely without laser treatment. Clinically significant macular edema requires focal laser if focal and grid laser if diffuse. Argon laser to the macula should be sufficient to produce only light burns, as laser scars can expand and affect vision. Sub-threshold treatment, in which no retinal burn is visualized at the time of treatment, and micropulse laser have been shown to be just as effective with less scarring. Intravitreal injections of triamcinolone or anti-VEGF agents are also effective.
By inducing regression of new vessels, pan-retinal laser photocoagulation (PRP) reduces the incidence of severe visual loss from proliferative diabetic retinopathy by 50%. Several thousand regularly spaced laser burns are applied throughout the retina to reduce the angiogenic stimulus from ischemic areas. The central region bordered by the disk and the major temporal vascular arcades is spared (Chapter 23). Patients at greatest risk of visual loss are those with high risk characteristics. If treatment is delayed until high risk characteristics have developed, it is essential that adequate PRP is achieved without delay. Treatment of severe nonproliferative retinopathy has not been shown to alter the visual outcome; however, if the patient has type II diabetes, poor glycemic control, or cannot be monitored sufficiently carefully, treatment before proliferative disease has developed may be justified.
Vitrectomy is able to clear vitreous hemorrhage and relieve vitreoretinal traction. Once extensive vitreous hemorrhage occurs, 20% of eyes will progress to no perception of light vision within 2 years. Early vitrectomy is indicated for type I diabetics with extensive vitreous hemorrhage and severe, active proliferation and whenever vision in the fellow eye is poor. Otherwise, vitrectomy can be delayed for up to a year as vitreous hemorrhage will clear spontaneously in 20% of eyes. Intravitreal anti-VEGF therapy a few days preoperatively is associated with a reduced re-bleed rate and better visual outcome post operatively. Vitrectomy for proliferative diabetic retinopathy with only mild vitreous hemorrhage is only useful in eyes that have already undergone PRP and have extensive new vessels that have started to fibrose. Tractional retinal detachment does not require vitrectomy until the detachment has involved the fovea. Rhegmatogenous detachment complicating proliferative diabetic retinopathy requires urgent vitrectomy.
Complications following vitrectomy are more common in the type I diabetics undergoing delayed vitrectomy and type II diabetics undergoing early vitrectomy. They include phthisis bulbi, raised intraocular pressure with corneal edema, retinal detachment, and infection.
Retinal vein occlusion is a common and easily diagnosed retinal vascular disorder with potentially blinding complications. The patient presents with sudden painless loss of vision. The clinical appearance varies from a few small scattered retinal hemorrhages and cotton-wool spots to a marked hemorrhagic appearance with both deep and superficial retinal hemorrhage (Figure 10–14), which rarely may break through into the vitreous cavity.
Central retinal vein occlusion with extensive superficial retinal hemorrhage obscuring macular and optic nerve detail.
In central retinal vein occlusion the retinal abnormalities involve all four quadrants of the fundus. In branch retinal vein occlusion typically they are confined to one quadrant because the occlusion usually occurs at the site of an arteriovenous crossing (Figure 10–15), but they may involve the upper or lower half (hemispheric branch retinal vein occlusion), or just the macula (macular branch retinal vein occlusion).
Branch retinal vein occlusion involves the superotemporal vein. The point of obstruction (arrow) is at an arteriovenous crossing.
Patients are usually over 50 years of age, and more than 50% have associated cardiovascular disease. Predisposing factors and investigations are discussed in Chapter 15. Chronic open-angle glaucoma should always be excluded (see Chapter 11). The major complications associated with retinal vein occlusion are reduced vision from macular edema, neovascular glaucoma secondary to iris neovascularization, and retinal neovascularization.
Macular Edema in Retinal Vein Occlusion
Macular dysfunction occurs in almost all eyes with central retinal vein occlusion. Although some will show spontaneous improvement, most will have persistent decreased central vision as a result of chronic macular edema, which is also the main cause of persisting impairment of visual acuity in branch retinal vein occlusion.
Macular edema due to central retinal vein occlusion does not respond to laser treatment. In branch retinal vein occlusion, grid-pattern macular argon laser photocoagulation may be indicated when vision loss due to macular edema persists for several months without any spontaneous improvement.
Intravitreal injection of anti-VEGF agents or steroids may be useful. The BRAVO and CRUISE studies, both large multicenter trials, have shown benefit from monthly ranibizumab injections for macular edema secondary to branch and central retinal vein occlusion, respectively. The SCORE study has shown that intravitreal preservative-free triamcinolone provides no benefit compared to laser in branch retinal vein occlusion, but improved outcome compared to observation in central retinal vein occlusion, although it is uncertain whether the optimal dose is 1 mg or 4 mg. Ozurdex (Allergan), an intravitreal implant containing 0.7 mg dexamethasone in a solid polymer drug delivery system, which can be injected into the vitreous using a 22 gauge needle and dissolves completely, has been shown to accelerate improvement in visual acuity compared to placebo in macular edema due to branch or central retinal vein occlusion. The most commonly reported adverse events during the first 6 months after treatment included increased intraocular pressure, but for which only 0.7% of patients required laser or surgical procedures.
Iris and Retinal Neovascularization in Retinal Vein Occlusion
Nearly one-third of central retinal vein occlusions are ischemic with significant retinal capillary nonperfusion seen on fluorescein angiography; one-half of these will develop neovascular glaucoma. The standard treatment for iris neovascularization is PRP, although it may also be controlled with intravitreal anti-VEGF agents.
In branch retinal vein occlusion, retinal neovascularization may develop if retinal capillary nonperfusion exceeds five disk diameters in area. Sectoral retinal laser photocoagulation to the area of ischemic retina reduces the risk of vitreous hemorrhage by one-half.
Clinical trials continue to investigate the role of vitrectomy, with or without arteriovenous sheathotomy, to facilitate reperfusion of the retina and reduction of macular edema.
Central retinal artery occlusion causes painless catastrophic visual loss occurring over a period of seconds; antecedent transient visual loss (amaurosis fugax) may be reported. Visual acuity ranges between counting fingers and light perception in 90% of eyes at initial examination. Twenty-five percent of eyes have cilioretinal arteries that continue to perfuse the macula, potentially preserving central vision. An afferent pupillary defect can appear within seconds, preceding any fundus abnormalities, which include opacification of the superficial retina due to infarction, and reduced blood flow in the retinal vessels, possibly manifesting as segmentation of the blood column in the retinal arterioles. A foveal cherry-red spot (Figure 10–16) develops due to preservation of the relatively normal appearance of the choroidal pigment and retinal pigment epithelium through the extremely thin retina overlying the foveola, surrounded by the pale swollen retina of the rest of the macula. The fundal abnormalities resolve within 4–6 weeks, leaving a pale optic disk as the major ocular finding. In older patients, giant cell arteritis must be excluded and if necessary treated immediately with high-dose systemic corticosteroids. Other causes of central retinal artery occlusion are arteriosclerosis and emboli from carotid or cardiac sources. These are discussed further in Chapter 15.
Acute central retinal artery occlusion with cherry-red spot (arrow) and preserved retina due to cilioretinal arterial supply (arrowheads). (Courtesy of Esther Posner.)
Branch retinal artery occlusion also causes sudden painless visual loss but usually manifesting as impairment of visual field. Visual acuity is only reduced if there is foveal involvement. The extent of the fundal abnormalities, primarily retinal opacification as in central retinal artery occlusion but sometimes accompanied by cotton-wool spots along its border, is determined by the extent of retinal infarction. The cause is often embolic disease, for which clinical evaluation and investigations need to be undertaken (see Chapter 15).
Irreversible retinal damage occurs within a few hours of complete central retinal artery occlusion. Sudden decrease in intraocular pressure resulting in increased retinal perfusion can be achieved with anterior chamber paracentesis and intravenous acetazolamide. This is particularly indicated in embolic central retinal artery occlusion. Inhaled oxygen–carbon dioxide mixture induces retinal vasodilation and increases the Po2 at the retinal surface. Thrombolytic therapy, infused directly into the ophthalmic artery or administered systemically, has been shown to be beneficial but patients rarely present sufficiently early to warrant treatment. Systemic anticoagulants are generally not employed unless necessitated by an embolic cause, such as atrial fibrillation.
Retinal Arterial Macroaneurysm
Retinal macroaneurysms are fusiform or round dilations of retinal arterioles occurring within the first three orders of arteriolar bifurcation. Most cases are unilateral, involving the superotemporal artery. Two-thirds of patients have associated systemic hypertension.
Macroaneurysms may result in retinal edema, exudation, or hemorrhage typically with an “hourglass” configuration due to bleeding deep and superficial to the retina. Hemorrhage is usually followed by fibrosis of the macroaneurysm such that no treatment is required. If edema threatens the macula, the macroaneurysm can be treated by confluent laser photocoagulation followed by a direct hit. There is a risk that this direct hit will result in hemorrhage, but this usually settles with fibrosis of the macroaneurysm.
Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a vasoproliferative retinopathy that affects premature and low-birth-weight infants. The etiology, classification (Table 10–1), screening regime, and treatment are also discussed in Chapter 17.
Table 10-1. Stages of Retinopathy of Prematurity |Favorite Table|Download (.pdf)
Table 10-1. Stages of Retinopathy of Prematurity
|Stage ||Clinical Findings|
|1 ||Demarcation line|
|2 ||Intraretinal ridge|
|3 ||Ridge with extraretinal fibrovascular proliferation|
|4 ||Subtotal retinal detachment|
|5 ||Total retinal detachment|
All babies younger than 30 weeks gestational age, or a birth weight of 1500 g or less, and those that receive prolonged supplemental oxygen therapy should undergo repeated screening from 2–4 weeks after birth until the retina is fully vascularized, the retinal changes have undergone spontaneous resolution, or appropriate treatment has been given. Treatment with peripheral retinal laser is recommended once there is stage 2 disease with venous dilation and arterial tortuosity in the posterior segment (“plus” disease), the latter now being the main indication for treatment. Vitreoretinal surgery may be appropriate for eyes with stage 4 or 5 disease but is only recommended when such disease occurs in the better eye as the visual prognosis continues to be poor.
A significant number of infants with ROP undergo spontaneous regression. Peripheral retinal changes of regressed ROP include avascular retina, peripheral folds, and retinal breaks; associated changes in the posterior pole may include straightening of the temporal vessels, temporal stretching of the macula, and retinal tissue that appears to be dragged over the disk (Figure 10–17). Other ocular findings of regressed ROP include myopia (which may be asymmetric), strabismus, cataract, and angle-closure glaucoma.
ROP with stretching of the macula and straightening of retinal vessels.
Retinal Detachment and Related Retinal Degenerations
Retinal detachment is the separation of the sensory retina, ie, the photoreceptors and inner retinal layers, from the underlying retinal pigment epithelium. There are three main types: rhegmatogenous, traction, and serous or hemorrhagic detachment.
Rhegmatogenous Retinal Detachment
The most common type of retinal detachment, rhegmatogenous retinal detachment is characterized by a full-thickness break (a “rhegma”) in the sensory retina, variable degrees of vitreous traction, and passage of liquefied vitreous through the break into the subretinal space. A spontaneous rhegmatogenous retinal detachment is usually preceded or accompanied by a posterior vitreous detachment and is associated with myopia, aphakia, lattice degeneration, and ocular trauma. Binocular indirect ophthalmoscopy with scleral depression (Figures 2–15 and 2–17), or slitlamp examination with a handheld or contact biomicroscopy lens, reveals elevation of the translucent detached sensory retina with one or more full-thickness sensory retinal breaks, such as a horseshoe tear, round atrophic hole, or anterior circumferential tear (retinal dialysis). The location of retinal breaks varies according to type; horseshoe tears are most common in the superotemporal quadrant, atrophic holes in the temporal quadrants, and retinal dialysis in the inferotemporal quadrant. When multiple retinal breaks are present, they are usually within 90° of one another.
The principal aims of detachment surgery are to find and treat all the retinal breaks, cryotherapy or laser being applied to create an adhesion between the retinal pigment epithelium and the sensory retina, thus preventing any further influx of fluid into the subretinal space, to drain subretinal fluid, internally or externally, and relieve vitreoretinal traction. Various surgical techniques are employed.
In pneumatic retinopexy air or expandable gas is injected into the vitreous to maintain the retina in position, while the chorioretinal adhesion induced by laser or cryotherapy achieves permanent closure of the retinal break. It has a lower success rate than other methods and is used only when there is a small accessible single retinal break, minimal subretinal fluid, and no vitreoretinal traction.
Scleral buckling maintains the retina in position, while the chorioretinal adhesion forms, by indenting the sclera with a sutured explant in the region of the retinal break. This also relieves vitreo-retinal traction and displaces subretinal fluid away from the retinal break. The success rate is 92%–94% in suitably selected cases. Complications include change in refractive error, diplopia due to fibrosis or involvement of extraocular muscles in the explant, extrusion of the explant, and possibly increased risk of proliferative vitreoretinopathy.
Pars plana vitrectomy allows relief of vitreo-retinal traction, internal drainage of subretinal fluid, if necessary by injection of perfluorocarbons or heavy liquids, and injection of air or expandable gas to maintain the retina in position, or injection of oil if longer-term tamponade or the retina is required. It is used if there are superior, posterior, or multiple retinal breaks, when visualization of the retina is inhibited, such as by vitreous hemorrhage, and if there is significant proliferative vitreoretinopathy. The introduction of 23 and 25 rather than 20 gauge vitrectomy instruments has made possible sutureless surgery, with the advantages of reduced operating time, less anterior segment inflammation, improved patient comfort, and more rapid recovery of vision, but greater risks of postoperative hypotony and endophthalmitis. The 25 gauge system is mainly recommended for macular surgery as there are reports of worse outcome with the 23 gauge system. Vitrectomy frequently induces or accelerates cataract formation and postoperative posturing may be required.
The visual results of surgery for rhegmatogenous retinal detachment primarily depend on the preoperative status of the macula. If the macula has been detached, recovery of central vision is usually incomplete. Thus, surgery should be performed urgently if the macula is still attached. Once the macula is detached, delay in surgery for up to 1 week does not adversely influence visual outcome.
Traction Retinal Detachment
Traction retinal detachment is most commonly due to proliferative diabetic retinopathy. It can also be associated with proliferative vitreoretinopathy, ROP, or ocular trauma. In comparison to rhegmatogenous retinal detachment, traction retinal detachment has a more concave surface and is likely to be more localized, usually not extending to the ora serrata. The tractional forces actively pull the sensory retina away from the underlying pigment epithelium toward the vitreous base. Traction is due to formation of vitreal, epiretinal, or subretinal membranes consisting of fibroblasts and glial and retinal pigment epithelial cells. Initially the detachment may be localized along the vascular arcades, but progression may spread to involve the midperipheral retina and the macula. Focal traction from cellular membranes can produce a retinal tear and lead to combined traction-rhegmatogenous retinal detachment.
Proliferative vitreoretinopathy is a complication of rhegmatogenous retinal detachment and is the most common cause of treatment failure.
Pars plana vitrectomy allows removal of the tractional elements followed by removal of the fibrotic membranes. Retinotomy and/or injection of perfluorocarbons or heavy liquids may be required to flatten the retina. Gas tamponade, silicone oil, or scleral buckling may be used.
Serous & Hemorrhagic Retinal Detachment
Serous and hemorrhagic retinal detachment occurs in the absence of either retinal break or vitreoretinal traction. They form as a result of accumulation of fluid beneath the sensory retina and are caused primarily by diseases of the retinal pigment epithelium and choroid. Degenerative, inflammatory, and infectious diseases, including the multiple causes of subretinal neovascularization, may be associated with serous retinal detachment and are described in an earlier section of this chapter. This type of detachment may also be associated with systemic vascular or inflammatory disease, or intraocular tumors (see Chapters 7 and 15).
Lattice degeneration is the most common vitreoretinal degeneration. The estimated incidence in the general population is 6%–10%, of which up to 50% have bilateral disease. It is more commonly found in myopic eyes with some familial tendency. It produces localized round, oval, or linear areas of retinal thinning, with pigmentation, branching white lines, and whitish-yellow flecks, and firm vitreoretinal adhesions at its margins. Lattice degeneration results in retinal detachment in only a small percentage of affected eyes, but 20%–30% of eyes with retinal detachment have lattice degeneration. Strong family history of retinal detachment, retinal detachment in the fellow eye, high myopia, and aphakia require the patient to be informed of the risks of retinal detachment and the relevant symptoms but rarely warrant prophylactic treatment with cryosurgery or laser photocoagulation.
Peripheral Chorioretinal Atrophy
Peripheral chorioretinal atrophy (paving stone degeneration) is a common benign chorioretinal degeneration found in nearly one-third of adult eyes. It is thought to be due to choroidal vascular insufficiency and is associated with peripheral vascular disease. The lesions appear as isolated or grouped, small, discrete, yellow-white areas with prominent underlying choroidal vessels and pigmented borders.
Degenerative retinoschisis is a common acquired peripheral retinal disorder that is believed to develop from coalescence of preexisting peripheral cystoid degeneration. The cystic elevation is most commonly found in the inferotemporal quadrant, followed by the superotemporal quadrant. It develops into one of two forms, typical or reticular, although clinically the two are difficult to differentiate.
Typical degenerative retinoschisis forms a round or ovoid area of retinal splitting in the outer plexiform layer. Posterior extension and hole formation in the outer layer is uncommon and therefore poses low risk of progression to retinal detachment.
Reticular degenerative retinoschisis is characterized by round or oval areas of retinal splitting in the nerve fiber layer forming a bullous elevation of an extremely thin inner layer. Retinal holes occur in 23%, and posterior extension or progression to rhegmatogenous retinal detachment may occur and requires treatment.
Degenerative retinoschisis is present in about 4% of the population and is bilateral in approximately 30% of affected individuals. Spontaneous regression occurs in up to 9% of cases. Progression to retinal detachment occurs in up to 2%, with increased risk for those with a family history of retinal detachment. Whether cataract extraction increases the risk of retinal detachment is uncertain. Retinal detachment occurs in one of two ways. A hole in the outer but not the inner retinal layer allows the cystic fluid through the defect. This type is usually not or is only slowly progressive, and therefore a demarcation line forms. It rarely requires treatment. In the second type, holes form in both the inner and the outer layers. This causes collapse of the schisis and full thickness retinal detachment forms. Progression is quick, and treatment is required by pneumatic retinopexy, scleral buckle, or vitrectomy, depending on the size and position of the retinal holes and whether there is any proliferative vitreoretinopathy.
Differentiation from Retinal Detachment
Retinoschisis causes an absolute scotoma in the visual field, whereas retinal detachment causes a relative scotoma. The cystic elevation of retinoschisis is usually smooth with no associated vitreous pigment cells. The surface of retinal detachment is usually corrugated with pigment cells in the vitreous (“tobacco dust”). Longstanding retinal detachment produces atrophy of the underlying retinal pigment epithelium, resulting in a pigmented demarcation line. As the retinal pigment epithelium is healthy in retinoschisis, there is no demarcation line. If argon laser photocoagulation to the outer retinal layer, aimed through an inner layer break, creates an equal gray response as in an adjacent area of normal retina, this is thought to be diagnostic of retinoschisis.
Macular hole is a full-thickness absence of the sensory retina in the macula. This disorder occurs most often in elderly patients and is typically unilateral. Biomicroscopy of the symptomatic eye reveals a full-thickness, round or oval, sharply defined hole measuring one-third disk diameter in the center of the macula, which may be surrounded by a ring detachment of the sensory retina (Figures 10–18 and 10–19). Visual acuity is impaired, and metamorphopsia and a central scotoma are present on Amsler grid testing. The Watzke-Allen slit beam test correlates well with the presence of a full-thickness macular hole. A slit beam of light positioned across the macular hole is described by the patient as being either thinned or broken.
Macular hole (large arrows) with surrounding sensory retinal detachment (small arrows). See Figure 19–10.
OCT of macular hole showing edema as well as detachment of the surrounding cuff of retina.
Macular hole results from tangential traction in the epiretinal vitreous cortex. Its development is divided into four stages. In stage 1, occult hole, there is a yellow spot at the foveola with loss of the foveal reflex. This stage is reversible if a posterior vitreous detachment occurs. In stage 2, there is enlargement with a deep perifoveal yellow ring. In stage 3, the well-circumscribed full-thickness macular hole is surrounded by a cuff of subretinal fluid. In stage 4, the full-thickness hole is associated with a posterior vitreous detachment (see Chapter 9).
OCT is the best method of diagnosis and assessment before and after surgery. Treatment to reattach the retina of the cuff surrounding the macular hole involves vitrectomy, separation of the posterior hyaloid, removal (peeling) of the retinal internal limiting membrane, and intravitreal injection of gas, which provides a scaffold for glial call repair. For a few days, patients may need to undertake face down posturing and to avoid sleeping on their back. Cataract due to the intraocular gas develops in most cases, but cataract surgery is often performed at the time of the macular hole surgery, if it has not been performed previously. Use of stains improves visualization of the internal limiting and has greatly improved the rate of closure of macular holes, but the potential toxicity of the stains is debated.
Anatomic closure of macular holes can be achieved in up to 90% of cases but does not always correlate with improvement of function. Twenty to twenty-five percent of patients with anatomically closed macular holes fail to achieve vision greater than 20/50, particularly in traumatic and chronic holes.
Fibrocellular membranes may proliferate on the retinal surface of the macula or peripheral retina. Contraction of these epimacular membranes (EMM) causes varying degrees of visual distortion, intraretinal edema, and degeneration of the underlying retina. Biomicroscopy usually shows wrinkling (striae) of the retina and distortion of retinal vessels (Figure 10–20). Rarely there may be retinal hemorrhages, cotton-wool spots, serous retinal detachment, and macular changes that simulate a macular hole (pseudo-macular hole). Posterior vitreous detachment is nearly always present. OCT is valuable in the identification of EMM and to monitor for development of macular edema. Disorders associated with EMM include retinal tears with or without rhegmatogenous retinal detachment, vitreous inflammatory diseases, trauma, and a variety of retinal vascular diseases.
EMM elevates retinal vessels (arrow) and produces retinal striae.
Visual acuity usually remains stable, suggesting that contraction of EMM is a short-lived and self-limited process. Surgical peeling of severe EMM can be performed to treat visual distortion, but recurrence occurs in some cases (see Chapter 9).
Traumatic and Related Maculopathies
Blunt trauma to the anterior segment of the eye may cause a contrecoup injury to the retina, commotio retinae. The retinal whitening in the macular area usually clears completely; however, it may result in a pigmented retinal scar or macular hole with permanent impairment of central vision. Traumatic choroidal rupture (Figure 10–21) also may result in permanent visual loss.
White sclera visible through a choroidal rupture.
Purtscher retinopathy, characterized by bilateral, multiple patches of superficial retinal whitening and hemorrhages, occurs after severe compression injury to the head or trunk. Terson syndrome, manifesting as retinal, preretinal, or vitreous hemorrhage, occurs in approximately 20% of patients with intracranial hemorrhage and elevated intracranial pressure, particularly being associated with subarachnoid hemorrhage due to rupture of intracranial aneurysm. Solar retinopathy, manifesting as bilateral sharply demarcated and often irregularly shaped partial-thickness hole or depression in the center of the fovea, occurs after sun-gazing.
Central Serous Chorioretinopathy
Central serous chorioretinopathy (CSR) is characterized by serous detachment of the sensory retina due to multi-focal areas of hyperpermeability of the choroidal vessels and alteration in the pumping function of the retinal pigment epithelium. It affects young to middle-aged men and is associated with type A personality, chronic steroid use, and stress. Presentation is with sudden onset of blurred vision, micropsia, metamorphopsia, and central scotoma. Visual acuity is often only moderately decreased and may be improved to near-normal with a small hyperopic correction.
Fundal examination reveals a round or oval area of retinal elevation, variable in size and position, but usually in the macula (Figure 10–22). There may be central yellowish-gray spots representing subretinal exudates. Occasionally there is a serous retinal pigment epithelial detachment in the superior portion. There may be evidence of previous episodes in the form of mild atrophic retinal pigment epithelial lesions. Diagnosis is most easily confirmed on OCT. Approximately 80% of eyes with CSR undergo spontaneous resorption and recovery of normal visual acuity within 6 months after the onset of symptoms. However, despite normal acuity, many patients have a mild permanent visual defect, such as a decrease in color sensitivity, micropsia, or relative scotoma. Twenty to thirty percent of patients will have one or more recurrence of the disease. Complications, including subretinal neovascularization and chronic CME, have been described in patients with frequent and prolonged serous detachments.
CSR showing a circular central retinal elevation (arrows).
Various patterns of abnormality are seen on fluorescein angiography, of which the most characteristic is a “smokestack” configuration of fluorescein dye leaking from the choriocapillaris followed by accumulation below the retinal pigment epithelium or sensory retina (Figures 10–23 and 10–24). Argon laser photocoagulation to the site of leak significantly shortens the duration of the sensory detachment with quicker recovery of central vision, but there is no evidence that prompt photocoagulation improves final visual outcome. It is not recommended for lesions close to central fixation because scar formation may cause permanent impairment of vision. For such lesions, PDT, including a low dose (fluence) technique, and micropulse laser have produced encouraging results without the scarring associated with conventional laser treatment. Treatment outcomes are less favorable for any CSR accompanied by retinal pigment epithelial detachment. In all cases, the duration and location of disease, the condition of the fellow eye, and occupational visual requirements are important considerations in determining treatment recommendations.
Early fluorescein angiogram showing a smokestack configuration of dye leakage in CSR.
Late fluorescein angiogram showing accumulation of dye in the serous detachment of CSR.
Retinal edema involving the macula may be due to intraocular inflammatory disease, retinal vascular disease, epimacular membrane, intraocular surgery, inherited or acquired retinal degeneration, or drug therapy, or it may be idiopathic. It may be diffuse when nonlocalized intraretinal fluid results in thickening of the macula. Focal macular edema, due to fluid accumulation in honeycomb-like spaces of the outer plexiform and inner nuclear layers, is known as cystoid macular edema (CME). It has a characteristic appearance on OCT, which is a good noninvasive method of monitoring response to treatment (Figure 10–25). On fluorescein angiography, fluorescein dye leaks from the perifoveal retinal capillaries and peripapillary region, accumulating in a flower-petal pattern around the fovea (Figure 10–26).
Flower-petal pattern of fluorescein dye in a patient with CME after cataract surgery.
The most frequent cause of CME is cataract surgery, especially if the surgery was complicated or prolonged. Complete posterior vitreous detachment seems to provide some protection against its development. After routine phacoemulsification surgery, CME is detectable on fluorescein angiography in approximately 25% of eyes and on clinical examination in about 2%. It usually manifests at 4–12 weeks postoperatively, but in some instances its onset may be delayed for months or years. Many patients with CME of less than 6 months' duration have self-limited leakage that resolves without treatment. Topical steroid and/or nonsteroidal anti-inflammatory therapy may accelerate improvement in visual acuity in patients with chronic postoperative macular edema. In resistant cases, treatment with orbital floor or intravitreal triamcinolone may be beneficial. If there is vitreous traction, early YAG laser vitreolysis (see Chapter 23) or vitrectomy should be considered. If an intraocular lens implant is the cause of postoperative macular edema, due to its design, positioning, or inadequate fixation, removal of the lens implant should be considered.
Angioid streaks appear as irregular, jagged tapering lines that radiate from the peripapillary retina into the macula and peripheral fundus (Figure 10–27). The streaks represent linear, crack-like dehiscence in Bruch's membrane. The lesions are rarely noted in children and probably develop in the second or third decade of life. Early in the disease, the streaks are sharply outlined and red-orange or brown. Subsequent fibrovascular tissue growth may partially or totally obscure the streak margins.
Multiple angioid streaks extending from the optic nerve.
Nearly 50% of patients with angioid streaks have an associated systemic disease, including pseudoxanthoma elasticum due to mutations in the recessive ABCC6 gene, Paget disease of bone, Ehlers–Danlos syndrome, hemoglobinopathy, or a hemolytic disorder. Complications that can result in significant visual impairment include direct involvement of the fovea, choroidal neovascularization, and traumatic choroidal rupture. Patients with angioid streaks should be warned of the potential risk of choroidal rupture from even relatively mild eye trauma.
Angioid streaks should be suspected in any patient who presents with choroidal neovascularization and no or few drusen in the fellow eye.
Retinal laser photocoagulation may be used on extrafoveal neovascular membranes, but recurrence is frequent and likely to occur on the foveal side of the resultant scar. PDT is unable to prevent the progression of the disease in most patients, and prophylactic treatment of angioid streaks before subretinal neovascularization develops is not recommended. Anti-VEGF therapy shows promising results, but information is limited to case reports.
Inflammatory Diseases Affecting the Retina, Retinal Pigment Epithelium, and Choroid
Presumed Ocular Histoplasmosis Syndrome (POHS)
POHS is characterized by serous and hemorrhagic detachments of the macula due to subretinal neovascularization, associated with multiple peripheral atrophic chorioretinal scars (histo spots) and peripapillary chorioretinal scarring (see Chapter 7) in the absence of vitreal inflammation. It usually occurs in healthy patients between the third and sixth decades of life, and the scars are probably caused by an antecedent subclinical systemic infection with Histoplasma capsulatum. However, only 3% of people with histoplasmosis develop histo spots, which usually remain quiescent, and only 5% of people with histo spots develop choroidal neovascularization. The visual prognosis depends on the proximity of the neovascular membrane to the center of the fovea. If it extends inside the foveal avascular zone, only 15% of eyes will retain 20/40 vision. There is a significant risk of choroidal neovascularization in the fellow eye, and patients should be instructed in the frequent use of an Amsler grid and the importance of prompt examination when abnormalities are detected.
Treatment options are similar to those for choroidal neovascularization due to AMD. Intravitreal injections have additional risks in younger patients because their posterior vitreous has not detached, but intravitreal bevacizumab produces significant improvement in vision at 1 year. Surgical removal of subfoveal membranes has been disappointing, with stabilization of vision occurring only in those with preoperative visual acuity worse than 20/100.
Acute Multifocal Posterior Placoid Pigment Epitheliopathy (AMPPPE)
AMPPPE typically affects healthy young patients who develop rapidly progressive bilateral vision loss in association with multifocal flat gray-white subretinal lesions involving the pigment epithelium (Figure 10–28). The cause is unknown, but it is associated with a preceding viral illness. The characteristic feature of the disease is the rapid resolution of the fundus lesions and a delayed return of visual acuity to near-normal levels. Although the prognosis for visual recovery in this acute self-limited disease is good, many patients will identify small residual paracentral scotomas when carefully tested. The prognosis in atypical cases, such as unilateral disease or older presentation, is more guarded. Extensive pigmentary changes resulting from AMPPPE may mimic widespread retinal degeneration, but the clinical history and normal electro-physiologic findings should lead to the correct diagnosis. Treatments include immunosuppressants, either local or systemic, the latter for severe cases including the rare cases associated with central nervous system disease, PDT, and anti-VEGF therapy.
Macular lesion of acute multifocal posterior placoid pigment epitheliopathy.
Serpiginous (Geographic Helicoid Peripapillary) Choroidopathy
This is a chronic progressive and recurrent inflammatory disease of the retinal pigment epithelium, choriocapillaris, and choroid. It characteristically involves the juxtapapillary retina and extends radially to involve the macula and peripheral retina. Unlike AMPPPE, the affected areas are contiguous. Recurrence is the norm. Patients tend to be older than those of AMPPPE. The active stage manifests itself as sharply demarcated gray-yellow lesions with irregular borders that appear to involve the pigment epithelium and choriocapillaris. Vitritis, anterior uveitis, and choroidal neovascularization may occur. Involvement is usually bilateral, and the cause is unknown. The natural history of this indolent inflammatory disease is variable and may correlate with the presence of disease in the fellow eye. Local, including intravitreal, or systemic corticosteroid treatment may be of benefit when active inflammation is present. Determination of optimal treatment of choroidal neovascularization is hampered by the rarity of cases.
Birdshot Retinochoroidopathy (Vitiliginous Chorioretinitis)
This is a syndrome characterized by diffuse cream-colored patches at the level of the pigment epithelium and choroid, retinal vasculitis associated with CME, and vitritis. Strong association with a subtype of HLA-A29 and other features suggest that genetic predisposition and retinal autoimmunity play a role in its manifestations. The course of the disease is that of exacerbation and remission with variable visual outcomes. Visual loss may be due to chronic CME, optic atrophy, macular scarring, or choroidal neovascularization. Electroretinography is useful for diagnosis and monitoring disease progression and response to treatment. Treatment with corticosteroids alone does not seem to be effective. Other immunosuppressants may be beneficial.
Acute Macular Neuroretinopathy (AMN)
AMN is characterized by the acute onset of paracentral scotomas and mild visual acuity loss accompanied by wedge-shaped parafoveal retinal lesions in the deep sensory retina of one or both eyes. The macular lesions are subtle, reddish-brown, and best seen with a red-free light. The patients are usually young adults with a history of acute viral illness. While the retinal lesions may fade, the scotomas tend to persist and remain symptomatic.
Multiple Evanescent White Dot Syndrome (MEWDS)
MEWDS is an acute and self-limited unilateral disease that affects mainly young women and is characterized clinically by multiple white dots at the level of the pigment epithelium, vitreous cells, and transient electroretinographic abnormalities. The cause is unknown. There is no evidence of associated systemic disease. The retinal lesions gradually regress in a matter of weeks, leaving only minor retinal pigment epithelial defects. Occasionally it progresses to become acute zonal occult outer retinopathy (AZOOR), with positive visual phenomena, symptomatic visual field impairment, typically manifesting as enlarged blind spots, that may be progressive, and angiographic, autofluorescence, and electrophysiological evidence of retinal dysfunction.
There seems to be overlap between AZOOR, MEWDS, AMN, birdshot chorioretinopathy, serpiginous choroidopathy, AMPPE, and the entities of multifocal choroiditis (MFC), diffuse subretinal fibrosis syndrome, and punctuate inner choroidopathy (PIC), each being a different manifestation of similar pathophysiological processes, such that the umbrella term white dot syndromes has been suggested. The treatment options for all of them include immunosuppressants, either topical or systemic, and PDT or anti-VEGF therapy if there is choroidal neovascularization.
Macular dystrophies are genetically determined although not necessarily evident at birth. They are not necessarily associated with systemic disease. Usually the disorder is restricted to the macula with symmetrical involvement. In the early stages of some macular dystrophies, visual acuity is reduced but the macular changes are subtle or not visible clinically, such that the patient's symptoms may be dismissed as spurious. Conversely, in other macular dystrophies, the fundoscopic changes are very striking when the patient is still asymptomatic. One method of classifying the more common macular dystrophies is according to which layers of the retina are presumed to be involved (Table 10–2).
Table 10-2. Anatomic Classification of Macular Dystrophies |Favorite Table|Download (.pdf)
Table 10-2. Anatomic Classification of Macular Dystrophies
|X-linked juvenile retinoschisis|
|Retinal pigment epithelium|
X-Linked Juvenile Retinoschisis
This X-linked recessively inherited disease affects young males and is characterized by a macular lesion called “foveal schisis.” On slitlamp examination, foveal schisis appears as small superficial retinal cysts arranged in a stellate pattern accompanied by radial striae centered in the foveal area (Figure 10–29). The disorder is slowly progressive. Visual acuity begins to fall during the middle of the teenage years, reducing to between 20/40 and 20/200 as the disease progresses. Fifty percent of patients have peripheral retinoschisis with peripheral visual field abnormalities. The posterior pole appears normal on fluorescein angiography, assisting differentiation from CME. X-linked retinoschisis is thought to be due to Muller cell dysfunction. There is a negative electroretinogram (ERG) (normal a-wave amplitude with reduced b-wave amplitude), which is typical of disorders affecting the inner retina leaving the photoreceptor cells intact. Female carriers have normal ERGs.
X-linked juvenile retinoschisis with typical superficial retinal cysts in the fovea.
The main differential diagnosis for foveal schisis is enhanced S-Cone (Goldmann-Favre) syndrome, which is an autosomal recessive condition with extinguished ERG and typical peripheral disk-like pigmentation (Figure 10–30).
Enhanced S-cone syndrome showing typical disk-like pigmentation around the vascular arcades.
The genetic abnormality in X-linked juvenile retinoschisis is a mutation in the RS1 gene, which codes for a retina-specific extracellular protein (retinoschisin), secreted by photoreceptors but involved in cell–cell interactions and cellular adhesion in the inner retina. Carriers can be identified by DNA analysis.
The cone-rod dystrophies constitute a relatively rare group of disorders that may be regarded as a single entity showing variable expressivity. Most cases are recessive, with mutation of the ABCA4 gene being the most common known cause, but autosomal dominant inheritance has also been recorded. There is predominant involvement of cone photoreceptors, with progressive color vision defects and loss of visual acuity. Photophobia is a common early symptom.
Fundal appearance varies greatly. In many patients, it is normal at initial presentation. There may be optic nerve pallor with no obvious macular changes, leading to misdiagnosis of optic nerve disease. The characteristic bilateral, symmetric bull's-eye pattern of macular depigmentation, visualized on fluorescein angiography as a zone of hyperfluorescence surrounding a central nonfluorescent spot, is relatively uncommon (Figure 10–31). If it occurs, chloroquine retinopathy has to be excluded. Fundus autofluorescence is becoming the preferred method of retinal imaging for both diagnosis and monitoring. Electroretinography shows marked loss of cone function and slight to moderate loss of rod function. It is essential for diagnosis and prognosis.
Cone dystrophy with bull's-eye pattern of macular depigmentation.
Stargardt Disease/Fundus Flavimaculatus
Stargardt disease is by far the most common macular dystrophy. It is an autosomal recessive disorder with mutations in the ABCA4 (retina-specific ATP-binding cassette transporter) gene, which are also the most common known cause of cone-rod dystrophies (see above).
Stargardt disease is associated with fundus flavimaculatus, which is characterized by multiple yellow-white fleck lesions of variable size and shape, confined to the retinal pigment epithelium (Figure 10–32). The different phenotypes can be partly explained by different mutations in the same genes. Severely pathogenic mutations tend to cause cone-rod dystrophies, moderately pathogenic mutations fundus flavimaculatus, and mildly pathogenic mutations Stargardt disease. The carrier rate for ABCA4 gene mutations is about 1 in 100.
Stargardt disease/fundus flavimaculatus with multiple irregular fleck lesions involving the macula.
Stargardt disease typically presents before age 15 with reduced central vision. About one-third of patients presents in the first decade of life, one-third in the second decade of life, and one-third over 20 years of age. Initially there is no macular abnormality clinically, but subsequently there develops a bronze metal appearance together with mid-peripheral retinal flecks, like those seen in fundus flavimaculatus. Fundus autofluorescence shows a range of abnormalities. Pattern ERG is completely extinguished, even when central vision is good. The full-field ERG is usually normal. Once visual acuity has dropped to 20/40, it will decline to 20/200 in 5 years. Gene mutations can be detected in 50%–75% of patients.
There is a dominant form of Stargardt disease, which is rare and has a genetic mutation in ELOVL4 gene.
Patients with fundus flavimaculatus present later than patients with Stargardt disease. They have retinal flecks distributed over the whole of the posterior pole of each eye. Central vision tends to be preserved until after 40 years of age, but full-field ERG changes are more common and are important for predicting prognosis.
Best Disease (Juvenile-Onset Vitelliform Dystrophy)
Best disease is an autosomal dominant disorder with variable penetrance and expressivity. Onset is usually in childhood. The fundoscopic appearance is variable and ranges from a mild pigmentary disturbance within the fovea to the typical vitelliform or “egg yoke” lesion located in the central macula (Figure 10–33). This characteristic cyst-like lesion is generally quite round and well demarcated and contains homogeneous opaque yellow material lying at the apparent level of the retinal pigment epithelium. The “egg yoke” may degenerate and be associated with subretinal neovascularization, subretinal hemorrhage, and extensive macular scarring. Visual acuity often remains good, and the ERG is normal. An abnormal electro-oculogram (EOG) is the hallmark of the disease. The genetic abnormality is a mutation in the BEST1 (VMD2) gene, which encodes a transmembrane calcium-sensitive chloride channel (bestrophin) expressed in retinal pigment epithelium.
Best disease with a well-demarcated cyst-like macular lesion.
Hereditary Retinal Degenerations
Retinitis pigmentosa is a group of heterogeneous hereditary retinal degenerations characterized by progressive dysfunction of the photoreceptors, associated with progressive cell loss and eventual atrophy of several retinal layers. Inheritance of the typical form can be autosomal recessive, autosomal dominant, or X-linked recessive. Digenic and mitochondrial inheritance may also be responsible.
The hallmark symptoms of retinitis pigmentosa are night blindness (nyctalopia) and gradually progressive peripheral visual field loss as a result of increasing and coalescing ring scotomas. The most characteristic fundoscopic findings are attenuated retinal arterioles, waxy pale optic disk, mottling of the retinal pigment epithelium, and peripheral retinal pigment clumping, referred to as “bone-spicule formation” (Figure 10–34). Although retinitis pigmentosa is a generalized photoreceptor disorder, in most cases rod function is more severely affected, predominantly leading to poor scotopic vision. The ERG usually shows either markedly reduced or absent retinal function. The EOG lacks the usual light rise.
Retinitis pigmentosa with arteriolar narrowing and peripheral retinal pigment clumping.
There has been rapid progress in identification of mutations in retinitis pigmentosa. Relevant genes identified so far can be found on the Retnet website (http://www.sph.uth.tmc.edu/Retnet/). Patients should be referred to specialized centers for genetic counseling and selective mutation analysis. Genetic analysis is useful to identify female carriers in families with X-linked disease and to diagnose dominant disease. In recessive disease, specific features are needed for genetic analysis to be worthwhile.
Fundus Albipunctatus/Retinitis Punctata Albescens
Fundus albipunctatus is an autosomal recessive nonprogressive dystrophy characterized by a myriad of discrete small white dots at the level of the pigment epithelium sprinkled about the posterior pole and midperiphery of the retina. Patients are night-blind with normal visual acuity, normal visual fields, and normal color vision. While the ERG and EOG are usually normal, dark adaptation thresholds are markedly elevated. Retinitis punctata albescens is the less common progressive variant of this dystrophy. Both conditions are extremely rare.
Leber Congenital Amaurosis
Leber congenital amaurosis (LCA) is an autosomal recessive disorder of rods and cones. It presents as a triad of severe visual impairment or blindness beginning in the first year of life, nystagmus, and generalized retinal dystrophy. The fundoscopic findings are variable; most patients show either a normal appearance or only subtle retinal pigment epithelial granularity and mild vessel attenuation. A markedly reduced or absent ERG indicates generalized photoreceptor dysfunction, and in infants this is the only method by which an absolute diagnosis can be made.
There may be ocular manifestations only (pure LCA), or there may be nonocular abnormalities, including mental retardation, oculodigital reflex (eye poking), seizures, and renal or muscular abnormalities. The division between these entities is unclear, and they are best classified on a genetic basis. Nine causal genes have been identified, accounting for 65% of cases. The RPE65 gene mutation has been extensively investigated, including successful gene therapy in dogs, the most famous of which is Lancelot, suggesting that subretinal delivery of the RPE65 vector in human subjects is feasible. Project 3000 aims to identify and perform genetic testing on all cases of LCA in the United States. Human clinical trials of gene therapy have started in England and the United States.
Gyrate atrophy is an autosomal recessive disorder due to reduced activity of ornithine aminotransferase (OAT), a mitochondrial matrix enzyme that catalyzes several amino acid pathways, resulting in raised serum ornithine. The OAT gene has been mapped to chromosome 10. The incidence of this disorder is relatively high in Finland, and the ophthalmologic features are the most prominent manifestations of the disease. Patients initially present with myopia and then develop nyctalopia within the first decade of life, followed by progressive loss of peripheral visual field. Characteristic sharply demarcated circular areas of chorioretinal atrophy develop in the midperiphery of the fundus during the teenage years and become confluent with macular involvement late in the course of the disease. The ERG is decreased or absent, and the EOG is reduced.
Reduction in dietary intake of arginine has been shown to slow progression of the disease. It is most effective when commenced during childhood. Other treatments include pyridoxine supplementation and supplemental dietary lysine.
Cone photoreceptors are responsible for color vision, visual pigments (opsins) in their outer segments absorbing light of wavelengths between 400 and 700 nm. Spectral sensitivity studies have identified blue, green, and red cone photoreceptors. A minimal requirement for color (hue) discrimination is the presence of at least two kinds of cone photopigment (opsin), and normal color vision requires the presence of all three (trichromacy). The red and green cone opsins are encoded by adjacent genes on the X-chromosome. The blue cone opsin is encoded on chromosome 7. Color vision testing is described in Chapter 2.
Color vision defects are either congenital (inherited) or acquired. Acquired color vision defects vary in type and severity, depending on the location and source of the ocular pathology, and frequently affect one eye more than the other. Males and females are equally affected.
Congenital color vision defects are constant in type and severity throughout life and affect both eyes equally. They are more common in men than women. The most common congenital color vision defect, red-green color deficiency, is a form of dichromacy, with only two out of three cone opsins functioning normally. It results from mutation in the gene encoding for either the red (protanopia) or green (deuteranopia) cone opsin. It is X-linked recessive and affects 8% of males and 0.5% of females. Although color discrimination is abnormal, visual acuity is normal. The third type of dichromacy, tritanopia, in which there is loss of blue-yellow discrimination due to defect in the blue cone opsin, is a rare autosomal dominant condition resulting from a mutation on chromosome 7.
There are two forms of monochromacy. Although both leave the affected individual completely without color discrimination (achromatopsia), they are two quite separate entities. In the less common cone monochromacy (1 in 100,000), visual acuity is normal but there is no hue discrimination. Only one type of cone photoreceptor is present. It is usually due to blue cone monochromacy, an X-linked recessive condition resulting from mutations in the genes encoding for both red and green cone opsins. In rod monochromacy (1 in 30,000), an autosomal recessive condition caused by mutations in genes encoding proteins of the photoreceptor cation channel or cone transducin, there are no functioning cones, resulting in achromatic vision, low visual acuity, photophobia, and nystagmus.