Acquired Macular Disease

Introduction

The anatomic macula is defined as the area of the posterior retina containing at least two layers of nuclei within the ganglion cell layer. Clinically, this area extends 6 to 7 mm from the temporal edge of the optic nerve and includes the area within the temporal vascular arcades. Virtually all retinal vascular and retinal inflammatory diseases may involve the macula, as do numerous metabolic, hereditary, degenerative, neoplastic, and traumatic entities. Even vitreous and peripheral retinal and choroidal disorders have potential for macular involvement. A discussion of all potential disorders involving the macula within the scope of a single chapter is thus impossible without some exclusion criteria. Thus, inherited macular dystrophies, inflammatory etiologies, and vascular diseases are not addressed in this chapter.

Acquired macular disorders include diseases that may initially manifest as retinal pigment epithelial derangements with subsequent retinal pathology, or a pathologic condition involving the neurosensory retina may over time effect features of the retina pigment epithelium. Thus, our categorization and organization of macular disorders is arbitrary and is an attempt to simplify the logical progression of this chapter. Topics discussed in this chapter include the following:

Disorders Arising From Retinal Pigment Epithelium and Choroid
- Age-Related Macular Degeneration (AMD)
- Central Serous Chorioretinopathy (CSC)
- Ocular Histoplasmosis Syndrome (OHS)
- Angioid Streaks
Disorders Arising From Retinal Pigment Epithelium (RPE), Choroid, and Retina
- Pathologic Myopia
Disorders Arising From Retina
- Epiretinal Membrane
- Macular Hole
- Cystoid Macular Edema
- Parafoveal Telangiectasis

Age-Related Macular Degeneration

Introduction

First described by Pagenstecher in 1875 and by Haab in 1889, AMD is now the most common cause of blindness in patients older than 60 years of age in the western hemisphere.¹^,² The incidence, prevalence, and other epidemiologic associations with AMD are provided in Table 23.1. Calculating the prevalence of macular degeneration has been complicated in the past with different definitions regarding severity of macular degeneration.³^,⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹ Typically, color fundus photography, grading by independent reading centers, and analysis of gender and racial subgroups are performed.⁸^,¹²^,¹⁶^,¹⁷^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷ Prevalence variations are apparent in various racial subgroups¹⁹^,²⁸^,²⁹^,³⁰ (Table 23.1).

Table 23.1 Prevalence of AMD Table

Study	Year of Study	Number Enrolled	Age Range	Drusen Prevalence	Geographic Atropy Prevalence	Choroidal Neovascular Prevalence	Late AMD Prevalence	Comments
Chesapeake Bay Watermen Study	1989	777		26% of patients age 80 years or older with large or soft drusen			Atrophic or exudative AMD prevalence 1.8%
Beaver Dam Eye Study	1987–1988	4,752	43–84	10.30%	1.20%	0.70%	1.60%	Late AMD defined as atrophy or exudative disease or both, enrollees predominantly Caucasian
National Health and Nutrition Examination Survey (NHANES III)	1988–1991	7,412	>40				Prevalence 9.2% in patients older than 40 years of age	AMD defined as presence of any drusen, RPE degeneration, geographic atrophy, exudative macular degeneration
Baltimore Eye Survey		4,361		5.80%	0.50%	0.50%	0.80%	Equal percentage of Caucasian- and African–descent enrollees
Barbados Eye Study		3,413		Not available	0.50%	0.10%	0.60%	All enrollees of African descent
Blue Mountains Eye Study		3,632		5.40%	1.40%	1.20%	2.10%	Predominantly Caucasian
Rotterdam Eye Study		6,774		3.60%	1.00%	0.70%	1.70%	Predominantly Caucasian
Salisbury Eye Evaluation Project		2,387			6.20%	1.60%	1.40%	75% Caucasian, 25% African descent
Melbourne Visual Impairment Project		4,339		4.10%	0.40%	0.30%	0.70%	Predominantly Caucasian

Growing evidence of an inherited or genetic component influencing the pathophysiologic nature of macular degeneration has accumulated in recent years.¹⁰^,¹⁵^,³¹^,³²^,³³ Malattia leventinese and Sorsby’s macula dystrophy are known genetic disorders with phenotypic expression identical or similar to the clinical presentation of AMD.³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹ Nevertheless, given the environmental and dietary factors implicated in influencing the expression and severity of disease, the inclusion of AMD in acquired macular diseases is appropriate.⁴⁰^,⁴¹^,⁴²

Pathogenesis of Age-Related Macular Degeneration

The pathogenesis of AMD involves a complex interaction involving genetic factors combined with senescence of vital structures that normally maintain the health of the photoreceptor-retinal pigment epithelium-Bruch’s membrane complex. The following factors are generally implicated in the development and complications of macular degeneration: genetic influences, extracellular changes, oxidative stresses, hydrodynamic alterations, hemodynamic changes, angiogenic elaboration, inflammatory influences, and apoptotic factors.⁴³^,⁴⁴

Genetic Factors

Although environmental insults that appear to exacerbate or accelerate complications of macular degeneration are undeniable, the influence of genetics is also clear. Twin-concordant studies suggested the initial impact of genetics.¹⁰^,¹⁵^,³¹^,³²^,³³^,⁴⁵^,⁴⁶^,⁴⁷ First-degree relatives of patients with AMD are also much more likely to develop exudative complications.⁴⁸^,⁴⁹ Monozygotic twins exhibit 90% concordance.⁴⁵^,⁴⁷^,⁵⁰ Mutations in the ATP-binding cassette transporter (ABCA4) gene, which is responsible for forms of Stargardt’s macular dystrophy, cone dystrophy, and retinitis pigmentosa, have been detected in patients with AMD.⁵¹ Linkage analysis and genotyping have further correlated genes associated with macular dystrophies similar to phenotypes in AMD. These include Bests disease, Doyne’s honeycomb retinal dystrophy, and Sorsby’s macular dystrophy.³⁶^,³⁸^,³⁹^,⁵²^,⁵³^,⁵⁴

With the advent of genetic analysis, three candidate genes have now been identified as strongly linked to the expression of AMD.

Variations in the regulators of complement activation (RCA) gene cluster on chromosome 1q25-q31 are now strongly correlated with macular degeneration. Replacing a tyrosine with histidine at position 402 of this encoding for complement factor H increases the risk of AMD of about fivefold. The risk variation is noted in approximately 40% of Caucasians.⁵⁵^,⁵⁶^,⁵⁷
Mutations in the LOC387715 gene have been implicated as disease-causing. Specifically, an alanine substitution for serine at position 69 increases the risk of AMD approximated sevenfold. This risk is noted in approximately 30% of Caucasians.⁵⁸^,⁵⁹^,⁶⁰^,⁶¹
The factor B (BF)/complement component 2 (C2) locus in the major histocompatibility (MHC) class III region on 6p21.⁵⁷

Extracellular Factors

Macular degeneration is associated with numerous changes within Bruch’s membrane. Bruch’s membrane separates the RPE from the choriocapillaris and is comprised of five layers: the basement membrane of the RPE, the inner collagenous zone, the elastic fiber layer, the outer collagenous zone, and the basement membrane of the choriocapillaris.⁶²^,⁶³^,⁶⁴^,⁶⁵ At birth, Bruch’s membrane averages approximately 2 microns, whereas in adults, Bruch’s membrane thickness varies from 4 to 6 microns.⁶⁴^,⁶⁵ Changes in membrane thickness are seen secondary to dynamic changes in protein composition, protein cross-linking, increased glycosaminoglycan size, and increased lipid content.⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹ These changes correspond to increased dysfunction in RPE cells that produce an excess of cell fragments, collagen, and basement membrane components that are not degraded due to increased impairment in matrix metalloproteinases.⁷²

The maintenance of a healthy Bruch’s membrane is dependent on an intricate balance among collagen, laminin, fibronectin, glycosaminoglycans, and matrix metalloproteinases.⁶²^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³ The aging Bruch’s membrane contains an ever-increasing amount of type I collagen, debris, and filamentous material.⁶⁶^,⁸⁴ An age-related decrease in laminin, fibronectin, and type IV collagen is also seen within the RPE basement membrane.⁶⁸^,⁶⁹^,⁸⁰^,⁸⁵^,⁸⁶^,⁸⁷ Glycosaminoglycans, specifically heparin sulfate, increase in size and content.⁶⁶^,⁶⁹^,⁸⁵^,⁸⁸ The end products of glycosaminoglycan accumulation result in macromolecules, which alter the normal physiologic negative electrical potential of the Bruch’s membrane–RPE complex.⁷⁷^,⁷⁸

Hydrodynamic Factors

Bruch’s membrane serves a vital function in the permeability of water.⁸²^,⁸³^,⁸⁹ Hydraulic conductivity decreases with age, with the inner collagenous layer of Bruch’s proposed as the primary site of hydraulic conductivity.⁷⁹^,⁸²^,⁸³^,⁹⁰^,⁹¹ An increase in this layer is noted as lipid and debris accumulate with age.⁶⁷^,⁶⁸^,⁶⁹ Lipids, the end product of long-chain polyunsaturated fatty acids found in photoreceptor outer segments may alter the negative electrostatic charge of Bruch’s membrane resulting in a change in hydraulic conductivity of special importance due its intimate relationship with the choriocapillaris.⁸²^,⁸³^,⁸⁹^,⁹¹

Age-related deterioration in hydraulic conductivity with Bruch’s membrane produces an increase impedance of diffusion of vital metabolic exchange between the choroid and the retina and may disrupt photoreceptor function.⁹⁰^,⁹¹ The net result may be the accumulation of large confluent hydrophobic drusen that predispose to RPE detachments and hydrophilic drusen that predispose to the formation of choroidal neovascularization.⁷⁴^,⁹²^,⁹³^,⁹⁴

Hemodynamic Factors

The choriocapillaris is not immune to age-related change.⁸⁵^,⁹⁵^,⁹⁶ The density of the choriocapillaris and lumen diameter decrease with age.⁹⁵^,⁹⁷ Subfoveal choroidal flow and perfusion based on indocyanine green angiography (ICG) are all noted to decrease with age.⁹⁵^,⁹⁷ Guymer et al. have proposed that choriocapillaris has a vital role in the clearance of metabolic end products from Bruch’s membrane.⁷⁶^,⁹⁸^,⁹⁹ The loss of normal vasculature within the choriocapillaris with advanced age may be a causal factor in the thickening of Bruch’s membrane.⁷⁶

Oxidative Factors

Oxidative stress results in the generation of factors implicated in macular degeneration.¹⁰⁰^,¹⁰¹ The interaction between the retina and the RPE is a prime candidate for potential oxidative stress.¹⁰⁰^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵ Reactive oxygen species may be stimulated by a spectrum of factors including genetic proclivity, phototoxic injury, inflammation, hemodynamic abnormalities, and reperfusion injury.¹⁰⁴ This results in the generation of free radicals. Within the eye, the photoreceptor and RPE receive high oxygen saturation due to their immense metabolic demands.¹⁰⁶ Any increase in toxic end products of metabolic activity may precipitate the acceleration of photoreceptor death.¹⁰⁰^,¹⁰⁷ Photoreceptor phagocytosis and vitamin A metabolism, the primary functions of the RPE, also result in oxidative stress.¹⁰⁶^,¹⁰⁸^,¹⁰⁹ Finally, the retina itself is exposed over a lifetime to cumulative levels of irradiation.¹¹⁰^,¹¹¹ Photosensitizers within the retina and RPE include rhodopsin, lipofuscin, and cytochrome c oxidase, all of which may generate free oxygen radicals.¹⁰¹^,¹¹²^,¹¹³

Angiogenic Factors

Choriocapillaris ingrowth into Bruch’s membrane is inhibited by a complex interaction of angiostatic factors. Several factors have been implicated in influencing choroidal neovascularization.

Vascular endothelial growth factor (VEGF)¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸
Basic fibroblast growth factor (BFGF)¹¹⁹^,¹²⁰^,¹²¹^,¹²²
Angiopoietins¹¹⁶^,¹²³^,¹²⁴^,¹²⁵^,¹²⁶^,¹²⁷
Pigment epithelium-derived factor (PEDF)¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³²
Nitric oxide¹⁰¹^,¹¹³

Vascular endothelial growth factor is expressed in embryonic vascular tissues. As an extremely powerful regulator of vascular endothelial cell division, VEGF is induced by hypoxia.¹¹⁵^,¹³²^,¹³³ In addition to its mitogenic role on vascular tissue, degradation of extracellular matrix, endothelial cell migration, and vascular permeability are also potent effects.¹¹⁴^,¹²⁶^,¹³² Within ocular tissues, VEGF has been experimentally shown to induce iris and retinal neovascularization in animal models.¹³⁴^,¹³⁵^,¹³⁶^,¹³⁷^,¹³⁸ Elevated levels have been implicated in disease states including diabetic retinopathy, vascular occlusion, retinopathy of prematurity, and neovascular glaucoma.¹³⁹^,¹⁴⁰^,¹⁴¹^,¹⁴²^,¹⁴³^,¹⁴⁴^,¹⁴⁵^,¹⁴⁶ Within the healthy eye, retinal pigment epithelium produces VEGF as a trophic factor to maintain a normal relationship between RPE and choriocapillaris.¹⁴⁷ Hypoxic-ischemic injury may alter the normal VEGF levels inducing aberrant endothelial cell growth, disruption of the normal extracellular matrix, and initiation of leakage from previously competent vessels.¹¹⁵^,¹³²

Other angiogenic factors include basic fibroblast growth factor, angiopoietins, PEDF, and nitric oxide. Basic fibroblast growth factor has also been detected in choroidal neovascular membranes.¹¹⁹^,¹²⁰ In porcine and rabbit models, fibroblast growth factor induces choroidal neovascularization.¹⁴⁸^,¹⁴⁹ Low-intensity photocoagulation stimulates the overexpression of BFGF in mice.¹⁵⁰ The angiopoietins are a family of molecules found in normal endothelial cells, but when exposed to elevated levels of VEGF lead to the development of enlarged caliber vessels.¹⁵¹^,¹⁵²

PEDF is a neurotrophic growth factor produced by RPE cells with inhibitory effects on angiogenesis.¹¹⁶^,¹¹⁷^,¹²⁸^,¹²⁹^,¹³¹^,¹⁵³^,¹⁵⁴ PEDF also acts as a potential counterbalance to the effects of VEGF, typically expressed in avascular tissues such as cornea and vitreous.¹²⁸^,¹²⁹^,¹⁵⁴^,¹⁵⁵ In the aging vitreous and senescent RPE cells, PEDF is found to be in declining concentrations.¹⁵³^,¹⁵⁴ Nitric oxide, a component known for its systemic effects on pulmonary and systemic blood pressure, may also induce angiogenesis by promoting endothelial cell migration and differentiation through effects on surface molecules such as integrins, which promote neovascularization.¹⁵⁶^,¹⁵⁷

Inflammation

Inflammation is an important stimulus of exudative AMD.⁹⁶^,¹⁵⁸^,¹⁶³ Components of drusen include immunoglobulin molecules and complement activators.⁶⁶^,¹⁵⁸^,¹⁶⁴^,¹⁶⁵^,¹⁶⁶^,¹⁶⁷^,¹⁶⁸ Hageman et al. suggested that choroidal dendritic cells recruited by senescent or damaged RPE cells mediate immune responses in a fashion similar to the development of atherosclerotic plaques.¹⁶⁹^,¹⁷⁰ Further evidence of inflammatory components includes the presence of immune cells such as macrophages, leukocytes, within degenerative RPE, as well as choroidal neovascular membranes.¹⁶²^,¹⁶⁶^,¹⁷¹^,¹⁷²^,¹⁷³ RPE debris and end products of Bruch’s membrane may provide the nidus for inflammation in eyes with macular degeneration.⁶⁷^,¹⁵⁹^,¹⁶²^,¹⁶⁹^,¹⁷⁴

Apoptosis

RPE senescence and eventual apoptosis may be a reflection of a combination genetic factors and inflammatory etiologies.¹³²^,¹⁶⁴^,¹⁷⁵^,¹⁷⁶ Senescence may be accelerated with the expression of genes that result from the exposure of RPE cells to oxidative stress and age.¹⁷⁵ Foveal RPE cells lose their shape and density throughout life.¹⁷⁷^,¹⁷⁸ Lysosomal activity in RPE cells decrease with age, and the resultant increase in end products may lead to reactive injurious compounds within Bruch’s membrane.¹⁷⁷^,¹⁷⁸^,¹⁷⁹ These changes appear accelerated in RPE cells exposed to ultraviolet radiation and anaerobic conditions.¹⁰⁵^,¹¹⁰^,¹¹¹

Drusen

Introduction

Donders first described the characteristics of drusen in 1854.⁸⁵^,¹⁸⁰ Drusen, he proposed, are the products of RPE conversion.⁸⁵^,¹⁸⁰ Muller suggested drusen arise via deposition from intact RPE.¹⁸¹ Friedman described blood end products as the source of drusen accumulation.¹⁸² Histopathologic studies by several authors including Sarks and later by Green et al. subsequently elucidated the currently accepted pathogenesis of drusen.⁸¹^,¹⁸³^,¹⁸⁴

Clinical Findings

Drusen may be broadly described as hard drusen, less than 63 microns with well-defined borders, and soft drusen, greater than 64 microns with ill-defined borders. Several more specific classifications based on histopathology have also been proposed. Sarks et al. described five general categories based on morphology: hard drusen, hard drusen clusters, soft cluster-derived drusen, soft membranous drusen, and basal laminar or cuticular drusen⁸¹^,¹⁸³^,¹⁸⁵ (Fig. 23.1). Hard drusen clusters are more confluent accumulations of drusen that may occur in excess of 63 microns. Soft cluster-derived drusen are also yellow in color but have indistinct margins. Typically, soft clusters are found in patients greater than 55 years. Soft membranous drusen are yellow, indistinct lesions smaller in diameter than soft cluster-derived drusen but are confined to the macula and are thought to predispose to choroidal neovascularization Fig. 23.2) Basal laminar drusen are small, well-demarcated drusen with an often radial distribution throughout the macula ⁸⁵^,¹⁸⁴^,¹⁸⁶ (Fig. 23.3)

FIGURE 23.1 Hard drusen are less than 63 microns in diameter with well-defined borders.

FIGURE 23.2 Soft drusen are larger than hard drusen with indistinct borders and tend to be confluent.

FIGURE 23.3 Basal Laminar Drusen is smaller, well demarcated formations that occasionally radiate from the macula.

Hard drusen are accumulations of hyaline over thinned RPE.⁸⁵^,¹⁸⁷^,¹⁸⁸^,¹⁸⁹ They may be noted at younger ages, though drusen less than 25 microns are difficult to detect clinically. Focal areas of increased density of Bruch’s membrane, termed microdrusen, precede the formation of hard drusen.¹⁸³ Although the presence of small hard drusen is not prognostic for the development of macular degeneration in young patients, a large abundance have been described in patients with RPE atrophy.¹⁹⁰^,¹⁹¹^,¹⁹² Hard drusen clusters occur later in life and are thought to regress over time evolving into a corresponding locus of atrophic RPE.¹⁹¹^,¹⁹²

Soft drusen are typically larger than 63 microns and have amorphous or poorly defined borders in contrast to hard drusen. Histologic studies suggest soft drusen are basal linear deposits external to the RPE membrane.¹⁸³^,¹⁸⁴^,¹⁹³ Soft cluster-derived drusen and soft membranous drusen are thought to be difficult to distinguish on biomicroscopy, and differences are present on a histologic basis. Large soft drusen accumulations may coalesce into pigment epithelial detachments in the absence of choroidal neovascularization (drusenoid pigment epithelial detachment)⁹²^,¹⁹³^,¹⁹⁴ (Fig. 23.4).

FIGURE 23.4 Large soft drusen may coalesce into pigment epithelial detachments. A: Right eye. B: Left eye.

Ancillary Tests

Angiographic characteristics of drusen vary. Hyperfluorescence generally occurs from a combination of RPE loss of pigment over drusen and dye leakage into sub-RPE deposits.¹⁹⁵ The timing of hyperfluorescence within angiographic studies is dependent on the constituents of the drusen and on the rate of staining of Bruch’s membrane.¹⁹⁵ Drusen may also demonstrate direct staining. If RPE hyperpigmentation is present, many drusen may be obscured by relative hypofluorescence due to blocked fluorescein transmission. Delays in normal choroidal fluorescence have been attributed in some to delays in staining of Bruch’s and sub-RPE contents rather to the true lack of perfusion of choroidal vessels.⁹⁷^,¹⁹⁶

Hard drusen and hard cluster-derived drusen typically appear as transmission defects due to overlying retinal pigment epithelial thinning or depigmentation.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ Hard drusen are thought to obtain greatest fluorescence minutes after injection with corresponding decrease in fluorescence paralleling background choroidal fluorescence.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ Angiography may reveal a greater number of hard drusen than are appreciated on biomicroscopy.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ Hard drusen are noted to fluoresce during angiography with indocyanine green dye (ICG).¹⁹⁸^,¹⁹⁹^,²⁰⁰^,²⁰¹^,²⁰²^,²⁰³

Soft drusen demonstrate progressive hyperfluorescence and dye pooling without leakage beyond their margins.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ Drusen that hyperfluoresce are thought to be hydrophilic secondary to the diffusion of water-soluble fluorescein.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ Alternatively, hypofluorescent drusen are possible hydrophobic due to the presence of neutral lipids. The hyperfluorescence is typically less intense and occurs later than the fluorescence exhibited by hard drusen.¹⁸⁴^,¹⁹⁵^,¹⁹⁷ On ICG angiography, soft drusen are typically hypofluorescent.¹⁹⁸^,¹⁹⁹^,²⁰⁰^,²⁰¹^,²⁰²^,²⁰³ Studies have also identified vascularization of soft drusen, which may account for a component of the hyperfluorescence. Membranous drusen characteristics include very faint delayed hyperfluorescence on fluorescein angiography and are not detected on ICG angiography.¹⁹⁸^,¹⁹⁹^,²⁰⁰^,²⁰¹^,²⁰²^,²⁰³ Angiography of basal laminar drusen reveal early, discrete hyperfluorescence and late fading that has been described as “stars-in-the-sky.”²⁰⁴ (Fig. 23.5)

FIGURE 23.5 Fluorescein angiography of basal laminar drusen demonstrating the radial hyperfluorescence and small transmission defects in the classic “star-in-the-sky.”

Optical coherence tomography (OCT) is a computer analysis tool that generates a cross-sectional view of the vitreomacular junction, neurosensory retina, retinal pigment epithelium, and Bruch’s membrane in a manner reminiscent of gross histological sections.²⁰⁵^,²⁰⁶^,²⁰⁷^,²⁰⁸ Due to the reflective qualities of these interfaces, OCT imaging is able to detect the density differences in anatomic structures. As the vitreous fluid is relatively homogenous, OCT images depict the vitreous as black when compared to more reflective interfaces such as the posterior hyaloid, internal limiting membrane, neurosensory retina, and retinal pigment epithelium. Each layer is assigned a schematic color representation for ease in clinical analysis. Software computations allow an estimate of retinal thickness to within 3 μm.²⁰⁹^,²¹⁰^,²¹¹ Drusen, which typically arise within the highly reflective retinal pigment epithelium layer, lead to local elevations, excrescences, and distort of the overall contour of the OCT-generated image²¹⁰^,²¹² (Fig. 23.6).

FIGURE 23.6 Optical coherence tomography of drusen typically reveals elevation of the retinal pigment epithelial layer.

Pigment Epithelial Detachment

Synonyms: Drusenoid pigment epithelial detachment, serous pigment epithelial detachment

Introduction

Soft drusen often accumulate and coalesce forming overlying detachment of the retinal pigment epithelium. Decreased hydraulic conductivity across Bruch’s membrane and a thickened, hydrophobic barrier mark some of the critical changes in Bruch’s membrane in eyes with macular degeneration.⁸²^,⁹¹ A thickened, less soluble, lipophilic Bruch’s results in a hydrophobic state, suggested as a primary factor in the formation of RPE detachments.⁹¹^,⁹²^,²¹³ Bird et al. have suggested that serous RPE detachments occur due to a combination of the aforementioned hydrophobicity of Bruch’s, the potential cleavage plane that may exist between the basement membrane of the RPE and the inner collagenous layer and the water accumulation secondary to ion transport dynamics at the level of the retinal pigment epithelium.⁷⁴^,⁹²

Clinical Features

The delineation between elevation of the retinal pigment epithelium due to drusen and leakage from an occult choroidal neovascular membrane can be quite difficult. Both are detected on biomicroscopy via elevation of the neurosensory retinal and retinal pigment epithelium in a blister like appearance. Drusenoid detachments because of their origination from drusen are themselves yellow, amorphous, and in many patients, asymptomatic (Fig. 23.7). Serous elevation in patients may be symptomatic and may not appear with drusen if related solely to serous fluid within the potential space of the sub-RPE. Detachments of the RPE may occur in isolation or may be seen with accompanying serous detachment of the neurosensory retina.

FIGURE 23.7 Drusenoid Pigment Epithelium Detachment

Roquet et al. followed 61 eyes of 32 patients and reported the clinical features of drusenoid pigment epithelial detachment.²¹⁴ Three different natural outcomes were noted: persistence, atrophy, and choroidal neovascularization. Drusenoid pigment epithelial detachment was associated with a 50% risk of progressing to atrophic lesions after 7 years. Drusenoid pigment epithelial detachments larger than two disc areas (DD) and those associated with metamorphopsia were associated with higher risk of progression to atrophy or choroidal neovascularization after 2 years.

Ancillary Tests

On angiography, serous RPE detachments are characterized by a uniform, well-demarcated leakage into a potential space resulting in pooling of fluorescence, which is correlated with a blister-like elevation of the RPE and neurosensory retina¹⁹⁵ (Fig. 23.8) Unlike a serous RPE detachment where angiographic pooling uniformly increases remains bright in the late phase, drusenoid RPE detachments are less fluorescent and either stain faintly or fade in the late phases of the study.¹⁹⁵ Optical coherence tomography is effective in detecting pigment epithelial detachment, revealing the irregular elevation of the RPE. Drusenoid detachments demonstrate a hyperreflectivity of the drusenoid material.²⁰⁶

FIGURE 23.8 Angiography of Serous Pigment Epithelial Detachment. A: Midvenous phase. B: Late pooling of fluorescence in serous pigment epithelial detachment.

Atrophic Age-Related Macular Degeneration

Synonyms: Dry macular degeneration, geographic atrophy

Introduction

Geographic atrophy is defined as confluent areas of RPE death which progress to overlying photoreceptor atrophy or death.⁹⁶^,¹⁹² Twenty percent of legal blindness is attributed to visual loss secondary to atrophic macular degeneration.²¹⁵ The estimated prevalence of geographic atrophy ranges from approximately 0.4% to 1.6% and increases with patient age.⁸^,²³^,²¹⁶ In the Beaver Dam study within the United States, in patients older than 75 years, the prevalence ranged from 3.5% to 7.1%.²¹⁶ The overall 5-year incidence of pure geographic atrophy development was 0.3%.⁴²^,²¹⁶ The presence of geographic atrophy does not exclude the possibility of later development of exudative forms of AMD.¹⁸⁴ In the eyes with choroidal neovascularization and a fellow eye with geographic atrophy, the incidence of future choroidal neovascularization in the fellow eye ranged from 30% to 50%.²¹⁷ Green et al. demonstrated a 34% incidence of geographic atrophy in histopathologic studies of patients with choroidal neovascularization.¹⁸⁴ Therefore, it is unlikely atrophic and exudative AMD represent two entirely different diseases.

Pathogenesis

Because of the dependence of the photoreceptors on the RPE, apoptosis of both the outer nuclear layer and the inner nuclear layer of the retina have been found associated with areas of RPE atrophy.¹⁶⁴^,¹⁷⁸^,²¹⁸ Sunness et al. have described the biologic etiologies of geographic atrophy.²¹⁷^,²¹⁹^,²²⁰^,²²¹^,²²²^,²²³^,²²⁴^,²²⁵^,²²⁶^,²²⁷^,²²⁸^,²²⁹^,²³⁰ Large drusen and pigmentary abnormalities are associated risk factors for the eventual development of atrophic areas.¹²^,¹⁶^,²³^,⁴³^,²²⁵^,²³¹^,²³² Perfusion abnormalities and decreased vascular density are also implicated in the development of RPE loss.⁹⁷^,¹⁹⁶^,²³³^,²³⁴ Vascular defects may result in a lack of trophic factors including VEGF that lead to subsequent RPE death and secondary photoreceptor depletion.¹⁵⁵

Lipofuscin is implicated as both a possible indicator of devitalized retinal pigment epithelium and as a generator of free radicals.¹⁰¹^,¹¹⁰^,¹¹²^,²³⁵ Lipofuscin can now be visualized with retinal pigment epithelial autofluorescence imaging and is often predictive of future sites of atrophic RPE.²³⁶^,²³⁷^,²³⁸^,²³⁹^,²⁴⁰ Lipofuscin may lead direct or indirectly to RPE cell death.⁷⁰^,¹⁰⁸^,²⁴¹^,²⁴²^,²⁴³^,²⁴⁴ Cells becoming engorged or laden with lipofuscin containing residual bodies may be unable to maintain normal cell metabolism. Lipofuscin is a known free radical generator but may also have direct toxic effects on cells by causing premature enzymatic lysosome release.¹⁰¹^,¹¹²^,²⁴⁵^,²⁴⁶ The highest turnover of outer segments involves rods just outside the fovea, which parallels the distribution of lipofuscin in the RPE.¹⁰¹^,¹¹² Subfoveal RPE contains a relative increased amount of macular pigments, the highest cone density, and a reduced rod density.¹⁷⁵^,¹⁷⁷^,¹⁸⁴^,²⁴⁷^,²⁴⁸ Thus, geographic atrophy often spares the fovea until advanced stages of macular degeneration.

Clinical Features

Atrophy may arise from areas of previous drusen, retinal pigment epithelial detachment, or choroidal neovascularization.⁴³^,⁸⁵^,¹⁹⁰^,¹⁹²^,²⁴⁹ Neovascularization tends to arise in close proximity to adjacent atrophied areas.¹⁹⁰^,¹⁹²^,²¹⁷^,²¹⁹ Geographic atrophy is bilateral in many patients and is typically associated with an atrophic choriocapillaris in which the larger caliber vessels of the choriocapillaris are evident on biomicroscopy. Large drusen and pigment derangements involving the retinal pigment epithelium evolve into atrophic loci in many patients (Fig. 23.9)

FIGURE 23.9 Color fundus photo of atrophic age related macular degeneration. The larger underlying choroidal vessels are evident as the retinal pigment epithelium atrophies. Surrounding drusen is also present.

Geographic atrophy leads to gradual and occasionally unpredictable visual loss.¹⁹²^,²⁵⁰ Visual acuity may not measure the degree of functional impairment in patients with scotoma near fixation.¹⁹²^,²²³^,²²⁵^,²²⁷^,²⁵¹ Visual acuity in dim illumination is preferentially affected secondary to a profound loss in retinal sensitivity.²²⁷^,²⁵¹ In patients with visual acuity of 20/50 or better, approximately 50% experience a loss of three or more lines over 2 years.¹⁹²^,²²¹^,²²⁸ Twenty-five percent of patients with geographic atrophy lose six or more lines over 2 years.²²⁸

Exudative Age-Related Macular Degeneration

Synonyms: Wet AMD, disciform macular degeneration

Introduction

Exudative AMD occurs when choroidal neovascularization occurs. Choroidal neovascularization is defined as the growth of blood vessels from choroidal vasculature. Exudative AMD accounts for 75% of severe visual loss in patients and if untreated is associated with an extremely poor visual prognosis.²¹⁶ The Macular Photocoagulation Study (MPS) demonstrated 62% to 65% of patients with extrafoveal and juxtafoveal lesions were associated with severe visual loss defined as the loss of six or more lines of Snellen visual acuity.²⁵²^,²⁵³^,²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷^,²⁵⁸ Severe visual acuity loss due to subfoveal lesions in the MPS ranged from 55% to 65%.²⁵⁵^,²⁵⁶^,²⁵⁹

Histopathologic characteristics of CNV in eyes with macular degeneration include early capillary ingrowth in larger soft drusen.⁹⁶^,¹⁸⁴^,¹⁸⁵^,²⁶⁰^,²⁶¹^,²⁶²^,²⁶³ The vessels enlarge in caliber over time and acquire both arterial and venular characteristics.¹⁸⁴ Separation of tissue planes within Bruch’s membrane allows for further choroidal vascular ingrowth.¹⁸⁴ Eventually, subretinal blood and exudates may lead to marked serous or hemorrhage detachment or the retina as well as retinal pigment epithelium.¹⁸⁴ The hemorrhage may resolve and often results in further proliferation of pigment epithelium and fibrous components within the subretinal space.¹⁸⁴ The final outcome in many cases is the development of disciform scar, composed of fibrous tissue proliferation secondary to the presence of hemorrhage and hyperplasia of the RPE itself.¹⁸⁴ Disciform lesions may lead to further complications including persistent exudation and even pressure necrosis of arteries communicated between the choroid and the fibrous scar resulting in massive hemorrhage within the sub-RPE or subretinal space.²⁶²^,²⁶⁴

Clinical Features

The presence of choroidal neovascular membranes may not result in symptomatic changes in the patient. Even on careful clinical examination, the presence of a small lesion is often difficult to detect. The presence of hemorrhage or subretinal exudation leads to elevation of the neurosensory retina or retinal pigment epithelium and resulting loss of visual acuity or metamorphopsia. On biomicroscopy, neovascular membranes are often described as gray or green subretinal tissue (Fig. 23.10)

FIGURE 23.10 Note the gray borders delineating the choroidal neovascular membrane in the macula in a patient with macular degeneration.

Ancillary Tests

The conversion to choroidal neovascular membranes in patients with macular degeneration is heralded by a variety of fluorescein angiographic changes. These changes may be limited to hyperfluorescence in a nonspecific pattern in the latter phases of the angiograms or may be easily apparent within the arteriovenous phases with prominent leakage or have a typical pattern of well-demarcated, “lacy” hyperfluorescence within the earliest fluorescein dye (Fig. 23.11) The myriad interpretive skills required to correctly diagnose and evaluate various choroidal neovascular membranes are beyond the scope of this chapter. Patients with “classic” choroidal neovascular membranes seen in the arteriovenous frames of the angiogram often are followed by profound leakage in the later phases.²⁵⁵^,²⁵⁶^,²⁵⁸^,²⁶⁵ (Fig. 23.12). Occult lesions may be characterized as any fluorescence not due to drusen that deviate from this “classic” pattern. Specifically, occult lesions may not demonstrate significant early-phase angiographic lesion but may demonstrate a “stippled” amorphous hyperfluorescence notable only in the late phases of the angiogram²⁵³^,²⁵⁴^,²⁵⁵^,²⁶⁶ (Fig. 23.13).

FIGURE 23.11 Fluorescein angiography of classic choroidal neovascular membranes is characterized by early lacy hyperfluorescence in the arteriovenous filling phase of the angiogram.

FIGURE 23.12 Fluorescein angiography of late leakage in classic choroidal neovascular membranes reveals profound hyperfluorescence that obscures the view of the borders of classic membrane.

FIGURE 23.13 Fluorescein angiography of occult choroidal neovascular membranes in contrast to classic choroidal neovascular membranes demonstrates early stippled fluorescence in the venous phase (A) with late leakage (B).

Optical coherence tomography is a useful ancillary and diagnostic tool used solely or in concert with angiograms and always coupled with clinical examination to stage, detect, and evaluate choroidal neovascular membranes.²⁰⁶^,²¹⁰^,²⁶⁷^,²⁶⁸ As choroidal neovascular membranes invade the subretinal space, they are characterized by disruption of the RPE. A physician interpreting an OCT scan may confuse the neovascular lesion with the RPE or choriocapillaris, as both have similar reflectivities. Neovascular membranes are associated with elevations caused by fluid leakage that accumulates in intraretinal or subretinal potential spaces²⁰⁶^,²¹⁰^,²⁶⁸^,²⁶⁹ (Fig. 23.14). The lesion itself may appear on OCT as a high backscattering lesion of well-defined thickening within the retinal pigment epithelial and choriocapillaris junction. OCT allows a measurement of retinal thickness and detection of the absence of RPE, detection of fibrotic scars, PED, and RPE tears. Distinguishing diffuse from cystoid macular edema, central serous chorioretinopathy from PED, and neurosensory retinal detachment from PED are all aided by the use of OCT.

FIGURE 23.14 OCT of choroidal neovascularization with intraretinal edema, subretinal fluid, and CNV.

Treatment

The treatments used to limit the progressive and occasionally catastrophic visual loss associated with the natural history of untreated choroidal neovascular membranes have undergone various stages of evolution and revolution. The benefit of placebo controlled, randomized, multicentered trials have aided in distinguishing effective treatments. Herein are significant treatment algorithms that have been applied treatment paradigms for exudative macular degeneration.

Multivitamin supplementation for prevention of severe loss for macular degeneration

The Age-Related Eye Disease Study (AREDS), an 11-center double-masked clinical trial, enrolled participants with extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in one or both eyes, or advanced AMD or vision loss due to AMD in 1 eye.⁴⁰^,²⁷⁰^,²⁷¹ Participants were randomly assigned to receive daily oral tablets containing:

Antioxidants (vitamin C [500 mg], vitamin E [400 IU], beta carotene [15 mg]
Zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide
Antioxidants plus zinc
Placebo

Photographic assessment of progression to or treatment for advanced AMD and at least moderate visual acuity loss from baseline were used as primary outcomes. Serum-level measurements, medical histories, and mortality rates were used for safety monitoring.⁴⁰^,²⁷⁰^,²⁷²

Average follow-up of the 3,640 enrolled study participants, ages 55 to 80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison between placebo and the patients receiving antioxidants plus zinc demonstrated a statistically significant odds reduction for the development of advanced AMD with odds ratio (OR), 0.72; 99% confidence interval (CI), 0.52–0.98. The ORs for zinc alone and antioxidants alone were 0.75 (99% CI, 0.55–1.03) and 0.80 (99% CI, 0.59–1.09), respectively.⁴⁰^,²⁷⁰

In addition to these findings the natural history of patients enrolled with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in the higher-risk groups. Statistically significant reduction in rates of moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54–0.99).⁴⁰^,²⁷⁰

Based on these findings, clinicians began recommending individuals older than 55 years with extensive intermediate-size drusen, at least one large druse, noncentral geographic atrophy in one or both eyes, or advanced AMD or vision loss due to AMD in one eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that formulated in the AREDS study.⁴⁰^,²⁷⁰^,²⁷³^,²⁷⁴^,²⁷⁵

Thermal laser photocoagulation treatment

The Macular Photocoagulation Study was a series of multicentered randomized controlled clinical trials designed to determine whether argon laser photocoagulation was effective for preventing or delaying severe visual loss in eyes with an extrafoveal and juxtafoveal choroidal neovascular membranes secondary to the following: age-related macular degeneration (Senile Macular Degeneration Study, SMDS), ocular histoplasmosis (Ocular Histoplasmosis Study, OHS), and idiopathic neovascularization (Idiopathic Neovascularization Study, INVS).²⁵²^,²⁵³^,²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷^,²⁵⁸^,²⁵⁹^,²⁶⁵^,²⁷⁶ Later, a cohort of patients with subfoveal choroidal neovascularization were also treated with laser photocoagulation and followed for treatment benefit in regards to visual loss prevention and recurrence rates.²⁵⁵^,²⁵⁶^,²⁶⁵

In the initial extrafoveal treatment algorithm, patients were randomized to treatment or to no treatment group until recruitment was terminated in 1982 (SMDS) and 1983 (OHS and INVS) due to significance of treatment benefit.²⁵²^,²⁵⁷ The relative risk of experiencing severe loss of vision after three years in eyes initially assigned to the no-treatment group in comparison with eyes assigned to the argon laser photocoagulation group was 1.4 in the SMDS (95% confidence interval [CI] 1.1 to 1.9), 5.5 in the OHS (95% CI: 3.9 to 10.8), and 2.3 in the INVS (95% CI: 0.8 to 6.5).²⁵²^,²⁵⁴^,²⁵⁷

Outcome measures for patients with juxtafoveal lesions included changes in visual acuity at 5 years of follow-up and rates of persistent and recurrent choroidal neovascularization.²⁵⁴ Data were accumulated for 276 (92%) of 300 patients with AMD, 236 (92%) of 256 patients with ocular histoplasmosis, and 38 (97%) of 39 patients with idiopathic choroidal neovascularization. In eyes with AMD, the estimated relative risk (RR) of a loss of six or more lines of visual acuity from baseline to any examination from 6 months through 5 years after enrollment for untreated eyes in comparison with treated eyes was 1.20 (p = .04).²⁵²^,²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷^,²⁶⁵ Normotensive patients were noted to have benefit from laser treatment (RR,1.82) but little or no benefit (RR, 0.93) was noted in hypertensive patients. Untreated eyes with ocular histoplasmosis were at much greater risk of a six-line decrease in visual acuity from the 1-year through the 5-year examination than were treated eyes (unadjusted RR, 2.60; RR, 4.26 after adjustment for visual acuity and hypertension at baseline; (p < .001 for both).²⁵² In idiopathic choroidal neovascularization, effects of treatment appeared to fall in between AMD and ocular histoplasmosis-related choroidal neovascularization.²⁵²^,²⁵⁶^,²⁵⁷^,²⁶⁵ On this basis the retina community recommended laser treatment of choroidal neovascularization in juxtafoveal locations with the caveat that hypertensive patients with AMD carried a much more guarded prognosis.²⁵²^,²⁵³^,²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷^,²⁵⁸^,²⁵⁹^,²⁶⁵^,²⁷⁶

Finally, the Macular Photocoagulation Study Group also reported the treatment outcomes and benefits of subfoveal lesions.²⁵⁵^,²⁵⁶^,²⁶⁵ Eyes of consenting patients were once again assigned randomly to laser treatment or no treatment. Visual acuity, reading speed, and contrast threshold were measured before random assignment 3 and 6 months later and at 6-month intervals thereafter.²⁵⁶ Four years after enrollment 39 (47%) of 83 untreated eyes and 17 (22%) of 77 laser-treated eyes had lost six or more lines of visual acuity from baseline levels (p = .002).²⁵⁶ At the 3-year examination of patients re-treated for recurrent choroidal neovascularization, 21 (36%) of 58 untreated eyes and 6 (12%) of 49 treated eyes had lost six or more lines of visual acuity from baseline levels (p = .009).²⁵⁶ However, treatment was associated with almost immediate three-line average loss of vision. This decrease in vision persisted as compared to untreated eyes at 3-month and 6-month follow up examinations.²⁵⁶ This profound, treatment-associated decrease in vision spurred clinicians to continue the search for improved treatment modalities.

Photodynamic treatment

Photodynamic therapy (PDT) involves a photosensitizer, a chemical activated in response to light. Prior the Federal Drug Agency (FDA) approval of PDT, the primary treatment for choroidal neovascularization secondary was thermal laser photocoagulation.²⁷⁷^,²⁷⁸^,²⁷⁹^,²⁸⁰^,²⁸¹^,²⁸²^,²⁸³^,²⁸⁴ Especially for subfoveal lesions, photocoagulation was often excessively destructive resulting in post-treatment-related acute declines in vision.²⁵⁹ Verteporfin is a specific photosensitizer infused intravenously, which is derived from porphyrin.²⁷⁷ The lipophilic drug is complexed with circulating low-density lipoproteins (LDL), which complexes with more rapidly dividing endothelial cells of growing blood vessels, but not by normally resting endothelial cells.²⁷⁷ Activation thus leads to direct oxidative damage to the neovascular endothelial tissue with progressive thrombosis. In the FDA approval process for Verteporfin, several variables were studied: dose of the drug given, amount of energy applied, and the interval between the infusion and application of laser. Verteporfin doses of 6 mg/mm² body surface area, infused 15 minutes before an application of 689 nm wavelength light at 600 mW/cm² was approved.²⁷⁷ An application of 83 seconds producing a total 50 J/cm² was delivered to the ocular tissues.

Several randomized trials produced data resulting in the widespread adoption of verteporfin for subfoveal choroidal neovascular membranes. The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Group (TAP) Trial included patients receiving PDT versus placebo for patients with AMD and subfoveal lesions with some degree of classic presentation.²⁷⁹^,²⁸²^,²⁸³ Specific inclusion criteria included lesions less than 5,400 μm in greatest linear dimension and visual acuity between 20/40 and 20/200. Primary outcome was loss of vision of less than 15 letters, or three lines, with examinations at 3-month intervals.²⁷⁹^,²⁸²^,²⁸³ Treatment was repeated in persistently leaking lesion, based on fluorescein angiography.

A benefit of PDT over placebo sustained over a 2-year study period was demonstrated, with 53% of the Verteporfin- and photodynamic-treated eyes losing three lines or less, compared to 38% of controls.²⁸² The secondary end point of prevention of severe visual loss (loss of 30 letters or six lines Snellen acuity) was also statistically significant with 82% treated eyes versus 70% control eyes maintaining vision. Additional analysis yielded observations regarding lesion size, which demonstrated a trend toward better maintenance with the Verteporfin group.²⁸² At 24 months of treatment, 23.1% of PDT eyes compared to 53.6% of control eyes had an increase in the lesion size. Fifty-one percent of Verteporfin-treated eyes versus 28.5% of placebo eyes had no classic features identified on angiogram.²⁸² In the first year, an average of 3.4 treatments was required, whereas in the second year 2.2 treatments were performed.²⁷⁹^,²⁸²

The Verteporfin in Photodynamic Therapy Study Group (VIP) examined the effects of PDT on lesions due to subfoveal choroidal neovascularization in which the lesions had no classic angiographic features and evidence of recent progression of disease and vision of at least 20/100.²⁷⁷^,²⁸¹^,²⁸⁵ Also, the benefit of treatment for classic CNV with vision better than 20/40 was also studied. The primary outcome was loss of at least 15 letters, a difference from the TAP study, being a measure of loss of vision rather than preservation of vision.²⁸⁵

The VIP study showed no treatment benefit at 12 months.²⁷⁷ At 24 months, however, statistical significance was achieved, with treatment significance for the secondary outcome of severe visual loss (loss of 30 or more letters).²⁸⁵ Further subgroup analysis demonstrated lesions benefiting were those composed of occult with no classic characteristics and small lesion size (less than four disc areas), or worse vision at baseline (20/50).²⁷⁷^,²⁸⁵^,²⁸⁶ On this basis, predominantly classic lesions and occult lesions less than four MPS disc areas with recent disease progression and vision worse than 20/50 were recommended for treatment.²⁷⁸ Additional studies including earlier treatment prior to 3 months and changes in light application settings (fluence) did not demonstrate statistically significant results.²⁸⁷

Clinicians described the use of combination therapy with PDT and triamcinolone injected within the vitreous cavity.²⁸⁸^,²⁸⁹^,²⁹⁰^,²⁹¹^,²⁹²^,²⁹³^,²⁹⁴^,²⁹⁵^,²⁹⁶^,²⁹⁷ Various dosages have been described with this combination treatment, but this treatment lacked the proof of randomized controlled trials to test its efficacy.¹⁶³

Anti-VEGF treatments

Antivascular endothelial-derived growth factor medications have heralded a new era in the treatment of exudative macular degeneration.¹¹⁴^,¹²⁶^,²⁹⁸^,²⁹⁹^,³⁰⁰^,³⁰¹^,³⁰² Beginning with the initial results of the use of pegaptanib, the concept of intravitreous delivery of medications via periodic injections have revolutionized the treatment of choroidal neovascular membranes.³⁰³ The most significant of these thus far has been the ranibizumab, an anti-VEGF aptamer. Ranibizumab was studied initially with combined use of verteporfin and PDT in a randomized single masked phase I/II trial. The safety and efficacy of ranibizumab in combination with verteporfin PDT versus verteporfin and PDT alone in patients with subfoveal predominantly classic CNV due to AMD demonstrated the significant benefits of ranibizumab.³⁰⁴ One week before the first administration of either intravitreal ranibizumab or sham injection to the study eye, patients were treated with verteporfin PDT and with as many as 23 additional monthly injections with ranibizumab or sham injection.³⁰⁴ Patients continued to receive verteporfin PDT at the discretion of the investigator, in accordance with product labeling. The primary efficacy endpoint was the proportion of patients losing fewer than 15 letters at 1 year. The study enrolled 162 patients.³⁰⁴

The results were significant, both statistically and clinically. Approximately 90% of patients treated with the combination therapy had stable or improved visual acuity, compared with approximately 68% of patients in the control arm of PDT alone. Patients treated with combination therapy had significantly improved vision compared to baseline acuity; mean vision in the PDT alone control group decreased from baseline.³⁰⁴

A phase III, multicenter, randomized, double-masked, sham-injection-controlled trial included 716 patients with minimally classic/occult CNV secondary to AMD.³⁰⁵^,³⁰⁶ Eligible patients had not previously received subfoveal laser treatment, verteporfin photodynamic therapy, or experimental treatments for their AMD in the study eye.³⁰⁵^,³⁰⁶ Patients were randomized 1:1:1 to sham injection or to ranibizumab (0.3 mg) or 0.5 mg injected intravitreally monthly for 24 months.³⁰⁵^,³⁰⁶ The primary efficacy end point was the proportion of subjects losing less than 15 ETDRS letters at 1 year. Approximately one-third of the patients had minimally classic CNV, and two-thirds had occult CNV.³⁰⁵^,³⁰⁶

At 1 year, approximately 95% of patients treated with ranibizumab lost fewer than 15 letters at 1 year versus 62% in the control group.³⁰⁵^,³⁰⁶ On average the patients treated with ranibizumab had a significant visual acuity improvement compared to baseline, whereas the control group experienced a substantial decrease from baseline in mean VA. Ocular adverse events included incidences of uveitis and endophthalmitis, each less than 1%.

Along with anecdotal reports of similar success with bevacizumab,³⁰¹^,³⁰²^,³⁰⁴^,³⁰⁶^,³⁰⁷ a molecular compound similar to ranibzumab, anti-VEGF treatments have increased hopes of many patients and clinicians that long-term stabilization or even visual acuity improvements are an attainable goal.

Central Serous Chorioretinopathy

Synonyms: Central serous retinopathy, idiopathic central serous choroidopathy

Introduction

Von Graefe described an entity termed “recurrent central retinitis” in 1866, composed of serous detachment involving the macula.³⁰⁸^,³⁰⁹ Bennett subsequently referred to this entity as central serous retinopathy, with Gass providing the term idiopathic central serous choroidopathy.³¹⁰ Central serous retinopathy is best characterized as a decompensation of the choroid and retinal pigment epithelium, resulting in a tell-tale detachment of the neurosensory retina or retinal pigment epithelium.³¹⁰^,³¹¹^,³¹²^,³¹³^,³¹⁴^,³¹⁵^,³¹⁶^,³¹⁷^,³¹⁸^,³¹⁹^,³²⁰^,³²¹^,³²²^,³²³^,³²⁴^,³²⁵ Since von Graefe’s original description, central serous retinopathy has remained a unique affliction, associated with Type A personality, emotional stress, and corticosteroid medication use.³²⁶^,³²⁷^,³²⁸^,³²⁹^,³³⁰^,³³¹^,³³²^,³³³^,³³⁴

Epidemiology

Central serous retinopathy has been characterized as affecting young and middle-age adults between the ages of 20 and 50 years of age, although multiple reports of CSR affecting individuals older than 60 years have been presented.³³⁵^,³³⁶^,³³⁷^,³³⁸^,³³⁹^,³⁴⁰^,³⁴¹ Men are more likely to be affected than women by a 9:1 ratio.³¹⁰^,³⁴² Spaide reported his experience with patients above 50 years of age.³⁴¹ In this retrospective cohort, the ratio of female to males was almost 1:1.³⁴¹ Central serous retinopathy in women should perhaps be considered a distinct clinical entity as opposed to the condition that afflicts younger males. Female cohorts are likely to be older on average and may be more likely to have fibrinous subretinal deposits.³³⁹^,³⁴⁰^,³⁴³

Pathogenesis

The exact mechanism of central serous retinopathy is unknown. The association between individuals with a Type A personality or individuals under increased emotional strain has been a curious observation.³⁰⁹^,³²⁶^,³⁴⁴ “Stress hormones” such as increased catecholamines and cortisol may lead directly or indirectly to central serous retinopathy.³⁴⁵^,³⁴⁶^,³⁴⁷ Primate animal studies exposing epinephrine to choroidal vasculature result in local vasoconstriction serving as a possible model by which stress and the resulting glucocorticoid and catecholamine release potentiate the risk of central serous retinopathy in at-risk patients.³²⁴^,³²⁵^,³⁴⁸^,³⁴⁹^,³⁵⁰^,³⁵¹

Clinical features

Patients affected with central serous retinopathy may be asymptomatic or may report decreased vision, metamorphopsia, scotoma, and micropsia.³⁵² Clinically, any of the following features may be consistent with central serous retinopathy:

Neurosensory serous retinal detachment³¹⁵^,³⁵³^,³⁵⁴^,³⁵⁵^,³⁵⁶
Retinal pigment epithelium detachment³⁵⁷^,³⁵⁸^,³⁵⁹^,³⁶⁰^,³⁶¹
Retinal pigment epithelium atrophy³⁵⁴^,³⁶²

Neurosensory retinal detachments may be diagnosed as round, oval, blister-like elevations. When the foveal region is affected, the normal foveal reflex is blunted or even absent. Occasionally, yellow subretinal fibrinous precipitates may be present, reminiscent of pseudovitelliform lesions. An atypical presentation is noted in certain predisposed patients. Those on systemic corticosteroid medications may be at greater risk for bullous serous retinal detachments that may be confused with rhegmatogenous retinal detachments in pseudophakic patients.³⁶³^,³⁶⁴^,³⁶⁵^,³⁶⁶^,³⁶⁷

Pigment epithelial detachments are also round, blister-like elevations as seen in neurosensory detachment, except that the underlying retinal pigment epithelium is detached. They may be so small as to escape detection on biomioscropy, thus the useful application of fluorescein angiography. Pigment epithelial detachments may be seen in isolation or in concert with overlying neurosensory detachment.

Retinal pigment epithelium atrophy occurs as the various serous detachments resolve. Atrophic changes are not specific to central serous retinopathy. Certain patterns of atrophy, specifically atrophic “tracts” or “guttering” are almost pathognomic of central serous retinopathy. Tracts or guttering are the consequence of gravity dependent shifts in subretinal fluid that progress to extramacular atrophic changes. These may be linear and are often noted predominantly in the inferior hemisphere³⁵⁷(Fig. 23.15).

FIGURE 23.15 Atrophic RPE tracts in central serous chorioretinopathy. Angiography (right) demonstrates fluorescence from the underlying choroids secondary to RPE transmission defects.

The differential diagnosis of serous retinal detachment includes any disease resulting in choroidal neovascularization, including macular degeneration, multifocal choroiditis, ocular histoplasmosis, and idiopathic choroidal neovascularization. Other causes of serous detachment include Harada’s disease, uveal effusion syndrome, and optic nerve pit. Patients presenting with retinal pigment atrophy should be evaluated for macular degeneration, pattern macular dystrophies, resolved rhegmatogenous detachment, and resolved Harada’s disease.

The clinical course is classically described as a self-limited disease with good prognosis of visual acuity retention. Typically, resolution occurs by about 3 to 4 months. However, recurrences are common in up to 49% of patients with 10% experiencing multiple recurrences.³⁴² In a minority of patients, visual acuity suffers when atrophic areas invade the fovea, cystoid macular edema occurs, or if choroidal neovascularization arises.³³⁸^,³⁶²^,³⁶⁸^,³⁶⁹

Women afflicted with central serous retinopathy warrant special consideration. Perkins et al. described the features of 84 eyes of 78 women diagnosed with central serous retinopathy.³³⁹ Central serous retinopathy was associated with subretinal precipitates, short duration (less than 5 months), absence of pigment epithelial detachment were associated with favorable prognosis, whereas those presenting with age older than 50 years or pigment epithelial detachment were likely to suffer extended clinical courses.³³⁹

Specific conditions are associated with increased rates or severity of central serous retinopathy and thus warrant discussion. Patients who are administered corticosteroids in almost any form may experience either acute central serous retinopathy or exacerbation of pre-existing retinopathy.³³¹^,³³²^,³⁷⁰^,³⁷¹^,³⁷² As early as 1966, Jain described the association between corticosteroids and central serous retinopathy.³⁷³ Since that time, epidural, intranasal, intramuscular, oral, intravenous, and topical corticosteroid uses have been reported to induce or exacerbate central serous retinopathy.³³²^,³³³^,³³⁴^,³⁷⁴

Ancillary Tests

Fluorescein angiography in classically described cases reveals focal hyperfluorescence with leakage into the subretinal space. In 7% to 20% of patients, a “smokestack” appearance is noted, hypothesized as an osmotic gradient that develops due to proteinaceous fluid³¹⁵^,³⁷⁰^,³⁷⁵^,³⁷⁶ (Fig. 23.16). Leakage sites have been noted in all quadrants with the superior nasal quadrant being the most frequently involved quadrant. Angiography typically depicts pigment epithelial detachments as homogenous, well circumscribed, and hyperfluorescence maintained throughout the angiogram.³¹⁵^,³⁷⁰^,³⁷⁵^,³⁷⁶ (Fig. 23.17). Atrophic areas are easily revealed with transmission of normal choroidal fluorescence.³⁶² Optical coherence tomography is effective in revealing neurosensory detachment and pigment epithelial detachment.³⁷⁷ OCT may underestimate the extent of involvement of atrophic extramacular retinal pigment epithelial tracts.

FIGURE 23.16 A: Blister like appearance of neurosensory detachment in central serous chorioretinopathy. B: Fluorescein angiography of smokestack leakage contributing to central serous chorioretinopathy.

FIGURE 23.17 A: Fundus photography demonstrating small PED temporal to the macular. B: Angiography of small PED in central serous chorioretinopathy. C: OCT of pigment epithelial detachment secondary to central serous chorioretinopathy.

Treatment

Given the benign clinical course in most patients, characterized by resolution and retention of vision of better than 20/40 in the majority of patients, the recommended treatment is typically limited to observation.³⁴² Laser photocoagulation has been shown to increase the rate of resolution of neurosensory retinal detachment but has not shown to improve visual outcomes at follow up.³⁷⁸^,³⁷⁹^,³⁸⁰^,³⁸¹ Thus, specific recommendations regarding treatment recommendations are not available. Patients with persistent detachment, occupational needs, and poor visual acuity due to central serous retinopathy in the fellow eye may elect to receive treatment.

Yannuzzi et al. reported the outcomes of patients who received verteporfin and photodynamic therapy for chronic or persistent central serous retinopathy.³⁸²^,³⁸³ The treatment was administered with the aid of indocyanine angiographic guidance. Twenty eyes of 15 patients were treated with PDT directed to areas of choroidal hyperpermeability detected via indocyanine green angiography. Treatment was associated with complete resolution of exudative macular detachments in 12 patients and incomplete resolution in the remaining 8 eyes. The vision improved in 6 eyes and remained unchanged in 14 eyes during a mean follow-up of 6.8 months.³⁸³

Ocular Histoplasmosis Syndrome

Synonyms: Presumed ocular histoplasmosis

Introduction

In 1942, Reid et al. described ocular abnormalities in a dying patient with acute disseminated histoplamsosis.³⁸⁴ Subsequently, other investigators reported chorioretinal lesions associated with histoplasmin skin testing. Woods et al. described 62 patients with histoplasmin reactivity, 19 of which demonstrated ocular lesions consisting of atrophic lesions now recognized as “histo spots.”³⁸⁵

The etiology of ocular histoplasmosis is believed to begin with infection of the respiratory tract with Histoplasma capsulatum, early in life.³⁸⁶^,³⁸⁷^,³⁸⁸^,³⁸⁹^,³⁹⁰ The fatal cases of histoplasmosis were typically the result of disseminated infection, associated with deficiencies in the immune system of the host. Histoplasmosis has the potential to affect almost all organ systems. Due to its proclivity to the immunocompromised patient, histoplasmosis is a common opportunistic infection in those with acquired immunodeficiency syndrome (AIDS).³⁹¹

Comstock et al. outlined a rough triangle with apices near Omaha, Nebraska; Columbus, Ohio; and Natchez, Mississippi, which include the Ohio and Mississippi river valleys as the endemic areas of histoplasmosis.³⁹² In this triangle, up to 60% of lifelong residents react positively to histoplasmin skin testing.

Presumed Versus Confirmed Ocular Histoplasmosis

Historically, the term presumed ocular histoplasmosis syndrome was used in the description of the disorder as the causative microbe was never confirmed in blood or tissue culture. A causal relationship between Histoplasma capsulatum and the ocular histoplasmosis syndrome was suggested given reactions to histoplasmin skin testing more commonly observed among patients who have disciform lesions than among controls.³⁸⁶^,³⁸⁸^,³⁸⁹^,³⁹³ Reactivation of apparently quiescent lesions of ocular histoplasmosis coincident with positive histoplasmin skin testing has been reported. Finally, Spencer extracted DNA from H. capsulatum isolated from the enucleated eye of a man with chronic choroidal lesions diagnosed as ocular histoplasmosis.³⁹⁴

One study in Walkersville, Maryland, identified 22 subjects of 842 with characteristic ocular histoplamsosis.³⁹³ All 22 reacted positively to the histoplasmin skin antigen compared with 59% of the general population with a p value for this association of 0.06 by the Fisher exact test. Of those who tested positive by skin reaction to H. capsulatum, 4.4% had clinical POHS.³⁹³

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Jul 10, 2016 | Posted by drzezo in OPHTHALMOLOGY | Comments Off

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