The anatomic fovea (fovea centralis) is 1.5 mm in diameter and centered 4 mm temporal and 0.5 mm inferior to the center of the disc (Fig. 1).^1,3 The inner retinal surface of the fovea is concave. Clinically, the rim of the concave slope, called the clivus, causes a change in the retinal light reflex and appears as a slightly oval ring. There are no blood vessels in the central fovea. This capillary-free zone (foveal avascular zone) in the fovea is 400 to 500 μm in diameter.^1,3

The center of the fovea is the foveola or foveal pit. The anatomic foveola is sometimes incorrectly referred to clinically as the fovea, much as the anatomic fovea is incorrectly referred to as the macula. It is roughly 350 μm in diameter and is contained within the foveal avascular zone. At its center it is free of cells except the outer segments of red and green cones. In the portion of the fovea surrounding the foveola, the nerve fiber, ganglion cell, and plexiform layers are present. At the center of the foveola is a small depression called the umbo. The foveola produces a reflected spot of light in the vitreous called the foveal light reflex. The parafoveal retina is about 500 μm wide and surrounds the fovea. It is characterized by the cellularity of the inner nuclear and ganglion cell layers. The nerve fiber layer is thicker, especially in the papillomacular bundle. The cone to ganglion cell ratio is 1:1. The perifoveal retina, 1500 μm wide, is the peripheral zone of the macular region. It extends to where the ganglion cell layer is reduced to the single layer of nuclei seen elsewhere in the peripheral retina.

AMD is classified in two categories: nonneovascular (dry, atrophic) and neovascular (wet, exudative). Neovascular AMD has a prevalence rate of 1.2% and dry AMD has a prevalence of 15.6% among adults aged 43 and older.¹¹ Geographic atrophy is the main cause of severe visual loss in nonneovascular AMD and has a prevalence of 0.6%.¹¹

It is important to use a uniform definition for AMD that has been proposed.¹² AMD is a disease of persons older than 50 years of age characterized by soft drusen 63 μm or larger, hyperpigmentation or hypopigmentation of the retinal pigment epithelium (RPE), RPE and associated neurosensory detachment, hemorrhage (retinal, subretinal), geographic atrophy of the RPE, and fibrous scarring. Visual acuity is not part of the definition.

Blindness associated with AMD is caused by degeneration of visual cells, a result of degenerative changes in the RPE. Whether the disease takes the form of localized degeneration without the complications of vascular invasion or whether cells are destroyed by the disruptive effects of neovascularization, degeneration of the RPE precedes or accompanies death of the associated rods and cones.^13–15 RPE degeneration in AMD is believed to be a consequence of abnormal cellular metabolism due to imperfections in the digestive mechanisms of the cells, resulting in the accumulation of abnormal material in the RPE. The useless residues of incomplete molecular degeneration increasingly interfere with normal metabolism, provoking aberrant excretions that aggregate in the form of basal laminar deposits and decay within Bruch's membrane. These abnormal extracellular deposits are associated with subretinal neovascularization (SRNV), which is also called choroidal neovascularization (CNV). They may also result in the death of RPE cells followed by degeneration of the rods and cones.

DRUSEN

Cells of the RPE continuously ingest photoreceptor outer segments that are shed throughout life. The residue of intracellular digestion may eventually fill the cell. Drusen are extracellular deposits that lie between the basement membrane of the RPE and the inner collagenous zone of Bruch's membrane. Drusen vary in size, shape, color, consistency, and distribution, although they are often bilaterally symmetric, clustered in the macular region, and tend to increase in number with advancing age.^16–19

SMALL, HARD DRUSEN

Hard drusen are small (less than 63 μm), round, discrete punctate nodules that are yellow-white (Fig. 2). Histopathologically, they are seen as either single enlarged RPE cells with lipid²⁰ or focal deposits of periodic acid-Schiff-positive hyaline material in Bruch's membrane.²¹ The material in hard drusen resembles the components of aging Bruch's membrane, containing coated, membrane-bound bodies, membrane fragments, vesicles, and granular material.^7,22,23 Because small, hard drusen are common, their presence does not justify a diagnosis of AMD. They are not associated with an increased risk for the development of SRNV²⁴ and are not age-related.¹¹

Dominant drusen refers to a dystrophy in which excessive numbers of hard drusen are seen in the macular area of younger patients. They tend to be bilaterally symmetric. These patients may be at increased risk for the development of SRNV later in life. Hard drusen behave like window defects on angiography.

SOFT DRUSEN

Soft drusen are large (greater than 63 μm), pale-yellow or gray, dome-shaped, occasionally confluent structures with indistinct margins. Clinically, they appear identical to pigment epithelial detachments. Angiographically, they hyperfluoresce early and either fade or stain late (Fig. 3). There are three histologically defined types of soft drusen. All types involve detachment of the RPE. Differences arise in the presence and location of deposits. Basal linear deposits (diffuse thickening of Bruch's membrane) have material deposited in the inner collagenous zone of Bruch's membrane. These deposits contain lipid-rich material. Basal laminar deposits are located between the plasma membrane and basement membrane of the RPE cell and do not involve Bruch's membrane. These deposits are mainly wide-spaced collagen. The three types of soft drusen are localized RPE detachments with diffuse basal linear deposits, localized RPE detachments with diffuse basal laminar deposits, and localized RPE detachments with only focal basal linear deposits.²²

Soft drusen are present in 13% to 20% of the population, and the prevalence is age-related.¹¹ Their presence increases the risk for development of RPE abnormalities, geographic atrophy, and SRNV.^24,25 For this reason, the presence of soft drusen is sufficient to make a diagnosis of AMD. The Macular Photocoagulation Study (MPS) showed that eyes with soft drusen had a 30% risk of CNV development, whereas eyes without large drusen or pigment abnormalities had only a 10% risk.²⁴

PERIPHERAL DRUSEN

Although drusen are most commonly found in the macular region, they may be present anywhere in the fundus. Peripheral drusen are often surrounded by rings of pigment. This pigmentation may be confluent, linear, or radiating, producing a reticular pattern referred to as senile reticular pigmentary degeneration. There is a strong correlation between peripheral drusen and pigmentation and the macular changes of AMD.^26,27

SICK RPE

Also known as degeneration of the RPE or nongeographic atrophy of the RPE, sick RPE is manifested by mottling of the pigment epithelium with hypopigmentation in a stippled pattern. This occurs in 8% to 10% of the population.²⁸ Degeneration of the RPE leads to degeneration of the overlying neurosensory retina. Fluorescein angiography reveals hyperfluorescence in areas of hypopigmentation alternating with blocked fluorescence in areas of pigment clumping. Histopathologically, there are basal linear and basal laminar deposits.²⁹ Eyes with sick RPE are at a higher risk of developing soft drusen, geographic atrophy, and choroidal neovascularization.

RPE HYPERPIGMENTATION

Focal hyperpigmentation of the RPE is more often seen in eyes with soft or large drusen (Fig. 4). Such a finding is correlated with a higher risk of developing geographic atrophy or more soft drusen. Focal hyperpigmentation also confers a higher risk of progression to neovascularization, particularly when large drusen or soft drusen are also present. Patients with choroidal neovascularization in one eye have a 58% to 73% risk of developing CNV in the fellow eye over 5 years if there are more than two large drusen and focal hyperpigmentation in the macula.³⁰

PIGMENT EPITHELIAL DETACHMENT

Serous detachment of the RPE is common in AMD. As drusen develop, there is a loosening of the adherence between the RPE basement membrane and the inner collagenous portion of Bruch's membrane, predisposing the patient to the development of a serous pigment epithelial detachment. The RPE and its underlying basal lamina may be elevated by serous fluid, and the overlying sensory retina may be detached as well. There is no practical difference between a serous pigment epithelial detachment and soft drusen formation. Although these detachments develop in a variety of morphologic patterns, they typically appear as sharply demarcated, dome-shaped, round to oval elevations of the RPE (Fig. 5). The surface of the pigment epithelial detachment may be smooth and homogeneous, or it may be associated with overlying pigment clumping or atrophy. The presence of an overlying sensory retinal detachment is usually evidence of underlying SRNV. A shallow sensory retinal detachment that extends beyond the area of the pigment epithelial detachment may result from the breakdown of the physiologic RPE pump or a disruption of the tight junctions between RPE cells, but usually it is the result of underlying SRNV.^31,32

A serous pigment epithelial detachment often causes visual distortion and loss of vision.³³ The prognosis for these detachments depends on the underlying disease process.³⁴ If present in younger patients, it may be part of central serous retinopathy and has a good prognosis. If, however, older persons develop serous pigment epithelial detachment, there is the likelihood for the development of underlying SRNV^33,35 in one third to one half of patients.^32,36 The size of the pigment epithelial detachment is important in determining the likelihood of SRNV development, with smaller detachments less likely to harbor underlying neovascular growth.^33,35 Although laser photocoagulation may flatten a detachment, no beneficial effect from laser therapy has been shown in the absence of SRNV.³⁷

Pigment clumping may develop on the dome of the pigment epithelial detachment, or the detachment may spontaneously collapse with associated RPE atrophy.^33,38,39 It is also possible that eyes with pigment epithelial detachments that go on to develop SRNV may already harbor unappreciated occult vessels.^40,41

Fluorescein angiography of a serous pigment epithelial detachment typically shows gradual and uniform staining of the sub-RPE material, similar to the increased intensity of light seen when the rheostat on a light bulb is turned up. There is, however, a great range of morphologic and angiographic findings with these detachments, and the presence of occult SRNV can be postulated on the basis of these patterns.⁴² Angiographic findings suggestive of underlying occult SRNV include irregular hyperfluorescence, multiple areas of intense hyperfluo-res-cence (“hot spots”) not associated with overlying window defect, and a notch sign.^32,42,43 A notch sign refers to an area of pigment epithelial detachment where the smooth, rounded border is crimped in toward the center of the detachment. This is believed to be caused by traction on the pigment epithelial detachment by an underlying occult SRNV membrane.

The pathogenesis of a pigment epithelial detachment has not been clearly elucidated. It has been postulated that the fluid may be derived from blood vessels growing on the inner surface of Bruch's membrane; however, subpigment epithelial neovascularization is not universal in these detachments.^42,44 It has also been suggested that the fluid may come, in part, from the RPE, rather than from the choroid. Fluid is actively transported across the RPE from the sensory retina toward Bruch's membrane. If Bruch's membrane is changed or compromised, perhaps by lipid deposition that renders it hydrophobic, then there would be significant resistance to water flow. The result would be fluid accumulation in the sub-RPE space.⁴⁵

ATROPHIC MACULAR DEGENERATION

The atrophic form of macular degeneration has been called geographic because the areas of RPE atrophy tend to form well-demarcated borders that do not relate to specific anatomic structures (Fig. 6).^3,13,38,46 It has also been called dry macular degeneration, senile choroidal sclerosis, and central areolar choroidal atrophy.^13,47,48 Atrophic macular degeneration leads to significant visual loss in almost all cases; patients describe a gradual and subtle blurring of vision that relates to the degree of foveal involvement. A minimum of 175 μm of the retina should be involved to classify a patient as having geographic atrophy.¹²

Atrophic macular degeneration may evolve in several ways. Areas of RPE atrophy often follow the fading of drusen. Dystrophic calcification may also be seen in soft drusen. Eventually, the overlying RPE atrophies.²¹ Initially, these areas form discrete patches of atrophy that coalesce with time. The areas initially affected usually involve the perifoveal area and spread around the fovea, preserving central vision. However, in most cases, with time the fovea is involved and central vision is lost.^7,39

Macular atrophy may occur in the absence of faded drusen. The RPE atrophy may be preceded by a reticular configuration of pigment clumping. The atrophy tends to expand more rapidly in all other directions than toward the fovea.³⁹ However, although the fovea shows a certain amount of resistance to the expansion of atrophy, it is ultimately involved, and in most cases central vision is lost. Occasionally, a bull's-eye ring of atrophy surrounds the fovea before the center is involved. This foveal sparing may be due to an accumulation of lipofuscin in the posterior pole or possibly to the presence of xanthophyll pigment.⁷ The progression of atrophy is variable, ranging from 15 to 375 μm a year.³⁹

Geographic atrophy may follow the spontaneous or laser-induced collapse of a serous pigment epithelial detachment, especially when formed by a confluence of soft drusen.^{7,49,33,36,39,49,50} In areas of geographic atrophy, the outer nuclear layer rests directly on the basal lamina. The outer plexiform layer is thinned and vacuolated, but the inner nuclear layer is less affected. The choroidal capillaries remain patent for a time, but in long-standing RPE atrophy, they end abruptly at the end of the atrophic area. The gradual obliteration of the choriocapillaris that follows RPE atrophy can be seen clinically as slow filling on fluorescein angiography that, in time, progresses to nonfilling.⁵¹

In cases of long-standing atrophy, choroidal arteries may appear to be sheathed, prompting the name choroidal sclerosis. Histologic examinations, however, reveal only a fibrous replacement of the arterial media, without thickening of the walls; the lumen remains patent.⁷ Choroidal atrophy occurs secondary to a reduction in nutritional demands of the outer retina. As the choriocapillaris and middle layer of choroidal vessels are lost, the larger choroidal vessels become more prominent.

Functional visual loss can result from a ring scotoma, despite good Snellen acuity. It takes approximately 10 years from the onset of atrophic change to reach a level of 20/200, although an interval of 5 years has been observed between the time of atrophic foveal encroachment and the loss of fixation.^7,52 Each year, 8% of eyes decrease from 20/50 or better to 20/100 or worse.³⁹ There is a great tendency for the areas of atrophy to become bilaterally symmetric with time. Also, SRNV can develop at the border of atrophic RPE, especially if there is a ring of soft drusen around the geographic atrophy. Because the neovascular response requires the presence of degenerating RPE, the SRNV is almost always found at the edge of atrophy rather than in the center of an atrophic area.

SUBRETINAL NEOVASCULARIZATION

The Eye Disease Case-Control Study Group showed that there is an increased risk to progression to SRNV if there is a history of cigarette smoking, elevated serum cholesterol, and multiparity.⁵³ A protective effect of carotenoids was also found. Serum levels of vitamins E and C were not associated with the risk of progression to SRNV.⁵⁴

SRNV refers to the growth of abnormal new vessels beneath the sensory retina or RPE. Choroidal neovascularization, another term for SRNV, emphasizes the choroidal vascular origin of the new vessels.⁵⁵ SRNV is an abnormality found in many diseases in which the integrity of the RPE, Bruch's membrane, and choriocapillaris has been compromised.^56–59 The effect on vision from SRNV derives from its tendency to leak fluid beneath and into the sensory retina, to bleed, and to create a fibrovascular disciform scar in the macular region.

Patients with AMD often develop SRNV and initially present with blurred or distorted vision, micropsia, or scotoma.⁶⁰ Clinically, the subretinal neovascular membrane may appear as a dirty-gray discoloration beneath the retina and may be accompanied by an overlying sensory retinal detachment and cystoid edema. A pigmented ring may encircle the membrane, caused either by RPE hyperplasia or pigment ingestion. Often subretinal or sub-RPE hemorrhage is present. In the absence of retinal vascular disease, trauma, or a choroidal tumor, subretinal hemorrhage should be considered to be caused by SRNV until proven otherwise. Rarely, hemorrhage from SRNV may dissect through the retina to create a vitreous hemorrhage. Occasionally, SRNV can be responsible for a turbid sensory retinal or RPE detachment. Turbidity indicates the presence of proteinaceous exudate, fibrin, and blood, all products of abnormally leaking vessels. Subretinal exudate is also a strong indicator of SRNV. If the RPE overlying the SRNV membrane has become thinned, then the arborized vascular structure of the membrane may be seen.⁶¹

The presence of a pigment epithelial detachment may also signal the presence of an SRNV membrane, especially if associated with sensory retinal detachment, subretinal exudate or blood, chorioretinal folds, or an RPE tear.^16,17,43 Subretinal or sub-RPE blood in the pigment epithelial detachment is also a sign of associated SRNV. The blood and proteinaceous content in a pigment epithelial detachment stains slowly with fluorescein compared with the rapid angiographic staining of a serous pigment epithelial detachment.

Fluorescein angiography is useful in confirming the presence and location of SRNV, which provides information concerning visual prognosis. The early angiogram in classic CNV may reveal a discrete, lacy, arborized plexus of vessels, with a nodular-appearing border (Fig. 7). The edges of the neovascular net are scalloped and irregular. Later in the angiographic study, there is an intense hyperfluorescent fuzziness to the border of the membrane, the result of dye leakage into the subretinal space (Fig. 8). As the study progresses, there is pooling of dye in the subretinal space. The newer, less mature vessels at the edge of the membrane tend to leak more than older vessels. Therefore, the border of the membrane becomes fuzzier and larger, as opposed to the well-defined edge of a serous pigment epithelial detachment. Staining of the fibrous tissue that accompanies all new vessel growth and the pooling of the dye under the pigment epithelial detachment or sensory retina cause the late hyperfluorescent pattern of SRNV. Accumulation of fluorescein dye in cystic spaces in the overlying retina may also contribute to the late hyperfluorescence.

The precise location of SRNV is not always clear. Often the SRNV is obscured by hemorrhage, turbid serous fluid, pigment epithelial detachment, or extensive pigment clumping. Such membranes are referred to as occult SRNV and may be seen when relatively intact RPE overlies thin and subtle SRNV (Fig. 9). Occasionally, clinical signs of SRNV (hemorrhage, exudate, serous detachment) are present, but the SRNV cannot be found by angiography. The visual prognosis is poorer for these eyes than for those with distinct, clearly defined SRNV membranes. In some cases, SRNV hyperfluoresces late in the angiogram but not early. There may be a gradual oozing of fluorescein through multiple pinpoint areas of RPE overlying the SRNV membrane. The slow hyperfluorescence may be related to a decreased flow of blood through the membrane or to a relatively intact RPE.

An RPE tear may occur at the junction of attached and detached RPE, where contraction of the SRNV may tear the RPE. The torn edge of RPE retracts and is pulled by the fibrovascular tissue (Fig. 10). In the acute period, a serous detachment of the sensory retina may occur because of the fluid leaking from the exposed choriocapillaris. The subretinal fluid usually resorbs in a few days.^43,62,63

Indocyanine green angiography is sometimes helpful in cases of occult CNV. Because indocyanine dye is protein-bound, it does not leak from the choriocapillaris as does fluorescein. On stimulation with an infrared source, the dye fluoresces weakly. Well-defined areas of fluorescence are termed hot spots and are assumed to represent CNV.

Feeder vessels can occasionally be seen extending from a natural or laser scar to an area of recurrent CNV (Fig. 11).⁶⁴ Although they can be seen on fluorescein angiography, high-speed indocyanine green video angiography is often used to increase detection in cases of new subfoveal CNV.⁶⁵ Feeder vessels can be thought of as having either an umbrella pattern or a racquet pattern.⁶⁶ In an umbrella pattern, the feeder vessel is oriented in an anteroposterior fashion between the CNV complex and choroidal space. With a racquet pattern, the feeder vessel passes more obliquely from the choroidal space toward the CNV complex.

HISTOLOGY

The SRNV arises from the choroid and passes through Bruch's membrane to invade the subpigment epithelial and subsensory retinal space. The vessels may pass through pre-existing breaks in Bruch's membrane or may produce breaks in the membrane.⁶⁷ However, breaks in Bruch's membrane can occur without any growth of vessels from the choriocapillaris. The SRNV proliferates under the RPE and destroys it. The vessels may also cause hemorrhagic or serous detachment of the RPE, the sensory retina, or both. Cystic changes may develop in the overlying sensory retina.

New vessel growth is accompanied by fibrous tissue, which ultimately becomes the dominant pathologic change and results in a disciform scar involving the choroid, RPE, and sensory retina.⁵⁹ Active neovascularization may intermittently bleed at the edges of the developing scar. Further, the overlying retinal vessels and the choroidal vessels supplying the scar may anastomose. Also, although found most frequently in the macular region, extramacular disciform lesions may occur and simulate choroidal melanomas.

PATHOGENESIS

The association between new vessel growth and drusen formation has been well described; both processes are related to degeneration of the RPE. Soft drusen represent the breakdown of the hyaline content in hard drusen or the focal accumulation of membrane debris that lies between the RPE basement membrane and the inner collagenous layer of Bruch's membrane. These detachments predispose to pigment epithelial detachment formation and to SRNV. Why SRNV develops is unknown, but evidence suggests that choroidal vessels, in the absence of an effective barrier and inhibitory factors released by normal RPE, may be exposed to mitogenic and chemotoxic retinal factors that stimulate SRNV.^57,68,69

TREATMENT

The MPS produced its first result in 1982 and continued with more than two dozen reports. As a prospective study, it helped define acceptable treatment for CNV associated with AMD, ocular histoplasmosis, and idiopathic CNV. The influence of different laser wavelengths used in treatment was also studied.⁷⁰ Laser treatment can be classified into subfoveal, juxtafoveal (1 to 199 μm from the center of the foveal avascular zone), and extrafoveal types.

EXTRAFOVEAL TREATMENT. The first MPS⁷¹ report found that 60% of untreated eyes and only 25% of treated eyes had severe visual loss (six or more lines of vision) in the AMD group. These results led to the termination of this arm of the study. The 3-year results⁷² found that 62% of untreated eyes and 47% of treated eyes had suffered severe visual loss. The 5-year results were similar to the 3-year results.⁷³ The higher incidence of severe visual loss in the treated group at the 3-year follow-up versus baseline was due to recurrent CNV, which was seen in 54% of eyes. Almost three quarters of recurrences occurred in the first year after treatment. Cigarette smoking was associated with a higher risk of recurrence (85% vs. 51%).

JUXTAFOVEAL TREATMENT. The 5-year data for AMD showed that treated eyes were less likely to have severe visual loss compared with untreated eyes (55% versus 65%) (Fig. 12). Recurrences occurred in 47% after 5 years in the treated group.⁷³ Peripapillary CNV was studied as well (Fig. 13): it was found that 14% of treated and 26% of untreated eyes had severe visual loss.⁷⁴

SUBFOVEAL TREATMENT. Three months after subfoveal treatment, 20% of treated eyes suffered severe visual loss compared with 11% of untreated eyes. After 2 years, 20% of treated eyes still had suffered severe visual loss, but now 37% of untreated eyes had suffered severe visual loss. After 4 years, 23% of treated and 45% of untreated eyes had suffered severe visual loss.

The size of the subfoveal CNV is important in predicting benefit from subfoveal laser treatment. CNV size is grouped as small lesion (1 MPS disc area or less), medium lesion (1 to 2 MPS disc areas), or large lesion (greater than 2 MPS disc areas). Lesion size is compared with preoperative visual acuity:

• For small lesions, if vision is 20/125 or worse, treated eyes uniformly do better than untreated eyes. If vision is 20/100 or better, treated eyes do worse in the first year and then better than untreated eyes thereafter.
  
• For medium lesions, if vision is 20/200 or worse, treated eyes uniformly do better than untreated eyes. If vision is 20/160 or better, treated eyes fare worse than untreated eyes in the first year and then do better thereafter.
  
• For large lesions, if vision is 20/200 or worse, treated eyes do only slightly better than untreated eyes. If vision is 20/160 or better, treated eyes do worse for 18 months and there is little difference between treated eyes and untreated eyes thereafter.⁷⁵
  

Many retina specialists use these criteria in considering which patient to treat with the laser based on the clinical setting. The patient must understand the goals of treatment and the high risk of persistence (13%) and recurrence (35%) with subsequent need for more laser therapy.⁷⁶ After the initial treatment, an angiogram is repeated after 2 weeks to evaluate the adequacy of treatment. Subsequent to this visit, patients may be seen at 3-month intervals for the first year and at 6-month intervals for the second year. Angiography is performed if needed.

The choice of laser wavelength for SRNV near the fovea depends on the clinical setting, but theoretically it should include the use of wavelengths not absorbed by yellow xanthophyll pigment (green, yellow, or red). The presence of blood or the degree of pigmentation in the area to be treated also may determine the choice of wavelength (e.g., krypton or dye red [620 to 630 nm] laser will be minimally absorbed by the red hemoglobin in blood). However, the MPS found no significant difference between argon green and krypton red laser.⁷⁵

Feeder vessels can be treated with laser, limiting the amount of damage done to retinal tissue. Ideally, a wavelength absorbed by hemoglobin (576 nm [dye yellow] or 530 nm [YAG green]) should be used. In a study by Shiraga and associates,⁶⁵ there was a 70% closure rate, with 30% having recurrent or persistent SRNV. Vision was stabilized or improved in 68%, and good preoperative vision, lack of fibrous scarring, small size of SRNV (less than 2 disc areas), and further distance from the foveal avascular zone were associated with better visual outcomes. Staur-enghi and colleagues⁶⁶ found that multiple treatments may be needed to close a feeder vessel. The dimensions and number of the feeder vessels can compromise success.

Complications from laser treatment for SRNV associated with AMD include inadequate treatment (because of inadequate intensity or inadequate coverage of the membrane), resulting in persistent or recurrent SRNV. Other complications are RPE tear, epiretinal membrane formation, inadvertent foveal photocoagulation, choroidal vascular obstruction, choroidal folds, hemorrhage caused by overly intense treatment, and nerve fiber layer defects that occur with heavy treatment of SRNV that lies beneath the papillomacular bundle.^59,77

Patients with AMD should test their vision daily with the Amsler grid chart. If they notice blurred vision or distortion, they should report immediately to their physician, who should perform a complete macular examination and fluorescein angiogram. If treatment is to be performed, it should be carried out immediately. SRNV can grow up to 40 μg per day, and a treatable membrane that initially is safely away from the foveal center may be beneath the fovea in a short time. Time is of the essence for patients with SRNV secondary to AMD.

Patients with CNV in one eye often ask about the risk to their fellow eye. The MPS³⁰ showed that the following are independent risk factors when found in the fellow eye: five or more drusen (RR = 2.1), focal hyperpigmentation (RR = 2.0), one or more large drusen (more than 63 μm, RR = 1.5), and hypertension (RR = 1.7). The 5-year incidence rates for development of CNV in the fellow eye ranged from 7% (no risk factors) to 87% (all four risk factors).

If patients have untreatable SRNV or bilateral disciform scars, they should be assured that SRNV almost never causes total blindness and that their functional abilities may be improved somewhat with low vision aids. They should be made aware of the range of services available to persons with a visual handicap, including large-print newspapers, books-on-tape, television viewers, and community support services, and they should be encouraged to continue independent, productive, and creative lives.

EXPERIMENTAL TREATMENT MODALITIES LIGHT.

Light in the visible and ultraviolet spectra has been postulated as contributing to macular degeneration.⁷⁸ Recent studies, however, have failed to confirm a link between photic stress and macular degeneration. These studies include the Chesapeake Bay Waterman Study,⁷⁹ the Eye Disease Case-Control Study,⁸⁰ and the Beaver Dam Eye Study.⁸¹

NUTRITION. Antioxidants have also been postulated to cause oxidative damage to the RPE, with a consequent increased risk of macular degeneration. The National Health and Nutrition Examination Survey found that people who ate diets rich in fruits and vegetables were less likely to have AMD.⁸² The Eye Disease Case-Control Study⁸⁰ found that increased levels of carotenoids were somewhat protective against SRNV in AMD. No benefit was found with increased levels of vitamins C and E or selenium. Zinc is involved in many of the enzymatic processes in the retina, and some believe that supplementation may be protective against AMD. The Eye Disease Case-Control Study, however, failed to find a benefit with higher zinc levels. Currently, the Age-Related Eye Disease Study is being conducted to study the relation between nutrition, diet, and AMD.

LASER TREATMENT OF DRUSEN. Laser treatment of soft drusen has been studied as a means of stabilizing acuity and preventing SRNV. One large study, the Choroidal Neovascularization Prevention Trial, found an increased risk of SRNV in laser-treated eyes that halted the study.⁸³ Olk and colleagues⁸⁴ used the infrared diode laser at 810 nm to treat patients with drusen. Treatment parameters included light and visible burns and invisible burns. Both treatment types led to reduction in the number of drusen in approximately 65%, but this happened earlier in the visible burn group (12 versus 18 months). Treated eyes did somewhat better in terms of vision compared with nontreated eyes. This difference was noted at 12 months and was still significant at the 2-year follow-up. Importantly, treated eyes had similar rates of visual loss as untreated eyes. The rate of development of CNV was similar between treatment and observation groups at 2 years. A forthcoming trial, the Prophylactic Treatment of AMD Trial, will compare subthreshold treatment of drusen with infrared laser to observation.

PHOTODYNAMIC THERAPY. Photodynamic therapy is a two-step process in which a photosensitizing drug is injected and then irradiated with monochromatic laser light. This results in the creation of a triplet state that combines with oxygen to create free radicals. Tumors and neovascular tissue have an affinity for the photosensitizing drug and are therefore more prone to free radical damage than healthy tissue. The primary damage is to endothelial cells.^85,86 It is hoped that with photodynamic therapy, the overlying healthy RPE and retina can be spared, therefore allowing vision to be maintained.

Two photosensitizers are undergoing trials by the Food and Drug Administration: verteporfin, a benzoporphyrin derivative, and purlytin (tin ethyl etiopurpurin, SnET2). Verteporfin has an absorbance peak at 689 nm, purlytin at 664 nm. Verteporfin (Visudyne; Ciba Vision, Duluth, GA) is being evaluated in the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Investigation (TAP) and the Verteporfin in Photodynamic Therapy study (VIP). The TAP study involves patients with subfoveal, classic CNV less than 5400 μm and visual acuity between 20/40 and 20/200. The VIP study includes cases of subfoveal CNV not included in the TAP study (occult CNV or visual acuity better than 20/40).

The dose of Visudyne to be injected is based on body surface area (6 mg/m2 body surface area). A 30-ml solution of the drug is injected over 10 min-utes. Five minutes after the infusion is complete, the macula is irradiated over 83 seconds with a spot size 1000 μm greater than the greatest size of the CNV complex.⁸⁷ One-year outcome data for phase 1 and 2 studies were recently released.⁸⁸ Sixty-one percent of treated eyes had lost fewer than 15 lines of vision compared with 46% of untreated eyes; restated, 15% of treated eyes showed a benefit from Visudyne. Eyes with more classic CNV (more than 50% of the lesion) did better with photodynamic therapy. There was no treatment benefit in lesions whose classic component made up less than 50% of the lesion. Leakage recurred by 12 weeks in all cases, although it was often less pronounced than before verteporfin therapy. Retreatment with Visudyne is effective in treating recurrent leakage, although long-term data are lacking.⁸⁹

Photodynamic therapy should still be considered experimental because long-term data are not available. Its application in the armamentarium against neovascular AMD will become clear as more data accumulate.

TRANSPUPILLARY THERMOTHERAPY. Transpupillary thermotherapy involves irradiating the macula with an infrared laser at 810 nm. Beam size is adjustable up to 3.0 mm to cover the lesion size. Power is adjusted so that an invisible to barely visible treatment effect is noted. The treatment lasts for 60 seconds. Reichel and colleagues⁹⁰ conducted a pilot study with 15 patients (16 eyes) who had occult CNV. Visual acuity was 20/400 or better in all patients. Follow-up ranged from 6 to 25 months. Two eyes received one retreatment (13%), and one eye required two retreatments (6%). Three eyes (19%) improved by two or more lines, nine (56%) were stable, and four (25%) lost two or more lines of vision. Fifteen eyes (94%) were judged to have less exudation. A larger trial should help define the use of transpupillary thermotherapy in the treatment of occult AMD.

RADIATION THERAPY. Studies evaluating x-ray irradiation for CNV in AMD have mostly been small.⁹¹ X-ray treatment appears to halt progression of CNV but may not cause regression. Many studies have not found a significant difference between radiation doses.⁹² The Radiation Therapy for Age-Related Macular Degeneration Study studied the effect of eight fractions of 2 Gy external beam radiation compared with sham treatment in a randomized, prospective, double-blind trial involving many centers. They found no benefit at the 1-year point.

Radiation-associated choroidal neovasculopathy was reported by Spaide at the 1998 American Academy of Ophthalmology meeting.⁹³ Twelve of 95 patients (13%) treated with 1000 cGy external beam radiation developed this, compared with 7 of 98 (7%) treated with 2000 cGy. There was significant loss of acuity.

PNEUMATIC DISPLACEMENT OF SUBMACULAR HEMORRHAGE. Dense submacular hemorrhage often results in poor vision, with acuity less than 20/200 in most cases.⁹⁴ Heriot⁹⁵ used tissue plasminogen activator (tPA) and C3F8 gas to displace subfoveal blood. The procedure should be performed within 3 weeks of symptoms. A dose of 25 μg tPA in 0.1 ml is injected into the vitreous cavity. A paracentesis is then performed, followed by injection of SF6 or C3F8. After 3 hours, prone positioning is assumed for the next day to 3 days. Alternatively, gas can be injected without tPA and the patient re-evaluated after 48 hours. If displacement is inadequate, tPA can then be injected.⁹⁶ Displacement of blood can allow earlier diagnosis of the cause of hemorrhage. The underlying pathology may dictate final visual acuity. This technique has not been evaluated in a prospective study.

SUBMACULAR SURGERY. Because laser photocoagulation of subfoveal CNV results in loss of central vision and is associated with a high rate of recurrence, the Submacular Surgery Trials were initiated to study whether removal of subfoveal CNV could alter the known history. This study has several arms that address new subfoveal CNV, subfoveal CNV associated with histoplasmosis or idiopathic, and submacular hemorrhage related to AMD. Long-term follow-up has found that AMD-related CNV treated with submacular surgery can result in better-than-expected stable vision. Nevertheless, damage to the RPE leads to loss of photoreceptors and choriocapillaris that ultimately degrades vision (Fig. 14).⁹⁷

MACULAR TRANSLOCATION. Techniques and indications for macular translocation are evolving. Machemer and Steinhors⁹⁸ initially reported a technique using 360-degree retinotomy with intraoperative removal of CNV and scleral resection. This has evolved to scleral imbrication with limited macular translocation. Postoperative laser photocoagulation is performed to the CNV. Complications are common. There is a 10% to 20% retinal detachment rate, with occasional proliferative vitreoretinopathy. Limited translocation with scleral imbrication results in formation of a retinal fold, which is usually directed inferiorly by detaching the inferior retina. As much as 30% of the time, the fold may go through the fovea.⁹⁹ As more experience is gained with macular translocation, its place in the treatment of CNV from multiple causes will become more clear.

TABLE 1. Conditions Associated With Subretinal Neovascularization

  Hereditary/Congenital
  Best's vitelliform dystrophy
  Adult-onset foveal pigment epithelial dystrophy (adult vitelliform dystrophy)
  Choroideremia
  Coloboma (chorioretinal, retinal)
  Fundus flavimaculatus (Stargardt's disease)
  Osteogenesis imperfecta
  Retinitis pigmentosa
  Dominant drusen
  Optic nerve pits
  Degenerative
  Age-related macular degeneration
  Angioid streaks
  Drusen (optic nerve head)
  Myopia
  Inflammatory/Infections
  Acute multifocal posterior placoid pigment epitheliopathy
  Birdshot choroidopathy
  Histoplasmosis
  Recurrent multifocal choroiditis (punctate inner choroiditis, multifocal choroiditis)
  Rubella
  Fungal chorioretinitis (Candida, Aspergillus, others)
  Sarcoidosis
  Serpiginous (geographic helicoid peripapillary choroiditis)
  Toxoplasmosis
  Vogt-Koyanagi-Harada
  Sympathetic ophthalmia
  Toxocara canis
  Syphilis
  Traumatic
  Intraocular foreign body
  Photocoagulation (endolaser photocoagulation)
  Cryotherapy
  Subretinal fluid drainage (internal, external)
  Scleral perforation
  Tumor
  Choroidal nevus
  Choroidal osteoma
  Combined retinal---retinal pigment epithelium hamartoma
  Choroidal melanoma
  Choroidal hemangioma
  Metastatic carcinoma
  Other
  Chronic retinal detachment
  Neovascularization of the ora serrata
  Idiopathic subretinal neovascularization of the young
  Retinal telangiectasis

HISTOPLASMOSIS

The presumed ocular histoplasmosis syndrome is a major cause of visual impairment in the central and eastern United States, especially in the Ohio and Mississippi River valleys. Histoplasma capsulatum is a dimorphic soil fungus that is acquired through the respiratory tract and usually results in an asymptomatic, self-limited infection, but it can develop into a disseminated infection in immunocompromised persons.^100,101 Presumed ocular histoplasmosis syndrome has been clinically linked to H. capsulatum, even though organisms are usually not found in autopsied eyes of patients known to have the disorder.

The triad of ocular findings in histoplasmosis comprises peripheral, punched-out, atrophic choroidal lesions; peripapillary choroidal scars; and macular lesions with or without SRNV. The peripapillary disc scarring consists of choroidal and RPE atrophy, with a line of pigment at the disc margin of the scar, as opposed to some normal eyes with optic nerve crescents that have pigment at the outer border of the scar. The active lesion of histoplasmosis is a small round area of choroiditis that can create a small overlying sensory retinal detachment. This picture can be difficult to differentiate from active SRNV. The areas of active choroiditis are not associated with vitreous cells. The lesions become quiet and create atrophic, and later pigmented, scars called histo spots, which appear symptomatically during the patient's lifetime.

SRNV may be associated with a previous area of histoplasmosis scarring (Fig. 15). The visual prognosis is poorer for eyes with SRNV and a perifoveal choroidal scar in the fellow eye. If such a scar exists, there is a 20% to 25% chance of the development of a neovascular membrane in 5 years; without such scars, there is only about a 4% chance of SRNV developing from the scarring around the disc.^102,103 A follow-up evaluation of patients in the MPS showed that choroidal neovascularization is often preceded by an atypical histo spot.¹⁰⁴ Macular SRNV, however, has been described in the absence of preceding atrophic scars.¹⁰⁵ Prognosis for vision remains good: 81% can be expected to have 20/20 or better acuity after 5 years when the fellow eye has had CNV.¹⁰⁴

Laser treatment has been shown to be an effective treatment of SRNV associated with presumed ocular histoplasmosis syndrome and located 200 μm or more from the center of the foveal avascular zone.¹⁰⁶ In the ocular histoplasmosis section of the MPS, 34% of untreated eyes versus 9% of treated eyes suffered severe visual loss of six or more lines after 18 months of follow-up. Corticosteroids are not believed to be of benefit for the associated SRNV.

Subretinal surgery for the removal of subfoveal CNV has been performed in ocular histoplasmosis. Berger and colleagues¹⁰⁷ reported that acuity improved by two lines in 35%, was unchanged in 44%, and worsened in 21%. Recurrence of the subfoveal CNV occurred in 38% and was more common in eyes that had undergone preoperative laser photocoagulation. The median time to recurrence was 5 months. Perfusion of the subfoveal choriocapillaris may have implications for visual improvement after subfoveal surgery.¹⁰⁸ If subfoveal membranes have an extrafoveal ingrowth site, the prognosis is better for visual recovery as opposed to a subfoveal or unidentifiable ingrowth site.¹⁰⁹ Melberg and colleagues¹¹⁰ studied recurrences and found that recurrent lesions were extrafoveal in 16%, juxtafoveal in 18%, and subfoveal in 66%. These eyes were treated with laser photocoagulation, further subfoveal surgery, or observation. Eyes amenable to laser did better in terms of vision.

The differential diagnosis of presumed ocular histoplasmosis syndrome includes a group of diseases of unknown cause that create multifocal choroidal scarring and are known variously as recurrent multifocal choroiditis, punctate inner choroidopathy, multifocal choroiditis with progressive subretinal fibrosis, and pseudohistoplasmosis.^111–114 Many patients who have these diagnoses also have associated vitreous inflammation, and the pattern of scarring changes with time more than in presumed ocular histoplasmosis syndrome.

MYOPIA

Degenerative, or pathologic, myopia is one of the leading causes of blindness in the world.¹¹⁵ The chorioretinal lesions that accompany myopia have been attributed either to progressive axial elongation or to a genetically determined atrophic process independent of anatomic eye wall changes.^116–118

The myopic disc is oval, with a long vertical axis, and may appear tilted or oblique; it often has a temporal concentric area of depigmentation, called a temporal crescent. Posterior pole staphyloma may be present early in life, and its incidence increases with age.¹¹⁹ The sensory retina, RPE, and choroid are thinned, and the underlying choroidal vessels are prominent (Fig. 16). Chorioretinal atrophy may be extensive and may appear as round or irregular yellow-white areas with focal deposits of pigment.

The margins of atrophy are well demarcated. There is a tendency for multiple small areas of focal atrophy to coalesce into large lesions that may involve the fovea and result in visual loss.

Lacquer cracks are linear or stellate ruptures in Bruch's membrane and RPE and are typical of pathologic myopia. They are usually fine, irregular in caliber, yellowish-white, horizontal, branching breaks that occur most often in the macular region (Fig. 17).

The occurrence or extension of a lacquer crack can be associated with a macular hemorrhage that may occur in the absence of SRNV. Because of the close anatomic relationship between Bruch's membrane, the RPE, and the choriocapillaris, a break in Bruch's membrane can result in a small, focal, round subretinal hemorrhage that usually resolves, leaving good central vision.^120,121

SRNV may occur in 5% to 10% of the myopic population; with highly myopic eyes, the chances of SRNV may exceed 40%.¹²² SRNV usually exhibits a small, juxtafoveal gray lesion with a shallow overlying sensory detachment and subretinal hemorrhage (Fig. 18). With time, an unusual pigmentary response, called a Fuchs spot, results in RPE hyperplasia over the SRNV. Progressive atrophy often develops around the Fuchs spot. The SRNV of pathologic myopia does not have the same proliferative potential as the SRNV of AMD. The visual prognosis in pathologic myopic eyes with SRNV is not clearly defined. Some investigators report the visual acuity stabilizing after an acute decrease in vision associated with the SRNV-related subretinal hemorrhage (Forster's spot).

The benefits of laser treatment for myopic SRNV are not well established. Some studies have shown an initial benefit with laser treatment of juxtafoveal SRNV, but it seems to have questionable long-term advantage.^115,120,123 Laser treatment in pathologically myopic eyes carries additional risks, with the precise location of the foveola difficult to determine. Moreover, the laser scar tends to enlarge with time and may extend through the fovea.^124–126 Additional, although experimental, treatment modalities include submacular surgery, macular translocation, and photodynamic therapy for CNV associated with high myopia.

ANGIOID STREAKS

Angioid streaks develop from pathologic alterations of the RPE, Bruch's membrane, and the choriocapillaris.^125,127 The primary change is a linear, cracklike dehiscence in Bruch's membrane. These cracks, called angioid streaks, radiate from the peripapillary area with irregular or serrated margins throughout the fundus. Angioid refers to the similarity between these reddish-brown cracks and blood vessels (Fig. 19).

SRNV may grow through the breaks in Bruch's membrane and result in disciform macular scarring. Vision may be lost because of slowly progressive macular atrophic changes related to the angioid streaks. Patients may also develop a serous pigment epithelial detachment associated with SRNV.

Angioid streaks are found in several conditions, including pseudoxanthoma elasticum (GronbladStrandberg syndrome), osteitis deformans (Paget disease), sickle cell anemia, senile elastosis (aging), and fibrodysplasia (Ehlers-Danlos syndrome).^59,127–131

Pseudoxanthoma elasticum is a systemic disease of elastic tissue primarily affecting the eyes, the cardiovascular system, and the skin. Its name derives from the peculiar confluent, yellowish papules (plucked chicken-skin appearance) that develop on the flexural surfaces of the neck and antecubital fossa. Most patients with pseudoxanthoma elasticum have angioid streaks. Other findings in pseudoxanthoma elasticum include peau d'orange pigmentation, caused by the mottled blending of posterior confluent yellow RPE lesions with the normal orange peripheral pigmentation; reticular pigmentary dots, occurring in 10% to 15% of patients with pseudoxanthoma elasticum and perhaps indicating a predisposition for the development of SRNV; punched-out RPE atrophic spots, often accompanied by central pearly white, crystalline lesions; and optic nerve drusen.^{59,125,127–129,132–134}

Paget disease, characterized by irregular thickening, rarefaction, and deformity of bone, results in calcification of Bruch's membrane and angioid streaks (10% to 15%). These patients may develop SRNV and disciform scarring, and some may show the peau d'orange pigmentary discoloration seen in pseudoxanthoma elasticum.^59,135,136

SRNV associated with angioid streaks may be treated with laser, which may improve the visual prognosis in some eyes. Other experimental treatments remain unproven.

CHOROIDAL RUPTURE

Traumatic choroidal ruptures may result from blunt ocular trauma (Fig. 20). They appear as crescent-shaped gaps in the RPE-Bruch's membrane-choriocapillaris complex. The rupturing of the Bruch's membrane and choriocapillaris can result in bleeding under the RPE and sensory retina. After the hemorrhage clears, the large curvilinear ruptures can be seen. They often run parallel, or concentric, to the disc and often pass through or near the fovea (Fig. 21). These choroidal ruptures may be associated with the development of SRNV. There is occasionally a history of trauma that leads to subretinal hemorrhage and SRNV. Laser treatment may be effective in treating SRNV that threatens the fovea.^137,138

Most patients with epiretinal membranes are asymptomatic. Those with more severe epiretinal membranes may notice blurred vision, distortion, diplopia, and even profound central visual loss. Most epiretinal membranes remain stable, although approximately 25% of eyes have progressive loss of visual acuity.^59,139,140 The thickness of the membrane on optical coherence tomography may correlate with the degree of visual loss.¹⁴⁶ Angiography may show vascular leakage and macular edema due to the membrane.

The ophthalmoscopic findings depend on the severity of the epiretinal membrane. A membrane may be present as a glistening, refractile sheen overlying the macula (cellophane maculopathy). More severe epiretinal membranes may wrinkle or pucker the macula. Vascular tortuosity and tethering, foveal ectopia, sensory retinal detachment, punctate hemorrhages, irregular vascular dilation, leakage and macular edema, cotton-wool spots or fluffy areas of whitish inner retina (presumably related to traction-induced axoplasmic stasis), and pseudoholes may also occur. A pseudohole occurs when an epiretinal membrane contracts and draws in the rim of the foveal depression, steepening the slope of the foveal depression. This alters the foveal light reflex, making it appear a darker red. The combination of a darker-red foveola and the steeper slopes of the depression underlying the epiretinal membrane may give the impression of a full-thickness macular hole (i.e., a pseudohole).

Different cell types may account for the formation of epiretinal membranes, although fibrous astrocytes have been implicated most frequently.^147–151 Other cell types, including fibrocytes, RPE cells, myofibroblasts, macrophages, inflammatory cells, hyalocytes, and vascular endothelial cells, have also been described as contributing to epiretinal membranes. Myofibrocytes may be a more common cell type in younger patients (aged 30 or younger).^152,153

When epiretinal membranes cause significant visual loss, surgical removal is considered. The surgery involves removing the posterior vitreous, elevating the epiretinal membrane edge with a fine instrument, and tangentially peeling the epiretinal membrane from the retina with an intraocular foreign body forceps (Fig. 22). The chances of improved vision with posterior vitrectomy and epiretinal membrane stripping are 70% to 80%.^{145,154–156} Patients can expect to regain approximately half of the vision lost due to the development of the membrane, with vision improving up to 9 months after surgery; however, most of the visual improvement comes in the first 2 or 3 months after surgery. Even with macular edema, vision can be expected to improve at least a few lines.¹⁵⁶ Juvenile idiopathic epiretinal membranes can also be successfully treated with vitrectomy.¹⁵⁷

The most common complication of vitrectomy and epiretinal membrane stripping surgery is increased nuclear sclerosis, occurring during the subsequent years in most patients.^145,158,159 Many of these patients require cataract surgery within several years of their vitrectomy. The surgery also carries with it the other complications associated with any posterior vitrectomy.

Spontaneous separation of the posterior vitreous occurs in approximately 11% of cases over 5 years.¹⁶⁸ Macular detachment secondary to vitreoretinal traction has also been reported.¹⁶⁹ Vitrectomy is indicated if progressive macular degeneration, macular detachment, cystic change, and decreased vision are present. The vitreoretinal anatomy is readily observed at the time of surgery. In some eyes, the gentle traction created by the initial central vitrectomy disengages the vitreous from the macula. In most cases, a tapered extrusion needle, an intraocular foreign body forceps, or a membrane-peeling instrument is needed to tease the posterior hyaloid face from its macular attachment. Histologic studies show that the fibrous astrocyte is the predominant cell type. Myofibrocytes can be present as well and can cause retinal traction.¹⁷⁰

When the vitreomacular traction is removed, the retinal vascular leakage usually stops, although the cystic retinal changes may remain unchanged. Macular cystic changes not associated with retinal vascular leakage may also disappear after surgical release of the vitreomacular traction. Visual acuity is seen to improve two lines in up to 75% of cases unless a macular traction detachment is present.^169,171,172 Forty percent may achieve better than 20/50 vision.¹⁷¹

TABLE 2. Conditions Associated With Macular Edema

  Retinal Vascular Diseases
  Diabetic retinopathy
  Venous occulsion (Branch vein occlusion, Central retinal vein occlusion)
  Radiation retinal vasculopathy
  Retinal telangiectasis (idiopathic juxtafoveal telangiectasis, Coats disease, Leber's miliary aneurysms)
  Retinal arterial macroaneurysm
  Retinopathy of prematurity
  Retinal Inflammatory Diseases
  Birdshot chorioretinopathy
  Pars planitis
  Sarcoidosis
  Toxoplasmosis
  Posterior scleritis
   Behçet's
  Cytomegalovirus
  Other intraoclar retinitis and infections
  Tumors
  Choroidal hemangioma
  Combined retinal---retinal pigment epithelium hamartoma
  Choroidal melanoma
  Toxic
  Epinephrine
  Nicotinic acid
  Latanoprost (Xalatan)
  Postoperative
  Cataract surgery (Irvine-Gass syndrome)
  Retinal detachment
  Keratoplasty
  Refractive surgery
  Photocoagulation (especially panretinal photocoagulation for proliferative diabetic retinopathy)
  Cryopexy
  Hereditary
  Familial exudative vitreoretinopathy
  Goldmann-Favre syndrome
  Infantile cystoid macular edema
  Juvenile X-linked retinoschisis
  Retinitis pigmentosa
  Optic pit
  Dominant cystoid macular edema
  Other
  Vitreoretinal traction syndrome
  Epiretinal membranes
  Subretinal neovascularization
  Postpartum cystoid macular edema
  Idiopathic cystoid macular edema

CME and visual loss may develop weeks to years after cataract surgery. This postoperative visual decline was first noted after intracapsular surgery in the 1950s; it was later demonstrated by fluorescein angiography to be due to intraretinal cysts.^173–176 These cysts result either from edematous, degenerating Müller cells or from expansion of extracellular spaces in the inner plexiform and inner nuclear layers caused by serous exudate.^177–179 The Irvine-Gass syndrome, initially referred to as CME after intracapsular cataract extraction, is often used to describe visually significant CME that follows cataract surgery, regardless of extraction technique or intraocular lens implantation (Fig. 24).

Although 50% to 70% of patients who have had an intracapsular cataract develop retinal vascular leakage on fluorescein angiography, few show clinical evidence of cystic change.^59,180 Extracapsular cataract extraction is associated with CME much less frequently than is intracapsular cataract extraction.¹⁸¹ Phacoemulsification is associated with CME in less than 0.5% of cases.¹⁸² YAG capsulotomy increases this risk to 1.2%.¹⁸³ A complete posterior vitreous detachment is usually present, and generally there is an inflamed disc on fluorescein angiography. Rarely, there is a vitreomacular attachment accompanying the wet macula. There may be photophobia and conjunctival injection if vitreous strands to the wound are present.

Eyes with vision that decreases to the 20/70 level or worse have roughly a one in three chance of spontaneous improvement.¹⁸⁴ Two thirds of patients with intracapsular cataract extraction with CME regain 20/30 or better vision 3 to 12 months after surgery.⁵⁹ Occasionally, spontaneous visual improvement takes place years after surgery, leaving 0.5% to 2% of patients with uncomplicated intracapsular cataract extraction with permanent visual loss secondary to CME.⁵⁹ The incidence is roughly the same for extracapsular cataract extraction and posterior lens implant, although it is increased with iris fixation and anterior chamber lenses.^185,186 More recently, it has been shown that the thickness of the macula correlates better with visual function than does leakage on angiography or visual acuity.¹⁸⁷

The pathogenesis of CME remains uncertain. Depending on the clinical situation, varying theories can be used to understand the pathogenesis. Considerable experimental and clinical evidence implicates prostaglandin-mediated inflammation. Prostaglandins are compounds derived from cell membrane phospholipids, specifically arachidonic acid. Prostaglandins and related compounds increase microvascular permeability, resulting in breakdown of the blood-ocular barrier and CME. In the event of vitreous incarceration to a cataract wound, a mechanical force may be exerted on the vitreomacular interface, leading to vascular decompensation and leakage.

TREATMENT

If CME has been present for 2 or more years, there likely has been irreversible change in the macula.¹⁸² Therefore, prompt treatment on recognition of the disorder is warranted. Studies have shown that prophylactic treatment before cataract surgery can be effective in reducing the incidence of angiographic CME and clinically significant macular edema.¹⁸⁷ Diclofenac (Voltaren; Ciba Vision) and flurbiprofen (Ocufen) are as effective as prednisolone for prophylaxis.¹⁸⁸

The pharmacologic treatment of CME has been directed at blocking prostaglandin activity, either by inhibiting the formation of arachidonic acid with corticosteroids or inhibiting the formation of prostaglandins from arachidonic acid with indomethacin (Indocin), diclofenac, or ketorolac (Acular; Allergan, Irvine, CA). In most cases, topical medication is initiated first.

If CME is refractory to topical medicines, repository steroids should be considered. Methylprednisolone acetate (Depo-Medrol) or triamcinolone acetonide (Kenalog) can be given in the sub-Tenon's space or in the retrobulbar location for a more concentrated and constant dose of anti-inflammatory medicine.¹⁸⁹ The usual dose is 40 mg delivered in 1 ml solution. The injection can be repeated after 3 months if there is no improvement. Most specialists stop after a total of three doses if there has been no improvement, because there are no prospective studies establishing the duration and frequency of injections. Caution must be used in eyes known to be sensitive to steroid-induced elevation of the intraocular pressure.

Acetazolamide (Diamox) has been used for CME associated with retinitis pigmentosa. Experimentally, acetazolamide facilitates transport of water from the subretinal space, across the retinal pigment epithelium, into the choroid.¹⁹⁰ It has been shown to lead to resolution of CME in postoperative pseudophakes as well.¹⁹¹ Dorzolamide (Trusopt), a topical carbonic anhydrase inhibitor, does not appear to be effective in treating CME associated with retinitis pigmentosa or chronic uveitis.^192,193 Another carbonic anhydrase inhibitor, methazolamide (Neptazane), does not appear to be as effective as acetazolamide in CME associated with retinitis pigmentosa.¹⁹⁴

In eyes with chronic CME, vitreous incarceration, photophobia, and peaked pupil, vitrectomy may be beneficial.¹⁸⁴ In postoperative eyes where there is an intact posterior capsule and an in-the-bag intraocular lens, justification of vitrectomy is less clear. Macular grid photocoagulation has been attempted in uveitis-associated CME, with resolution of the edema and improvement or stabilization of vision in some patients.¹⁹⁵

Secondary causes of juxtafoveal telangiectasis include retinal venous obstruction, macroaneurysms, diabetes, radiation retinopathy, carotid occlusive disease, sickle retinopathy, retinal hemangiomas, retinal astrocytoma, intraocular inflammation, Eales disease, and tapetoretinal degenerations.¹⁹⁷ These should be excluded to classify a patient as having IJRT. It has been suggested that patients with juxtafoveal telangiectasis be tested specifically for diabetes, because patients with early background diabetic retinopathy may have changes very similar to IJRT.

The ophthalmoscopic appearance varies between the subsets of IJRT. Table 3 summarizes the features of the different groups. Group 1A patients are usually male with unilateral involvement. Most are white. The area of involvement is located temporal to the fovea and is often more than 2 disc diameters and straddles the horizontal raphe. There is vascular compromise of the telangiectatic vessels with exudate and retinal edema. Gass believed that this is developmental and in the spectrum of Coats syndrome. Loss of vision is due to exudate into the fovea and macular edema, often with cystoid change. Laser photocoagulation to prevent accumulation of lipid in the fovea is helpful. Spontaneous resolution of the edema with improvement in vision can occur over many years. Close to half of these patients have peripheral telangiectasis.¹⁹⁸ Group 1B patients are similar except that the involved area is smaller (Figs. 25 and 26). Laser treatment is effective for macular edema and exudates.

TABLE 3. Idiopathic Juxtafoveolar Retinal Telangiectasis

Group 2A is the most common form of IJRT (Fig. 27). The patients are older than in group 1, with an equal incidence of men and women. The disease occurs bilaterally. Gass believed that this is probably an acquired disorder. Visual loss occurs from atrophy of the foveal retina rather than exudation or retinal edema. However, leakage does occur and can be shown angiographically.¹⁹⁹ This is centered within 1 disc diameter of the fovea. Patients have metamorphopsia or decreased vision.

Gass described five stages in the evolution of this group. The earlier stages are often noted in the less-involved eye of symptomatic patients.

Stage 1 involves staining of the vessel wall due to its thickening. This is often in the deep capillary plexus. Green and associates²⁰⁰ showed histologically that there is thickening of the basement membrane with loss of endothelial cells and pericytes, very similar to diabetic vascular change. These capillaries do not adequately carry on metabolic exchange, leading to derangement in retinal function with eventual loss (stage 2). As the outer capillary bed becomes more involved, right-angled venules from the inner retina form to drain the bed (stage 3). Further metabolic compromise leads to loss of photoreceptor cells and consequently a decline in visual acuity. Gass did not explain the role of the RPE in the nourishment of the photoreceptors in relation to this disease. With loss of retinal tissue, a lamellar macular hole may form (stage 4).^197,201 This loss of retinal cells induces intraretinal neovascularization, SRNV, exudation, and hemorrhage. RPE cells can form pigment plaques after having migrated into the retina. Development of neovascularization can lead to rapid loss of vision. In Gass' study, no patient had a neovascular complex that was amenable to treatment, either because loss of vision was due to foveal atrophy or the neovascularization was located below the fovea.

In Gass' study, patients who were treated before the development of neovascular membranes often did worse. There have been two patients who have had subretinal hemorrhage after laser treatment. These were probably due to SRNV that developed after treatment.^197,202 Patients who seem to have group 2A lesions have been treated successfully with laser.²⁰³ However, a more recent report of 14 patients²⁰⁴ did not show any improvement or stabilization of vision after parafoveal laser treatment. Retinal hemorrhage, vascularized retinal scars, and RPE changes can develop after laser treatment, but this does not seem to affect visual acuity. Consequently, the treating ophthalmologist and the patient must decide on the best course of action. A stereo-angiogram showing leakage, combined with a recent decline in vision, may warrant a trial of treatment. Untreated, vision may worsen, stabilize, or, rarely, improve.

Golden refractile deposits near the inner surface of the retina were seen to occur in the reports by Gass^196,197 and Moisseiev and colleagues.²⁰⁵ The number of deposits does not appear to correlate with the degree of visual loss. These may be the footplates of degenerating Müller cells, as Gass suggested, or calcium or cholesterol deposits. Group 2A patients have developed diabetes, and some persons with diabetes have had disease resembling group 2A IJRT. Consequently, a fasting blood sugar may be advisable in these patients.

There are few reports of group 2B IJRT occurring in families and affecting younger patients. This group does not show right-angled venules, retinal deposits, or pigmented plaques but does display SRNV. Both patients in Gass' paper were males who had bilateral disease with visual loss to 20/70.

Group 3A disease has been seen in women. There is telangiectasis with mild exudation. The major finding is capillary occlusion with enlargement of the foveal avascular zone. Visual acuity, though, is better than would be expected and may be maintained for years. The disease is bilateral, and there can be familial involvement. Arthritis, polycythemia vera, and hypoglycemia can be associated.

Interestingly, Mansour and Schachat²⁰⁶ found the foveal avascular zone to be smaller in IJRT; however, they did not use the current classification of IJRT. Because group 2A is the most common form of IJRT, most patients studied probably belonged in this group.

Group 3B patients have an enlarged foveal avascular zone with associated central nervous system vasculopathy. They are often men, and the disease can run in families. Thus, all group 3 patients should be evaluated for systemic diseases.

IJRT probably represents different diseases. Group 1 is more often associated with leakage and is in the spectrum of Coats syndrome. Group 2 patients display some leakage, but ultimately visual loss is from foveal atrophy. Group 3 is associated with changes in the foveal avascular zone. Photocoagulation is useful in group 1 and often group 2 but would not be beneficial, theoretically, in group 3. Treatment spots are usually 100 to 500 μm and applied as light burns in a grid pattern to the areas of leakage outside the foveal avascular zone. The vessels do not need to be treated directly. Neovascular membranes, when treatable, are treated with confluent, more moderate burns.

THEORY

Various theories have been advanced attempting to explain the pathogenesis of macular holes. Historically, patients diagnosed with a macular hole usually had a history of significant ocular trauma. Consequently, trauma was believed to be the cause of macular holes. Cystic degeneration at the fovea was noted by Fuchs and Coats, leading to the theory that trauma or vascular changes could cause cystoid changes in the fovea. The cystic spaces would then coalesce to form a macular hole.²¹⁹ Involutional macular thinning was proposed by Morgan and Schatz.²¹⁴ It was believed that choroidal vascular changes led to foveal and RPE changes. Cystic degeneration then caused permanent architectural changes at the fovea and RPE, leading to involutional macular thinning. Vitreous traction at the thin retina would then lead to a macular hole. The vitreous has been implicated in the pathogenesis of macular holes since the early 20th century.²¹⁹ Initially, vitreous bands were thought to develop, although none were clinically observed. Worst²²⁰ described a premacular vitreous bursa which was attached to the macula and could exert anteroposterior traction on the fovea. However, no anteroposterior traction bands were clinically observed that would have led to a macular hole. It is generally believed that detachment of the posterior vitreous is not a causal event in the evolution of a macular hole.²¹⁹

CLASSIFICATION

Gass²²¹ is credited with the currently accepted classification and theory of macular hole formation. Tangential vitreous traction is thought to be the cornerstone of premacular and macular hole formation.^212,222 Tangential traction of the prefoveal cortical vitreous detaches the foveola, creating a yellow spot 100 to 200 μm in diameter. This is a stage 1A hole (Fig. 28). Intraretinal xanthophyll is thought to impart the yellow color. As the fovea elevates, the yellow spot becomes a ring, a stage 1B lesion (Fig. 29). Vision is in the 20/25 to 20/70 range. Fine, radiating retinal striae may also be seen clinically. As the hole progresses, a dehiscence of the photoreceptors occurs at the umbo, creating an occult hole. As the prefoveal vitreous cortex separates, an eccentric hole is revealed. Detachment of the posterior hyaloid may occur, creating a pseudo-operculum. This is termed a stage 2 hole and is defined as being less than 400 μm in diameter. The yellow ring may disappear because traction is relieved with separation of the prefoveal vitreous cortex. Histopathologic studies of opercula show two types. Pseudo-opercula are composed of astrocytes, Müller cells, and internal limiting membrane. True opercula have glial elements as well as avulsed foveal cones.²²³ A stage 3 hole is reached when the hole enlarges to more than 400 μm in diameter (Fig. 30). This may occur because of myofibroblastic activity near the internal limiting membrane.²²⁴ Yellow, nodular deposits are seen on the surface of the RPE in half of stage 3 holes. Nearly all stage 3 holes have a cuff of surrounding neurosensory detachment. If a posterior vitreous detachment occurs (with a Weiss ring), a stage 4 hole is reached. Vision is between 20/70 and 20/400 in stage 3 and 4 holes.

DIAGNOSIS

Diagnosing a macular hole is best done clinically with either a contact or non-contact lens at the slit lamp. The main considerations in the differential are a fenestrated epiretinal membrane (a pseudohole) and lamellar macular holes. Useful clinical tests include the Watzke-Allen sign and the laser aiming beam test. Both tests are subjective. In the Watzke-Allen test, a narrow beam of light is focused on the retinal defect. The patient is then asked whether the light beam appears to narrow or whether there is a break in the narrow slit beam. In the laser aiming beam test, a 50-μm spot size is used; with a full-thickness macular hole, the spot disappears when placed in the area of the hole.²²⁵ Technologies such as scanning laser ophthalmoscopy and optical coherence tomography can elegantly show macular holes but are not widely available and may not add significant new information.²¹⁹ Lamellar macular holes do not progress to full-thickness macular holes.²¹² Scanning laser ophthalmoscope microperimetry can differentiate between a lamellar hole and a full-thickness hole by evaluation whether a scotoma is present.²²⁶

HISTOLOGY

Histopathologic analysis of eyes with full-thickness macular holes shows oval or round retinal defects with rounded retinal edges and a surrounding cuff of retinal detachment with subretinal fluid. Up to 79% have CME, and 68% have epiretinal membranes.^219,227 Surgically, Blain and coworkers²²⁸ found that an epiretinal membrane was removed in only 30% of cases. There is a variable amount of photoreceptor disruption in the area of neurosensory detachment. Madreperla and colleagues²²⁹ studied a treated macular hole and found the hole to be sealed by Müller cell processes; photoreceptors adjacent to the hole appeared normal. Rosa and associates²³⁰ also found that Müller cell proliferation in a postoperative macular hole case had closed the hole.

NATURAL HISTORY AND FELLOW EYES

The evolution of stage 1 macular holes to full-thickness macular holes was studied by the Vitrectomy for Prevention of Macular Hole Study Group.²³¹ The study was designed to compare surgery and observation for stage 1 lesions in patients with full-thickness macular holes in their fellow eyes. Although the study was terminated due to poor recruitment, it was found that 40% of those in the observation group progressed to full-thickness holes over 2 years, whereas 37% progressed in the vitrectomy group (not statistically significant). Another finding was that in eyes with stage 1 holes, visual acuity was predictive of progression to full-thickness holes. Eyes with acuity between 20/50 and 20/80 had a 66% rate of progression; eyes with acuity between 20/25 and 20/40 had a 30% risk of progression.²³² Most stage 2 macular holes go on to become stage 3 or 4 full-thickness macular holes irrespective of the presence of a full posterior vitreous detachment.²¹⁹

The Vitrectomy for Macular Hole Study Group also reported on vitrectomy versus observation for stage 2 macular holes.^233,234 Vitrectomy was performed with removal of the posterior hyaloid and fluid-gas exchange. After 1 year, 71% of eyes randomized to observation progressed to full-thickness macular hole, whereas only 20% of eyes assigned to surgery progressed. In eyes that developed full-thickness holes after surgery, the size of the hole was found to be smaller and reading ability was better than in observation eyes that progressed.

The risk to the fellow eye is reported as being between 3% and 22%.^189,235 More recently, the 5-year risk for normal fellow eyes was reported at 15.6%.²³⁶ Chew and colleagues²³⁷ found the rate of development of a new macular hole during follow-up in fellow eyes that were unaffected at baseline was 4.3% for 3 or fewer years of follow-up, 6.5% for 4 to 5 years of follow-up, and 7.1% for 6 or more years of follow-up. Spontaneous regression of the macular hole occurred in 8.6%. If the macula is normal and a posterior vitreous detachment is present, the risk is believed to be closer to 3%. In the presence of a stage 1 lesion and no posterior vitreous detachment, the risk is probably 40%.²¹⁹

TREATMENT

In 1991, Kelly and Wendel²³⁸ reported on vitrectomy with removal of the posterior hyaloid and fluid-gas exchange followed by postoperative face-down positioning to treat full-thickness macular holes. Their initial results were 58% anatomic success. In these successfully repaired eyes, vision improved by two lines or more in 73% (42% overall). In their follow-up study,²³⁹ anatomic success was achieved in 73%, with 55% showing visual improvement of two lines or more. They also suggested that holes of less than 6 months' duration have better outcomes. This appears to be confirmed by other studies (Fig. 31).^240,241

The critical step in surgery for macular holes involves removing the posterior hyaloid face, thereby relieving the traction forces on the hole. If an epiretinal membrane is present, it should be removed to facilitate flattening of the edges of the macular hole. Removal of the internal limiting membrane has recently been advocated by some surgeons.^242,243 One study found a 96% closure rate after internal limiting membrane removal versus a 71% closure rate without removal.²⁴²

Adjuvants had been advocated to encourage closure of the hole after surgery. Substances have included autologous blood and blood products,²⁴⁴ transforming growth factor β2,²⁴⁵ and thrombin. Transforming growth factor β2 was later found not to be effective,^246,247 and most surgeons have moved away from using autologous blood products.²⁴⁸ Tamponade of the break is then created by filling the vitreous cavity with a nonexpansile concentration of gas, either C3F8 or SF6. Strict face-down positioning is maintained for 7 to 14 days by patients with gas tamponade. When this position is maintained, debris may be seen in some cases on the corneal endothelial surface.

Air and silicone oil have also been used. The use of silicone oil requires removal of the oil in approximately 6 weeks. There can be slight progression of nuclear sclerosis. The oil should fill greater than 90% of the vitreous cavity.²⁴⁹

VISUAL OUTCOMES

The Vitrectomy for Treatment of Macular Hole Study Group evaluated surgery versus observation for stage 3 and 4 macular holes.²⁵⁰ Although follow-up was only 6 months, improvement in visual function was noted with macular hole surgery. More than three fourths had progression of nuclear sclerotic cataract, confounding the visual acuity testing. Other studies have noted continual improvement of visual acuity several years after surgery. In a recent study,²⁵¹ median acuity increased from 20/125 before surgery to 20/50 1 year after. Median acuity was 20/30 3 years after macular hole surgery. The authors found that progression of nuclear sclerotic cataract masks visual improvement in the first year. Patients consequently have good visual recovery after cataract surgery.

COMPLICATIONS

Significant complications have been reported with macular hole surgery. Patients may develop neck and shoulder pain from strict face-down positioning. Use of intraocular gas can cause intraocular pressure elevations in the postoperative period; this can usually be managed medically.²⁵² As with any vitreous surgery, especially with the use of gas, phakic patients will have progression of nuclear sclerosis.

Surgery involves forcible detachment and peeling of the posterior hyaloid face. This can lead to formation of retinal breaks and retinal detachment. It is recommended that an indirect, depressed ophthalmoscopic examination be performed during surgery before fluid-air exchange. Nevertheless, retinal breaks can develop in the postoperative period: the Vitrectomy for Treatment of Macular Hole Study Group reported a rate of 11%.²⁵³ Others have reported an incidence of retinal detachment and retinal tears between 1% and 14%.^239,254,255 One study found the average time between surgery and retinal detachment was 5.5 weeks.²⁵⁶ There is a higher likelihood that breaks will be located inferiorly.^254,256 These detachments can be treated with good anatomic and visual results. Heier and colleagues²⁵⁶ used vitrectomy techniques with scleral buckling to repair the detachments, reasoning that vitrectomy allows removal of all subretinal fluid by endodrainage, thus preventing postoperative accumulation of fluid in the posterior pole, and thereby opening the macular hole.

Visual field defects, some symptomatic, have been noted after uneventful macular hole surgery.^257–261 The incidence, when reported, ranges between 7% and 23%. Most commonly, a dense, wedge-shaped temporal scotoma is found on visual field testing. There can be segmental pallor of the optic nerve head along with defects in the nerve fiber layer corresponding to the visual field loss. The exact cause is unclear. Theories include trauma to the optic nerve during inducement of the posterior vitreous detachment or during the fluid-air exchange, compression of the nerve fibers by gas tamponade, or dessication of the nerve fiber layer during prolonged exposure to air before air-gas exchange.

The Vitrectomy for Macular Hole Study Group reported a 33% incidence of RPE alteration.²⁵³ Poliner and Tornambe²⁶² evaluated 12 successful macular hole repairs and found angiographic evidence of RPE swelling that resolved over time. However, a mottled fluorescence pattern was still seen. Steroids had no effect. Because the light pipe is held close to the macula during peeling of membranes from around the hole, phototoxicity may result; this can compromise visual recovery in an otherwise successful surgery.

Reopening of macular holes can occur either early in the postoperative period or after the intraocular gas has dissipated. Duker and colleagues²⁶³ reported a 4.8% incidence of late reopening. The mean time for reopening was 12.5 months but ranged from 2 to 22 months. Acute loss of vision was reported by patients, and visual recovery can occur with reoperation. The authors also reported that in one patient an epiretinal membrane sealed the hole and improved vision. Johnson and associates²⁶⁴ evaluated in-office air-fluid exchange for early reopening of macular holes 1 to 8 weeks after macular hole surgery. They were able to achieve closure of the hole in 74%, with improvement of vision in all cases. Ohana and Blumenkranz²⁶⁵ evaluated in-office laser treatment to the base of the hole followed by fluid-gas exchange. Yellow wavelength was used with a spot size of 50 to 100 μm. Twelve to 27 spots were placed one burn-width apart at 0.1-second duration and 45 to 100 mW power in a circular pattern to the RPE at the base of the open hole. The end point of the burn was a light-gray color. They were able to achieve an 87% closure rate with one or more in-office procedures. Vision improved in all patients whose holes were closed.

The initial visual complaint is usually blurred vision, although positive scotoma, micropsia, and metamorphopsia may also be noted.^{59,267,270,277,278} Visual acuity ranges from 20/20 to 20/200, but it is most commonly 20/40 or better.^59,267

The ophthalmoscopic appearance reveals a well-defined, somewhat round, shallow elevation of the sensory retina^59,270 (Fig. 32). Usually the serous fluid is clear, although in some cases it may appear turbid and may obscure the underlying choroidal vascular markings.^59,270 A light reflex may be seen along the margin of the serous retinal elevation. In some cases, when central serous retinopathy has been present for several weeks, fine yellow subretinal precipitates may be visible on the back surface of the elevated retina.^59,267,270 A small detachment of the RPE is frequently detectable in the area of the serous retinal elevation. Usually the RPE detachment is small and appears as a grayish or yellowish, well-circumscribed elevation at the level of the RPE. Sometimes the RPE detachment is outside the area of apparent sensory retinal detachment, or several RPE detachments may be detectable. Occasionally, an RPE detachment without an overlying serous retinal detachment is observed.⁵⁹ Rarely, the area of the RPE detachment is obscured by a whitish fibrinous subretinal exudate overlying its surface.⁵⁹

In the severe, recurrent form of this disease, the retinal detachment may extend from the macular or optic nerve area to the inferior retinal periphery in a teardrop shape, forming a dependent retinal detachment.²⁷⁹ Chronic fluid accumulation may produce extensive depigmentation and alterations of the RPE (Fig. 33). In some chronic cases, lipid retinal exudate, retinal telangiectasis, pigment migration, and CME may be observed.²⁷⁹ Another unusual variant of central serous retinopathy presents as a bullous sensory retinal detachment with shifting fluid, turbid subretinal fluid, and multiple RPE detachments.^280–282

In a study of multifocal central serous disease with exudative retinal detachment and subretinal fibrosis, Sharma and colleagues²⁸³ found the macula to be involved in the detachment 72% of the time. Corticosteroid therapy was found to be of no benefit, whereas laser therapy resulted in resolution of the exudative retinal detachment in all cases. Improvement of visual acuity by greater than 2 lines was obtained in 69%. A mean of 6.7 leaks was found.

Fluorescein angiography usually demonstrates a small area of early hyperfluorescence and leakage near the margin of the RPE detachment.^59,268 Occasionally, the leak rises superiorly like a smokestack and spreads to fill the serous retinal detachment. Convection currents within the serous retinal elevation are believed to influence and cause the superiorly rising leak.²⁸⁴ Most cases (90%), however, do not demonstrate this appearance; they show, instead, a focal area of leakage that spreads in a diffuse manner.^268,271 Usually, only one area of leakage occurs, which is most frequently within 1 mm of the central fovea and located superonasally.^266,271 The active leak in some cases, however, is outside the macula. Although bilateral involvement occurs in approximately 20% of cases,^59,277 careful examination of the fellow eye shows evidence of previous or current disease in one third to two thirds of patients.²⁷⁷ RPE detachments or small areas of RPE disturbances can be demonstrated in such cases.

In severe, recurrent, or chronic cases, alterations and depigmentation of the RPE may alter the angiographic appearance. In such cases, mottled diffuse hyperfluorescence may be seen in the macular area. A distinct smokestack leak is usually not seen; rather, one or more small leaks, or hot spots, or a diffuse ooze is present. In some of these cases, large vertically oriented tracts or gutters of RPE depigmentation are evident, extending from the posterior pole to the inferior periphery.

NATURAL HISTORY

Central serous retinopathy is usually a self-limited disease with a good prognosis for visual recovery.^{59,267,269,270,285} Spontaneous reattachment of the retina occurs in most cases in 3 to 6 months,^{265,269,277,285} after which visual acuity improves and continued subjective improvement may be noted for 6 or more months. Despite this improvement, some patients may be aware of a mild persistent visual deficit, metamorphopsia, or micropsia.^267,269,277 Some patients with prolonged or recurrent episodes develop some degree of permanent reduction in the visual acuity to 20/200 or less.^265,276

Recurrences affect 20% to 50% of patients.^{59,270,277,285–287} When a recurrence develops, the leakage area is most frequently within 500 μm of the previous leakage area.²⁷¹ The prognosis for visual recovery is progressively poorer with each recurrence.^269–288

PATHOGENESIS

The cause of central serous retinopathy is not known. Similar psychological and personality profiles are noted in many patients with central serous retinopathy. A major life stress, either work-related or personal, is present in many persons shortly before the development of the disorder.²⁷⁸ One study evaluated psychological profiles and found that a type A personality profile, particularly a hard-driven and competitive personality, was much more common in patients with central serous retinopathy than in the control group.²⁸⁹ It has been postulated that higher plasma catecholamine levels in these patients may play a role in formation of the serous detachments. Similar detachments have been produced in monkeys after intravenous injections of epinephrine, suggesting a possible mechanism by which a personality trait may predispose to central serous retinopathy.

Adrenocorticoid and glucocorticoid steroids have been associated with central serous retinopathy. Gass and Little²⁹⁰ reported on three patients who developed central serous retinopathy with bullous retinal detachment after institution of oral steroid therapy. Two of the patients had a history of chronic recurrent retinal detachments before institution of corticosteroid treatment. In one patient, bilateral chronic inferior retinal detachment developed. All three patients had severe permanent visual loss in one or both eyes. Haimovici and colleagues²⁹¹ reported on six patients who developed central serous retinopathy with inhaled or intranasal steroid therapy. Retinopathy developed between 1 day and 7 years after institution of steroid treatment for asthma, bronchitis, or allergic disorders. Leakage resolved in patients who discontinued the steroids. Three patients continued using steroids; retinopathy resolved in two and improved in the third. Three others stopped steroids, with resolution of central serous retinopathy. Glucocorticoids may lead to central serous retinopathy by increasing catecholamine release. This could lead to pump dysfunction at the RPE or increased permeability of the choroidal vasculature.²⁹¹ Zamir²⁹² reported on one patient who developed bilateral central serous retinopathy after intramuscular synthetic adrenocorticotrophic hormone (ACTH) treatment for arthritis. The retinopathy resolved 2 months after discontinuation. Again, RPE pump dysfunction or vascular permeability is hypothesized to lead to central serous retinopathy.

The exact physiologic alterations that occur to produce the characteristic RPE leak associated with central serous retinopathy are not clear.^293,294 The RPE has a tremendous capacity to remove fluid from the subretinal space.²⁹³ For serous retinal detachment to form and be maintained, there must be an alteration in the net balance of fluid flow into the subretinal space. A focal leak in the RPE may produce a serous retinal detachment because of a dysfunction in a larger area of the RPE that prevents adequate removal of this fluid. The serous retinal detachment then increases until enough healthy RPE is exposed to this fluid and begins to pump it into the underlying choriocapillaris. At this point, the broken equilibrium is divided equally between the rate of fluid influx and efflux. How the RPE detachment that is associated with many cases of central serous retinopathy occurs is not clear.

TREATMENT

Laser photocoagulation of the RPE leak is associated with shortening the duration of the serous detachment but has not been shown to be of benefit in terms of final visual acuity or recurrence.^{266,269,286,287,295–300} Khosla and colleagues³⁰¹ reported that laser treatment is associated with significant loss and slower recovery of contrast sensitivity.

Laser treatment is not necessary in most situations because of the generally self-limited nature of central serous retinopathy and the good visual prognosis. If a serous retinal detachment has been present 10 to 12 weeks, or if examination reveals retinal degenerative change, laser treatment is considered.^288,302,303 At that time, if the location of the leak is 500 μm or more from the center of the fovea, treatment is directed to the leaking area using a 200-μm spot size and enough energy to achieve a light intensity burn.^59,288,302 Treatment within 500 μm of the foveal center is believed to carry an increased risk of subsequent SRNV development. After laser treatment, the serous retinal detachment resolves within 1 to 4 weeks.^274,296,304 Indirect treatment in the area of the sensory retinal detachment but away from the active leak has been demonstrated to be ineffective.²⁸⁷ There is no evidence to indicate any treatment benefit from corticosteroids,²⁸⁵ and some have suggested that they may exacerbate central serous retinopathy.^290,305

Laser treatment for central serous retinopathy that has persisted for 4 months appears to shorten the duration of the serous detachment, to improve final acuity, and to decrease the incidence of recurrence. There may be some benefit of using dye yellow versus argon green in hastening the resolution of subretinal fluid.³⁰⁶

Clinically, there are two characteristic findings. A sub-RPE vascular branching network is usually located in the area of the papillomacular bundle but can be isolated below the fovea. Reddish-orange nodules, called choroidal excrescences, are found at the edge of the vascular networks. Recurrent exudation and hemorrhage can occur under the RPE or retina (Fig. 34). Breakthrough bleeding into the vitreous is possible. Over time, the orange masslike lesions flatten with resolution of the leakage. New tubular vessels emanate from the flattened orange lesion.

Fluorescein angiography shows filling of IPCV lesions with the choroidal vasculature. There is blocked fluorescence due to hemorrhage, exudate, or the RPE. IPCV vessels can leak, although not as much as in a choroidal neovascular membrane seen in AMD. The polypoid structures are hyperfluorescent and stain or leak on late frames. Indocyanine green angiography shows that IPCV vessels fill slower than choroidal vessels. The network of abnormal vessels is also larger than suspected clinically. The polypoid structures leak dye slowly.³⁰⁸

Vision is typically better in IPCV than in AMD, and vision can be improved with treatment of the lesions. In some cases, scarring can occur with attendant visual loss. Treatment is carried out to areas of leakage from the choroidal excrescences. Unlike in AMD, the entire complex need not be treated in IPCV.

IPCV can be differentiated from AMD in the following ways. AMD patients are usually white. They usually have typical drusen and RPE changes that are often bilateral. The vessels seen in CNV due to AMD are not clinically visible. There is frequent scarring in AMD.^308–311

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