Clinical Features

Idiopathic central serous chorioretinopathy (ICSC), previously referred to as central serous retinopathy, idiopathic flat detachment of the macula, and central angiospastic retinopathy, is a specific disease that typically affects young and middle-aged males with type A personalities between 20 and 45 years of age. Unusual emotional stress frequently accompanies the onset of visual symptoms. There may be a history of headaches, which occasionally are of the migraine type. Males are affected more commonly than females by approximately 10 to 1. Before the onset of symptoms, most patients develop one or more small areas of serous detachment of the RPE in the macula or paramacular area ( Figure 3.02 A–C). This may be followed by serous detachment of the overlying and surrounding retina ( Figure 3.02 D–F). If the detachment does not extend into the central macular area, the patient is usually asymptomatic ( Figure 3.02 A–C). The retinal detachment may resolve spontaneously ( Figure 3.02 G). When the detachment spreads into the central macular area, the patient typically develops metamorphopsia, a positive scotoma, and micropsia ( Figures 3.02 D, 3.03 , and 3.04 ). An occasional patient will describe macropsia with the affected eye. Macropsia is the result of crowding of the photoreceptors in a unit area and micropsia is due to decrease in their number in a unit area. A relatively positive central scotoma and metamorphopsia can usually be demonstrated on Amsler grid testing. The micropsia may be unappreciated by the patient until demonstrated by confrontational comparison of image size of the examiner’s head. Some describe the micropsia as “objects being farther away with the affected eye as compared with the normal eye.” The visual acuity is often only moderately decreased and may be improved to near normal with the addition of a small hyperopic correction. There is a delay in retinal recovery time after exposure to bright light, loss of color saturation, and loss of contrast sensitivity. The patient’s past medical history, family history, and general physical findings are usually unremarkable. The author has seen two instances of ICSC occurring in siblings.

Idiopathic central serous chorioretinopathy.

A–C: Localized serous detachment of the retinal pigment epithelium (RPE: arrows, A) with a small halo of surrounding retinal detachment in a 34-year-old man with a serous detachment of the macula in the right eye. He was asymptomatic in the left eye. Note that the detachment does not extend into the fovea. His visual acuity was 20/15. Angiography outlines the area of RPE detachment (B). Six months later spontaneous reattachment of the RPE occurred (C).

D–I: A 37-year-old woman with blurred vision secondary to serous detachment of the retina. Note slight cloudiness of the subretinal exudate and the moderately large underlying RPE detachment (arrows, D). The RPE is mottled where it is detached. There is a small RPE detachment outside the area of macular detachment superiorly. Stereoscopic angiograms (E and F) showed dye pooled in the region of the RPE detachment beneath the retinal detachment as well as beneath the smaller RPE detachment superiorly (arrow, F). Two months later there was spontaneous resolution of the retinal detachment and slight enlargement of the RPE detachment (G). In the right eye she had developed three paracentral RPE detachments (H and I). She was asymptomatic in both eyes.

J–L: This 40-year-old man had serous retinal detachment, multiple small subretinal precipitates, and a small serous detachment of the RPE (arrows, J and K). Angiography demonstrated the site of a serous detachment of the RPE (arrow, K). L is a diagram of J. The black dots represent fluorescein that stains the exudate beneath the detached RPE but does not enter the subretinal space. SRP, subretinal precipitates.

Idiopathic central serous chorioretinopathy.

A–F: Young woman with serous retinal detachment. Note small retinal pigment epithelium (RPE) leak inferonasally and window defect temporally in B. Angiograms B–D, including stereoangiograms D, show dye streaming superiorly into the subretinal space. Note evidence of small focal leak (arrow, D) in the area of the window defect temporally. E is a diagram illustrating diffusion of the dye (stippling) from the choroid into the sub-RPE space and then into the subretinal space through a break (arrow) in the RPE. F is a representative optical coherence tomography showing a small RPE detachment within the area of serous retinal detachment.

G–I: Serous retinal detachment overlying moderately large RPE detachment with fluorescein streaming through small defect (arrows, H and I) in dome of RPE detachment into subretinal space.

J–L: Serous detachment of retina with whitish subretinal fibrin surrounding small RPE detachment in a 40-year-old man. Note heavy fluorescein staining in area of fibrinous exudate as well as the serous exudate elsewhere in the subretinal space.

Idiopathic central serous chorioretinopathy.

A–C: This 48-year-old man had a large serous detachment of the retinal pigment epithelium (RPE). Seven years previously he had serous macular detachment in his left eye that resolved spontaneously within 2 months. Visual acuity in the right eye was 20/50. Note the sharp margin of the serous detachment of the RPE (A). There was no serous detachment of the surrounding retina. Note also the pigment figure on the surface of the detached RPE. Angiography showed diffuse leakage of dye across Bruch’s membrane into the sub-RPE space (B). Note the pigment figure outlined on the background of fluorescein. The patient was observed at yearly intervals without change in his visual acuity or the appearance of the fundus. When he returned 9 years after the photograph in A, the serous detachment of the RPE had almost disappeared (C) and his visual acuity was 20/50.

D–I: Idiopathic central serous chorioretinopathy in a 34-year-old man with a persistent serous detachment of the macula for longer than 4 months (D). Arteriovenous phase revealed presence of either an RPE detachment or defect in the RPE, which is extremely minute (arrow, E). The dye leaked into the subretinal space and was carried superiorly (F). The dye pooled superiorly in the subretinal fluid in the dome of the detachment (G). One day after treatment the single application of low-intensity xenon photocoagulation was visible (lower arrow, H). The two small round spots are light reflex artifacts. Upper arrow indicates test spot. The retina was flat 3½ weeks after photocoagulation (I). Visual acuity was 20/15. The test spot was no longer visible.

J–L: Subretinal fibrin surrounding RPE detachment (arrows, J–L) in two pregnant women who developed idiopathic central serous chorioretinopathy during the seventh month of pregnancy. The detachment disappeared early postpartum in both patients.

(A–C from Gass et al. ; J and K from Gass. , © 1991, American Medical Association. All rights reserved.)

Ophthalmoscopically and biomicroscopically, a well-defined round or oval area of shallow elevation of the retina in the macular region is the typical finding ( Figures 3.02 – 3.04 ). This area usually presents a slightly darker color than the surrounding normal retina. The foveal reflex is attenuated or absent. The detachment may be relatively inconspicuous ophthalmoscopically but is usually readily apparent on slit-lamp examination of the macula with a fundus lens. The stereopsis obtained by using a wide light beam directed from a few degrees off the visual axis is generally adequate to appreciate separation of the retina from the underlying RPE. Observation of the increased distance separating a retinal vessel from its shadow cast on the underlying RPE is another helpful clue to the presence of serous detachment of the retina. Separation of the narrow light-beam reflex traversing the retina from that striking the RPE, when demonstrable, is further evidence of a serous detachment. In some instances, particularly in the presence of a shallow detachment, this separation may be impossible to demonstrate.

The detached retina is usually transparent and of normal thickness. The subretinal serous fluid is usually clear. There may be a small round yellow spot, probably caused by increased visibility of the retinal xanthophyll, in the center of the fovea. This may be mistaken for a small RPE detachment. In some cases the posterior surface of the retina may be partly covered with multiple yellowish dotlike precipitates ( Figure 3.02 J). In approximately 10% of eyes the subretinal space may be partly filled with a gray-white serofibrinous exudate that may be misinterpreted as a focal area of acute retinitis, an ischemic infarction of the retina, or a subretinal neovascular membrane ( Figure 3.03 J). Serofibrinous exudate is often associated with a larger area of retinal detachment as well as more prominent fluorescein leakage into the subretinal fluid ( Figure 3.03 A and L). The serous detachment of the RPE underlying the retinal detachment is variable in size and in some patients is often impossible to detect without the aid of fluorescein angiography ( Figure 3.03 A). Typically, it appears as a round or oval, yellowish or yellowish-gray lesion that is less than one-fourth disc diameter in size ( Figure 3.02 J). The surface of the RPE detachment may be finely mottled ( Figure 3.02 A, D, G, and H).

A small RPE detachment is easiest to detect in retroillumination adjacent to the slit beam of light focused on the RPE. It is usually located beneath the superior half of the area of retinal detachment. It occurs infrequently in the center of the fovea. In some cases the RPE detachment may appear to lie beyond the superior margin of the retinal detachment. Because of gravity the subretinal fluid tends to pool inferior to the area of serous detachment of the RPE. Positioning the patient may be required to demonstrate continuity of the areas of retinal and RPE detachment. Focal detachments of the RPE are difficult to visualize biomicroscopically when they are small in size, shallow in depth, or obscured by turbid subretinal exudate. Fluorescein angiography may be necessary to detect the site of RPE detachment.

Multiple RPE detachments may occur ( Figures 3.02D and H, and 3.05 ). Occasionally one or several detachments of the RPE may lie outside the primary area of retinal detachment ( Figure 3.02 D). In lieu of a discrete RPE detachment there may be an irregular, round, or flask-shaped area of mottled depigmentation of the RPE beneath the retinal detachment ( Figure 3.05H–J, 3.06, and 3.07 ). This occurs often in patients subject to recurrent serous elevation of the RPE and surrounding retina in the paracentral area before they become symptomatic from spread of retinal detachment into the central macular area.

Multifocal and recurrent idiopathic central serous chorioretinopathy.

A–N: This 42-year-old woman with lupus nephropathy who had undergone a renal transplant 7 years previously noted a change in vision in her left eye in 2005. The right eye was uninvolved and saw 20/20 while vision in the left eye had dropped to 20/30. A single pocket of subretinal fibrosis (SRF) associated with orange flecks was seen extending temporally from the disc (A). An angiogram revealed leopard-spot change with transmission hyperfluorescence of the area not blocked by the orange pigment that remained dark. There were four hot spots of hyperfluorescence. She was observed and the serous detachment resolved spontaneously in 2 months. She returned 3½ years later with symptoms in her right eye from a pocket of SRF temporal to the fovea. An angiogram revealed patchy leopard-spot change in both eyes, five hot spots on the right, and a single one on the left. She underwent focal laser to the hot spots in the right eye with resolution of fluid in 2 months (K–N). Autofluorescence images show increased autofluorescence corresponding to the orange pigment and decreased autofluorescence corresponding to the retinal pigment epithelium loss (I and J).

Chronic recurrent idiopathic central serous chorioretinopathy associated with large dependent zones of depigmentation of the retinal pigment epithelium (RPE) and migration of pigment into the overlying retina.

A–C: A 47-year-old man complained of bilateral loss of paracentral and superior fields of vision and difficulty driving at night of 4 years’ duration. Note zones of atrophy of RPE (arrows, A and B). Angiography showed multiple zones of RPE atrophy and multiple leakage sites (arrows, C). Electroretinography was within normal limits.

D–I: Composite of fundi of a 64-year-old man with a long history of bilateral recurrent episodes of loss of vision caused by serous detachment of the retina. His vision could be corrected to 20/25– on the right and 20/50 on the left. Note prominent zones of RPE changes extending to the ora serrata inferiorly. The areas of RPE loss appear hypoautofluorescent (E and H). Increased autofluorescence is seen surrounding these areas, suggesting the neighboring RPE cells are ingesting broken down photoreceptor and other cellular material. The right eye was dry (F); the left showed shallow subretinal fluid (I), for which he received low-fluence photodynamic therapy. He did not recall steroid intake but may have received injections to his wrist joint.

(A–C from Gass. )

Chronic recurrent idiopathic central serous chorioretinopathy resulting in pseudoretinitis pigmentosa.

This presently 53-year-old man was followed for more than 17 years with recurrent and chronic central serous chorioretinopathy. A few episodes of acute leak were treated with gentle focal laser in both eyes. The right eye lost central vision insidiously about 6 years into the disease. Dark adaptation became difficult in the past 5 years. Note the focal areas of deep chorioretinal atrophy and generalized loss of retinal pigment epithelium (RPE) and superficial choroid in the inferior fundus. Bone spicule pigment migration is seen in both eyes (A and B). The vision in his right eye is 20/400 and in the left eye 20/20–. Autofluorescence imaging shows gutters of RPE loss from fluid gravitating inferiorly arrows, (C and D).

Although RPE detachments are typically small in patients with ICSC, in some patients they may encompass a disc diameter or larger. When larger, the blisterlike RPE detachment may be surrounded by a reddish or salmon-pink halo caused by a marginal serous separation of the retina ( Figures 3.02A, G, and H, and 3.04A ). Large RPE detachments are typically circumscribed, oval or round, dome-shaped, and orange or yellow-gray; they present a solid rather than a translucent appearance. It is these features that occasionally cause a misdiagnosis of a choroidal hemangioma, hypopigmented melanoma, or metastatic carcinoma of the choroid ( Figure 3.04 A). The junction of the detached and attached RPE typically produces a discrete and circumscribed halo surrounding the base of the lesion, in contrast to the less discrete light reflex halo surrounding an area of serous detachment of the retina. The choroidal pattern that is often visible posterior to the serous detachment of the retina is usually not visible behind the serous detachment of the RPE, except in the rare case in which there is extensive thinning and depigmentation of the detached RPE. Fine mottling of the pigment and clumping of pigment on the surface of the detached RPE are common ( Figures 3.02 and 3.04 ). This pigment clumping may produce a cruciate (hot cross bun) or triradiate pigment figure ( Figure 3.04 A and B). The vitreous in patients with ICSC contains no inflammatory cells.

Fluorescein Angiography

Angiography in patients with ICSC shows a variety of patterns. In the presence of serous detachment of the retina, fluorescein angiography identifies the area where the RPE is detached and where serous exudate derived from the choriocapillaris is gaining entrance into the subretinal space (see Chapter 2). In those cases with a discrete blisterlike detachment of the RPE, fluorescein rapidly diffuses out of the choriocapillaris across Bruch’s membrane and stains the exudate beneath the RPE, creating a discrete, often round spot of hyperfluorescence, corresponding to the size of the RPE detachment ( Figures 3.02 – 3.04 ). In cases of a shallow detachment of the RPE, the spot of hyperfluorescence enlarges concentrically during the course of angiography. In some patients the dye is confined to the sub-RPE space ( Figure 3.02 B, E, F, I, and J). In others the dye may diffuse slowly through the detached RPE to produce a faint fluorescent haze in the subretinal exudate surrounding the RPE detachment. In less than 10% of cases the dye passes through a small hole in the RPE, often at the margin of, and occasionally within, the dome of the detached RPE, and streams upward in a smokestack configuration into the subretinal exudate to form an umbrella pattern of fluorescein staining ( Figure 3.03 A–I). This upward movement of the dye is probably caused both by convection currents and by the relatively higher specific gravity of the dependent subretinal exudate. Eventually the entire subretinal exudate may stain and appear hyperfluorescent, except in the foveal area, where the luteal retinal pigment obstructs the pathway of the exciting blue as well as the emitted fluorescent light. Retinal detachments associated with “smokestack” leaks are generally larger in area than those with focal leaks.

In patients with irregular RPE detachments and atrophy, the pattern of hyperfluorescence is correspondingly irregular, particularly during the early phases of angiography ( Figure 3.05 B and C). Patients with gray-white subretinal serofibrinous exudate usually show streaming of dye into the subretinal space near the exudate ( Figures 3.03J–L, 3.06A–C, and 3.08A–D ). After resolution of the macular detachment, the angiographic findings may return to normal. However, angiographic evidence of the small RPE detachment may persist in some patients. Irregular loss of pigment from the RPE after prolonged retinal detachment will be evident angiographically as mottled areas of hyperfluorescence that tend to fade during the course of angiography. Angiography is helpful in detecting the large zones of extramacular depigmentation of the RPE caused by chronic retinal detachment in patients with a more severe chronic form of this disease ( Figures 3.05 and 3.06 ). In the majority of cases the leaking site is found within one disc diameter of the center of the fovea. The foveolar area, however, is infrequently affected.

Severe idiopathic central serous chorioretinopathy (ICSC) with bullous retinal detachment in otherwise healthy patients receiving systemic corticosteroid therapy.

A–C: This 45-year-old man initially presented with a serous detachment of the macula in the right eye. It was attributed to choroiditis and the patient received oral prednisone. This was followed by bilateral bullous retinal detachment associated with multiple large serous retinal pigment epithelium (RPE) detachments, some of which were surrounded by a cloud of white fibrinous subretinal exudation (arrows, A). Fluorescein dye streamed through small breaks (arrows, B) in the dome of the RPE detachments into the subretinal space. Resolution of the subretinal exudate occurred after photocoagulation of RPE detachments and stopping the corticosteroids. The patient had no further episodes of macular detachment until 69 years of age, when he developed subretinal neovascularization at the site of treated RPE detachment superior to the right fovea.

D–L: This 27-year-old man developed bilateral serous detachment of the macula (D) in 1982. In 1990, in addition to a chronic complaint of subnormal vision, he developed floaters. Bilateral peripheral bullous retinal elevation inferiorly and several tufts of retinal neovascularization were noted (arrow, E). These changes were attributed to X-linked juvenile retinoschisis. In 1991, in spite of fluorescein angiographic findings that suggested chronic recurrent ICSC (F and G), the diagnosis was retinal vasculitis and treatment with systemic corticosteroids resulted in severe bilateral bullous retinal detachment, incorrectly attributed to uveal effusion syndrome. In 1993, bilateral scleral windows, vortex vein decompression, and larger doses of corticosteroids resulted in massive subretinal serofibrinous exudation (H and I). Arrows indicate foci of retinal neovascularization. Fluorescein angiography revealed multifocal areas of RPE elevation and decompensation posteriorly, leakage from several foci of retinal neovascularization (arrows, J), and a broad zone of retinal capillary nonperfusion inferiorly in both eyes (K). After discontinuance of the corticosteroids the retinal detachment resolved promptly, leaving subretinal fibrous bands in the macular region of both eyes.

(D–L from Gass and Little. )

Approximately 30% occur in the superior nasal quadrant and 25% in the papillomacular bundle area. Angiography, however, should always include photographs of the paramacular areas as well as the macular regions of both eyes. It is particularly important to photograph those areas superior to the macula and optic disc on the side of the macular detachment to detect eccentric areas of leakage, which, because of gravity, may lie superior to the area of detachment. Scanning the fundus during the later phases of angiography may be necessary to detect extramacular areas of fluorescein leakage. Failure to find evidence of a leak angiographically in a patient with a serous detachment of the macula should suggest the following possibilities: (1) a leak has occurred outside the macular area, usually superiorly; (2) the leaking area has healed and the detachment will disappear within the next few days or weeks; (3) presence of a peripheral retinal hole or choroidal tumor (usually superiorly located); (4) a congenital pit of the optic nerve head is present; and (5) idiopathic uveal effusion syndrome (IUES) is present.

Studies of patients with ICSC with indocyanine green have shown congested and dilated choroidal vein and capillaries, choroidal staining, and leakage into the extracellular space that appears as areas of hyperfluorescence in the middle and late phases. This renders evidence of a broader area of choroidal involvement than that demonstrated by fluorescein angiography, hence the better name, ICSC.

Autofluorescence imaging depicts a variety of findings in ICSC. The orange spots seen in acute ICSC that may be sites of fibrin; the subretinal orange deposits within an area of serous detachment which could be fibrin alone or mixed with photoreceptor elements; and serofibrinous plaques that resemble retinitis all show increased autofluorescence ( Figure 3.09 D (arrow) and I). In eyes with chronic and recurrent ICSC/steroid-related/organ transplant retinopathy, areas of RPE atrophy are seen as wide gutters of hypoautofluorescence, the edges of which show increased autofluorescence ( Figures 3.06E and H, and 3.07C and D ). Autofluorescence imaging with its mixed areas of increased and decreased autofluorescence is extremely typical and is a useful noninvasive technique in eyes suspected of chronic recurrent ICSC.

Central serous chorioretinopathy in the elderly.

Acute idiopathic central serous chorioretinopathy (ICSC) with sildanefil use.

A–F: This 84-year-old man presented with a drop in vision in his right eye to 20/30. There was a smooth serous retinal detachment without any drusen extending from the disc edge to the fovea (A). Angiogram showed a mild late hyperfluorescent spot temporal to the disc edge that was hyperautofluorescent (B–D). The serous detachment was smooth on optical coherence tomography (OCT) without evidence of drusen or other RPE abnormalities (E). Light laser to this spot caused resolution of most of the subretinal fluid (F) within 4 weeks and return of vision to 20/20.

New-onset steroid-induced ICSC with leopard-spot change in the elderly.

G–M: This 72-year-old male with no previous ocular history experienced fluctuating vision more in his left eye than right. His glasses prescription had to be corrected twice and he underwent cataract surgery in the left eye. Four weeks following cataract surgery he was noted to have cystoid macular edema on the left eye and received a sub-Tenon injection of triamcinalone. His vision dropped further. When examined a month later, his vision was correctable to 20/30 on the right and 20/50 on the left. In addition to the flask-shaped serous detachment in the left eye there were chorioretinal folds (G and H). No peripheral choroidal detachments were seen. Inner retinal fluid was present in both eyes and subretinal fluid in the left eye on OCT (J and K). Fluorescein showed only a leopard-spot change corresponding to the subretinal fluid without significant breakdown of the RPE (L and M). There was mild hyperfluorescence at the disc edge that was attributed to peripapillary atrophy. He denied steroid intake at any time, he was a well-controlled diabetic and hypertensive with a blood pressure of 130/78 mmHg in the office, and was in good health. His serum light chains were slightly elevated but M-protein spike was absent. On further questioning and speaking to his primary physician, he was found to have received three intramuscular injections of steroids over the previous 18 months for nasal congestion and used penile injections of papaverine, prostaglandin, and phentolamine for impotence for the previous 2 years.

Choroidal congestion and thickening can be confirmed by ultrasound B scan, and more recently with enhanced depth imaging on optical coherence tomography (OCT) using Spectralis. The patient’s eye is brought closer to the OCT machine than during conventional retinal scanning, and this enables the choroid to be visualized. Eyes with ICSC have been found to have a thicker choroid as compared to normal eyes. High-resolution imaging of the cones in the posterior pole with adaptive optics scanning laser ophthalmoscope may prove to be useful in monitoring progression in eyes with chronic/steroid-associated ICSC. The technology is still evolving and the instrument cost precludes its use routinely.

Chronic ICSC

Some patients, particularly Latins and Orientals, develop multiple sites of prolonged and recurrent serous retinal detachment in one or both eyes ( Figures 3.06 and 3.07 ). These initially may be confined to the juxtapapillary, peripheral macular, or extramacular areas, and these patients may be asymptomatic for many years before they develop a localized detachment of the macula. By this time there may be multiple, often teardrop or long-necked, flask-shaped areas of atrophy of the RPE extending inferiorly from the paracentral and particularly the peripapillary areas to the equator, or ora serrata ( Figures 3.06 and 3.07 ). Occasionally, large dependent areas of highly elevated chronic serous detachment may be mistaken for retinoschisis ( Figure 3.08 D–L). Recurrent detachment in these areas causes atrophy of both the RPE and retinal receptor elements. A bone corpuscular pattern of migration of pigment into the atrophic retina may occur in these zones and may be misinterpreted as evidence of retinitis pigmentosa ( Figure 3.06 G and 3.07 A and B ). These patients may have extensive loss of the superior visual fields, and some may complain of difficulty driving at night. Angiography often reveals multiple focal areas of staining that usually are most prominent near the superior aspect of the multiple zones of hyperfluorescence that correspond to the areas of RPE atrophy. This atrophy and staining are frequently prominent in the juxtapapillary region of both eyes ( Figure 3.06 C). Autofluorescence imaging is particularly useful in detecting the complete extent of the RPE involvement and is a useful noninvasive method to monitor the progression in patients ( Figures 3.06E and H and 3.07C and D ). The involved RPE is hypoautofluorescent with the area just outside it being hyperautofluorescent, suggesting increased metabolic activity in the adjacent intact RPE ( Figure 3.06 E and F). These patients are particularly prone to recurrent macular detachment and may permanently lose significant visual acuity and paracentral field. With chronic detachment lipid exudates and cystoid macular edema may occur in the absence of angiographic evidence of subretinal neovascularization. Chronic serous detachment of the inferior retina may cause, in addition to large areas of retinal and RPE atrophy, loss of the retinal capillaries, retinal neovascularization, vitreous hemorrhage, and electroretinographic changes ( Figure 3.08 ). Long-term follow-up studies of patients with typical ICSC have demonstrated that these patients with chronic recurrent detachment and severe visual loss are part of the spectrum of ICSC.

Acute Bullous Retinal Detachment

Multiple areas of serous detachment of the retina may occasionally develop rapidly in the same or both eyes of patients with ICSC. These may occur in the midperiphery of the fundus as well as in the posterior pole. In a few patients these detachments may become confluent and result in a large bullous retinal detachment involving the lower half or more of the fundus ( Figures 3.08A–C, and 3.10 ). This acute severe form of ICSC is particularly likely to occur in otherwise healthy patients who, as the result of a misdiagnosis, receive systemic corticosteroids. Multiple serous detachments of the RPE, often ½–1 disc diameter or larger in size, are typically present. They are frequently partly obscured by cloudy and at times gray-white fibrinous subretinal exudate. A similar picture often develops in the second eye within several days or weeks. These patients may be misdiagnosed as having a rhegmatogenous detachment, multifocal chorioretinitis, metastatic carcinoma, Harada’s disease, or uveal effusion. The angiographic demonstration of multiple serous detachments of the RPE ( Figures 3.08 B and C) underlying shifting subretinal fluid permits an accurate diagnosis. Fluorescein characteristically streams through a hole in the pigment epithelium at the edge of the large RPE detachments into the subretinal exudate ( Figures 3.08B and C, and 3.10C and D ). Occasionally, large RPE rips may occur at the edge of large RPE detachments ( Figure 3.10 H, J, and K).

Severe idiopathic central serous chorioretinopathy (ICSC) with bullous retinal detachment in otherwise healthy patients receiving systemic corticosteroid therapy.

A–F: This 31-year-old man developed detachment of the left macula associated with a focus of subretinal fibrin that was misinterpreted as acute retinitis. Treatment for toxoplasmosis, including prednisone, was given. One week later the patient had bullous serofibrinous retinal detachment in the right eye and juxtapapillary and macular retinal detachment in the left eye (A and B). Large serous detachments of the RPE surrounded by subretinal fibrin were present bilaterally. The detachment resolved completely within 2 weeks after all medications were stopped. He remained asymptomatic and at last examination, 11 years later, had 20/20 bilaterally.

G–K: This 54-year-old man maintained near normal visual acuity in spite of a 31-year history of recurrent episodes of ICSC, until he developed an epiretinal membrane in the right eye. One day before scheduled vitrectomy he developed ICSC in the fellow eye. He was started on a course of prednisone 100 mg/day preoperatively. Within several days of surgery he developed bilateral bullous retinal detachment. Postoperatively the oral prednisone was supplemented by retrobulbar injection of corticosteroids. Six weeks postoperatively his visual acuity was 20/400, right eye, and counting fingers at 2 feet (60 cm), left eye. There was total bullous retinal detachment associated with multiple large retinal pigment epithelium (RPE) detachments bilaterally associated with fibrinous exudation and subretinal fibrous band formation (G and H). In the left eye there was a 300° tear (arrows) along the edge of a large RPE detachment involving the superior macular region (H). Angiography confirmed the presence of multiple RPE detachments in the right eye (I) and the RPE tear in the left eye (J). Note the irregular retracted edge (arrow) of the torn RPE and the fluorescein staining within the area of missing RPE. Eighteen months later, after corticosteroids were stopped, and after multiple operative procedures, a tractional retinal detachment was still present in the right eye, but the retina in the left eye was reattached (K) and the visual acuity had returned to 20/30.

(G–K from Gass and Little. )

All of the otherwise healthy patients with bullous retinal detachment complicating ICSC seen by Gass have been middle-aged men. By the time he examined them many of them had diagnoses other than ICSC and were receiving oral corticosteroids. This same clinical and angiographic picture may, however, occur occasionally in women, particularly those receiving corticosteroids for systemic disease, e.g., disseminated lupus erythematosus, Crohn’s disease, rheumatoid arthritis, hemodialysis, and renal transplantation ( Figures 3.11 and 3.12 ). In addition to these disorders Gass has seen this severe form of ICSC in women with hemolytic anemia, cryoglobulinemia, eosinophilic fasciitis, severe allergic bronchitis after commencement of systemic corticosteroid therapy, and in one woman with multiple peculiar cutaneous and mucous membrane vascular malformations infiltrated with mast cells ( Figure 3.11 A–F).

Serofibrinous retinal pigment epithelium (RPE) and retinal detachment occurring in patients receiving corticosteroid treatment for systemic disease.

A–C: Bilateral multifocal RPE detachments surrounded by fibrinous subretinal exudate in a woman receiving systemic corticosteroids for treatment of lupus erythematosus.

D–F: Bilateral multifocal RPE detachments surrounded by fibrinous subretinal exudate in a patient receiving systemic corticosteroid treatment for lupus erythematosus.

G–I: Bilateral multifocal RPE detachments and subretinal fibrin in a woman receiving systemic corticosteroid treatment for nodular fasciitis.

J–L: This woman with a 6-year history of continuous prednisone therapy for lupus erythematosus and Sjögren’s syndrome developed exudative detachment of the right macula associated with multiple serous RPE detachments (arrows), subretinal serofibrinous retinal detachment, and a pigment epitheliopathy resembling fundus flavimaculatus in her right eye. Her left eye had been enucleated following Pseudomonas endophthalmitis. Two years previously she had multiple amputations of the fingers and both legs (J). Laser photocoagulation of the RPE detachments failed to produce resolution of the macular detachment. There was progression of the pigment epitheliopathy to involve most of the fundus (J). Angiography revealed a leopard-spot pattern of nonfluorescence and multiple focal sites of leakage throughout the posterior fundus (L). Note persistent areas of RPE detachment (arrows).

Bilateral serofibrinous retinal pigment epithelium (RPE) and bullous retinal detachment occurring in patients receiving renal dialysis and after renal transplantation.

A–D: A 37-year-old Native American woman receiving renal dialysis developed bilateral serofibrinous retinal detachment. She had well-controlled hypertension. Note the fibrin enveloping the RPE detachments (arrows, A and B). Angiograms (C and D) show multiple RPE detachments in right eye.

E–H: Inferior bilateral bullous detachment in a 40-year-old Native American man 1 month after receiving a renal transplant. He was receiving systemic corticosteroids and antimetabolites. He had well-controlled hypertension. Note white fibrinous exudation surrounding RPE detachments (arrows, E and F). Angiography revealed “smokestack” leaks from the areas of RPE detachment. Nine days later he developed rapid loss of vision in the left eye. Within 4 weeks visual loss progressed to no light perception. Computed tomography revealed evidence of thickening of the left optic nerve and orbital tissue. The left eye was enucleated. Histopathologic examination revealed fibrinous exudate in the sub-RPE space (arrows) and subretinal space (G and H). No definite pathologic changes in the choriocapillaris were identified. Separate tissue removed from the orbital apex revealed aspergillosis of the optic nerve and orbit.

(From de Venecia. )

At the 1982 Eastern Ophthalmic Pathology Society meeting Dr. Gilbert de Venecia reported the histopathologic findings in one eye of a 40-year-old Native American man who soon presented after a kidney transplant with bilateral bullous retinal detachment and multiple serous RPE detachments surrounded by white subretinal exudate ( Figure 3.12 E and F). He found histopathologic evidence that the whitish exudate beneath and surrounding the RPE detachment was fibrinous in type ( Figure 3.12 G and H).

ICSC Associated with Chorioretinal Folds

ICSC may occasionally occur in eyes with chorioretinal folds in the macular area secondary to choroidal congestion ( Figure 3.09 L and M).

ICSC in Women

ICSC in otherwise normal women is similar to that in males except that onset tends to be at an older age in women. ICSC in women receiving exogenous corticosteroids is more likely to be associated with bilateral involvement and subretinal fibrin.

ICSC may occur in healthy women during the latter half of otherwise uncomplicated pregnancy. For unknown reasons it is associated with white subretinal exudation surrounding the RPE detachment in over 90% of affected pregnant women. It is important not to mistake this serofibrinous exudation for evidence of subretinal neovascularization, focal retinitis, or focal retinal infarction, all of which may suggest investigations including fluorescein angiography, which are usually unnecessary in the differential diagnosis. The detachment resolves spontaneously soon after delivery and the visual prognosis is excellent. ICSC may or may not recur during subsequent pregnancies.

ICSC in the Elderly

Although most patients with ICSC are young and middle-aged males, some first develop symptoms in the later decades of life ( Figure 3.11 C–H). The clinical picture may be identical to that occurring in younger patients, although a larger percentage of the older patients will manifest fundoscopic evidence of previous episodes of subclinical eccentric retinal detachment, as described previously. In older patients there is more concern that the focal leak demonstrated angiographically may represent a focus of occult choroidal neovascularization. Although an occasional patient with ICSC will eventually develop evidence of AMD, there is no evidence that the two diseases are more than casually related.

ICSC Simulating Pattern Dystrophy

Patients presenting with the typical findings of ICSC may over a period of years develop multiple focal yellow lesions with pigmented centers in one or both eyes, simulating that seen in patients with pattern dystrophy. These lesions may also simulate Elschnig spots caused by fibrinoid necrosis associated with severe hypertension, collagen vascular disease, and disseminated intravascular coagulopathy (DIC).

Other Associations with ICSC

The author has seen ICSC occurring in 2 women in association with retinitis pigmentosa (see Figure 5.41A–C) and with episcleritis.

Chronic and Recurrent ICSC

Lowering or discontinuing systemic steroids in those receiving steroids should be tried as the first step. Failure of resolution of fluid should prompt light focal laser to the leaks ( Figure 3.05 ) if demonstrated on an angiogram. In those eyes with widespread chorioretinal involvement as seen on fluorescein or indocyanine green angiography, photodynamic therapy is beneficial in most cases. Both full- and reduced-fluence treatments and full- and half-dose have been used; more recently reduced fluence has been advocated to reduce toxic effects of the therapy. The spot size is determined by the area of staining on the angiograms. An extra 500-μm zone is not necessary, as in treating choroidal neovascularization. Care must be taken to avoid including the foveal center if no significant subfoveal fluid is present.

Jampol et al. have shown resolution of subretinal fluid by the use of mifepristone, an antiglucocorticoid and antiprogesterone medication used as an abortifacient. A daily dose of 200 mg caused dramatic resolution of subretinal fluid, but it recurred once the drug was discontinued. The drug works by blocking the glucocorticoid receptors via negative-feedback control of adrenocorticotropic hormone and cortisol, causing an increase of both in the serum.

Typical or Exudative Drusen

The earliest sign of AMD is the development of multiple, usually discrete, round, slightly elevated, variably sized, sub-RPE deposits in the macula and elsewhere in the fundus of both eyes ( Figures 3.14 – 3.16 ). These deposits are called drusen. The German word “druse” (plural “drusen”) means nodule, referring in particular to areas of clear crystallization within stones. The term “typical” or “exudative” drusen is used here to differentiate these variably sized deposits of extracellular material lying between the basement membrane of the RPE and the inner collagenous zone of Bruch’s membrane from uniformly small, round, nodular thickenings of the RPE basement membrane (basal laminar drusen, cuticular drusen) that probably have a different pathogenesis (see p. 132). Typical or exudative drusen may develop in early adulthood but infrequently are visible biomicroscopically until middle life or later. Early in their development drusen may be inapparent ophthalmoscopically because of their small size and relatively normal overlying RPE. Usually, however, they can be detected in retroillumination with the slit lamp as semitranslucent bodies.

Typical or exudative drusen.

A–C: Macular, peripapillary, and peripheral drusen in a 24-year-old man with 20/20 visual acuity in both eyes (A). Angiograms showed hyperfluorescent spots corresponding with drusen (B and C).

D–F: Multiple variably sized drusen in a 42-year-old man with 20/20 visual acuity.

G–I: Confluence of multiple large drusen in a 68-year-old man. Note the irregular pattern of staining of the larger drusen centrally. Visual acuity was 20/80.

J: Schematic diagram showing variations in the fluorescent pattern of exudative drusen in which the retinal pigment epithelium (RPE) basement membrane (bm, arrow) is of normal or near normal thickness. Black dots represent fluorescein molecules. A hyalinized drusen (1) may transmit the intrachoroidal fluorescence because of thinning of the overlying RPE but may be sufficiently dense that diffusion of dye across Bruch’s membrane (BM) into the sub-RPE material does not occur. In the case of drusen with less dense material beneath the RPE (2, 3), the dye may diffuse into the sub-RPE material and cause intensification of fluorescence of the drusen during the later stages of angiography.

Natural course of typical (exudative) drusen.

A and B: Multiple large drusen, some of which are confluent, in a 65-year-old woman with a visual acuity of 20/40. Several drusen are partly calcified (arrows, A). Same patient 4 years later (B) showing fading and disappearance of drusen. Visual acuity was still 20/40.

C and D: Note the change in distribution, shape, and size of the drusen in this 73-year-old patient over a period of 3 years. Visual acuity in C was 20/25 and in D was 20/30.

E and F: This 73-year-old patient developed multiple focal areas of geographic atrophy of the retinal pigment epithelium (RPE) over a period of 2 years. Her initial visual acuity was 20/30. Her visual acuity when last seen (F) was 20/40.

G–L: Progression of large drusen to “drusenoid” RPE detachments of the RPE (arrows, I and L) in a 67-year-old woman. Left eye, July 1986 (G), April 1991 (H), February 1993 (I and J). Right eye, July 1986 (K), and February 1993 (L).

Morphologic variations of typical or exudative drusen.

A: Multiple hyalinized “firm” nodular drusen.

B: Granular “soft” drusen.

C: Combined granular and hyalinized drusen (arrow).

D: Calcified “crystalline” drusen. Note new vessel (arrow) beneath the retinal pigment epithelium.

E: Diffuse deposition of granular drusen material (probably both basal laminar and basal linear deposits) in macular area. Note focal calcification (arrows) of Bruch’s membrane, widening of the intercapillary pillars of the choriocapillaris, and partial obstruction of the choriocapillaris.

F: Extramacular area of same eye. Note relatively normal Bruch’s membrane and choriocapillaris.

As the deposit enlarges and the overlying RPE thins, drusen assume a yellow or gray color and are more easily detected. They vary widely in size from yellow punctate nodules (“hard” drusen; Figure 3.14 A) to large, pale yellow or gray-white, placoid or dome-shaped structures indistinguishable from localized serous detachments of the RPE (“soft” drusen; Figures 3.14D and G and 3.15A ). Drusen are often clustered in the macular or paramacular area. Whether centrally or eccentrically located, their distribution is usually symmetric in both eyes. Drusen change in size, shape, distribution, color, and consistency with the passing years ( Figure 3.15 ). Although they tend to increase in number and size ( Figure 3.15 C and D), drusen may also fade from view and decrease in number ( Figure 3.15 A and B). In some cases, areas of geographic atrophy of the pigment epithelium may remain following disappearance of drusen ( Figure 3.15 E and F). Drusen may become calcified and crystalline in appearance ( Figure 3.15 A, and see Figure 3.29 ). This change suggests dehydration of the drusen and often precedes the development of geographic atrophy of the RPE. Occasionally drusen develop a polychromatic or golden sparkling appearance indicative of cholesterol deposits. Some drusen may become ossified and assume a white appearance. A few may appear pink secondary to choroidal neovascular tufts growing through Bruch’s membrane into the drusen. In some patients the sub-RPE deposits are distributed diffusely rather than focally and are evident ophthalmoscopically only as an ill-defined area of slightly mottled yellow color of the RPE in the macula.

Most patients with the predisciform stage of the disease have excellent visual acuity and are asymptomatic. Some with many drusen centrally complain of decreased ability to read, particularly in dimmed illumination, and mild metamorphopsia. Loss of contrast sensitivity is common and may be out of proportion to loss of Snellen acuity. This loss may involve the entire macula and is not confined to the areas with drusen. Early loss of sensitivity may be a predictor of severe visual loss. Patients frequently experience difficulty with driving an automobile at night. Electrophysiologic tests in most patients are normal. Some may have mild to moderate reduction in electro-oculographic responses.

Drusen are not always confined to the macular area. In some patients they may be present nasal to the optic disc. In others they may be largely confined to the peripheral macular area, particularly in the areas of the major vascular arcades. Drusen in this latter distribution may have a somewhat granular, less discrete appearance and may be seen in black patients, who infrequently develop drusen in the macular area. Many widely scattered drusen are usually visible with a three-mirror gonioprism in the peripheral fundus. In contrast to drusen in the posterior pole, these drusen often have a halo of pigment at their base. In some patients these drusen are arranged in a confluent, linear, and triradiate pattern to produce a prominent pigmented network visible ophthalmoscopically in the midperiphery of the fundus ( Figure 3.17 ). This is usually most evident nasally and is referred to as senile reticular pigmentary degeneration. A narrow, indistinct, yellow or gray zone caused by the deposition of sub-RPE drusen material often surrounds the temporal half or more of the optic disc.

Peripheral senile reticular pigmentary degeneration.

A–F: Macular drusen, choroidal neovascularization, and peripheral reticular pigmentary degeneration (A–C). Angiography revealed a triradiate pattern of peripheral drusen at the equator peripherally (D–F).

G–I: Note the peripheral drusen and pigment changes in this 75-year-old man whose eye was enucleated because of a small malignant melanoma of the choroid. Angiography showed evidence of multiple drusen and irregular loss of pigment from the retinal pigment epithelium (RPE) (H). Note the reticular pattern of nonfluorescent pigment. Histopathologic section of G showed multiple drusen, irregular thinning of the RPE, and clumps of large pigment-laden cells (arrow, I). The retina (not shown) showed mild loss of the receptor elements.

J and K: Peripheral cross-hatch-like pigment changes of senile reticular pigment degeneration show up as triradiate hyperautofluorescent changes.

(G–I from Gass. )

Patients with multiple large drusen and with focal areas of hyperpigmentation in the macular area are at greater risk of developing subretinal neovascularization. Fluorescein angiographic findings in drusen are variable and depend upon their size, height, degree of pigmentation of the RPE on their surface, and the contents and consistency of the material lying between the RPE and Bruch’s membrane. Most drusen cause focal well-defined hyperfluorescence. The time of appearance of their early fluorescence depends upon the rate of staining of Bruch’s membrane and the sub-RPE material, and their translucency. The intensity of their later staining with fluorescein depends primarily on their consistency ( Figure 3.14 ). Although a delay in the appearance of the background choroidal fluorescence occurs in some patients with drusen, it is probable that this is caused by a delay in staining of Bruch’s membrane and the sub-RPE material, both of which in some patients may have a higher lipid content, rather than a delay in perfusion of the choroidal blood vessels. Smaller nodular (“hard”) drusen typically show a peak fluorescence within several minutes of injection, and fading paralleling that of the background choroidal fluorescence. Fluorescence of medium and large drusen may be delayed until the later stages of angiography ( Figure 3.14 G–J). This may be caused by the thickness of the drusen as well as the lipid content of the drusen and the underlying Bruch’s membrane ( Figure 3.14 G–J). Angiography may reveal the presence of more drusen than are apparent ophthalmoscopically.

Histopathologically, most drusen consist of focal collections of eosinophilic material lying between the basement membrane of the RPE and Bruch’s membrane ( Figure 3.16 ). They therefore represent focal detachments of the RPE. The detached RPE cells may be thinned and hypopigmented. The sub-RPE material may appear homogeneous and hyalinized ( Figure 3.16 A), finely granular ( Figure 3.16 B), or a combination of both ( Figure 3.16 C). In some cases it may contain calcium, cholesterol clefts, and bone ( Figure 3.16 D). The variable histopathologic appearance and composition of drusen suggest that their consistency probably varies from watery or mushy in the case of the large placoid drusen ( Figure 3.16 B), to firm in the case of the nodular hyalinized periodic acid–Schiff (PAS)-positive drusen ( Figure 3.16 A), to hard in the case of calcified or ossified white drusen ( Figure 3.16 D). It is these histopathologic variations that have given rise to physicians’ use of the terms “hard” and “soft” to describe the clinical appearance of small, discrete and larger, often placoid drusen, respectively.

As might be expected from the variability of the clinical and histopathologic appearance of drusen, there is heterogeneity in regard to their ultrastructural and histochemical makeup. There is evidence in monkeys and humans that the earliest development of some drusen involves the outward evagination of portions of the basal cell wall and cytoplasm of the RPE cell into the sub-RPE space between the inner collagenous portion of Bruch’s membrane and the RPE cell. These vesicles of cytoplasm become pinched off, degenerate, and form a nidus for the accumulation of an admixture of metabolic products and substances derived from the surrounding RPE, retina, and choriocapillaris. Histochemical and electron microscopic studies of typical or exudative drusen reveal a variety of substances and materials accumulating between the relatively normal basement membrane of the detached RPE and the inner collagenous zone of Bruch’s membrane. These include sulfated and nonsulfated glycoconjugates; lipid material; plasma membranelike material; vesicles; amorphous material; types I, III, IV, and V collagen; fibronectin; immunoglobulins; degenerated RPE organelles; and viable cell processes. Some investigators have attributed these viable cell processes surrounded by basement membrane to macrophages, or pericytes, rather than RPE cells.

Histopathologically there may be minimal degeneration of the retinal receptor elements overlying drusen. Many eyes with focal drusen show, in addition, a thin layer of fine granular eosinophilic material separating the RPE from Bruch’s membrane throughout most of the macular region ( Figure 3.16 E). Ultrastructurally this sub-RPE deposit may lie between the RPE plasma membrane and its basement membrane (basal laminar deposit) or between the inner collagenous zone of Bruch’s membrane and the basement membrane of the RPE (basal linear deposit). The basal laminar deposit is composed primarily of wide-spaced collagen; the basal linear deposit is composed of vesicular and granular electron-dense, lipid-rich material. Some authors believe that basal laminar deposit, which is primarily type IV collagen, is a unique feature found in eyes predisposed to the development of AMD, whereas others have presented evidence that it, along with the thickening of Bruch’s membrane and drusen, is an aging change and is not unique for AMD. Both types of deposit are particularly noticeable in eyes with multiple large so-called “soft” drusen and disciform detachments.

Other important histopathologic changes in the macula accompany drusen. There is irregular thickening and thinning of Bruch’s membrane associated with calcific degeneration of the elastic and collagen tissue comprising this structure. In the underlying choriocapillaris there is thickening and hyalinization of the intercapillary stromal pillars secondary to the deposition of a PAS-positive material that effectively reduces the surface area of the capillary bed ( Figure 3.16 E). The large choroidal vessels are unaffected. There is no indocyanine green angiographic or rheologic evidence of impaired choroidal perfusion in patients with drusen. The changes in Bruch’s membrane and the choriocapillaris that accompany macular drusen have been referred to previously as senile macular choroidal degeneration. It is uncertain, however, whether these changes are manifestations of a dominantly inherited dystrophy or are merely degenerative changes secondary to aging.

Histopathologically, a few scattered drusen are found frequently in the peripheral fundus, particularly in the aging eye of white patients. When numerous they are arranged in a reticular pattern and are associated with hyperplasia of the RPE between drusen that produces a reticular pattern of pigmentation ophthalmoscopically that may be mistaken clinically for that in retinitis pigmentosa ( Figure 3.17 ). In all, 80–90% of patients with many peripheral drusen show evidence of age-related macular changes.

The pathogenesis of typical or exudative drusen is unknown. Although most recent authors have favored the view that aging or dystrophic changes in the RPE are primarily responsible for the accumulation of abnormal material beneath its basement membrane, it is uncertain whether the primary locus of the disease resides in one or a combination of the retina and RPE, Bruch’s membrane, or choriocapillaris. The demonstration of viable cell processes within drusen in their early development and the later finding of incompletely digested RPE and retinal cell organelles within the sub-RPE material suggest that the posterior evagination of buds of RPE cell basal cytoplasm and basement membrane is an important stage in the development of drusen. Accumulation of lipids in Bruch’s membrane is part of the aging process of Bruch’s membrane and makes it to some degree a hydrophobic barrier to the movement of water and ions toward the choroid. This may be an important factor in fostering enlargement of drusen (conversion from hard to soft drusen), and confluence of drusen to form serous detachments of the pigment epithelium. Although there is much evidence to suggest that typical or exudative drusen may be inherited as an autosomal-dominant characteristic, the role of heredity in the causation of drusen in most patients is uncertain. Drusen have been produced experimentally in animals with intravitreal injection of aminoglycosides.

Other retinal flecks that may clinically simulate drusen include those occurring in patients with cuticular or basal laminar drusen (see p. 132), Stargardt’s disease (see p. 275), North Carolina fundus dystrophy (see p. 292), fundus albi punctate dystrophy (see p. 322), Alport’s disease (see p. 312), and ring-17 chromosome retinopathy (see p. 316). In monkeys and humans focal lipidization of RPE cells may cause fundus lesions that resemble small drusen. These punctate, yellow lesions usually are not evident angiographically. A few of them are often found in the central macular area of otherwise normal fundi in adults of all ages. Their pathogenesis and their relationship to drusen formation are unknown.

The primary cause of significant loss of central vision in patients with AMD is serous and hemorrhagic detachment of the RPE and retina caused by choroidal neovascularization.

Occult Choroidal Neovascularization

The ingrowth of new vessels extending from the choroid into the sub-RPE space in one or more areas occurs frequently and is the most important histopathologic change that predisposes patients with drusen to macular detachment and loss of central vision (see discussion of type I choroidal neovascularization in Chapter 2). Neovascular buds invade and penetrate the degenerated Bruch’s membrane and proliferate beneath the RPE ( Figures 2.05–2.07 and 3.18 ). In addition, capillaries may invade the sub-RPE drusenlike deposits adjacent to the optic disc by extension through or around the edge of Bruch’s membrane ( Figure 3.18 D). It is not known whether the granulomatous inflammatory response to degenerated Bruch’s membrane found in some cases is an important factor in the process of subretinal neovascularization. The accumulation of phospholipid-containing membranes in the outer collagenous zone of Bruch’s membrane and of lipid within drusen may be responsible for attracting these macrophages.

Occult choroidal neovascularization in patients with drusen.

A–D: This 69-year-old man with a few drusen (arrows, A) in the macula of the right eye presented with a large serous detachment of the retina in the macula of the left eye (see Figure 3.10 ). He died of complications of laryngeal surgery and serial sections of the right macula at the site of one drusen (temporalmost arrow in A) revealed six round breaks in Bruch’s membrane. Through each of these breaks passed a small capillary tuft from the choriocapillaris into the sub-retinal pigment epithelium (RPE) space (arrows, B and C). Similar sub-RPE capillary tufts were found beneath the temporal margin of the right optic disc (arrow, D).

E: Large sub-RPE occult choroidal neovascular membrane (CNVM; arrows). Note relatively normal RPE and retina as well as absence of exudation.

(E from Green and Key. )

The new capillaries that penetrate Bruch’s membrane grow in a flat cartwheel or seafan configuration away from their site of entry into the sub-RPE space (see Figure 2.07). The retinal blood flow in these vessels initially is slow, and the integrity of the capillary endothelium is adequate to prevent exudation ( Figure 3.18 E). In some cases the slow proliferation of new vessels and fibroblastic proliferation may produce a solid elevation of the RPE (see Figure 2.06). These organized RPE detachments or mounds may vary in size and shape and are often irregular in elevation (see Figure 3.22 A and D). Because the fine biomicroscopic details of the elevated RPE and drusen look much the same as the surrounding RPE, and because of the minimal angiographic changes in the area of these organized RPE mounds, they may be easily overlooked without careful contact lens examination and good-quality stereoscopic fluorescein angiograms. Occasionally these organized RPE detachments may assume tumorlike proportions and simulate choroidal hemangiomas clinically (see Figure 3.28 E). Failure to recognize areas of organized RPE detachment adjacent to areas of high-flow choroidal neovascular membranes (CNVMs) or adjacent to large serous detachments of the RPE is responsible for many of the poor results of photocoagulation. The structure and function of the RPE and retina overlying these occult CNVMs or mounds may be minimally affected ( Figure 3.18 ). During this occult stage of choroidal neovascularization the patient is usually asymptomatic and the new vessels may not be apparent either ophthalmoscopically or angiographically. The stimulus causing neovascular invasion of the sub-RPE space and the explanation for its more frequent occurrence near the center of the macula and the peripapillary region is unknown. The histopathologic observation of choriocapillary atrophy in the vicinity of neovascular ingrowth suggests that ischemia may be an important factor. Experimentally, type II subretinal choroidal neovascularization can be produced by photocoagulation damage to the choriocapillaris–Bruch’s membrane–RPE complex. There is no experimental model for type I sub-RPE choroidal neovascularization that occurs in AMD.

Disciform Detachment Stages

Although most patients with AMD are in their seventh decade at the time of onset of symptoms, loss of acuity in some patients may occur in the fifth decade or earlier. Significant loss of central vision in these patients occurs primarily by three mechanisms: (1) confluence of drusen to form multilobulated exudative RPE detachments (5% or fewer of cases); (2) geographic atrophy of the RPE and retina (5–10%); and (3) subretinal neovascularization with serous and hemorrhagic detachment of the RPE and retina (80–90%).

Exudative Detachment of the Retinal Pigment Epithelium Unassociated with Choroidal Neovascularization (Avascular Serous RPE Detachment)

Unlike patients with ICSC, patients with drusen infrequently develop large areas of serous retinal detachment overlying small serous RPE detachments, but they frequently present with large serous RPE detachments and minimal serous retinal detachment ( Figures 2.04, 2.09, and 3.19 ). The normal aging changes in the inner zones of Bruch’s membrane as well as those that may be peculiar to AMD cause loosening of the adherence of the RPE basement membrane to Bruch’s membrane. Increased lipidization of Bruch’s membrane renders it hydrophobic and a barrier to normal movement of fluid by the RPE into the choroid. This predisposes patients with AMD to the formation of soft drusen and to progressive enlargement and confluence of drusen to form a focal area of RPE detachment, often with scalloped borders, a slightly irregular surface, and a triradiate pattern of orange or gray pigmentation on its surface. These avascular RPE detachments, referred to by some as drusenoid RPE detachments, typically develop slowly and initially may cause minimal complaints of blurring and metamorphopsia ( Figures 3.14G–I and 3.15G–L) . Angiography in these slowly developing avascular serous RPE detachments shows a gradual staining of the sub-RPE exudate and outlines the nonfluorescent pigment figure on its surface ( Figures 3.14H and I and 3.15J ). There may be some irregularity of the late staining pattern caused by irregular density of the sub-RPE material. A few patients may experience abrupt visual loss and distortion caused by a more rapidly developing, round or oval, smooth-surfaced, dome-shaped area of serous detachment of the RPE in the absence of any evidence of occult neovascularization ( Figure 3.19 A–D). These rapidly developing avascular RPE detachments show a pattern of rapid even fluorescein staining ( Figure 3.19 B) that is unlike that seen with most serous RPE detachments caused by choroidal neovascularization (see discussion of vascularized RPE detachments, p. 106) as well as those lesions that may simulate serous RPE detachment, such as metastatic carcinoma, amelanotic melanomas, or other solid tumors.

Serous detachment of the retinal pigment epithelium (RPE) in patients with age-related macular degeneration.

A–D: This 64-year-old man experienced the onset of metamorphopsia in the right eye. Visual acuity was 20/30. A serous detachment of the RPE was present (A). Drusen were present in the left macula. Angiography revealed rapid, even staining of the sub-RPE exudate (B). The dark zone centrally is caused by the retinal xanthophyll. Argon laser applications were placed straddling the margin of the RPE detachment (C). Nine months later the detachment had resolved (D). Visual acuity was 20/30.

E and F: A 60-year-old woman with serous detachment of the RPE (arrows, E). One month after ruby laser treatment to the margins of the RPE detachment, it had resolved (F). Visual acuity was 20/40.

G: Histopathology of serous detachment of the RPE in a 68-year-old woman with macular drusen. This lesion was misdiagnosed as a malignant melanoma. Arrow indicates small drusen that are detached along with the RPE. Sub-RPE exudate extends through a small microrip in the RPE into the subretinal space near the left end of the photomicrograph.

(G from Zscheile. , © 1964, American Medical Association. All rights reserved.)

Because of prognostic and therapeutic implications, it is important to look for signs of choroidal neovascularization, which usually is the cause of these rapidly developing detachments of the RPE. The vision of patients with subfoveal serous RPE detachments can usually be corrected to 20/25–20/40 with the addition of plus lenses. When there is no choroidal neovascularization there may be only minimal progression of visual loss over many months or years. The detachment may enlarge slowly and occasionally may spontaneously flatten. The value of photocoagulation ( Figure 3.19 ) is uncertain.

Serous and Hemorrhagic Detachment of the Retina Caused by Choroidal Neovascularization

At any stage in the development of an occult CNVM beneath the RPE, blood flow may become sufficient to cause leakage of serous exudate and diapedesis of red cells into the subpigment space around the CNVM. This may progress to produce a variety of ophthalmoscopic pictures of exudative and hemorrhagic detachment of the macula. The most frequent sequence of events giving rise to symptoms is the decompensation of the RPE overlying the CNVM and serous detachment of the overlying and surrounding retina ( Figure 3.20 ). A light-grayish discoloration usually occurs in the area of the CNVM. The blood vessels comprising the CNVM may or may not be visible biomicroscopically ( Figure 3.20 ). Small foci of subretinal blood or yellow, lipid-rich exudate may occur near the margins of the CNVM. In cases where the neovascular membrane extends beneath the retinal capillary-free zone, cystoid macular edema may occur. The reasons for the accumulation of intraretinal exudate in this instance are uncertain, but it may be caused in part by disruption of the retinal outer limiting membrane–receptor cell barrier to the intraretinal migration of subretinal exudate and the paucity of the retinal capillaries in this area to remove it (see Figure 2.15 and discussion in Chapter 2). The ability of stereoscopic fluorescein angiography to localize a CNVM accurately depends primarily on the rate of blood flow through the membrane and the presence or absence of material anterior to the membrane that may obstruct the view of the fluorescence within the capillary network.

Sub-retinal pigment epithelium (RPE) neovascularization in patients with drusen.

A–C: This elderly woman complained of mild blurring of vision. The new-vessel membrane was largely obscured by the grayish-yellow exudate (arrows) in the sub-RPE space (A). A few red capillaries were visible near the upper margin of the membrane. Note dye perfusing the sub-RPE vessels that were arranged in a seafan pattern (B and C). The dye leaked from these vessels and stained the surrounding exudate in the sub-RPE space.

D and E: Another patient with choroidal neovascularization (D). Angiogram showed seafan configuration of new vessels (E).

F: Large choroidal neovascular membrane (arrows) that extended through break in Bruch’s membrane (left arrow).

The typical cartwheel or seafan pattern of the new vessels is visible in high-flow membranes with minimal extravasated blood, cloudy exudate, or fibrous tissue anterior to it ( Figure 3.20 ). In some membranes with only a moderate blood flow rate, an ill-defined ooze of fluorescein appears late in the area of the membrane ( Figure 3.21 ). When the serous retinal detachment is caused by leakage of exudate from the surface of an occult sub-RPE neovascular complex, angiography may show only a multifocal pinpoint or irregular pattern of staining at the surface of the organized RPE detachment ( Figure 3.22 B and C). The accurate localization of choroidal neovascularization in such cases is difficult. It is also difficult or impossible if part of the CNVM is obscured by blood located beneath either the RPE or the retina. Stereoscopic angiograms are essential to the detection and localization of most CNVMs, particularly that part of the CNVM complex that is occult. Areas of irregular elevation of the RPE that do not stain probably harbor occult new vessels. Once exudation begins, most CNVMs progressively enlarge to 1–2 disc diameters in size or larger and cause progressive loss of visual function.

Notched serous detachments of the retinal pigment epithelium (RPE) caused by choroidal neovascularization.

A–F: A 74-year-old woman with an RPE detachment caused by two occult choroidal neovascular membranes (CNVMs: arrows, C) within notched zones (A). Stereoscopic view of the late angiogram (B and C) and early angiogram (D). Argon laser treatment was applied to the two neovascular membranes, and two focal laser burns were placed at the 4:30 margin of the RPE detachment (E). Twelve days later the retina and RPE were reattached (F). Subretinal blood was present at the sites of photocoagulation of the CNVMs.

G–L: A 56-year-old man with a large RPE detachment, dark fluid level (small arrow, G), and notch (large arrow, G). Six months later the RPE detachment was larger (H). Note slow staining of sub-RPE fluid, nonfluorescent fluid level, and late fluorescein staining in the area of the notch (J, arrows). Argon laser treatment was placed along the margin of the detachment and at the site of occult neovascularization (arrow, K). Note dark blood that appeared just above new-vessel membrane (arrow) during treatment. Four weeks later the retinal and RPE detachments had resolved (L). Visual acuity was 20/40.

Serous Detachment of the Retinal Pigment Epithelium Caused by Choroidal Neovascularization (Vascularized RPE Detachment)

In patients with AMD, acute visual loss is caused by a large, sharply circumscribed, smooth-surfaced, serous detachment of the RPE in approximately 10% of cases. In the majority of cases, this detachment is caused by choroidal neovascularization. Because of the cartwheel or seafan pattern of sub-RPE CNVM and because of the relatively firm connection established between the new capillaries and the base of the overlying RPE, there is a predilection for serous exudation and/or hemorrhage to occur near the margin of the CNVM. This results in detachment of the adjacent RPE around the margin of the CNVM, and production of a variety of shapes of large RPE detachments (see Figures 2.09, 2.10, 3.21, and 3.22 ). If the detachment occurs at one segment of the edge of the CNVM, a flat-sided, reniform, or notched RPE detachment is the result ( Figures 3.21 and 3.22 ). If the detachment extends away from the entire margin of the CNVM, a doughnut-shaped RPE detachment may occur. Any of these irregularly shaped RPE detachments should suggest the probable presence of a CNVM that for the most part lies outside the area of RPE detachment, within either the notch or the central depressed area of the RPE detachment ( Figures 3.21 and 3.22 ). Biomicroscopically there may or may not be any other evidence of the presence of the CNVM in these areas. If serous detachment of the RPE overlying the CNVM occurs, a round or oval, dome-shaped detachment identical to an avascular RPE detachment may result. If serous detachment of the RPE develops adjacent to an organized sub-RPE detachment, an irregularly elevated, oval or dumbbell-shaped RPE detachment develops ( Figures 3.22A–C and 3.23A ). The details of the RPE and drusen are better preserved in the less-elevated, organized part of the detachment ( Figure 3.22 D). The presence of a dark meniscus (blood or blood pigment) at the dependent part of the serous RPE detachment ( Figure 3.21 G) or of subretinal blood or yellow exudate near its margin is evidence of the presence of a CNVM located either just outside of the edge of, or beneath, the RPE detachment.

Partly organized retinal pigment epithelium (RPE) detachments.

A–B: Two notched serous RPE detachments surrounding an elevated organized RPE detachment. The latter stained irregularly with fluorescein (B, stereo; arrows).

C–H: RPE tear occurring in partly organized serous RPE detachment in an 85-year-old man. Note drusen and pigment epithelial markings evident overlying nasal organized half of RPE detachment (arrows, C). Note uneven and incomplete staining of nasal part of RPE detachment (D and E). Several weeks later a tear has occurred along the temporal margin of the detachment (F). The edge of the tear has curled under and retracted nasally against the organized part of the detachment (arrow). Angiography showed minimal staining within the pigmented mound, indicating presence of choroidal new vessels (G). Several weeks later there was subretinal bleeding from the choroidal new vessels within the pigmented mound (arrows, H).

RPE tear posttreatment with ranibizumab.

I–L: This 65-year-old woman with a strong family history of age-related macular degeneration developed a fibrovascular pigment epithelial detachment that was asymptomatic (I) and found during follow-up of cataract surgery. She received intravitreal ranibizumab and noted distortion of vision after the second injection. A tear in the RPE was found and her vision had dropped to 20/40, quickly worsening to 20/400 in 3 weeks due to further retraction of the pigment epithelium (K). Four years later a large disciform scar with chronic subretinal fluid and blood in the eye could be seen.

Retinal pigment epithelium (RPE) tears in patients with age-related macular degeneration.

A–F: This 59-year-old woman developed metamorphopsia in the left eye. Arrowheads indicate angiographic evidence of partly organized portion of a bilobate RPE detachment (A and B) in April 1984. Note delay in complete staining of the inferonasal part of the RPE detachment (stereoscopic views B and C). In May 1984 she developed a rip in the RPE that extended beneath the center of the fovea (D and stereoscopic views E and F). Two months later, in spite of the subfoveal rip and serous detachment of the retina, her visual acuity corrected to 20/20. Ten months later the acuity was reduced to 20/200.

G: Diagram showing pathogenesis of RPE tear. Stage 1, Organized RPE detachment (arrow). Stage 2, Serous detachment of the adjacent RPE. Stage 3, Tear in the RPE and serous detachment of the retina. Stage 4, Free edge of torn RPE has rolled toward fibrovascular tissue and nonpigmented RPE has grown across the defect, causing resolution of the serous retinal detachment that occurred following the tear. Rr, retinal receptors; RPE, retinal pigment epithelium; cc, choriocapillaris.

H–K: This 88-year-old male developed an RPE detachment with subretinal and intraretinal fluid in his left eye (H). A rip occurred after his second intravitreal ranibizumab injection but the vision remained at 20/40 (I). A vertical section on optical coherence tomography reveals the discontinuity of the pigment epithelium (J) and the dark zone bereft of RPE on autofluorescence imaging (K).

(A–F case presented at Fluorescein Club Meeting November 11, 1984; G from Gass. )

The fluorescein angiographic findings are important in differentiating vascularized from nonvascularized serous RPE detachments. In vascularized serous RPE detachments, the sub-RPE exudate usually stains more slowly, presumably because of the presence of a large amount of protein and blood pigment within the exudate, and incompletely because of an uneven distribution of blood or a mound of fibrovascular tissue present beneath the RPE detachment ( Figures 3.21 and 3.22 ). When a serous RPE detachment arises at one edge of either a flat or elevated organized CNVM, angiography often shows early fluorescein staining of the sub-RPE serous exudate in the area of serous detachment but delayed and uneven or, occasionally, no staining in the area of the CNVM. In some cases, however, there may be an intensification of the staining of the sub-RPE exudate adjacent to the CNVM ( Figure 3.21 I). When exudate from the CNVM detaches the overlying as well as adjacent RPE to produce a round or oval detachment, slow or uneven staining of the sub-RPE exudate in the area of the neovascular complex may be the only clue to the presence of the underlying CNVM.

Serous RPE detachments caused by choroidal neovascularization are likely to be large, to develop evidence of hemorrhage and organization (sub-RPE fibrovascular proliferation), and to cause significant loss of central vision soon after onset of symptoms. Because portions of the CNVM are nearly always hidden from view beneath the RPE detachment, treatment with photocoagulation is difficult and of uncertain value.

Retinal Pigment Epithelial Tear

Patients who develop a serous RPE detachment extending away from one part of an organized RPE detachment are at some risk of developing an RPE tear spontaneously, during or following photocoagulation, and even following anti-VEGF therapy ( Figures 3.19 G, 3.22 , and 3.23 ). Typical pretear findings are: (1) a large, round, oval, or slightly dumbbell-shaped elevation of the RPE with one area less elevated than the other; (2) preservation of the RPE details, including drusen in the smaller, less elevated, organized portion of the RPE elevation; and (3) irregular and incomplete fluorescein staining in the area of less elevation, and delayed but even more intense staining of the sub-RPE exudate in the more elevated serous portion of the RPE detachment ( Figures 3.22 and 3.23 ). There may be no other biomicroscopic signs of underlying choroidal neovascularization. Either spontaneously or following treatment, an acute RPE tear may occur at or along the border of the serous RPE detachment on the side opposite the location of the new vessels. These patients usually notice an abrupt increase in visual loss caused by the passage of serous exudation from beneath the RPE into the subretinal space. Occasionally, however, patients may retain excellent visual acuity in spite of extension of the rip beneath the foveal center ( Figure 3.23 A–F, I, and J). Only if seen within 24 hours after the tear will the free edge of the RPE be seen before it rolls under and retracts toward the area of subretinal neovascular tissue.

By the time most patients present there is a crescent-shaped geographic zone of absent RPE adjacent to an elevated hyperpigmented mound composed of the retracted and rolled-under RPE collapsed against the surface of the fibrovascular tissue ( Figures 3.22 G and K). The retinal detachment resolves soon after development of the tear, presumably because of regrowth of hypopigmented RPE cells across the defect and perhaps also because of partial closure of the choriocapillaris ( Figures 3.22 and 3.23 ). In some patients this new growth of RPE is visible biomicroscopically as a blunting of the edges of the tear by ingrowth of a faintly opaque layer of tissue into the area of the tear. In some cases a prominent layer of fibrous metaplastic RPE grows into and obliterates evidence of the tear. Subretinal blood and lipid exudate frequently appear soon after development of the tear. Angiography done after the tear usually shows evidence of early nonfluorescence and mottled late staining in the area of the retracted and organized RPE mound, as well as marked diffuse early and late hyperfluorescence in the area of absent or hypopigmented RPE and staining of any subretinal fluid that is present ( Figure 3.22 ).

Hoskin and associates suggested that the pretear picture was best explained by separation of the RPE from its basement membrane in the area of maximum elevation, predisposing it to tear. This explanation, however, is unlikely because of the tight adhesion of the RPE to its basement membrane in normal as well as pathologic conditions, and because it does not explain the clinical and angiographic findings that suggest that underlying choroidal neovascularization is the primary cause of both the pretear and posttear appearance. Chuang and Bird and Bird and Marshall have stressed the importance of the hydrophobic nature of the lipidized Bruch’s membrane acting as a barrier to passage to fluid into the choroid in the pathogenesis of RPE tears in patients with AMD. The biomicroscopic and angiographic findings, however, strongly suggest that hydrostatic pressure generated by leakage of exudate from the margin of occult sub-RPE new vessels is the primary precipitating cause of most of the large, smooth-surfaced, blisterlike serous RPE detachments as well as the acute RPE tears that occur in patients with AMD ( Figure 3.20 G). Occasionally, however, rents developing in the thinned RPE at the edge of long-standing avascular serous RPE detachments are responsible for their spontaneous collapse. Patients with large RPE tears associated with AMD are at high risk of developing RPE tears in the fellow eye.

Angiographic evidence of microrips at the edge of smaller RPE detachments, with streaming of fluorescein dye into the subretinal space similar to that seen in patients with ICSC, occasionally occurs in patients with AMD. Likewise, large RPE tears similar to those associated with AMD occasionally occur in otherwise healthy patients with ICSC with large, often multifocal serofibrinous RPE detachments, and in patients with systemic lupus erythematosus and the same findings ( Figure 3.10 ). The RPE tears in these patients are presumably caused by hydrostatic pressure generated by severe focal damage to the permeability of the choriocapillaris (see discussion in earlier section on ICSC).

Tears in the RPE may occur along the juncture of fibrovascular elevation of the RPE and serous RPE detachment during applications of photocoagulation to the neovascularization. These tears occur most frequently during treatment of hypopigmented, thick subretinal neovascular membranes with krypton red laser and are caused by contraction of the fibrovascular tissue comprising the membrane.

Radiating Chorioretinal Folds Surrounding Partly Organized RPE Detachments

Spontaneous contraction of the fibrovascular tissue often hidden beneath serous RPE detachments may pucker Bruch’s membrane and cause a series of radiating chorioretinal folds around the base of the RPE detachment (see Figure 4.04). The radial pattern of yellow rays seen ophthalmoscopically and the hyperfluorescent rays seen angiographically are produced by the linear ridges of infolding of the RPE and choroid. This pattern of folds may be the only ophthalmoscopic sign of occult choroidal neovascularization detectable in some patients with large serous detachments of the RPE. It is curious that this radiating pattern of folds does not occur more often in response to photocoagulation of CNVM. The forces producing this radiating pattern of chorioretinal folds are similar to those responsible for a finer pattern of superficial inner retinal folds radiating outward from a contracted epiretinal fibrocellular membrane.

Linear Chorioretinal Folds Associated with Organized RPE Detachments

A series of slightly irregular chorioretinal folds may develop on the surface of organized RPE detachments if the superficial portion of the sub-RPE fibrovascular tissue undergoes shrinkage.

Hemorrhagic Detachment of the RPE and Retina

Bleeding from the margin of a CNVM may be mild and cause only mild blurring of vision. Spontaneous rupture of a blood vessel usually near one margin of a CNVM, however, may cause sudden loss of central vision secondary to a large hemorrhagic detachment of the RPE and retina ( Figures 3.24 and 3.25 ). Initially the blood may be confined to the sub-RPE space and ophthalmoscopically may cause a dark, almost black, discretely elevated mound beneath the retina. Drusen are often evident on the surface of this mound. At the time of the hemorrhage or within a few days or weeks the blood dissects through the edge of the RPE detachment and spreads in a shallow layer into the subretinal space, where it often appears as a reddish halo at the margin of the RPE detachment ( Figure 3.24 ). The dark appearance of blood beneath the RPE is caused by the moundlike collection of blood and not by its mere presence beneath the RPE. The reddish appearance of the surrounding subretinal blood is caused by the absence of the filtering effect of the RPE but also by the thinness of the layer of blood. Large mounds of blood, whether beneath the RPE or the retina or within the vitreous cavity, often have a black appearance. In a few patients during the early weeks after the bleeding episode there may be remarkable retention of visual function in spite of a large subfoveal hematoma.

Hemorrhagic disciform detachment stages occurring in patients with drusen.

A and B: Hemorrhagic detachment in a 68-year-old man with drusen. Most of the blood is in the subretinal space and was derived from a choroidal neovascular membrane in the papillomacular bundle region (arrows, A). Visual acuity in this eye was 20/50. There was spontaneous resolution of subretinal blood and return of visual acuity to 20/25. B was taken 3 years after A.

C and D: Spontaneous resolution of large black hemorrhagic detachment of retinal pigment epithelium (RPE) and retina (C). The disciform scar (D) extended to the inferior edge of the foveal center.

E and F: This patient was referred for treatment of a choroidal melanoma. The irregular brown color change in the sub-RPE and subretinal blood was responsible for the misdiagnosis. Angiography showed no evidence of fluorescence within the lesion (F).

G: Large hemorrhagic detachment of the RPE in a patient with macular drusen. Bleeding occurred from new vessels lying beneath the RPE (arrow).

(From Gass. )

Severe intraocular hemorrhage caused by age-related macular degeneration (AMD).

A–E: Three months after a large hemorrhagic detachment of the retina and retinal pigment epithelium (RPE) (A) in the left eye, this elderly man returned with blood staining of the vitreous (B) and iris (arrow, C). Over a 6-month period the vitreous cleared and the iris returned to its normal blue color (D). A large disciform scar was present in the macula (E).

F: Secondary subretinal hemorrhage occurring at the temporal edge of a disciform scar. Compare with J.

G and H: Extensive subretinal, suprachoroidal, and intravitreal bleeding occurring spontaneously in the left eye of an elderly patient with AMD and a disciform lesion in the right eye.

I: Massive subretinal and intravitreal hemorrhage caused by bleeding from a focal area of sub-RPE neovascularization in the macular area (arrow). This occurred in a 66-year-old man with essential hypertension, chronic lymphatic leukemia, and drusen in the macula of the opposite eye.

J: Secondary sub-RPE hemorrhage occurring at the temporal margin of an old disciform scar (arrow) in the macula of an elderly patient whose eye was misdiagnosed as having a malignant melanoma of the choroid.

(I and J from Gass. )

Blood in the subretinal and sub-RPE space typically obscures completely the underlying choroidal fluorescence and most or all of the fluorescein leaking from the neovascular complex ( Figure 3.24 ). The absence of subretinal fluorescence serves to differentiate a dark mound of blood from a choroidal melanoma, which always shows evidence of late staining because of blood vessels near its surface ( Figure 3.24 E and F). Once bleeding occurs in the sub-RPE space, varying degrees of organization of the blood occur and there is usually extensive degeneration of both the overlying pigment epithelium and retina. Conversely, blood present in the subretinal space may reabsorb completely with variable and often minimal permanent damage to the structure and function of the overlying retina ( Figure 3.24 A and B).

Many patients who develop large hemorrhagic macular detachments will experience transient loss of peripheral vision that in most cases is caused by diffusion of hemoglobin, rather than whole blood, into the vitreous several weeks or months after the hemorrhagic detachment occurs. The fundus may be completely obscured from view for many months ( Figure 3.26 A–E). This process of anterior diffusion of hemoglobin across the relatively intact retina after damage to the outer barrier structures of the retina by the subretinal blood is similar to that which occurs in some patients after a massive hyphema with hemoglobin diffusing across damaged corneal endothelium and Descemet’s membrane to cause blood staining of the cornea. The breakdown products of blood may stain not only the vitreous but also the iris stroma. This causes a yellow-brown discoloration of the vitreous and a noticeable heterochromia in lightly pigmented individuals ( Figure 3.26 B and C). Usually after 3–6 months or longer, as the blood pigment is phagocytosed, the iris regains its normal color, the vitreous clears, and the peripheral vision returns. Poor central vision and a large disciform scar are usually the end result ( Figure 3.26 E). In elderly patients presenting with intravitreal blood, AMD should always be considered as a possible cause. Evidence of AMD in the opposite eye is an important clue to the correct diagnosis. Ultrasonographic demonstration of a mass of variable reflectivity in the macular area of these patients is helpful in excluding some of the other causes of vitreous hemorrhage.

Massive exudative and hemorrhagic detachment of the retinal pigment epithelium (RPE) and retina caused by pre-equatorial type I sub-RPE neovascularization.

A–C: This 83-year-old woman with macular drusen developed loss of central vision bilaterally because of posterior extension of subretinal lipid exudation arising in a large peripheral exudative and hemorrhagic subretinal neovascular complex (A and B). Laser photocoagulation and transscleral cryopexy were successful in destroying the new vessels and causing resolution of the submacular exudation (C).

D–F: Multiple areas of peripheral hemorrhagic detachment of the RPE and retina in an 87-year-old man with minimal evidence of macular degeneration.

G–J: Histopathologic findings in an elderly woman who initially had the same ophthalmoscopic findings seen in D–F. She developed massive sub-RPE, subretinal, and vitreous hemorrhage just before death while in the hospital. Arrow (G) indicates site of sub-RPE neovascular network and hemorrhage. Bleeding from a neovascular network lying along the inner side of Bruch’s membrane (white arrows, H) near the equator was responsible for the hemorrhagic detachment of the RPE (black and white arrows). Note rupture of blood vessels in sub-RPE neovascular network (black arrows, I) internal to Bruch’s membrane (white arrows). J shows sub-RPE neovascular network (black arrows) on the inner surface of the Bruch’s membrane (white arrows) in another area of the same eye.

In patients with moderate to large areas of hemorrhagic detachment of the RPE and retina, photocoagulation is often not effective because the blood obscures at least part of the CNVM from view. In cases where the bleeding appears to have occurred from one edge of the CNVM and where the configuration of the CNVM suggests that it does not extend far beneath the blood, photocoagulation of the CNVM with a long-wavelength laser may be of some value.

Chronic Exudative and Hemorrhagic Stages

Once the process of exudation and hemorrhage begins, the CNVM usually continues to enlarge, often in a concentric manner. Oozing of blood cells from the outer dilated margin of the CNVM occurs frequently and is responsible for the flecks of subretinal blood that may intermittently appear at its margins ( Figure 3.27 A). The dark irregular areas often seen angiographically at the edge of these sub-RPE membranes, even in the absence of biomicroscopic evidence of blood, are probably caused by breakdown products of blood accumulating there. The yellow exudate that occurs in the outer retinal layers and subretinal space peripheral to the area of choroidal neovascularization is caused by precipitation of the lipid component of the exudate as water is drawn into the normal blood vessels of the retina and choroid (see pp. 46–47). The expanding neovascular complex causes nutritional damage to the outer layers of the overlying retina, and once the membrane has grown beneath the center of the fovea, loss of useful central vision is usual, but not always a certainty. Involution of this neovascular process may occur at any stage of its development and typically occurs within several years. Approximately 70% of eyes that develop detachment caused by a CNVM extending into the capillary-free zone of the retina will have a visual acuity of 20/200 or less within 1 year.

Reparative and cicatricial stages of disciform macular detachment in patients with drusen.

A: Partial resolution of hemorrhagic detachment of the retinal pigment epithelium (RPE) and retina. Note evidence of degradation of the blood lying beneath the RPE (arrows). There has been little change in the subretinal blood that surrounds the RPE detachment (see G).

B: Partly organized, pigmented subretinal disciform mass (arrows) stimulating a melanoma.

C: Large, white fibrovascular disciform scar with retinochoroidal anastomosis (arrow).

D–F: Bilateral patchy fibrous proliferation and diffuse atrophy of the retinal pigment epithelium with extracellular pigment clumps (D and E). The autofluorescence image reveals the diffuse loss of RPE resulting partly from atrophy and partly from retraction by the fibrovascular tissue (F).

G: Photomicrograph of hemorrhagic detachment of the RPE and retina in a patient similar to A. Blood in the sub-RPE space has undergone greater degradation than that in the subretinal space.

H: Photomicrograph of a pigmented vascularized subretinal scar following hemorrhagic detachment of the RPE and retina. Note degeneration of the outer retinal layers and degeneration and proliferation of the RPE overlying fibrovascular scar. Arrow indicates Bruch’s membrane.

(C from Gass ; G and H from Gass. )

Cicatricial Stage

Involution of the neovascular complex eventually occurs and is associated with varying degrees of subretinal scar tissue, depending primarily on the duration and extent of hemorrhage and exudation ( Figure 3.27 ). In some cases, neovascularization extending throughout the macula may be associated with minimal reactive hyperplasia and fibrous metaplasia of the RPE, and the large neovascular membrane after involution may be difficult or impossible to demonstrate biomicroscopically or angiographically. In some cases the larger radial vascular trunks of the involuted membranes may be visible as red vessels superimposed over the usually partly yellow-colored larger choroidal vessels ( Figure 3.27 D–F). The slow rate of blood flow in these involuted neovascular membranes may prevent their demonstration angiographically. Angiography may demonstrate nothing more than a circular area of mottled or early hyperfluorescence and minimal or no staining. In some cases, cystoid macular edema and degeneration may be present overlying flat, difficult-to-detect, involuted neovascular membranes that extend into the center of the fovea (see pp. 42 and 43).

Following development of a large hemorrhagic detachment of the RPE and retina, degradation of the blood beneath the RPE usually causes a brown or yellowish sub-RPE mass to form ( Figure 3.24 E). The blood in the subretinal space surrounding the RPE detachment often requires a longer period of time before a color change is noted and before the blood is degraded ( Figure 3.27 A). There is a gradual organization of the sub-RPE blood and exudate by further ingrowth of new vessels and fibroblasts from the choroid ( Figure 3.27 G). Eventually the exudative mass may be replaced by fibrous tissue containing varying degrees of hyperplastic RPE ( Figure 3.27 B, C, and H). The cicatricial lesions vary in color from white to brown or even to black and may be mistaken for choroidal melanomas ( Figure 3.27 B). Often anastomosis between the retinal circulation and underlying choroidal circulation develops within these old disciform scars ( Figure 3.27 C). There is a general tendency for the development of a similar pattern and size of disciform detachment in the fellow eye. Fluorescein angiography in the cicatricial stages of disciform detachment demonstrates a wide variety of pictures, some of which may be similar to that produced by choroidal neoplasms.

Massive Exudative Detachment of the Retina (Senile Coats’ Syndrome)

In most patients with drusen, the area of disciform detachment is confined to the macular area and peripheral vision is maintained. A few patients, however, show progressive exudative detachment of the retina that spreads far beyond the macular region and may cause severe loss of peripheral as well as central vision ( Figure 3.28 D–J). Multifocal areas of eccentric choroidal neovascularization and serous detachment of the RPE and retina may occur. Extensive deposition of yellowish exudate occurs in the subretinal space and in the outer layers of the retina. It typically spreads initially in an inferior direction. The fundus may resemble that usually seen in younger patients with massive yellowish exudative detachment of the retina secondary to congenital telangiectasis of the retinal vessels (the most common cause of Coats’ syndrome in young patients). The cause of this unusual degree of exudation from the choroid in these elderly patients is unknown. The exudate may eventually resolve spontaneously, but it leaves in its wake marked widespread degenerative changes in the RPE and retina. Retinal neovascularization and vitreous hemorrhage may arise as complications of the chronic exudative detachment.

Bullous Serous Retinal Detachment

Rarely these patients will develop massive bullous serous detachment of the retina caused by chronic leakage of serous exudate from large, highly vascularized RPE detachments or disciform mounds that are usually located in or near the macular area ( Figure 3.28 D–J). Long-duration, moderately intense, large-size applications of laser photocoagulation to these fibrovascular RPE detachments, occasionally photodynamic therapy and anti-VEGF therapy may cause reattachment of the retina and return of ambulatory vision ( Figure 3.28 ).

Massive exudative retinal detachment (Coats’ syndrome) caused by age-related macular degeneration.

A and B: Right eye of patient with large disciform detachment and subretinal and intraretinal lipid exudation that extended to the ora serrata inferiorly.

C: Histopathology of massive lipoproteinaceous subretinal exudation overlying a large macular and juxtapapillary choroidal neovascular complex in an elderly patient with age-related macular degeneration.

D–J: Massive exudative bullous retinal detachment caused by a large, orange, organized extramacular retinal pigment epithelium (RPE) detachment (arrows, D–H) in the right eye of a 74-year-old man whose left eye was blind from rubeotic glaucoma caused by a similar massive exudative retinal detachment complicating age-related macular degeneration. Note that the organized RPE detachment located temporal to a white disciform scar showed minimal evidence of fluorescein staining (arrows, E–G). Argon photocoagulation was placed on the surface of the organized RPE detachment (arrows, I) and was successful in causing resolution of the bullous retinal detachment and restoration of ambulatory vision 4 months after treatment (J).

Secondary Hemorrhage from a Disciform Scar

A secondary exudative or hemorrhagic detachment of the RPE can develop around the edge of an old disciform scar and produce a lesion adjacent to the scar that on occasion may cause the physician to remove the eye because of a suspected melanoma ( Figure 3.25 F and J).

Vitreous Hemorrhage

The initial hemorrhage from CNVMs may dissect its way into the retina where it is visible biomicroscopically as a focal intraretinal hemorrhage. The bleeding may be sufficiently intense that blood may break through the retina into the vitreous and cause a massive vitreous hemorrhage ( Figure 3.01 ). This process of dissection of blood through a defect in the retina is different from that of blood staining of the vitreous, which occurs more frequently in these patients as a delayed phenomenon following large hemorrhagic detachments of the RPE and retina (see previous discussion).

Massive Hemorrhagic Detachment of the RPE and Retina

Rarely hemorrhage from a CNVM in the macular region may produce a massive detachment of the RPE, retina, and choroid, as well as vitreous hemorrhage, closed-angle glaucoma, and loss of the eye. This is more likely to occur in patients receiving anticoagulant therapy or with a systemic disease affecting the clotting mechanism ( Figure 3.25 G–I).

Peripheral Exudative and Hemorrhagic Disciform Detachment

Elderly patients with macular drusen or without evidence of AMD may develop serous and hemorrhagic detachment of the retina secondary to one or more sites of sub-RPE neovascularization in the equatorial or pre-equatorial area, usually in the temporal half of the eye ( Figure 3.26 ). Large areas of serous or dark-colored hemorrhagic detachment of the RPE in the periphery may be mistaken for a choroidal melanoma because of the detachment’s unusual peripheral location. Many of these patients will show some evidence of peripheral sub-RPE neovascularization in the temporal portion of the opposite eye. These detachments will usually resolve spontaneously without treatment. In those cases complicated either by bullous exudative retinal detachment or by extension of yellowish exudate derived from the neovascular network into the macula, photocoagulation or cryotherapy may be beneficial ( Figure 3.26 A–C). Peripheral sub-RPE neovascularization frequently develops as part of the normal aging process in the peripheral fundus and is derived primarily from the ciliary body rather than the choroid ( Figure 3.26 ). (See discussion of peripheral idiopathic choroidal neovascularization, p. 140.)

Geographic or Central Areolar RPE Atrophy

Although most patients with drusen lose useful central vision because of complications of choroidal neovascularization, approximately 5–10% lose central vision as a result of the development of one or occasionally more sharply circumscribed geographic areas of atrophy of the RPE and retina in the posterior pole ( Figure 3.29 ). Dehydration and calcific crystallization of drusen are often the forerunners of geographic atrophy that may begin either centrally or paracentrally. Loss of central vision occurs slowly and progressively as the area of atrophy concentrically enlarges. A similar pattern of atrophy is often seen in the second eye. Approximately 20% of these patients, however, who develop geographic atrophy in one eye will develop choroidal neovascularization and its complications in the second eye. Fluorescein angiography shows varying degrees of loss of the choriocapillaris within the area of geographic atrophy ( Figure 3.29 G and H). Histologically the area of geographic atrophy is associated with focal loss of the retinal receptor cells and RPE and varying degrees of atrophy of the choriocapillaris ( Figure 3.29K and L ).

Geographic atrophy in patients with macular drusen.

A–C: Gradual enlargement of area of geographic atrophy occurred in a 63-year-old man over a 6-year period. Visual acuity in A was 20/60 and in C was 20/200. Note changing pattern of drusen, some of which are calcified (arrows).

D–F: In 1970 this 61-year-old woman presented with bilateral large drusen and a serous detachment of the retinal pigment epithelium (RPE) (arrows, D) in both eyes. Note the scalloped border of the RPE detachment resulting from confluence of large drusen. Visual acuity was 20/30 bilaterally. The right eye was treated with laser applications to the margin of the RPE detachment. The RPE detachment in the left eye spontaneously collapsed and was replaced by a pattern of geographic atrophy that changed very little between 1974 (E) and 1985 (F), at which time both fundi looked similar and the visual acuity was 20/50 bilaterally.

G–J: Geographic atrophy of the RPE in a 71-year-old woman with large drusen. Similar changes were present in the fellow eye. Early angiogram showed evidence of partial preservation of the choriocapillaris in the area of geographic atrophy (H). Late angiogram showed staining of the choroid (I). Several years later many of the drusen have faded and the area of geographic atrophy has enlarged. Note calcification of some of the drusen (arrows).

K and L: Geographic atrophy in a 65-year-old man with drusen. His visual acuity was 3/200 in the right eye and 20/80 in the left eye 4 months before he died. Histopathologic examination revealed a sharp margin between the relatively normal retina and choroid and a zone of absence of the outer retinal layers and RPE (L). There was partial closure of the choriocapillaris in the region of the geographic atrophy.

The pathogenesis of these sharply circumscribed areas of atrophy is not understood. It is not known whether the partial obstruction and atrophy of the choriocapillaris are the primary cause of, or the result of, the overlying RPE and retinal atrophy. Geographic atrophy of the RPE, retina, and choriocapillaris is an ophthalmoscopic finding that occurs in association with many other diseases, including Sorsby’s central areolar choroidal sclerosis, basal laminar drusen, Stargardt’s disease, Best’s vitelliform macular dystrophy, cone dystrophies, rod–cone dystrophies, chloroquine retinopathy, ICSC, and traumatic maculopathy. In patients with AMD, geographic atrophy may develop in at least the following three ways: (1) with no precursor lesion other than macular drusen; (2) following an acute tear in the RPE (see pp. 108 and 111); and (3) following collapse of a long-standing serous RPE detachment.

Surgical Treatment for Complications of AMD

Pars plana vitrectomy has proved useful in removal of vitreous blood that fails to reabsorb spontaneously ( Figure 3.30 H–L). It also appears to have some usefulness in the evacuation of large subretinal hematomas in the macular area, particularly when used in association with tissue plasminogen activator. Surgical excision of CNVMs, which lie in the sub-RPE space in patients with AMD, appears to offer no advantages over laser photocoagulation in regard to restoration or preservation of visual function. Both result in permanent loss of retinal function in the area of the neovascular membrane. (See discussion of surgical excision of types I and II choroidal neovascularization in Chapter 2.) There is hope that transplantation of RPE after surgical excision of subfoveal membranes, or other modifications of the surgical technique, will improve the visual results. Surgical relocation of the macular retina has been suggested as another possible method of restoring central vision in patients with AMD.

The high susceptibility of the retina to oxidative stress because of the close proximity of high concentrations of polyunsaturated fatty acids in the photoreceptor outer-segment membrane, where exposure to short-wavelength light may generate free radicals, has suggested the possible value of antioxidants in retarding the development of AMD. There is evidence that increased serum levels of alpha-tocopherol, and an antioxidant index, including ascorbic acid, alpha-tocopherol, and beta-carotene, are protective for AMD. There is, however, no evidence to show that daily supplementation of vitamins or minerals is of any value in preventing or ameliorating AMD. The Age-Related Eye Disease Study found retardation of progression of nonexudative AMD in approximately 29% of patients treated with antioxidant viatamins, zinc, and copper. Several pilot studies have suggested that low-dose external-beam irradiation treatment may be of value in the treatment of subfoveal neovascularization. Recognition of the earliest symptoms of macular detachment by the patient and prompt examination (within several days after onset) by the ophthalmologist are the best means of preventing loss of vision in this disease. Patients should be instructed in regard to the use of the Amsler grid and near-vision chart and the importance of prompt examination. The role of trauma, intraocular surgery, and anticoagulants in precipitating exudation and hemorrhage in these patients is uncertain.

Most patients who have lost central vision in both eyes will benefit from the use of any one or several of the wide variety of low visual aids available.