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Clinicopathologic Correlation of Successfully Treated Choroidal Neovascularization Lying Within the Notch of a Large Serous Retinal Pigment Epithelial Detachment
Arch Ophthalmol. 2004;122:1383-1390.
We report the histopathologic features of a successfully treated serous retinal pigment epithelial detachment (RPED) with accompanying choroidal neovascularization (CNV) in a 74-year-old woman with age-related macular degeneration (AMD). These findings were correlated with antemortem fluorescein and indocyanine green (ICG) angiographic studies. Histopathologic studies showed that the serous RPED represented a separation of the retinal pigment epithelium (RPE) and its basal lamina from the remainder of the Bruch membrane with no intervening CNV. Laser photocoagulation had successfully closed the accompanying sub-RPE (Gass type 1, presumed intra-Bruch) choroidal neovascular membrane. The RPED resolved, leaving a fairly well-preserved RPE monolayer, which reapposed the Bruch membrane, allowing retention of very good vision for 21 months. Additionally, in an area of drusen resorption, only small calcific deposits remained and there was no remaining basal laminar deposit.
Only a limited number of previous reports describe histopathologic correlative studies with recent fluorescein and ICG angiography in eyes with CNV associated with AMD.1-2 In this study, we report, to our knowledge, the first such case of an eye successfully treated with laser photocoagulation for a serous RPED with CNV and resorption of accompanying drusen.
Report of a Case
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A 74-year-old woman with AMD had a 2-month history of blurred central vision in her right eye. The vision in her left eye had been poor for 10 years because of exudative AMD. Her medical history was remarkable for hypertension, coronary artery disease, peripheral vascular disease, and colon cancer. She did not smoke.
On examination, visual acuity was 20/30 OD with no scotomata or metamorphopsia by Amsler grid testing. Visual acuity OS was counting fingers at 4 ft. Funduscopic examination results of the right eye disclosed a sharply circumscribed, dome-shaped detachment of the macular RPE, with a shallow overlying sensory retinal detachment. Large drusen were seen throughout the posterior pole, and there was a small patch of geographic atrophy temporal to the fovea within the area of detached RPE. Examination results of the left eye revealed disciform macular scarring, exudation, subretinal fibrosis, RPE migration, and hyperplasia (Figure 1). The fluorescein angiogram of the right fundus revealed a well-circumscribed area of early hypofluorescence with progressive hyperfluorescence in the later phases corresponding to the RPE elevation seen clinically. Along the nasal border of the lesion, a notched area was present in which there was delayed filling and irregular late hyperfluorescence. Results of ICG angiography demonstrated well-demarcated hypofluorescence corresponding to the RPED in the early and late phases. Within the nasal notch of the RPED, an expanding area of focal hyperfluorescence was present (Figure 2). Another less well-defined notch superior to the border of the RPED shows stippled leakage in the later fluorescein phases and staining in the late ICG angiography phases.
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Figure 1. Fundus photograph from a 74-year-old woman with a sharply circumscribed, dome-shaped elevation of the retinal pigment epithelium in the right eye with overlying serous retinal detachment (arrowheads) and a nasal notch (white arrowhead). Large drusen are scattered throughout the posterior pole, and a small patch of geographic atrophy is located temporal to the fovea (arrow).The left eye (OS)shows disciform macular scarring, exudation, subretinal fibrosis, retinal pigment epithelium migration, and hyperplasia.
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Figure 2. A-C, Fluorescein angiographic results of the right eye show a well-circumscribed area of early hypofluorescence with progressive hyperfluorescence in the later phases corresponding to the retinal pigment epithelium elevation seen clinically. Along the nasal border of the lesion, a notched area was present in which there was delayed filling and irregular late hyperfluorescence. D-F, Indocyanine green angiographic results of the right eye show well-demarcated hypofluorescence corresponding to the retinal pigment epithelial detachment (RPED) in the early and late phases. E, Within the nasal notch of the RPED, an expanding area of focal hyperfluorescence was present (arrowhead). F, Laser treatment results of the right eye. Argon green laser photocoagulation was applied to the area of choroidal neovascularization (arrow). Additionally, isolated laser applications were placed along the margin of the RPED (arrowheads).
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Argon green laser photocoagulation (175 applications; 200-µm spot size; 0.2-second duration burns up to 220 mW) was applied to the focal area of the presumed CNV at the nasal border of the RPED. Additionally, isolated laser applications were placed along the margin of the RPED (Figure 2).
The patient returned 1 month later. Visual acuity was 20/40 OD, and the macula was flat. Fluorescein and ICG angiographic study results revealed no leakage from the CNV and no hyperfluorescence in the area of the RPED (Figure 3). The patient returned at 3, 5, and 8 months with no evidence of CNV or RPED recurrence.
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Figure 3. A, One month posttreatment, fundus examination results show flattening of the retinal pigment epithelial detachment with a nasal laser scar. B and C, Fluorescein angiographic results show late staining without leakage in the areas of photocoagulation. D and E, The indocyanine green angiogram shows hypofluorescence in these areas. No focal or plaque hyperfluorescence was noted.
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Fifteen months after treatment, visual acuity was 20/25 OD. Fundus examination results revealed a flat macula with a photocoagulation scar nasal to the fovea. When compared with pretreatment photographs, drusen were fewer in the posterior pole (Figure 4).
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Figure 4. Fundus photographs compare the right eye pretreatment (A) and 15 months posttreatment (B).The posttreatment photograph shows a flat macula, nasal laser scar, and reduction in drusen compared with the pretreatment photograph.
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Twenty-one months after laser photocoagulation and 5 months after her most recent examination, the patient died following treatment for recurrent colon cancer.
Results
The eyes were enucleated 3 hours post mortem and fixed 13 hours thereafter in 4% buffered formaldehyde. The paraffin-embedded serial sections were cut parallel to the pupil, optic nerve, and macula plane, and the slides were stained with hematoxylin-eosin. Using a microscope fitted with a calibrated reticule, histopathologic features were measured and plotted to yield a 2-dimensional cylindrical projection of the optic disc and macula (Figure 5). This cartographic method has been described previously.3-5 The histopathologic and angiographic correlates are summarized in Table 1.
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Figure 5. Histopathologic map of the left eye. CNV indicates choroidal neovascularization; RPE, retinal pigment epithelium.
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Correlation of Histopathologic Features With Angiographic Findings
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We studied the following regions: resolved RPED (Figure 6), successfully photocoagulated CNV (Figure 7), photocoagulation scars, and resorbed drusen (Figure 8).
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Figure 6. In the region of resolved retinal pigment epithelial detachment, the photoreceptor nuclear density is attenuated (arrowhead). Hypocellular, eosinophilic fibrous tissue remains between the retinal pigment epithelium and its basal lamina and the presumed outer layers of the Bruch membrane (arrows). A mildly disrupted retinal pigment epithelial monolayer has reapproximated the Bruch membrane (hematoxylin-eosin, original magnification x100 (A); original magnification x200 [B]).
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Figure 7. The photocoagulated choroidal neovascularization (asterisk) resides between the plane of the retinal pigment epithelium (arrowhead) and the presumed outer layers of the Bruch membrane (arrow). Note the scarring of the inner choroid, absence of choriocapillaris, and loss of retinal pigment epithelial cells and outer nuclear layer as a result of laser photocoagulation (hematoxylin-eosin, original magnification x200).
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Figure 8. Resorbed soft drusen. Sub–retinal pigment epithelium (presumed intra-Bruch) calcification present in areas where drusen resorbed (arrows). No basal laminar deposit is seen. The outer nuclear layer is attenuated (arrowheads) (hematoxylin-eosin, original magnification x200).
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In the region of resolved RPED, a mildly disrupted RPE monolayer apposed the Bruch membrane. The neurosensory retina was thinned, and the photoreceptor nuclear density was reduced. One to 3 layers of cell nuclei were found in the outer nuclear layer of this eye compared with 7 to 9 layers found in previously studied normal-aged retinas.6-7 A thin layer of hypocellular eosinophilic fibrous tissue was beneath the RPE. This material was different than its basal laminar deposit because it lacked the anteroposterior striated appearance described by Sarks and Sarks.8 This region did not exhibit any distinguishing angiographic characteristics. There was no transmission defect to suggest RPE atrophy. During tissue processing, serial sections did not include the region superior to the RPED. Therefore, no histopathologic commentary could be made about the corresponding area of stippled leakage in the later fluorescein phases and staining in the late ICG phases.
Good histopathologic correlation was seen with the clinical and angiographic findings of successfully treated CNV.9-10 Hypocellular fibrous tissue was found beneath the RPE and its basal lamina. This treated CNV is a sub-RPE (Gass type 1, presumed intra-Bruch) membrane, which communicates with the choroid via 2 endothelium-lined breaks in a layer presumed to be the outer layer of the Bruch membrane (Figure 9). This region corresponded to hypofluorescence in early and late phases with no leakage in both fluorescein and ICG angiography.
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Figure 9. A choroidal vessel perforated the presumed outer layer of the Bruch membrane (arrow) to communicate with the photocoagulated sub–retinal pigment epithelium (RPE) (Gass type 1, presumed intra-Bruch) choroidal neovascularization (CNV) (asterisk). The CNV resided in the same plane and adjacent to the RPE detachment, between the plane of the RPE (arrowhead) and the outer layers of the Bruch membrane (hematoxylin-eosin, original magnification x200).
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The regions of photocoagulation at the nasal notch and at the margin of the RPED were characterized by thinning of the neurosensory retina with destruction of the inner nuclear, outer plexiform, and photoreceptor layers. There was hyperplasia of the retinal pigment epithelial cells. Fibrocellular tissue was found beneath the retina and in the inner choroid, along with destruction of adjacent choroidal vessels. This area corresponded to well-demarcated hypofluorescence in early phases with staining of the edges in the late phases on the fluorescein angiogram. On the ICG angiogram, the photocoagulation scars corresponded with well-demarcated hypofluorescence in both the early and late phases.
Examination of the area of drusen resorption disclosed separation of the Bruch membrane into an inner layer (RPE basal lamina) and an outer layer, whose elastic layer was undulated. Calcification was evident in this presumed intra-Bruch space. No basal laminar deposit was present in this area. This region displayed no distinguishing angiographic features.
Comment
Serous RPEDs from the Bruch membrane have distinctive clinical and angiographic features and often contribute to loss of central vision in patients with AMD.11-12 Serous RPEDs have been qualified as avascular or vascularized to denote the absence or presence of associated CNV.
Avascular serous RPEDs, sometimes referred to as drusenoid RPEDs, presumably form as soft drusen progressively accumulate, enlarge, and coalesce. These elevations of RPE typically develop slowly and initially may cause milder complaints of blurring and metamorphopsia. Angiographic results outline these lobular or scalloped lesions as the material beneath the RPE stains with fluorescein. The late staining may be irregular depending on the density of the material beneath the RPE. In the absence of CNV, vision loss may be minimal or progress slowly. Occasionally, the detachment may spontaneously flatten.13-14
With vascularized RPEDs, patients tend to experience acute vision loss as they develop sharply demarcated, dome-shaped elevations of the RPE, often accompanied by elevation of the overlying neurosensory retina. In AMD, serous RPEDs are usually accompanied by angiographic evidence of CNV and constitute approximately 15% of eyes with neovascularization (M.L.K., unpublished data, 1998). If the detachment occurs at the edge of the CNV, a reniform detachment results. In these lesions, the sub-RPE material within the dome stains slowly and unevenly. Irregular early hyperfluorescence and evidence of late staining may or may not occur in the area of CNV that lies in the notch.13-14
In 1984, Gass13 presented the concept that notched serous RPEDs are often caused by occult, flat sub-RPE CNV lying within the notch outside the margin of the serous RPED and reported the case of successful treatment of these lesions with focal laser directed to the area of the notch with or without laser of the margin of the RPED. He also demonstrated the clinical and histopathologic findings of flat, focal, occult sub-RPE CNV lying within the notch causing a large hemorrhagic RPED. Since then, the term notched serous RPED has gained wide usage in describing these commonly occurring, potentially treatable lesions.14
For the last 20 years, the value of laser photocoagulation in such cases has been unclear. Investigators have reported that laser treatment is of no value.12, 15-17 Others report that if the CNV is identified and treated, flattening of the RPED will occur and vision can be preserved,18-19 as happened in this case. A basic assumption in treating such eyes is that the adjacent CNV is confined to an area identified on fluorescein or ICG angiography and not also located under the serous RPED. This study illustrates the histopathologic basis for successful treatment of CNV associated with a serous RPED, which is the absence of CNV in the area under the collapsed RPED. To our knowledge, only 2 other clinicopathologic cases of serous RPED with cartographic reconstruction have been reported.20-21 In both cases, the serous RPEDs were not treated and were represented histopathologically as a serous separation of the RPE and its basal lamina from the remainder of the Bruch membrane. Frank et al20 in 1973 correlated the fluorescein angiographic and histopathologic features of drusen, serous RPED without CNV, and serous neurosensory detachment in a patient with AMD. In 1976, Small et al21 reported a patient (case 2) with a serous RPED accompanied by an adjacent subfoveal CNV and correlated the fluorescein angiographic features with the histopathologic features also using cartographic reconstruction. In this patient, the subfoveal CNV, composed of fibrovascular tissue, resided beneath the RPE within a split in the Bruch membrane (Gass type 1) and was adjacent to serous separation of the RPE.
By correlating both fluorescein and ICG angiographic features with histopathologic characteristics and cartographic reconstruction, we demonstrated in this case that identification and ablation of extrafoveal CNV with argon laser treatment allowed the adjacent serous RPED to resolve, enabling the patient to maintain a visual acuity of 20/25 OD.
Another unique feature of this study was the histopathologic findings of resorbed drusen. Although resorption of drusen has been recognized clinically following laser photocoagulation,22-27 no information has been reported describing the histopathologic findings in an eye in which this has occurred.
In this eye, soft drusen were characterized by a localized RPED with underlying amorphous eosinophilic material and basophilic calcifications (Figure 10). Areas of drusen resorption were identified using cartographic correlation. In these areas, calcification was present within the Bruch membrane and no basal laminar deposit was evident (Figure 9). There was also separation of the presumed inner and outer layers of the Bruch membrane with an undulating contour. Although the separation may be an artifact of tissue processing, it does suggest the prior presence of some material in areas where drusen have resorbed. Additionally, in this region, the outer nuclear layer is attenuated indicating photoreceptor loss.
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Figure 10. Soft drusen. Localized detachment of the retinal pigment epithelium with underlying amorphous eosinophilic material (asterisk) and basophilic calcifications (arrowheads) (hematoxylin-eosin, original magnification x200).
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The phenomena of disappearing neighboring drusen after flattening both vascularized and nonvascularized RPEDs is seen frequently.14 This observation was partly responsible for the interest in using focal photocoagulation of some drusen to clear the macula of drusen. In this case, it is unclear whether disappearance of drusen was as a consequence of the development and flattening of the RPED itself or due to photocoagulation at the nasal notch and at the margin of the RPED. Histopathologic clues to resorption of drusen seen in this study have implications for trials such as the Complications of Age-related Macular Degeneration Prevention Trial28 in which a standardized grid of laser photocoagulation is applied to the macula in hopes of reducing drusen and preventing CNV. Although there are no clinical features that correspond to basal laminar deposits, it is almost certain basal laminar deposits were present in the area of resorbed drusen. Basal laminar deposits were present elsewhere, primarily nasal to the optic nerve head. This suggests that resorption of clinically apparent drusen may serve as a marker for resorption of basal laminar deposits. The RPE in the area of drusen resorption remained intact. Although there was some reduction in the thickness of the outer nuclear layer, there was clearly an intact photoreceptor-RPE complex in the area of drusen resorption.
In conclusion, when correlated with both fluorescein and ICG angiographic findings, this study illustrates histopathologic evidence for 2 important points. Eyes with serous RPED and adjacent CNV may be successfully treated if the CNV can be completely identified and photocoagulated. With closure of the CNV, the serous RPED can resolve, the RPE monolayer is relatively preserved, and vision can improve if the CNV is outside the fovea. Serous RPEDs probably develop because of a cleavage plane between the elastic portion of the Bruch membrane and the RPE and underlying basal laminar deposits. Fluid leaking out of adjacent CNV is able to dissect along this cleavage plane resulting in the serous RPED. Closure of the CNV with laser allows the resolution of the RPED (Figure 11).13-14 In areas of resorbed drusen, there is a relatively normal relationship between the RPE and the overlying photoreceptors.
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Figure 11. Diagrammatic representation.13,14 An extrafoveal sub–retinal pigment epithelium (RPE) (Gass type 1, presumed intra-Bruch) choroidal neovascularization adjacent to a serous RPE detachment was treated with laser photocoagulation. In this case, successful treatment resulted in closure of the choroidal neovascularization, resolution of the RPE detachment, relative preservation of the RPE monolayer, and preservation of good vision for 21 months.
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The authors have no relevant financial interest in this article.
This study was supported by an unrestricted fund from Research to Prevent Blindness, New York, NY, and the Heed Ophthalmic Foundation, Cleveland, Ohio (Dr Yoken).
This study was previously presented at the Verhoeff Society annual meeting; April 23, 1999; Portland, Ore, and the Association for Research in Vision and Ophthalmology annual meeting; May 10, 1999; Fort Lauderdale, Fla.
AUTHOR INFORMATION
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Andreas K. Lauer, MD;
Jonathan Yoken, MD;
Michael L. Klein, MD;
David J. Wilson, MD
Portland, Ore
Correspondence: Dr Lauer, Casey Eye Institute, Oregon Health and Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239.
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SECTION EDITOR: W. RICHARD GREEN, MD
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