Clinicopathologic Correlation of Successfully Treated Choroidal NeovascularizationLying Within the Notch of a Large Serous Retinal Pigment Epithelial Detachment

We report the histopathologic features of a successfully treated serousretinal 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 indocyaninegreen (ICG) angiographic studies. Histopathologic studies showed that theserous RPED represented a separation of the retinal pigment epithelium (RPE)and its basal lamina from the remainder of the Bruch membrane with no interveningCNV. Laser photocoagulation had successfully closed the accompanying sub-RPE(Gass type 1, presumed intra-Bruch) choroidal neovascular membrane. The RPEDresolved, leaving a fairly well-preserved RPE monolayer, which reapposed theBruch membrane, allowing retention of very good vision for 21 months. Additionally,in an area of drusen resorption, only small calcific deposits remained andthere was no remaining basal laminar deposit.

Only a limited number of previous reports describe histopathologic correlativestudies with recent fluorescein and ICG angiography in eyes with CNV associatedwith AMD.^1,2 In this study,we report, to our knowledge, the first such case of an eye successfully treatedwith laser photocoagulation for a serous RPED with CNV and resorption of accompanyingdrusen.

A 74-year-old woman with AMD had a 2-month history of blurred centralvision in her right eye. The vision in her left eye had been poor for 10 yearsbecause of exudative AMD. Her medical history was remarkable for hypertension,coronary artery disease, peripheral vascular disease, and colon cancer. Shedid not smoke.

On examination, visual acuity was 20/30 OD with no scotomata or metamorphopsiaby Amsler grid testing. Visual acuity OS was counting fingers at 4 ft. Funduscopicexamination results of the right eye disclosed a sharply circumscribed, dome-shapeddetachment of the macular RPE, with a shallow overlying sensory retinal detachment.Large drusen were seen throughout the posterior pole, and there was a smallpatch of geographic atrophy temporal to the fovea within the area of detachedRPE. 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 revealeda well-circumscribed area of early hypofluorescence with progressive hyperfluorescencein the later phases corresponding to the RPE elevation seen clinically. Alongthe nasal border of the lesion, a notched area was present in which therewas delayed filling and irregular late hyperfluorescence. Results of ICG angiographydemonstrated well-demarcated hypofluorescence corresponding to the RPED inthe early and late phases. Within the nasal notch of the RPED, an expandingarea of focal hyperfluorescence was present (Figure 2). Another less well-defined notch superior to the borderof the RPED shows stippled leakage in the later fluorescein phases and stainingin the late ICG angiography phases.

Argon green laser photocoagulation (175 applications; 200-µm spotsize; 0.2-second duration burns up to 220 mW) was applied to the focal areaof the presumed CNV at the nasal border of the RPED. Additionally, isolatedlaser applications were placed along the margin of the RPED (Figure 2).

The patient returned 1 month later. Visual acuity was 20/40 OD, andthe macula was flat. Fluorescein and ICG angiographic study results revealedno 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.

Fifteen months after treatment, visual acuity was 20/25 OD. Fundus examinationresults revealed a flat macula with a photocoagulation scar nasal to the fovea.When compared with pretreatment photographs, drusen were fewer in the posteriorpole (Figure 4).

Twenty-one months after laser photocoagulation and 5 months after hermost recent examination, the patient died following treatment for recurrentcolon cancer.

The eyes were enucleated 3 hours post mortem and fixed 13 hours thereafterin 4% buffered formaldehyde. The paraffin-embedded serial sections were cutparallel to the pupil, optic nerve, and macula plane, and the slides werestained with hematoxylin-eosin. Using a microscope fitted with a calibratedreticule, histopathologic features were measured and plotted to yield a 2-dimensionalcylindrical projection of the optic disc and macula (Figure 5). This cartographic method has been described previously.^3-5 The histopathologicand angiographic correlates are summarized in Table 1.

We studied the following regions: resolved RPED (Figure 6), successfully photocoagulated CNV (Figure 7), photocoagulation scars, and resorbed drusen (Figure 8).

In the region of resolved RPED, a mildly disrupted RPE monolayer apposedthe Bruch membrane. The neurosensory retina was thinned, and the photoreceptornuclear density was reduced. One to 3 layers of cell nuclei were found inthe outer nuclear layer of this eye compared with 7 to 9 layers found in previouslystudied normal-aged retinas.^6,7 Athin layer of hypocellular eosinophilic fibrous tissue was beneath the RPE.This material was different than its basal laminar deposit because it lackedthe anteroposterior striated appearance described by Sarks and Sarks.⁸ This region did not exhibit any distinguishingangiographic characteristics. There was no transmission defect to suggestRPE atrophy. During tissue processing, serial sections did not include theregion superior to the RPED. Therefore, no histopathologic commentary couldbe made about the corresponding area of stippled leakage in the later fluoresceinphases and staining in the late ICG phases.

Good histopathologic correlation was seen with the clinical and angiographicfindings of successfully treated CNV.^9,10 Hypocellularfibrous tissue was found beneath the RPE and its basal lamina. This treatedCNV is a sub-RPE (Gass type 1, presumed intra-Bruch) membrane, which communicateswith the choroid via 2 endothelium-lined breaks in a layer presumed to bethe outer layer of the Bruch membrane (Figure9). This region corresponded to hypofluorescence in early and latephases with no leakage in both fluorescein and ICG angiography.

The regions of photocoagulation at the nasal notch and at the marginof the RPED were characterized by thinning of the neurosensory retina withdestruction of the inner nuclear, outer plexiform, and photoreceptor layers.There was hyperplasia of the retinal pigment epithelial cells. Fibrocellulartissue was found beneath the retina and in the inner choroid, along with destructionof adjacent choroidal vessels. This area corresponded to well-demarcated hypofluorescencein early phases with staining of the edges in the late phases on the fluoresceinangiogram. On the ICG angiogram, the photocoagulation scars corresponded withwell-demarcated hypofluorescence in both the early and late phases.

Examination of the area of drusen resorption disclosed separation ofthe Bruch membrane into an inner layer (RPE basal lamina) and an outer layer,whose elastic layer was undulated. Calcification was evident in this presumedintra-Bruch space. No basal laminar deposit was present in this area. Thisregion displayed no distinguishing angiographic features.

Serous RPEDs from the Bruch membrane have distinctive clinical and angiographicfeatures and often contribute to loss of central vision in patients with AMD.^11,12 Serous RPEDs have been qualifiedas avascular or vascularized to denote the absence or presence of associatedCNV.

Avascular serous RPEDs, sometimes referred to as drusenoid RPEDs, presumablyform as soft drusen progressively accumulate, enlarge, and coalesce. Theseelevations of RPE typically develop slowly and initially may cause mildercomplaints of blurring and metamorphopsia. Angiographic results outline theselobular or scalloped lesions as the material beneath the RPE stains with fluorescein.The late staining may be irregular depending on the density of the materialbeneath the RPE. In the absence of CNV, vision loss may be minimal or progressslowly. Occasionally, the detachment may spontaneously flatten.^13,14

With vascularized RPEDs, patients tend to experience acute vision lossas they develop sharply demarcated, dome-shaped elevations of the RPE, oftenaccompanied by elevation of the overlying neurosensory retina. In AMD, serousRPEDs are usually accompanied by angiographic evidence of CNV and constituteapproximately 15% of eyes with neovascularization (M.L.K., unpublished data,1998). If the detachment occurs at the edge of the CNV, a reniform detachmentresults. In these lesions, the sub-RPE material within the dome stains slowlyand unevenly. Irregular early hyperfluorescence and evidence of late stainingmay or may not occur in the area of CNV that lies in the notch.^13,14

In 1984, Gass¹³ presented the conceptthat notched serous RPEDs are often caused by occult, flat sub-RPE CNV lyingwithin the notch outside the margin of the serous RPED and reported the caseof successful treatment of these lesions with focal laser directed to thearea of the notch with or without laser of the margin of the RPED. He alsodemonstrated the clinical and histopathologic findings of flat, focal, occultsub-RPE CNV lying within the notch causing a large hemorrhagic RPED. Sincethen, the term notched serous RPED has gained wideusage in describing these commonly occurring, potentially treatable lesions.¹⁴

For the last 20 years, the value of laser photocoagulation in such caseshas been unclear. Investigators have reported that laser treatment is of novalue.^12,15-17 Othersreport that if the CNV is identified and treated, flattening of the RPED willoccur and vision can be preserved,^18,19 ashappened in this case. A basic assumption in treating such eyes is that theadjacent CNV is confined to an area identified on fluorescein or ICG angiographyand not also located under the serous RPED. This study illustrates the histopathologicbasis for successful treatment of CNV associated with a serous RPED, whichis the absence of CNV in the area under the collapsed RPED. To our knowledge,only 2 other clinicopathologic cases of serous RPED with cartographic reconstructionhave been reported.^20,21 Inboth cases, the serous RPEDs were not treated and were represented histopathologicallyas a serous separation of the RPE and its basal lamina from the remainderof the Bruch membrane. Frank et al²⁰ in1973 correlated the fluorescein angiographic and histopathologic featuresof drusen, serous RPED without CNV, and serous neurosensory detachment ina patient with AMD. In 1976, Small et al²¹ reporteda patient (case 2) with a serous RPED accompanied by an adjacent subfovealCNV and correlated the fluorescein angiographic features with the histopathologicfeatures also using cartographic reconstruction. In this patient, the subfovealCNV, composed of fibrovascular tissue, resided beneath the RPE within a splitin the Bruch membrane (Gass type 1) and was adjacent to serous separationof the RPE.

By correlating both fluorescein and ICG angiographic features with histopathologiccharacteristics and cartographic reconstruction, we demonstrated in this casethat identification and ablation of extrafoveal CNV with argon laser treatmentallowed the adjacent serous RPED to resolve, enabling the patient to maintaina visual acuity of 20/25 OD.

Another unique feature of this study was the histopathologic findingsof resorbed drusen. Although resorption of drusen has been recognized clinicallyfollowing laser photocoagulation,^22-27 noinformation has been reported describing the histopathologic findings in aneye in which this has occurred.

In this eye, soft drusen were characterized by a localized RPED withunderlying amorphous eosinophilic material and basophilic calcifications (Figure 10). Areas of drusen resorption wereidentified using cartographic correlation. In these areas, calcification waspresent within the Bruch membrane and no basal laminar deposit was evident(Figure 9). There was also separationof the presumed inner and outer layers of the Bruch membrane with an undulatingcontour. Although the separation may be an artifact of tissue processing,it does suggest the prior presence of some material in areas where drusenhave resorbed. Additionally, in this region, the outer nuclear layer is attenuatedindicating photoreceptor loss.

The phenomena of disappearing neighboring drusen after flattening bothvascularized and nonvascularized RPEDs is seen frequently.¹⁴ Thisobservation was partly responsible for the interest in using focal photocoagulationof some drusen to clear the macula of drusen. In this case, it is unclearwhether disappearance of drusen was as a consequence of the development andflattening of the RPED itself or due to photocoagulation at the nasal notchand at the margin of the RPED. Histopathologic clues to resorption of drusenseen in this study have implications for trials such as the Complicationsof Age-related Macular Degeneration Prevention Trial²⁸ inwhich a standardized grid of laser photocoagulation is applied to the maculain hopes of reducing drusen and preventing CNV. Although there are no clinicalfeatures that correspond to basal laminar deposits, it is almost certain basallaminar deposits were present in the area of resorbed drusen. Basal laminardeposits were present elsewhere, primarily nasal to the optic nerve head.This suggests that resorption of clinically apparent drusen may serve as amarker for resorption of basal laminar deposits. The RPE in the area of drusenresorption remained intact. Although there was some reduction in the thicknessof the outer nuclear layer, there was clearly an intact photoreceptor-RPEcomplex in the area of drusen resorption.

In conclusion, when correlated with both fluorescein and ICG angiographicfindings, this study illustrates histopathologic evidence for 2 importantpoints. Eyes with serous RPED and adjacent CNV may be successfully treatedif the CNV can be completely identified and photocoagulated. With closureof 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 probablydevelop because of a cleavage plane between the elastic portion of the Bruchmembrane and the RPE and underlying basal laminar deposits. Fluid leakingout of adjacent CNV is able to dissect along this cleavage plane resultingin the serous RPED. Closure of the CNV with laser allows the resolution ofthe RPED (Figure 11).^13,14 Inareas of resorbed drusen, there is a relatively normal relationship betweenthe RPE and the overlying photoreceptors.

The authors have no relevant financial interest in this article.

This study was supported by an unrestricted fund from Research to PreventBlindness, 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 Visionand Ophthalmology annual meeting; May 10, 1999; Fort Lauderdale, Fla.

Correspondence: Dr Lauer, Casey Eye Institute, Oregon Health andScience University, 3375 SW Terwilliger Blvd, Portland, OR 97239.