Clinicopathologic Reports, Case Reports, and Small Case Series
September 2004

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

Author Affiliations



Copyright 2004 American Medical Association. All Rights Reserved.Applicable FARS/DFARS Restrictions Apply to Government Use.2004

Arch Ophthalmol. 2004;122(9):1383-1390. doi:10.1001/archopht.122.9.1383

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.

Report of a Case

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.

Figure 1.
Image not available

Fundus photograph from a 74-year-oldwoman with a sharply circumscribed, dome-shaped elevation of the retinal pigmentepithelium in the right eye with overlying serous retinal detachment (arrowheads)and a nasal notch (white arrowhead). Large drusen are scattered throughoutthe posterior pole, and a small patch of geographic atrophy is located temporalto the fovea (arrow).The left eye (OS)shows disciform macular scarring, exudation,subretinal fibrosis, retinal pigment epithelium migration, and hyperplasia.

Figure 2.
Image not available

A-C, Fluorescein angiographicresults of the right eye show a well-circumscribed area of early hypofluorescencewith progressive hyperfluorescence in the later phases corresponding to theretinal pigment epithelium elevation seen clinically. Along the nasal borderof the lesion, a notched area was present in which there was delayed fillingand irregular late hyperfluorescence. D-F, Indocyanine green angiographicresults of the right eye show well-demarcated hypofluorescence correspondingto the retinal pigment epithelial detachment (RPED) in the early and latephases. E, Within the nasal notch of the RPED, an expanding area of focalhyperfluorescence was present (arrowhead). F, Laser treatment results of theright eye. Argon green laser photocoagulation was applied to the area of choroidalneovascularization (arrow). Additionally, isolated laser applications wereplaced along the margin of the RPED (arrowheads).

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.

Figure 3.
Image not available

A, One month posttreatment, fundusexamination results show flattening of the retinal pigment epithelial detachmentwith a nasal laser scar. B and C, Fluorescein angiographic results show latestaining without leakage in the areas of photocoagulation. D and E, The indocyaninegreen angiogram shows hypofluorescence in these areas. No focal or plaquehyperfluorescence was noted.

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).

Figure 4.
Image not available

Fundus photographs compare theright eye pretreatment (A) and 15 months posttreatment (B).The posttreatmentphotograph shows a flat macula, nasal laser scar, and reduction in drusencompared with the pretreatment photograph.

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.35 The histopathologicand angiographic correlates are summarized in Table 1.

Figure 5.
Image not available

Histopathologic map of the lefteye. CNV indicates choroidal neovascularization; RPE, retinal pigment epithelium.

Image not available
Correlation of Histopathologic Features With Angiographic Findings

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

Figure 6.
Image not available

In the region of resolved retinalpigment epithelial detachment, the photoreceptor nuclear density is attenuated(arrowhead). Hypocellular, eosinophilic fibrous tissue remains between theretinal pigment epithelium and its basal lamina and the presumed outer layersof the Bruch membrane (arrows). A mildly disrupted retinal pigment epithelialmonolayer has reapproximated the Bruch membrane (hematoxylin-eosin, originalmagnification ×100 (A); original magnification ×200 [B]).

Figure 7.
Image not available

The photocoagulated choroidalneovascularization (asterisk) resides between the plane of the retinal pigmentepithelium (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 aresult of laser photocoagulation (hematoxylin-eosin, original magnification×200).

Figure 8.
Image not available

Resorbed soft drusen. Sub–retinalpigment epithelium (presumed intra-Bruch) calcification present in areas wheredrusen resorbed (arrows). No basal laminar deposit is seen. The outer nuclearlayer is attenuated (arrowheads) (hematoxylin-eosin, original magnification×200).

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.

Figure 9.
Image not available

A choroidal vessel perforatedthe presumed outer layer of the Bruch membrane (arrow) to communicate withthe photocoagulated sub–retinal pigment epithelium (RPE) (Gass type1, presumed intra-Bruch) choroidal neovascularization (CNV) (asterisk). TheCNV resided in the same plane and adjacent to the RPE detachment, betweenthe plane of the RPE (arrowhead) and the outer layers of the Bruch membrane(hematoxylin-eosin, original magnification ×200).

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.12,1517 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,2227 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.

Figure 10.
Image not available

Soft drusen. Localized detachmentof the retinal pigment epithelium with underlying amorphous eosinophilic material(asterisk) and basophilic calcifications (arrowheads) (hematoxylin-eosin,original magnification ×200).

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.

Figure 11.
Image not available

Diagrammatic representation.13,14 An extrafoveal sub–retinal pigment epithelium (RPE) (Gasstype 1, presumed intra-Bruch) choroidal neovascularization adjacent to a serousRPE detachment was treated with laser photocoagulation. In this case, successfultreatment resulted in closure of the choroidal neovascularization, resolutionof the RPE detachment, relative preservation of the RPE monolayer, and preservationof good vision for 21 months.

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.

Lauer  AKWilson  DJKlein  ML Clinicopathologic correlation of fluorescein and indocyanine greenangiography in exudative age-related macular degeneration. Retina. 2000;20492- 499
Chang  TSFreund  KBde la Cruz  ZYannuzzi  LAGreen  WR Clinicopathologic correlation of choroidal neovascularization demonstratedby indocyanine green angiography in a patient with retention of good visionfor almost four years. Retina. 1994;14114- 124
Borodkin  MJThompson  JT Retinal cartography: an analysis of two-dimensional and three-dimensionalmapping of the retina. Retina. 1992;12273- 280
Snyder  JP Map Projections: A Working Manual, USGS ProfessionalPaper.  Washington, DC US Government Printing Office1987;
Muehrcke  P Map Use: Reading, Analysis and Interpretation.  Madison, Wis JP Publications1986;
Kornzweig  AL The eye in old age, V: diseases of the macula, a clinicopathologicstudy. Am J Ophthalmol. 1965;60835- 843
Green  WR Retina. Spencer  WHed.Ophthalmic Pathology: An Atlasand Textbook.4th Philadelphia, Pa WB Saunders Co1996;669- 676
Sarks  SHSarks  JP Age related maculopathy: nonneovascular age related macular degenerationand the evolution of geographic atrophy. Ryan  SJSchachat  AJeds.Retina. 3rd St Louis Mo Mosby Inc2001;10701077;
Green  WR Clinicopathologic studies of treated choroidal neovascular membranes:a review and report of two cases. Retina. 1991;11328- 356
Meyer  DHarris  WPFine  SLGreen  WR Clinicopathologic correlation of argon-laser photocoagulation of anidiopathic choroidal neovascular membrane in the macula. Retina. 1984;4107- 114
Gass  JD Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967;63l1- 139
Braunstein  RAGass  JD Serous detachments of the retinal pigment epithelium in patients withsenile macular disease. Am J Ophthalmol. 1979;88652- 660
Gass  JD Serous retinal pigment epithelial detachments with a notch. Retina. 1984;4205- 220
Gass  JD Stereoscopic Atlas of Macular Diseases: Diagnosisand Treatment. 4th St Louis Mo Mosby1997;24- 32 80- 87 1032- 1045
Baumal  CRDuker  JSWong  JPuliafito  CA Indocyanine green hyperfluorescence associated with serous retinalpigment epithelial detachment in age-related macular degeneration. Ophthalmology. 1997;104761- 769
Bird  ACMarshall  J Retinal pigment epithelial detachments in the elderly. Trans Ophthalmol Soc UK. 1986;105 ((pt 6)) 674- 682
Slakter  JSYannuzzi  LASorenson  JAGuyer  DRHo  ACOrlock  DA A pilot study of indocyanine green videoangiography-guided laser photocoagulationof occult choroidal neovascularization in age-related macular degeneration. Arch Ophthalmol. 1994;112465- 472
Lim  JIAaberg  TMCapone  A  JrSternberg  P  Jr Indocyanine green angiography-guided photocoagulation of choroidalneovascularization associated with retinal pigment epithelial detachment. Am J Ophthalmol. 1997;123524- 532
Maguire  JIBenson  WEBrown  GC Treatment of foveal pigment epithelial detachments with contiguousextrafoveal choroidal neovascular membranes. Am J Ophthalmol. 1990;109523- 529
Frank  RNGreen  WRPollack  IP Senile macular degeneration: clinicopathologic correlation of a casein the predisciform stage. Am J Ophthalmol. 1973;75576- 586
Small  MLGreen  WRAlpar  JJDrewry  RE Senile macular degeneration: a clinicopathologic correlation of twocases with neovascularization beneath the retinal pigment epithelium. Arch Ophthalmol. 1976;94601- 607
Ho  ACMaguire  MGYoken  J  et al.  Laser-induced drusen reduction improves visual function at 1 year:Choroidal Neovascularization Prevention Trial Research Group. Ophthalmology. 1999;1061367- 13731974;(discussion).
Olk  RJFriberg  TRStickney  KL  et al.  Therapeutic benefits of infrared (810-nm) diode laser macular gridphotocoagulation in prophylactic treatment of nonexudative age-related maculardegeneration: two-year results of a randomized pilot study. Ophthalmology. 1999;1062082- 2090
Figueroa  MSRegueras  ABertrand  JAparicio  MJManrique  MG Laser photocoagulation for macular soft drusen: updated results. Retina. 1997;17378- 384
Frennesson  ICNilsson  SE Laser photocoagulation of soft drusen in early age-related maculopathy(ARM): the one-year results of a prospective, randomised trial. Eur J Ophthalmol. 1996;6307- 314
Little  HLShowman  JMBrown  BW A pilot randomized controlled study on the effect of laser photocoagulationof confluent soft macular drusen. Ophthalmology. 1997;104623- 631
Sigelman  J Foveal drusen resorption one year after perifoveal laser photocoagulation. Ophthalmology. 1991;981379- 1383
 Complications of Age-Related Macular Degeneration Prevention Trial(CAPT) National Institutes of Health National Eye Institute Web site. November6 2001;Available at: 13, 2003