Clinicopathological correlation of retinal pigment ...bjo.bmj.com/content/bjophthalmol/85/4/454.full.pdf · Clinicopathological correlation of retinal pigment epithelial tears in

Clinicopathological correlation of retinal pigmentepithelial tears in exudative age related maculardegeneration: pretear, tear, and scarred tear

B A Lafaut, S Aisenbrey, C Vanden Broecke, R Krott, C P Jonescu-Cuypers, S Reynders,K U Bartz-Schmidt

AbstractAims—To analyse the histopathology ofvascularised pigment epithelial detach-ments and tears of the retinal pigmentepithelium (RPE) in age related maculardegeneration (AMD).Methods—The light microscopic architec-ture of 10 surgically removed subretinalspecimens—three vascularised pigmentepithelial detachments, four recent tears,and three scarred tears as a manifestationof AMD—were studied and correlatedwith the angiographic findings.Results—Recent tears: a large fibrovascu-lar membrane was found to be originallysituated in Bruch’s membrane. About halfof the surface of the fibrovascular tissuewas denuded of RPE and diVuse drusen.The RPE and diVuse drusen had retractedand rolled up, covering a neighbouringpart of the intra-Bruch’s fibrovascularmembrane. The rolled up RPE and diVusedrusen were not interspersed with fibro-vascular tissue but lay superficial to theintra-Bruch’s fibrovascular membrane it-self. Scarred tears: a collagen capsule sur-rounded the rolled up diVuse drusen andRPE. Fibrovascular tissue was found in-side the rolled up material, predominantlyat its choroidal side.Conclusion—The area of choroidal neo-vascularisation associated with a vascu-larised pigment epithelial detachment anda tear of the RPE may be larger than washitherto thought or indicated by fluores-cein angiography. This neovascular tissuemay be present within the bed of the RPEtear, as well as at the site of the scrolled upRPE.(Br J Ophthalmol 2001;85:454–460)

A tear of the retinal pigment epithelium (RPE)is a common complication of a pigmentepithelial detachment (PED) in the elderly,either occurring spontaneously or after laserphotocoagulation.1–10 The patient usually expe-riences a sudden drop in visual acuity at thetime of tearing; good vision is only rarely main-tained after tearing of the macular RPE.11 12

Hoskins et al1 described the clinical andfluorescein angiographic characteristics oftears of the RPE for the first time in 1981.Hoskins et al1 and Chuang and Bird10 did notrecognise choroidal neovascularisation in themajority of their patients and suggested that itplayed only a minor part if at all, whereas

Coscas et al2 and Gass6 7 believed that choroi-dal neovascularisation was instrumental in thetearing of the RPE. Coscas et al13 identifiedangiographic indications for high risk oftearing by analysis of pretear angiograms. Theyrecognised uneven filling of the PED with aremarkably hypofluorescent paracentral area asthe most noteworthy feature.13

Very few clinicopathological correlations oftears are available.14 These demonstrate his-topathologically the presence of associatedchoroidal neovascularisation.14 Green et al15

have recognised tears of the RPE in a series ofpostmortem eyes with disciform scars that mayrepresent an end stage.

Recently, surgical specimens of vascularisedPED and tears of the RPE have become avail-able as new interest has arisen in the surgicalremoval of choroidal neovascularisation in agerelated macular degeneration. Foveal translo-cation or displacement of the foveal neu-roretina towards an area with healthier RPEmay oVer a better functional outcome thanremoval of the neovascular membrane alonewhere the foveal neuroretina lies on a defect inthe RPE.

We have analysed the histoarchitecture ofsurgically removed submacular tissue in threeeyes with a vascularised PED and in seven eyeswith a tear of the RPE. We suggest a flow chartof events that eventually lead to a scarred tearsupported by the available clinicopathologicalstudies. This may contribute to a better under-standing of this vision threatening complica-tion of age related macular degeneration.

Materials and methodsSTUDY POPULATION

All surgical specimens from eyes with either aPED or a spontaneous tear of the RPE selectedfrom a consecutive series of 200 age relatedmacular degeneration specimens are includedin this study with the exclusion of eight PEDassociated with a “deep retinal vascularanomalous complex” or a “chorioretinal anas-tomosis” which are the subject of a separatestudy.16 Three eyes with a vascularised PED(cases 1–3) as well as seven eyes with an estab-lished tear (cases 4–10) were included. Allpatients had experienced a recent drop invisual acuity (within 3 months) in the study eyeexcept for three patients with a less recent tearof the RPE (cases 8–10).

CLINICAL EXAMINATION

All 10 patients had a standard ophthalmologi-cal examination including fundus photographyand fluorescein angiography not more than 14

Br J Ophthalmol 2001;85:454–460454

University Eye Clinic,Joseph-Stelzmann-Strasse 9, D-50931Cologne, GermanyB A LafautS AisenbreyR KrottC P Jonescu-CuypersK U Bartz-Schmidt

Ghent UniversityHospital,Ophthalmology, DePintelaan 185, B-9000Gent, BelgiumB A LafautS Reynders

Ghent UniversityHospital, PathologyC Vanden Broecke

Correspondence to:B A Lafaut, GhentUniversity Hospital,Department ofOphthalmology, DePintelaan 185, 9000 Ghent,[email protected]

Accepted for publication27 November 2000

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days before surgery. Seven also had indocya-nine green angiography not more than 14 daysbefore surgery. Indocyanine green angiographywas not performed in two patients because of amassive subretinal haemorrhage. In one it wascontraindicated because of allergic anteced-ents. Angiographic documents from earlierexaminations were available in four patientswith a torn RPE. The fluorescein angiogramwas obtained after intravenous injection of 5ml sodium fluorescein 10% (Alcon PharmaGmbH, Freiburg, Germany) with a Canonfundus camera (Canon Inc, Neuss, Germany)linked to a Kodak high resolution camera(OIS, Ophthalmic Imaging Systems, PolytechOphthalmologie GmbH, Rossdorf, Germany).Pictures were taken up to 10 minutes afterintravenous injection. The indocyanine greenangiogram was obtained after intravenousinjection of 50 mg indocyanine green (PulsionMedical Systems, Munich, Germany) dis-solved in 10 ml with the same camera system.Pictures were taken up to 30 minutes afterintravenous injection. None of these patientshad diseases, such as high myopia, multifocalchoroiditis, and angioid streaks, predisposingto choroidal neovascularisation other than agerelated macular degeneration. The clinicalfindings are summarised in Table 1.

SURGICAL PROCEDURE

The macula was translocated in nine patients(full macular translocation with 360° retin-otomy). In one patient the specimen wasextracted without rotation at the time ofremoval of a massive subretinal haemorrhage.

HISTOLOGICAL ANALYSIS

The specimens were fixed in 10% neutrallybuVered formalin, dehydrated, and embeddedin paraYn for light microscopy. The mem-branes were serially sectioned and stained in astepped fashion with Masson trichrome(MTC) and periodic acid SchiV (PAS). Multi-ple sections of each membrane were stainedwith phosphotungstic acid haematoxylin histo-chemical stain for fibrin (PTAH).

ResultsThe fluorescein and indocyanine green angio-graphic findings of these patients are summa-rised in Table 1.

PRETEAR STAGE—PED

Two of three PED had pretear characteristics(cases 1 and 2)—namely, a non-homogeneousfilling with a paracentral hypofluorescent zone.Indocyanine green angiography revealed aplaque undermining the PED in these twocases. Fibrovascular tissue was found in thetwo corresponding specimens. In one speci-men the fibrovascular membrane was locatedwith certainty in the Bruch’s membrane orunder the RPE as it was entirely covered byRPE and diVuse drusen; however, in thecentral two thirds of the specimen the RPE anddiVuse drusen had detached from the fibrovas-cular membrane itself (Fig 1). The fibrovascu-lar membrane of the other specimen could notbe oriented as no adherent RPE and diVusedrusen were found on serially sectioned mate-rial, but RPE and diVuse drusen were locateddistant from the fibrovascular membrane itself.The third PED (case 3) had a notch onfluorescein angiography that corresponded to amarginal hot spot on indocyanine green angio-graphy. Fibrovascular tissue was found thatwas at least in part located in the Bruch’smembrane. Another part of the membranecould not be oriented as it was not covered byRPE and diVuse drusen. Some RPE anddiVuse drusen were located distant from thefibrovascular tissue.

FRESH TEAR STAGE

Three relatively recent tears of the RPE withcharacteristic angiographic features (cases 4, 5,and 7) had a rather similar histoarchitecture. Alarge fibrovascular membrane was found to beoriginally situated in the Bruch’s membranesince at its edges native RPE and diVusedrusen were recognised and allowed orienta-tion (Figs 2 and 3). About half of the surface ofthe fibrovascular tissue was denuded of RPEand diVuse drusen except for its outer margin.

Table 1 Summary of the clinical findings

Case Sex Age Tearing Fundus and fluorescein angiographic findings Indocyanine green angiographic findings

1 F 61 — Vascularised PED, non-homogeneous filling Underlying ill defined plaque2 M 79 — “Pretear” PED, paracental hypofluorescent zone Plaque occupying entire lesion/PED3 M 63 — Vascularised PED, notch Marginal hot spot4 F 78 1 month No subretinal fibosis, some surrounding blood vascular

net at level of rolled up RPE,Speckled hyperfluorescence in rolled up RPE, surrounded byplaque, denuded area isofluorescent

−1 month Tearing vascularised PED, vascular net inside PED smallsubretinal haemorrhages at one edge

—

5 F 75 4–6 weeks No subretinal fibrous tissue, no vascular net —−5 months “Pretear” PED, paracentral hypofluorescent zone —

6 M 80 2 months Vascular net at level of rolled up RPE and in the area ofdenuded RPE

Speckled hyperfluorescence in rolled up RPE disappearingwithin a hyperfluorent plaque, denuded area included

−3 months Vascularised PED, notch Marginal plaque7 F 75 2 1⁄2 months Rolled up RPE embedded in massive subretinal

haemorrhage, no vascular net—

8 M 65 4 months Some subretinal fibrosis, some surrounding blood novascular net

Speckled hyperfluorescence in rolled up RPE

9 M 76 4 months No subretinal fibrous tissue, no vascular net Speckled hyperfluorescence in rolled up RPE, surrounded byplaque, denuded area hyperfluorescent

−3 months Rolled up RPE, some subretinal blood Speckled hyperfluorescence in rolled up RPE, surrounded byplaque, denuded area hyperfluorescent

10 F 75 5–6 months Rolled up RPE surrounded by subretinal fibrous tissueand massive subretinal haemorrhage

—

Previous angiographic documentation, indicated in italics, is available for four patients. The indication of time corresponds to the time interval between first and sec-ond angiographic examination.

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The RPE and diVuse drusen appeared to haveretracted and rolled up, covering a neighbour-ing part of the intra-Bruch’s fibrovascularmembrane. The rolled up RPE and diVuse

drusen were not interspersed with fibrovascu-lar tissue but lay superficial to the intra-Bruch’sfibrovascular membrane itself. The rolled upRPE and diVuse drusen were partially covered

Figure 1 Specimen corresponding to a vascularised pigment epithelial detachment with non-homogeneous fluoresceinfilling. Indocyanine green angiography revealed an ill defined underlying plaque (case 1). The RPE and diVuse drusenhave partially detached from the intra-Bruch’s fibrovascular tissue. Masson trichrome, bar = 100 µm.

Figure 2 Specimen corresponding to a recent tear (case 5). (A) At one edge of the specimen intra-Bruch’s fibrovascular tissue is recognised, more centrallyto it rolled up RPE and diVuse drusen are seen that are only partially covered by fibrovascular tissue and amorphous debris on their retinal side. (B)Towards the opposite edge, rather fibrous fibrovascular membrane is observed denuded of RPE and diVuse drusen but covered by a thin layer of amorphousdebris. Periodic acid SchiV, bar = 50 µm in (A) and 25 µm in (B).

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by proteinaceous debris and the remains ofouter segments in two specimens partially cov-ered by a thin fibrovascular membrane in onespecimen and entirely covered by a thin fibrov-ascular membrane in another specimen. Thecovering fibrovascular tissue was only poorlyvascularised. A moderately dense infiltration ofinflammatory cells (predominantly lym-phocytes) was seen in the neighbourhood ofthe rolled up RPE and diVuse drusen.

The angiographic appearance of case 6 wassomewhat unusual: fluorescein angiographyidentified a vascular net with profuse leakage,indocyanine green angiography indicated therolled up RPE with speckled hyperfluorescenceembedded in a plaque. The correspondingspecimen consisted of fibrovascular tissuelocated subretinally as well as under the RPE.The subretinal component was smaller indiameter than the intra-Bruch’s component.

Figure 3 Specimen corresponding to a recent tear (case 7). (A) At the level of the rolled up RPE and diVuse drusen, atboth edges RPE and diVuse drusen allow orientation of the section. (B) Distant to the rolled up RPE and diVuse drusen,fibrovascular tissue is found that is centrally denuded from RPE and diVuse drusen. The latter structures are, however,identified at the edge of the section and suggest that at least the majority at this level is situated in the Bruch’s membrane.Masson trichrome, bar = 100 µm in (A) and (B).

Figure 4 Specimen corresponding to a less recent tear (case 8). Rolled up RPE and diVuse drusen, which are covered by athin fibrocellular membrane on their retinal side, are readily recognised. On their choroidal side fibrovascular tissue isobserved with large bore vessels and a moderately strong inflammatory cell infiltration. Adjacent to this part of thespecimen, fibrovascular tissue denuded of RPE and diVuse drusen but covered by a thin layer of amorphous debris is found.At one edge of the specimen, RPE, diVuse drusen, and a thin layer of intra-Bruch’s fibrovascular tissue are found that has,however, turned over as shown on serial sectioning. At the opposite edge, RPE, diVuse drusen and a thin layer ofintra-Bruch’s fibrovascular tissue is found that has also turned over but does not physically make contact with the edge ofthe section itself at this level. Periodic acid SchiV, bar = 100 µm.




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Rolled up RPE and diVuse drusen were identi-fied in between the two components and a partof the sub-RPE component was denuded ofRPE and BLD.

SCARRED TEAR STAGE (CASES 8–10)Basically an identical architecture was recog-nised as well in the three scarred tears of theRPE. The presence of a collagen capsulesurrounding the rolled up diVuse drusen or therolled up diVuse drusen and RPE were themost marked characteristic: the capsule wasthin in case 8 (Fig 4) but thick and dense in theother two (Fig 5). Fibrovascular tissue wasfound inside the rolled up material in cases 9and 10, predominantly at its choroidal side. Amoderate inflammatory cell infiltration wasseen near the diVuse drusen in cases 8 and 10.Melanin bearing cells had migrated distantfrom the diVuse drusen, either towards theretinal surface of the capsule or towards theadjacent fibrovascular membrane denuded ofRPE and diVuse drusen in cases 9 and 10.Such pigmented cells appeared to separate thedensely collagenised capsule from the remain-der of the specimen.

DiscussionIt has recently been recognised that diVeringhistoarchitectural characteristics may explainfluorescein angiographic features of age relatedchoroidal neovascularisation.17 This study was

undertaken to find out whether the architec-ture of a pretear PED and of a tear of the RPEcould be reconstructed from a series ofsurgically removed specimens. We have usedlight microscopy as the major cellular compo-nents (RPE, vascular endothelium, fibrocytes,macrophages, and photoreceptors) as well asextracellular components (collagen, diVusedrusen, and fibrin) can be correctly identifiedby light microscopy alone.18 The diVuse drusenare seen as an extra layer between the RPE andthe outer Bruch’s membrane (defined here asBruch’s membrane), which is a granular, PASpositive deposition that stains metachromati-cally blue-purple on MTC. DiVuse drusen is alight microscopic term that corresponds tobasal laminar and basal linear deposits, whichare the electron microscopic characteristics ofage related macular degeneration.19 20

Because there are almost no clinicopatho-logical correlations of neovascularised PED,the histoarchitecture of this lesion is onlypoorly known.7 20 21 Fluorescein angiographyalready gives an indication of the presence ofneovascularisation when a notched or a reni-form PED is demonstrated.22 Fluoresceinangiography allows the identification of a“chorioretinal anastomosis” or a “deep retinalvascular anomalous complex” which is a pecu-liar lesion associated with a PED.23 24 The latterlesion is not further elaborated here. Specifictypes of vascularised PED have been described

Figure 5 Specimen corresponding to a scarred tear (case 10). (A) Rolled up RPE and diVuse drusen are found centrallyembedded in a fibrous capsule. At one side an intra-Bruch’s fibrovascular membrane is recognised whereas the fibrovasculartissue at the other side of the specimen cannot be attributed since it is entirely denuded of RPE and diVuse drusen. In someareas the diVuse drusen are not accompanied by pigmented cells and a group of pigmented cells has migrated from thediVuse drusen and appears to separate the densely collagenised nodule from the remainder of the specimen. A moderatelystrong inflammatory cell infiltration is seen at the choroidal side of the rolled up diVuse drusen. (B) Detail of rolled updrusen with interspersing fibrovascular and inflammatory tissue at their choroidal side. Masson trichrome, bar = 100 µm in(A) and 25 µm in (B).




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with indocyanine green angiography. Either amarginal hot spot (a late hyperfluorescencesmaller than one disc area) or a marginalplaque (a late hyperfluorescence equal or largerthan one disc area) are the typical lesionsobserved.25 26 The majority of these late hyper-fluorescent lesions lie outside the PED itself.The hot spot or the plaque often correspond toa notch that was already identified by fluores-cein angiography. It is hypothesised that theselesions correspond to intra-Bruch’s fibrovascu-lar choroidal neovascularisation at the edge of aPED (Fig 6A).25 26 Less frequently, indocya-nine green angiography may, however, reveal aplaque that has largely or even entirely under-mined the associated PED as in cases 1 and 2.This angiographic pattern suggests the pres-ence of an intra-Bruch’s fibrovascular mem-brane at the site of the PED (Fig 6B). Theintra-Bruch’s fibrovascular tissue was demon-strated in at least one pretear specimen. Anextensive area of separation of the RPEtogether with the diVuse drusen from underly-ing intra-Bruch’s fibrovascular tissue wasobserved. The detachment appears not to bean artefact because some proteinaceous fluidfilled the lumen of the separation. In thesecond pretear specimen the RPE and diVusedrusen had entirely separated from the fibrov-ascular tissue. This would not have been likelyif a pre-existing weakened adhesion was notpresent because it was not observed in aconsecutive series of 31 classic or occultneovascular membranes without an associated

PED in age related macular degeneration.17 Itappears that in these two cases detachment ofthe RPE and diVuse drusen from the underly-ing fibrovascular tissue corresponds to theclinical PED. Another argument that RPE anddiVuse drusen may detach from underlyingfibrovascular tissue if present is that a tear cor-responds to rolled up RPE and diVuse drusenwithout associated fibrovascular tissue in rela-tively fresh specimens (Fig 6D). Fibrovasculartissue grown into the rolled up RPE and diVusedrusen is, however, observed in more chronic,scarred lesions (Fig 6E). Furthermore, theoverlying proteinaceous fluid may intuitivelyexplain the poor angiographic indication of theassociated choroidal neovascularisation. Intra-Bruch’s fibrovascular tissue was also found inthe vascularised PED with a marginal hot spot.Unfortunately, the surgical specimens are frag-ile and may have been distorted when passingthrough the sclerotomy. More correlations willbe needed to better understand the architec-ture of a vascularised PED.

Coscas et al2 and Gass6 7 indicated the role ofassociated occult choroidal neovascularisationin the process of tearing. Their concept hasbeen reinforced since the advent of indocya-nine green angiography. The rolled up RPE ishypofluorescent on fluorescein angiographydue to blockage by its pigmentation. A charac-teristic speckled hyperfluorescence of a vari-able degree is observed on indocyanine greenangiography that indicates the presence ofunderlying choroidal neovascularisation.27–29

The indocyanine green angiographic charac-teristics of tears are, however, more complex.The speckled hyperfluorescence of the rolledup RPE may be associated with a plaque thatmay partly or entirely occupy the area denudedof RPE. This angiographic finding suggeststhat choroidal neovascularisation may even bepresent in areas denuded of RPE. It is wellknown that tearing triggers the formation of adisciform scar and that a disciform scar mayexplain the presence of a plaque.30 However,such associated plaques are also found shortlyafter tearing of the retinal pigment epitheliumbefore the tranformation into a scar hasoccurred. For example, we found a relativelylarge area of fibrovascular tissue, denuded ofRPE and diVuse drusen neighbouring therolled up tear in three of four relatively freshtears (Fig 6D). This fibrovascular tissue maybe responsible for the plaque surrounding thetear as was shown by indocyanine green angio-graphy in the two examined cases. Theobservation suggests that choroidal neovascu-larisation is instrumental in the pathogenesis ofpigment epithelial tears, but also indicates thatthe area of fibrovascular tissue may be moreextensive than was hitherto thought. It is likelythat the neovascular tissue had partly orentirely undermined the PED before tearingtook place. This extent may not be readily rec-ognised angiographically because of interfer-ence with the proteinaceous exudate of theoverlying PED itself.

In conclusion, we suggest that the RPE withits diVuse drusen may progressively detach

Figure 6 Hypothesis of a flow chart for the histoarchitectural stages that ultimately maylead to a scarred tear of the retinal pigment epithelium. (A) Corresponds to a vascularisedPED with a plaque or hot spot, (B) corresponds to a pretear PED, (C) and (D) correspondto fresh tears respectively without or with denuded intra-Bruch’s fibrovascular tissue, andfinally (E) represents a scarred tear.




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from the underlying intra-Bruch’s fibrovascu-lar membrane as a variant pathogenetic mech-anism of a vascularised PED. It may not onlyexplain a plaque largely undermining a PEDbut also a plaque surrounding torn RPE.Within a matter of months, the torn and rolledup RPE becomes embedded in a thickcollageneous capsule, and melanin bearingcells, either RPE or melanophages, migrate.Both these changes may explain why the char-acteristic appearance of a tear of the RPE dis-appears with time.

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