The Pathogenesis of Tears of the Retinal Pigment Epithelium

Elaine L. Chuang, M . D . , and Alan C. Bird, M . D .

We compared drusen in the fellow eye of patients with unilateral retinal pigment epi­thelial tears with those in an age- and sex-matched group of patients with unilateral pri­mary neovascular disciform lesions. In the fellow eye of patients with tears, drusen were more confluent and manifested less fluores­cence on angiography than in the comparison group. These observations are in accord with the concept that Bruch's membrane represents a significant barrier to fluid flow, and that fluid beneath detached pigment epithelium is de­rived in part or wholely from the pigment epithelium.

RIPS OR TEARS of the retinal pigment epitheli­um have been recognized increasingly as a cause of severe loss of central vision in age-related macular degeneration.116 Patients expe­rience the sudden onset of distortion or a pre­cipitous drop in central acuity coincident with the tear if the fovea is involved. The typical acute fundus appearance is that of an abrupt discontinuity in the pigment epithelium at its border of previous detachment. The conse­quent defect in the pigmented monolayer and the production of redundant folds of the re­maining detached tissue lead to a characteristic acute angiographic appearance of hyperfluo-rescence in the bed of the tear, with adjacent hypofluorescence corresponding to the retract­ed mound of pigment epithelium. With time, progressive scarring and other alterations ren­der the origin of the lesion more difficult to recognize.15

Recently, tears have been shown to occur

Accepted for publication Jan. 4, 1988. From the Department of Clinical Ophthalmology, In­

stitute of Ophthalmology, Moorfields Eye Hospital, London. This study was supported in part by Medical Research Council grant No. G.8320019 N.

Reprint requests to Elaine L. Chuang, M.D., Bascom Palmer Eye Institute, 900 N.W. 17th St., Miami, FL 33134.

bilaterally more frequently than would be pre­dicted by chance alone.16 This could imply that the age-related changes in Bruch's membrane in eyes destined to manifest tears are different from those present in eyes not at risk of sus­taining this complication. In this study, we compared the changes in the fellow eye of patients with unilateral tears of the pigment epithelium with those changes seen in the fel­low eyes of patients with unilateral neovascular disciform lesions. Our primary goal was to contribute to the understanding of the patho­genesis of pigment epithelial detachments that are destined to tear, and perhaps of pigment epithelial detachments in general.

Patients and Methods

We reviewed our clinical and photographic records between 1976 and 1986 to identify pa­tients in whom the diagnosis of a pigment epithelial tear was made in one eye and in whom the contralateral eye had adequately recorded drusen in the posterior pole. Fellow eyes with evidence of exudative lesions or sig­nificant pigmentary atrophy were excluded.

Thirty-one patients with unilateral tears of the retinal pigment epithelium met these crite­ria. For comparison, a patient group with uni­lateral neovascular disciform degeneration and contralateral drusen was matched by age and sex as well as by the year of first clinical exami­nation (in order to reduce differences resulting from changes in photographic and angio­graphic techniques). There were 17 women and 14 men in each group. They ranged in age from 55 to 80 years (mean, 71 and 70 years in women and men, respectively) in the tear group, and 56 to 83 years (mean, 69 and 67 years in women and men, respectively) in the disciform group.

Color photographs and fluorescein angio-grams of each group were analyzed by both of us independently for size, density, and early

©AMERICAN JOURNAL OF OPHTHALMOLOGY 105:285-290, MARCH, 1988 285

286 AMERICAN JOURNAL OF OPHTHALMOLOGY March, 1988

and late angiographic behavior of macular drusen; one of us was masked from the diagno­sis in the eye with visual loss. The posterior pole was divided into two areas: outside and within 1,600 \xm of the foveola. The drusen were divided according to size (0 to 50 u.m, 50 to 500 |xm, and greater than 500 (xm), and distri­bution was classified as scattered, sub-confluent, or confluent. Fluorescence of drusen was assessed as equal to choroidal fluores­cence, slightly greater than choroidal fluores­cence, or brightly fluorescent. In most cases the drusen were uniform in size, distribution, and fluorescence in each area of the macula; when this was not the case the classification was determined by the largest, most densely packed and most fluorescent lesions. A few eyes were not included in each category of analysis because of the lack of transit or late photographs.

Drusen were present in both eyes of five patients who were examined before the devel­opment of a pigment epithelial tear in either eye.

The number of eyes in each group was deter­mined according to the above criteria. The Yates' corrected chi square test was applied to the data to assess the probability of these re­sults occurring by chance alone.

Results

Drusen displayed a greater degree of conflu­ence in fellow eyes of patients with pigment epithelial tears compared to fellow eyes of pa­tients with primary neovascular lesions (Table 1). This was true in the central macula (P = .032), but the difference between the two pa­tient groups did not reach a statistically signifi­cant level in the peripheral macula (P = .240). There was a tendency for drusen to be larger in the eye contralateral to eyes with tears in the central macula, but the difference was not sta­tistically significant.

The angiographic behavior of drusen in the setting of tears was found to differ significantly from that in fellow eyes of neovascular disci-form lesions (Table 2). In transit photographs of both the central and peripheral macula, the degree of fluorescence of drusen in fellow eyes of those with rips was less than that in fellow eyes of those with primary neovascular disci-form lesions (P < .001 and P < .006, respective­ly) (Figure). Similarly, late staining of macular

drusen was less intense in the study patients than in the comparison group centrally and peripherally (P < .0001 and P < .0002, respec­tively) (Figure).

The findings in the five eyes in which exami­nation of drusen was performed before the development of a pigment epithelial detach­ment, which then tore, were not different from those of the 31 contralateral study eyes.

Discussion

These results indicate that age-related chang­es at the level of Bruch's membrane in eyes destined to suffer rips are different from those at risk of developing primary neovascular le­sions. The properties of the drusen probably reflect the nature of the changes in Bruch's membrane that place the eye at high risk of suffering a retinal pigment epithelial detach­ment, which will eventually tear.

It would have been desirable to characterize the nature of these alterations in eyes before development of the pigment epithelial detach­ment. However, because of the nature of this study, only a limited number of such eyes were observed. It was for this reason that we exam­ined drusen in the fellow eye of patients with tears. The relevance of an analysis of drusen is based on the following rationale. Drusen are the manifestation of age-related change in the region of Bruch's membrane that is most ame­nable to analysis. It has been shown previously that fellow eyes in patients with unilateral pig­ment epithelial tears are at high risk of sustain­ing a similar lesion.16 Furthermore, since there is remarkable symmetry of drusen in the elder­ly,1718 it is reasonable to assume that drusen in the fellow eye to one with a unilateral tear would be similar to those that existed in the first eye before detachment of the pigment epithelium.

The significance of the hypofluorescence of drusen may be assessed in relationship to con­cepts of pathogenesis of retinal pigment epi­thelial detachments. Originally, it was consid­ered likely that detachment was induced by the passage of fluid from the choroid through Bruch's membrane, the physical attachment of the pigment epithelium having been disturbed by the accumulation of debris on the inner surface of Bruch's membrane.19 This presup­poses that hydrostatic pressure in the choroid is higher than that in the retina, and yet the

Vol. 105, No. 3 Retinal Pigment Epithelial Tears 287

TABLE 1 COMPARISON OF SIZE AND DENSITY OF MACULAR DRUSEN IN FELLOW EYES*

GROUP

Study group*

Comparison group'

LOCATION OF

DRUSEN

Central macula

Peripheral macula

Central macula

Peripheral macula

0-50 )JLM

0

2

3

3

SIZE

50-500

25

27

26

25

>500 (1M

6

1

2

1

SCATTERED

6

19

15

23

DENSITY

SUBCONFLUENT

18

10

11

6

CONFLUENT

7

1

5

0

'Numbers of eyes in central (0 to 1,600 M.m from foveola) and peripheral (>1,600 p.m from foveola) macula segregated by size and density of drusen. Three fellow eyes lacked peripheral macular drusen: one from the tear group and two from the neovascUlar disciform lesion group.

'Fellow eyes in patients with unilateral retinal pigment epithelial tears. 'Fellow eyes in patients with unilateral neovascUlar disciform lesions.

evidence suggests that the reverse is the case.20

Recently, it has been suggested that fluid in the subpigment epithelial space may be de­rived, at least in part, from the pigment epithe­lium rather than the choroid.21 It is widely accepted that fluid crosses the retinal pigment ' epithelium from the neurosensory retina to­ward Bruch's membrane because of active transport of ions. It was argued that age-related changes in Bruch's membrane might cause increased resistance to water flow, caus­ing fluid to accumulate in the subpigment epi­

thelial space. It was further postulated that this reduced permeability of Bruch's membrane to water might result from deposition of lipid and lipoprotein, and that the resistance could be higher in some eyes than in others. The concept of the pigment epithelial pump causing detach­ment of the pigment epithelium from a hydro-phobic Bruch's membrane is analogous to dome formation of a pigment epithelial mono-layer when cultured on plastic.22

Previous studies of human ocular material lend some credibility to these postulates. There

TABLE 2 COMPARISON OF FLUORESCEIN ANGIOGRAPHIC STAINING OF MACULAR DRUSEN IN FELLOW EYES*

GROUP

Study group*

Comparison group*

PHASE OF

ANGIOGRAM

Early Late Early Late

SAME AS

CHOROID

10 2 3 2

CENTRAL MACULA

MINIMALLY BRIGHTER

tHAN CHOROlb

3 23 6 6

FLUORESCENCE

BRIGHT

0 4

12 23

SAME AS

CHOROID

7 2 3 2

PERIPHERAL MACULA

MINIMALLY BRIGHTER

THAN CHOROID

6 20 7 5

BRIGHT

0 7 9

22

"Numbers of eyes in central (0 to 1,600 |xm from foveola) and peripheral (>1,600 \xm from foveola) macula with early and late staining of drusen.

'Fellow eyes in patients with unilateral retinal pigment epithelial tears. 'Fellow eyes in patients with unilateral neovascular disciform lesions.

288 AMERICAN JOURNAL OF OPHTHALMOLOGY March, 1988

Figure (Chuang and Bird). Red-free photographs and early and late fluorescein angiograms of the fellow eyes of a patient with a pigment epithelial rip (left) and of a patient with unilateral vascular disciform macular disease (right). In the former the drusen remain hypofluorescent, whereas in the latter the drusen are hyperfluorescent throughout the study.

Vol. 105, No. 3 Retinal Pigment Epithelial Tears 289

is evidence of variation in the hydrophobicity of drusen,21 and plaques of lipid have been identified in Bruch's membrane of eyes from the elderly.23 Ultrastructural studies have been interpreted as showing evidence of impedance to fluid flow in the presence of a "basal linear deposit" on the inner surface of Bruch's mem­brane.24 Finally, investigations into changes in the hydraulic conductivity of Bruch's mem­brane in human eyes show a marked fall in the ability of water to move across Bruch's mem­brane with age.25

Retinal pigment epithelial detachments that are destined to tear tend to become progres­sively larger and more highly detached, there­by generating sufficient tangential stress in the detached tissues to cause a rupture.11 This sug­gests that it is in these lesions that the resist­ance to water flow across Bruch's membrane would be highest. The hypofluorescence of drusen observed in this study reflects limited entry of fluorescein into the lesions because of their hydrophobicity.21 The proposed hydro­phobicity and confluent tendency of such dru­sen imply that there would be high resistance to water flow at the level of Bruch's membrane in these eyes.

Much of the evidence concerning the origin of tears and detachments of the retinal pigment epithelium is circumstantial, and many patho-genetic factors are undoubtedly involved. However, the concept of increased resistance to fluid outflow from the subpigment epithelial space is attractive in that it accounts for three observed clinical phenomena that remain unex­plained to date. First, it has been shown that in lesions destined to tear, the appearance of fluorescence is slowed during angiography.156

Because it is water soluble, fluorescein would pass slowly through a lipid-laden Bruch's membrane from the choroid into the sub-pigment epithelial space. Secondly, flattening of pigment epithelial detachment occurs in a large percentage of lesions after photocoagula-tion26; by destroying a proportion of retinal pigment epithelial cells, treatment would effec­tively reduce the quantity of fluid being active­ly pumped into the subpigment epithelial space. Finally, spontaneous flattening of pig­ment epithelial detachments in the elderly is accompanied by loss of vision.9 Both would result from metabolic failure of the pigment epithelium as was proposed by Casswell, Kohen, and Bird.9

It has been suggested that subpigment epi­thelial neovascularization is essential to the pathogenesis of pigment epithelial tears.6 Al­though new vessels are undoubtedly common

in these lesions, the evidence at present sug­gests that subpigment epithelial neovascular­ization is not universal in pigment epithelial detachments.15 Growth of blood vessels from the choroid toward the retina would occur in response to separation of pigment epithelium from Bruch's membrane, if, as has been report­ed by Glaser and associates,27 the pigment epi­thelium is responsible for suppressing vascu-larity of neighboring structures. Subpigment epithelial neovascularization may thus occur as a secondary phenomenon. Interestingly, this sequence of events was originally proposed by Gass in his 1967 monograph.19 This is not to deny the potential importance of choroidal neovascularization as a determinant of the clin­ical behavior of pigment epithelial detachments and tears, but does argue against this process as the primary pathogenetic mechanism in these lesions.

Two further considerations may be relevant. Blood vessels growing on the inner surface of Bruch's membrane would not cause large de­tachments unless there was significant resist­ance to water flow out of the cavity at the level of Bruch's membrane. Plasma constituents leaking from these blood vessels into the sub­pigment epithelial space may compromise fur­ther the permeability of Bruch's membrane. Finally, these concepts do not exclude loss of adhesion of pigment epithelium to Bruch's membrane as a possible contributory mecha­nism in the pathogenesis of pigment epithelial detachments.

Future histopathologic, biochemical, and prospective clinical studies will elicit more in­formation on the nature of the age-related changes at the level of Bruch's membrane. If more evidence for hydrophobicity of Bruch's membrane is found, and further support is derived for the retinal pigment epithelium as a source, or at least, a major contributor to fluid in the subpigment epithelial space, there may be therapeutic implications. Treatment directed at reducing the pigment epithelial pump or increasing the permeability of Bruch's mem­brane might reduce the risk not only of tears complicating retinal pigment epithelial detach­ments, but also of pigment epithelial detach­ments in general.

References

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290 AMERICAN JOURNAL OF OPHTHALMOLOGY March, 1988

2. Coscas, G., Quentel, G., Pinon, F., and Soubrane, G.: Dechirure spontanee de I'epithelium pigmentaire dans la region maculaire. Bull. Soc. Ophtalmol. Fr. 82:815, 1982.

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