Pigmentary Glaucoma and the Glaucoma Associated with the Exfoliation­pseudoexfoIiation Syndrome: Update

Robert N. Shaffer Lecture SAUL SUGAR, MD

I am greatly honored at having been invited by the Shaffer Society and the National Society for the Prevention of Blindness to deliver this lecture in honor of Dr. Robert Shaffer. I have known and admired Dr. Shaffer for many years and I am grateful to him for what he has taught me. It is in the spirit of Dr. Shaffer's interests in all aspects of glaucoma that I present the following material.

PIGMENTARY GLAUCOMA

In 1940, while discussing pigment in the trabecular spaces in a paper on the chamber angle, I mentioned I the case of a 29-year-old man, seen in February 1939, in whom the trabecular pigment deposit was so heavy that it suggested itself as the cause of the glaucoma. In 1947 I saw a second man, aged 33, in consultation with my medical school classmate, Dr. Fleming Barbour of Flint, Michigan, and we reported the condition as pigmentary glaucoma.2 Both cases showed moderately elevated pres­sure, Krukenberg spindles and trabecular pigment de­posits. They reacted like any chronic open-angle glaucoma case except that whenever homatropine was used for cy­cloplegia the tension rose to the high 40's within one hour.

By 1966, 128 cases were collected from the literature. Twenty-three percent were women with a mean age of 48.7 years as compared to 77% men with a mean age of 33.8 years.3

Pigmentary glaucoma constitutes about 1.5% of the glaucoma population.3 The clinical picture of the syn­drome will be considered under the following headings:

Presented at the Eighty·eighth Annual Meeting of the American Academy of Ophthalmology, October 30-November 3, 1983.

(1) refractive error, (2) pigment dispersion, (3) glaucoma, (4) course and (5) treatment.

REFRACfIVE ERROR

Most patients are myopic with deep anterior chambers. My series showed 78% of myopes of 1 diopter or more and 10% hyperopes. The remaining 12% were emme­tropes.

THE PIGMENT DISPERSION SYNDROME

The pigment changes associated with pigmentary dis­persion include: (a) loss of pigment epithelium of the iris midperiphery and the pupil border, (b) deposition of pig­ment on the posterior corneal surface, (c) deposition of pigment on the trabecular surface and within the tra­becular meshwork, (d) deposition of pigment on the an­terior iris surface and (e) on the lens surface.

Pigment epithelium is lost from the midperiphery of the iris and, sometimes, from the pupil margin area. The extent of atrophy is usually proportional to the density and size of the associated Krukenberg spindle. Scanning microscopy has shown early pigment dispersion from the pigment epithelium at the site of the zonule packets.

Pigment deposited on the posterior corneal surface is usually recognized in the form of the typical Krukenberg spindle or, sometimes, as punctate deposits offairly diffuse distribution. Occasional cases of pigmentary glaucoma show no spindle. The typical Krukenberg spindle is a vertical spindle of brown pigment varying in length from 1 to 6 mm and up to 3 mm wide. Biomicroscopy is usually necessary for recognition.

Pigment deposited on the trabecular surface and within the trabecular meshwork is usually markedly denser than is seen in any other condition.

Concerning deposits of pigment on iris and lens sur­faces: I have seen one instance of heterochromia in a case

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of the pigment dispersion syndrome without glaucoma. This was in a young physician in whom it was obviously due to the greater deposition of pigment granules on the anterior iris surface of one eye than on the other. This type of heterochromia was present in one unilateral and two bilateral cases of pigmentary glaucoma. Zentmayer was apparently the first to describe the ring of pigment on the posterior lens surface in association with a Kru­kenberg spindle. This is also called the Scheie line.

The pigment dispersion syndrome is the preglaucoma­tous phase of pigmentary glaucoma. It may take many years for the transition to glaucoma to occur. I believe that there is a definite relationship between the dispersed pigment and the glaucoma; there are those who do not agree. The pigment dispersion may decrease or, rarely, definitely disappear, just as the glaucoma may disappear. Thus, the condition may be self-limited. An example of such a case follows:

The patient, age 29, with typical pigment dispersion syndrome, had refractive error of -3.00 + 0.25 X 65 = 20/20 in the right eye, -2.25 + 0.75 X 95 = 20/20 in the left eye. Po 24 in the right eye, 22 in the left eye, C 0.09 in the right eye, 0.08 in the left eye, applanation 22 in the right eye, 22 in the left eye, fields normal. Tension, after cycloplegia was 26 in the right eye, 22 in the left eye. The patient was treated with Ocuserts and epineph­rine in 1973. Highest tension was 31. Then the tension decreased to the midteens in 1976 and to as low as 11 in 1977. In 1978 epinephrine was discontinued and the tension rose to the upper teens and, rarely, to the low twenties. In 1979 on no medication the tension never rose above 18 and continues so to the present time.

Pigmentary glaucoma generally follows much the same course as that of chronic open-angle glaucoma in patients of the same age group.

Most theories about the cause of pigment dispersion, including those of Fine et al4 and Kupfer,5 were related to congenital anomalies. I objected to them on the basis of my failure to clinically recognize the presence of con­genital anomalies.

In 1979 David Campbell showed that myopia in the pigment dispersion syndrome is associated with a convex posterior iris surface and is related to the mechanical dispersion of pigment in the area of the 65 to 80 anterior zonule fiber packet insertions.6 The number of zonule packet insertions matches the number of ciliary processes between which they lie and the folds of iris pigment ep­ithelium which continue from the processes, plus the number of transilluminating areas of iris. Campbell's work has been confirmed by Kampik, Green, Quigley and Pierce.7 I would like to add to these findings that the extensions of the transilluminating areas toward the pupil as time goes on indicates that there is more involved than the zonule fiber packets alone. I suggest that the radial folds of iris pigment epithelium, each of which may have 2 or 3 subsidiary folds, rub against the lens capsule itself.

Thus, despite my objections to the congenital or de­velopmental anomaly theories, the introduction of Campbell's work has made me realize that the myopic

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convexity of the peripheral posterior iris surface which permits mechanical rubbing between the anterior zonule packets and lens and the iris is in itself an anatomical variation which is probably genetically determined. Cer­tainly, there is evidence in the literature of a hereditary factor in this disease which suggests an autosomal dom­inant multifactorial inheritance.

Medical treatment of pigmentary glaucoma has been much the same as that of chronic open-angle glaucoma in the same age groups. The early cases seem to be easier to handle than those with open-angle glaucoma, while some of the advanced cases requiring surgery have been reported as being resistant to medical treatment. Likewise, my own experience indicates that if the age of the patient is considered there is no difference in surgical results be­tween pigmentary glaucoma and open-angle glaucoma. Laser trabeculoplasty appears to be favorably indicated for the treatment of pigmentary glaucoma. Some advise that the power level be reduced while others believe it shoul<;l be increased. Laser iridoplasty to flatten the pe­ripheral iris convexity has also been suggested.8

Any drug which allows posterior displacement of the iris increases contact with the zonule packets and causes more pigment dispersion which tends to acutely block some of the trabecular spaces. This may explain my find­ings with homatropine, aside from its anticholinergic ef­fect. With miotics the iris convexity is decreased, de­creasing contact. The effect of thymoxamine and weak pilocarpine may be important in preventing contact be­tween the zonule packets, lens, and posterior iris surface.

THE EXFOLIATION-PSEUDO EXFOLIATION SYNDROME

Following its first descriptions by Lindberg in 19179

and Vogt in 1925, IO Busacca 11 suggested that the capsular material was not an exfoliation but a deposit of an un­known substance on the normal capsule. In 1954 Geor­gianna Dvorak-Theobald,12 following Busacca's view, named the condition "pseudoexfoliation of the lens cap­sule", a name which was subsequently adopted by most clinicians. We now know that both exfoliation and pseu­doexfoliation or deposition participate in the syndrome. When electron microscopy by Bertelsen in 1964 13 revealed that there actually was involvement of the lens epithelial cells and capsule, the subject became confused by rever­sion to the lens as the source of the deposits; I am con­vinced that the lens is not their source.

The syndrome is unilateral in a third of the cases and becomes bilateral in about 25% more within 5 years. I have seen this change from the monocular to the binocular syndrome in 11 cases while they were under observation.

The clinical picture reveals that In 6% of normal eyes, depigmentation of the pupil border occurs. In the exfoli­ation syndrome the frequency is 74%. This is attributed in large measure to the abrasive pupillary border move­ment. Particles of grayish material on the pupil border

SUGAR • EXFOLIATION·PSEUDOEXFOLIATION SYNDROME

are a most important clue to the presence of the pseu­doexfoliation syndrome.

Grayish flakes of such size as to suggest exfoliated pieces of pericapsular membrane (zonular lamella) are occa­sionally found on the posterior corneal surface, and in aphakes on the anterior surface of the hyaloid, from which they may be dislodged. In addition, small pigment gran­ules may be present.

In the undilated condition, small deposited particles of exfoliated zonular lamella may be seen on the central disc. Slit-lamp microscopic examination without dilata­tion may fail to reveal the presence of the syndrome. When the pupil is dilated the picture is usually unmis­takable. The central disc, when seen, is actually normal central anterior capsule with its zonular lamella outlined by the cleared ring immediately surrounding. The clear ring is the area abraded by moving iris. Just peripheral to the clear area one sees an area of superficial granular whitish opacity, usually beginning abruptly where the clear area ends. Sometimes, in fairly early cases, a bridge of material remains where the abrasive action has not resulted in a complete ring. At the peripheral edge of the clear ring a floating irregular cellophane-like membrane which is continuous with the granular zone may remain attached. It appears to be the elevated edge of the zonular lamella, together with the exfoliative material deposited on its surface. If movement of the iris is stimulated by the slit-lamp beam one may see undulations of the mem­brane remnants. In eyes in which a clear area has been present, a secondary granular line may appear in its pe­riphery.

The granular area on the anterior capsule varies in width and has a serrated peripheral border which cor­responds to the outline of direct iris contact.

Although the central capsule is not involved in the usual case of the syndrome, it was involved in an unusual case with eccentric pupil due to perforation of the lower cornea with iris prolapse and incarceration. Here the granular material was deposited on the central capsule in the area of iris contact due to the drawn-down pupil. The patient, age 11 months, suffered a perforation of the left cornea by glass. An iris prolapse was excised. Healing was uneventful, leaving a down-drawn pupil. When the patient was seen 21 years later the left eye showed a number of fuzzy whitish deposits on the left pupil border and, after dilatation, the pseudoexfoliation syndrome with an unusual eccentrically-located iris-fold pattern. The right visual acuity was 20/20, the left 20/70 (amblyopic). Whitish material was gonioscopically visible on the zonule and ciliary processes. The intraocular pressure was normal and has remained so. The deposits had increased when the patient was later examined but showed desquamation of some of the material on the capsule. A sphincterectomy was performed in February 1977 to avoid the down-drawn position of the pupil and to avoid further iris contact. Four years later, more desquamation of the deposits had occurred.

The pigmentation dispersion observed immediately af­ter mydriasis occurs more frequently in the pseudoex-

foliation syndrome than in normal eyes. Even without mydriasis, the constant iris movement against the irregular capsule results in enough pigment granule dispersion into the aqueous humor to leave a pigment ring in addition to the exfoliated material in the trabecular spaces as the aqueous filters out. I have always found much greater trabecular pigmentation in the involved eye in monocular exfoliation syndrome cases.

Increased intraocular pressure was found in 55% of 643 cases in the literature up to 1947 and 81.8% of the series reported by Gradle and myselfY We reported the development of ocular hypertension or glaucoma in four patients while under observation. I have observed eight additional cases since that report. The increased intra­ocular pressure is attributed to obstruction of aqueous outflow by pigment and exfoliative material. There is good correlation between the amount of pigment in the angle and the severity of the glaucoma, especially notable in unilateral cases.

The normal lens capsule consists of two layers which differ in staining characteristics. The very thin, more su­perficial, deeper-staining layer is the zonular lamella or pericapsular membrane. The deeper fibrillar layer con­stitutes most of the capsule thickness and, like the su­perficial layer, is entirely homogeneous. In the pseu­doexfoliation syndrome, a third amorphous layer is found in the intermediate and peripheral areas of the lens be­tween the fibrillar layer and the lens epithelium. It may constitute up to two-thirds of the total capsule thickness in this location.

The most important microscopic characteristic of the syndrome is the peculiar serrated iris pigment epithelium covered by pink-staining material which extends far be­yond the area of contact with the capsule so it cannot be considered as due to abrasion. The material apparently is transferred to the capsule only where there is contact, as shown in the case with the drawn-down pupil. After intracapsular lens extraction the exfoliative material has been said to diminish and regress but this is not true. In one of my cases, an 89-year-old patient, the material appears to have gradually increased in each eye over a period of 15 years. In three other cases where there was no evidence of exfoliation before cataract extraction, the exfoliation began afterward. Ghosh and Speakman 17 have corroborated these findings after cataract extraction.

Ringvold 18 described exfoliative material in the limbal conjunctival vessels close to the basement membrane of the endothelial cells without obvious disruptions in the basement membrane, as well as beneath the basement membrane of the conjunctival epithelium and in the stroma. I have attempted to counter the idea of multiple separate sources of the material. 14

DISCUSSION

With the findings we have discussed, I hope that we can accept the idea that there are two components of the exfoliative process and that the term pseudoexfoliation

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no longer serves as an overall substitute for exfoliation. Both terms are necessary to cover the subject even though the term pseudoexfoliation is confusing and might better be defined as deposition.

I believe that only the ciliary epithelium and iris epi­thelium are the source of the fibrillar material, and that the lens epithelium does not contribute, in spite of Ber­telson's theory,16 since I do not conceive of the material being able to penetrate the capsule. In my opinion the syndrome fits a basement membrane disease in which aging and possibly trauma are causes.

It is interesting to note the differences and similarities in the two conditions we have discussed. Similarities in­clude the presence of the trabecular pigment ring, dis­persion of some pigment from pigment epithelium of iris although much more in pigmentary glaucoma, and de­velopment of glaucoma after several years. Differences include the age of affliction, usually young in pigmentary glaucoma, old in exfoliation syndrome, that Krukenberg's sign is spindly only in pigmentary glaucoma, that myopia appears frequently in pigmentary glaucoma, the possibility of self-limitation in pigmentary glaucoma, and types of early treatment: mild miotics in pigmentary glaucoma, Timoptic in pseudoexfoliation syndrome.

REFERENCES

1. Sugar HS. Concerning the chamber angle. 1. Gonioscopy. Am J Ophthalrnol 1940; 23:853-66.

2. Sugar HS, Barbour FA. Pigmentary glaucoma; a rare Clinical entity. Am J Ophthalmol1g49; 32:90-2.

3. Sick MW. Sex differences in pigmentary glaucoma. Am J Ophthalmol 1962; 54:831-7.

4. Fine BS, Yanoff M, Scheie HG. Pigmentary "glaucoma;" a histologic study. Trans Am Acad Ophthalmol Otolaryngol1974; 78:0P314-25.

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5. Kupfer C, Kuwabara T, Kaiser-Kupfer M. The histopathology of pig­mentary dispersion syndrome with glaucoma. Am J Ophthalmol1975; 80:857-62.

6. Campbell DG. Pigmentary dispersion and glaucoma; a new theory. Arch Ophthalmol 1979; 97:1667-72.

7. Kampik A, Green WR, Quigley HA, Pierce LH. Scanning and trans­mission electron microscopic studies of two cases of pigment dis­persion syndrome. Am J Ophthalmol 1981; 91 :573-87.

8. Dueker DK. Pigmentary glaucoma treatment may include laser iri­doplasty. IOL Intraocul Surg News 1983; 1(17):1, 15-6.

9. Lindberg JG. Klinska und undersokingar over depigmenteringen av Pupillarrenden och genomlysbarheten av iris. Helsingfors, 1917.

10. Vogt A. Ein neues Spaltlampenbild: Abschilferung der Linsenvor­derkapsel als wahrscheinliche Ursache von senilem, chronischem Glaukom. Schweiz Med Wochenschr 1926; 56:413-5.

11. Busacca A. Struktur und Bedeutung der Hautchenniederschlage in der vorderen und hinteren Augenkammer. Albrecht von Graefes Arch Ophthalmol 1928; 119:135-76.

12. Dvorak-Theobald G. Pseudo-exfoliation of the lens capsule. Relation of "true" exfoliation of the lens capsule as reported in the literature and role in the production of glaucoma capsulocuticulare. Am J Ophthalmol 1954; 37:1-12.

13. Bertelsen TI, DrablCis PA, Flood PR. The socalled senile exfoliation (pseudoexfoliation) of the anterior lens capsule, a product of the lens epithelium. Fibrillopathia epitheliocapsularis; a microscopic, histo­chemic and electron microscopic investigation. Acta Ophthalmol1964; 42:1096-113.

14. Sugar HS, Harding C, Barsky D. The exfoliation syndrome. Ann Ophthalmol 1976; 8:1165-81.

15. Gradle HS, Sugar HS. Concerning the chamber angle. II. Exfoliation of the zonular lamella and glaucoma capsulare. Am J Ophthalmol 1940; 23:982-97.

16. Bertelsen TL, Ehlers N. Morphological and histochemical studies on fibrillopathia epitheliocapsularis. Acta Ophthalmol 1969; 47:476-88.

17. Ghosh M, Speakman JS. The origin of senile lens exfoliation. Can J Ophthalmol, 1983; 18:340-3.

18. Ringvold A. Electron microscopy of the limbal conjunctiva in eyes with pseudoexfoliation syndrome (PE syndrome). Virchow's Arch [Pa­thol Anat] 1972; 355:275-83.