Doyne Lecture the Pathology of the Outflow System in Primary and Secondary Glaucoma

DOYNE LECTURE THE PATHOLOGY OF THE OUTFLOW SYSTEM IN PRIMARY AND SECONDARY GLAUCOMA W. R. LEE Glasgow On behalf of my specialty of ophthalmic pathology, I noted that since the contribution of Doyne himself, am indebted to the Master of the Oxford Congress few pathologists have been honoured. Professor for the invitation to present the Doyne Memorial Norman Ashton and the late Professor David Lecture on the pathology of the outflow system in Cogan were the only ophthalmic pathologists primary and secondary glaucoma. Although I regard included in the list. In 1960, Professor Ashton3 the Doyne Lecture as an awesome responsibility, it chose to lecture on the pathology of the outflow has been an enjoyable exercise in preparing for it to channels in glaucoma and I was interested to see that go through the contributions of previous Doyne in the final paragraph of his text he wrote 'no doubt lecturers and to read the remarks made by those who this topic will again be chosen by a Doyne Lecturer'. knew Doyne personally. From the various very Thus it is appropriate that the problem of glaucoma distinguished Doyne lecturers who have preceded should again be addressed by a pathologist some 35 me, I sense that the ethos of this lecture is that years later. In this lecture I have drawn freely on the speculation is an integral requirement of the speaker. research material which my colleagues and I have This is not so easy for a pathologist, but I hope that been studying in Glasgow for the past 25 years and I some of the text will be sufficiently controversial to have used this to re-interpret conventional morphol stimulate further research work. ogy in the light of modern technology which uses It has also been an enjoyable task to review some molecular biology. of Doyne's published work and to read descriptions In the 1970s and early 1980s, I had the privilege of of the man and his attitudes to work and to collaborating with Ian Grierson and Paul McMena relaxation. The account of the life of Doyne prepared by Catford1 was of great value to those min in the investigation of the response of the sub who, like myself, were aware of the name only in the human primate outflow system to a variety of short context of this lecture. The illustrations in Catford's term stresses such as alterations in intraocular paper highlight the many facets of the character of pressure and exposure to enzymes. Non-survival Doyne - scholar, musician, clinician , fencer and experiments such as these provided valuable infor sailor - elegantly combining the attitudes of the mation on the functional morphology of the normal Anglo-Saxon and the Celt to recreation and tissue. contemplation. In his generation so many great The study of diseased tissue was not so easily men appeared to have a multitude of talents, which undertaken due to a paucity of suitable. specimens is something of a rarity in contemporary society. appropriately fixed and prepared for sophisticated However, the statement which I personally found pathological investigations. Accordingly for the last most endearing and of greatest encouragement when 25 years I have adopted the policy of preparing any I started to prepare for this lecture, was written in potentially interesting specimen for electron micro 2 Doyne's textbook in 1896, viz. 'Glaucoma was the scopy in the hope that eventually it would be possible most dreaded of all eye diseases'. to generate a cohesive description of those disease On looking through the list of Doyne medallists, I processes which test the outflow system to destruc tion. The intention was to integrate the results of Correspondence to: Professor W. R. Lee. Department of Ophthalmology. The University of Glasgow. Glasgow Gil 6NT. pathomorphological investigation with the massive UK. amount of factual information currently available in Eye (1995) 9, 1-23 © 1995 Royal College of Ophthalmologists 2 W. R. LEE Fig. 1. A giant vacuole (v) in the lining endothelium of Fig. 2. There is marked distension of the cribriform layer Schlemm's canal in a 60-year-old male suffering from of the rhesus monkey subject to an intracameral perfusion at partial angle closure with overperfusion in this part of the 50 mmHg for 1 hour prior to fixation. The collector channel meshwork. The underlying cribriform layer contains a fine (cc) is blocked and the giant vacuoles (arrowheads) are fibrillar extracellular matrix (arrowheads) and electron adherent to the outer wall endothelium. (Transmission dense clumps (arrows). (Transmission electron micrograph, electron micrograph, X 900) X 5000) the many excellent textbooks dealing with the clinical occurs after a hole or pore forms in the cytoplasm 4 6 aspects of glaucoma in all its forms. - which bulges into Schlemm's canal. The structure In this lecture it is appropriate to first review the (Fig. 1) then acts as a transcellular channel which current status of knowledge concerning the func permits rapid fluidtransport when the pressure in the tional anatomy of the outflow system. Thereafter cribriform layer is high; conversely with collapse of various pathological processes will be described in the cribriform layer at low intraocular pressure, order to provide an understanding of the mechan blood refluxis prevented - hence the concept of the isms which can lead to breakdown of the tissue and 'one-way valve' (for review see Tripathi and an increased resistance to aqueous outflow and, TripathiI4). ultimately, to intractable glaucoma. In the following decades the importance of the It is currently accepted that the outflow systemhas giant vacuole system in bulk flow through an the following functional properties and can behave endothelial monolayer became accepted, not only . as: 7 for transport of aqueous from the eye, but also for 1. a one-way valve; passage of cerebrospinal fluid into the intracranial 7 2. a resistor which maintains intraocular pressure; venous sinuses.14 The pressure-sensitive nature of the 3. a selective filterS which (a) removes particulate giant vacuole bulk transfer system was demonstrated materials (endogenous and exogenous), (b) per in 1973 by Johnstone and Grantl5 working in Boston mits the escape of cellular infiltrates and (c) acts as on human autopsy eyes and on monkey eyes, and an immunological recognition system;9 their studies emphasised the importance of intra 4. a pressure sensor.lO ocular pressure on the numbers of giant vacuoles in the lining endothelium of Schlemm's canal. The hypothesis of transcellular bulk flow did not THE NORMAL OUTFLOW SYSTEM go unchallenged and the possibility that the vacuolar The Outflow System as a One-Way Valve structures were autolytic artefacts persisted? How Morphological investigation of the mechanisms for ever, subsequent conclusive studies proved the aqueous transport across the lining endothelium of opposite.16 In the early 1970s the working hypoth Schlemm's canal was initiated by Garron et at. I I in esis of Grierson and myself was that, if the giant 1958 and Holmbergl2 in 1959 with the discovery that vacuoles were not artefactual, there would be an the monolayer contained large membrane-bound increase in number and size in response to pressure spaces which were subsequently described as giant and the concomitant flow of aqueous through the vacuoles. The nature of giant vacuoles was not fully trabecular tissues. Painstaking morphometric studies appreciated until Tripathil3 provided the hypothesis carried out on the monkey eye by Grierson17-l9 that a giant vacuole is preceded by the formation of provided data to prove that the number and size of an invagination and that emptying of the vacuole giant vacuoles increased with a pressure rise (as THE OUTFLOW SYSTEM IN GLAUCOMA 3 ous physiological studies of aqueous outflow dynamics. The importance of glycoproteins in resistance to aqueous outflow was investigated by McMenamin, who conducted a series of experiments in which the baboon anterior chamber was perfused in vivo with a solution containing hyaluronidase at physiological pressures (18 mmHg).27,28 The prolonged perfusion experiments with and without the addition of hyaluronidase for periods of 4-6 hours on the primate eye, i.e. with a combination of physiological measurements and morphometry,27 failed to demon strate any effect of the enzyme. This was because the perfusion technique caused such distension in the control tissue that an enzyme effect, if it indeed exists, was totally obscured. Our observations were Fig. 3. A light micrograph to show numerous giant confirmed by another recent study29 which also vacuoles (arrowheads) in the human lining endothelium demonstrated that the distension of the cribriform of Schlemm's canal after fixation perfusion at 30 mmHg. (X 475) layer obstructed the collector channels. Our conclu sion was that the pliability of the monkey outflow maintained by a manometer in vivo) in the normal system rendered our physiological data unreliable. physiological range. Thus a 'giant vacuole count' Coincidental with the experimental work, it was became a mathematical indicator of both pressure our policy to study drug effects on the human outflow and flow through the outflow system, particularly if system using eyes obtained immediately after this was associated with distension of the cribriform surgical enucleation, in most cases in treatment for layer. posterior uveal melanoma. In the early experiments Similarly the number of flow channels and pores the globes were fixed immediately by immersion in (as determined by scanning and transmission elec glutaraldehyde. We found that pre-enucleation 0 tron microscopy) in the lining endothelium also treatment of the patients with topical pilocarpine3 increased in response to an increase in intraocular resulted in a rotation of the scleral spur and a pressure?O-23 The morphological observations with statistically significantincrease in the number of giant regard to the response of the outflow system to vacuoles in the lining endothelium of Schlemm's intraocular pressure were confirmedand accepted by canal.

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