Eye (1987) 1, 318-322

Reappraisal of the Mechanisms of Glaucomatous Damage

HARRY A. QU IGLEY Baltimore, Maryland

Glaucoma is a progressive optic neuropathy frequently occurs without with a typical appearance and a par­ any past lOP elevation and that the two are not ticular loss of sensitivity in visual field testing. causally related. Our own study (the Baltimore Its disc appearance includes enlargement of Eye Survey) shows that most persons with the disc cup toward the rim, undercutting of glaucomatous neuropathy selected at random the rim tissue, and deepening of the cup floor. from the population have easily demonstrable These features are all included in the term elevated lOP. Only a tiny minority appear to glaucomatous cupping, though the individual have damage and normal lOP (so­ nerve head may exhibit only some of them. called low tension glaucoma). Glaucomatous Some eyes can simulate glaucoma cupping neuropathy results from lOP elevation after even though they are normal or have another steroid use, trauma, or in flammation.Chronic optic neuropathy, but these are rare.l In lOP elevation in a monkey eye leads to disc and glaucoma, this pattern is recognised in nearly nerve damage indistinguishable from that of every case. In a visual fieldtest, glaucoma first the human eye.3 This brief report will sum­ shows abnormality between 5 and 30 degrees marise the recent additions to information from fixation. The abnormality expands into about how elevated lOP causes optic nerve an arcuate shape, isolating the central and tem­ damage. poral fieldinto islands. Again, while other dis­ orders can simulate this field pattern, they Where Does Glaucoma Damage Nerve almost never have glaucomatous cupping. Fibres? Most glaucoma eyes have an intraocular Over the last 10 years, I examined more than pressure (lOP) that is higher and more unsta­ 150 human glaucoma eyes with known clinical ble than normal. However, all eyes with ele­ histories.3.4 This material indicated that the vated lOP do not have glaucomatous optic nerve fibre injury occured within the optic neuropathy at the time abnormal lOP is dis­ nerve head at the level of the , the scleral covered. This does not mean that these eyes do lamina cribrosa. Here, axons were swollen not have glaucoma or that they never will have with accumulations of their intracellular con­ it. Some have not had elevated lOP long tents that would normally have been moving enough to be damaged. Others are already past this area, but were held up by the injury. damaged, but the visual fieldtest is too insensi­ Vrabec5 confirmed that this is the location of tive to detect it. 2 It is therefore deceptive to injury inhuman glaucoma eyes, anditis the site defineglaucoma solely by fieldtest results or to of damage in chronic lOP elevation in use a different diagnostic term (ocular hyper­ monkeys, as well. The intracellular contents tension) for persons with normal fieldsbut ele­ that accumulate at the scleral lamina in vated lOP. glaucoma move by axonal transport, the Some have suggested that glaucomatous system by which the cell body supplies its axon

Professor of and Director, Glaucoma Service, Wilmer Institute, 10hns Hopkins University School of Medicine, Baltimore, Maryland, USA. Correspondence to: Professor A. Quigley MD, Maumenee B-110, Wilmer, 10hns Hopkins Hospital, Baltimore, MD 21205, USA. REAPPRAISAL OF THE MECHANISMS OF GLAUCOMATOUS OPTIC NERVE DAMAGE 319 and synaptic terminals with materials. Inter­ to greater damage to the bundles passing ference with axonal transport is sufficient to through their zones. Therefore, the pattern of cause cell death. But, axonal transport might hourglass optic atrophy is explained by the be disturbed by anoxia, by mechanical com­ regional laminar architecture. pression, or by build-up of toxic substances. This hypothesis is local and is supported by Hence, the fact that transport blockade is pres­ examinations of human glaucomatous eyes.8 ent in glaucomatous neuropathy does not Compression of the lamina cribrosa is seen establish what is (are) the intervening link(s) even in eyes that have not yet developed field between elevated lOP and cell death. loss. Laminar compression worsens with each succeeding stage of optic nerve damage. Most Optic Nerve Head Anatomy Explains Field importantly, this change is greater at the Loss in Glaucoma superior and inferior poles than in the tem­ The scleral lamina cribrosa consists of ten suc­ poral-nasal axis. cessive connective tissue plates with perfor­ ations through which neural bundles pass. Does Loss of Glial Cells Contribute to Astrocytic glial cells surround the bundles, Glaucoma Cupping? maintaining proper ionic concentration for Seventy years ago, Fuchs reported that neural impulse transmission. Optic nerve glaucomatous eyes lose glial cells of the optic cross-sections from h4man glaucomatous eyes nerve head. Since he had no accurate tonome­ have a selectively greater loss of fibresentering try, gonioscopy, or field testing, we have no the upper and lower optic disc poles. It is way of knowing how the eyes he studied would believed that these are the fibresthat subserve be classifiedtoday. Shaffer later suggested that the arcuate area in which typical glaucoma field loss of glial cells might cause the increased cup loss occurs. The susceptible regions form the size that precedes fieldloss. In both human and shape of an hourglass. Kirsch and Anderson6 experimental primate glaucomatous eyes, I observed that some glaucomatous eyes lose the have found no disproportionate loss of astro­ upper or lower disc rim first, producing ver­ cytes (glial cells).4 Why, then, did Fuchs find tically oval cup shape or a local notch of rim loss that glia had disappeared? Astrocytes make up at6 or 120'clock. Since the site of damage is the about 10% of the nerve head tissue. Once all scleral lamina, and the pattern of loss is nerve fibres are gone, the nerve head would hourglass-shaped, I examined the laminar look empty, even if all the glia were preserved. anatomy for some feature that would fit the In nerve heads with advanced glaucoma damage pattern.7 With the scanning electron damage, the lamina is compressed and microscope, the upper and lower poles of the expanded outward into the and sclera. normal lamina cribrosa can be seen to have The surface area of the nerve head becomes 3 larger pores for the passage of nerve bundles. times greater than normal. The remaining glia Hence, the structural support is less there than are therefore spread out over a much bigger in the nasal and temporal nerve heads. The area and look fewer in number even if the origi­ conclusion from these observations has direct nal number is present. implications for glaucoma pathogenesis. If lOP increases, two forces act on the lamina. Further Steps in the Damage Pathway Firstly, there is an inside-out push, tending to Direct mechanical effects on nerve fibres compress the laminar sheets and to bow them Might distortion and compression of the lam­ outward. Secondly, increased lOP raises scle­ ina cribrosa directly compress optic nerve ral tension, pulling on the perimeter of the lam­ fibres, leading to subsequent cell death? Or, inar sheets. Both actions might distort the does laminar compression impair function of lamina, pressing on either the nerve fibres optic nerve head capillaries? The physical themselves or on their nutrient capillaries that forces generated at the lamina could be con­ are located within the laminar sheets. Resis­ siderable. Forces generated by laminar shape tance to distortion would vary within the nerve change could far exceed the simple increase in head. The upper and lower poles, with the least pressure gradient across the nerve head caused collagenous tissue, would distort first,leading by elevated lOP. The normal gradient is lOP 320 H. A. QUIGLEY minus optic nerve tissue pressure, or about flowwas normal, only that the normal propor­ 10 mm Hg. With chronic glaucoma, this would tion of vessels is unchanged. increase to 20 mm Hg at lOP = 30 mm Hg. But, the shearing force caused by pinching of Disc haemorrhages two adjacent laminar sheets could exceed this Capillaries do atrophy in glaucoma, propor­ considerably. At these lOP levels, axonal tionately with loss of neural tissue. What transport is blocked under experimental happens to these vessels? Capillaries of the conditions. nerve head are a continuous plexus extending from the to the myelinated optic nerve. Is vascular insufficiency a cause of neural Compression of the lamina cribrosa and loss of loss? surrounding nerve fibre bundles places this The evidence for vascular insufficiency as a plexus under physical stress. Forced to cause for glaucomatous optic neuropathy is increase in antero-posterior length, and indirect. Previous reports discuss 'ischaemia' unsupported by adjacent neural tissue, an without definingwhat is meant by the term. In occasional capillary is stretched to the break­ the central nervous system, fibretracts supply ing point and a flame-shaped haemorrhage themselves with energy and most nutrients by occurs into the superficial nerve fibrelayer of axonal transport. If one places a fibre in a the disc rim. Drance, astutely, noted that such chamber and progressively eliminates haemorrhages are mOre likely to occur in nutrients from the surrounding medium, axo­ glaucomatous eyes that are in the process of nal function proceeds normally as long as oxy­ developing progressive optic nerve damage. gen is supplied, carbon dioxide is eliminated, This is certainly compatible with the above and a minimal amount of calcium is present. explanation. Clinicians must re-evaluate the Glucose and amino acids are not apparently need for more intense therapy in any needed since they arrive by axonal transport. glaucomatous eye that has adisc haemorrhage. While there is general agreement about the Oxygen levels clinical significance of disc haemorrhage, the Ernest showed that the oxygen level of the pathogenesis of the haemorrhage is not univer­ nerve head is constant despite substantial sally agreed upon. It was speculated that disc increase in lOP. Either blood flow does not haemorrhage indicates ischaemia of the nerve decrease with increased lOP or flow decreases head. But there is no direct evidence that without affecting oxygen delivery. If tissue haemorrhage results from insufficientvascular oxygen tension is increased during acute function. Haemorrhage occurs with trauma, experimental glaucoma, obstruction of axonal elevated intravascular pressure, or abnormal transport is similar to animals breathing room capillary fragility. Certainly there are clear air (an experiment carried out by Minckler in differences between the glaucoma eye with a our laboratory). This suggests that oxygen haemorrhage and anterior ischaemic optic supply at the lamina is unaffected by moder­ neuropathy. The glaucoma patient does not ately elevated lOP. have disc swelling, often does not have an immediately definable new loss of field, and Effects on capillary number almost never suffers loss of acuity with the Christini and Fran�ois suggested that optic event. nerve head capillaries are selectively lost in glaucoma. The eyes that they examined were Blood flow in human glaucoma: fluorescein blind and detailed histories were not provided. angiography I studied human and primate glaucoma eyes Unfortunately, there is no reliable method at with quantitative methods.3 There is no present to measure human nerve head blood selective loss of capillaries in the nerve head. flow in vivo. Fluorescein angiography shows Capillaries disappear from the nerve head as vessels of the superficialnerve head, but capill­ nerve fibres disappear, but at just the rate aries of the scleral lamina are surrounded by necessary to maintain the usual ratio of capill­ collagenous sheets and are not detected in aries to tissue. This does not prove that blood clinical angiography.3 Furthermore, fluor- REAPPRAISAL OF THE MECHANISMS OF GLAUCOMATOUS OPTIC NERVE DAMAGE 321 escein angiography does not quantitate blood not assume that nerve head flow willchange as flow.Spaeth demonstrated that glaucomatous systemic blood pressure changes. For discs have a slower filling time than normal example, the drug clonidine is not used in the discs. While this is interesting, it gives no direct US to lower lOP because it lowers blood pres­ information about the adequacy of nutrition of sure. The assumption underlying this reluc­ the nerve head. Slow fillingmight result if the tance is that the 'perfusion' of the nerve head path from ophthalmic artery to retina is length­ (blood pressure minus lOP) would not be ened by cup excavation. Hayreh and Schwartz helped if the drug lowered both. It is clear that report that glaucomatous discs have areas drugs can change blood pressure with no without detectab le vessels by angiography. detectable effect on blood flow. Sperber and Many of the published examples of such 'filling Bill have shown th at aerobic metabolism con­ defects' are in eyes with clear nerve loss (large tinues normally in the nerve head despite lOP cup/disc ratios and known field defects). As elevation until lOP leaves the clinical range discussed above, at this stage of damage, neu­ (comes within 25 mm Hg of mean blood ronal loss is accompanied by a proportionate pressure). loss of capillaries. Hence, the disc with moder­ ate or severe cup enlargement will naturally Faulty autoregulation have fewer detectable vessels in the anterior Sossi and Anderson speculate that normal disc. Scleral lamina capillaries in the filling autoregulation might not be present in the defect zones are patent but unseen glaucomatous eye. They suggest that circu­ angiographically.3 The fluorescein obser­ lating vasoconstrictors might in fluence nerve vations are interesting and understandable in head blood flowby entering from the choroid. the light of the histological events, but provide Weinstein found, however, that a potent no direct evidence for inadequate nutrition to vasoconstrictor, metaraminol, substantially axons. affected the systemic vasculature without increasing or decreasing nerve head blood Blood flowin experimental glaucoma flow. The suggestion that glaucoma damage In recent experiments, we produced chronic consists of elevated lOP plus faulty auto­ lOP elevation in monkeys by laser treatment of regulation overlooks the fact that normal the trabecular meshwork and measured blood human eyes or experimental monkey eyes that flowby a histological method. 9 In experiments suffer chronic lOP elevation develop with acute lOP elevations, there was no signifi­ glaucomatous optic neuropathy. cant blood flow decrease as long as lOP was kept below 75 mm Hg. With lOP below Low tension glaucoma 75 mm Hg, flow was equal to that in normal Some eyes appear to have glaucomatous disc eyes. In animals with chronic glaucoma, with cupping and fieldloss with apparently normal mean lOP from 25t0 45 mm Hg, the blood flow lOP. Some feel that these eyes support vascu­ in the glaucoma eye was equivalent to normal lar insufficiency as a mechanism of glaucoma eyes. Nor was the flowaffected to any greater damage. The argument is made that if these degree in the superior and inferior poles of the patients do not have high 10P, then what could nerve head where damage happens most. Sossi have damaged them? The ready conclusion is and Anderson also found normal flow in cat that they have deficient blood supply-yet eyes with acute lOP elevations (25 mm Hg or there is no direct evidence for this. These eyes more below mean blood pressure ). Weinstein might have an optic neuropathy caused by confirmedthat flowwas maintained at a stable early senescence of neurons or a toxic neuropa­ level in the nerve head despite substantial thy with an as-yet unidentifiedagent. The most increases or decreases in systemic blood pres­ interesting paradox of low tension glaucoma is sure. This experiment is particularly important the fact that they have disc cup configurations to clinicians, since some reports suggested that similar to "high lOP" glaucomatous eyes. How decrease in brachial blood pressure might did the cup come to look this way? Either the decrease blood flowin the optic nerve head. It lamina became distorted without elevated lOP is clear from Weinstein's work that we should or lOP was elevated at some point but went 322 H. A. QUIGLEY undetected. If the lamina spontaneously and subserve colour vision and fine acuity. stretched into a glaucomatous shape, then the Others are large and are colour insensitive, connective tissues of these eyes might be inher­ giving instead information on motion or pres­ ently different. This stretching cannot be pro­ ence/absence of illumination. These cell types duced by experimental vascular insufficiency, have particular terminal zones for their axonal so it must be a primary defect. Alternatively, projections in the brain. We have produced lOP might have been elevated in the past, or is chronic experimental glaucoma in monkeys still elevated intermittently, requiring and have traced which ganglIon cell types are repeated monitoring to detect it. most susceptible to glaucoma damag\!.Both in studies of central connections and in measures Cavernous optic nerve degeneration of cell diameter, 10 cells of larger size are more Schnabel reported that glaucomatous nerves sensitive to damage than are smaller cells. This suffer a cavernous optic atrophy, in which will direct us to develop psychophysical tests spaces in the retrobulbar nerve are filled with that are geared to the functions that these cells hyaluronic acid. Similar pathology was perform. reported in other optic neuropathies. The similar histologic end-results were interpreted References to mean that the pathogenesis of the disorders J Quigley HA and Anderson DR: Cupping of the optic disc in ischemic optic neuropathy. Trans. Am. must be the same. Because optic nerve infarc­ Acad. Ophthalmol. Otolaryngol. 1977, 83: 755- tion from was among the con­ 62. ditions with cavernous atrophy, it was assumed 2 Quigley HA, Addicks EM and Green WR: Optic that this supported infarction as a cause of nerve damage in human glaucoma. III. Quantita­ glaucomatous neuropathy. In 150 glaucoma tive correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, optic nerves, I found only four with cavernous , and toxic neuropathy. Arch. degeneration. These were from cases with Ophthalmol. 1982, 100: 135-46. rapid loss of all vision from very high lOP. In 3 Quigley HA, Hohman RM, Addicks EM and Green chronic, moderate lOP elevation eyes, neu­ WR: Blood vessels of the optic disk in chronic glaucoma. Invest. Ophthalmol. Visual Sci. 1984, rons atrophy without detectable caverns. Why 25: 918-31. does cavernous degeneration occur? There is a 4 Quigley HA, Addicks EM, Green WR and normal movement of fluidfrom vitreous cavity Maumenee AE: Optic nerve damage in human to retrobulbar nerve tissue. This flowincreases glaucoma. II. The site of injury and susceptibility if lOP is elevated. With a rapid loss of many to damage. Arch. Ophthalmol. 1981, 99: 635-49. 5 Vrabec F: Glaucomatous cupping of the human optic nerve fibres,the unoccupied space in the retro­ disk. A neurohistologic study. Albrecht. von bulbar nerve fillswith fluidcontaining vitreous GraefesArchiv. klin. expo Ophthalmol. 1976, 198: hyaloronate. This happens in any rapid atro­ 223-4. phy, regardless of its cause. Acute or neo­ 6 Kirsch RE and Anderson DR: Identification of the glaucomatous disc. Trans. Am. Acad. vascular glaucoma would be commonly Ophthalmol. Otolaryngol. 1973,77: 143-60. associated, and these eyes would have come to 7 Quigley HA and Addicks EM: Regional differences Schnabel's pathology laboratory, removed as in the structure of the lamina cribrosa and their blind and painful. Yet, other disorders share relation to glaucomatous optic nerve damage. this common pathway, accounting for Arch. Ophthalmol. 1981, 99: 137-43. 8 Quigley HA, Hohman RM, Addicks EM, Massof RS reported non-glaucomatous cavernous and Green WR: Morphologic changes in the lam­ degeneration. ina crib rosa correlated with neural loss in open­ angle glaucoma. Am. J. Ophthalmol. 1983, 95: 673-91. Selective Loss of Particular Ganglion Cell 9 Quigley HA, Hohman RM, Sanchez R and Addicks Types EM: Optic nerve head blood flow in chronic Our inability to detect early glaucoma damage experimental glaucoma. Arch. Ophthalmol. has been hampered by the lack of knowledge of 1985, 103: 956-62. which retinal ganglion cells are the firstto dis­ JO Quigley HA, Sanchez RM, Dunkelberger GR, appear. Recent experimental work in mam­ L'Hernault NL and Baginski TA: Chronic glaucoma selectively damages large optic nerve mals has shown that there are a variety of fibers. Arch. Ophthalmol. 1986 (submitted for ganglion cell types. Some cells are small in size publication) .