THE HISTOLOGY OF HUMAN GLAUCOMA CUPPING AND OPTIC NERVE DAMAGE: CLINICOPATHOLOGIC CORRELATION IN 21 EYES HARRY

A.

QUIGLEY,

MD

and

w.

RICHARD GREEN,

We have examined by light and electron microscopy the retina, optic nervehead, and optic nerves of 21 human eyes from glaucoma patients in whom clinical information was available for comparison. In several cases it was possible to correlate the degree and distribution of optic nerve damage with the clinical appearance of the optic disc and visual field studies. There was no selective loss of astrocytes of the optic nervehead in early glaucoma cupping. Acquired increases in optic disc cup size prior to detectable visual field loss probably represent loss of ganglion cell axonal fibers which is not yet significant enough to produce field defects. It is unlikely that the mechanism of axonal damage in chronic human glaucoma involves early loss of astrocytic glial cells at the optic nervehead. At the level of the retrobulbar optic nerve, the ganglion cell axonal fibers of the superior and inferior quadrants seem to be lost earlier than the fibers of the nasal and temporal nerve periphery. Since the superior and inferior poles of the optic nerve may contain the fibers of arcuate area ganglion cells, these data confirm the presumption from visual field testing

Submitted for publication Oct 25, 1978. From the Glaucoma Service and Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins University School of Medicine. This investigation was supported in part by U.S. Public Health Service Research Grants EY-02120 (Dr Quigley), EY -01684 (Dr Green), and Core Facility Grant EY-01765, awarded by the National Eye Institute, National Institutes of Health. Reprint requests to Glaucoma Service, Wilmer B-2, The Johns Hopkins Hospital, Baltimore, MD 21205 (Dr Quigley).

MD

that arcuate area ganglion cell fibers are selectively more susceptible to damage in chronic glaucoma.

INTRODUCTION

OuR understanding of the significance of optic disc changes in glaucoma has been limited by the lack of clinicopathologic correlation in glaucomatous eyes. While there have been some microscopic descriptions of advanced glaucoma damage, 1- 8 few eyes have been examined with early or moderate damage, and none has had detailed clinical correlation. For example, many feel that optic disc changes occur prior to detectable visual field loss. 9 · 11 Does early glaucomatous cupping signify loss of nerve fibers, or does it represent no actual neuronal damage, but rather glial cell loss or posterior movement of still intact disc tissue? If neuronal damage occurs prior to detectable visual field loss, how much damage is undetected? Clinicopathologic correlations could also define the degree of selectivity in early glaucoma damage and perhaps identify features of the most susceptible axons which point to the mechanism of damage.

This report summarizes a series of eyes from glaucoma patients with correlation between clinical parameters and light and electron microscopic features of optic nerve-

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head and optic nerve. The material illustrates the practicality and potential significance of this investigative approach.

METHODS Eyes were obtained either at surgical enucleation, as autopsy specimens, or after donation to an eye bank. Eyes were fixed by immersion in either 10% aqueous formalin (13 eyes) or 5% phosphate-buffered glutaraldehyde (8 eyes). Time between patient death and fixation varied from 6-24 hours. Since such material is frequently not perfectly preserved due to postmortem autolysis prior to fixation, 14 control human eyes with no history of glaucoma were examined from persons 10-80 years old, using a similar variety of fixation materials and protocols.

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In eyes examined only in paraffin-embedded sections, serial sections of the optic nervehead were performed and stained by a variety of standard histochemical techniques. For electron microscopy, the optic nerve was marked for orientation by razor cuts and crosssectional disks of optic nerve were removed 2-4 mm behind the globe. The optic disc was divided into four segments by a vertical and horizontal razor cut and embedded in exact orientation to examine anteroposterior sections at the 12, 3, 6, and 9 o'clock meridians. In some eyes, separate specimens of retina were also obtained. These specimens were post-fixed in 2% osmium tetroxide in phosphate buffer and embedded in epoxy resin. The remainder of the globe was embedded in paraffin. Thick sections in epoxy resin were stained with paraphenylenediamine and examined by phase contrast micro-

TABLE 1 SUMMARY OF TISSUE ExAMINED

H 147 OU H 159 OU H 162 OD H 170 OD H 179 OU H 190 OU H 195 OU H 196 OD H 197 OD H 198 OD H 200 OS H 202 OU H 203 OU H 204 OD

ELECTRON MICROSCOPY

AVAII..ABLE VISUAL FIELD

OPI'IC NERVE CROSS SECTION

X X X X X X X X X X

X X

X

NLP

X X X

X X

NLP

X X NLP NLP NLP

X X X

NLP, no light perception. *Optic nerve cross section reconstructed from serial paraffin sections.

*

X X X

*

X X

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Fig !.-Photograph of optic discs from postmortem specimens and visual fields (A, C: right eye; B, D: left eye) of patient, with mild glaucoma damage (H 159). The right disc has loss and undermining of the upper rim while the left disc has no apparent cup abnormality. Note that the superior tangent field defect (blind spot elongation) does not correspond to the most abnormal disc area in this case.

scopy. Thin sections were stained with lead and uranyl acetate and examined with a JEOL lOOB electron microscope. A summary of the material obtained is given in Table 1. CASE REPORTS

History of Elevated Intraocular Pressure-Normal or Mild Field Defect H 159. This 76-year-old white man had open-angle glaucoma diagnosed nine years

prior to death, with good intraocular pressure (lOP) control on epinephrine and pilocarpine drops. At the last examination six months prior to death, vision was 20/25 OD, 20/20 OS; lOP was 18 mm Hg (applanation); and the optic discs had a cup/disc ratio of 0.5 OD and 0.3 OS. The right eye had an arcuate area field defect on tangent screen (Fig 1), while the left field demonstrated no abnormality. H 162. This 78-year-old white female was treated with miotics for 13 years prior to death, with good lOP control. The left eye had undergone cataract extraction and unsuccessful retinal detachment repair and is

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not presented here. At the last exam prior to death, vision in the right eye was 20/60 due to cataract and lOP was 16 mm Hg (applanation). No visual fields were available. The optic disc in the enucleated specimen had a vertical cup/disc ratio of 0.6, with relative loss of the superior disc rim. H 179. This 58-year-old white male had been told at an examination by a university eye clinic that his lOP was "borderline" normal without signs of eye damage. No other information was available. H 196. This 47-year-old white femal was noted nine years prior to enucleation of the right eye to have bilateral elevated lOP. After two years of unsuccessful medical therapy, two filtering procedures were performed on the right eye, leading to permanent lOP control below 22 mm Hg. One year prior to enucleation, a cataract extraction with vitreous loss was performed. A fibrovascular ingrowth occurred from the site of surgery, leading to severely painful corneal edema. Best postoperative vision was 20/60 with recognized cystoid macular edema, but lOP continued normal on no medication. Goldmann perimetry 11 months prior to enucleation showed a full field (Fig 2) and the optic disc showed no glaucomatous cupping. At the last examination two days prior to enucleation, the vision was 4/200 with compatible corneal opacity and the lOP was 22 mm Hg (applanation). Since two retrobulbar alcohol injections had given no relief of severe ocular pain and since the eye was cosmetically unacceptable to the patient, enucleation was performed.

Glaucoma with Moderate to Severe Visual Field Loss H 147. This 77-year-old white man had been treated for eight years with pilocarpine and epinephrine, with lOP under 24 mm Hg on therapy. Outflow facility on therapy was 0.08 OD and 0.20 OS. Hemorrhages had occurred on the nasal disc rim in the right and left eyes five and six years prior to death, respectively. These were not associated with progression of visual field changes. At the last examination four months prior to death, the vision was 20/60 OD and counting fingers OS. The photographs of the optic discs documented advanced glaucomatous cupping in both eyes and there was advanced visual field loss, greater in the left than in the right eye (Figs 3 and 4). H 195. This 64-year-old black woman had known open-angle glaucoma for six years, with poor compliance with medical therapy

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of pilocarpine and epinephrine. Intraocular pressure varied between 29 and 35 mm Hg OD and 23-25 mm Hg OS. At the last examination four months prior to death, the vision was 20/200 OD and 20/50 OS, with estimated cup/disc ratio of 0.95 OD and 0.8 OS. Visual fields showed more advanced damage to the right eye (Fig 5). H 202. This 74-year-old white woman presented five years prior to death with lOP of 75 mm Hg in each eye and vision of 20/40 OS and no light perception OS. A diagnosis of chronic angle-closure glaucoma was made. Peripheral iridectomy was performed on the right eye and lOP was subsequently maintained below 23 mm Hg on pilocarpine and epinephrine. During five years of follow-up there was no change in the advanced disc cupping or visual field defects present initially (Fig 6). At the last examination two months prior to death, vision was 20/200, with compatible cataract opacity. · H 203. This 71-year-old black woman was followed for 22 years with open-angle glaucoma. Initially, the vision was 20/30 in both eyes, lOP was 35-40 mm Hg, outflow facility was 0.09-0.10, and the discs showed advanced cupping. Filtering operations failed in both eyes and ten years prior to death she underwent cyclodiathermy of the right eye and cyclocryotherapy of the left eye. The lOP was subsequently controlled under 22 mm Hg. The visual fields had progressed to advanced damage (Figs 7 and 8) and were difficult to evaluate because of dense cataract. Vision was 11200 OD and hand motions OS. The last examination was 11 months prior to death. H 204. This 66-year-old white woman had a normal eye exam three years prior to surgical enucleation of the right eye for melanoma of the ciliary body. One month prior to enucleation the right eye showed vision 20/20, lOP was 28 and 40 mm Hg (applanation, two visits), the cup/disc ratio was 0.8, and superior visual field defect was present (Fig 9).

Glaucoma, No Light Perception H 170. This 50-year-old white man had trauma to the right eye as a child and advanced secondary glaucoma. The eye was enucleated due to no light perception and lOP of 50 mm Hg. H 190. This 65-year-old black man had no light perception in both eyes and advanced disc cupping. The eyes were obtained at autopsy without detailed eye examination.

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Fig 2.-Normal optic nerve (A, C) and visual field (B) from patient H 196 with two years of medical therapy followed by successful filtering surgery. The low power nerve cross section taken 3 mm posterior to the globe shows normal black osmium staining of intact myelinated axons seen at higher power in C. S, superior; N, nasal; I, inferior; T, temporal. (Paraphenylenediamine, A = X30; C = Xl25).

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cross section of H 147 OD, with marked Fig 3.-Clini cal photogra ph of disc, visual field, and optic nerve axons, with light zones containin g few or glaucom a damage. Dark areas are remainin g intact myelinat ed no axons (paraphe nylenedi amine, X40).

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Fig 4.-Clinical disc photograph, visual field, and optic nerve cross section of H 147 OS, with advanced glaucoma damage. Dark areas are remaining axons (paraphenylenediamine, X40).

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Fig 5.-Schematic optic nerve cross sections and visual fields of right and left eyes of H 195. In each optic nerve, serial longitudinal paraffin sections were stained with phosphotungstic acid and the degree of remaining axons in each nerve bundle was graded on a scale from 100% (equal to staining in normal nerve bundles) to 0% (no axons).

H 197: This 23-year-old woman had no light perception and lOP of 52 mm Hg OD, secondary to trauma seven years prior to enucleation. H 198. This 76-year-old white woman had known open-angle glaucoma for nine years, with advanced disc cupping and bare light perception in the right eye. The lOP was 67 mm Hg at enucleation.

H 200. This 61-year-old black woman had bilateral peripheral iridectomy for chronic angle-closure glaucoma ten years prior to enucleation of the left eye. While the right eye maintained normal lOP on medical therapy, the lOP of the left eye averaged 30 mm Hg and vision was stable at questionable light perception. Retrobulbar alcohol was given two years prior to enucleation.

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RESULTS

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Elevated lOP, No Known Field Loss

Each of the four eyes in this group (H 159 OS, H 179 OU, H 196 OD) had some exposure to elevated lOP. Only H 179 OD had evidence of loss of optic nerve fibers, a loss of the most peripheral nerve bundles in the inferior quadrant of the optic nerve cross section (Fig 10). The cytoarchitecture of the optic nervehead in each eye was completely normal within the limits of histologic examination. Nerve fiber bundles passed through columns of astrocytes and capillaries in the anterior disc (Fig 11). Each of these elements seemed present in their usual numbers and ultrastructural appearance. At the scleral lamina cribrosa, axons passed through the pores in collagenous sheets that were in apparently normal position. In summary, one of the four eyes had definite slight axon loss and in none was there evidence of astrocyte loss or posterior bowing of the scleral lamina cribrosa.

I

Moderate Disc CuppingModerate Visual Field Loss

Each of these eyes (H 159 OD, H 162 OD, H 204 OD) demonstrated definite abnormality of the optic nervehead. The major change was loss of axons passing over the neuroretinal disc rim into the nervehead. In areas seen to have loss of disc tissue either clinically or in enucleated gross examination, axonal fibers were obviously gone with some remaining astrocytes and capillaries (Figs 12 and 13). In H 159 OD and H 162 OD, the rim was more damaged superiorly than inferiorly, judged by the loss of axons. It might be assumed then,

Fig 6.-Schematic inferior optic nerve reconstruction (as in Fig 5) and visual field of H 202 00. CRA = central retinal vessels.

that the inferior rim was at an earlier stage of the process and would show the first sign of cellular change. Significantly, there was no loss of either astrocytes or capillaries in these inferior disc rims (Fig 14).

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s

N

I Fig ?.-Postmortem optic disc photograph, visual field, and optic nerve cross secion of H 203 OD. Dark· stair.ing, remaining axons are seen only in the superonasal periphery (paraphenylenediamine, X40).

The scleral lamina cribrosa was not pushed significantly posteriorly in any of these eyes. In one specimen (H 159 OD), in addition to the loss of several nerve bundles in one

area, the lamina lacked collagenous cross struts throughout a zone three or four nerve bundles in width leading to an ectatic pit (Figs 1A and 15). Either the struts were originally

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present in this zone and were lost or they were absent as a congenital defect. The lack of this tissue in one area is extremely uncommon in the normal optic nervehead. The ectatic area would simulate an optic nerve pit. Thus, the overall change in these early damaged discs was loss of axons without selective astrocyte or capillary loss and without major posterior laminar bowing. In H 204, the appearance of a well-preserved optic nerve cross section could be compared to a visual field study performed just before enucleation (Fig 9). The selectively greater loss of axons in the inferior nerve corresponds to the superior field defect. Note that the axon loss extended around the nasal periphery of the nerve, including some atrophy in superior nerve bundles. While the available visual

Fig 8.-0ptic nerve cross section and visual field of H 203 OS. Intact axons (dark dots) are found only in the inferior nasal and temporal periphery (paraphenylenediamine, X50).

field study was incomplete in defining only the 14 isopter, no major relative inferior field loss is seen. Apparently this loss of axons was not yet significant enough to produce major change in the appropriate field area, although with-

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Fig 9.-0ptic nerve cross section and visual field of H 204 OD. While the temporal and central nerve is normal (lower left inset), the inferior and superior poles show axonal loss (lower and upper right insets). The inferiorly more pronounced atrophy is mirrored in the greater superior depression in the I/4 Gold· mann isopter of the visual field (paraphenylenediamine, X30; insets, X350).

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Fig 10.-0ptic nerve cross section of ocular hypertensive H 179 OD. There is a small inferior peripheral zone of axonal loss (arrows) (paraphenyle nediamine, X28).

head in these eyes (H 147 OU, H 195 OU, H 202 OD, H 203 OU) were quite marked and consisten t. Significa nt tissue loss anterior to the scleral lamina had occurred. In areas without detectable axons, only typical astrocyte s and occasiona l capillarie s remained anterior to the collageno us portion of the lamina (Fig 16). The most striking physical Advanced Cupping -Advanc ed change in the tissues was a backField Defects ward and lateral excavatio n of the us structure of the nervecollageno The changes at the optic nerve-

out a more extensive field study this cannot be determin ed with certainty. Note also that the loss of axons is rather diffuse in affected areas, without specific localizati on to one bundle and sparing of adjacent bundles. The central and temporal nerve was normal.

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Fig 11.-Normal optic disc structure in H 196, with history of elevated intraocular pressure without field loss. Nerve fiber bundles pass vertically between columns of astrocytes and capillaries in the nervehead opposite the retina and choroid (A). The nervehead in the scleral lamina cribrosa (B) is likewise normal. (C) An electron micrograph of normal relationship between astrocytes (a) and axonal fibers (n). (A, B = paraphenylenediam ine phase contrast, X200; C = Xl2.500).

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Fig 12.-Histology of optic nervehead rim in early glaucoma damage, H 162 OD. At right, the normal neural rim tissue passes from the retina downward into the lamina on the nasal side of this disc. At the left, the superior pole of the disc, where a "notch" or local increase in cupping is shown to be caused by a loss of axonal fibers. The remaining rim tissue is composed chiefly of astrocytes (paraphenylenediamine, X470).

head. Posteriorly, the scleral lamina sheets were placed significantly behind their normal position, often posterior to the termination of the subarachnoid space and even outside the posterior sclera itself (Fig 17). Laterally the excavation extended well into and behind the choroid, with the seemingly unyielding edge of Bruch's membrane projecting like a knife edge at the disc rim (Fig 17). Only a few glial cells and large blood vessels made up the tissue passing over this rim. The entire excavation in each case was everywhere lined by typical astrocytes with occasional capillaries. This glial covering was so thin that in many areas the collagen of the scleral lamina was nearly bared to the vitreous cavity (Fig 18). Astrocytes spread downward into the laminar pores formerly filled with nerve fiber bundles. It is impossible to determine whether the remaining astroglial cells in these nerveheads represent

all of the astrocytes originally present. Certainly many astrocytes were able to survive and to thrive under conditions that caused the loss of most axons. The major difficulty in estimating astrocyte numbers is that the surface area of the excavated cups in these eyes is at least doubled by the posterior and lateral tissue extension. In optic atrophy produced by orbital nerve transection, eight to ten layers of astrocytes remain anterior to the scleral lamina after loss of all axons by descending degeneration. 12 In these glaucoma discs, there were from one to four layers of astrocytes anterior to scleral lamina. Since the surface area had at least doubled, this result is consistent with no true glial cell loss or hyperplasia: it is simply a redistribution and spreading out to cover the increased area. The astrocytes seemed healthy (Fig 19) and had actively produced basement membrane and other forms of collagen around themselves.

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Fig 13.-High power light micrograph of damaged optic disc rim in Fig 12, right. The remaining tissue consists of astrocytes (arrows) and capillaries with few identifiable axons (paraphenylenediamine, X470).

In some eyes, neuronal loss on all sides of a blood vessel led to the lack o~ any supporting structure around the vessel. In most cases, the vessel is collapsed backward, usually toward the nasal disc rim. However, in a few examples, the

vessel remained approximately in its original position, essentially hanging unsupported (Fig 20). Occasionally, an epiretinal membrane consisting chiefly of astrocytes was present on the inner

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Fig 14.-In noncupped inferior portion of the nervehead of H 159, astrocytes and capillaries (arrows) as well as axonal fibers are present in normal numbers (paraphenylenediamine, X700).

retinal surface (Fig 21). These cells were continuous with the astrocytes at the disc rim and cup. Whether the disc cup changes made this epiretinal proliferation more likely is speculative. The correlation of optic nerve cross section and/ or serial disk sections with visual field studies shows a distinct pattern of selective damage and preservation. Using the general scheme of topographic axon

location described by Hoyt, 13 we can predict the visual field defects in H 147 somewhat precisely from the optic nerve findings (Figs 3 and 4). In the right nerve, superior nasal and a few inferior nasal fibers remain, corresponding to the inferior and superior temporal islands of visual field. The tiny central island (20/60 acuity) is represented by a peripheral, temporal island of fibers. Note that if the macular area fibers, as suggested

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by Hoyt, represent at least a majority of the optic neurons, then major loss of macular fibers had occurred with still quite functional vision. In H 147 OS, again peripheral nasal fibers remain, corresponding to a temporal visual field island; in addition, a small number of temporal fibers remain despite the loss of central acuity in this eye.

Fig 15.-Pitlike change in the optic nervehead of H 159 OD. There is a defect in the collagenous struts of lamina cribrosa combined with nerve bundle loss. The wall of the pseudopit is lined by astrocytes and loose collagen (paraphenylenediamine, X140).

In H 202 OD, the inferior half of the disc and attached nerve were reconstructed from serial paraffin sections (Fig 6). In this patient, central vision was reduced most probably due to cataract. A dense superior arcuate field defect was present. The axon loss was greatest at the inferior pole of the nerve, with only moderate nasal and minimal temporal damage. Again, the macular fibers (temporal nervehead) seemed less affected.

Fig 16.-In discs with significant cupping, the nervehead anterior to the scleral lamina cribrosa consists of layers of typical astrocytes (A) and capillaries (arrows). There are capillaries containing red blood cells in their normal position within the collagenous scleral lamina (left= H 147 OS, right= H 197; paraphenylenediamine, X400).

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In H 203, there was nearly complete loss of axons, corresponding to the advanced field loss (Figs 7 and 8). In the right optic nerve, only superior nasal peripheral fibers remained, while in the left nerve, scattered inferior peripheral nasal and temporal fibers were seen. The last visual fields in this case were performed ten years prior to obtaining the eyes and specific correlations are, therefore, diffcult to interpret. In H 195, serial section reconstruction of the inferior optic nervehead demonstrated in the right eye a peripheral remaining arc of fibers nasally and a tiny area of preserved fibers at the temporal periphery (Fig 5). Presumably, the nasal fibers corresponded to the superior temporal island of vision, while the small number of temporal fibers represented the tiny central island of vision, although without enough residue to preserve central vision (acuity 20/200). In the left inferior nerve reconstruction, the

Fig 17.-Deeply excavated cup with floor of remaining tissue well posterior to mid-sclera. Note extension under choroid into sclera lateral to termination of Bruch's membrane. Section from temporal (9 o'clock) rim of right eye, H 147 paraphenylenediamine, X125).

Fig 18.- In some areas, nearly all disc tissue anterior to collagenous scleral lamina (L) is lost, leaving a thin covering of astrocytes (A) and capillaries in contact with the vitreous cavity (V) (paraphenylenediamine, X550; H 147).

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Fig 19.-Typical astrocytes remain in nervehead of advanced damage specimen H 170 (X5400).

temporal and nasal peripheral equatorial areas were relatively preserved, with complete loss in the mid-inferior sector and significant loss at the inferior pole of the nerve (Fig 5). This eye retained 20/50 vision and had a dense paracentral superior scotoma, which was a

Fig 20.-"Hanging" blood vessel (arrow) in nervehead rim left unsupported by tissue loss around it (H 190; paraphenylenediamine, X80).

probable result of the loss of the central inferior nerve. Interestingly, the inferior pole was relatively spared compared to the zone just superior to it. In summary, this group of eyes demonstrate that the fibers in the superior and inferior poles of the optic nerve are particularly susceptible to damage. Second, with advanced damage the remaining fibers were more frequently found grouped in the nerve periphery. Third, the temporal fibers presumptively representing maculopapillary bundle sustained significant damage with retention of useful, although not normal, vision. Yet, in two cases, central vision had been lost with the preservation of a small area of peripheral, temporal fi hers.

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Absolute Damage The microscopic findings in these eyes (H 170, H 190, H 197, H 198, H 200, H 202 OS) were very similar to those in group 3 above, except that the loss of nerve fibers was complete. No remaining axons were identified in optic nerve cross sections. In only one patient was socalled cavernous degeneration observed, with large cystic spaces posterior to the lamina (Fig 22) containing hyaluronidase-sensitive mucopolysaccharide. The history on this patient was incomplete and it is unclear what factors led to this picture in these two eyes compared to the others of this category. Certainly cavernous degeneration was unusual in the eyes examined and may represent a different time course of lOP elevation or an associated disease process.

Fig 21.-Cells (arrow) abnormally present on vitreous side of internal limiting membrane of retina. Nerve fiber layer (N) is composed of astrocytes filling site of atrophied axonal bundles (paraphenylenediamine, X550; H 170).

DISCUSSION

The early events in glaucomatous damage at the optic nervehead are crucial to our understanding of both the clinical progress of the disease and the mechanism of neuronal damage. One of the most perplexing findings has been the observation that optic disc cup size increase precedes demonstrable visual function loss. One possible explanation is that early cupping involves no direct loss of ganglion cell axons but consists either of simple mechanical posterior movement of disc tissue without cellular loss or ofloss of glial cells. 1 •14 There is now accumulating evidence that the initial cup size increase in adult glaucoma represents not loss of glial cells but actual neuronal damage. First, the material examined in this study shows that in optic nerveheads from early glaucoma

Fig 22.-An exceptional example of advanced atrophy illustrating cavernous degeneration in the retrobulbar optic nerve. The former nerve bundle is occupied by scattered astrocytes in a greatly enlarged extracellular space (H 190 OD; paraphenylenediamine, X400).

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eyes there is no selective loss of glial cells. Furthermore, in more advanced glaucomatous damage, only glial cells remain after nerve fiber loss. In both acute and more chronic experimental lOP elevation in primates, disc astrocytes seem more resistant to damage than the ganglion cell axons. 15 •16 In addition, the elegant anatomic studies of Minckler et aF 7 show that astrocytic glial cells make up only a small proportion of the anterior optic disc tissue. Even loss of all disc astrocytes anterior to the scleral lamina cribrosa would not, therefore, lead to changes characteristic of moderate glaucoma damage, such as loss of most of the disc rim at the vertical poles. Finally, clinical examination in red-free light demonstrates loss of nerve fiber bundles of the peripapillary retina in early cupped discs prior to demonstrable visual field loss. 18 •19 Thus, it is quite unlikely that selective astrocyte loss explains disc cupping prior to field loss. It is also, therefore, unlikely that the mechanism of neuronal damage in glaucoma involves the loss of astrocytic support at the disc early in the process. Could the early cup size increase prior to field defect be due to simple posterior movement of disc tissues without loss of any cellular elements? The histologic material reviewed here, as well as the study of Emery et al,6 shows that the scleral lamina cribrosa does move posteriorly in advanced glaucoma damage. Since this rarely, if ever, occurs in the absence of elevated lOP, the deep excavation most probably results from the mechanical force exerted. However, this may represent a late change in the disc, which, while helpful in clinical diagnosis, does not necessarily indicate that mechanical compres-

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sion causes the early axonal damage. No specimen was observed with posterior laminar movement without significant neuronal loss. In infant eyes with glaucoma, a reversible stage of cup size increase occurs that is felt to represent passive posterior movement of the disc tissue. 20 However, this phenomenon is rarely observed in adult optic discs and probably occurs due to the incomplete development of the structural connective tissue of the nervehead in infant eyes. While macroscopic, reversible laminar movement may occur in rare adult eyes, there is no support for this concept as a general explanation for early clinical cup size increase in adult eyes. Histologic examination is limited in its ability to detect small changes in the position of the scleral laminar plates relative to each other. While it seems unlikely that gross laminar movement is occurring early in the glaucoma process, even small movements of the laminar plates undetected by histologic examination could occur and exert considerable mechanical compressive force on disc axons. This possiblity must be considered one of the possible mechanisms of axonal damage in glaucoma. It is possible that the optic nerve damage in glaucoma occurs by lOP-mediated decrease in vascular supply to the optic nervehead. In this regard, it is pertinent that no major selective loss of optic disc capillaries was observed in early examples of glaucoma discs. With advanced cup size increase, all disc tissue (axons, astrocytes, capillaries) anterior to the scleral lamina cribrosa is apparently decreased. Yet, many patent capillaries are still observed within the subjacent scleral lamina, even in severely cupped

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discs. While the anatomic presence of blood vessels does not insure their normal physiologic function, the histologic material presented provides no direct support for poor vascular supply as the mechanism of glaucoma damage. The concept that ganglion cell axons are lost, leading to early cupping prior to detectable visual field loss, raises a question about the sensitivity of perimetry. Apparently, significant numbers of axons can be lost, leading to cup size increase and nerve fiber layer defects, without testable perimetric abnormality (even by static quantitative methods). This is not surprising, since there is almost surely some overlap in the retinal receptive areas of ganglion cell units, with a considerable number of cells responding to a stimulus in a given area. It would only be after loss of many cells in such a situation that a high contrast perimetric target would not be perceived. In similar fashion, central acuity testing by Snellen chart indicates normal vision in some glaucoma eyes that have demonstrable abnormalities of foveal function using more sensitive testing such as grating acuity. 21 These conclusions point to the need for intensive investigation of more sensitive test procedures for optic nerve damage. It is increasingly clear that normal visual field testing and Snellen acuity do not insure the lack of optic nerve damage. If early cupping in adult glaucoma represents loss of ganglion cell axons, then we must evaluate the implication of this assumption for glaucoma therapy. Generally, it seems clear that the presence of typical visual field changes indicate that optic nerve damage has occurred at the lOP level observed

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and lOP lowering is indicated. However, with normal visual fields, the need for therapy has been more controversial. Considerable data suggest that patients with unequivocally normal optic discs and fields and lOP below 30 mm Hg have a 90% or better chance of suffering no detectable damage for extended periods untreated. 22 -24 Thus, many such patients are being carefully followed without therapy. A number of patients fall into an intermediate group, with normal fields but suspicious disc signs (asymmetric cups, vertically oval cups, local notches to the disc rim). It has been previously unclear whether these signs represent optic nerve damage (and thus indicate the need for therapy) or whether the lack of visual field loss indicates no neuronal damage and, therefore, no need for therapy. The determination of which disc signs truly indicate damage must await further histopathologic correlations. However, a change in a disc cup under observation should be generally agreed to represent an important sign of optic disc damage and, therefore, to constitute an indication for therapy, even without accompanying visual field abnormality. Likewise, definite asymmetric cupping is so rare in normal eyes that it should be interpreted as an acquired disc change representing tissue loss, requiring therapy. In general, the evidence presented supports the view that acquired disc change, even without field loss; is proof enough of neuronal damage to necessitate therapy. The visual field defects in early glaucoma are usually found in the area between 5° and 30° from fixation. Furthermore, central vision and the temporal field seem to be affected only late in the process in

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most eyes. These findings have been interpreted as indicating selective damage to arcuate area axons in early glaucoma. In general, the optic nerve and visual field correlations presented here correspond to selectively greater effects on axons in the optic nerve position thought to contain arcuate area ganglion cell axons. At the level of the retrobulbar optic nerve, the specimens examined show a predisposition for loss of axonal fibers at the superior and inferior poles of the nerve. In a study of acute experimental glaucoma in primate eyes, a similar predisposition for greater interruption of axonal transport in optic nerve axons at the superior and inferior disc poles was suggested. 25 This supports the possible relevance of such studies in defining the mechanism of axonal damage mediated by elevated lOP. We have not as yet acquired a large number of eyes with early glaucomatous damage in which excellent visual field-optic nerve correlations could be made. Thus, we can comment fully only on the findings after significant damage has occurred. In this situation, most of the fibers of the superior, inferior, and midoptic nerve are gone. The remaining fibers are those of the nasal and temporal-most peripheral bundles. The late survival of peripheral nasal and temporal fibers compared to those of the mid-optic nerve or the vertical poles is as yet unexplained. Many more nervefield correlations are needed before the findings reported here can be confirmed and expanded. Our knowledge of the position of the optic nerve axons com pared to the site of their cell bodies in the retina is only approximate. We need to know where these fibers pass through the presumptive site of damage, the scleral lamina cribrosa. 8 •26 It is

OPHTH AAO

quite likely that with the combined information of the degree of selectivity of damage and the position of fibers within the disc the mechanism of damage can be clarified further. ACKNOWLEDGMENTS We appreciate the skillful technical help of E. Barry Davis and Earl Addicks. This study would have been impossible without the cooperation of the following colleagues in providing clinical records of their patients: Rafael Hernandez, Ralph E. Kirsch, Alfred Kronthal, A. Edward Maumenee, Phillip Paston, and R. H. Pfeiffer. Special photography was performed by Chester F. Reather, RBP, FBPA.

REFERENCES 1. Fuchs E: Uber die Lamina Cribrosa. Graefes Arch F Ophthalmol 91:435-485, 1916. 2. Cristini G: Common pathologic basis of the nervous ocular symptoms in chronic glaucoma: A preliminary note. Br J Ophthalmol 35:11-20, 1951. 3. Teng CC: Glaucomatous cupping: Optic degeneration due to vitreous effect in association with glaucoma. Am J Ophthalmol 58:379-427, 1964. 4. Francois J, Neetens A: Vascularity of the eye and the optic nerve in glaucoma. Arch Ophthalmol 71:219-225, 1964. 5. Komzweig AL, Eliasoph I, Feldstein M: Selective atrophy of the radial peripapil· lary capillaries in chronic glaucoma. Arch Ophthalmol 80:696-702, 1968. 6. Emery JM, Landis D, Paton D, Boniuk M, Craig JM: The lamina cribrosa in normal and glaucomatous human eyes. Trans Am Acad Ophthalmol Otolaryngol 78:0P290-0P-297, 1974. 7. Daicker B: Selektive Atrophie der Radialen Peripapillaren Netzhautcapillaren und Glaukomatose Gesichtsfelddefekts. Al· brecht von Graefes Arch Klin Ophthalmol 195:27-32, 1975. 8. Vrabec F: Glaucomatous cupping of the human optic disk: A neurohistologic

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study. Albecht von Graefes Arch Klin Ophthalmol 198:223-234, 1976. 9. Chandler P A, Grant WM: Lectures on Glaucoma. Philadelphia, Lee & Febiger, 1965, pp 14, 16. 10. Read RM, Spaeth GL: The practical appraisal of the optic disk in glaucoma: The natural history of cup progression and some specific disc-field correlations. Trans Am Acad Ophthalmol Otolaryngol 78:0P-2550P-274, 1974. 11. Gloster J: Vertical ovalness of glaucomatous cupping. Br J Ophthalmol 59:721724, 1975.

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the rhesus optic nerve head studied by electron microscopy. Am J Ophthalmol 82:179187, 1976. 18. Sommer A, Miller NR, Pollack I, Maumenee AE, George T: The nerve fiber layer in the diagnosis of glaucoma. Arch Ophthalmol 95:2149-2156, 1977. 19. Hitchings RA, Spaeth GL: The optic disc in glaucoma: I. Classification. Br J Ophthalmol 60:778-785, 1976. 20. Quigley HA: The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 84:358-370, 1977.

12. Quigley HA, Anderson DR: The histologic basis of optic disk pallor in experimental optic atrophy. Am J Ophthalmol 83: 709-717, 1977.

21. Arden GB, Jacobson JJ: A simple grating test for contrast sensitivity: Preliminary results indicate value in screening for glaucoma. Invest Ophthalmol Vis Sci 17:23-32, 1978.

13. Hoyt WF, Luis 0: Visual fiber anatomy in the infrageniculate pathway of the primate. Arch Ophthalmol 68:124-136, 1962.

22. Armaly MF: Ocular pressure and visual fields: A ten year follow-up study. Arch Ophthalmol 81:25-40, 1969.

14. Anderson DR: Pathogenesis of glaucomatous cupping: A new hypothesis, in: Symposium on Glaucoma: Transactions of the New Orleans Academy of Ophthalmology. St Louis, CV Mosby, 1975, pp 81-94. 15. Anderson DR, Davis EB: Sensitivities of ocular tissues to acute pressure-induced ischemia. Arch Ophthalmol 93:267-274, 1975. 16. Quigley HA, Addicks, EM: Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci (in press). 17. Minckler DS, McLean IW, Tso MOM: Distribution of axonal and glial elements in

23. Graham PA: The definition of preglaucoma: A prospective study. Trans Ophthalmol Soc UK 88:153-165, 1968. 24. Perkins ES: The Bedford glaucoma survey: I. Long-term follow-up of borderline cases. Br J Ophthalmol 57:179-185, 1973. 25. Quigley HA, Anderson DR: The distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head. Invest Ophthalmol 16:640-644, 1977. 26. Quigley HA, Anderson DR: The dynamics and location of axonal transport blockage by acute intraocular pressure elevation in primate optic nerve. Invest Ophthalmol 15:606-616, 1976.