PATHOGENESIS OF GLAUCOMATOUS OPTIC NERVE DISEASE* BYJ. Terry Ernest, MD, PHD INTRODUCTION

RICHARD

BANNISTER FIRST DESCRIBED GLAUCOMA IN 1622 AND DIFFERENTIATED

between absolute glaucoma and cataract. ' Von Graefe was the first to clearly describe the association between the optic nerve atrophy, the cupping, the elevated intraocular pressure, and the visual field defects characteristic of glaucoma.2 Since then a variety of theories have been proposed to explain the pathogenesis of glaucomatous optic nerve disease but not one correlates the pattern of visual function loss with the primary atrophic process. Any acceptable theory must explain the selectivity, pattern, and progression of the loss of visual function. While it is clear that the primary process affects the nerve fibers, it does so in a manner that affects initially the superior and inferior temporal nerve fibers. Moreover, the initial arcuate visual field defect is not contiguous with the blind spot suggesting selective involvement of specific fibers of the optic nerve.3 The morphologic changes occurring at the optic disk have been carefully documented in man and many experimental studies of the optic disk have been carried out in animals with induced glaucoma. Although the functional loss in glaucoma in man has been extensively studied, only gross correlations have been made between the visual impairment and the optic nerve atrophy and excavation. It is evident that pressure on a nerve always suggests the possibility of interference with the circulation to the nerve. Nonetheless it has been shown that pressures of 10 pounds per square inch have little effect on the function of isolated peripheral nerves.4 This observation is important because maximum pressure exerted on the optic disk rarely exceeds 2 pounds per square inch. Direct pressure upon the optic disk in pressure levels observed in angle-closure glaucoma may force *From the Eye Research Laboratories, The Department of Ophthalmology, The University of Chicago, 950 East 59th Street, Chicago, Illinois 60637. Supported in part by United States Public Health Service Grant EY-00792 and a Career Development Award EY70633 from the National Eye Institute, National Institutes of Health. TR. AM. OPHTH. Soc., vol. LXXIII, 1975

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hyaluronic acid from the vitreous into the optic nerve and such infiltration has been postulated as contributing to optic atrophy, cupping, and cavernous degeneration.5 It is well known that in angle-closure glaucoma the blood supply to the eye may be shut off and so a rapid loss of vision is understandable. Unfortunately, most of the models of glaucoma in experimental animals fall into this category of angle-closure glaucoma and are not helpful for the study of the early pathological changes seen in human primary open-angle glaucoma. Direct pressure upon the optic disk may damage the optic nerve in a more subtle manner than by ischemia. In 1944, Weiss reported that constriction of a peripheral nerve resulted in a blockage of the normal movement of axoplasm from the cell body to the axon terminals.6 It has since been shown that there is a slow axoplasmic flow associated with the movement of microtubules and neurofilaments plus intermediate and fast flows associated with intra-axonal protein movement.78 In 1968, Lampert and co-workers suggested that the increased intraocular pressure of glaucoma caused damming-up of the axoplasm. 9 Minckler and Tso have shown that there is a normal gradient of axoplasm across the lamina cribrosa consisting of the slow flow. 10 Anderson and Hendrickson, however, demonstrated that elevated intraocular pressure abnormally dammed-up the fast component at the lamina cribrosa. " Maumenee12 has postulated and Emery and associates13 have presented some evidence suggesting that the arching backwards of the lamina cribrosa in the glaucomatous eye may result in narrowing of the optic nerve fiber apertures and compression of the nerve fibers with blockage of the axoplasmic flow. Unfortunately anoxia also stops axoplasmic flow and thus it is difficult to separate the effects of pressure on the circulation from the direct effects of pressure on the axoplasmic flow. 4 The theory does not explain the mechanism of formation of the early visual field defects in glaucoma. Its proponents do not explain how minimal disturbance of the relatively homogeneous lamina cribrosa (see Figure 1, Ernest and Potts15) would selectively affect the superior and inferior temporal nerve fibers. Furthermore, Bietti showed that an induced elevation of the intraocular pressure causes an immediate enlargement of the blind spot.16 Gafner and Goldman17 and Vanderburg and Drance'8 have shown that elevations in the intraocular pressure in normal subjects causes immediate albeit transient Bjerrum scotomas. It is difficult to imagine how a sudden interference with axoplasmic flow that at its fastest only moves approximately one centimeter an hour, could cause an immediate and transient interruption in function. It may be, however, that further

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along the course of the disease after loss of supporting elements and bowing back of the lamina cribrosa, primary axoplasmic flow obstruction develops. The other possibility for the pathogenesis of glaucomatous optic nerve disease is that the intraocular pressure elevations obstruct the intraocular vasculature. Adamiuk in 1867, suggested that the cupping was secondary to a decrease in nutrition.'9 LaGrange and Beauvieux in 1924 suggested that a decrease in the circulation might be the cause of the optic nerve degeneration.20 Elschnig, in sections of severely glaucomatous eyes noted a lack of capillaries in the degenerated anterior optic nerve segments.21 Reese and McGavic in 1942 found that visual field loss in glaucoma was more pronounced in patients with relatively low systemic blood pressure.22 In 1951 Cristini studied 40 eyes with advanced glaucoma using the benzidine reaction to demonstrate small vessels.23 He showed that in both the distal intraocular and the extraocular segment of the optic nerve the number of small vessels was reduced, there was fragmentation of the capillary network meshes and many of the individual capillary lumina were obliterated. Harrington has reviewed the work prior to 1960 suggesting that vascular insufficiency is the chief factor in the production of visual field loss and optic atrophy in glaucoma.24 In support of a vascular theory for the pathogenesis of glaucomatous optic nerve disease, it is first of all important to point out that the intraocular capillaries are subjected, even when the intraocular pressure is normal, to a tissue hydrostatic pressure ten to fifteen times greater than that found elsewhere in the body. In fact there is some evidence suggesting that the normal interstitial hydrostatic pressure outside of the eye and brain is actually slightly negative.25 Thus the intraocular blood pressure must normally be relatively high and therefore there may be little reserve left to equalize an abnormal elevation in the intraocular pressure. In 1967, Henkind proposed a theory that the radial peripapillary capillaries of the retina had a role in Bjerrum scotoma formation.26 Elevation of the intraocular pressure in the cat caused a decreased filling of the retinal capillaries.27 There are no data correlating visual field loss with atrophy of the radial peripapillary retinal capillaries.28 Furthermore, it will be most difficult to analyze changes in these retinal capillaries independent of the capillaries of the distal segment of the optic nerve. There are further problems, however, in considering the radial peripapillary capillaries of the retina responsible for the Bjerrum scotoma. These radial capillaries are found three hundred and sixty

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degrees around the optic disk,29 yet the Bjerrum scotoma is only in the visual field nasal to the blind spot. Moreover, Hayreh has found that the retinal circulation is not significantly affected by acute elevation of the intraocular pressure.30 He believes that the filling defects that Henkind notes in the cat eye with induced elevations of intraocular pressure represent normal variations in filling of the retinal vasculature. Hayreh states, rather unequivocally, that "the lesion in nerve fiber bundle defects in glaucoma . . . is due to the involvement of the choroidal supply to the disc."30 Blumenthal and co-workers supported the contention by fluorescein angiogram studies in which they correlated defects in peripapillary choroidal fluorescence with field loss in patients with glaucoma.31 We have previously pointed out, however, that the human optic disk does not appear to depend on the peripapillary choroidal vasculature as evidenced by normal optic disk vasculature in patients with peripapillary choroidal atrophy.32 Furthermore, we were able to show normal temporal optic disk filling on fluorescein angiography without filling of the temporal peripapillary choroidal vasculature in monkeys. Nonetheless, some of the blood vessels supplying the papilla appear to come from the peripapillary choroidal vasculature.33 It is evident that the circulation of the optic disk must be more clearly elucidated before progress can be made in the understanding of glaucomatous optic nerve disease. Although Leber34 had concluded from his injection studies that the central retinal artery branched into the nerve substance at the level of lamina cribrosa, this has not been confirmed by subsequent investigators.3537 In man, as Zinn38 and Haller39 demonstrated more than 200 years ago, the ciliary arteries enter the sclera and form a relatively incomplete circle around the optic nerve. Branches from this circle furnish the distal segment of the optic nerve in the area of the lamina cribrosa. Most investigators are agreed that the central retinal artery does not branch into the optic disk anterior to the lamina cribrosa. The controversy arises as to the origin of the vessels in this critical area of the lamina cribrosa and the papilla that is subjected to the intraocular pressure. The following anatomical study was undertaken in an attempt to clarify the origin and nature of the optic disk circulation. THE VASCULATURE OF THE OPTIC DISK MATERIALS AND METHODS

A total of 50 human eyes obtained from 25 cadavers at autopsy were studied. The eyes were from adults ranging in age from 43 to 87 years

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and there was no known systemic vascular disease or ocular disease. The eyes were removed by first making an incision through the conjunctiva at the limbus and carrying it around the circumference of the eye. The conjunctiva was dissected back to the level of the four rectus muscles. A knife was then inserted into the opened conjunctival incision and a three hundred and sixty degree cut made around the orbital margins through the periosteum preserving all of the conjunctiva. After the brain had been removed, the orbit was unroofed, the ophthalmic artery was excised at the carotid siphon, the periosteum was stripped from the walls of the orbit, and the orbital contents were removed en bloc. The eyes were prepared, studied, and photographed with a Bausch and Lomb dissecting microscope. The vortex veins were ligated close to their exits from the globe. The central retinal vein and usually the artery were cut close to their entrance into the optic nerve. The anterior chamber was opened with a razor blade and the lateral posterior ciliary artery exposed for cannulation. A 30-gauge needle with a 1 ml plastic disposable syringe was used to force saline through the lateral posterior ciliary artery followed by the injection material. The injection material used in this study was either India ink or a 6:3:1 mixture of neoprene latex, pigment, and saline. The neoprene latex and the salinedispersed metal-organic chelate pigment having a particle size of 2-4 microns (Red RW-635P) were supplied by the DuPont Corporation. The eyes were then fixed, dehydrated and cleared by the method described by Potts. 40

FIGURE 1

Illustration of the vasculature of the distal segment of the optic nerve.

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RESULTS

When the posterior pole sclera is cleared, the circle of Haller and Zinn is clearly visualized as an arterial circle made up of the anastomoses of temporal and medial short posterior ciliary artery branches. This incomplete arterial circle in the sclera around the exit of the optic nerve sends branches into the lamina cribrosa, anterior into the papilla and posterior into the optic nerve substance behind the lamina cribrosa. The anterior branches anastomose in the papilla with branches from the choroidal arteries. No capillaries were ever seen coming from the choriocapillaris and entering the optic nerve substance. The posterior branches from the arterial circle anastomosed with branches from the central retinal artery and from the pial branches which had filled in a retrograde fashion. The venous drainage was entirely into the central retinal vein. Figure 1 is a diagram in which the vasculature of the distal segment of the optic nerve is illustrated. DISCUSSION

The distal segment of the optic nerve may be divided into the optic disk composed of axons of ganglion cells that leave the eye through the sieve-like lamina cribrosa, the lamina cribrosa itself, and the area just posterior to the lamina cribrosa. The blood supply to the lamina cribrosa and the optic disk has its origin from the short posterior ciliary arteries through the incomplete intrascleral circle of Haller and Zinn and through the choroidal arteries. The choriocapillaris has an extremely high flow rate41 and thus it would be expected that there is a relatively large blood pressure drop in this micro-circulation but it does not furnish capillaries to the optic disk. The choroidal arteries furnish branches to the optic disk and they anastomose with similar branches from the intrascleral arterial circle. The arterioles to the optic disk and lamina cribrosa have their origins in the nerve periphery since the central retinal artery does not branch in this area. In this study the density of the capillaries appeared similar in the periphery and the central nerve substance. It might be expected that the capillaries first compromised by elevations in the intraocular pressure would be those furthest from the feeding arterioles and thus at the center of the disk. The fibers from the retina closest to the disk do occupy a central position42 and thus enlargement of the blind spot might be anticipated with early optic disk vascular compromise. Scotomas in Bjerrum's area, however, are found only superior and inferior nasally. Anatomical study of the vasculature of the optic disk does not reveal the reason for such specific visual defects. The vascular anatomy of the distal segment of the optic nerve, however, may offer an explanation for the optic nerve degeneration that

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is seen in glaucoma posterior to the lamina cribrosa. The difficulty in understanding why there is optic nerve degeneration in this area stems from the fact that, at least initially, the intraocular pressure is not transmitted across the lamina cribrosa.15 It may be, however, that the retrograde branches from the intrascleral circle of Haller and Zinn are critical for the maintenance of the integrity of the optic nerve in the area immediately posterior to the lamina cribrosa. If this is so, the fact that the intrascleral vascular circle is subjected, at least to some degree, to the intraocular pressure may account for optic nerve fiber degeneration in the area posterior to the lamina cribrosa. OPTIC DISK OXYGEN TENSION MATERIALS AND METHODS

Eight male and female Rhesus monkeys weighing 5 to 6 kg were anesthetized with 100 mgm/kg of a 10% solution of alpha Chloralose in polyethylene glycol administered intravenously.4344 The animals were then paralyzed with 1 ml of a mixture of tubocurarine chloride 0.4 mgm/ml and gallamine triethiodide (Flaxedil) 2 mgm/ml adminstered intravenously and intubated with a 3 cm cuffed Foregger endotracheal tube. The animals were given artificial respiration (respirator model 671, Harvard Apparatus Co.) and maintained anesthestized with 2 ml increments of the alpha Chloralose and maintained paralyzed with 1 ml increments of the curare and Flaxedil solution. The arterial blood pressure was monitored from a cannulated femoral artery with a pressure transducer (model P23De, Statham Laboratories, Inc.). The animal's temperature was measured with a rectal thermometer (Tele-Thermometer model 43TD, Yellow Springs Instrument Co.) and the temperature maintained at 38.0°C with a thermo-blanket. Arterial blood samples were analyzed throughout each experiment for pH, PCO2 and PG2 by a blood micro system and recorded on a digital acid-base analyzer (Models BMS 3 and PHM 72, The London Co. and Radiometer A/S). The cornea was removed, a complete iridectomy carried out and the lens removed. A plano-concave contact lens (ocular fundus contact lens, Hansen Ophthalmic Development Laboratory) was placed on the anterior hyaloid. The operating microscope with axial illumination was then used to visualize the optic disk. The partial pressure of oxygen (PO2) of the optic disk was measured as previously described.45 In brief, the technique consisted of placing the tip of an oxygen microelectrode (micro-oxygen sensor No. 721, Transidyne Gerneral Corp.) into the optic

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FIGURE 2

An illustration showing the oxygen microelectrode placed through the pars plana cannula into the eye.

disk. Two micromanipulators were used, one to place a cannula through the pars plana and a second to move the microelectrode through the cannula (Figure 2). All the parameters were recorded on a polygraph (model 7, Grass Instrument Co.) with a paper speed of 2.5 mm/second and 5 second time marks. The optic disk oxygen tension was recorded on one channel and the tracing was integrated on a second channel. In 3 eyes, the microelectrodes were advanced under microscope control until the tips encountered the optic disk. This was signaled by a transient fluctuation in current. The microelectrode was then withdrawn 10 microns. Three optic disk areas were explored; immediately adjacent to the central retinal artery (CRA), the areas midway between

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TABLE I: OPTIC DISK OXYGEN TENSIONS

Trial 1 2 3 4 5 Av.

Periphery Control Step*

Oxygen Tension mm Hg

Intermediate Control Step*

Adjacent to CRA Control Step*

2 3 4 3 3 3.0

3 1 14 20 % 3 1 0 13 20 3 % % 15 22 1 12 2.5 0 19 14 3.5 1 0 21 3.0 1.0 0.2 20.4 13.6 *The step-change increase in oxygen tension measured from the control level associated with an increase in the PaO2 of approximately 350 mm Hg.

the CRA and the temporal edge of the optic disk both above and below, and along the temporal edge of the disk. RESULTS

Five sets of measurements from a representative animal are shown in Table I. These surface area oxygen fields represent only average PG2 levels because the micro-oxygen sensor is a relatively long distance from the micro-circulation. The average difference between the control oxygen tensions at the periphery of the nerve and half way between the periphery and the CRA was 2 mm Hg. If a step-change in blood oxygen tension was induced, however, the difference between the two oxygen fields became more pronounced. The step-change in the oxygen tension of the arterial blood (PaO2) was accomplished by changing the inspiratory gas from room air to 100% oxygen for 15 seconds. The hemoglobin saturation, already near maximum, did not change significantly but the PaO2 increased to approximately 350 mm Hg because of dissolved oxygen. The magnitude of the step-change in the PaO2 varied from animal to animal and from hour to hour but it was constant for the few minutes required for the three relative optic disk area measurements to be obtained. The oxygen field that was measured adjacent to the CRA and its disk branches was estimated to be within approximately 100 microns of the vessel wall. The oxygen tension in this area was several times greater than that in the intermediate area or the periphery of the disk. The stepchange increase averaged more than double the control value. DISCUSSION

The optic disk surface oxygen fields distant from the CRA are relatively low compared to the vitreous levels reported by Tsacopoulos and co-

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workers although these investigators' measurements were extremely variable (16 + 10 mm Hg).46 It may be that close to the optic disk surface oxygen mixing is poor as the molecules diffuse from the various microcirculatory beds. Although the differences between the peripheral disk oxygen tensions and those midway between the periphery and the CRA were small, the step-change results reveal the nature of the circulation. As previously discussed, feeding arterioles to the optic disk have their origin in the peripheral tissue, both from the choroidal arteries and the circle of Haller and Zinn. Thus the step-change in PO2 is less over the mid-central disk tissue because the oxygen increment is diluted by the increased vascular volume of the optic disk capillaries and oxygen has diffused out of the circulation by the time blood reaches the more central area of the optic disk. The unusual finding is that the oxygen tension adjacent to the CRA is relatively high. As previously pointed out the CRA does not send branches into the lamina cribrosa or the nerve substance anterior to it. In fact the capillaries of the optic disk empty into the central retinal vein and thus a relatively low P02 would be anticipated in the center of the optic disk. That this is not the case may be explained by diffusion of oxygen out of the central retinal artery. The distance that oxygen can penetrate by simple diffusion is determined by the respiratory rate of the tissue and its oxygen diffusion coefficient.47 Neither one of these factors is known for the distal segment of the optic nerve but there is evidence that oxygen does diffuse out of arteries. First, arteries with walls thinner than 0.5 mm do not have vasa vasorum.48 The fact that the artery walls are avascular can only mean that oxygen diffuses 500 microns through tissue. Furthermore, an oxygen gradient has been demonstrated with an oxygen micro-electrode across the avascular zone adjacent to the lumen of the thoracic aorta.49 Second, a longitudinal gradient in the oxygen tension has been demonstrated along the surface of 100 micron arterioles.50 The approximately 200 micron central retinal artery has a wall thickness of only about 30 microns.51 Thus it is not unreasonable to expect that oxygen diffuses out of the central retinal artery. It is difficult to know the magnitude of this oxygen diffusion but it could account for an early sparing of the nerve fibers closest to the CRA and thus result in the maintenance of vision in the Bjerrum area close to the blind spot. That is to say, the most susceptible nerve fibers are those located in the mid-central optic disk area. This does not explain, however, why the first fibers affected are located superior and inferior temporally.

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AUTOREGULATION IN THE RHESUS MONKEY

In 5 eyes, the lateral wall of the orbit was removed, the lateral rectus muscle was cut 5 mm posterior to its insertion and a clamp attached to the muscle to draw the whole eye forward. An operating microscope was used and the orbital fat surrounding the optic nerve was carefully removed until the central retinal artery could be clearly seen and cut. A few drops of tolazoline (Priscoline) were placed on the short posterior ciliary arteries and the incision closed. The tip of the oxygen probe was advanced into the substance of the mid-central superior or inferior temporal optic disk approximately 25 microns. The systemic blood pressure was reversibly decreased by increasing the expiratory resistance. The expiratory resistance was increased by submerging tubing from the expiratory valve of the animal's respirator below water to a depth corresponding to approximately 10 mm Hg. In a separate experiment it was determined that the P02 of the arterial blood did not decrease providing the periods of increased expiratory resistance were less than approximately 90 seconds. The increased expiratory resistance resulted in an elevation of the systemic venous blood pressure measured in the brachial vein of only about 1 mm Hg. RESULTS

The mean systemic blood pressure was decreased 30 mm Hg and maintained at this level (Figure III). The optic disk oxygen tension initially decreased 15 mm Hg, but then returned to control levels in 50 seconds. 52 DISCUSSION

The difficulty of analyzing the optic disk circulation independent from the retinal circulation was overcome by elimination of the latter. This had not been a problem in the cat since the cat, unlike the subhuman primate, does not have a central retinal artery. The results, however, were the same in the Rhesus monkey as they had been in the cat. The optic disk oxygen tension is autoregulated, that is to say, there is an intrinsic tendency on the part of the tissue of the optic disk to maintain constant oxygen tension despite changes in the perfusion pressure. The several methods which may be operating to restore the oxygen tension to normal after a decrease in the perfusion pressure have been previously discussed.53 A criticism of this experiment is that the perfusion pressure was lowered by decreasing the systemic blood pressure rather than elevating the intraocular pressure. The intraocular pressure could not be changed because the Rhesus monkey sclera is so thin that slight pressure changes

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40 -

Optic Disk P02 200100-

IOP (mmHg)

50-

0200BP (mmHg) 100-

_

0-

Integrated P02

iuuinuu%uuii FIGURE 3

Photograph of a segment of one of the polygraph records in which the systemic blood pressure was decreased by increasing expiratory resistance. The oxygen tension of the optic disk decreased but then returned to the control value. The time marks are at five-second intervals.

caused excessive movement of the micro-electrode and induced invalidating errors in the oxygen tension measurements. Thus it is possible that while the decreased blood pressure is compensated for after a few seconds, an elevation in the intraocular pressure would result in a permanent decrease in optic disk oxygen tension. This was not the case in the cat but Alm and Bill have suggested that the optic disk blood flow is not autoregulated.54 They base their conclusion on two points. First, the size of the prelaminar vessels is very small, 7-17 microns,33 and they believe these vessels probably do not have smooth muscle and thus cannot autoregulate. There is no reason to believe, however, that the intraocular pressure is not affecting the larger arterioles supplying the disk which have the potential for autoregulation since they are intraocular in the case of the choroidal arterioles and intrascleral in the case of the circle of Haller and Zinn. Second, using the radioactively labeled microsphere technique of O'Day et al.55 Alm and Bill measured the

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effect of intraocular pressure on optic disk blood flow.54 The authors used 15 micron microspheres and were unable to show optic disk autoregulation. Although we were able to duplicate their microsphere results in the study of the choroidal vasculature, we were unable to obtain valid optic disk measurements.556 The reason microsphere impaction studies on the optic disk circulation are not valid is because the vessels are so small relative to the size of the microspheres. Thus we found that it was not possible to obtain impaction of 15 micron microspheres in the 7-17 micron vessels of the optic disk in numbers large enough to be statistically significant. It is not possible to be absolutely certain, however, if the optic disk blood flow is restored to normal after a decrease in the perfusion pressure even though the oxygen tension does return to normal. There may be increased oxygen extraction from the blood; a more efficient distribution of the blood flow in the capillaries; or decreased cellular utilization of the tissue available oxygen.5 Any one or all of these mechanisms may be working but if the tissue available oxygen becomes normal at the expense of cellular utilization, then there could be damage to the retinal ganglion cell axons at the optic disk even though the average extracellular oxygen tension was not decreased. Finally, there is no information on the long term effects of a decreased perfusion pressure on the mechanism or mechanisms responsible for autoregulation. It may be that there is only a resetting of the "barostat" to a higher level where it continues to regulate the optic disk oxygen tension. On the other hand, the mechanism may break down with a resultant decrease in tissue oxygen tension and damage to the axons. It may be that the ability of the autoregulatory mechanism to function is highly variable from patient to patient and this accounts for the fact that some human eyes appear more resistant to elevated intraocular pressures than others. AUTOREGULATION IN MAN

Bietti, over 20 years ago, provided excellent studies implicating a vascularischemic mechanism to account for the pathogenesis of glaucomatous optic nerve disease.57 He showed that the inspiration of 100% oxygen reversed the enlargement of the blind spot that occurred when the intraocular pressure was mechanically elevated by an ophthalmodynamometer. Once nerve fiber damage occurred the administration of 100% oxygen would not be expected to have a therapeutic effect. It is persuasive that a transient anoxia induced by ocular compression is

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relieved by an increase in the blood oxygen tension. Additionally, Bietti indicated that hypoxia induced by a decrease in inspired oxygen from the normal of 20% to 10% caused similar enlarged blind spots."6 Gafner and Goldmann could not confirm this hypoxia effect. 17 Study of hypoxia is difficult because the visual effects are modified by general central nervous system effects.58 The distinction between anoxia and ischemia is important. Anoxia may be defined as a decrease in tissue available oxygen that is induced by hypoxia which is the inspiration of oxygen concentrations that are below normal. Ischemia is a decrease in the circulation and thus represents a decrease in nutrients and in waste material removal as well as a decrease in oxygen. Bietti, however, showed that the ischemia induced by ocular compression and anoxia had similar retinal effects.57 Gafner and Goldmann showed that induced elevations in the intraocular pressure in normal subjects produces a reduction in sensibility in the Bjerrum area. 17 Tsamparlakis showed that compression of the eyes of glaucoma suspects usually produced visual field defects and that compression of the eyes of glaucoma patients with Bjerrum area scotomas resulted in an enlargement of these scotomas.59 Vanderburg and Drance studied the visual field defects induced by compression of the eye with a suction cup ophthalmodynamometer. 8 The Bjerrum areas adjacent but separate from the blind spot are the most sensitive to induced elevations in the intraocular pressure. The following study was carried out to determine if the loss in visual function induced by an elevation in the intraocular pressure persists or recovers within approximately 90 seconds as would be predicted if the oxygen tension autoregulates. MATERIALS AND METHODS

One subject, the author, a 39-year-old white man in excellent general health with no ocular disease, was used. Static perimetry was performed on the left eye with a modified Goldmann-Weekers adaptometer.60'61 Background illumination was adjusted to the same order of magnitude as that of the Goldmann perimeter. The fixation target was a projected circular white light that subtended one-third degree on the retina. The fixation light was adjusted so that a Y4 degree white test target was in the Bjerrum area adjacent to the blind spot on the 135 degree axis 15 degrees from fixation. The target was presented continuously and the method of limits was used. The test target light intensity that was just not visible was started with and its intensity increased until it was just seen. The intensity of the test light was then decreased until it was no longer visible. Approximately three ascending and three descend-

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ing thresholds were obtained every 30 seconds and the measurements were continued for 90 seconds and then the intraocular pressure was changed. The threshold intensities were mechanically recorded on a logarithmic (log.) scale. The threshold for each 30 second segment was measured as the arithmetic mean of the upper and lower log. values. The self-recording, semi-automatic scleral suction cup modeled after Kukinu3 was used.63 The suction cup, because of its relatively large volume, maintains the intraocular pressure at a constant level as long as the negative pressure remains constant and calibration was carried out as previously described.64 The suction cup was applied to the temporal scleral area of the globe and the negative pressure decreased to -50 mm Hg. The negative pressure was maintained at this level for 90 seconds and the difference thresholds measured. The negative pressure was then decreased in 25 mm Hg increments, pausing for 90 seconds at each level and testing. The intraocular pressure was thus raised until the visual threshold was grossly elevated. The suction cup pressure was then slowly brought back to 1 atmosphere and removed. One hour after the first testing sequence, the suction cup was again applied to the same eye and the intraocular pressure elevated in approximately 3 seconds to the maximum level reached during the first session. The pressure was held at this level for 90 seconds.

TABLE II: INTRAOCULAR PRESSURE VERSUS BJERRUM AREA THRESHOLDS

Increase in Visual Threshold with Elevation of the IOP

IOP mg Hg 35 41 47 53 60 66 72

(log. micromicrolamberts) 90 seconds at each IOP level 90 seconds at maximum IOP level 1st 30" 2nd 30" 3rd 30" 1st 30" 2nd 30" 3rd 30" Control Control 0.00 0.05 0.06 0.16 0.08 0.01 0.22 0.20 0.08 0.38 0.35 0.19 0.36 0.22 0.28 0.44 0.51 0.28 1.01 3.01 1.38

RESULTS

The experiment was performed three times one week apart. In Table II, the results from the first session are shown. The data from the three sessions were not averaged because slightly different testing conditions were employed but the results were similar. Elevation of the intra-

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ocular pressure (IOP) had little effect on the visual threshold in the Bjerrum area until 47 mm Hg was reached. The thresholds decreased toward the control value over the course of each of the 90 second testing periods. It is important to point out that the subject's blood pressure, 135/85, did not change between the first testing session and the second, one hour later. During the second testing session, the threshold obtained during the first 30 seconds after the IOP had been quickly elevated to 72 mm Hg was 1 log. higher than the control level. It was also double the threshold obtained during the first session when the IOP had been gradually elevated. After 30 seconds, however, the visual threshold increased 3 logs. over the control level. The threshold then returned toward the original level. DISCUSSION

The visual threshold in the Bjerrum area was elevated to a maximum of approximately 0.5 log. at an intraocular pressure of 72 mm Hg providing the pressure was elevated slowly over a period of 10 minutes. The fact that the visual threshold increased 3 logs. when the intraocular pressure was elevated rapidly to the same level means that the intraocular visual apparatus is able to compensate given time. Moreover, each of the 90 second testing sequences obtained during the first session show a gradual lowering of the visual thresholds toward normal following the initial elevation. This compensation is a form of autoregulation wherein local changes take place to restore homeostasis and normal function following intraocular pressure elevation. This is most evident from the fact that the visual threshold had returned toward control levels by 90 seconds even after it had been acutely elevated. One to two minutes are required for blood flow and tissue oxygen to return to normal following a decrease in perfusion pressure. It is important to note that axoplasmic flow blockage would be expected to take longer. The observation that the visual threshold remained low and then increased steeply after 30 seconds of increased intraocular pressure in the second testing session is evidence that the reduced function was due to ischemia rather than direct pressure on the optic nerve. Direct pressure effects would be expected to act instantly while the effects of vascular compromise require time since oxygen and metabolites must be exhausted before there can be decrease in function. Subjective testing of the type that causes patients discomfort even though minimal, is difficult to carry out reliably. Nonetheless, perhaps the ocular autoregulatory facility should be measured in glaucoma patients

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since it may be this variable that accounts for the differences in susceptibility between eyes with similar elevations in the intraocular pressure and normal blood pressures. Thus a knowledge of this autoregulatory variable might make it possible to predict which glaucoma suspects are at jeopardy. FINAL DISCUSSION

It was the purpose of this study to obtain physiological data from subhuman primates and psychophysical data from man which would contribute to the understanding of the pathogenesis of glaucomatous optic nerve disease and explain the development of the Bjerrum scotoma. I did not study the vessels posterior to the lamina cribrosa because I had previously shown that the intraocular pressure is not transmitted outside the eye although its effects may be. 15 In the introduction to this work a number of criticisms were leveled against the theories of the pathogenesis of glaucomatous optic nerve disease which did not take into account the circulation. It is important to point out that the author believes that vascular compromise is the initial, precipitating event but that progressive degeneration may be due to other factors perhaps unrelated to the vasculature. The evidence for a vascular pathogenesis of glaucomatous optic nerve disease, in spite of the literally hundreds of experimental studies that have been carried out, is surprisingly little. The experimental models have all used intraocular pressures many times greater and for a much shorter period of time than those seen clinically in primary open-angle glaucoma. Nonetheless, certain points do stand out. First of all, most clinicians have observed the profoundly detrimental effects on the visual field of glaucoma patients caused by a precipitous decrease in systemic blood pressure whether due to hemorrhage or too vigorous systemic hypertension therapy. Second, careful analysis of glaucoma patients suggests that those with low systemic blood pressures do less well than those with relatively high blood pressures. 22.24 Third, if the measurement is sensitive enough, it can be shown in the experimental animal that an elevation of the intraocular pressure of as little as 5 mm Hg does compromise the circulation of the optic disk, however transiently.65 Fourth, the Bjerrum visual field defect induced by an elevation of the intraocular pressure, albeit relatively high, is reversed by 100% oxygen, thus suggesting its anoxic origin.57 If the vascular theory for the pathogenesis of glaucomatous optic nerve disease is to be ascribed to, then it is necessary that the theory explain

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the characteristic visual field defects. It has been suggested that the central retinal artery "leaks" oxygen thus initially preserving the adjacent nerve fibers. This would account for the fact that the scotomas in the Bjerrum area may first appear away from the blind spot. We are still left, however, without an explanation for the fact that the disease is initially limited to the superior and inferior temporal nerve fibers. Some investigators have observed a selective decrease in the temporal vasculature with experimentally elevated intraocular pressures in animals.66 We have not been able to confirm this finding and furthermore the capillary density of the normal human optic disk is, if anything, greater on the temporal side. There is a difference, however, between the superior and inferior temporal areas and the remaining optic disk. The superior and inferior arcuate bundles, because of the presence of the temporal papillo-macular bundle, are concentrated to a greater degree than the corresponding fibers on the nasal side of the optic disk.67 Thus a homogeneous compromise of the optic disk vasculature might initially affect the superior and inferior nerve fibers with their greater per volume metabolic demand. For the purposes of this discussion, autoregulation has been defined as a local optic disk process operating to maintain the tissue available oxygen at a constant level despite variation in the perfusion pressure. Perfusion pressure is the difference in pressure between the systemic blood pressure as measured in the femoral artery and the intraocular pressure. Because the ophthalmic artery blood pressure is less than the femoral artery blood pressure the actual perfusion pressures are 5 to 10 mm Hg lower than recorded.68 For relatively small decreases in the perfusion pressure of the subhuman primate eye, the optic disk oxygen tension is autoregulated (Figure 3). Moreover, a similar autoregulation must occur in the human eye since the Bjerrum scotoma induced by pressure does not persist (Table II). The various possibilities for the maintenance of a normal optic disk oxygen tension have been discussed. Whether the stimulus for compensation depends on a local decrease in the oxygen tension, an increase in carbon dioxide tension or a direct effect of the intraocular pressure on the vascular tone of the small vessels themselves is not known.69 Duke-Elder in 1955 pointed out that there is often little correlation between the intraocular pressure at any given time and atrophy and excavation of the optic disk in primary open-angle glaucoma.70 There appears to be another factor which Duke-Elder believed was-the circulation. I would like to go a step further and suggest that the missing variable is not the circulation per se but rather its ability to maintain the "milieu

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interne." It was Claude Bernard who proposed the concept of a stable, self-regulated "milieu interne" which he mistakenly believed was blood. 71 Nonetheless the concept is correct and Walter Cannon expanded it and showed that the body has extensive mechanisms to maintain the internal environment, or extracellular fluid, uniform.72 This is Cannon's doctrine of "homeostasis" which means an unchanging internal environment. The autonomic nervous system is constantly making adjustments in the circulation in order to facilitate homeostasis. Autoregulation is a kind of local homeostasis in which the autonomic nervous system is not involved and the adjustments are made without disturbing the general circulation. An elevation in the intraocular pressure does not compromise the circulation in the sense that the circulation is decreased as the intraocular pressure increases. If this were the case, the venous pressure would be affected since it is at the lowest level of pressure and the result would be papilledema. What appears to occur is optic disk circulation autoregulation with dilation of the arterioles and reduction in arteriolar resistance so that the capillary blood pressure increases to balance the increased intraocular pressure. At some point probably related to the level of the intraocular pressure elevation, its duration and the inherent ability of the optic disk circulation to autoregulate, the homeostasis begins to break down. This is probably not a sudden occurrence but rather the periods when the circulation is not adequate become longer and longer as time passes. There is a time when normalization of the intraocular pressure allows the autoregulatory mechanisms to restore homeostasis. In some patients, however, the autoregulatory system breaks down permanently and the optic nerve goes on to atrophy and excavation in spite of normalization of the intraocular pressure. The response of the circulation of the optic disk to the elevated intraocular pressure must be studied in order to understand why some eyes tolerate elevated intraocular pressures while others are immediately at jeopardy. It is only through an understanding of autoregulation as it pertains to the eye that it will be possible to know when to start therapy and at what level the intraocular pressure must be maintained to prevent optic nerve damage and visual loss. SUMMARY AND CONCLUSIONS

The pathology of glaucomatous optic nerve disease has been discussed by dividing the various theories into either mechanical or vascular. The mechanical theories are those proposing that pressure causes nerve

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damage directly, secondarily by vitreous percolation through the lamina cribrosa or by blockage of axoplasm flow. The vascular hypothesis is that a decrease in the circulation results in ischemic nerve damage. The theories were discussed and criticized in terms of how compatible they were with the development of the Bjerrum scotoma. In the first part of the work, the circulation of injected cadaver eyes was studied to elucidate the vasculature of the distal segment of the optic nerve. The short posterior ciliary arteries furnish the branches to the optic nerve in the region of the lamina cribrosa through the incomplete circle of Haller and Zinn and through choroidal arteries. The second study was the measurement of the optic disk oxygen tension in Rhesus monkeys. It was shown that the central retinal artery "leaks" oxygen and it was hypothesized that this might protect the nearest nerve fibers from the early effects of an elevated intraocular pressure. Moreover, by the process of autoregulation the optic disk oxygen tension was shown to compensate for changes in the perfusion pressure. The third study was a measurement of the visual effects of induced elevations in the intraocular pressure in man. It was shown that the visual threshold in the Bjerrum area is elevated with an increase in the intraocular pressure but that the eye is able to compensate with a reduction in threshold toward normal given ample time. It was thought that glaucomatous optic nerve disease results when there is a failure of local homeostatic circulatory mechanisms to compensate for sustained elevation of the intraocular pressure. The following conclusions were made: 1. The initiating pathogenic event in glaucomatous optic nerve disease is a breakdown in the homeostatic mechanisms responsible for normal perfusion and oxygenation of the optic disk. 2. The superior and inferior temporal nerve fibers are affected first since these are in highest concentration relative to the optic disk blood

supply. 3. The first fibers affected in the superior and inferior nerve fiber bundles are those midway between the disk circumference and the central retinal artery since this is the area of relatively lowest oxygen tension. ACKNOWLEDGMENTS

The author is grateful to Vivianne Smith-Pokorny, Ph.D. and Walter H. Stern, M.D. for their help with the psychophysical studies and Ursula Williams for technical assistance.

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