Mechanisms of optic nerve damage in primary open angle glaucoma

SURVEY OF O P H T H A L M O L O G Y VOLUME 39. NUMBER 1 JULY-AUGUST 1994 •

MAJOR REVIEW

Mechanisms of Optic Nerve Damage in Primary Open Angle Glaucoma ROBERT D. FECHTNER, MD, l AND ROBERT N. WEINREB, MD 2

1Department of Ophthalmology and Vizual Sciences, University, of LouLsviUe, Louisville, Kentucky, and 2Glaucoma Center and Research Laboratories, University of California, San Diego, La Jolla, Cal~ornia Abstract. Several mechanisms have been postulated to explain the optic nerve damage that occurs in primary open angle glaucoma (POAG). No single mechanism can adequately explain the great variations in susceptibility to damage and the patterns of damage seen in this syndrome. The etiology of POAG is likely to be multifactorial. Mechanical, vascular and other factors may influence individual susceptibility to optic nerve damage. An enhanced understanding of the nature of the optic nerve damage in POAG and improved methods of study may result in earlier diagnosis or may allow us to distinguish among different pathological processes all currently grouped under the diagnosis of POAG. As we gain a better understanding of the neuropharmacology and cellular biology of injury and repair of the visual system we will undoubtedly refine the concepts ofglaucomatous optic neuropathy. (Surv Ophthalmol 39:23--42, 1994)

Key words, glat, coma • open angle glaucoma • primary open angle glaucoma • optic nerve ° retinal ganglion cell

the decades, particularly in non-English publications, are not included. We hope this article presents a balanced view and stimulates f u r t h e r thought. Most of the theories concerning the pathogenesis of glaucoma can be g r o u p e d in two broad categories, mechanical (or pressure-related) and vasogenic. T h a t the pathogenesis of POAG remains unclear and controversial indicates that this may be a multifactorial syndrome, that multiple etiologies may result in a c o m m o n clinical presentation, and that it is difficult to settle these controversies with c u r r e n t experimental techniques.

Primary o p e n angle glaucoma (POAG) is a synd r o m e of progressive optic n e u r o p a t h y with characteristic optic nerve d a m a g e and defects in retinal sensitivity leading to loss o f visual function. Although clinical changes of the glaucomatous optic nerve have been well described, the mechanism o f this d a m a g e is not clear. Anatomic, physiologic and psychophysical investigations are a d d i n g to o u r u n d e r s t a n d i n g o f the factors which may be i m p o r t a n t in the d e v e l o p m e n t of optic nerve d a m a g e in POAG. A clearer understanding o f the mechanisms involved in glaucoma may allow us to treat this s y n d r o m e more effectively. This review will highlight historical and c o n t e m p o r a r y aspects o f investigations concerning mechanisms of optic nerve d a m a g e in p r i m a r y o p e n angle glaucoma. T h e review is not comprehensive, and many contributions over

I. M e c h a n i c a l ( I O P - r e l a t e d ) Mechanism of Damage T h e mechanical theory concerning POAG sug23

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FECHTNER, WEINREB tients with asymmetric visual fields only 13 had a statistically significant mean IOP diffierence (one standard deviation) that was higher in the eye with the m o r e severe field detect (two had lower mean lOP in tile worse eye), r'* suggesting that factors o t h e r than IOP must also play an important role in the d e v e l o p m e n t of field loss in NTG. While high lOP is a p r o m i n e n t risk factor for POAG, this does not explain why some individuals with ocular hypertension never develop d a m a g e while others with relatively low pressures d o . [7:~ Factors o t h e r than IOP must play a modulating role. T o u n d e r s t a n d how IOP may d a m a g e the optic nerve in glaucoma, certain aspects of optic nerve anatomy need to be considered. In particular, there is experimental and histologic evidence that the damaging effect of lOP oil optic nerve fibers (retinal ganglion cell axons) occurs at the level of tile lamina cribrosa (see below). A. LAMINA CRIBROSA

/.ig. 1. Scanning electron micrograph of human lamina cribrosa, demonstrating pores through which pass axons of the retinal ganglion cells, also called nerve fibers. Witlain the collagenous I)cams of the lamina cribrosa are blood vessels which contribute to the nouvislament of the nerve fibers. Also, the lamina cribrosa otfi:rs a conduit for nerve tibcrs and provides structural support. (Courtesy of Donald S. Minckler, M D)

gests that IOP can induce optic nerve d a m a g e t h r o u g h biomechanical o r structural thctors. Several lines of evidence have been used to support this theory. Elevated lOP is known to be a p r o m i n e n t risk factor for developing optic nerve d a m a g e in glaucoma.; T h e direct relationship between lOP and glattcomatous damage supports the concept that high lOP can contribute to optic nerve danaageY :-'s'";'-' When lOP is experimentally elevated in monkeys to a sufficiently high level ancl for a sufficiently long time, an optic n e u r o p a t h y develops which is clinically ancl histologically indistinguishable fi'om h u m a n POAG. 4:~'t:v-'Further, it is well recognized that a patient may develop optic ilerve damage following unilateral increased lOP in secondary glauconaa. It is also interesting to note that in patients with normal tension glaucoma (NT(;) and asymmetric IOP, the eye with the higher lOP tends to have greater visual field loss. I~''-':''~'~However, in one study of 60 NTG pa-

1. Structure "File lamina cribrosa consists o f about ten lamellar sheets with pores which align to form about 400 to 500 channels t h r o u g h which pass the axons of the retinal ganglion cells g r o u p e d into optic nerve fiber bundles. It has been rep o r t e d that there are an average of 392 channels at the level o f the choroid and 550 channels more posteriorly in the lamina cribrosa (Fig. 1).":' Branching and division of the nerve fiber bundles in tiffs region correlates with this increase.":' Nerve fiber bundles follow essentially a direct path t h r o u g h an aligned set o f pores. T h e axons ai'e s u p p o r t e d and separated by tile lamina cribrosa. Within tile collagenous beams of the lamina cribrosa are blood vessels and extracellular matrix c o m p o n e n t s which, in conjunction with axonal transport, contribute to the n o u r i s h m e n t of tile axons. T h e lamina cribrosa offers a conduit for optic nerve fibers, provides structural s u p p o r t along that path, and contains the vascula r supply for that portion of tile optic nerve. It has been suggested that tile lamina cribrosa is a site where IOP may exert its effect on tile optic nerve; one must examine how this could lead to characteristic glaucomatous optic n e u r o p a t h y . 2. Regional Differences in the Lamina Cribrosa It is cleat" that high presstire can lamina cribrosa in v i t r o . :~4''~:''ts3'ts4 It clear how lOP influences the lamina vivo. Although the forces fi'om lOP

distort the is far less cribrosa in should be

MECHANISMS OF OPTIC NERVE DAMAGE IN POAG

25

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F~¢. 2. Rep,esentatiCm of typical hourglass avraugcmerit o1 pores in human lamina cribrosa. The largest pores arc found in the superior and inti:rior poles.

tmitbrmly distributed across the optic nerve, there are regional dilt~erences in the lamina cribrosa which inay make specific portions of the optic nerve m o r e susceptible to distortion by pl'essttl'e. T h e largest pores of the lamina cribrosa are typically a r r a n g e d in an hourglass contiguration at the superior and inferior poles of the optic nerve head (Fig. 2). p-'r''~:~' T h r o u g h these areas pass the axons of the retinal ganglion cells subserving the arcuate regions. T h e connective tissue septae are thinner in these quadrants and may offer Jess structural s u p p o r t in maintaining the integrity of the pores. ~:~)An lOP-related contbrmational change within the lamina cribrosa might resuh in a change in orientation or collapse of the laminar channels which could damage retinal ganglion cell axons. Co,lversely, the lamina cribrosa septae are more closely packed and thicker along the horizontal meridian o f the nerve, including the areas which c o r r e s p o n d to retinal nerve fibers subserving tile cenn'al and temporal portion of the visual field which are relatively spared. ~-''v-'
I.ig. 3. Intnaoculan pressure pu'oclucing two vector

tortes on oplic nerve head: posterior distm+ting torce (large arrow) acts to compress laminar plates and is in direction of scleral canal, and radial distorting R)rce (smaller arrmvs) pulls on the sclcral insertion ~f the lamina crib]~)sa.

two vector components. First, there is a posterior fin'ce vector compressing the laminar plates or pushing o u t through the scleral canal. T h e r e is a second force vector contributed by the stress in the eye wall which pulls radically on the scleral insertion of the lamina (Fig. 3). This latter c o m p o n e n t contributes, in large part, to the stress within the scleral wall. LaPlace's equatitm for a spherical shell relates the pressure and radit, s to the wall stress:"': s = (pi-p,.)R/2h where: s = stress

(Pi-P,.) = transmural pressure (or difference between internal and external pressure) R = radius of sphere h = thickness of sphere It fi)llows from LaPlace's equation that, tbr a given transmural pressure, the larger the radit, s of the globe (i.e., the greater tile axial length), the greater the wall stress and, hence, the greater the potential distorting [brce on the optic nerve. This nlay, ill part, explain why eyes with axial myopia (which have a greater axial length than e m m e t r o p i c eyes) may have increased risk tbr developing glaucoma. 3. C h a n g e s in the L a m i n a C r i b r o s a in P O A G

Although an adult eye in which the optic nerve

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Surv Ophthalmol 39 (1)July-August 1994

FEGHTNER, WEINREB

head has become substantially excavated is a well-recognized endpoint for glaucomatous optic neuropathy, there is a progression of morphologic changes that precedes this dramatic alteration in topography. In human eyes with moderate glaucomatous visual field loss, morphologic study has recognized compression of the lamina cribrosa plates. TM In eyes with more severe loss there was posterior rotation of the peripheral lamina cribrosa leading to bowing of this structure. ~:~4Collapse or alteration in the orientation of the laminar plates may change the alignment of the axonal channels causing direct mechanical impingement on nerve fibers. One must consider that changes in the laminar beam which alter the relationship between axons and lamina may cause axonal damage not only through mechanical means, but may also compromise blood flow and delivery of nutrients to the axons. In addition to the morphologic observation of compression of the laminar plates, there have been changes observed in the pores of the lamina cribrosa associated with POAG. "u Miller and Quigley observed elongated lamina cribrosa pores in some eyes with moderate to severe visual field damage compared to eyes with normal visual fields. These changes were not consistently recognized in all glaucomatous eyes with visual field damage. They hypothesized that an increase in pore size may occur through stretching of coilagenous beams or by rupture of smaller beams."'4 If this is true, it may explain the clinical axiom that eyes with progressive glaucomatous damage have increased susceptibility to further damage. In other words, if axons which pass through larger pores are more susceptible to glaucomatous damage because they have less structt, ral support, then an increase in pore size would further decrease that support and lower the threshold tbr damage. Yablonski and Asamoto have suggested another explanation of how mechanical forces may result in damage to the axon. I~" They propose that there is an inherently unstable condition predisposing to collapse of axons at the lamina cribrosa due to the steep pressure gradient across the lamina. This tendency is offset by the supporting structures of the lamina that prevent collapse of the axons. Elevated lOP causes disruption of these structures with subsequent collapse of the axons and blockage of axonal transport. Tiffs theory awaits further support fi'om studies of the structural components of the lamina such as those discussed in the section on ex-

tracellular matrix. Several investigators have studied the effect of acute changes in pressure on the optic nerve. Levy et al examined the effect of an acute elevation of lOP on displacement of the optic nerve head in primate eyes in vitro. Using a platinum wire as a marker at the level of the scleral lamina cribrosa, they showed significant retrodisplacement of the lamina with increasing IOP. :~5 Zeimer and Ogura used a laser Doppler technique to detect the movement of optic nerve tissue in cadaver eyes in response to a pulsed change in pressure. They found significant movement of this tissue in response to the pulses. In addition, the amount of deformation at a given pressure was decreased in glaucomatous eyes, suggesting an associated change in the elasticity or the mechanical support of the optic nerve. Is4 In our laboratory, we have observed such changes directly using a confocal laser scanning ophthahnoscope (Fig. 4). In vitro, prepared fi'esh enucleated cynomolgus monkey eyes were imaged with this instrument while perfused with balanced salt solution at varying pressures. We tbund a linear relationship between pressure and the depth of the surface of the optic nerve head of these eyes (Fechtner RD, Weinreb RN, unpublished data). In a similar experiment with post-mortem human eyes, there was a correlation between depth and experimentally controlled lOP in some, but not all, eyes (Fig. 5)) 4 Because these were in vitro studies, the effects of lOP could only be assessed by examination of the structural components of the optic nerve; the influence of an active vascular bed could not be evaluated in these models. This may have significance because of the potential for the vasculature to resist the effects of lOP throngh autoregulation or by acting as a fluid ct, shion. Although these studies show that IOP has the potential to distort the lamina cribrosa, the relevance of these in vitro findings to optic nerve damage is uncertain. In support of these in vitro studies, Coleman et al used a retinal analyzer to study changes in optic nerve head topography induced by acute changes in lOP in cynomolgus monkey eyes in vivo. '-'2They reported that lowering lOP in eyes with experimentally induced glaucoma caused anterior movement of the surface of the nerve head. Raising IOP in normal eyes caused posterior movement of the surface of the nerve head, although the magnitude of the change was small and may have been below the reproducibility of their measuring technique. Similar results have

M E C H A N I S M S OF O P T I C NERVE DAMAGE IN POAG

27

Fig. 4. Topographic representation of human optic nerve obtained fi'om laser tomograplfic sca,mcr. In this image (512 × 512 pixels) each pixel corresponds to image depth. Darkest areas are above reference plane, lighter areas arc below (o,iginal was color coded fin" depth). Line graph rep,cscnts depth ahmg the horizontal meridian.

been r e p o r t e d by B u r g o y n e et al. I~ Reversal o[" g l a u c o m a t o u s c u p p i n g tbllowing lowering of I O P has been observed clinically by n u n t e r o u s investigators. This is most often recognized in infantile and juvenile glat, coma, but also has been observed in "ddtl]tS. 'l'7!~'s'i's:''lhs'l:'-'' ~,,s.,;,,.,;s.17:,.m, T h e s e studies have been reviewed by Lusky et al. ''~ Increased c u p p i n g in glaucontatous eyes has been observed following s h o r t - t e r m elevation of I O P with reversion to baseline when l O P was lowered. ~"; T h e s e observations are consistent with the theory that tltere is a reduction of r e t r o d i s p l a c e m e n t of the lamina with lowering of lOP. O t h e r e x p h m a t i o n s such as filling in of the cup with astroglial tissue or an increase of" intracellular or extracellular fluid must also be considered in these clinical cases. T h e s e studies suggest that the optic nerve, in at least some eyes, nlay have all elastic response to p r e s s u r e with m o v e m e n t of the surface of the optic nerve head cup ill r e s p o n s e to acute changes in lOP. T h a t tiffs response is m o r e clearly d e m o n s t r a t e d in vitro titan in vivo suggests that o t h e r factors (such as the vascular bed) may help resist the effect of pressure on the optic nerve head.

axonal t r a n s p o r t ( - 4 0 0 ram/day) and slow axonal flow ( - 0 . 5 - 3 ram/day). In addition, cellular c o m p o n e n t s to be recycled and neu,'otrophic factors which are taken up by the presynaptic bouton are carried back to the cell body by f~tst retrog r a d e axonal transport.:" Axonal t r a n s p o r t is essential for the normal functioning of neurons. Disturbances of axonal t r a n s p o r t u n d e r conditions of" experimentally elevated I O P in cats and primates have been detected. Both o r t h o g r a d e and r e t r o g r a d e blockage of radio[abeled tracers within axons at the level of the lamina cribrosa have been d e m o n st,ated. T r a c e r s introduced by intravitreal injection ( o r t h o g r a d e transport) and tracers injected into the geniculate nuclei or optic tracts (retrog r a d e transport) accunaulated at the level of" the posterior lamina cribrosa u n d e r conditions of experimentally elevated IOP. Uhrastructural r o o f

4. A x o n a i T r a n s p o r t D i s t u r b a n c e s with Elevated I O P

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Besides having an effect on the structural comp o n e n t s of tim hmtina cribrosa, lOP has been s h o w n to inlluence either directly or indirectly (througla its effect on the lamina) the nerve tibers within the optic nerve head. Axonal t r a n s p o r t is an enevgy-depe,tdelat process which moves ,~euronal c o m p o n e n t s f l o m their site o f synthesis in the cell body to sites o f utilization along the axon and at the nerve terminals. At least two processes can be disti,lguished in o r t h o g v a d e (away from the cell body) tlow; t~tst

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Surv Ophthalmol 39 (1)July-August 1994

phologic alterations also were observed at this site, including intra-axonal collections of vesicles and mitochondria and disorganization of microtubules and n e u r o f i l a m e n t s . 9~'~°6'~°7'~27::~8 Although similar studies cannot be performed in human patients, Vrabec studied 20 postmortem human eyes with primary and secondary glaucoma. Using Jabonero's silver carbonate method of staining, he found disruption of the axons at the level of the lamina cribrosa in all cases. TM This is consistent with the experimental data from animals, indicating that axoplasmic transport is impeded at the level of the lamina cribrosa in glaucoma. Minckler et al investigated whether impairment of optic nerve microcirculation contributes to the observed axoplasmic flow blockade. They injected avian erythrocytes intravenously into monkeys with experimentally increased lOP a few minutes prior to sacrifice. ~°~ Since the avian erythrocytes were nucleated, they could be detected microscopically in regions that were perfused at the time of injection. Avian erythrocytes were detected in the capillaries of the lamina in these experiments, suggesting this region was perfused. However, there were no erythrocytes in the choroidal portion of the optic nerve, indicating that capillary circulation in the choroid was compromised by moderate to high experimental IOP. Of note, the regions of capillary collapse did not correspond with the zones of blockage of axonal transport. This suggests that capillary nonperfusion was not an initiating factor in axoplasmic transport block in this model. Disturbances in axonai transport have been reported in the rabbit vagus nerve under experimental conditions with extracellular pressures as low as 30 mmHg. "-'7These investigators suggested that neuronal ischemia was likely to underlie this effect. Direct pressure on isolated nerve fibers in organ culture has also been reported to impede axonal transport, t~ While it seems plausible that either ischemia or mechanical distortion could impair axonal transport, it is not clear which predominates in the disturbance ofaxonal transport seen in experimental models of glaucoma and human histopathology. Further, it is not clear how impaired axoplasmic transport in the optic nerve leads to retinal ganglion cell dysfunction and death in POAG. There is considerable evidence indicating that target-derived molecular signals provide essential trophic support for the survival of ganglion cells) ~7:5'-' This suggests the ganglion cell death in glaucoma may be due, in part, to compromise

FECHTNER, WEINREB of the delivery of such trophic signals to the ganglion cell body. Although the contribution of locally derived trophic support to the maintenance of ganglion cell survival is poorly understood, survival and differentiation of purified ganglion cells in a chemically defined microenvironment'~6 should facilitate future investigations. 5. Summary As described above, regional differences in the lamina cribrosa may account for some of the characteristic patterns of damage seen in glaucoma. Clinical observation has shown that vertical elongation of the optic cup or thinning of the optic nerve head rim at the superior and inferior poles are early signs of glaucomatous d a m a g e : s These regions of the optic nerve head correspond to areas of possible weakness in tile lamina cribrosa, j'-'5'14° Quantitative analysis of optic nerve fibers in glaucomatous human eyes has shown regional variation with the greatest damage occurring in the superior and inferior poles. J2,, The role of IOP as a risk factor may relate to a direct effect on the retinal ganglion cell axons mediated through mechanical compression, altered support of the axons due to pressureinduced distortion of the lamina cribrosa, or an indirect effect such as induced ischemia (see below). A recent clinical report associated intrapapillary retinal vessels with preservation of the adjacent nerve fiber layer. These anthors suggest that dense gliai tissue or extracellular matrix surrounding the vessels may prevent distortion of the lamina cribrosa. '-'~ Although eyes with high IOP are at increased risk for the development of glaucomatous optic nerve damage, some eyes seem more resistant to these changes. Individual variation in the structure of the lamina could be invoked to explain different susceptibility to pressure, but such differences have yet to be identified clearly. B. EXTRACELLULAR MATRIX 1. Extracellular Matrix of the Optic Nerve Recent attention has been directed at understanding the composition and role of the cytoskeleton and extracellular matrix of the optic n e r v e head. 41'4"-'48'74'7"~:]0 The extracellular matrix surrounds and anchors the nerve fibers and glial cells within the nerve (Fig. 6). In addition to providing structural support, it may be involved in facilitating delivery of nutrients to the retinal ganglion cell axons. Changes in the extracellular matrix with aging have been described which may lead to a less flexible lamina cribrosaY

MECHANISMS OF OPTIC NERVE DAMAGE IN POAG

29

2. Changes in Extracellular Matrix in POAG It has been suggested that changes in extracellular matrix may be associated with elevated intraocular pressure and may be more evident with more severe glaucomatous damage. "~9 In cynomolgus monkeys, Morrison et al studied normal eyes, eyes with experimentally induced glaucoma and eyes in which the optic nerve was transected. Two eyes with very severe glaucomatous optic atrophy had demonstrable changes in the extracellular matrix, including thickening of laminar basement membranes, disorganized laminar beams and increased collagen types I, III and IV within the laminar pores. Two eyes with mild to moderate glaucomatous damage showed no difference fi'om normal eyes. 1°9 The changes in extracellular matrix in the severe glaucoma eyes were notably different fi'om eyes with optic nerve transection and descending optic atrophy. T h e latter eyes also had thickening of the laminar basement membrane, but the laminar beams appeared orderly. Increased collagen type IV labeling in the optic atrophy eyes was attributed to redundant astrocyte basement membrane and there was no deposition of abnormal material within the laminar pores. Since these investigations were performed in a monkey model of markedly elevated lOP, the derived data may not be directly analogous to changes found in human POAG. However, differences between the extraceilular matrix of normal and glaucomatous human eyes have been demonstrated. 72 In eyes with glaucoma, collagen type IV and basement membrane material were relatively increased in quantity and appeared to accumulate in the laminar pores formerly occupied by nerve fiber bundles. Of interest, the alterations in extracellular matrix in POAG resembled the pattern seen in the primate model o f glaucoma and may be characteristic ofglaucomatous damage. Elastin is normally found in the sclera immediately adjacent to the lamina, as well as in the laminar beams. TM Changes in the appearance of elastin in the optic nerve have been observed in both monkeys with experimental glaucoma and human glaucoma. 7t'r-'~ In one study, there was no observable difference in the appearance of the elastin in control eyes and eyes with mild damage. With moderate damage, the elastin lost its normally straight orientation and appeared curvilinear. With the most severe damage, the extreme changes in the laminar architecture made interpretation of the results difficult. The number ofelastin fibers could not be quantified by the

Fig. 6. Longitudinal section of human optic nerve

stained for Type 3 collagen. Darkly stained areas correspond to type 3 collagen, unstained light areas correspond to nerve fiber bundles and glial cells.

experimental technique. ~2s In mild POAG, Hernandez observed loss of the tubular structure of elastic fibers and microfibrillar bundles as might be seen in conditions of abnormal or increased elastogenesis. In advanced POAG, there were marked changes in elastic fibers as well as disorganization of the extracellular matrix. 7~ It is not known whether the changes in elastin contribute to the neuronal damage in glaucoma or whether they are a secondary result of disorganization of the lamina cribrosa. Changes in elastin or other structural elements of the lamina may alter the biomechanical response to tensile forces. This would be consistent with observed changes in the compliance of the optic nerve head in advanced glaucoma. ~s4 To summarize, subtle alterations in extracellular matrix may cause loss of structural support resulting in alterations of axoplasmic flow, compromised delivery of nutrients to axons, or both. Evidence from a primate model suggests that the changes in extracellular matrix seen in glaucoma can be induced by markedly elevated IOP. It is not known if these changes are a direct effect of elevated pressure, or a secondary change in response to structural, vascular or axonal damage.

II. V a s o g e n i c M e c h a n i s m o f D a m a g e Although much evidence indicates that the lamina cribrosa is a site of injury in POAG, elevated lOP alone cannot be invoked to explain many of the clinical and experimental observations. Any tmifying theory about the mechanism of

30

Surv Opllthalmol 39 (1)July-August 1994

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Schematic representation of blood supply of the optic nerve. C = choroid, CIL-~ = central retinal artery, LC = lamina cribrosa, NFL = nerve fiber layer, ON = optic nerve, P = pia, PCA = posterior ciliary artery, PLR = prelaminar region, R = retina, IL-k = retinal arteriole, S = sclera. (Reprinted fi-om Hayreh SS'~4 with permission of the author and Georg Thieme Verlag.) Fig,. 7.

damage in glaucoma must account fbr a large body of seemingly inconsistent data. l;~Uv7 As many as half of patients will not have elevated IOP when POAG is detected, v-''~6:~ In addition, there is a group of patients with normal tension glaucoma in whom elevated IOP is never detected. While investigations attempting to identify differences in visual field findings and optic n e r v e appearance between POAG with high IOP and NTG have reported conflicting findings, 1~:7:-'~v-':~' 52.:',3.71~.."4fi.M7.93.111.12(I there s e e m s t o be considerable overlap between the groups, and there are NTG patients in whom optic nerve and visual field changes occur which can be indistinguishable fiom those in patients with POAG and elevated IOP. It is clear that one must consicter mechanisms other than pressure-induced biomechanical changes in the lamina cribrosa to explain a large body of data. There is considerable evidence suggesting that compromise of the microvasculatm'e of the optic nerve may have a role in the damage seen in glaucoma. 6:~'65As new techniques have been developed to study the ocular circulation in vivo, more evidence has accumulated supporting the role of the microvasculature in the development

Tile vascular supply of the optic nerve head has been the subject of n u m e r o u s investigations and has been reviewed in detail: 4'6~ Blood supply to the optic nerve head is generally considered to have three major sources (Fig. 7): 1) retinal (from the retinal arterioles); 2) prelaminar (fi-om peripapillary choroid); and 3) laminar (fi'om centripetal branches of the short posterior ciliary arteries), q'6"'7°':~4 Variations fi'om this scheme have been reported. ''':'~l In the region of the lamina cribrosa, the blood supply is from centripetal branches of the short posterior ciliary arteries. Although capillary branches arising fi-om the central retinal artery have been identified in this r e g i o n y 'N this has not been confirmed widely. :~9'5:~':~4 Many angiographic, histologic, and postmortem injection studies have identified centripetal branches of peripapillary choroidal arteries as the main blood supply to this region, a':~:~'5~-m:~7' 70.,..',4 It is generally believed that these choroidal arteries (and not the peripapillary choriocapillaris) contribute branches to the prelaminar region. ~ The vessels fi'om the lamina cribrosa region also may contribute significantly to the blood supply in the prelaminar region of some eyes. 64 T h e origin of the blood supply to the prelaminar region of the optic nerve has evoked controversy. One study of the angioarchitecmre of the optic nerve head and peripapillary choroid in monkeys showed that the prelaminar, laminar, and retrolaminar regions were supplied mainly by short posterior ciliary arteries. The prelaminat and laminar regions received occasional contributions fi'om the peripapillary c h o r o i d . : " It also has been suggested that the microvascular supply in this region of the optic nerve head of monkeys and humans might be part of a single retina-optic nerve vascular supply system with a primary contribution from the posterior ciliary arteries and no significant contribution fi'om the peripapillary chol'oid. '~':~2""'t Hayreh has questioned the inethods and interpretation of results leading to this conclusion and maintains that choroidal circulation contributes significantly to the optic nerve head microvasculature in the prelaminar region. 6t~ This distinction is important since the choroidal circulation differs fi'om the posterior ciliary circulation in being a relatively high flow, low pressure system in which

MECHANISMS OF OPTIC NERVE DAMAGE IN POAG

blood flow falls as lOP is elevated? "Faking these studies into account, and considering the small n u m b e r o f studied eyes, it seems evident that there can be significant interindividual variation in the pattern o f blood supply to the optic nerve. However, caution is necessary in interpreting these studies. It is difficult to study optic nerve blood flow in vivo, since only the surface vessels are visible. In some techniques, such as fluorescein angiography, filling of the surthce vessels obscures observation o f the d e e p e r circulation. Further, much of o u r u n d e r s t a n d i n g o f the blood supply of the optic nerve arises fi'om anatomic studies ofintravascular casts and serial histologic sections as described above. Any hypothesis based on the results o f histologic studies of microvasculature must be verified by physiologic study, since the anatomic presence of a vascular system does not indicate its functional role and relative contribution to microperfl~sion. B. THE ROLE OF OPTIC NERVE HEAD MICROCIRCULATION

T h e microvasculature o f the optic nerve might fail to nourish the axons t h r o u g h any o f several mechanisms, including: 1) changes in capillaries, including loss of capillaries or alteration of blood flow within existing capillaries; 2) o t h e r changes which interfere with the delivery of nutrients or removal of metabolic products from the axons; 3) alterations in choroidal blood flow; 4) failure of regulation o f bh)od flow; 5) delivery of injurious vasoactive substances to the blood vessels of the optic nerve; and 6) a combination of Factors. 1. C o m p r o m i s e d Capillaries

Early reports suggested that the capillaries of the optic nerve head are selectively lost in glaucoma. '-'(~'4"More recent work does not s u p p o r t that theory. In monkey eyes with experimentally induced glaucoma, the loss of capillaries and nerve tissue o c c u r r e d at the same rate, so the proportion o f tissue consisting o f capillaries remained stable. J:~:~Examination of normal and glaucomatous humala eyes showed no qualitative difference in the n u m b e r of capillaries per unit volume. I'-'(~'~:~l Capillaries and axons a p p e a r e d to have been lost at the same rate in the eyes studied. At present, there is no experimental evidence to s u p p o r t the theory of elevated lOP causing selective loss of optic nerve head capillaries with resulting loss of axons. Neither is there evidence to clearly refute this theory. It is worth repeating that the morphologic presence of capillaries

31

gives no information about their contribution to blood flow in situ. Changes which occur in the extracellular matrix of the optic nerve in glaucoma have been described above. It is not known whether these or o t h e r changes interfere with the delivery of nutrients or removal o f metabolic waste by the capillaries. 2. Alteration o f C h o r o l d a l B l o o d Flow

Early theories for a vascular mechanism of glaucomatous optic nerve damage emphasized the role of choroidal circulation in optic nerve perfusion. (~(''v° H a y r e h emphasizes the importance of the choroidal contribution to the prelaminar portion of the optic nerve. Such vessels could be uniquely susceptible to compromise by elevated IOP since choroidal vessels manifest little or no autoregulatioll (i.e., blood flow changes with change of lOP). :~'(~:~'"6 T h e choroid receives its blood supply fi'om the posterior ciliary arteries (PCAs). Fundus fluorescein angiography and experimental PCA occlusion have d e m o n s t r a t e d segmental filling of the choroid, with the PCAs functioning as end arteries with distinct distributions. (~ T h e b o r d e r between the segmental distributions can be considered as a "watershed zone." T h e presence of such zones is well recognized in the cerebral circulation. Variations in the pattern of PCAs result in different filling patterns of the choroid. Hayreh has suggested that when the watershed zone falls in the area of the optic nerve, the c o r r e s p o n d i n g portion of the nerve may be relatively susceptible to ischemic injury. (~(~This could be implicated in the d e v e l o p m e n t of POAG when the watershed zone includes a portion of the optic nerve head. If the watershed zone is located far from the nerve head, the nerve may be relatively less susceptible to ischemic damage. This inight, in part, explain individual variations in susceptibility to glaucomatous optic nerve damage. Newer techniques of real-time digital angiography and the use o f i n d o c y a n i n e green may make it possible to study this in greater detail. 3, Other C h a n g e s o f C o m p r o m i s e d Microcirculation

T h e r e are other indications that vascular abnormalities are related to POAG. Flame-shaped optic nerve head h e m o r r h a g e s have been associated with POAG and represent a microvascular hemorrhagic eventY () In a prospective study, these h e m o r r h a g e s were observed to occur more fi'equently in normal tension glaucoma than in

32

Surv Ol)llthalmol 39 ( 1 ) J uly-August ! 994

FECHTNER, WEINREB

POAG. '~:' St, ch helnorrhages may be tblh)wed by ibcal cupping of the optic nerve and corresponding visual field loss. It has been suggested that they are indicative of h)cal capillary ischemia.:U While this may be the case, an alternative interpretation is that these h e m o r r h a g e s are the result of" mechanical trauma to tile capillaries from loss of structural support by the lamina as described above rather than a plqmary event, u~v While it is not clear whether these laemorrhages are primarily a vascular event or a mechanical injury, it seems clear that observable optic nerve and visual field defects can fbllow this microvascular insult to the optic nerve. Hayreh has advanced the idea that perfusion pressure rather than IOP is tile important f:actor ill optic nerve blood flow. 63 Ill a recent study, tile role of nocturnal hypotension in ocular occlusive and ischemic disorders was examined using 24h o u r ambulatory blood pressure m o n i t o r i n g ) '~ T h e finclings suggest that nocturnal hypotension, in tile presence of other vascular risk factors, may play a role in the patlaogenesis ofglaucon3atous optic nerve damage. T h e r e p o r t e d increased prevalence of glaucoma in patients with diabetes, hypertension, and migraine headache, diseases with well known microvascular or angiograplaic al3nm'malities, also supports tile idea of a vascular naechanism of danlage ill g l a t l C o l n a . 1°'ll'2:Ls:LII9 However, Olle recent study clemonstrated limitecl, if any, association of POAG with systemic hypertension or diabetes.~7'-' It may be that tile systemic microcirculatory abnormalities, c o m m o n in these conditions, increase tile susceptibility of tile optic nerve to damage, but the role of such abnormalities in POA(; remains unclear. In this regard, tile role of synaptically-released excitatory amino acid neurotransmitters are of particular interest. ':~ T h e y play a key role ill ischenfic and hypoxic brain damage, and cause neurotoxicity. (;lutamate and related excitatory amino acids account lot most of tile excitatory synaptic activity in the mammalian centra[ nervous system ancl are released by an estimated 40% of all synapses. T h e actions of these amino acids are mediated t h r o u g h three principal groups of receptors defined by their selective activation by N-methy[-Daspartate, quisqualate or kainate. '-'4 In c u h u r e d retinal cells and intact a d u h r a t retinas exposed to tile exogenous excitotoxins L-glutamic acid and N-methyl- D-aspartic acid (N M DA), M K-801 (an NIVlDA receptor antagonist) and kynurenic acid (a broad-spectrum excitotoxin antagonist) protect retinal n e u r o n s fi'om hypoxic damage

and from the toxicity of the e x o g e n o u s excitotoxins. ~ T h e role, if any, that excitotoxins play in either d a m a g i n g the optic nerve or increasing its susceptibility to d a m a g e in POAG is unknown. C. A U T O R E G U L A T I O N

OF B L O O D F L O W

T h e p u r p o s e o f a u t o r e g u l a t i o n of blood flow is to maintain flow d u r i n g changes in the perfusion pressure. T h e i m p o r t a n c e of autoregulation in the optic nerve was suggested by Ernest, who postulated that fiaulty autoregulation o f ocular microcirculation may play a role in the pathogenesis of P()AG. :~'2':~:~Althougla there is no evidence of major autoregulation of choroidal blood flow, the optic nerve, like the retina, app e a r s to be capable of efficient autoregt, lation of blood flow. While much is still not known about the microvascular circt, lation of the optic nerve bead, recent studies have eh,cidated a considerable a m o u n t o f new information. It has been d i f ficu[t to quantif!¢ optic nerve head blood flow experimentally. Several techniques have yielded conflicting results and there are many unanswered questions on this topic. Carefully perfiwmed studies, however, strongly suggest the presence of autoregulation of optic nerve blood tlow. Using microsphere perfusion in m o n k e y eyes, Ge!jer anti Bill found that blood flow ill the retina, the prelanfinar portion of the optic nerve and the first millimeter of nerve behind the lalnina was not markedly decreased until lOP was raised above approximately 70 m m H g . Flow in the portion of the nerve more than 1 mm behind tile lamina was unatl;ected by lOP. 4'; Evidence frmn studies ill cats using tile tracer iodoantipyfine 1-125 suggests that blood flow in the retina and the optic nerve head was maintained over a wide range of intraocular pressures and perfusion pressures. Again, there was no decrease in blood flow with lOP elevations until extremely high pressures were reached. "~:' Studies in monkey eyes using tritiated iodoantipyrine as a tracer d e m o n s t r a t e d stable blood llow ill the optic nerve until tile IOP reached tile level of the diastolic blood p r e s s u r e . ~:r' A criticism has been raised that these teclmiques may denmnstrate not only I~loocl tlow, Ilut also diffusion.';:' "Fhese experimental studies suggest that tile normal optic nerve is capable of efficient autoregulation and can maintain stable blood flow t h r o u g h a wide range o f p e r f u s i o n pressures and lOPs. Obviously, tbese techniques cannot be used in hulll:/.llS. Eltbrts have been clivected to develop noninvasive teclmiques to measure optic

MECHANISMS OF OPTIC NERVE DAMAGE IN POAG

33

nerve head microcil-culation. 1. Optic N e r v e B l o o d Flow

Several techniques (including angiography, optic nerve reflectance, visual evoked potentials and Doppler velocimetry) have been employed to measure optic nerve blood flow in normal subjects and glaucoma patients. Fluorescein angiography has been used extensively to examine bh)od flow in the optic nerve head (Fig. 8). 6°''I';'~7' 77.112.1-,3.11il1In glaucomatous h u m a n eyes with increased IOP, delayed filling of the optic nerve head vessels has been reported.~-'4 These investigators also observed localized relative anti absolute filling de[?ects. T h e absolute localized detects were correlated with visual field loss and with nerve fiber layer defects. 36'~~:~'c,4 I n some patients, absolute filling defects were found in patients who subsequently developed c o r r e s p o n d i n g visual field defects.171 Fluorescein angiographic study of the microvascular circulation of the optic nerve head has some significant limitations. It is often dilticuh to get adequate resolution of the fine naicrovasculature due to technical factors or media opacities. Once the surf:ace vessels fill, the d e e p e r vessels are obscured anct little further in|brntation can be obtained about the d e e p e r circulation. T h e r e is an element of chance in correctly tinting the acquisition of images using traditional techniques. High resolution videoangiography with c o m p u t e r assisted image analysis may allow one to extract more infi)rmation fi'om tluorescein studies in the future. H'-' Alternatively, indocyanine green angiogvaphy may provide information about choroidal vessels :'~'vs While previous investigations using I('G and a conventional fundus camera suggested that tilling cle[?ects in the optic nerve head correlated with visual field changes, H~ detailed studies of the blood flow were impossible due to the poor contrast and motion-induced image blur. T h e introduction of a tightly confbcal imaging mode in scanning laser ophthalnaoscopy allows sequential section of the optic nerve head and peripapillary retina to be employed with ICG to obtain angiographic images.iTS Robert et al have used the brightness of reflectance ['FoIll the optic nerve head as a measure of capillary perfusion of the optic nerve head. H:' Using a plaotopapillometer, they studied the effect of artificial elevation of lOP on normal and glaucomatous eyes. Following elevation of I()P there was a latency period d u r i n g which baseline brightness persisted. T h e latency was significant-

F~,,r. ,S'. Fluorescein angiogram demonstrating micro-

vascular filling of the optic nerve in an ocular hypertensive eye. Note tilling defcct in center of disk and peripal~illary choroid. (Courtesyo[ Bernard Schwartz, M.I)., Ph.D.)

ly shorter in ghmcomatous eyes than in the normal eyes. T h e authors suggest this may be due to a ctefi~ct in autoregulation in the glauconlatous eyes. Pilhmat et al have studied visual evoked potentials u n d e r conditions of varying experimentally elevated lOP to obtain an indirect measure of optic nerve blood |low. v-'Lv-'~For each eye, a perfilsion-pressuve amplitude curve is constructed. This curve in normal eyes shows a kink or plateau which the investigators interpret as a sign of vascular autoregulation. This was not detected in patients with POA(; v-''-'or NT(;, v-'~supporting the concept of defective autoregulation in these conditions. Optic nerve blood flow also has been studied with laser Doppler velocimetry (LDV). In this technique, a low-intensity laser beam (often a HeNe laser) is fi)cused on a small area of the optic nerve, avoiding visible vessels. T h e light is scattered by the moving red blood cells within the tissue. T h e light scattered by the red blood cells undergoes a Doppler shift in ti'equency proportional to the velocity of the red blood cells. A range o f & e q u e n c y shifts is measured as a Doppler power spectrum. This value is related to the total blood flow within the volume of tissue measured. Using this technique, Riva et al reported that the optic nerve head in humans may be capable of autoregulating blood flow in response to lOP changes induced experimentally with a suction cup.":~ Sebag et al reported decreased blood flow in experimental optic atrophy and clinical neu-

34

Surv Ophthalnml 39 (1)July-August 1994

rogenic optic atrophy. 151i.157While it appears that acute changes in IOP and optic nerve disease can alter optic nerve blood flow as measured by LDV, the relevance of these findings to POAG is uncertain. Further, it is not cleat" whether LDV measures flow only in the surface layer of the nerve which is supplied by the retinal circulation, or whether deeper layers which may receive contributions fi'om the choroidal circulation are nleasured. With ftn'ther study and refinement, this technique may contribute to out" understanding of the role of the microcirculation in glancoma.

2. Retinal Blood Flow Retinal blood flow abnormalities in glaucoma have been suggested by several fluorescein angiographic studies. 49"1':u~ The presence of these abnormalities is supported by studies that use the blue-field entoptic phenomenon to quantify retinal blood flow in the macula. In this technique, the subject can perceive bright particles believed to be leukocytes as they pass through the macular capillaries. In normal patients, leukocyte velocity slows when IOP is rapidly raised by a scleral suction cup system. The highest lOP at which leukocyte velocity was not slowed was about 30 mnaHg. TM There is a perceived hyperemic response (increased leukocyte velocity) when lOP is returned to baseline tbllowing removal of the scleral suction cup. 5~ Presumably, flow was maintained through autoregulation by vasodilatation during the period of elevated IOP; when the lOP was suddenly returned to baseline, capillaries remain transiently vasodilated and there is a brief increase in leukocyte velocity. In glaucoma patients, the highest acutely elevated lOP at which macular flow could be ntaintained was significantly lower. Further, the hyperemic response was absent in a significant ntmlber of glaucoma patients, suggesting they have abnormal autoregulation of macular blood flow. 5-' Baseline retinal blood flow may also be abnormal in glaucoma. Glaucoma patients with asymmetric damage reported a slower perceived leukocyte velocity in the eye with more advanced glaucoma, r'' In a study of 12 patients with glaucoma or ocular hypertension there was a significant positive correlation between asymmetry of visual function (visual field and spatial contrast sensitivity) and perceived retinal leukocyte velocity, u~'j The eye with the better visual function had the higher leukocyte velocity. It was not possible for the investigators to determine if the vascular

FECHTNER, WEINREB changes were a primary or secondary event.

3. Ophthalmic Artery Blood Flow A noninvasive technique to measure the flow velocity in the ophthalmic artery has been developed using various transcranial Doppler ultrasound systems. '
4. Basis for Autoregulation Autoregulation of blood flow appears to exist

MECHANISMS OF O P T I C NERVE DAMAGE IN POAG

in the normal h u m a n optic nerve and retina. Considerable evidence suggests that a regulatory abnormality may be present in the eyes of some glaucolna patients. Examination of the cellular and molecular mechanisms regulating blood flow in the microvasculature may provide clues about the biological basis for such abnormalities. For example, the endothelial cell which is positioned between circulating blood and the vascular smooth muscle may play a role in local autoregulation of blood flow. In response to various stimuli, these cells can release endothelium-derived relaxing factor (EDRF), a potent vasodilator (found to be indistinguishable from nitric oxide). n~,~ It has been shown that in the h u m a n ophthalmic artery, nitric oxide is released u n d e r basal conditions. Production of nitric oxide can be markedly stimulated by c o m p o u n d s such as bradykinin, acetylcholine, and histamine. This results in profound vasct, lar relaxation, and may play an important protective role against vasospasm. 57 In contrast, endothelin-1 has a vasodilator effect through the release of prostaglandins and potent vasoconstrictor properties mediated t h r o u g h endothelin.~ receptors, m'-' These findings suggest that in the h u m a n ophthahnic artery, endotheliuna-derived nitric oxide may play an important role in the regulation of local blood flow in the eye. Functional changes in the endothelium, such as impaired synthesis of nitric oxide, may contribute to abnormalities of the ophthalmic artery flow in glaucoma (see above) or other changes in optic nerve head, retinal, or choroidal microcirculation. ~TV D. I N F L U E N C E O F P E R I P A P I L L A R Y TISSUE

The strt, cture of the peripapillary (or parapapillary) tissues may be related to glaucomatous optic neuropathy. It has long been recognized that peripapillary (or parapapillary) atrophic changes can accompany glaucoma.5'~;°'l'-':~'v-'4't'~"J ouas et al have classified this atrophy i,a two zones: a peripheral zone "alpha," which is characterized by irregt, lar hypo- and hyperpigmentation of retinal pigment epitheliuna, and a central zone "beta" with white color and visible choroidal vessels in which there is absence of retinal pigment epitheliuna. The size and Dequency of this atroplay is greater in glaucoma eyes than in normals. "~l's" Peripapillary atrophy is significantly correlated with decreasing neuroretinal rim area. '~ In one retrospective study, the location of the peripapillary changes correlated with the di-

35

rection of the visual field deflects in glaucoma.' ~j There are conflicting reports as to whether the area of atrophy is greater in the affected eye in cases of unilateral glaucoma, sl't ~4 Progression of optic nerve changes and progression of peripapillary atrophy do not always correlate. In addition, the peripapillary retinal pigment epithelium (RPE) can show progressive changes in some normal individuals. N,i It seems clear that peripapillary chorioretinal atrophy is associated with glaucoma in some individuals. It has not been determined whether this atrophy precedes and predisposes to structural and functional defects of the optic nerve or simply accompanies the damage. Glaucomatous eyes with normal or mildly elevated IOP have more marked peripapillary atrophy than eyes with high IOP. v'''~j While it is possible that this atrophy is a variable response to the disease process, one can speculate that the structure of the peripapillary tissues can influence the course of optic nerve damage in glaucoma." This could explain why some eyes with peripapillary atroplay but only mildly elevated IOP have optic nerve damage. Anderson has raised the question whether circulating vasoactive substances and the structure of the peripapillary tissue may influence POAG) ~ In an experimental model investigating the el: fect of IOP on optic nerve axonal transport, elevation of systemic blood pressure was induced by angiotensin to evaluate whether this could protect the optic nerve fi'om damage by better maintaining perfusion. Unexpectedly, greater blockage of axonal transport was observed in the animals receiving angiotensin, u~4 Despite the protection of perfusion through elevated blood pressure, the angiotensin was indt,cing a deleterious effect on axonal transport. It has been shown that circulatory vasoactive agents such as angiotensin can cause vasoconstriction of the retinal vasculature. :~-'Anderson postulated that such substances could gain access to the optic nerve microvasculature via diffusion fi'om the choroid. 6 In the presence of peripapillary atrophy, there may be loss (or altered permeability) of the retinal pigment epithelial barrier. In the absence of an intact barrier, vasoactive substances could leak fi'om the choroid and directly influence the microvasculature of the optic nerve by compromising their autoregulation.
36

Surv Ophthalmol 39 (1)July-August 1994

FECHTNER, WEINREB

pigment epithelium barrier might effectively increase and allow a greater concentration of vasoactive factors, such as angiotensin or larger vasoactive molecules, access to the optic nerve microvasculature.

related damage. ~3~ A study of normal and glaucomatous human eyes post-mortem also demonstrated preferential loss of larger nerve fibers. The pattern of atrophy was similar. The most damaged portions of the nerve were the superior and inferior poles in an hourglass distribution, but large fibers were lost throughout the nerve, v-'9

E. SUMMARY The microcirculation of the optic nerve head is a topic of considerable current interest. There is a large body of evidence supporting the concept that changes within the microcirculation may be relevant to the development of POAG. By various techniques, optic nerve, retinal and ophthalmic artery flow have been found to be abnormal in patients with POAG. Further work is needed to better understand the role of the microcirculation in POAG. III. Selective Susceptibility of Nerve Fibers and Ganglion Cells In addition to the many lines of evidence which suggest mechanical and/or vascular factors are involved in the pathogenesis of POAG, some understanding of glaucoma can be gained through study of the cellular and functional results of this damage. While vision is initiated by the absorption of photons of light at the photoreceptor level, it is the post-receptor organization of the visual system which processes and modulates the response to light. At the ganglion cell layer, there is initial processing which permits the emergence of visual functions, such as color perception, detection of movement and the ability to detect low contrast objects. Animal and human data have suggested that various functions are mediated by separate parallel visual pathways. :~7'9~'m51In part, these different pathways are determined by different classes of ganglion cells. There is some evidence that these classes of cells may differ in their susceptibility to glaucomatous damage. A. NERVE FIBER SIZE In cynomolgus monkeys with experimentally induced glaucoma, remaining optic nerve fiber size was examined to determine if there was selective injury of nerve fibers of a particular size. All sizes of fibers were affected, but fibers larger than the mean diameter showed more rapid atrophy. The superior and inferior peripheral portions of the nerve were preferentially affected. These areas contained a high proportion of large diameter fibers. Large diameter fibers were preferentially lost in other areas of the nerve, suggesting an increased vulnerability to pressure

B. GANGLION CELLS Quigley et al examined the number and diameter of remaining retinal ganglion cells in six human eyes with known glaucoma and five age-matched normal eyes. v~° In normal eyes, regional differences in ganglion cell size were found with the region receiving foveal input containing cells which were all small and similar in size and the nonfoveal region containing cells of diverse size. A selective loss of ganglion cells with a diameter larger than the mean in nonfoveal areas was demonstrated in glaucomatous eyes. These data are consistent with the finding of loss of large nerve fibers within the optic nerve. ~'-'9 The loss of ganglion cells was also correlated with visual field loss. Previously, three of the glaucomatous eyes had undergone static threshold perimetry testing. It was found that areas of the visual field with decreased sensitivity corresponded to areas of the retina with decreased ganglion cell density. I:~" Damage may not be limited to ganglion cells. In one study of 23 enucleated eyes with secondary angle-closure glaucoma and high lOPs, photoreceptor counts were significantly lower than in control eyes enucleated for malignant melanoma. ~' This may indicate that glaucoma is associated with loss of photoreceptors or other neural elements. C, CORRELATION BETWEEN GANGLION CELL LOSS AND FUNCTIONAL DEFECTS Much of what is known about the postreceptor organization of the visual pathway is derived from animal experiments. Clearly, interspecies variation exists. Much of what is presumed to be true about the human visual pathway is derived from animal and nonhuman primate studies and must be viewed with caution. Keeping this in mind, study of the psychophysical abnormalities found in glaucoma may allow one to make inferences about the site and mechanism of damage in human POAG. Although more than one subgroup of ganglion cells is likely damaged by glaucoma, an anatomic selective susceptibility of one subgroup would result in vulnerability of par-

MECHANISMS OF OPTIC NERVE DAMAGE IN POAG

ticular psychophysical functions. Reports of histological evidence for earlier damage to large optic nerve fibers 47'1:~6have stimulated interest in the M ganglion cells (cells which project to the magnocellular layers of the dorsal lateral geniculate nucleus) and the functions they handle. However, blue-yellow ganglion cells and P ganglion cells (cells which project to the parvocellular layer of the dorsal lateral geniculate nucleus) serving the peripheral retina also have large axons relative to M ganglion cells near the fovea, iS° Considerable research is directed at probing specific functional visual defects in POAG. Further work is needed to correlate these psychophysical abnormalities with their anatomic substrate. IV. Summary

Glaucomatous optic neuropathy can occur in the presence or absence of detectable high IOP. Any unifying theory concerning the mechanism of damage must consider a large body of sometimes conflicting data. Neither the mechanical nor the vasogenic theories resolves all the conflict. It seems likely that POAG can be induced by several factors, either alone, or in combination. There may be several processes which result in clinically identical manifestations. There is evidence that the lamina cribrosa is an important site for damage in POAG. Mechanical factors such as distortion of the lamina may resuit in direct compression of the retinal ganglion cells axons 01" may induce perturbations in axonal transport leading to cell damage. Regional differences in the structure of the lamina may lead to specific patterns of damage. Changes in the extracellular matrix of the optic nerve have been demonstrated in POAG. Changes in the extracellular matrix may compromise the structural support, delivery of nutrients, 01" removal of metabolic products relating to the neural elements of the optic nerve. It may be that such changes in the human eye are a secondary event following damage rather than a contributing factor. There is considerable evidence indicating that the optic nerve microcirculation may be involved in the pathogenesis of POAG. The collagenous beams of the lamina cribrosa are the conduits for the microvascular supply of the optic nerve. Blood flow in these vessels may be altered by mechanical distortion from increased IOP. Contribution to the optic nerve microvasculature by the peripapillary choroidal circulation may be particularly susceptible to pressure due to the absence (or paucity) ofautoregulation in the low

37

pressure choroidal circulatory system. Watershed zones in the choroidal circulation frequently fall in the region of the optic nerve. This may influence individual variations in susceptibility to optic nerve damage. While there is no direct evidence that capillary loss or alteration precedes neural loss, there is a rich microvascular supply to the optic nerve head which may be deficient in other ways. Autoregulation of blood flow seems to be present in the normal optic nerve head and the retina. Autoregulation of retinal blood flow appears abnormal in glaucoma. Similar abnormalities of autoregulation in the optic nerve head may be a contributing factor in the development of the optic nerve damage in POAG. Optic nerve circulation may also be influenced by leakage of vasoactive substances from the peripapillary choroid. The damage to the optic nerve caused by POAG can be broadly defined as diffuse or focal. Diffuse nerve damage would be evidenced by an enlargement of the optic cup with a reduction in the neuroretinal rim area. Diffuse damage to the visual field might result in increased fluctuation, generalized depression or constriction. Focal damage would result in asymmetric enlargement of the optic cup with notching of the neuroretinal rim. Visual field changes would be expected to follow an arcuate pattern corresponding to the area of damage. Nerve fiber layer photographs have revealed both diffuse and localized patterns of loss (Fig. 9)." Either or both patterns may be present in an eye. Different mechanisms may be involved in producing different patterns of damage. For example, mechanical distortion of the lamina cribrosa with impingement on the retinal ganglion cell axons might result in diffuse damage. Similarly, a generalized compromise of optic nerve head blood flow may result in diffuse damage. In contrast, localized damage may be related to a focal area of weakness in the lamina, and even the formation of an acquired pit of the optic nerve head. A localized vascular event such as one heralded by a flame hemorrhage also would produce local damage. Several mechanisms have been postulated to explain the optic nerve damage that occurs in POAG. No single mechanism can adequately explain the great variations in susceptibility to damage and the patterns of damage seen in glaucoma. The etiology of POAG is likely to be multifactorial. Mechanical, vascular and other factors may influence individual susceptibility to optic

38

Stlrv Oplathahnol 39 (1) July-August 1994

Fig. 9. N e r v e fiber la),er p h o t o g r a p h o f h t n n a n eye with g l a u c o m a d e m o n s t r a t i n g n e r v e fiber b u n d l e defect in s u p e r i o r a r c u a t e region.

nerve damage. For example, one patient may suffer mainly fi-om an intrinsic defect in autoregulation while another has poor support of the ganglion cell axons within the lamina cribrosa. An enhanced understanding of the nature of the optic nerve damage in POAG and improved methods of study may result in earlier diagnosis or may allow us to distinguish among diffi~rent pathologic processes all currently grouped under the diagnosis of POAG. Ocular hypotensive treatment alone may benefit only some glauconta patients. As we gain a better understanding of the neuropharmacology and cellular biology of injury and repair of the vist, al system, I:'~'we will undot, btedly reline our concepts of glaucomatous optic neuropathy. Vision-saving therapies designed to treat the underlying pathologic process will be directed toward protecting or repairing the optic nerve in glaucoma.

References I. Abtl El-Asrar AM, Morse PH, Mailn~lne D. et ;.i]: MK801 prott'cls retinal nCtll'Ons t1"o111hypoxia and the toxicity ofglulanlale ;,ind ;iSpal'lale. IIIt'I'sl ()phlhalmol I "i.s.S't'i 33:3463-3468. 1992 2. Airaksinen I'.1, Drancc SM. Douglas (;R: Dill'use and localized nerve ill)el" hiss in glaufonla..-Ira./Ophlhahmd 98:566-57 I, 1984 3. Ahn A, Bill A: Ocuhu" and optic nerve blood tlow at normal and increased inll'aoctllar pressures in nll)llkeys (Macaca irus): A study with radioactively hibellcd nficrosphcres induding Ilmv dc'lermin,ltions in br;lin and some other tissues. Exp Ew' Re~ 15:15-29, 1973 4. Anderson DR: Vascular suppiy to the optic nerve of primales..-Ira J Ophlhahmd 70:341-351, 1970 5. Anderson DR: Correlation of the iJcripapilhu'y anatollIV with the disc danlage and lield almorlnalities in gl~ltlCOilla. Do: Ophthalmol Proc ,'h,r 3511-1(I, 1983

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39 (1) J u l y - A u g u s t 1994

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Outline I, Mechanical (IOP-related) mechanism of danaage A. L a m i n a c r i b r o s a 1. S t r u c t u r e 2. R e g i o n a l d i f f e r e n c e s in t h e l a m i n a cribrosa 3. C h a n g e s in t h e l a m i n a c r i b r o s a in P O A G 4. Axonal t r a n s p o r t d i s t u r b a n c e s with elevated lOP 5. S u m m a r y B. E x t r a c e l l u l a r m a t r i x !. E x t r a c e l l u l a r m a t r i x o f t h e optic n e r v e 2. C h a n g e s in e x t r a c e l l u l a r m a t r i x in POAG II. V a s o g e n i c m e c h a n i s m o f d a m a g e A. V a s c u l a r s u p p l y o f t h e optic n e r v e h e a d B. T h e role o f optic n e r v e h e a d m i c r o c i r c u l a tion 1. C o m p r o m i s e d capillaries 2. A l t e r a t i o n o f c h o r o i d a l b l o o d flow 3. O t h e r c h a n g e s o f c o m p r o m i s e d microcirculation C. A u t o r e g u l a l i o n o f b l o o d flow I. O p t i c n e r v e b l o o d flow 2. Retinal b l o o d flow 3. O p h t h a h n i c a r t e r y blood flow 4. Basis fbr a u t o r e g u l a t i o n D. I n f l u e n c e o f p e r i p a p i l l a r y tissue E. S u m m a r y II1. Selective susceptibility o f n e r v e fibers a n d g a n glion cells A. N e r v e fiber size B. G a n g l i o n cells C. C o t ' r e l a t i o n b e t w e e n g a n g l i o n cell loss a n d f u n c t i o n a l deti~cts IV. S u m m a r y

The authors thank Pamela Sample, Ph.D. a n d J a m e s Lindsey, Ph.D. from the (_;lancoma Center and Research Laboratories, University of California, San Diego, [or their critical discussion and suggestions. This work was supported, in part, by N I H grants EY06621 (RDF) and EY06006 (RNW) and 1992 Alcon Research Institute Prize (RNW). Reprint Addcess: Robert D. Fechtner, M.D., Department of Ophthahnology and Visual Science, University of Louisville, Louisville, KY 40292.