6

2I

3

4

5

1 CRA

Fig. 12-3  Composite illustration of the various optic nerve vascular arrangements. Venous vessels and the superficial central retinal artery (CRA) plexus are not drawn in full. Retrolamina: (1) Pia mater as the source of transverse and longitudinal vessels. (2,2 ) Recurrent short posterior ciliary artery (SPCA) to the retrolamina and pial vessels to the lamina cribrosa. (3,3 ) Pial-derived longitudinal arterioles course to and anastomose with the laminar vasculature. (4) Occasionally realized large pial arteriole courses longitudinally through the laminar tissue. (5) Intraneural branching of central retinal artery, with anastomosis to the laminar and retrolaminar systems. Lamina cribrosa: (6) Transverse entry of scleral SPCAs that dominate the laminar vasculature and mingle with the longitudinal microcirculation. Prelamina: (7) Branch of the SPCA courses through Elschnig’s tissue (E)

at the level of the choroid (CH) and enters into the nerve. (8) Occasional choroidal vessel to the prelamina; S, sclera. Superficial nerve fiber layer (SNFL): (9) Choriocapillaris ‘spurs’ capillary anastomoses with other retinal and prelaminar vessels. (10) Both epipapillary and peripapillary branches of the central retinal artery anastomose with prelaminar vessels.

(From Lieberman MF, Maumenee AE, Green WR: AmJ Ophthalmol 82:405, 1976.)

intra-orbital space.46,48b Alterations among trans-laminar pressure gradients, as with traumatic CSF leaks, may clinically contribute to glaucomatous progression.48c,48d

Yet the inner retina is apparently another site of damage to both the retinal ganglion cell (RGC) and astroglial populations. It has been

hypothesized that intraretinal or intravitreal glutamate levels that are neurotoxic to ganglion cells play a role in glaucoma.49–52 Such

biochemical specifics suggest possible strategies of neuroprotective intervention.53–57 This approach is being actively pursued in other neurologic degenerative conditions such as Parkinson’s disease and Alzheimer’s disease58,59 although equivocal results in large studies caution enthusiasm for effective glaucoma interventions at this time.60

The growing appreciation of astroglial roles in CNS neurotransmission61,62 significantly expands the scope for research into this heretofore overlooked cellular population’s possible role in neurodegenerative diseases, such as glaucoma.48,63,64

Although the role of vascular perfusion remains relevant to elucidating glaucomatous pathophysiology, localization to specific vascular beds within the globe remains problemmatic.65 If generalized vascular insufficiency at the level of the retinal or choroidal circulations were primarily involved in glaucomatous optic atrophy, extensive deleterious effects on other retinal cell types would be expected, but this is not the case in the histopathology of glaucoma.66,67 Diffuse vascular insufficiency of an ocular layer, as is reportedly responsible for diffuse inner choroidal thinning in glaucoma,68 may contribute to the glaucomatous pathogenesis indirectly or in ways that remain unknown.

What Injures Ganglion Cells?

This is a fascinating topic for which the impressive strides of recent glaucoma epidemiology bear directly on histopathologic events.69

For example, unequivocal clinical risk factors for developing glaucoma include IOP, increasing age,3b race, high myopia, family history of POAG, and a variety of vascular indexes. These factors should be distinguished from associated clinical findings that reflect early but established glaucomatous damage before manifesting as defects in the visual field. Such associated findings include large cup/disc ratio9 (and related indexes from ONH imaging); disc hemorrhages; nerve fiber layer defects; and abnormal psychophysical changes such as short-wavelength (blue-yellow) perimetric defects70–75 or altered contrast sensitivity.76

Both risk factors and early alterations must necessarily be expressed at the cellular level. Quigley4 considers four aspects of potential ganglion cell injury.

Ganglion Cell Susceptibility

There are an average of one million ganglion cells per human eye, with tremendous variability by a factor of three to four.77 The size of the optic disc is a marker for axon number: the larger the scleral canal, the more nerve fibers are present.78–80 Interestingly, eyes with POAG do not have larger discs than do age-matched normals, and this also holds true for blacks who generally have larger optic discs than do whites.81 These data exemplify the paradoxic nature of many ‘susceptibility factors’: a larger optic disc would theoretically be more deformable and thus exacerbate axonal loss (see below); yet such large discs have more axons, whose greater numbers might reduce susceptibility to glaucomatous atrophy.

Aging takes a toll on the number of nerve cells throughout the brain, with a loss of approximately 25% over a lifetime, including loss of the retinal cell populations. Any acceleration of this process could manifest as clinical glaucoma. Elevated IOP, even in normal eyes, may be one such accelerant for subclinical axon loss.82 Thus increased age and elevated IOP may converge in hastening the natural attrition of ganglion cells.

Susceptibility may also reside in the specific subtype of ganglion cells. There are significant variations of ganglion cell populations

among mammalian and primate eyes,77 with at least 13 varieties of RGCs reported in primates.25,83 The most commonly encoun-

tered ganglion cells in the human retina are small (parvo) cells and large (magno) cells, in a ratio of approximately 8:1, respectively. The parvo cells transmit acuity and color data; the magno cells convey motion perception and scotopic information.84

The preferential loss of the magnocellular population in early glaucoma, reported by several investigators,24 may reflect one of several scenarios. Perhaps there is a genuine but unexplained intrinsic sensitivity of the magno cells to the (unknown) earliest toxic effects of glaucoma. A likelier explanation is that diffuse damage occurs to all axons in the ONH but manifests as an early magnocellular defect because there are fewer such fibers to begin with, and they tend to congregate in susceptible portions of the lamina cribrosa (see below).This is compatible with reports of early glaucoma damage to both parvocellular pathways (tested by shortwavelength perimetry) and magnocellular pathways (assessed by motion-automated perimetry).75 It is important to conceptualize the ‘redundancy’ or abundance of ganglion cells relative to actual clinical visual function. Approximately 25% RGC loss is required for an afferent papillary defect; approximately 35% RGC loss

before defects are detected with computerized threshold white- on-white perimetry; and 40% RGC loss before acuity worsens.24,25

Clinical tests that can preferentially exploit the early loss of differ-

ent ganglion cell populations and their functions are actively being pursued.85,85b (See Chapter 11.)

Connective tissue structures within the optic nerve head

Because excavational cupping of the ONH is an essential characteristic of progressive glaucoma, the vulnerability and behavior of the structural elements of the optic nerve are a focus of intense interest. From a clinical perspective, the greater susceptibility of the myopic eye than the emmetropic or hyperopic eye to sustain glaucomatous damage suggests altered scleral rigidity or deformation of the posterior scleral structures as contributory factors.69,86 Research on the biomechanics of laminar and prelaminar tissues implicates the interplay of IOP and aging factors on the development of glaucomatous cupping.3b

Optic disc excavation is the consequence of three related events:

(1) loss of neural rim axons; (2) elongation, stretching, and collapse of the laminar beams and their posterior axial displacement (bow-

ing); and (3) outward, centrifugal rotation of the laminar insertion into the scleral insertion zone (Fig. 12-4).28,87,88 Histopathologically,

many cellular and subcellular alterations of the normal laminar structures89,90 have been associated with this distinctive form of

optic atrophy. Changes include specific remodeling of the extracellular matrix of the laminar tissue and astrocytic reactivation,64,91–94

variations in elastin, suggestive of decreased compliance,95–97 and concomitant loss of the intralaminar microvasculature as the axonal mass is diminished. Combined, these various changes can result in an altered mechanical compliance of the ONH.98,99

Another intriguing characteristic of the laminar architecture that bears directly on axonal injury in the ONH is the lower density

of support in the upper and lower laminar pores, a finding seen in perhaps as many as 50% of glaucomatous eyes.88,100–102 The pores

tend to be larger in the superior and inferior areas of the lamina cribrosa; this is thought to allow less support for, and more compressibility of, the arcuate axon bundles (Fig. 12-5).103 Such vulnerability would result in their earlier loss in glaucoma in an hourglass configuration, manifesting as the arcuate visual field defects.

These regional anatomic differences of the lamina are the most dramatic demonstrable asymmetric structures that correlate with the clinical patterns of damage seen in glaucoma, but are not exclusive. For example, the finding of extremely thin lamina cribrosal structures in highly myopic eyes has led to the speculation that this could expose the ONH to steeper translaminar pressure gradients between the IOP and cerebrospinal fluid space, accounting for greater sensitivity to glaucomatous damage in such eyes.104Variations in astroglial structures within the laminar region have also been reported.105

Clearly the clinical risk factors of race and family history could be expressed as genetic aberrations in any one of the myriad cellular and synthetic processes alluded to above. Undiscovered alterations in the production or function of collagen, elastin, extracellular matrix, astrocytes, laminar architecture, or other structures in the ONH could result singly or jointly in the overall susceptibility of the ONH to excavational damage. Similarly, unknown genetic variations in ganglion cell populations, numbers, or sensitivities could also manifest as clinical disease.

Intraocular pressure level

Although it is unclear which cellular and histologic alterations are primary or secondary, elevation of the IOP is the most consist-

ent and reproducible experimental model for producing pathognomonic glaucomatous excavation of the optic disc.35,29,106–108

Physicians have anecdotally observed excavational cupping, similar to that seen with glaucoma, in a variety of circumstances,102 includ-

ing arteritic anterior ischemic optic neuropathy,109–111 compressive optic neuropathy,112,113 and optic nerve infarction. Under laboratory

circumstances, however, neither optic nerve transection nor ischemic insults recapitulate the consistent ONH alterations seen both in prolonged experimental IOP elevation and in clinical glaucoma.

Precisely how IOP induces these unique changes remains unclear.114 Clinically it has been well established that there is

a continuum of association between IOP and POAG, much as a dose-response curve.69,115 In actuality, there is no ‘normal’ IOP that

serves as a fail-safe reading for determining the presence or absence of the risk or progression of glaucoma.116

Some of the ambiguity surrounding the role of IOP is epidemiological: among Japanese or African-Americans, sensitivity to IOP levels for developing glaucomatous atrophy appears greater than in whites,4 although non-pressure factors, such as population-specific mean IOP values or the pressure-independent risk of central corneal thickness, may confound our understanding. Some of the ambiguity is technological: for example, pachymetric investigations of the effect of corneal thickness on applanation pressure readings suggest that even the categories of ‘ocular hypertensives’ and ‘low-tension glaucoma eyes’ may

reflect instrument artifact, with thinner corneas reading lower IOPs and thicker corneas higher IOPs.117,118 Similarly, the intriguing pos-

sible relationship between IOP and the pressure gradient experienced

by the ONH adjacent to the retrolaminar’s cerebrospinal fluid pressure remains to be elucidated experimentally and clinically.46,48b,119

Vascular nutrition of the optic disc

In the search for the other pathogenic factors involved in glaucomatous atrophy, either independent of or in concert with IOP, much has

been published regarding the vascular status of the glaucomatous eye and patient. Some clinical reports have observed anecdotal worsening

of glaucomatous field defects and the disc with therapeutic or pathologic reduction of the systemic blood pressure120–129; yet there is a

contradictory study of glaucomatous patients who sustained severe hypotension without clinical deterioration.130 Epidemiologic assess-

ments have revealed a complex relationship between systemic hypertension and glaucoma, involving age as a factor.131,132 High blood

pressure is relatively protective against glaucoma in younger individuals; in older patients systemic hypertension is a risk factor. Conversely, a low diastolic blood pressure in conjunction with elevated IOP (average 26 mmHg) increases the glaucoma risk eight-fold.132

Thus it may be particularly valuable to evaluate the synergy of risk factors such as blood pressure and IOP together, rather than approaching the problem from either a vasogenic or mechanical

hypothesis of causation.4 In fact, retrospective multivariate analyses show complicated groupings of various factors.133,134

Peripheral vasospasm has been found by some to be associated with low-tension (normal pressure) glaucoma.135,136 The hypoth-

esis is that peripheral vasoconstriction, as measured in the finger’s nail-bed capillary responses to cold water immersion, correlates with altered endothelial autoregulation of the blood supply of the ONH.137 However, correlation with observable parameters such as peripapillary retinal arteriolar narrowing138 has not been clinically

convincing. Similarly, other vasculopathic diseases such as migraine and diabetes mellitus have been both reported139–141 and reported not132,142,143 to be associated with glaucoma.