Various investigators noted patients with POAG had (1) increased plasma levels of cortisol;204 (2) increased suppression of plasma cortisol with different doses of exogenous dexamethasone;205 (3) continued suppression of plasma cortisol by dexamethasone despite concomitant administration of diphenylhydantoin (phenytoin);206,207

(4) disturbed pituitary adrenal axis function,208 and (5) increased inhibition of mitogen-stimulated lymphocyte transformation by glucocorticoids.209,210 Researchers postulated that endogenous corticosteroids affected trabecular function by altering prostaglandin metabolism, glycosaminoglycan catabolism, release of lysosomal enzymes,176 synthesis of cyclic adenosine monophosphate,211 or inhibition of phagocytosis.209

The corticosteroid hypothesis came under attack as subsequent studies in glaucomatous patients failed to confirm the increased

sensitivity of non-ocular tissues to the effects of glucocorti- coids.212–216 In addition, the IOP response to topical corticoster-

oids was shown to lack reproducibility217 and to be less controlled by inheritance than previously thought.218–220

Recent data have re-opened the corticosteroid issue. Trabecular endothelial cells from patients with POAG have an abnormal metabolism of glucocorticoids, with increased levels of delta-4 reductase and reduced levels of 3-oxidoreductase.221 The importance of this observation, and whether it represents a primary or a secondary change in the tissue, is unclear at present. Most recently, a gene mutation (GLC1A) has been associated with juve- nile-onset glaucoma and a small fraction of adult-onset POAG.222 Mutations of this gene (trabecular meshwork-inducible glucocorticoid response (TIGR)) are associated with the production of an abnormal glucocorticoid-inducible stress-response protein (myocilin) in the trabecular meshwork that may affect glycosaminoglycan and other glycoprotein metabolism, as well as cell-surface properties.223 In addition to giving a genetic basis for some types of glaucoma, the TIGR gene could tie in a possible role for corticosteroids in the glaucomatous process. Furthermore, patients who respond to topical steroids with a very high IOP are more likely to develop visual field loss than moderate responders.224 In this study, none of those who were low responders developed visual field loss.

Dysfunctional adrenergic control

In analogous fashion to the corticosteroid theory, others have proposed that the diminished outflow facility in patients with POAG could be explained by an increased sensitivity to adrenergic agonists.Various reports indicated that patients with POAG had

(1) a greater IOP reduction after the administration of topical adrenaline (epinephrine);225 (2) a greater response to adrenaline (epinephrine) or theophylline in inhibiting mitogen-stimulated lymphocyte transformation,226,227 and (3) more frequent premature ventricular contractions after topical administration of adrenaline (epinephrine).225 Furthermore, ocular hypertensive subjects who demonstrated a fall in IOP greater than 5 mmHg after topical adrenaline (epinephrine) administration had a higher rate of developing visual field loss.228 However, additional studies have generally failed to confirm an increased sensitivity to adrenergic agonists in patients with POAG.229

Abnormal immunologic processes

Other investigators have explained the diminished aqueous humor outflow in POAG by abnormal immune responses. Increased levels

of -globulin and plasma cells have been detected in the trabecular meshwork of patients with POAG.230,231 Furthermore, glau-

coma patients were noted to have a high prevalence of antinuclear antibodies.232,233 However, subsequent, more detailed studies have

failed to confirm these findings.234–236 An association between

POAG and certain human lymphocyte antigens was reported237 and then refuted by multiple studies.238–240 Endothelin-like

immunoreactivity has been noted to be increased in the aqueous of glaucoma patients, suggesting a role for this molecule in IOP regulation.241 Antibodies to heat shock protein, an indicator of cell stress, have been noted to be increased in the serum of glaucoma patients.242 Evidence for immunologic factors in open-angle glaucoma, especially in the retinal ganglion cell layer, have led some to propose vaccination as a potential neuroprotecting treatment in glaucoma.243

Oxidative damage

Interest has developed in the question of whether the trabecular meshwork could be damaged by oxidative insult. The meshwork contains glutathione, which may protect the endothelial cells from

the effects of hydrogen peroxide (H2O2) and other oxidants. This interesting hypothesis is still the subject of active research.244,245

Other toxic influences

Lütjen-Drecoll has postulated that transforming growth factor (TGF) beta2 may be involved in the pathogenesis of open-angle glaucoma.246 Dan and co-workers have shown that there is a threefold increase in the levels of plasminogen activator inhibitor in the aqueous humor of glaucoma patients compared to cataract patients without glaucoma.247 These findings suggest that this protein may play some role in the pathogenesis of increased IOP.

In summary, the cause of the trabecular dysfunction in POAG is unclear at present. To date, no single theory explains the pathophysiology.

Optic nerve cupping and atrophy

The second major issue to be addressed in the pathogenesis of POAG is the cause of the optic disc cupping and atrophy.This topic is dealt with in detail in Chapter 12. Cupping consists of backward bowing of the lamina cribrosa, elongation of the laminar beams, and loss of the ganglion cell axons in the rim of neural tissue.248 Cupping is the hallmark of glaucomatous damage, although it is seen occasionally in ischemic states and compressive lesions in the posterior optic nerve and chiasm. Histologic studies indicate that optic nerve cupping includes the loss of all three elements of the disc – axons, blood vessels, and glial cells. Glial cells appear to atro-

phy as a secondary phenomenon, and some glial cells are present even in advanced stages of glaucomatous optic atrophy.249,250 Other

investigators have reported selective loss of capillaries in the disc substance251,252 or in the peripapillary retina.253,254 These findings

have not been confirmed, however and blood vessels actually seem to be lost in proportion to the loss of axons.249,255A recent study

of the submicroscopic histopathology and immunohistochemistry of the optic nerve showed fibrosis, arterioscerotic changes and loss of capillaries in glaucomatous optic nerves compared to nonglaucomatous ones.256 These changes were not present in the higher IOP eyes with pseudoexfoliative glaucoma.

Most authorities believe that the lamina cribrosa is the site of glaucomatous optic nerve damage.255,257 The lamina is a relatively rigid

structure that surrounds the densely packed axons. Furthermore, the lamina is the tissue that divides the higher IOP space from the lower subarachnoid pressure space. Early in glaucoma, the lamina is compressed. In the later stages of the disease, the laminar sheets become fused, and the entire lamina bows backward.258