an association of open-angle glaucoma with diabetes mellitus,135,136 but the most recent population studies strongly support an association with diabetes mellitus. These include the Blue Mountains Eye Study in Australia,137 the Rotterdam Study,138 and the Beaver Dam Eye Study in Wisconsin.139 The explanation for this relationship remains obscure, but some investigators have proposed that diabetes affects the small blood vessels supplying the optic nerve, thereby rendering it more susceptible to glaucomatous damage.

Other investigators have proposed a relationship between POAG and thyroid disease.140–142 In one study, open-angle glaucoma was

associated with chronic thyroid orbitopathy.143 A more recent study confirmed the association of Graves’ disease with not only openangle glaucoma but also normal-tension glaucoma and ocular hypertension (not surprising as the IOP can be raised with restric-

tive muscle conditions).144 However, not all studies have shown this association.145,145a In the Veteran’s Hospital in Birmingham,

Alabama, an association was found between males with open-angle glaucoma and hypothyroidism.146

Corticosteroid function and systemic vascular disease, and their relationships to POAG, are discussed in greater detail later in this chapter. Having open-angle glaucoma does not seem to influence mortality; this is an important observation since decisions about the

intensity of treatment can be made against the background of typical life expectancy for age.147,148

Vascular disease has long been suspected of contributing to glaucomatous damage. In the Barabados study, baseline systemic hypertension seemed actually to reduce the risk of incident open-angle glaucoma while low blood pressure (or more accurately, low perfusion pressure) seemed to increase the risk.149 Studies of blood flow in and around the eye in the laboratory strongly suggest that blood flow is reduced or disordered in glaucoma.150 However, whether this abnormal blood flow is a primary causal phenomenon or secondary to the optic atrophy has not been shown. One study of American veterans suggests that long-term oral statin or other anticholesterol use is associated with a lower risk of open-angle glaucoma.151 A subsequent study in a broader population has confirmed this observation.152 The Blue Mountains Eye Study suggests an association between open-angle glaucoma and migraine.153

A few studies have linked primary open-angle glaucoma with sleep apnea.154–156 The mechanism of this is not clear but may

relate to the respiratory disturbance leading to transient nocturnal episodes of hypoxia, which may increase the propensity of the optic nerve to damage.157 However, not all studies have been able to confirm this association.158

The Rotterdam study produced an unexpected and as yet unexplained association between early menopause and glaucoma.159

Pathophysiology

A detailed discussion of POAG must address two fundamental issues:

(1) the mechanism(s) of IOP elevation, and (2) the mechanism(s) of progressive optic nerve cupping and atrophy.

Diminished aqueous humor outflow facility

It is generally accepted that the increased IOP seen in most cases of POAG is caused by a decreased facility of aqueous humor outflow. Although there have been a few reports of patients with

hypersecretion of aqueous humor, these reports were based on tonographic estimates of aqueous humor production rather than on direct measurements such as fluorophotometry. If the entity of hypersecretion exists, it must be exceedingly rare and therefore will not be discussed further here.

In enucleated normal human eyes, Grant160 demonstrated that incising the entire trabecular meshwork reduced the resistance to outflow by 75%. This finding was confirmed by Peterson and co-workers.161 From this observation, most investigators inferred that the increased resistance to outflow seen in glaucoma must also lie between the anterior chamber and the lumen of Schlemm’s canal.162 The main site of resistance to outflow is probably in juxtacanalicular tissue,163 where the greatest concentration of mucopolysaccharides and the greatest phagocytic activity reside.164 This was further confirmed by careful microcannulation and pressure measurements at various locations within the trabecular meshwork area; the resistance was found in a region 7–14 mm internal to the inner wall of Schlemm’s canal.165

It should be emphasized that not all authorities accept this hypothesis. Others have also proposed that outflow facility is reduced because the trabecular meshwork prolapses into Schlemm’s

canal, thus occluding the lumen and preventing circumferential flow of aqueous humor to the collector channels.166–169 The argu-

ment against this theory is that Schlemm’s canal only collapses at very high levels of IOP. No evidence exists to show that the canal is occluded when IOP is in the range of 25–35 mmHg,169 which is the situation in most eyes with POAG.

The decreased outflow facility in glaucoma has also been ascribed to an obstruction of the intrascleral collector channels.

This obstruction could be caused by an accumulation of glycosaminoglycans in the adjacent sclera.170–173 Krasnov has proposed

that POAG is really several different diseases with different sites of resistance.174 He believes that obstruction in the collector channels accounts for approximately 50% of the cases of POAG. This theory was partially refuted by experiments that demonstrated that unroofing Schlemm’s canal did not reduce resistance to outflow in glaucomatous eyes until the canal was entered; that is, no scleral blockage was noted.175

If the hypothesis is accepted that the trabecular meshwork or the endothelium of Schlemm’s canal is the site of the increased resistance to outflow in POAG, the question of what process interferes with normal aqueous elimination must be asked. Several theories have been proposed to explain this phenomenon, including those that follow:

1.  An obstruction of the trabecular meshwork by foreign material. Several investigators have noted the accumulation of foreign material in the trabecular meshwork and juxtacanalicular tissue, including pigment, red blood cells, glycosaminoglycans,176,177 amorphous material,178,179 extracellular lysosomes,180 plaquelike material,181–183 and protein.184 Lütjen-Drecol and Rohen have postulated that the electron-dense material consists of collagen and elastin and that these materials are responsible for the increased resistance to aqueous outflow.185 It is also possible that a normal constituent that is catabolized insufficiently or synthesized excessively obstructs the meshwork.

2.  A loss of trabecular endothelial cells. Glaucomatous eyes

have fewer endothelial cells than normal eyes, although the rate of decline in the two is similar.186,187 This suggests a premature aging

process in glaucomatous eyes.186 A loss of endothelial cells would interfere with various important trabecular functions, including

phagocytosis and synthesis and degradation of macromolecules.The lack of a complete endothelial covering could allow the trabecular beams to fuse.

3.  A reduction in pore density and size in the inner wall endothelium of Schlemm’s canal.The endothelium lining the inner

wall of Schlemm’s canal accounts for 10–20% of the total resistance.163,188 Ultramicroscopic pores can be found in the endothe-

lium of the inner wall of Schlemm’s canal, and they seem to be reduced in both size and density in open-angle glaucoma.189

4.  A loss of giant vacuoles in the inner wall endothelium of

Schlemm’s canal. Giant vacuoles may play a crucial role in moving fluid from the meshwork into the lumen of Schlemm’s canal.179,190

A reduction in the number and size of these microstructures is seen in glaucoma. Alvarado and Murphy191 found a reduction in the area of ‘cul-de-sacs’ in the juxtacanalicular tissue in glaucomatous eyes; this reduction could account for the increased resistance to outflow.

migration from the beams.192,193

6.  Disturbance of neurologic feedback mechanisms. Nerves, whose function is unknown, have been found in the trabecular meshwork.194 Nerve endings, some of which could be mechanoreceptors, have been located in the scleral spur of humans.195 It has been speculated that these nerves could function to slow down aqueous formation or speed outflow when IOP is elevated. Theoretically, some interference with this feedback mechanism could lead to unchecked elevation of IOP.

Histopathologic study of the conventional aqueous drainage system from patients with POAG reveals a number of abnormalities, including those that follow (Fig. 17-1):

 1. Alterations in the trabecular beams, including fragmentation

of collagen, increased curly and long-spacing collagen, and coiling of fiber bundles170,196

 2. Thickened basement membranes

 3. Narrowed intertrabecular spaces173,197,198

 4. Fused trabecular beams199

 5. Decreased number of trabecular endothelial cells186,199

 6. Reduced actin filaments200

 7. Accumulation of foreign material179,181

 8. Decreased number of giant vacuoles

 9. Narrowing of collector channels199

10.Closure of Schlemm’s canal199,201

11.Thickened scleral spur.

However, these histopathologic changes must be interpreted with caution. Most of the glaucoma specimens are obtained at surgery; thus artifacts are common, and it is impossible to fix the tissues at their normal IOP levels. In addition, the specimens generally come from eyes with advanced damage. Furthermore, it is difficult to know whether the changes seen are primary phenomena or secondary to the effects of increased IOP or medical and surgical treatment. Finally many of the histopathologic alterations are also seen in older, normal eyes. In fact, some researchers have proposed that the outflow changes of POAG could be an acceleration of the normal aging process.186

Fig. 17-1  Sagittal section through trabecular meshwork in openangle glaucoma (trabeculectomy specimen). Basement membranes are thickened, trabecular sheets are widened, and curly collagen has accumulated (arrows). BM, Basement membrane; EL, elastic fibers; N, nuclei ( 7500; inset 15 000).

(From Rohen JW, Witmer R: Graefes Arch Clin Ophthalmol 183:251, 1972.)

Although it is impossible to be sure of the fundamental defect of aqueous humor outflow in POAG, the balance of the evidence favors the trabecular meshwork or the endothelium of Schlemm’s canal as the site of the increased resistance. If we accept this hypothesis, we must still ask why outflow facility is reduced in POAG.Various investigators have linked the increased resistance to outflow with altered corticosteroid metabolism, dysfunctional adrenergic control, abnormal immunologic processes, and oxidative damage.

Altered corticosteroid metabolism

Soon after the early descriptions of corticosteroid-induced IOP elevations, Armaly202 and Becker and Hahn203 noted that patients with POAG were quite responsive to topical glucocorticoids.These researchers proposed that the IOP response to topical corticoster-

oids was inherited and that this inheritance was either the same as, or closely linked to, the inheritance of POAG.202,203 The corticos-

teroid hypothesis was then extended to include a generalized sensitivity to the effects of glucocorticoids in patients with POAG.