Having a basic understanding of the physiology of the eye is helpful to understanding the pathophysiology, diagnosis, and management of glaucoma. Many clinicians and scientists now believe that several factors are involved in the pathogenesis of glaucoma, such as apoptosis, altered blood flow to the optic nerve, and possible autoimmune reactions. However, intraocular pressure (IOP) remains one of the most important risk factors for the disease syndromes. In addition, lowering of the IOP is the only rigorously proven treatment for glaucoma. Although we have some understanding of the physiology of IOP, we do not yet fully understand how the eye regulates IOP at the cellular and molecular levels. However, fundamental research continues to further our understanding of the molecular mechanisms. Someday, we may have the answer to what many patients have asked—what exactly causes glaucoma? As we identify the normal molecular processes, we can elucidate the pathophysiologic mechanisms to directly intervene and disrupt the dysregulation—otherwise known as “disease-modifying” therapy.

Aqueous is formed in the ciliary processes (pars plicata region of the retina) (Fig. 2-1A-D). The epithelial cells of the inner nonpigmented layer are felt to be the site of aqueous production (Fig. 2-2A and B). Aqueous is produced by a combination of active secretion, ultrafiltration, and diffusion. Many of the IOP-lowering agents work by decreasing aqueous secretion in the ciliary body.

Aqueous then flows through the pupil and into the anterior chamber, nourishing the lens, cornea, and iris (Fig. 2-3). Aqueous drains through the anterior chamber angle, which contains the trabecular meshwork (TM) and ciliary body face (Fig. 2-4A and B).

Between 60% and 90% of aqueous outflow is through the TM—the so-called conventional pathway—with the remaining 10% to 40% through the ciliary body face—the so-called uveoscleral or alternative pathway. The TM is thought to be the region where regulation of aqueous humor outflow takes place. Within the TM, especially under conditions of elevated
IOP, the juxtacanalicular area appears to have the highest resistance to outflow (Fig. 2-5).

IOP is physiologically determined by the rate of aqueous production in the ciliary body, resistance to outflow through the conventional outflow tract (TM and Schlemm canal [SC]), resistance to outflow through the unconventional outflow tract (uveoscleral outflow), and episcleral venous pressure. In the Goldmann equation [IOP = (F/C) + P_v], P_v is the episcleral venous pressure, F is the rate of aqueous formation, and C is the facility of outflow, which roughly corresponds to the inverse of the total resistance to outflow. As one can imagine, elevations of episcleral venous pressure can result in an elevated IOP (Fig. 2-6).

With open-angle glaucomas, the pathophysiology is increased aqueous drainage resistance through the TM. With primary open-angle glaucoma (POAG), there is an alteration of juxtacanalicular extracellular matrix homeostasis, TM and SC endothelial cell cytoskeleton causing cellular stiffness, and TM cellularity. With POAG, the aqueous humor has an elevated level of transforming growth factor beta-2. Certain proteins or their functions—such as myocilin, gremlin, secreted frizzled-related protein (sFRP) (aka frizzled protein), cochlin, secreted protein acidic and rich in cysteine (SPARC) (aka osteonectin), and serum amyloid A—have been shown to be important to the IOP elevation in POAG. Selectin E may be a unique marker for POAG. With pseudoexfoliation glaucoma, the pseudoexfoliative material accumulates in the juxtacanalicular extracellular matrix increasing outflow resistance; there is also an elevation of transforming growth factor beta-1 in the aqueous humor of patients with pseudoexfoliation glaucoma. With pigment dispersion glaucoma, the ingested debris from the pigmented iris epithelial cells causes TM endothelial cell death, and the denuded TM beams fuse to increase the outflow resistance. With steroid-induced glaucoma, there is an alteration of extracellular matrix within the juxtacanalicular region, but distinct in electron microscopic features and components than POAG, as well as alterations to TM and SC cell cytoskeleton that causes an elevation of outflow resistance.

As discussed earlier, the basis of IOP can be described by the Goldmann equation. Because most research suggests that the amount of uveoscleral outflow is relatively insensitive to changes in pressure,¹ the Goldmann equation can be modified as: IOP = (F – U)/C + P_v, where P_v represents the episcleral venous pressure, F is the rate of aqueous formation, U is the rate of aqueous outflow through the pressure-insensitive uveoscleral pathway, and C is the outflow facility. Each of these parameters can be measured except U, which must be calculated from IOP and the remaining variables.

Outflow facility is measured clinically using tonography. The concept of tonography involves placing a weighted tonometer on the surface of the eye, causing an elevation in IOP, and measuring the rate at which IOP returns to its baseline value over a fixed time interval (usually 2 or 4 minutes).² Different devices can be used for tonography measurements, including weighted pneumatonometers or electronic Schiotz tonometers. These devices share the characteristic of being able to record IOP continuously over the measurement interval, either on a paper chart or electronically (Fig. 2-7). Regardless of the device, all share the same limitations including the assumption that aqueous humor production rate, episcleral venous pressure, and outflow facility are constant during the measurement interval.³ In normal individuals, outflow facility is typically between 0.23 and 0.33 µL/min/mm Hg.⁴