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Pharmaceutical, Laser and Surgical Treatments for Glaucoma: An Update

Lorne Yudcovitch, OD, MS, FAAO

 

Contents

Introduction

Glaucoma is one of the leading causes of blindness in the developed world. Recent advances in examination techniques and instrumentation, e.g., pachymetry, selective automated perimetry and scanning laser ophthalmoscopy, have resulted in earlier diagnoses and more effective monitoring of progression for this group of diseases.

Current research and clinical findings obtained over the last decade have also greatly expanded the therapeutic armamentarium that care providers can use for the management of glaucoma. Never before has there been such a wide range of treatments for this disease.

This course is designed to provide the reader with a summary of landmark studies, clinical management flowcharts, and a review of glaucoma treatment modalities.

Clinical Trials

 

Many large-scale prospective, randomized clinical trials designed to assess the efficacy of glaucoma treatment have been conducted over the last several years. These studies have focused on the role of lowering intraocular pressure (IOP) in the prevention of glaucomatous field loss and optic nerve damage. A summary of these studies is presented in Table 1.

Table 1. Summary of Clinical Trials

Study Description Summary
Collaborative Normal Tension Glaucoma Study (NTGS) Compared topical drug and/or surgical treatment to no treatment for normal-tension glaucoma patients Over 10 years, it was found that a 30% IOP reduction cut glaucoma progression by 50%
Advanced Glaucoma Intervention Study (AGIS) Compared effect of trabecular surgery type on black and white glaucoma patients After 10 years, IOP was lower for both racial groups (but the best surgery type was race-specific)
Collaborative Initial Glaucoma Treatment Study (CIGTS) Compared trabecular surgery first versus topical drug treatment first for glaucoma patients Both groups had equal IOP reductions after 5 years
Ocular Hypertensive Treatment Study (OHTS) Compared topical drug treatment versus no treatment for ocular hypertensives Treatment reduced progression to glaucoma by over 50%
Early Manifest Glaucoma Trial (EMGT) Compared effects of Argon Laser Trabeculoplasty (ALT) plus betaxolol treatment versus no treatment over an average period of 6 years Argon Laser Trabeculoplasty plus betaxolol reduced progression of glaucoma by 50% more than progression without treatment

The studies cited in Table 1 demonstrate that lowering IOP can reduce the rate of glaucomatous field and optic nerve change. The studies also suggest that to reduce the damage caused by open angle glaucoma, clinicians should strive to lower IOP by the following percentages for patients with the diagnoses specified. (Table 2.)

Table 2. Target IOP Reductions Required to Reduce the Rate of Open Angle Glaucoma-Related Damage

Diagnosis Target IOP Reduction
Ocular hypertensive patients who have risk factors such as ethnicity, vascular compromise, etc. 20%
Early glaucoma patients who have been identified by field loss 30%
Patients with moderate to severe glaucoma as identified by field loss and optic nerve head appearance 40 to 50%

However, the reduction percentages in Table 2 do not take into account individual variability in optic nerve structural damage and functional loss from glaucoma. As such, target pressures or target pressure reductions for individual patients may deviate from these general IOP reduction percentages. Doctors must take into account all risk factors and examination information before determining the amount of IOP reduction desired.

Treatment Algorithm

Current treatments for glaucoma can be divided into three main modalities:

Based on these three treatment modalities, Figure 1 shows a basic flow chart for glaucoma patient treatment decision-making. It should be noted that this decision-making flow chart is based on a North American treatment perspective with pharmaceutical treatment provided first and surgical treatment provided only when pharmaceutical treatment is no longer effective. The European treatment perspective typically involves providing surgical and/or laser treatment first and then adding pharmaceutical treatment later if warranted.

IOP = Intra-Ocular Pressure, VF = Visual Field, ONH = Optic Nerve Head, ALT = Argon Laser Trabeculoplasty, SLT = Selective Laser Trabeculoplasty. Modified from American Optometric Association (AOA)/American Academy of Ophthalmology (AAO) Practice Guidelines (1996)/Preferred Practice Patterns (2002).

*AOA and AAO recommend more frequent visits (e.g., 2 days, 1 week, 1 month, 2 months) if inadequate IOP control, treatment side-effects, or rapid progression is noted. Initiating treatment would also require more frequent visits to assess efficacy.

Figure 1. Basic decision-making algorithm for glaucoma management.

It goes without saying that definitively diagnosed glaucoma should be treated. However, increasing evidence shows that ocular hypertension in one or both eyes should also be considered as an indication for treatment. Risk factors, such as age, family history of glaucoma, ethnicity, and vascular disease should be included in the treatment decision-making process. The care provider must weigh the benefits of treatment against short and long-term safety, efficacy, expense, and lifestyle change issues that can directly or indirectly affect the patient.

Physiology of Aqueous Production and Outflow

To understand the mechanisms by which pharmaceutical, laser, and surgical treatments reduce glaucoma progression, it is necessary to review the structural and functional elements of the eye that are associated with glaucomatous damage.

Intraocular pressure is maintained by three main elements:

Figure 2 shows the basic structures involved in aqueous production and outflow.

Figure 2. Basic anterior chamber structures involved in aqueous production, movement, and outflow. Top: normal aqueous flow from the ciliary body to the trabecular meshwork and Schlemm’s canal. Bottom: normal aqueous uveoscleral outflow from the ciliary body to other ocular tissues. (Figure from http://www.xalatan.com/hcp/image_library/anatomy_and_physiology/G_013_28_glaucoma_conventional_aqueous_outflow.asp)

The ciliary body secretes aqueous fluid primarily from the non-pigmented ciliary epithelium. This active secretion utilizes the enzyme carbonic anhydrase and provides about 80% of the aqueous production. The other 20% occurs by passive secretion via ultra-filtration and diffusion from the ciliary body. Figure 3 presents a schematic diagram of the tissues in this region.

Figure 3. Non-pigmented ciliary body histological section showing the ciliary processes and ciliary muscle. The darkly-stained layer of cells along the edge of the ciliary processes is the non-pigmented ciliary epithelium where the action of enzyme carbonic anhydrase produces aqueous. (Figure from http://www.xalatan.com/hcp/image_library/glaucoma/G_068_49_glaucoma_carbonic_anhydrase_inhibitors_cais_.asp)

Eighty to 90% of aqueous outflow occurs primarily through the trabecular meshwork in the anterior chamber of the eye. Aqueous enters the trabecular meshwork after flowing through the pupil from the posterior chamber. The cellular matrix of the trabecular meshwork facilitates aqueous outflow via metabolic phagocytosis.

As a side-note, it is thought that steroids (topical or oral) can interfere with metabolic function of the trabecular meshwork cells thus producing decreased aqueous outflow and subsequent elevation of IOP. Patients who demonstrate this side-effect are termed steroid responders and may be at higher risk for developing glaucoma than are non-responders. Approximately 15% of the population can potentially develop elevated IOP from steroid use.

From the trabecular meshwork, aqueous flows from Schlemm’s canal to collector channels and venous plexi. It then exits from the eye through the episcleral veins. Episcleral venous pressure level can affect the outflow with higher venous pressure reducing the outflow. Figure 4 shows a schematic of the trabecular meshwork and venous collector channels.

Figure 4. Schematic anatomical cross-section of the trabecular meshwork (pink cross-bridges) and venous collector channels (blue) involved in aqueous outflow. (Image from http://www.xalatan.com/hcp/image_library/anatomy_and_physiology/G_013_26_glaucoma_trabecular_meshwork.asp)

An additional 10 to 20% of the eye's aqueous exits via the through uveoscleral pathway. Following this pathway, aqueous enters tissues in the anterior chamber angle and passes through the ciliary muscle into the supraciliary and suprachoroidal spaces. It then exits the eye via the sclera.