Chapter 232 – Which Therapy to Use in Glaucoma?
• The aim of glaucoma therapy is to preserve visual function with minimal side effects.
• The choice of therapy (alone or in combination) for patients who have open-angle glaucoma includes medical treatment, laser treatment, and filtering surgery.
The aim of glaucoma therapy is to preserve visual function with minimal complications. Added to this is the need to ensure that quality of life is maintained. It is essential, therefore, that each patient be assessed individually before a treatment decision is made.
Although raised intraocular pressure (IOP) appears to be the main risk factor for damage in glaucoma (hence the need for a specific target pressure in an individual eye), other factors, such as vascular and mechanical ones, are involved in the pathogenesis of glaucoma and must also be considered. Additional factors may be responsible for preservation of the optic nerve in this disease.
The primary goal of current therapy is to reduce IOP to the point where deterioration of the disc or field ceases, with a minimum of complications or side effects. It is not possible to predict accurately what level of IOP will be satisfactory for an individual patient. A wide range of suggested “normal” values has been reported. The suggestion that an IOP of 21?mmHg (2.8?kPa) or less prevents further glaucomatous damage was based on population statistics; however, some patients continue to develop progressive glaucomatous disease at IOPs below this level. Thus, this IOP value cannot be accepted as the sole criterion for either control of the disease or the boundary between health and disease.
Establishing in advance the degree to which IOP must be lowered to preserve vision is difficult in individual cases, but it is clear that lowering IOP often arrests the progression of visual loss. Recent evidence supports the value of lower IOPs in the preservation of visual function.  Individual factors that are not yet fully understood may govern the susceptibility of the optic nerve head to damage mediated by IOP.
The choice of therapy for patients who have open-angle glaucoma consists of medical treatment, laser trabeculoplasty, filtering surgery, or a combination of these. The selection of the most appropriate therapy must take into account factors that pertain to the individual patient and to each individual eye, such as age, stage of glaucoma, and other risk factors.
Topical medications to treat glaucoma were first used in the 1870s, with the discovery of physostigmine and pilocarpine. Since then, many other drugs have been added to the treatment armamentarium, including epinephrine (adrenaline) and acetazolamide, followed by ß-blockers in the 1970s. ß-Blockers became the medical therapy of choice in the majority of newly diagnosed cases of open-angle glaucoma. More recently, additional glaucoma preparations have been introduced, such as topical carbonic anhydrase inhibitors (dorzolamide, brinzolamide), prostaglandins/prostamides (latanoprost, travoprost, bimatoprost, unoprostrone), and a-adrenergic agonists (brimonidine, apraclonidine). Combination products are also available (timolol-dorzolamide, timolol-latanoprost, and timolol-pilocarpine). In the past, these were recommended as adjuvant therapy or when ß-blockers were contraindicated. Longer experience with these products is establishing their use earlier in the therapeutic course.
Argon laser trabeculoplasty (LTP) was first described by Wise and Witter in 1979. The technique has been revised and modified in an attempt to improve results and reduce complications, such as the postoperative spike in IOP. Initial short-term success was followed by less than satisfactory long-term control in many cases, with the result that this technique is not used as much as it was initially. Selective laser trabeculoplasty has been suggested as a more effective alternative, but results of long-term studies are still awaited.
Filtering surgery in the form of trabeculectomy was described by Cairns in 1968. This procedure has been improved and modified over the years to give better results and fewer complications. Recent modifications include the use of antimetabolites such as 5-fluorouracil or mitomycin.  Nonpenetrating filtering surgery, such as deep sclerectomy or viscocanalostomy, has its advocates.
Advantages and disadvantages exist with all three methods of therapy.
A wide range of topical and systemic antiglaucoma medications is available ( Box 232-1 ). Topical medications include miotics, ß-blockers, epinephrine derivatives, carbonic anhydrase inhibitors, a-agonists, and prostaglandin analogs prostamides. These may be used alone or in combination. It is impractical, however, to use more than two or three topical medications simultaneously. Both ocular and systemic side effects may occur with medications (see Chapters 233 and 234 ).
Many variables can affect the success or failure of medical treatment for glaucoma. Patient-related factors such as compliance, coincident systemic diseases, drug interactions, and side effects must be considered.
The most common side effects of drugs prescribed for glaucoma are neither life nor sight threatening. Such effects include miotic-induced brow ache, dimming of vision caused by pilocarpine, vasodilatation and the allergic reactions caused by epinephrine and dipivefrin, effects on pulmonary function that result from ß-blockers, and the acidosis syndrome induced by
Classification of Antiglaucoma Drugs
Miotics (Direct Parasympathomimetics)
• travoprost, bimatoprost, unoprostone, latanoprost
Topical Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
acetazolamide. More serious side effects include aplastic anemia after the use of carbonic anhydrase inhibitors and retinal detachment associated with miotic therapy. However, many patients are able to tolerate one or more of these medications with no side effects. Drugs used in combination may interact to produce either a beneficial effect or none.
Inadequate compliance may be the most serious limiting factor in the nonsurgical therapy of glaucoma. Factors that influence compliance include complexity of the medical regimen, side effects of the medications, and patient understanding of the disease and its treatment. 
After the initial description of the protocol for argon LTP, many other studies followed, and LTP has become a frequently performed procedure for glaucoma. It is simple to perform and cost effective (see Chapter 235 ). However, the long-term efficacy of this treatment is unclear. The subsequent IOP rise may be sudden rather than gradual, so it is important to keep these patients under continual observation.
The conventional operation used most frequently for primary open-angle glaucoma is referred to generally as a filtering procedure. Although a number of variations have been described, all filtering operations share the same basic mechanism of action and general surgical principles (see Chapter 240 ). The most
Figure 232-1 Mean intraocular pressures. Medicine versus laser versus surgery. (Moorfields Primary Treatment Trial from Migdal C, Gregory W, Hitchings R. Long term functional outcome after early surgery compared with laser and medicine in open angle glaucoma. Ophthalmology. 1994;101:1651–7.)
Figure 232-2 Time to treatment failure by treatment group. Medicine versus laser versus surgery. (Moorfields Primary Treatment Trial from Migdal C, Gregory W, Hitchings R. Long term functional outcome after early surgery compared with laser and medicine in open angle glaucoma. Ophthalmology. 1994;101:1651–7.)
frequently performed operation is the trabeculectomy. With improvements in microsurgical technique, this procedure is now relatively safe and effective. However, complications such as cataract or endophthalmitis can occur, although fortunately, they are not common. In nonpenetrating filtration surgery (deep sclerectomy), the advantages of not entering the anterior chamber must be balanced against the steep learning curve of the technique, the frequent need for adjunctive medications or laser iridotomy, and the tendency to produce IOPs that are higher than those following trabeculectomy.  
Traditionally, the initial standard therapy for primary open-angle glaucoma is medical, with LTP and surgery reserved for patients who fail medical therapy. A number of clinical studies have challenged this traditional therapeutic approach and deserve reappraisal.    
A long-term, multicenter, prospective follow-up study in Scotland compared early trabeculectomy with conventional medical therapy and found better IOP control in the early surgery group, with less visual field decay. Approximately half the patients in the conventional medical therapy group required surgical intervention sooner or later. No difference was noted between the visual acuities of the surgical and medical groups.
In the Moorfields Primary Treatment Study,  the group of patients successfully treated by trabeculectomy achieved a mean IOP of 14.5?mmHg (1.93?kPa) at 5 years, compared with 18.5?mmHg (2.46?kPa) for the patients successfully treated with
Figure 232-3 Inflammatory changes in the conjunctival tissue. Representative photomicrograph from the group of patients who received long-term eyedrop therapy. The substantia propria shows a round cell infiltrate of mainly lymphocytes.
Figure 232-4 Drainage bleb. Diffuse, avascular, well-functioning bleb from a primary trabeculectomy.
Figure 232-5 Vascularized, encysted drainage bleb with ultimate failure. From a trabeculectomy following long-term eyedrop therapy.
laser or medication ( Fig. 232-1 ). The significantly lower IOPs in the surgical patients were maintained throughout the initial 5-year follow-up period. There was a markedly higher success rate of 98% (in terms of IOP control) in the surgical group at 5 years, compared with 80% in the medical group and only 60% in the laser patients ( Fig. 232-2 ). Mean visual acuities in the three groups differed by less than one line on the Snellen chart.
With the newer glaucoma medications now available, it may be possible to achieve lower target IOPs with drugs. Polypharmacy, however, is to be avoided, and it is preferable to switch from one drug to another rather than to just add more drops. Prior topical antiglaucoma medications may influence the subsequent outcome of glaucoma filtering surgery. A comparison of conjunctival biopsies from patients who underwent primary surgery and from those who received at least two topical medications for a minimum of 1 year before surgery showed a significantly greater increase in the number of macrophages, lymphocytes, mast cells, and fibroblasts in the conjunctiva and Tenon’s capsule, and a significantly greater decrease in the number of goblet cells, in the medically treated group ( Fig. 232-3 ). These results suggest that long-term medications can induce chronic inflammatory changes in the bulbar conjunctiva (as a result of the active drug, the preservative, or both), which may enhance the risk of external bleb scarring and subsequent failure of filtering surgery.
Further evidence of better results with early filtering surgery was found when patients who underwent surgery as part of the primary treatment were compared with patients who underwent trabeculectomy after failed medical therapy ( Figs. 232-4 and 232-5 ). The only identifiable difference between the two groups was the duration of topical drops. However, the success rate in the long-term medical therapy group was only 79%, compared with 98% in the primary surgery group. Most trabeculectomy failures occurred within the first 3 months. This early failure was associated with a hypercellular response in the conjunctiva.
A number of controlled clinical trials to evaluate treatment options in open-angle glaucoma have reported their results. Each of these landmark clinical trials deals with the management of a different subgroup of glaucoma patients and has added to the scientific evidence available on which to base our clinical management. The Advanced Glaucoma Intervention Study was set up to investigate the outcome of treatment with either LTP or trabeculectomy in patients who had failed previous medical treatment. In the Early Manifest Glaucoma Trial, the combination of medicine and LTP, as opposed to no treatment, was evaluated for a cohort of patients with newly diagnosed primary open-angle glaucoma. The Collaborative Initial Glaucoma Treatment Study was set up to recruit newly diagnosed patients with primary open-angle glaucoma and randomize them to treatment with either medicine or trabeculectomy. The outcomes of these trials will continue to modify the criteria by which therapy is chosen. Trial results are based on group values, whereas many factors affect the individual outcome. It is nevertheless still essential to carefully evaluate each patient when deciding the most appropriate treatment protocol to follow for that individual.
Several conclusions can be drawn from the completed studies with regard to the current role of medicine, laser, and surgery in the management of primary open-angle glaucoma. There is now a tendency to aim for lower target pressures, particularly in those patients with extensive optic nerve damage or other risk factors.
Medical therapy still has a definite place in the management of primary open-angle glaucoma and results in satisfactory IOP control in a good percentage of cases. The wider choice of different eyedrops makes it even more important to select the most appropriate therapy for the individual patient. However, multiple therapy (in the form of more than two topical medications) or a systemic carbonic anhydrase inhibitor is rarely indicated.
LTP appears to be effective for the short-term control of IOP, but there is concern about the long-term efficacy of this treatment. It may be indicated in certain patients, such as elderly patients who are unfit for surgery or those who do not use eyedrops. However, these patients require continual monitoring,
Guidelines for Therapy in the Individual Patient
ASSESS RISK FACTORS
Stage of disease
Other risk factors
ESTIMATE A TARGET PRESSURE
Achieves satisfactory intraocular pressure (IOP) control in many cases
No more than two topical medications
Maximal medical therapy no longer indicated
If problems with inadequate IOP, side effects, or compliance, consider alternative therapy
Elderly who cannot tolerate medical therapy
Patients who are controlled inadequately and cannot/will not undergo surgery
If low IOP required or target IOP not reached with other treatments
Borderline control with medicine or laser
Failed therapy with medicine or laser
Consider earlier surgery where appropriate, not only as a last resort!
because IOP control may suddenly be lost, with a resultant acute rise in pressure.
Performed early, filtering surgery gives excellent IOP control with minimal complications. Early surgery is still a useful option if the IOP is not controlled by simple medical therapy, if a low target pressure is required and cannot be achieved with medical therapy, or if compliance is a problem. Guidelines for therapy in individual patients are given in Box 232-2 .
1. Odberg T, Jacobsen JE, Hulkgren SJ, Halseide R. The impact of glaucoma on the quality of life of patients in Norway. 1. Results from a self-administrated questionnaire. Acta Ophthalmol Scand. 2001;79:116–20.
2. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Edward Jackson Memorial Lecture. Am J Ophthalmol. 1989;108:485–95.
3. Schumer RA, Podos SM. The nerve of glaucoma! Arch Ophthalmol. 1994;112: 37–44.
4. Grant WM, Burke JF Jr. Why do some people go blind from glaucoma? Ophthalmology. 1982;89:991–8.
5. AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS) 7: the relationship between control of IOP and visual field deterioration. Am J Ophthalmol 2000;130:429–40.
6. Wise JB, Witter SL. Argon laser therapy for open angle glaucoma. Arch Ophthalmol. 1979;97:319–22.
7. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study: 7. Results. Am J Ophthalmol. 1995;120: 718–31.
8. Cairns JE. Trabeculectomy. Preliminary report of a new method. Am J Ophthalmol. 1968;5:673–9.
9. Fluorouracil Filtering Surgery Study Group. 5-Year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol. 1996;121:349–66.
10. Khaw PT, Migdal CS. Current techniques in wound healing modulation in glaucoma surgery. Curr Opin Ophthalmol. 1996;7:24–33.
11. Kass MA, Gordon M, Morley RE Jr, et al. Compliance with topical timolol treatment. Am J Ophthalmol. 1987;103:188–93.
12. Kass MA, Meltzer DW, Gordon M, et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol. 1986;101:515–23.
13. Chiselita D. Non-penetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma. Eye. 2001;15:197–201.
14. Jonescu-Cuypers CP, Jacobi PC, Konen W, Krieglstein GK. Primary viscocanalostomy versus trabeculectomy in white patients with open-angle glaucoma: a randomized clinical trial. Ophthalmology. 2001;108:254–8.
15. Jay JL, Allan D. The benefit of early trabeculectomy versus conventional management in primary open angle glaucoma relative to the severity of the disease. Eye. 1989;3:528–35.
16. Migdal C, Hitchings R. Control of chronic simple glaucoma with primary medical, surgical and laser treatment. Trans Ophthalmol Soc UK. 1986;105:653–6.
17. Migdal C, Gregory W, Hitchings R. Long term functional outcome after early surgery compared with laser and medicine in open angle glaucoma. Ophthalmology. 1994;101:1651–7.
18. Sherwood M, Grierson I, Millar L, et al. Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon’s capsule in glaucomatous patients. Ophthalmology. 1989;96:327–35.
19. Lavin MJ, Wormald RPL, Migdal CS, Hitchings RA. The influence of prior medical therapy on the success of trabeculectomy. Arch Ophthalmol. 1990;108:1543–8.
20. Wilson MR, Gaasterland D. Translating research into practice: controlled clinical trials and their influence on glaucoma management. J Glaucoma. 1996;121: 139–46.
21. Migdal C, Hitchings R. The role of early surgery for open angle glaucoma. In: Caprioli J, ed. Contemporary issues in glaucoma. Ophthalmol Clin North Am. 1991;4:853–9.
22. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–79.
23. Lichtre PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943–53.