Supplements Managed Care Issues in Glaucoma: Emerging Trends and Treatment
Disease Progression and the Need for Neuroprotection in Glaucoma Management
Glaucoma, the second leading cause of worldwide blindness, is a progressive optic neuropathy characterized by a loss of retinal ganglion cells and their axons beyond typical age-related baseline loss. Diagnosis is defined by optic disc and visual field changes, and the primary goal of glaucoma treatment is to preserve vision. Proven existing therapies (ie, pharmacotherapy, laser, and surgical) focus on reduction of intraocular pressure (IOP), although elevated IOP is no longer a diagnostic feature of glaucoma. New neuroprotectant drugs are being investigated, with the goal of reducing retinal ganglion cell loss, either prophylactically or after the insult has occurred. Various treatment strategies are being evaluated, and include a neuroprotectant only, or a complete therapy approach comprised of both a neuroprotectant supplemented by an IOP-lowering therapy. Dually targeted complete therapy may directly preserve the optic nerve, decrease the risk factors that cause glaucoma damage, and reduce glaucoma-related morbidities. Neuroprotectant therapy outcomes should include functional and structural effects of disease progression and neuroprotectant therapies, as well as patient functioning and economic impact.
(Am J Manag Care. 2008;14:S15-S19)Glaucoma is a multifactorial, progressive optic neuropathy with a characteristic loss of retinal ganglion cells (RGCs) beyond typical age-related baseline loss and the second leading cause of blindness in the world.1 Prevalence models estimate that 8.4 million individuals will suffer from glaucoma-induced bilateral blindness in 2010, rising to 11.1 million in 2020.2 In the United States, blindness from glaucoma has been estimated to cost $1.5 billion annually in benefits, lost tax revenues, and health expenses.3 Glaucoma-related vision loss, particularly in field of vision, is asymptomatic in the early stages and irreversible.4 As a result, a significant proportion of patients are undiagnosed; thus, economic and clinical scopes are larger than the numbers suggest.5 Population-based screening is not recommended,6 and although there are no known ways to prevent glaucoma, early detection in high-risk individuals and treatment help prevent progression and vision loss.6,7
Elevated intraocular pressure (IOP) is an important risk factor for glaucoma that has remained a clinical focus for several reasons, including ease of measurement, the number of available IOP-reducing therapies, and the relationship of elevated IOP to disease progression.8 However, the relationship between IOP reduction and glaucoma damage is less clear,9-11 and such ambiguities suggest that factors other than IOP may be responsible for some of the long-term damage from glaucoma. Further complicating the issue is the current debate over which measurement of IOP (diurnal, peak, visit-to-visit) is the most significant contributor to disease progression and subsequent vision loss.12-14 In particular, central corneal thickness has also been shown to be associated with disease progression in open-angle glaucoma,15 which accounts for 90% of glaucoma cases.16
Glaucoma is no longer diagnosed by elevated IOP levels,7,17 and it is now recognized as a neuropathy defined by characteristic optic disc and visual field change.18 The absence of reliance on IOP level as a diagnostic criterion has occurred because 20% to 30% of glaucoma patients have IOP in the normal range (typically 10-21 mm hg).19,20 Furthermore, the annual progression rate is 9% to 10% even in patients treated with IOP-lowering medical, laser, or surgical therapy.21-27 The Early Manifest Glaucoma Trial28,29 found that although the mean IOP during follow-up was significantly associated with the risk of progression, this risk was highly variable, and several other baseline factors were significant independent predictors whose combined effect might be as important as IOP. These additional independent predictors included presence of bilateral disease, worse mean deviation, degree of baseline exfoliation, age older than 68 years, presence of frequent disc hemorrhages, and duration between follow-up visits.28-30 The Ocular Hypertension Treatment Study found a relationship between IOP reduction and glaucoma incidence10; however, progression was not confirmed in 85% of cases.31 The Collaborative Normal-Tension Glaucoma Study found that visual field progression could occur in both treated and untreated normal tension glaucoma patients, and no study analyses detected a relationship between a change in the IOP and visual field progression.32,33 This clinical evidence of continued disease progression despite IOP management has provided the basis for proposed alternative risk factors and treatment approaches that could modify the clinical course of glaucoma.
The primary goal of glaucoma treatment is to preserve vision.7 However, because current knowledge of the factors causing optic nerve damage and visual loss is limited, the predominant focus of therapy is to reduce IOP while maintaining patient quality of life.7,17 Currently, IOP-lowering therapies (ie, pharmacotherapy, laser, or surgical) are the only proven treatment available. Recent advances in topical medications that more effectively control IOP have diminished the need for surgical intervention.34 Despite these improvements, multiple medications are often needed to control the disease,34 and disease progression continues to occur. A multidrug approach may be useful, which includes agents targeted toward lowering IOP as well as an agent directed at preserving and protecting the optic nerve from glaucomatous damage.
Glaucoma: A Neurodegenerative Disease
Neurodegenerative diseases include a variety of heterogeneous disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and glaucoma.35 All neurodegenerative diseases are characterized by excitotoxic cell death, which contributes to neuronal cell injury and death. Excitotoxicity is caused, in part, by overstimulation of N-methyl-D-aspartate–type glutamate receptors and excessive calcium ion influx, which cause free radical formation.35 Most neurons and glial cells contain high concentrations of glutamate, the major excitatory neurotransmitter in the brain, and glutamate- mediated synaptic transmission is critical for normal functioning of the nervous system. If neurons or glial cells are injured and unable to properly control regulation or clearance of glutamate, secondary damage can result, even if the primary cause of the disease is not related to glutamate. Injured neurons are more vulnerable to even normal levels of glutamate, and become overstimulated and die.35
Glaucoma is the most common optic neuropathy. For more than 60 years, it has been known that excitotoxicity occurs in RGCs.35 The disease is characterized by a progressive decrease in the numbers of RGCs and their axons when nerve fibers, at the point where the optic nerve exits the eye, become pinched and die. This condition leads to thinning of the neural rim and progressive enlargement of the optic nerve cup.35,36 After loss of more than 40% of the nerve fibers, patients may notice a gradual loss of peripheral vision, or “tunnel vision.”7,16,37,38 This vision loss is permanent.7
Therapies directed at neuronal loss, either prophylactically or after the insult has occurred, are currently being investigated.39 The target is RGC loss, not the elevated IOP that indirectly causes the death of the RGC.34 By strict definition, a neuroprotectant is directed at the neuron itself.39
There are many treatment strategies being evaluated. One includes a neuroprotectant only, whereas a complete therapy management approach includes a neuroprotective agent supplemented by an IOP-lowering therapy. This dually targeted therapy would provide several potential benefits, including direct preservation of the optic nerve, decreasing one of the most important factors that cause glaucoma damage, and potentially reducing the significant economic40,41 and quality-of-life42,43 consequences associated with disease progression.
Developments in Assessing Neuroprotection Outcomes in Glaucoma
Glaucoma is a slowly progressing, long-term disease. Because of a significant amount of redundancy in the retina, particularly in the ganglion cell layer, a substantial dysfunction or loss in RGCs is required to clinically detect reduced retinal sensitivity.34 Glaucoma progression is currently measured by event-based progression at predefined end points, but these are limited by the fact that most patients do not reach an efficacy end point.44 Ratebased progression defined glaucoma progression as a function of parameter-based change over time and, today, is not widely used.44 Visual field (a functional end point) testing is limited by the variability in results,5 but multiple tests are used to reduce the variability and increase specificity.44 Tests such as the Short Wavelength Automated Perimetry and Frequency Doubling Technology (FDT) are available that detect abnormalities in the visual field in patients with early or mild glaucomatous damage but who have normal results on Standard Automated Perimetry.34,45-47 The FDT may also be used as a potential screening test for early-stage glaucoma by selectively targeting the function of magnocellular ganglion cells.34,47
Neuroprotection therapy is fundamentally linked to neuronal death; therefore, outcomes should also assess this end point.39,48,49 Some evaluations aim to detect ganglion cell damage at an early stage using quantitative morphologic evaluation of RGC layers,48 nerve fiber layer and focal thickness, size of the neuroretinal rim, and number of ganglion cells or axons.5,39
It is also important to assess patient-reported functional outcomes as they relate to therapies for neuroprotection, including health-related quality of life (HRQOL) using vision-specific, glaucoma-specific, and generic instruments. Numerous evaluations have demonstrated that HRQOL is reduced in glaucoma as a result of visual impairment and its relationship to patient functioning.42,50,51 Furthermore, HRQOL instruments should assess patient-reported metrics as they relate to peripheral and color vision loss, which can be used in concert with objective measures of this outcome, as well as other parameters of disease impact from glaucoma and visual loss, including psychological and social well-being.50 It is important that these self-assessment instruments have adequate sensitivity and specificity to detect the differences between therapeutic modalities as well as changes in disease progression over time.
Economic outcomes, including cost-effectiveness analysis of interventions,52 are important assessments for future investigative therapies directed at neuroprotection,53 and managed care organizations will need to understand the potential costs and benefits associated with these glaucoma treatment paradigm changes. Prior research has demonstrated that more severe or progressive glaucoma has been associated with increased medical costs, as well as increased risk of depression, injury, and hospital or ancillary unit admissions.40,41,43,54-60 Althin et al suggests that economic evaluations of glaucoma should include outcomes that are relevant and meaningful for current clinical practice, address the diversity of treatment options and practices, incorporate therapy discontinuation, and consider the variability in patient response.53 As such, research on neuroprotectants should consider these objectives and ensure that end points are relevant for managed care decision- makers, providers, and patients.
The treatment of glaucoma is no longer restricted to managing vision loss related to elevated IOP. The focus has shifted to reducing disease progression and loss of visual function that result from neurodegeneration. Alternative strategies that include neuroprotectants may be useful in preventing optic nerve damage, thereby improving the structural, functional, and other patient-reported outcomes as well as reducing the economic impact of glaucoma.
Acknowledgment: Laurie Kozbelt assisted in the preparation of this manuscript.
Author Affiliations: From University of Southern California, Los Angeles, CA; Xcenda, Palm Harbor, FL; Allergan, Inc, Irvine, CA.
Funding Source: The research and manuscript were funded by Allergan, Inc.
Author Disclosures: The author (RV) received an honorarium from Allergan, Inc; the author (PP) received compensation from Xcenda, which is a consultant to Allergan, Inc; the author (JGW) is employed by Allergan, Inc; author (TJB) is employed by Xcenda.
Authorship Information: Concept and design (RV, PP, JGW, TJB); acquisition of data (RV, PP, JGW); analysis and interpretation of data (RV, PP, JGW, TJB); drafting of the manuscript (RV, PP, TJB); critical revision of the manuscript for important intellectual content (RV, JGW, TJB); and supervision (TJB).
Address Correspondence to: Rohit Varma, MD, 1450 San Pablo St, Room 4900, Los Angeles, CA 90033. E-mail: firstname.lastname@example.org.
1. Quigley HA. New paradigms in the mechanisms and management of glaucoma. Eye. 2005;19:1241-1248.
2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262-267.
3. Distelhorst JS, Hughes GM. Open-angle glaucoma. Am Fam Physician. 2003;67:1937-1944.
4. Weston BC, Aliabadi Z, White GL. Glaucoma—review for the vigilant clinician. Clin Rev. 2000;10:59-74.
5. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363:1711-1720.
6. Hatt S, Wormald R, Burr J. Screening for prevention of optic nerve damage due to chronic open-angle glaucoma. Cochrane Database Syst Rev. 2006;4:CD006129.
7. American Academy of Ophthalmology, Glaucoma Panel. Primary open-angle glaucoma. Preferred practice pattern. San Francisco, CA: American Academy of Ophthalmology; 2000:1-36.
8. American Academy of Ophthalmology. Primary openangle glaucoma suspect preferred practice pattern; 2005. www.aao.org/education/library/ppp/poags_new.cfm. Accessed September 28, 2006.
9. Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated glaucoma suspects. Ophthalmology. 1991;98:301-307.
10. Kass MA, Heur DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
11. Epstein DL, Krug JH Jr, Hertzmark E, Remis LL, Edelstein DJ. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology. 1989;96:1460-1467.
12. Palmberg P. What is it about pressure that really matters in glaucoma? Ophthalmology. 2007;114:203-204.
13. Bengtsson B, Leske MC, Hyman L, Heijl A; Early Manifest Glaucoma Trial Group. Fluctuation of intraocular pressure and glaucoma progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114:205-209.
14. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111:1627-1635.
15. Gordon MO, Beiser JA, Brandt JD, et al.T he Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-720; discussion 829-830.
16. Riordan-Eva P,Vaughan DG. Eye. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 40th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2001:185-216.
17. Sponsel WE. Glaucoma. In: Conn HF, Rakel RE, eds. Conn’s Current Therapy 2001: Latest Approved Methods of Treatment for the Practicing Physician. Philadelphia, PA: Saunders; 2001:976-979.
18. Walland MJ, Carassa RG, Goldberg I, et al. Failure of medical therapy despite normal intraocular pressure. Clin Exp Ophthalmol. 2006;34:827-836.
19. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109: 1090-1095.
20. Friedman DS, Nordstrom B, Mozaffari E, Quigley HA. Glaucoma management among individuals enrolled in a single comprehensive insurance plan. Ophthalmology. 2005;112:1500-1504.
21. Katz J, Gilbert D, Quigley HA, Sommer A. Estimating progression of visual field loss in glaucoma. Ophthalmology. 1997;104:1017-1025.
22. Airaksinen PJ, Tuulonen A, Alanko HI. Rate and pattern of neuroretinal rim area decrease in ocular hypertension and glaucoma. Arch Ophthalmol. 1992;110:206-210.
23. Zeyen TG, Caprioli J. Progression of disc and field damage in early glaucoma. Arch Ophthalmol. 1993;111:62-65.
24. Smith SD, Katz J, Quigley HA. Analysis of progressive change in automated visual fields in glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1419-1428.
25. Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma. Ophthalmology. 1994;101:1651-1657.
26. Gliklich RE, Steinmann WC, Spaeth GL. Visual field change in low-tension glaucoma over a five-year follow up. Ophthalmology. 1989;96:316-320.
27. Eendebak GR, Boen-Tan TN, Bezemer PD. Long-term follow-up of laser trabeculoplasty. Doc Ophthalmol. 1990;75:203-214.
28. 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;120:1268-1279.
29. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121:48-56.
30. Leske MC, Heijl A, Hyman L, Bengtsson B, Komaroff E. Factors for progression and glaucoma treatment: the Early Manifest Glaucoma Trial. Curr Opin Ophthalmol. 2004;15:102-106.
31. Greenfield DS, Bagga H. Clinical variables associated with glaucomatous injury in eyes with large optic disc cupping. Ophthalmic Surg Lasers Imaging. 2005;36:401-409.
32. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126:487-497.
33. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126:498-505.
34. Tsai JC, Kanner EM. Current and emerging medical therapies for glaucoma. Expert Opin Emerging Drugs. 2005;10:109-118.
35. Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx. 2004;1:101-110.
36. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5:160-170.
37. Grierson I. The patient with primary open-angle glaucoma. Practitioner. 2000;244:654-658.
38. Horton JC. Disorders of the Eye. Chapter 25. In: Harrison TR, Braunwald E, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004:163-176.
39. Levin LA. Neuroprotection and regeneration in glaucoma. Ophthalmol Clin North Am. 2005;18:585-596.
40. Gieser DK,Tracy Williams R, O’Connell W, et al. Costs and utilization of end-stage glaucoma patients receiving visual rehabilitation care: a US multisite retrospective study. J Glaucoma. 2006;15:419-425.
41. Javitt JC, Zhou Z, Willke RJ. Association between vision loss and higher medical care costs in Medicare beneficiaries: costs are greater for those with progressive vision loss. Ophthalmology. 2007;114:238-245.
42. Ringsdorf L, McGwin G Jr, Owsley C. Visual field defects and vision-specific health-related quality of life in African Americans and whites with glaucoma. J Glaucoma. 2006;15:414-418.
43. Haymes SH, LeBlanc RP, Nicolela MT, Chiasson LA, Chauhan BC. Risk of falls and motor vehicle collisions in glaucoma. Invest Ophthalmol Vis Sci. 2007;48:1149-1155.
44. Greenfield DS, Liebmann JM, Ritch R, Krupin T; Low- Pressure Glaucoma Study Group. Visual field and intraocular pressure asymmetry in the low-pressure glaucoma treatment study. Ophthalmology. 2007;114:460-465.
45. Hood DC,Thienprasiddhi P, Greenstein VC, et al. Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci. 2004;45:492-498.
46. Yudcovitch L. Use of Short Wavelength and Frequency Doubling Perimetry for Glaucoma Diagnosis and Management. Pacific University College of Optometry Continuing Education, COPE #13902-GL Expires: 08-01-2008. http://opt.pacificu.edu/ce/catalog/13902-GL/FieldTest.html#INTRODUCTION. Accessed April 23, 2007.
47. Delgado MF, Nguyen NT, Cox TA, et al. Automated perimetry: a report by the American Academy of Ophthalmology. Ophthalmology. 2002;109:2362-2374.
48. Ritch R. Complementary therapy for the treatment of glaucoma: a perspective. Ophthalmol Clin North Am. 2005;18:597-609.
49. Greenfield DS. Measuring Neuroprotection in Glaucoma Clinical Trials. Chapter 8. In: Glaucoma Neuroprotection Monograph.Weinreb RW, ed. Philadelphia, PA: Wolters Kluwer Health; 2004.
50. Tripop S, Pratheepawanit N, Asawaphureekorn S, Anutangkoon W, Inthayung S. Health related quality of life instruments for glaucoma: a comprehensive review. J Med Assoc Thai. 2005;88(suppl 9):S155-S162.
51. Janz NK, Wren PA, Lichter PR, Musch DC, Gillespie BW, Guire KE. Quality of life in newly diagnosed glaucoma patients: the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2001;108:887-897.
52. Noecker RJ, Walt JG. Cost-effectiveness of monotherapy treatment of glaucoma and ocular hypertension with the lipid class of medications. Am J Ophthalmol. 2006;141(suppl 1):S15-S21.
53. Althin R, Grima DT, Dhawan R, Bernard LM. Considerations in developing model-based economic evaluations of glaucoma treatment. J Glaucoma. 2006;15:541-547.
54. Lee PP, Levin LA, Walt JG, et al. Cost of patients with primary open-angle glaucoma: a retrospective study of commercial insurance claims data. Ophthalmology. 2007;114:1241-1247.
55. Lee PP,Walt JG, Doyle JJ, Kotak SV, et al. A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol. 2006;124:12-19.
56. Hitzl W, Ortner C, Hornykewycz K, Grabner G, Reitsamer HA. Resource use and costs for a glaucoma screening program in Austria: an 8-year review: a cost-consequence analysis based on the Salzburg- Moorfields Collaborative Glaucoma Study. Eur J Ophthalmol. 2006;16:92-99.
57. Kobelt G, Jonsson L, Gerdtham U, Krieglstein GK. Direct costs of glaucoma management following initiation of medical therapy. A simulation model based on an observational study of glaucoma treatment in Germany. Graefes Arch Clin Exp Ophthalmol. 1998;236:811-821.
58. Denis P, Lafuma A, Berdeaux G. Medical predictive factors of glaucoma treatment costs. J Glaucoma. 2004;13:283-290.
59. Oostenbrink JB, Rutten-van Molken MP, Sluyter-Opdenoordt TS. Resource use and costs of patients with glaucoma or ocular hypertension: a one-year study based on retrospective chart review in the Netherlands. J Glaucoma. 2001;10:184-191.
60. Chou SL, Misajon R, Gallo J, Keeffe JE. Measurement of indirect costs for people with vision impairment. Clin Exp Ophthalmol. 2003;31:336-340.