What is the gold standard in glaucoma diagnosis?
Patricia M. Khu, MD, MS
Currently, the diagnosis of glaucoma is based on definitive changes in the optic-nerve head (ONH)
and/or repeatable changes in the visual field tested by standard achromatic perimetr y (SAP). Elevated
intraocular pressure (IOP) defined as IOP greater than 21mm Hg was part of the definition of glaucoma more
than 10 years ago. But several studies have shown that many patients with ocular hypertension demonstrated no signs of glaucomatous damage during follow-up periods of up to 20 years, even if the condition was left untreated. 1-4 Given the complex relationship between IOP and glaucoma damage, researchers and professional organizations emphasized a new glaucoma concept in which the disease was described as an optic neuropathy, with IOP as only one of several risk factors. 5-7 In a single glaucoma examination, critical ONH evaluation is more sensitive and specific for diagnosing glaucoma than IOP measurement or visual field assessment. ONH evaluation has approximately 85% sensitivity and 90% specificity while visual-field examination has approximately 75% sensitivity and 95% specificity. 8 Examination of either one alone, however, is inadequate because the correlation between structural and functional damage in glaucoma is not exactly linear, especially in the early stage of the disease. Several studies have shown that detectable damage to the ONH and retinal-ner ve-fiber layer (RNFL) is generally present before detectable alteration in the visual field. 9, 10 Approximately 40 to 50% loss of ganglion cells was present before the first defect was detected in
the visual field. 11 In recent years, several instruments have been developed to assist clinicians in detecting the presence or absence of glaucoma. They were tested for their accuracy against a “gold standard.” In glaucoma, the choice of a gold standard poses several problems. Each of the tools employed in making the diagnosis of
glaucoma involves looking at different aspects of the disease. In evaluating the ONH, one looks for the presence of structural damage. In visual-field testing, one looks at the functional damage. Generally, structural damage in the ONH corresponds to functional damage in the visual field with characteristic glaucomatous
defects. In the early stage of the disease, however, there may already be structural damage in the ONH without
detectable damage in the visual field (preperimetric stage). Hence, combining both features will increase the
sensitivity and specificity in the assessment of glaucoma by standard methods. Var ying sensitivities and specificities have been reported for these new glaucoma instruments, the cause of which is probably an imperfect gold standard. The ideal gold standard should be the best available method of differentiating between those with and without the disease. It should effectively discriminate these groups across the full spectrum of the disease. Many times a “perfect” gold standard is still not available. As a result, an imperfect but considered the best available standard may be chosen as the standard of validity. Many investigators used the glaucoma experts’ diagnosis as the gold standard, which was derived from integrating the results of the different glaucoma tests (battery of glaucoma tests) as shown in the article on the Diagnostic Properties of a Nerve-Fiber Analyzer (see pages 66 to 72). Others used the definitive diagnosis of glaucoma derived after several years of following up the patient (natural history of the disease). The latter may be more accurate but more time consuming and difficult because of the long latency of the disease.
Among the recently published randomized controlled trials in glaucoma, most investigators used the findings
on SAP as definite diagnosis that glaucoma is present. This may be appropriate for the Advanced Glaucoma
Intervention Study (AGIS) 12, 13 or the Collaborative Initial Glaucoma Treatment Study (CIGTS) 14 but for
studies involving early glaucoma such as The Early Manifest Glaucoma Trial (EMGT) 15 or the Ocular Hypertension Treatment Study (OHTS), 4 a combination of glaucomatous optic-disc findings and/or visual-field defects is used. Since the publication of the results of several landmark studies in glaucoma, much has been discussed about the role of IOP lowering. We have included in this issue a commentary on several of these randomized controlled studies, summarizing the results, outlining their strengths and weaknesses, and more importantly, analyzing their implications on and application to clinical practice.
—The Editor in Chief
1. Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated
glaucoma suspects. Ophthalmology 1991; 98: 301-307.
2. Lundberg L, Wettrell K, Linner E. Ocular hypertension. Acta Ophthalmol 1987;
3. Kass MA, Gordon MO, Hoff MR, et al. Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. Arch Ophthalmol 1989; 107:1590-1598.
4. Kass MA, Heuer 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.
5. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study. Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120:714-720.
6. 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.
7. 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.
8. Quigley HA, Schwartz B. Open-angle glaucoma. In: Shingleton BJ, Berson FG, Cantor L, et al, ed. Basic and Clinical Science Course. Section 10. San Francisco: American Academy of Ophthalmology, 1994; 66-69.
9. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber layer atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991; 77-83.
10. Zeyen TG, Caprioli J. Progression of disc and field damage in early glaucoma. Arch Ophthalmol 1993; 111: 62-65.
11. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve-fiber loss and visual-field defect in glaucoma, ischemic optic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 1982; 100: 135-146.
12. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual-field deterioration. Am J Ophthalmol 2000; 130: 429-440.
13. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison of glaucoma outcomes in black and white patients within the treatment groups. Am J Ophthalmol 2001; 132; 311-320.
14. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the collaborative initial glaucoma treatment study comparing initial treatment randomized to medication or surgery. Ophthalmology 2001; 108: 1943-1953.
15. 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.