Although glaucoma is a progressive optic neuropathy, clinicians do not have to wait for progression or obvious optic nerve head (ONH) damage to make a diagnosis. To assist with the glaucoma verdict and prevent vision loss, ophthalmologists can take advantage of the many available diagnostic tools and tests. “The timing of the diagnosis of glaucoma and commencement of treatment is open to personal interpretation by each ophthalmologist, but that is the art of medicine,” says Noga Harizman, MD, of the New York Eye and Ear (NYEE) Infirmary of Mount Sinai. “If identifying glaucoma was clear cut, it would be easy.”

Here are some favorite tips from glaucoma specialists for early detection.

START WITH THE BASICS

Technology has made the detection of ocular diseases easier than ever. But, I. Paul Singh, MD, of The Eye Centers of Racine and Kenosha, reminds his colleagues to still evaluate the ONH of every patient with slit-lamp biomicroscopy using a handheld 78-D or 90-D lens. The stereoscopic view and magnification allow for evaluation of the neural retinal rim contour, cupping, peripapillary atrophy, nerve fiber layer defects, optic disc vessels and possible hemorrhages.¹

Knowledge of the ONH architecture makes other diagnostic tools more powerful,” says Dr. Singh.

Also, don’t miss the opportunity to take baseline fundus photographs to document and follow all of your patients, Dr. Singh advises. “Five to 10 years later, you can utilize the baseline images to determine if the cupping that you are noting is physiological or if there has actually been a change.” Rather than comparing consecutive photos from the last visit to the current appointment for the diagnosis of glaucoma, it is essential to compare the newest images to baseline.

According to Drs. Singh and Harizman, most of the available mydriatic and nonmydriatic fundus cameras take excellent photos. For glaucoma diagnosis and monitoring specifically, they say the ability to take stereo photographs adds to a camera’s versatility and functionality.

WHILE AT THE SLIT LAMP, DO GONIOSCOPY

Most of the risk factors for glaucoma reside in the anterior chamber angle, so Drs. Singh and Harizman strongly recommend gonioscopy at every baseline visit. When it comes to gonio lenses, Dr. Singh uses a Volk 4 mirror. “It doesn’t require any coupling gel, and you can perform compression gonioscopy.”

Dr. Harizman’s preference is a Posner gonioprism, because it provides full control and stability on indentation. She reminds ophthalmologists that it is essential to do gonioscopy in the dark. “You want the patient’s pupils to be dilated as much as possible so that the angle becomes crowded. Turn off all ambient light, including your computer monitor.”

Pigment in the angle can be a source of outflow resistance. If it is noted, “be sure to have another look at the cornea for a Krukenberg spindle and examine the iris for transillumination defects, indicative of pigment dispersion syndrome,” Dr. Harizman says. As an aside, with respect to treatment for patients with pigment dispersion glaucoma, she recommends avoiding medications that lower aqueous production. “What you want instead is a prostaglandin analogue to increase outflow, reducing the IOP and washing away some of the excess pigment.”

GET THE MOST OUT OF YOUR VISUAL FIELD TEST

Visual field testing provides the relationship between structural damage and functional loss. However, there is a redundancy of ganglion cells in the eyes such that there has to be significant structural impairment in order to see functional deficit. Standard automated visual field testing may not be the ideal first-line diagnostic test for glaucoma, but if used effectively it can provide valuable information.

According to a study by Saunders et al, Humphrey’s SITA Standard is more precise than SITA Fast at lower visual field sensitivities, but the difference is unlikely to have a substantial impact in monitoring disease progression.² Both Drs. Singh and Harizman prefer the 24-2 SITA Standard, but Dr. Singh has recently started using the SITA Fast program. “It provides 50% faster testing while maintaining reproducibility and the ability to combine all SITA strategies for guided progression analysis (GPA) reports,” says Dr. Singh.

Humphrey’s 24-2 visual fields have been the standard of care for monitoring subjective glaucomatous severity and progression for two decades, in spite of the test-retest reliability issues.³ The 24-2 tests a total of 54 points that are 6 degrees apart, testing only 12 points within the central 10 degrees of fixation.⁴ In addition to the 24-2, Drs. Singh and Harizman recommend using the Humphrey’s 10-2 program, which examines 68 test points that are 2 degrees apart, agreeing that closely spaced test points may better detect progression.⁴

When dealing with more advanced glaucoma and monitoring progression of central vision loss, if the field looks dark, yet the patients can still see the Snellen chart, Dr. Singh recommends increasing the stimulus spot size from III to V, to attain a more functional field map that can be followed.

Selective visual field testing, such as blue-on-yellow perimetry or short wavelength automated perimetry (SWAP), and frequency doubling technology (FDT), also are options. Dr. Singh has used SWAP testing because it can detect early visual field loss before a reduction in differential light sensitivity is seen with standard white-on-white (W-W) perimetry.⁵ Additonally, he notes, previous research shows that “deficits on SWAP are seen in around 20% to 25% of patients who are at risk of developing glaucoma and who have repeatedly normal visual field results using standard automated perimetry.”⁶

But SWAP testing has disadvantages as well, Dr. Singh points out. Among them: It usually runs two to three minutes longer than the standard automated full threshold W-W perimetry, for a total of 15 to 20 minutes per eye. “It also takes the patient two to three minutes to adapt to the yellow light,” he says. “There are faster testing automated strategies now.”

Increased variability with SWAP, which can make it difficult to determine if there is progression, is another drawback, explains Dr. Singh. “It’s important to also realize there can be a higher amount of false positive and artifact, and patients do state it’s a more difficult test than standard W-W.”

Dr. Harziman concurs. “It’s a tough test to perform, so if the patient is elderly, I wouldn’t recommend it.”

FDT, which detects loss of function in certain parts of the nerve fiber layer, is a superior test for screening and detecting early field loss, Dr. Singh finds. He points to a longitudinal study by Medeiros et al that followed a group of glaucoma suspects with baseline normal visual fields using SAP testing. “They determined 59% of the patients had FDT defects four years before SAP detected the same defect,” Dr. Singh says.⁷ “They also found that 18% of SAP converters were not found to have repeatable abnormalities on FDT.” Another reason to use it: FDT perimetry takes “a lot less time” to complete than SAP or SWAP and is also more portable than other tests, Dr. Singh says. “And, since there tends to be less intra- and intertest variability compared to SAP, it may be a useful test to monitor long-term progression of visual field loss.”

OCT IS BENEFICIAL IN EARLY GLAUCOMA

OCT algorithms have been readily available that can provide retinal nerve fiber layer analysis as a biomarker for glaucoma assessment and progression. However, ganglion cell complex thickness analysis at the macula via OCT may show progression even earlier.⁸ “There is a redundancy of ganglion cells,” explains Dr. Singh, “but once you go over that cliff, there is no coming back. Some patients still go blind from glaucoma. Once glaucoma advances to a late stage, OCT is no longer as helpful. You get a “floor effect” or bottoming out and there is nowhere else to go. That’s when visual field testing becomes the better indicator of progression.”

OCT angiography (OCTA) detects blood flow through the motion contrast of red blood cells in the retinal vasculature. Because the loss of retinal vessel density is linked to the development and progression of glaucoma, OCTA may be useful from a pathophysiological standpoint, although algorithms are not yet readily available.

A 2018 systematic review of 80 references on the topic of OCTA for glaucoma concluded that it is repeatable and reproduceable, can detect normal eyes from glaucomatous eyes (even in early cases), is correlated with visual function and reaches a floor effect at a later stage than OCT.⁹

Both Drs. Singh and Harizman concur that poor blood flow is a significant risk factor in normal-tension glaucoma, and OCTA studies confirm this by showing a pattern of microvascular compromise with respect to blood flow index and vessel density, which differs from the pattern in POAG.⁹

A NEW ERA IN PERG TESTING

Historically, pattern electroretinography (PERG), which measures the signal from the retinal ganglion cells, was invasive and reserved for academic institutions. Now, Diopsys offers ERG technology via electrodes that sit on the lower lid. “PERG may be helpful when visual field testing is difficult to perform or before visual field defects can be detected, allowing us to start or change treatment earlier in the disease to prevent further damage,” Dr. Singh says.

PERG testing is able to detect viable but dying cells before apoptosis, making it possible to intervene with glaucoma therapy before it progresses. This is feasible because, even though some ganglion cells are lost in the early stages of glaucoma, complete retinal ganglion cell death may actually take months or years to occur.¹⁰ In fact, Banitt et al showed PERG takes two to 2.5 years to lose 10% of its initial amplitude, while the RNFL thickness measured with OCT takes 10 to 10.5 years to lose 10% of its initial thickness.¹¹

WHAT INFLUENCE DOES THE CORNEA HAVE?

Central corneal thickness is a static measure that can be correlated with glaucoma and can affect the accuracy of an IOP reading, underestimating it in patients with thin corneas and overestimating it in those with thick corneas. Dr. Harizman, who in addition to being codirector of the glaucoma clinic at NYEE is a cornea and external disease specialist, reminds her colleagues to watch for comorbidities, such as bullous keratopathy, that can cause corneal edema and skew central corneal thickness measurements.

Also, pay attention to corneal hysteresis, a measure of the biomechanics of the cornea and pathophysiological indicator of glaucoma, says Dr. Singh. Corneal hysteresis is the ability of the cornea to absorb and release energy during and after applanation and, by extension, the lamina cribrosa.

The ocular response analyzer (ORA) by Reichert, which Dr. Singh uses in his practice, has been the most impactful addition to his glaucoma diagnostic arsenal in recent years. “If you decrease the IOP using drops, MIGS or laser, the corneal hysteresis values increase,” he says. “Additionally, eyes with a low corneal hysteresis respond well to prostaglandin analogues.”

Studies have demonstrated that when raising the IOP to 64 mm Hg using a LASIK suction ring while viewing the lamina using high-resolution OCT, one can see significantly greater movement of the lamina in patients with higher hysteresis than those who have lower hysteresis. This suggests that those patients with low hysteresis are not able to “adapt” and “absorb” large pressure fluctuations.¹²

A 2018 review of recent literature conducted by Liang et al concluded that the corneal hysteresis values in all types of glaucoma are lower than in those individuals without the disease.¹³ It’s a particularly effective index if the clinician has concerns about asymmetrical glaucoma. The researchers also found that lower values were associated with thinner retinal nerve fiber layers and lower visual field indices. Mierderos et al and Susanna et al showed that corneal hysteresis was a powerful predictor of patients developing glaucoma and those who are likely to progress.^14,15

SO, WHAT ABOUT THE IOP?

Goldmann tonometers remain the standard of care in clinical practice for measuring the IOP, with the more portable Perkins tonometer using the same underlying principle of applanation. The Tono-Pen by Reichert combines applanation and indentation in a compact, lightweight device.¹⁶ The Icare and Icare HOME tonometers are hand-held, anesthetic drop-free instruments that calculate IOP based on the deceleration and rebound time over a series of consecutive measurements.¹⁷

IOP is the only real modifiable risk factor for glaucoma. Both Drs. Singh and Harizman remind readers of the OHT study, which showed that although the IOP declined in the treatment arm over the five-year period, patients’ ocular hypertension advanced to POAG.¹⁸ In fact, 5% of patients still progressed to the diagnosis of glaucoma despite a 20% reduction in IOP compared with approximately 10% in the observation arm.

“The OHT study demonstrated the importance of reducing the IOP to help prevent progression, but 20% may not be enough,” Dr. Singh says. “In studies such as AGIS, we see more significant reductions of IOP along the lines of 35% to 45% actually halting progression.”¹⁹

Fluctuation in IOP may also be an important risk factor. “In the AGIS study,” he notes, “those advanced glaucoma patients whose IOP fluctuated greater than 3 mm Hg throughout the study had a higher risk of progression.”¹⁹

Moreover, in a subgroup analysis published by Caprioli et al, only 9% of patients who had a mean IOP of 10.8 mm Hg and fluctuated less than 3 mm Hg throughout the study actually progressed, as compared to the 30% of patients who progressed when their IOPs fluctuated greater than 3 mm Hg.²⁰

Dr. Singh cautions that “various studies show mean, peak and fluctuating IOP are all risk factors for glaucoma progression, so don’t become complacent on IOP and the fluctuation.”

CONCLUSION

Essential tools in your glaucoma diagnostics arsenal are your slit lamp and condensing lens, gonioscopy, visual field testing and OCT. Drs. Singh and Harizman also recommend color vision testing, OCTA, PERG, pachymetry and corneal hysteresis.

Glaucoma is a progressive optic neuropathy, but with all the ocular and systemic pathophysiological features to consider and diagnostic tools available, ophthalmologists can base their diagnosis on a combination of tests and risk factor analysis without the need to wait for noticeable progression or optic nerve head destruction. OM

REFERENCES

1. Reis ASC, Toren A, Nicolela MT. Clinical optic disc evaluation in glaucoma. European Ophthalmic Review, 2012;6:92-97.
2. Saunders LJ, Russell RA, Crabb DP. Standard or Fast? Differences in precision between SITA Standard and SITA Fast testing algorithms and their utility for detecting visual field deterioration. Invest Ophthalmol Vis Sci. 2014;55:3010.
3. Khoury JM, Donahue SP, Lavin PJ, Tsai JC. Comparison of 24-2 and 30-2 perimetry in glaucomatous and nonglaucomatous optic neuropathies. J Neuroophthalmol. 1999;19:100-108.
4. Rao HL, Begum VU, Khadka D, et al. Comparing glaucoma progression on 24-2 and 10-2 visual field examinations. PLoS One. 2015;10:e0127233.
5. Johnson C A, Adams A J, Casson E J, et al. Blue-on-yellow perimetry can predict the development of glaucomatous visual field loss. Archives of Ophthalmology. 1993;111: 645-650.
6. Qi S, Jiang Y. Short wavelength perimetry in diagnosis of early glaucoma: comparison with standard automated perimetry. ZhoghuaYan Ke za Zhi2002:38:31-35.
7. Medeiros, FA, Sample PA, Weinreb RN. Fre-quency doubling technology perimetry abnormalities as predictors of glaucomatous visual field loss. American Journal of Ophthalmology. 2004;137:863-871.
8. Bhagat PR, Deshpande KV, Natu B. Utility of ganglion cell complex analysis in early diagnosis and monitoring of glaucoma using a different spectral domain optical coherence tomography. J Curr Glaucoma Pract. 2014;8:101-106.
9. Van Melkebeke L, Barbosa-Breda J, Huygens M, et al. Optical Coherence Tomography Angiography in Glaucoma: A Review. Ophthalmic Res 2018;60:139-151.
10. Osborne NN, Wood JP, Chidow G, et al. Ganglion cell death in glaucoma: what do we really know? Br J Ophthalmol. 1999;83:980-986.
11. Banitt MR, Ventura LM, Feuer WJ, et al. Progressive loss of retinal ganglion cell function precedes structural loss by several years in glaucoma suspects. Invest Ophthalmol Vis Sci. 2013; 54:2346-2352.
12. Wells AP, Garway-Heath DF, Pootstchi A, et al. Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients. Invest Ophthalmol Vis Sci. 2008;49:3262-8.
13. Liang L, Zhang R, He LY. Corneal hysteresis and glaucoma. Int Ophthalmol. 2018:1-8.
14. Medeiros FA, Meira-Fretas D, Lisboa R, et al. Corneal hysteresis as a risk factor for glaucoma progression: a prospective longitudinal study. Ophthalmology. 2013;120:1533-1540.
15. Susanna CN, Diniz-Filho A, Daga FB, et al. A prospective longitudinal study to investigate corneal hysteresis as a risk factor for predicting development of glaucoma. Am J Ophthalmol. 2018;187:148-152.
16. Aziz K, Friedman DS. Tonometers – which one should I use? Eye. 2018;32:931-937.
17. Icare HOME Instructional Manual for Health Care Professionals. Page 6. http://www.icaretonometer.com/wp-content/uploads/2015/09/Icare_HOME_instruction_manual_TA022-036_EN-3-2_HIRES.pdf . Accessed August 22, 2017.
18. 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.
19. 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.
20. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressures in the advanced glaucoma intervention study. Ophthalmology. 2008;115:1123-1129.
21. Pacheco-Cutillas M, Edgar DF. Acquired colour vision defects in glaucoma — their detection and clinical significance. Br J Ophthalmol. 1999;83:1396-1402.
22. Mallick J, Devi L, Malik PK, et al. Update on Normal Tension Glaucoma. J Ophthalmic Vis Res. 2016;11:204-208.
23. Liu S, Lin Y, Liu X. Meta-analysis of association of obstructive sleep apnea with glaucoma. J Glaucoma. 2016;25:1-7.
24. Hao K, Zhang X. Intraocular pressure during continuous positive airway pressure. Med Princ Pract. 2017;26:93.