Article

The argument for early glaucoma detection

Electroretinography reveals nascent functional changes, before apoptosis of retinal ganglion cells.

Treatment of glaucoma is changing; it is less about hoping that the patient’s peripheral vision outlasts the person’s life while instilling three drops twice a day. Its management is more about early detection and intervention to slow this chronic disease. But, physicians seem to prefer visual field testing as the barometer for functional loss in early glaucoma. Are the structural changes to the retinal nerve fiber layer (RNFL) seen on OCT early enough in the disease process to prevent vision loss?

VISUAL FIELDS

Glaucoma is a progressive, optic neuropathy characterized by retinal ganglion cell (RGC) loss, changes to the optic nerve head and visual field defects. 24-2 visual fields with the Humphrey visual field analyzer (Zeiss) have been the standard of care for monitoring subjective glaucomatous severity and progression for two decades. But, automated perimetry has poor test-retest reliability in unhealthy eyes, often leading to inconclusive results.1 In glaucoma suspects or those with mild disease, the mean deviation (MD), which indicates generalized functional loss, is only weakly correlated with visual field index, accounting for media opacities.2

About 30% of RGC must die prior to detectable visual field loss.3 RGCs are densely packed in the central and perifoveal retina, so even if some RGCs are no longer functional, others will still perceive the visual field stimulus.4 Based on this, visual field testing is necessary to monitor progression in advancing glaucoma but is not sensitive enough for early disease detection.

OCT

OCT shows structural changes to the RNFL with normative databases reflecting the associated, hypothetically predicted functional loss. OCT can measure the RNFL thickness at the nerve head, which is a biomarker for glaucoma assessment and progression analysis and may be useful prior to perimetry.5 However, it is not a direct measure of RGC loss. Ganglion cell complex (GCC) thickness analysis at the macula may show progression earlier than RNFL analysis in early glaucoma without visual field defects.6,7

PERG

In 1987, Dodt showed the amplitude of pattern electroretinogram (PERG), which reflects the RGC status, was decreased in patients with ocular hypertension, without visual field loss or optic nerve changes, if the IOP was greater than 26 mm Hg.8 Also, PERG may have better sensitivity and specificity for early glaucoma detection than automated perimetry.9 A 12-year prospective study concluded that, based on amplitude reduction, PERG could help predict progression from ocular hypertension to glaucoma at least a year before transition.10 Banitt et al. showed that PERG takes two to two and a half 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 In other words, RNFL thickness changes lag behind PERG changes by approximately eight years in glaucoma suspects.

Electrodiagnostic testing has historically been reserved for academic institutions because of the invasive nature of the corneal electrodes and the length of time required to perform the test. A new era in electrodiagnostic testing for glaucoma began in 2013 when Diopsys introduced clinical PERG testing with the Neuro Optic Vision Assessment (NOVA) ERG.12 For glaucoma diagnosis, it uses a contrast sensitivity threshold whereas for localized pathologies, like AMD, it uses concentric stimulus fields.13 The NOVA PERG allows for rapid, noninvasive, objective, functional RGC testing for early glaucoma detection using skin electrodes, putting electrophysiology into the realm of primary glaucoma care.

Mark Latina, MD, inventor of SLT, says he wonders why PERG isn’t used more often to detect early-stage glaucoma.

“Since … PERG is the only objective and functional test approved by the FDA to measure function, it is unclear why we as ophthalmologists do not adopt this critical technology that could provide important diagnostic information that will improve the management of ophthalmic diseases that can result in blindness.”

Thomas Mundorf, MD, in Charlotte, N.C., says PERG can reveal diminished RGC performance, helping to treat and assess intervention on function with objective data. This is important with regard to patients of African ancestry, as these patients, in the Gracitelli et al. study (this page), showed more variability with their field tests, hampering “the evaluation of their glaucoma status, the level of control, and potential to worsen.”

“This [early diagnosis] makes it even more important to diagnose [correctly] early and intervene early to improve their prognosis and to protect their vision,” Dr. Mundorf added.

PERG INTERPRETATION

  • Signal quality – Look for a green signal
  • Sinusoidal peaks – There should be three similar upward peaks
  • Magnitude color – Green is normal, yellow is borderline and red is outside normal limits

PERG repeatability is a good measure of disease status. It can be used to confirm that the target IOP is sufficient to stabilize the RGC. What may be even more exciting is that PERG amplitude has been shown to improve with IOP lowering in early glaucoma, indicating improved function of the RGC, provided they haven’t undergone apoptosis.14 So why hasn’t clinical PERG become the standard for early glaucoma detection?

STRUCTURE VS. FUNCTION

Improvements in PERG amplitude after the lowering of IOP indicate that functional changes may occur prior to structural changes within the RGC.15 The implication is that RGC function can be restored by reducing the IOP in open-angle and normal-tension glaucoma.14 Greater PERG amplitude improvements were correlated with normal fields or only mild visual field defects.14 In advanced glaucoma, however, the RGC function may not be restored and there may not be significant PERG improvement. Visual field losses, by contrast, show functional changes that occur due to definitive structural loss, reflecting the health status of the RGC and RNFL.

So, for very early disease detection and monitoring, electrodiagnostic testing of the RGC may be indicated over VF or OCT RNFL analysis. If PERG can predict glaucoma, why wait for the VF and OCT to show change? Theoretically, if the IOP can be reduced and the PERG amplitude restored, indicating a rejuvenation of the RGC, then glaucomatous damage could be halted. However, considering the many factors that underlie glaucoma, if the PERG amplitude continues to decrease, indicating structural changes to the RGC including cell death, then it is assumed that structural changes to the RNFL will follow. Hence, monitoring with VF and OCT becomes essential.16

SLT

If PERG can show improvements with IOP lowering, it behooves the glaucoma specialist to choose treatment options that can halt or potentially reverse early glaucoma. Compliance rates with glaucoma drops are poor. One study revealed that nearly 45% of patients who were aware that they were being monitored with an electronic device and were given drops for free used their drops less than 75% of the time.17

SLT, performed with a Nd:YAG laser such as the Tango SLT/YAG (Ellex), uses photothermolysis in short pulses to target only the melanin-rich cells in the trabecular meshwork, improving aqueous outflow.18 SLT also has been shown to cause biological changes, e.g., gene expression, cytokine secretion, matrix metalloproteinase induction, and trabecular meshwork remodeling.19

SLT is an effective first-line therapy for a sustained reduction in IOP that is comparable to argon laser trabeculoplasty and medical therapy.20 It is generally successful for two to three years at which time it may need to be repeated. It has been shown to have no statistically significant difference in success the second time.21 If performed prior to other glaucoma therapies, SLT has an even stronger IOP lowering efficacy and it can stabilize diurnal variations.22

In his SLT trial, Dr. Latina said SLT was proven to be equivalent to using prostaglandin analogues as primary therapy with similar reductions of IOP and less need for increasing therapy to achieve target IOP. SLT, he says, provides the maximum IOP lowering without medications, helping with patient compliance, medication costs and adverse effects. Also, SLT works around the clock so it reduces diurnal IOP variation. Many patients can remain medication-free for years. In the original Glaucoma Laser Trial, patients who had laser trabeculoplasty as primary therapy had less visual field progression than those in the medication arm, indicating these patients have a long-term benefit from SLT and improved prognosis.

Similar to PERG, in which the higher the IOP the better the amplitude results when the IOP is lowered, the best predictive factor of SLT success is elevated baseline IOP. The amount of IOP reduction is greater if the preoperative IOP is higher. However, the magnitude of IOP reduction may not be enough with SLT alone and medical means may be necessary to control glaucomatous progression. Also, those with normal-tension glaucoma with IOP less than 14 mmHg may not benefit from SLT at all.23

Cost is also a consideration when choosing a first-line treatment. One retrospective chart review of 151 records found the yearly cost of treatment for a U.S. glaucoma suspect was $623 while the cost for a patient with end-stage disease was $2,511.24 Thus, early, effective diagnosis and treatment that delays progression will reduce the disease’s lifetime cost burden. SLT has been shown to be less costly than medications if amortized over a year; there are more savings after two to three years.21

A prospective clinical trial is underway benchmarking glaucoma management with SLT or trabecular stent bypass MIGS, using Diopsys PERG protocols.25 Research and time will disclose which treatment option can best effect RGC restoration function in early glaucoma. OM

For more information, visit ellex.com and diopsys.com .

REFERENCES

  1. 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.
  2. Sousa MC, Biteli LG, Dorairaj S, Maslin JS, Leite MT, Prata TS. Suitability of the visual field index according to glaucoma severity. J Curr Glaucoma Pract. 2015;9:65-68.
  3. Kerrigan-Baumrind LA, Quigley HA, Pease ME, Kerrigan DF, Mitchell RS. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci. 2000;41:741-748.
  4. Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol. 1989;107:453-64.
  5. Ishikawa, H. Where does ganglion cell analysis fit? The role of macular optical coherence tomography in glaucoma assessment. Glaucoma Today, May/June 2016. 43-44.
  6. 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.
  7. Lee WJ, Na KI, Kim YK, Jeoung JW, Park KH. Diagnostic ability of wide-field retinal nerve fiber layer maps using swept-source optical coherence tomography for detection of preperimetric and early perimetric glaucoma. J Glaucoma. 2017;26:577-585.
  8. Dodt E. The electrical response of the human eye to patterned stimuli: clinical observations. Doc Ophthalmol. 1987;65:271-286.
  9. Graham SL, Drance SM, Chauhan BC, et al. Comparison of psychophysical and electrophysiological testing in early glaucoma. Invest Ophthalmol Vis Sci. 1996;37:2651-2662.
  10. Bach M, Unsoeld AS, Philippin H, et al. Pattern ERG as an early glaucoma indicator in ocular hypertension: a long-term, prospective study. Invest Ophthalmol Vis Sci. 2006;47:4881-4887.
  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. Diopsys. Our History. http://diopsys.com/about-diopsys-electrophysiology/our-history/ . Accessed March 4, 2018.
  13. Shengelia A, Tello C, Siegfried J, Ritch R. Diopsys NOVA-ERG System: Reference values of healthy subjects and thresholds for discriminating abnormal visual function from healthy subjects. ARVO 2015, Annual Meeting, Abstract/Poster #1030-B0164.
  14. Ventura LM, Porciatti V. Restoration of retinal ganglion cell function in early glaucoma after intraocular pressure reduction: A pilot study. Ophthalmology. 2005;112:20–27.
  15. Ventura LM, Porciatti V. Reversible pattern ERG loss in glaucoma: Restoring the activity of dysfunctional retinal ganglion cells in patients with early disease. Glaucoma Today, January/February 2006. 10-12.
  16. Abe RY, Diniz-Filho A, Zangwill LM, et al. The relative odds of progressing by structural and functional tests in glaucoma. Invest Ophthalmol Vis Sci. 2016;57:OCT421–OCT428.
  17. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically the Travatan Dosing Aid study. Ophthalmology. 2009;116:191-199.
  18. Ellex. SLT: Overview. http://www.ellex.com/us/physicians/treatment-portfolio/slt/overview/ . Accessed March 10, 2018.
  19. Kagan DB, Gorfinkel NS, Hutnik CM. Mechanisms of selective laser trabeculoplasty: a review. Clin Exp Ophthalmol. 2014;42:675-681.
  20. Katz LJ, Steinmann WC, Kabir A, et al. Selective laser trabeculoplasty versus medical therapy as initial treatment of glaucoma: a prospective, randomized trial. J Glaucoma. 2012;21:460-468.
  21. Garg A, Gazzard G. Selective laser trabeculoplasty: past, present, and future. Eye. 2018;1:1-15.
  22. Jindra LF, Donnelly JA, Gupta A, Miglino EM. Selective laser trabeculoplasty as primary and secondary therapy in patients with glaucoma: 8 year experience. Invest Ophthalmol Vis Sci. 2010;51:4428.
  23. Pillunat KR, Spoerl E, Elfes G, Pillunat LE. Preoperative intraocular pressure as a predictor of selective laser trabeculoplasty efficacy. Acta Ophthalmol. 2016;94:692-696.
  24. Lee PP, Walt JG, Doyle JJ, et al. A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol. 2006;124:12-9.
  25. ClinicalTrials.gov . Benchmarking Management of Glaucoma Using the Diopsys VEP/PERG Protocols. https://clinicaltrials.gov/ct2/show/study/NCT02594280?view=record . Accessed March 10, 2018.