A paradigm for the treatment of ocular hypertension in glaucoma suspects

Although glaucoma treatment can take many forms, including medical and procedural-based approaches, one underlying principle for improving outcomes is that earlier treatment affords greater opportunity to affect better results. Consequently, there is sincere interest in discovering the earliest precursory indicators of glaucoma and ways they can be detected in the clinic.

Our current understanding of glaucoma suggests that changes in and around the retinal ganglion cells surrounding the optic nerve are some of the earliest signs of the disease. While there are several theories as to what may be the initial inciting event, the prevailing thought is that progressive loss in the ganglion cell layer eventually leads to the hallmark optic neuropathy that characterises the glaucomas.

The ability to successfully prevent deterioration of visual function associated with later glaucoma may, therefore, hinge on monitoring the viability of this crucial cell layer at an early stage of the disease.

Modern visual electrophysiology devices, such as Diopsys NOVA (Diopsys), are making this possible in clinical practice through pattern electroretinography (PERG). PERG testing, which measures an electrical signal from the retina ganglion cells in response to a stimulus, may provide clinicians actionable information regarding the viability of the ganglion cell layer.

An irregular PERG test indicates abnormal function in the ganglion cell layer that precedes cell death by months or years. In addition to early detection benefits, PERG testing also indicates response to treatment.

Unlike other standard diagnostic modalities, such as optical coherence tomography (OCT) and perimetry testing, which are useful for measuring disease progression, PERG testing can indicate functional improvements. In other words, while serial OCT and visual fields may tell you when treatment has failed, PERG can serve as an index for when treatment is working. This information is invaluable if the intent is to treat glaucoma disease parameters that do not have apparent clinical correlates.

Early glaucoma detection and treatment

Several studies highlight the role of PERG testing in the detection of maculopathies before clinical evidence is apparent.^1,2 These studies validate that objective functional testing of the retina provides important diagnostic and prognostic information to the clinician.

PERG testing has also been shown to demonstrate response to treatment, with improvements in PERG signal correlating with disease improvement. Oner et al showed that PERG signals improved after combined photodynamic therapy and anti-VEGF injections for the treatment of age-related macular degeneration, yet there was no change after photodynamic therapy alone.³

Moreover, the changes seen in the combined treatment group correlated with improvements in visual acuity that were not observed in the monotherapy group. The ability to detect response to treatment using PERG has been corroborated in other studies.^4-6

PERG testing is also a reliable means to detect early indicators of glaucoma in eyes with ocular hypertension.^7-9 Moreover, the use of PERG has been shown to predict pattern loss on visual field¹⁰ and anticipate an equivalent loss of structure on OCT by several years.¹¹  

Whilst early detection of glaucoma is important for prognostic purposes, there were, previously,  few treatment options.  Topical therapy has traditionally only been considered for individuals with clinically apparent glaucoma, or who already have visual deficits, yet there is an emerging belief that procedural treatments might pose less risk of unwanted outcomes even in mild to moderate glaucoma.

Nevertheless, the tolerance for risk among individuals with ocular hypertension and/or the absence of obvious signs of optic nerve damage is understandably lower. It is important to consider that any early-stage treatment undertaken should only expose patients to minimal risk of complications.

Selective laser trabeculoplasty (SLT) is an alternative, procedure-based approach to treatment that avoids risks associated with topical therapy. In recent years, compelling evidence has emerged that suggests a role for SLT in newly diagnosed and treatment-naïve glaucomas.

Due to the fact that SLT selectively ablates pigmented cells, it yields minimal damage to the trabecular meshwork, making it a safe and repeatable treatment for various types of glaucoma, including primary open-angle, pigmentary and exfoliative glaucomas, as well as ocular hypertension. In the context of patients without signs of damage on OCT and/or visual field progression, the application of SLT to improve aqueous outflow would reduce the potential for a relevant risk factor (i.e., compromised outflow) to have an injurious effect.

Theoretically, therefore, the combined use of PERG and SLT would represent a mechanism to detect early pattern irregularities indicative and predictive of glaucoma, to apply treatment, and then to monitor for effect – all at a time during the natural course of glaucoma when the disease has not yet ravaged important ocular structures.

Case study

A recent case in my clinic demonstrates the application of this approach for a 64-year-old woman complaining of visual disturbances in both eyes. The patient, who had a family history of glaucoma, presented with visual acuity of 20/25 OD and 20/30 OS. Fundus examination was normal in each eye, and cup-to-disc ratio was 0.4 OU; IOP measured 25 mm Hg OD and 24 mm Hg OS. Based on the evaluation, she was diagnosed as a glaucoma suspect.

Visual field testing and OCT imaging did not indicate any obvious signs of active glaucoma (Figure 1, slides 29 and 30). However, PERG testing indicated irregular patterns in both eyes (Figure 2a, slide 31). The patient consented to SLT in both eyes, which was performed for 180° OU. Two months later IOP decreased to 16 mm Hg OU and PERG shows retinal function improvement (Figure 2b, slide 32).

Conclusion

One of the most important factors in the success of glaucoma treatment is an ability to detect the disease before it has damaged ocular structures that result in damaged vision. Of equal importance is access to an intervention that introduces minimal risk while yielding definitive benefit at a time when vision and the health of the eye are not immediately threatened. It would appear that the combined use of PERG testing to detect early glaucoma indicators and SLT to improve aqueous outflow represents a mechanism that delivers on the promise of early diagnosis and treatment.

The case noted above demonstrates some important principles. Importantly, it shows it is feasible to detect and treat very early indicators of glaucoma. In this case, the drop in IOP suggests a successful SLT application, which was correlated with improvements in PERG signal.

Certainly, longer-term follow up is required to demonstrate a durable effect; however, the improvement in functionality in the retinal ganglion cell layer, shown by change in PERG signal, offers promise that treatment prolonged progression of the patient’s glaucoma.

References:

1. Neubauer AS, et al. The multifocal pattern electroretinogram in chloroquine retinopathy. Ophthalmic Res. 2004;36:106-113.
2. Ventura LM, et al. The PERG in diabetic glaucoma suspects with no evidence of retinopathy. J Glaucoma. 2010;19:243-247.
3. Oner A, et al. Pattern electroretinographic results after photodynamic therapy alone and photodynamic therapy in combination with intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration. Doc Ophthalmol. 2009;;119:37-42.
4. Neveu MM, Tufail A, Dowler JG, Holder GE. A comparison of pattern and multifocal electroretinography in the evaluation of age-related macular degeneration and its treatment with photodynamic therapy. Doc Ophthalmol. 2006;113:71-81.
5. Varano M, et al. Macular function after PDT in myopic maculopathy: psychophysical and electrophysiological evaluation. Invest Ophthalmol Vis Sci. 2005;46:1453-1462.
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7. Bach M, 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.
8. Parisi V, et al. Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma. Ophthalmology. 2006;113:216-228.
9. Bode SF, Jehle T, Bach M. Pattern electroretinogram in glaucoma suspects: new findings from a longitudinal study. Invest Ophthalmol Vis Sci. 2011;52:4300-4306..
10. Bayer AU, Erb C. Short wavelength automated perimetry, frequency doubling technology perimetry, and pattern electroretinography for prediction of progressive glaucomatous standard visual field defects. Ophthalmology. 2002;109:1009-1017.
11. Banitt MR, 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.