Updates in Glaucoma Research

Top: Janelle Tong, Dr Ashish Agar. Bottom: Eleanor Hall, Edward Trang.

IOP: MORE THAN JUST ONE MEASUREMENT

Measurement of intraocular pressure (IOP) variations has garnered increasing interest, especially considering that patients with glaucoma typically show larger diurnal variations.¹ However, inoffice measurements may not adequately represent diurnal IOP profiles, particularly when considering that peak IOPs occur outside of office hours in up to 69% of patients.² Various methods of measuring IOP outside of office hours have been developed, including rebound tonometry, contact lens sensors and surgically implanted sensors. Out of these, rebound tonometers such as the Icare HOME are the most practical to implement. Using the Icare HOME, peak IOPs were found outside of office hours in 48% of glaucoma patients and glaucoma suspects, with 85% exhibiting peak IOPs in the morning.³ Subsequently, comparisons of Icare HOME and applanation IOPs have enabled derivations allowing for identification of significant IOP elevations warranting further clinical review.⁴ At the Centre for Eye Health, the Icare HOME has become routinely incorporated into glaucoma management, enabling identification of patients with significant IOP peaks and fluctuations and therefore those that would benefit from treatment initiation or modification.

At the Centre for Eye Health, the Icare HOME has become routinely incorporated into glaucoma management…

Zeiss’ new Cirrus 6000, 100kHz ultra-fast optical coherence tomography (OCT) system.

THE FUTURE OF HUMPHREY VISUAL FIELDS TESTING

While the 24-2 SITA Standard is the current mainstay of clinical visual field testing, its relatively long test duration introduces potential fatigue-related artefacts and limits frontloading of results. This has driven the development of SITA Faster, which has reduced test time by approximately 50%.⁵ Although SITA Faster is more likely to produce unreliable results, threshold sensitivities are comparable to SITA Standard,⁶ and the time saving afforded with SITA Faster offsets the additional time required for repeat testing. Facilitation of multiple same-day visual fields testing in turn enables best practice care, and in this way, SITA Faster has revolutionised the way visual fields can be conducted in practice.

The Icare Home allows patients to measure intraocular pressure at home at different times of the day.

Furthermore, the central 20° is only sampled by 16 test locations using the 24-2 test grid, which may miss paracentral damage detected using higher density grids like the 10-2.⁷ To reduce the need to perform both 10-2 and 24-2 visual fields, the 24-2C grid includes 10 additional paracentral test locations that are susceptible to glaucomatous damage,⁸ however at this stage we are awaiting further research to determine the capability of the 24-2C to precisely characterise central visual field defects. Nonetheless, more frequent use of the 24-2C could potentially change the way glaucoma is characterised and staged.

Melbourne Rapid Fields 

In Australia, the most commonly used modality is the Humphrey Field Analyser (HVF) 24-2 SITA Standard. The greatest downfalls of HVF are its bulkiness, cost and relatively long test durations. It is well-known that factors such as testing time, level of distraction and exhaustion⁹ can reduce arousal and alertness and significantly hinder the reliability of the results.¹⁰

Glaukos iStent Inject (top and above).

These barriers can be addressed through rapid tablet-based programs. Melbourne Rapid Fields (MRF) was developed by Dr George Kong from the RVEEH to use the iPad’s large dynamic luminance range with 8-bit luminance control and high spatial resolution.¹¹ A research group at UNSW trialled the VF screening parameter offered by MRF on 67 glaucoma patients and 18 glaucoma suspects (139 eyes) from the Prince of Wales Hospital eye clinic and the Outback Eye Service in western NSW. Using HVF 24-2 standard results as the reference test, MRF screening achieved a sensitivity of 94.6%, specificity of 66.3%, positive predictor value of 65.4% and negative predictor value of 94.8%. Overall, MRF screening was 2.9 times faster than HVF and post-test surveys showed patients preferred MRF for its ease and testing experience.

MRF is suitable as a low-cost, userfriendly portable device for rapid vision testing. Future VF tests may involve the introduction of home testing and complementary use of iPad perimetry in access-poor settings, with referrals to standard testing in glaucoma suspects.

Accurate detection of glaucoma is dependent on clinician expertise and, particularly in the early stages of disease, is quite subjective

Hydrus Microstent canal based ab interno MIGS device.

DEVELOPMENTS IN OCT

The 24-2 test grid is typically used in visual fields testing for all glaucoma patients despite individual anatomical variations and the nature of underlying structural deficits. As such, there is exciting work into customisation of test grids based on optical coherence tomography (OCT) measurements of the retinal nerve fibre layer, with additional test locations added to the borders of areas with significant structural deficits.^12,13 This technique characterises the extent of visual field defects with greater precision, which could herald the move towards customised visual fields testing rather than the current ‘one test fits all’ approach.

Despite advances in visual field testing algorithms, there is still a significant burden associated with repeated visual fields testing for both patients and clinicians. As such, techniques to predict visual field sensitivity from OCT are currently being researched,¹⁴ with current efforts hampered by factors contributing to excessive variability. Computational analysis methods are able to redistribute this variability, enabling accurate prediction of visual field sensitivity from OCTderived retinal measurements.¹⁵ Work to apply these findings to prediction of visual field sensitivity in glaucoma patients is currently underway, with the future clinical impact potentially including OCT playing an increasing role in guiding glaucoma management decisions.

Ellex iTrack Canaloplasty Microcatheter.

AUTOMATED GLAUCOMA DETECTION: ROLE OF AI

Accurate detection of glaucoma is dependent on clinician expertise and, particularly in the early stages of disease, is quite subjective.¹⁶ Therefore, it may be possible to apply a more objective artificial intelligence (AI) approach to clinical results, such as clinician-assisting technologies, to help overcome problems with subjective evaluation.¹⁷ Machine and deep learning have been applied in numerous aspects of the glaucoma examination, from optic nerve head images¹⁷ and OCTs¹⁸ to anterior chamber angle profiles,¹⁹ with sensitivities and specificities exceeding 90%.¹⁷ While promising, as these approaches are typically stand-alone, work to integrate findings from AI systems covering different aspects of the glaucoma examination is required before wide-spread use of these systems will be possible.

MINIMALLY INVASIVE GLAUCOMA SURGERIES

Subconjunctival Xen gel implant in place forming a low diffuse bleb.

Minimally invasive glaucoma surgeries (MIGS) are relatively new to the glaucoma treatment paradigm and there has been much discussion on when and to whom they should be offered. Two primary MIGS exist on the Australia-New-Zealand market, the Ivantis Hydrus and the Glaukos iStent Inject. Both devices can be inserted as a standalone procedure or in conjunction with cataract surgery. Emerging literature continues to confirm MIGS as highly safe devices which can provide varying IOP and medication reductions.^20,21,22,23

MIGS are routinely performed as a combined surgery, but evidence is building for their use as standalone devices. Significant reductions have been demonstrated with standalone Hydrus in prospective cases series;^{24 23} ± 5.1mmHg to 16.5 ± 2.6mmHg, with 47% of eyes medication free at 12 months (n= 31) and retrospective case series²⁵ finding an IOP reduction from 24 ± 6mmHg to 15 ± 3mmHg at 24 months.

Insertion of the Cypass MicroStent.

Literature available on the iStent has shown a favourable reduction in IOP when compared to pharmacological treatments.^26,27,28 Comparisons between MIGS is sparse, however 12 month results from the COMPARE study, the first RCT comparing standalone Hydrus with standalone iStent are available. They demonstrate a reduction in IOP and medications in both groups, with the Hydrus arm achieving a greater rate of surgical success (p< 0.001) with more patients’ medication free (difference = -0.6 medications, P = 0.004).23 Future research, particularly that using large databases such as the Hydrus Worldwide Registry, could help identify the specific population who would benefit most from a MIGS device.

PolyActiva implant in place.

Janelle Tong graduated with a Bachelor of Optometry (Hons)/Bachelor of Science degree from UNSW Australia. She was the recipient of the University Medal and several other academic awards throughout her university career. Prior to joining CFEH, she worked in a full-scope private practice in Sydney, where she developed her interest in managing posterior ocular disease. Janelle is involved in both clinical and research aspects of CFEH, with her current research looking at modelling normal ageing changes to the eye using advanced imaging. 

Dr Ashish Agar is a glaucoma consultant at the Prince of Wales and Sydney Eye Hospitals, and a partner at Marsden Eye Specialists. He obtained his Glaucoma Fellowship from Oxford and is a Conjoint Senior Lecturer at the University of New South Wales, engaged in clinical studies as well as laboratory research with a PhD in glaucoma pathogenesis. He provides glaucoma services in far western NSW with the Outback Eye Service, and is involved in Indigenous health, medical education and international ophthalmology. 

Monaco, distributed by Optos, is an ultra-widefield retinal imaging device with integrated OCT.

Eleanor Hall and Edward Trang are UNSW medical students who have completed an independent research year with Dr Agar at the Prince of Wales Hospital and Outback Eye Service. Ms Hall studied MIGS devices and Mr Trang trialled the MRF iPad visual field device. Dr Agar noted that both have shown a flair for investigational research and data analysis that belies their early researcher status. 

The research from Centre for Eye Health cited in this article has been supported by independent grant funding and research support from Guide Dogs NSW/ACT. There are no financial conflicts of interest to disclose regarding the companies cited. 

References 

1. Sihota R, Saxena R, Gogoi M, Sood A, Gulati V, Pandey RM. A comparison of the circadian rhythm of intraocular pressure in primary chronic angle closure glaucoma, primary open angle glaucoma and normal eyes. Indian J Ophthalmol 2005;53(4):243-7. 
2. Barkana Y, Anis S, Liebmann J, Tello C, Ritch R. Clinical utility of intraocular pressure monitoring outside of normal office hours in patients with glaucoma. Arch Ophthalmol 2006;124:793-7. 
3. Huang J, Katalinic P, Kalloniatis M, Hennessy MP, Zangerl B. Diurnal intraocular pressure fluctuations with selftonometry in glaucoma patients and suspects: A clinical trial. Optom Vis Sci 2018;95(2):88-95. 
4. Huang J, Phu J, Kalloniatis M, Zangerl B. Determining significant elevation of intraocular pressure using selftonometry. Optom Vis Sci 2019. 
5. Heijl A, Patella VM, Chong LX, et al. A new sita perimetric threshold testing algorithm: Construction and a multicenter clinical study. Am J Ophthalmol 2019;198:154-65. 
6. Phu J, Khuu SK, Agar A, Kalloniatis M. Clinical evaluation of sita-faster compared to sita-standard in normal subjects, glaucoma suspects and glaucoma patients. Am J Ophthalmol 2019; doi:10.1016/j.ajo.2019.08.013. 
7. Grillo LM, Wang DL, Ramachandran R, et al. The 24-2 visual field test misses central macular damage confirmed by the 10-2 visual field test and optical coherence tomography. Transl Vis Sci Technol 2016;5(2):15. 
8. Hood DC, Raza AS, de Moraes CG, Liebmann JM, Ritch R. Glaucomatous damage of the macula. Prog Retin Eye Res 2013;32:1-21. 
9. Montolio, F.G.J., Wesselink, C., Gordijn, M. and Jansonius, N.M., 2012. Factors that influence standard automated perimetry test results in glaucoma: test reliability, technician experience, time of day, and season. Investigative ophthalmology & visual science, 53(11), pp.7010-7017. 
10. Glen, F.C., Baker, H. and Crabb, D.P., 2014. A qualitative investigation into patients’ views on visual field testing for glaucoma monitoring. British Medical Journal open, 4(1), p.e003996. 
11. Vingrys, A.J., Healey, J.K., Liew, S., Saharinen, V., Tran, M., Wu, W. and Kong, G.Y., 2016. Validation of a Tablet as a Tangent Perimeter. Translational vision science & technology, 5(4), pp.3-3. 
12. Ballae Ganeshrao S, Turpin A, McKendrick AM. Sampling the visual field based on individual retinal nerve fiber layer thickness profile. Invest Ophthalmol Vis Sci 2018;59:1066-74. 
13. Turpin A, Morgan WH, McKendrick AM. Improving spatial resolution and test times of visual field testing using arrest. Transl Vis Sci Technol 2018;7(5):35. 
14. Guo Z, Kwon YH, Lee K, et al. Optical coherence tomography analysis based prediction of humphrey 24-2 visual field thresholds in patients with glaucoma. Invest Ophthalmol Vis Sci 2017;58(10):3975-85. 
15. Tong J, Phu J, Khuu SK, et al. Development of a spatial model of age-related change in the macular ganglion cell layer to predict function from structural changes. Am J Ophthalmol 2019; doi:10.1016/j.ajo.2019.04.020. 
16. Blumberg DM, De Moraes CG, Liebmann JM, et al. Technology and the glaucoma suspect. Invest Ophthalmol Vis Sci 2016;57(9):OCT80-5. 
17. Liu S, Graham SL, Schulz A, et al. A deep learningbased algorithm identifies glaucomatous discs using monoscopic fundus photographs. Ophthalmology Glaucoma 2018;1(1):15-22. 
18. Maetschke S, Antony B, Ishikawa H, Wollstein G, Schuman J, Garnavi R. A feature agnostic approach for glaucoma detection in oct volumes. PLoS One 2019;14(7):e0219126. 
19. Phu J, Wong B, Lim T, Kalloniatis M. Can anterior segment optical coherence tomography describe gonioscopic features as a continuum of change? Implications for the clinic and artificial intelligence. Americal Academy of Optometry; Orlando, FL2019. 
20. Pfeiffer, N, Garcia-Feijoo, J, Martinez-de-la-Casa, JM, Larrosa, JM, Fea, A, Lemij, H, Gandolfi, S, Schwenn, O, Lorenz, K, and Samuelson TW 2015, ‘A Randomized Trial of a Schlemm’s Canal Microstent with Phacoemulsification for Reducing Intraocular Pressure in Open-Angle Glaucoma’, Ophthalmology, vol. 122, no.7, pp. 1283-1293. 
21. Fea, AM, Ahmed, IIK, Lavia, C, Mittica, P, Consolandi, G, Motolese I, Pignata, G, Motolese, I, Rolle, T and Frezzotti, P 2017, ‘Hydrus microstent compared to selective laser trabeculoplasty in primary open angle glaucoma: one year results’, Clinical & Experimental Ophthalmology, vol. 45, no. 2, pp. 120-127, DOI:10.1111/ceo.12805. 
22. Samuelson, TW, Chang, DF, Marquis, R, Flowers, B, Lim, KS, Ahmed, IIK, Jampel, HD Aung, T, Crandall, AS, Singh, K, HORIZON Investigators 2019, ‘A Schlemm Canal Microstent for Intraocular Pressure Reduction in Primary Open-Angle Glaucoma and Cataract: The HORIZON Study’, Ophthalmology, vol. 126, no. 1, pp. 29-37. 
23. Ahmed, IIK, Fea, A, Au, L, Ang, RE, Harasymowycz, P, Jampel, H, Samuelson, TW, Chang, DF and Rhee, DJ 2019, ‘A Prospective Randomized Trial Comparing Hydrus and iStent Microinvasive Glaucoma Surgery Implants for Standalone Treatment of Open-Angle Glaucoma: The COMPARE Study’, Ophthalmology, accessed July 2019, DOI:10.1016/j.ophtha.2019.04.034. 
24. Fea, AM, Ahmed, IIK, Lavia, C, Mittica, P, Consolandi, G, Motolese I, Pignata, G, Motolese, I, Rolle, T and Frezzotti, P 2017, ‘Hydrus microstent compared to selective laser trabeculoplasty in primary open angle glaucoma: one year results’, Clinical & Experimental Ophthalmology, vol. 45, no. 2, pp. 120-127, DOI:10.1111/ceo.12805. 
25. Gandolfi, SA, Ungaro, N, Ghirardini, S, Tardini, MG, & Mora, P 2016, ‘Comparison of Surgical Outcomes between Canaloplasty and Schlemm’s Canal Scaffold at 24 Months’ Follow-Up’, Journal of Ophthalmology, vol. 2016, art. no. 3410469, DOI:10.1155/2016/3410469. 
26. Fea, a.m., Belda, J.I., Rękas, M., Jünemann, A., Chang, L., Pablo, L., Voskanyan, L. And Katz, L.J., 2014. ‘Prospective unmasked randomized evaluation of the iStent inject versus two ocular hypotensive agents in patients with primary open-angle glaucoma’. Clinical ophthalmology, 8, pp. 875-882. 
27. Vold, S.D., Voskanyan, L., Tetz, M., Auffarth, G., Masood, I., AU, L., Ahmed, I.I.K. and Saheb, H., 2016. Newly Diagnosed Primary Open-Angle Glaucoma Randomized to 2 Trabecular Bypass Stents or Prostaglandin: Outcomes Through 36 Months. Ophthalmology and therapy, 5(2), pp. 161-172 
28. Lavia, C, Dallorto, L, Maule, M, Ceccarelli, M, and Fea, AM 2017, ‘Minimally-invasive glaucoma surgeries (MIGS) for open angle glaucoma: A systematic review and metaanalysis’, PLOS ONE, vol. 12, no. 8, DOI: 10.1371/journal. pone.0183142.