WHEN IT COMES TO TREATING presbyopia, our surgical solutions simply cannot deliver the accommodation of youth with refractive correction, and they come with a variety of limitations. Today’s commercially available refractive correction treatments for presbyopia employ a form of monovision, multifocality, extended depth of focus, or blended vision. All of these solutions, while offering some form of spectacle free vision, come with limitations in depth perception and loss of distance vision and still may require glasses for optimal stereoscopic vision, such as for night driving. The toughest demographic consists of patients who are presbyopic with a plano refraction and minimal to no cataractous changes. These patients are seeking a solution for presbyopia, but our current technology may not be able to give them the desired visual outcomes they need without compromise. Aside from monovision approaches, whether they are refractive or contact lens driven, there is more of a void than ever in the space.

Why are we at this standoff between patient motivation and market desaturation? With our current refractive solutions, patient management has been geared toward underpromising rather than overdelivering, and the industry has experienced a stalemate between patient uptake of current presbyopia treatments and innovative treatments that have sustainable market penetration. Although it is well known that presbyopia is multifactorial, there still has never been an exploratory or diagnostic evolution to understand its pathogenesis. Until now, there has only been a focus on the manipulation of optics to address near vision focal points. Presbyopia, however, is an extraordinarily complex but solvable problem if we delve into the core biomechanical aspects that impact the visual system with age.

The eye is made of primarily connective tissue that is impacted much like the other connective tissues of the body with age. Aging of connective tissues increases its stiffness, making it difficult for the cells to obtain oxygen and nutrients and impacting the biological efficiency of the organ.¹ The cause of this stiffness that occurs with age is the accumulation of advance glycation end products (AGEs), which provoke excessive crosslinking in the collagenous tissues of the eye.² The sclera, being 5/6 of the eye’s fibrous outer covering, is largely impacted, which is why ocular rigidity (OR) is correlated with age. Ocular rigidity has also been correlated with a progressive loss of Dynamic Range of Focus (DRoF), as well as a variety of ocular conditions, including but not limited to glaucoma, age-related macular degeneration, and decreased pulsatile ocular blood flow.^3,4

Presbyopia formation is also poorly documented and understood. A novel algorithm has been developed by Professor Olga Rozanova research at the Fyodorov Microsurgical Institute which is illuminating the underlying mechanisms of presbyopia formation as well as studying algorithms of this disease process using artificial neural networks to quantify the transformation of the visual system wth presbyopia progression. Her results quantified the hierarchy of impact of four core elements in presbyopia dysfunction including: 1) Reducing of accommodative (52%); 2) Reduction of binocularity field (22%); 3) Change of pupil diaphragmatic function(15%); and 4) “Noise” in light reception(11%). Her results provided conclusive evidence that aging and presbyopia formation lead to deterioration of relationships in Eye-Brain-Binocularity System.⁵ Presbyopia formation is accompanied by a significant reorganization of the visual system activity and by the creation of the new visual processing interactions and therefore individual binocularity parameters must be taken into account when determining the best presbyopia solution as well as understanding unhappy patients.⁶

Emerging therapeutics have shown promise in being able to satisfy these patients, and as already noted, studies have shown these patients are not motivated to undergo near vision correction procedures.⁷ In addition, these procedures mandate a degree of patient selection. Safety is paramount; however, there must be some consideration of patient selection regarding patient satisfaction, given the inherent compromises regarding visual function and quality of vision in exchange for spectacle independence.

Frustration with the lack of penetration in the market thus far by current multifocality approaches, whether laser or lenses, has sparked a recent interest in therapeutic alternatives to reading glasses. Two new approaches, miotic drops and laser scleral microporation (LSM), are illuminating neuromuscular facilitation, either at the sphincter pupillae (iris) through pharmacological stimulation, or at the ciliaris muscles through biomechanical restoration of neuromuscular efficiency. These two therapeutics will hopefully shift some attention from vision correction to therapeutic vision recovery solutions and illuminate additional insights into the mechanisms that produce our dynamic range of vision. The characterization of therapeutics can be understood as a biomechanical biopharmaceutical event that results in an optical impact.

Miotic drops constrict the sphincter pupillae, or the diaphragm of the iris muscle. By controlling the diameter of the pupil, the iris plays a role in the accommodative apparatus to trigger the neuromuscular response and control the amount of light entering the eye.⁸ Various recent alternative miotic therapeutic solutions are entering the market, one of which was recently FDA approved.

Miotics provide a reasonably minimally invasive temporary solution to one aspect of the loss of DRoF or pupillary miosis, and they can be utilized for near vision function. FDA trials for Vuity (Allergan) reported a 3-line increase or more in mesopic distance corrected near visual acuity in 31% of subjects in Gemini I and 26% in Gemini II.⁹ These drops must be reapplied every day. Results of long-term use of these formulations are currently unknown and should be studied for the impact on neural receptor recovery.

Another nonpharmacologic therapeutic option on the horizon is LSM, which is a biomechanical-based laser therapy that aims to recover the DRoF lost with age by improving the biomechanical efficiency of the accommodative apparatus. LSM specifically targets ocular rigidity in the sclera by “uncrosslinking” scleral microfibrils, thereby reducing the load on the intraocular structures required to dynamically move to facilitate the change in shape of the crystalline lens. This movement is the primary responsibility of the ciliary muscles, assisted by the elastic Bruch’s membrane (BM)–choroid complex (BMCC) translated through the zonular complex and the capsule to the lens.^10,11 By utilizing the laws of mechanics to increase the resultant forces on the lens, LSM indirectly facilitates DRoF recovery without directly treating the optics of the system (lens or cornea).

Preliminary pilot studies at 2 sites at the Asian Eye Institute (AEI) under the direction of Dr. Robert Ang are showing compelling results that a biomechanical application not only restores DRoF for all ranges but also demonstrates a side effect of reduced intraocular pressure (IOP) in normotensive eyes. Preliminary findings were reported at the 2022 ASCRS meeting in Washington, DC, from a pilot study of 54 eyes of 24 patients in which LSM was performed.¹² Binocular uncorrected visual acuity (VA) at 40 cm improved from 0.4 logMar (20/50.2) at baseline to 0.17 logMar (20/29.6) at 6 months and 0.23 logMar (20/34) at 12 months. Binocular distance-corrected VA at 40 cm improved from 0.43 logMar (20/53.8) at baseline to 0.16 logMar (20/28.9) at 6 months and 0.21 logMar (20/32.4) at 12 months. Near Activity Visual Questionnaire (NAVQ) scores demonstrated improvement from “moderate to extreme difficulty” to “no to little difficulty” at both the 6- and 12-month time points. Dr. Ang also reported on IOP reduction from baseline in normotensive eyes showing a drop in mean IOP from baseline of 14.82mmHg to 13.0 mmHg at 3 months, 12.24 at 6 months, and 11.83 mmHg at 12 months.

Early evidence is therefore showing not only the visual aspect of DRoF recovery but also the physiological impact of restoring the natural functions of the accommodative system. A small subset of the patients at AEI was also measured with a custom binarmeter developed by Prof. Olga Rozanova at the Fyodorov Microeyesurgery Institute, which was used to measure the binocular area in LSM patients. Pre- to post-treatment results showed LSM patients to have recovered 3 times more binocular area of summation after the procedure.¹³ The neuromuscular aspects of the LSM treatment are still being studied and are not yet completely understood. However, the patient’s subjective satisfaction with visual function has been corroborated by this data.

Classificatory tools are essential to redefine presbyopia as an age-related disease and not a refractive error to reflect the inherent progressive nature of this type of DRoF loss. This point should be emphasized if physicians want to be able to have relatable patient education, awareness, and treatment solutions that more precisely fit the patient’s experience wherever they are at in the cycle of aging. Presbyopia, much like wrinkles, is progressive, and will require different treatment options at different stages. Therefore, understanding the presbyopia development and progression pathway and utilizing more formal terms could provide a platform for building a treatment solution decision tree. Dysfunctional lens syndrome is a term coined to describe the natural aging changes in the crystalline lens.¹⁴ This index allows for a grading system from presbyopia to cataract development. Stages of classification of presbyopia is another staging system that correlates the stage of disability with the required reading add.¹⁵ These are important emerging classification tools to help physicians choose the right solution at the right time, as well as to help our patients understand the benefits and limitations of any given technology at their particular stage so that their expectations can be set appropriately. In addition, as more therapeutics develop, there will also be an eventual need for dosing regimens by stage for presbyopia and functional vision disability.

Technology is developing a new range of solutions for all of the various indications for the eye. Emphasis on the presbyopia market is critically needed due to the impact that uncorrected refractive error caused by presbyopia has on the increase in age-related vision impairment.¹⁶ A paradigm shift is absolutely necessary to tease out the core issues if we are to be able to finally have appropriate constructs to address this market, which to date still represents an increasingly large population with an unmet need. ■

References

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4. Pallikaris IG, Kymionis GD, Ginis HS, Kounis GA, Tsilimbaris MK. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci. 2005;46(2):409-414.
5. Rozanova OI, Shchuko AG, Mischenko TS. Fundamentals of Presbyopia: visual processing and binocularity in its transformation. Eye Vis (Lond). 2018;5:1.
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8. Bloom J, Motlagh M, Czyz CN. Anatomy, Head and Neck, Eye Iris Sphincter Muscle. Published 2018. Accessed August 10, 2022. https://www.ncbi.nlm.nih.gov/books/NBK532252/
9. Vuity Full Prescribing Information. Accessed August 8, 2022. https://www.rxabbvie.com/pdf/vuity_pi.pdf%20%20
10. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res. 2010;29(2):144-168.
11. Wang X, Teoh CKG, Chan ASY, Thangarajoo S, Jonas JB, Girard MJA. Biomechanical Properties of Bruch’s Membrane–Choroid Complex and Their Influence on Optic Nerve Head Biomechanics. Invest Ophthalmol Vis Sci. 2018;59(7):2808-2817.
12. Ang R, Hipsley AM, Jackson M. A Pilot Prospective Study of Laser Scleral Microporation (LSM) on Emmetropic Presbyopes: One Year Outcomes. Presentation as 2022 ASCRS, Washington DC.
13. Rozanova O, Hipsely AM. Concepts in Presbyopia Formation and treatment of presbyopia while preserving binocularity using LaserACE procedure. Presentation at ASCRS 2021 at Las Vegas, NV.
14. Waring GO, Rocha KM. Characterization of the Dysfunctional Lens Syndrome and a Review of the Literature. Current Ophthalmology Reports. 2018;6(4):249-255.
15. Hipsley AM, Waring G, Rocha K. Development of a Presbyopia Progression Classification System. Presentation at ASCRS 2022, Washington DC.
16. Fricke TR, Tahhan N, Resnikoff S, et al. Global Prevalence of Presbyopia and Vision Impairment from Uncorrected Presbyopia: Systematic Review, Meta-analysis, and Modelling. Ophthalmology. 2018;125(10):1492-1499.

Dr. Hipsley is founder & CEO of Ace Vision Group. She has been an entrepreneur for over 30 years, founding her first private practice in 1991. She is the inventor of the revolutionary LaserACE and the newly developed Laser Scleral Microporation (LSM) procedure, both aimed at restoring physiological dynamic accommodation. Over the past 20+ years, she has trained over 100 ophthalmic surgeons worldwide in the use of near infrared lasers for biological tissue microporation.

Dr. Ang is a senior consultant at the Asian Eye Institute, Philippines. In addition to his clinical responsibilities, his passion includes teaching fellows and residents, and performing research studies on presbyopia, IOL technology, and glaucoma devices.

Prof. Rozanova is ophthalmologist, senior researcher, and head of the medical department at FSAI Academician S N Fedorov National Medical Research Center Intersectoral Research and Technical Complex Eye Microsurgery, Irkutsk Branch, Russia.