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Presbyopia Physician

Article

Pathogenesis of Presbyopia: A New Understanding of an Age-Old Disease

The Progressive Presbyopia Problem

By: ANNMARIE HIPSLEY, DPT, PHD, Max Colbert, MD, MBA
Presbyopia Physician June 1, 2022 Vol 2, Issue June 2022 Page(s): 20-22

FOR MOST OF HISTORY, PRESBYOPIA has been defined as a "normal" refractive error caused by age, with discussion limited to the loss of near vision beginning in our 40s. Because we have had no effective therapeutic interventions available, presbyopia has been accepted as a natural part of life and treated primarily by changing power at either the cornea or the lens, hallmarked with some type of visual compromise. The reality is that presbyopic solutions have failed to adequately address this large unmet market, frustrating both physicians and industry. This has led to a waning interest in presbyopic treatments and a currently empty space for devices and therapeutics to treat this growing population. Recent developments in pharmacological presbyopia therapeutics have sparked a renewed enthusiasm in the advancement of presbyopia treatments. However, the real etiology of the loss of accommodative function and its impact on the eye as we age – beyond just the loss of near vision – has yet to be addressed. As we enter this exciting new age of presbyopia therapeutics, it is essential to understand the complex pathophysiology of the aging eye, as well as the pathogenesis of biomechanical dysfunction of accommodation. Illuminating these pathogeneses must be achieved to realize an effective approach to this progressive disease, which to a large extent has age-related biomechanical implications.

 

Figure 1. Changes in tissue elasticity with age. Materials’ properties came from References 2-5.
Figure 1. Changes in tissue elasticity with age. Materials’ properties came from References 2-5.

 

A New Paradigm

The word presbyopia derives from the Greek roots presby and opia, meaning “aging” and “eye,” respectively. In fact, the same pathophysiologic changes of age-related crosslinking that contribute to the loss of dynamic range of focus (DRoF) known as presbyopia also lead to the development and progression of other age-related ophthalmic disorders, such as ocular hypertension, age-related macular degeneration, and even age-related cataracts. The biomechanical issues that are impacted by crosslinking create a cascade or “chain reaction” of changes in oxidative stress and biomechanical properties, creating increased biomechanical stiffness in the sclera and loss of elasticity of the lens, choroid, Bruch’s membrane, and other elastic structures of the eye.1 Both lenticular and extralenticular factors impact the progression of presbyopia with age and must be considered when conceiving of a therapeutic restoration of accommodation that impacts the whole eye. The clinical manifestation of this pathogenesis is called presbyopia.

 

Figure 2. Collagen crosslinking. Three collagen strands are coiled together in a helix. Covalent crosslinking within and among helices occurs, forming fibrils that are bundled into fibers. With aging, the amount of crosslinking increases, causing greater tissue stiffness. In the eye, this results in increased ocular rigidity and is associated with presbyopia and other ocular diseases.
Figure 2. Collagen crosslinking. Three collagen strands are coiled together in a helix. Covalent crosslinking within and among helices occurs, forming fibrils that are bundled into fibers. With aging, the amount of crosslinking increases, causing greater tissue stiffness. In the eye, this results in increased ocular rigidity and is associated with presbyopia and other ocular diseases.

 

The Root of the Presbyopia Problem is AGEs

As humans age, we accumulate harmful molecules called advanced glycation end products (AGEs) through both endogenous formation and exogenous sources.6 These AGEs contribute to the development of many age-related pathologies, such as presbyopia, diabetes, cardiovascular disease, neurodegenerative diseases, and various malignancies.6,7 AGEs contribute to the development of presbyopia by behaving as reactive oxygen species, which negatively impact the aging eye through oxidative stress, inflammation, and collagen crosslinking.6,7 At a high level, presbyopia begins to manifest as AGEs damage an array of ocular structures, namely the sclera, Bruch’s membrane-choroid complex, lens, ciliary muscle, and pupil. Most interventions to date have aimed to alleviate the symptoms of presbyopia, but few have targeted the underlying pathophysiology. Understanding how age-related damage to each of these structures impairs accommodative biomechanics is necessary for appreciating the complex aging disease of presbyopia and its impacts on visual accommodation, aqueous outflow hydrodynamics, pulsatile ocular blood flow, and so on. This paradigm shift could provoke a new understanding of these mechanisms and lead to the development of more effective and lasting therapeutic approaches.

The Future of the Aging Eye

Loss of visual accommodation, or DRoF, which is labeled presbyopia today, is biomechanical dysfunction that requires a biomechanical solution to have the possibility of restoring this mechanical muscular driven function. Ocular rigidity caused by progressive crosslinking and scleral stiffness has been linked to the etiology of the initial stages of loss of visual accommodation.2 This creates a clinically significant reason to treat ocular rigidity. A new innovative therapy called laser scleral microporation (LSM, Ace Vision Group) is a treatment for the aging eye, and it is a laser technology designed to reverse the effects of crosslinking created by AGEs and decrease biomechanical stiffness, thereby allowing the ciliary muscle forces to impart a larger resultant shape change to the lens with accommodative stimulus. The VisioLite system is designed with capacity to customize the microporation pattern, allowing for re-treatment, expansion, and control of the treatment nomograms. LSM is a dosable, re-treatable solution to the ever-progressive problem of crosslinking and age-related vision loss. The procedure is performed in an exam room setting and takes 6-8 minutes. It is a touchless, painless therapy that is not aimed at the visual optics of the eye but rather at the white part or scleral connective tissues of the eye. The results are restorative and therefore are noticeable on the same day or next day, but they improve over time without refractive compromise.

In addition to the manifestation of presbyopia, age-related crosslinking imposes risks of the development and incidence of age-related ocular diseases that are united by etiologies that likely include age-related changes to the rigidity of ocular tissues. Therefore, therapies aimed at restoring healthy material properties in the eye may be successful in treating/preventing multiple diseases.7 LSM is the first comprehensive biomechanical solution to restoring the biomechanics of the accommodation apparatus, which potentially has visual, as well as ocular, health implications.

Conclusion

It is an exciting time in ophthalmology: for the first time ever, we are able to offer our presbyopic patients more than a pair of readers as a solution to their visual disabilities. As more and more interventions are developed, it is important to see presbyopia as the incredibly complicated aging disease that it is. The symptoms experienced are not explained by changes in any of the structures discussed above but are a result of many age-related and biomechanical changes occurring throughout the eye, creating a “chain reaction” of pathophysiological issues that challenge the eye’s ability to respond to stress. It is our duty to our patients to learn how each of these structures is impacted by the aging process, to appreciate the clinical significance of these changes, and to embrace therapeutic approaches that address the aging eye. Perhaps the famous quote “The definition of insanity is to keep doing the same thing over and over and expecting different results” should be seriously pondered in the arena of presbyopic treatment solutions. It is time to unveil and understand the truth about the aging eye. Assigning ourselves to truly address a “lifetime vision” opportunity for our patients will require not only innovation but more importantly changing the current presbyopic treatment paradigm from “vision correction only” approaches “to vision restoration and visual sustainability.” ■

Figure 3. LSM therapy for presbyopia. (Upper left) Collagen crosslinking increases with age, causing increased stiffness. (Upper right) LSM creates micropores in the sclera overlying the accommodative apparatus. (Lower left) LSM disrupts the weave of collagen fibers, reversing the effect of crosslinking. (Lower Right) Accommodative function is restored.
Figure 3. LSM therapy for presbyopia. (Upper left) Collagen crosslinking increases with age, causing increased stiffness. (Upper right) LSM creates micropores in the sclera overlying the accommodative apparatus. (Lower left) LSM disrupts the weave of collagen fibers, reversing the effect of crosslinking. (Lower Right) Accommodative function is restored.
Figure 4. Ocular diseases associated with elevated ocular rigidity.
Figure 4. Ocular diseases associated with elevated ocular rigidity.

References

  1. Hipsley A, Hall B, Rocha KM. Scleral surgery for the treatment of presbyopia: where are we today? Eye Vis (Lond). 2018;5:4.
  2. 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.
  3. Friberg TR, Lace JW. A comparison of the elastic properties of human choroid and sclera. Exp Eye Res. 1988;47(3):429-436.
  4. Starita C, Hussain AA, Pagliarini S, Marshall J. Hydrodynamics of ageing Bruch’s membrane: implications for macular disease. Exp Eye Res. 1996;62(5):565-572.
  5. Ugarte M, Hussain AA, Marshall J. An experimental study of the elastic properties of the human Bruch’s membrane-choroid complex: relevance to ageing. Br J Ophthalmol. 2006;90(5):621-626.
  6. Rungratanawanich W, Qu Y, Wang X, Essa MM, Song BJ. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp Mol Med. 2021;53(2):168-188.
  7. Schultz DS, Lotz JC, Lee SM, Trinidad ML, Stewart JM. Structural factors that mediate scleral stiffness. Invest Ophthalmol Vis Sci. 2008;49(10):4232-4236.
  8. Croft MA, Lütjen-Drecoll E, Kaufman PL. Age-related posterior ciliary muscle restriction--A link between trabecular meshwork and optic nerve head pathophysiology. Exp Eye Res. 2017;158:187-189.
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. 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. Colbert is an ophthalmology resident at the New York University Department of Ophthalmology. He is the head of marketing for an ophthalmic imaging device start-up and has previously worked as a Venture Associate with Flying L Partners. Prior to medical school, Dr. Colbert worked in drug development at the National Institutes of Health.

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