Comparing the Utility of Retinal Nerve Fiber Layer and Ganglion Cell Inner Plexiform Layer OCT Changes to Detect Glaucoma Progression

Pham AT, Bradley C, Yohannan J. Comparing the Utility of Retinal Nerve Fiber Layer and Ganglion Cell Inner Plexiform Layer OCT Changes to Detect Glaucoma Progression. Ophthalmology. 2026 Jan;133(1):12-23.

Question

What is the comparative utility of measuring circum-papillary retinal nerve fiber layer vs measuring macular ganglion cell-inner plexiform layer in detecting glaucoma progression in eyes with and without visual field progression across a broad range of disease severity.

Background/Summary of Findings

Optical coherence tomography (OCT) plays a critical diagnostic and monitoring role in glaucoma. OCT measurement of the retinal nerve fiber layer can reflect retinal ganglion cell axonal loss and may be an early indicator of progression. OCT measurement of the Ganglion cell-inner plexiform layer directly assesses the macula, which contains the highest density of retinal ganglion cells in the eye. Both measurements have been shown to have value in disease detection and as biomarkers of management success or failure. Notably, when retinal nerve fiber layer has thinned to a level at which OCT can no longer detect structural change, ganglion cell-inner plexiform layer measurements may still provide viable information due to the inherently larger concentration of retinal ganglion cell bodies in the macula and subsequently measurable residual tissue thickness. Previous studies on ganglion cell-inner plexiform layer thickness have mostly focused on early detection and progression in more mild disease states. Studies comparing retinal nerve fiber layer thinning to ganglion cell-inner plexiform layer thinning in progression are also limited. Determining which measure is more associated with progression at each stage of disease would help optimize how patients are monitored.

This was a retrospective, longitudinal study including a total of 2464 eyes with longitudinal testing ( ≥ 5 reliable circum-papillary retinal nerve fiber layer, macular ganglion cell-inner plexiform layer, and visual field measurements). All circum-papillary retinal nerve fiber layer and macular ganglion cell layer measurements were within a year of a visual field test. The authors used linear regression to measure rates of thinning in suspect, mild, moderate, and advanced glaucoma (severity defined by Hodapp-Parrish-Anderson criteria). Thinning rates were compared between eyes with and without visual field progression and then logistic mixed effects models were used to estimate the impact of cpRNFL and mGCIPL thinning rates on the probability of visual field progression. Lastly, general linear hypothesis testing was used to assess the effect of retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning rates in each stage of severity. The main outcome measures were the rates of circum-papillary retinal nerve fiber layer and macular ganglion cell-inner plexiform layer thinning (μm/year), stratified by disease severity.

The authors found that both retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning rates were significantly faster in progressing eyes (—1.02 and —1.04 μm/year, respectively) than in nonprogressing eyes (—0.41 and —0.41 μm/year, respectively). The effect of cpRNFL and mGCIPL thinning on the probability of visual field progression was similar overall (2.4% vs. 2.1% increased probability per 1 μm/year faster rate of thinning) but differed depending on the glaucoma severity. The effect of cpRNFL thinning was greatest in glaucoma suspects but was not statistically significant in advanced glaucoma. In contrast, the effect of macular ganglion cell-inner plexiform layer thinning was smallest in suspects, increased with worsening disease severity, and was still statistically significant in advanced disease. The authors concluded that circum-papillary retinal fiber layer and macular ganglion cell-inner plexiform layer changes serve complementary roles in monitoring glaucoma progression depending on the stage of disease severity. Retinal nerve fiber layer is more strongly associated with visual field progression in early glaucoma when compared to ganglion cell-inner plexiform layer, whereas ganglion cell-inner plexiform layer is more strongly associated with progression in later stages of disease when compared to retinal nerve fiber layer.

Clinical Value/Implications

Although concurrent retinal nerve fiber layer and GC-IPL assessment is recommended in glaucoma care, this study demonstrates that the severity of the disease should steer the relative emphasis we place on each parameter, with the consideration that the individual utility of each may be contingent on how much remaining neural tissue can be captured.

Ophthalmic Drug Shortages in the United States: Survey of the University of Utah Drug Information Service Drug Shortage Database

Eakins RT, Lowrie LN, Stagg BC, Okudo A, Simpson R, Larochelle M, Fox ER, Pitha I. Ophthalmic Drug Shortages in the United States: Survey of the University of Utah Drug Information Service Drug Shortage Database. Ophthalmology. 2026 Feb 26:S0161-6420(26)00125-9

Question

What is the extent and complexion of ophthalmic drug shortages in the United States over the past 23 years?

Background/Summary of Findings

Prescription drug shortages represent a serious and well-recognized public health threat in the United States. There are a multitude of factors that contribute to shortages. The consequences can be substantial and can jeopardize both patient safety as well as their trust in the healthcare system, whose ability to deliver necessary medications has become increasingly more uncertain. Ophthalmology is not immune to shortages with certain aspects of ophthalmic drugs potentially elevating their risk of shortage. These include the need for specialized facilities for ophthalmic drug production, a greater proportion of generic drugs that are associated with lower profit margins and, therefore, less incentive to avoid and fix shortages, and limited redundancy in drug production. The impact of recent ophthalmic medication shortages underscores the need to study and understand these shortages. The University of Utah Drug Information Service offers a comprehensive recording of nationwide drug shortages since January 2001. The University of Utah Drug Information Service collects and publishes critical shortage information on a public website hosted by the American Society of Health-System Pharmacists. A drug is considered to be in shortage when there is a “supply disruption that affects how the pharmacy prepares or dispenses a drug product or that influences patient care when prescribers must use an alternative agent.” Reports of shortages are submitted voluntarily through the American Society of Health-System Pharmacists website and are verified by the University of Utah Drug Information Service clinical pharmacists. Verification involves identifying all potential manufacturers, contacting them directly to confirm whether a shortage exists, and collecting information on its cause and estimated resolution date. In this study, the authors utilized the University of Utah Drug Information Service database to survey ophthalmic drug shortage reports from January 2001 through June 2024.

Using a retrospective review of the University of Utah Drug Information Service database, drug shortage reports from 2001 to 2024 were reviewed, excluding shortages due to drug discontinuation, business decision, or duration of 1 day or less. Included were 3086 drug shortage reports, subsequently reviewed by a panel of four ophthalmologists and a clinical pharmacist. Drugs used in ophthalmology were highlighted, and their clinical applications were established. Drug delivery route (local vs systemic), the cause of the shortage, the duration of the shortage, and whether the drug was patent protected during the shortage were assessed.

The results showed that of the shortage reports, 379 were of ophthalmic medications, of which, 329 shortages had been resolved, and 50 remained active as of June 2024. On average, ophthalmic medications accounted for 15% of active shortages at any given time. Systemic and locally delivered medications were equally represented; most shortages were of anti-infective medications (35%) and steroids (26%). The leading causes of ophthalmic medication shortages were unknown (63%), manufacturing problems (20%), and supply/demand mismatch (10%). Median duration of ophthalmic medication shortage was 326 days (IQR, 145-695); nearly 30 days longer than the median duration for all drugs (298 days, IQR, 111-619, p = .023). Mean shortage duration of ophthalmic medications that were patent protected during each shortage was significantly less (184 days; IQR 48-422) than medications that experienced a shortage while off-patent (359 days, 164-755, p < .0001).

Clinical Value/Implications

Ophthalmic drug shortages comprise a significant percentage of drug shortages overall and are certainly not rare. The average length of ophthalmic drug shortages is substantial, with generic medications more likely to be unavailable for longer. We as practitioners need to be aware of the characteristics of drug shortages, not be surprised when they occur, and adapt our therapies to most effectively address patient care needs if, and when, their current medication becomes unavailable.

Utilization Patterns and Costs of Ocular Amniotic Membrane Grafts in the Medicare Population

Vail DG, Nudleman E, Abdeljaber L, Haque ME, Pershing S. Utilization Patterns and Costs of Ocular Amniotic Membrane Grafts in the Medicare Population. Ophthalmology. 2026 Jan;133(1):51-59

Question

What were the trends in the volume, cost, and clinical indications associated with the ophthalmic use of suture less amniotic membrane grafts in a Medicare population from 2011-2020.

Background/Summary of Findings

A recent New York Times investigation concluded that substantial fraudulent billing for wound care occurs in fee-for-service Medicare. The investigation focused on the use of “skin substitutes” used for treatment of patients with chronic wounds and described a confluence of factors that have contributed to overuse of preserved tissue bandages in wound care, including a “buy and bill” reimbursement design combined with readily available manufacturer discounts, which allow administering physicians to purchase tissue for much less than they are reimbursed for it by the Centers for Medicare & Medicaid Services. The authors report that billing for skin substitutes in Medicare has increased rapidly, reaching $10 billion in 2024, and that the increase has little clinical justification. Similar concerns about overuse of skin substitutes were documented by the Office of the Inspector General in 2023.

The use of amniotic membrane grafts (AMGs) in ophthalmology has not received similar attention, despite relying on a reimbursement model similar to the use of skin substitutes in wound care.

Amniotic membrane grafts have proven clinical benefits in certain severe vision-threatening conditions such as Stevens-Johnson Syndrome and severe chemical burns; however, the clinical benefits, specifically of suture less AMGs, in some other indications are controversial. A cursory review of online resources for eye practitioners demonstrates many instances of authors touting the financial awards associated with using AMGs. There is a discrepancy between the reimbursement and the cost of tissue acquisition because Centers for Medicare & Medicaid Services reimburses providers based on the list price of the tissue (the Wholesale Acquisition Cost) rather than the true cost of the tissue after considering rebates and manufacturer discounts (the average sales price). In 2021, Congress attempted to address this by requiring manufacturers of skin substitutes and other Part B products to report their true average sales price to Centers for Medicare & Medicaid Services (after accounting for all manufacturer discounts), but a 2023 report from the Office of the Inspector General noted that approximately half of manufacturers had failed to comply with the new requirements. Although billing for skin substitutes in the Medicare population is a topical concern for policymakers, the use of ophthalmic AMGs in fee-for-service Medicare has not been previously analyzed.

Vail et al explored this question, employing a retrospective cohort study which included both a 20% sample of Medicare Part B fee-for-service claims for patients who received suture less amniotic membrane grafts and the billing patterns of eye care providers who billed for suture less amniotic membrane grafts from 2011 to 2020. The main outcome measures were Clinical indications for AMG use, time from patients’ first encounter with a provider to their first AMG, use of AMGs for dry eye, and costs to Medicare.

The study demonstrated that dry eye accounted for 44% of all suture less AMG use in 2020, increasing from 7% in 2011. Charges for ocular suture less AMGs increased from $3.5 million in 2011 to $95.6 million in 2020; charges for AMGs used to treat dry eye increased from $250,000 to $41.4 million over this period. Some 28% of all claims for AMGs were submitted by 1% of providers. Patients were more likely to receive an AMG when seen by an optometrist (hazard ratio, 1.16; P < .001). The annual costs to Medicare for a patient with dry eye have increased dramatically among providers who use AMGs.

The authors concluded that the costs to Medicare for skin substitutes are inflated by reimbursement models that encourage their use even when there is little clinical indication. These concerns may be applicable to eye care as well, where spending on amniotic membrane grafts has increased dramatically, particularly for indications where clinical benefit may be limited. By requiring AMG manufacturers to report accurate sales prices, policymakers could reduce costs without limiting coverage of AMGs for appropriate clinical indications

Clinical Value/Implications

Amniotic membranes can be an incredible asset to practitioners in their management of a multitude of anterior segment conditions. Further research and subsequent policy changes will likely provide guidance on their appropriate use as well as achieving greater cost efficiency for larger payers such as Medicare.

The Association between Glaucoma and Dementia in a National Cohort of All of Us Participants

Pham K, Salowe R, Di Rosa I, Hamedani AG, Ying GS, O’Brien JM. The Association between Glaucoma and Dementia in a National Cohort of All of Us Participants. Ophthalmology. 2026 Feb;133(2):194-202.

Question

Is there an association between glaucoma and the incidence of dementia and its subtypes?

Background/Summary of Findings

Glaucoma and dementia are both age-related neurodegenerative diseases that have multiple shared risk factors, including age and family history. Dementias are characterized by loss of cognitive function, particularly in memory and language, which results in a decline in a person’s everyday functioning. Glaucoma results from progressive degeneration of retinal ganglion cells and is the most common cause of irreversible blindness worldwide. Over the past 2 decades, studies from around the world have had varying results regarding any potential link between these 2 neurodegenerative conditions.

The National Institute of Health All of Us Research Program provides a large, diverse nationwide cohort. Unlike previous studies which were unable to match genetic substructures within cohorts of glaucoma and dementia, this study leverages the whole-genome sequencing data in All of Us which allows for the ability to match genetic similarities between these 2 conditions.

Among the 47220 people included in the study (individuals with glaucoma diagnoses and matched controls without glaucoma), dementia was diagnosed in 1063 individuals (2.25%) during the observation period (median 6.5 years). Glaucoma subtypes included primary open-angle glaucoma, normal-tension glaucoma, and angle-closure glaucoma. Dementia subtypes included all-cause dementia, Alzheimer’s disease, and vascular dementia.

Overall, 305 individuals (3.2%) with glaucoma and 822 control individuals (2.2%) were diagnosed with dementia during the observation period. When comparing controls matched based on race, ethnicity, sex, and age, glaucoma was associated with significantly higher risk of all-cause dementia, Alzheimer’s disease, and vascular dementia. In the United States, a glaucoma diagnosis was associated with an increased risk of dementia, particularly primary open-angle glaucoma with Alzheimer’s disease.

Clinical Value/Implications

This study suggests a link between glaucoma diagnosis and higher risk of dementia in this United States cohort. Once a glaucoma diagnosis is made, monitoring patients for dementia may facilitate earlier detection and intervention. Eye care providers should also keep in mind that dementia could lead to poorer compliance with glaucoma medications and treatment regiments.

Hong AT, Luu IY, Keenan JD, Stewart JM. Long-Term Metformin Use and Reduced Risk of Age-Related Macular Degeneration: A Large Database Study. Ophthalmol Retina. 2026 Feb;10(2):135-141.

Question

Is there an association between long-term metformin use and the risk of developing age-related macular degeneration among patients with diabetes?

Background/Summary of Findings

Macular degeneration is a leading cause of visual impairment worldwide. Currently, treatments mainly target later stages of the disease when vision loss may already be advanced. AREDS2 vitamins have also only shown to be efficacious when the intermediate stage of the dry macular degeneration is seen. Identifying potential treatments or medications to prevent macular degeneration development would improve long-term prognosis as well as decrease disease incidence.

Metformin, used in the treatment of diabetes, has anti-inflammatory, antiangiogenic, and antioxidative properties that have made it a possible agent for reducing macular degeneration risk. Given the slow progression of macular degeneration, duration of therapy would likely be a key factor in a potential protective mechanism of metformin.

This study was performed using a large cohort from a nationwide database, the US Collaborative Network within the TriNetX Analytics platform. Patients were required to have no macular degeneration diagnosis at 2 eye care visits more than 1 year apart. Metformin use equal to or over 5 years in duration was also a requirement. The primary outcome was incident macular degeneration. Secondary outcome measure was a new diagnosis of dry macular degeneration and wet macular degeneration.

Overall, 3748 patients had more than or equal to 5 years of metformin use for diabetes treatment. Incident macular degeneration was documented in 122 (3.3%) of patients who were taking metformin compared to 184 (4.9%) who had not taken the medication. The metformin group had lower rates of both dry and wet macular degeneration. Metformin use for 6 or more years showed consistent protective effects against macular degeneration development.

Negative control analysis using insulin, a medication not thought to be associated with macular degeneration, found no relationship, which strengthened the findings of this study. Positive control analysis using statins, which have previously been shown to reduce macular degeneration risk, showed a similar effect to metformin in this study.

Clinical Value/Implications

Overall, this study showed that metformin use greater than or equal to 5 years in patients with diabetes was associated with a lower risk of developing macular degeneration, with significant differences in the dry form of the disease and a nonsignificant trend in wet macular degeneration. Future studies should be conducted that consider both metformin duration and dosage to clarify its potential role in macular degeneration prevention and its efficacy at various stages of the disease.

Tsai HR, Lin YJ, Loh CH, Lee YC, Huang HK. Risk of Alzheimer Disease and Related Dementia after Retinal Vascular Occlusion: A Nationwide Cohort Analysis. Ophthalmol Retina. 2026 Feb;10(2):117-127.

Question

Is there an increased risk for Alzheimer Disease and dementia in patients after retinal vascular occlusion?

Background/Summary of Findings

Dementia is a leading cause of dependency and disability among older adults, imposing significant costs on health care and caregiving systems. Neurodegeneration, neuroinflammation, and cerebral small vessel disease may all be contributing factors and play a substantial role in dementia development.

Retinal vascular occlusions, including both retinal artery occlusion and retinal vein occlusion, can have devastating visual sequelae but may also be a marker of potential future cognitive complications as well. Previous studies have found that retinal microvasculature abnormalities are associated with reduced cognitive performance, suggesting that retinal vasculature may act as a marker for the cerebral microvascular system. Given their shared embryological origin and physiological properties, vascular pathology in dementia may suggest a link between vascular occlusion and the development of dementia.

This nationwide population-based cohort study used claims data from Taiwan’s National Health Insurance Research Database to evaluate the risk of dementia among patients with retinal vascular occlusion.

Overall, patients with retinal vascular occlusion had increased risk of Alzheimer Disease, vascular dementia, and all-cause dementia. Both retinal artery occlusion and retinal vein occlusion were associated with increased risk for Alzheimer Disease, vascular dementia, and all-cause dementia.

Clinical Value/Implications

This study illustrates the importance of assessing dementia risk in patients with history of retinal vascular occlusion. Besides monitoring for ocular sequelae of retinal vascular occlusion and identifying systemic comorbidities that need to be addressed, monitoring for early signs of dementia should be part of follow-up care for patients with retinal vascular occlusion. Detection of dementia in the subclinical phase may allow for early detection and possibly secondary preventative measures.

Conflict of Interest

Edward Chu – not applicable
Andrew Rixon – not applicable

Funding Sources

Edward Chu – not applicable
Andrew Rixon – not applicable