Current Issue

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In this week’s issue

• When AJCC classification is challenging in uveal melanoma, a new staging system is proposed which incorporates tumor volume, clinical risk factors, and genetic alterations.
• GLP-1 receptor agonists are linked to a >90% reduced risk over 10 years of developing nonexudative AMD when compared to other weight-loss drugs in obese, non-diabetics.
• Migraines are independently associated with higher rates of central serous chorioretinopathy when compared to controls (5-year risk HR 2.74).
• Eye drops containing siRNA (GalNAc-modified siHOTAIR) are comparable to anti-VEGF injections, suppressing inflammation, vascular mediators, endothelial permeability, and angiogenesis in diabetic rats.

Spotify Link:

https://creators.spotify.com/pod/show/5xxCPPPznB0yONJbNOIC4I/episode/690v3mr4Eo9o4dkpQXxt1X/wizard 

Ophthalmology

A novel staging model for uveal melanoma

Could risk stratification of uveal melanoma be improved? Uveal melanoma (UM) is the most common primary intraocular cancer in adults. 94-96% of UM cases are posterior, whereas 4-6% are anterior in the iris. Posterior UM carries a higher risk of metastatic spread than iris UM, occurring in >50% of cases. The AJCC classification is the only system for posterior UM that has undergone formal validation. Recent studies have suggested that combining genetic information with AJCC staging can provide improved prognostication for UM. In this retrospective cohort study of 3696 patients diagnosed with UM from 1943 to 2022 (3062 choroidal melanomas, 245 ciliary body melanomas, and 389 iris melanomas), researchers sought to develop a comprehensive staging system for UM integrating tumor volume (T0-T5), clinical risk factors, and genetic alterations that resolves classification challenges while improving risk stratification integrating staging (S0-S6) with genetic enhancement (GS1-GS6). Tumor volume demonstrated strong risk stratification with T0 tumors (<12 mm) showing 0% mortality throughout follow-up, whereas 20-year mortality progressively increased from T1 (23%) to T5 (63%). The integrated staging system showed excellent discrimination with a 5-year mortality ranging from 0% (S0) to 54% (S6). Genetic analysis revealed that combined monosomy 3 and 8q-gain (HR 12.6), carried stronger prognostic weight than the conventional staging, with risk stratification (10-year mortality 0% for GS1 to 77% for GS6). Incorporating volume-based categorization, clinical factors, and genetic status can be another accurate way to classify UM, especially when there are classification ambiguities.

JAMA Ophthalmology

How do GLP-1 receptor agonists affect AMD in non-diabetics?

Glucagon-like peptide 1 receptor agonists (GLP-1RA) - more than meets the eye? GLP-1RAs have become well known for their weight loss, neuroprotective, and anti-inflammatory benefits. However, their effect on age-related macular degeneration (AMD) is unclear. Since chronic inflammation and metabolic dysfunction are linked to the development of AMD, this retrospective cohort study using data from TriNetX, a global health network database, aimed to study GLP-1RA use and its association with development or progression of AMD compared to other weight loss drugs. A total of 91,408 non-diabetic and overweight patients were included that used GLP-1RAs or other weight-loss medications. GLP-1RA use was associated with an 83.5% and 91% lower risk of developing nonexudative AMD at 5 and 10 years, respectively, compared to other weight loss agents such as lorcaserin, setmelanotide, diethylpropion, sibutramine, fenfluramine, mazindol, phentermine, and orlistat. No weight loss medication use group was associated with increased risk of developing non-exudative AMD at 5 and 10 years compared to GLP-1RA use. These findings suggest GLP-1RAs could offer a surprising protective effect against AMD onset in non-diabetic patients.

American Journal of Ophthalmology (AJO)

Migraine and risk of central serous chorioretinopathy

Migraines might cause more than just throbbing headaches, they may affect your eyes as well. Central serous chorioretinopathy (CSCR) is a disease driven by neurosensory detachment due to increased permeability of choroidal vasculature and retinal pigment epithelium dysfunction. Migraines involve vascular and autonomic dysfunction, and share similar mechanisms to CSCR such as dysregulation of vascular tone, increased susceptibility to fluctuating stress hormones, and comorbidities such as anxiety or depression. This retrospective cohort study used the TriNetX Global Collaborative Network to compare the 5-year incidence of CSCR in 413,663 propensity score-matched adults with migraine and matched controls. Migraine was associated with a higher 5-year risk of CSCR compared to controls (HR 2.74). This positive association was consistent across all subgroups (sex, migraine type, aura, age, follow-up duration, corticosteroid exposure) and was not influenced by migraine-related medication use. These findings support an association between migraine and an increased risk of CSCR, pointing to the possibility of a shared pathophysiology. 

Investigative Ophthalmology & Visual Science (IOVS) 

Can a topical RNA therapy outperform single-target anti-VEGF?

Noncoding RNA eye drops to treat diabetic retinopathy. Vascular dysfunction in diabetic retinopathy is currently treated by inhibiting VEGF alone, leading to therapeutic resistance and incomplete disease control. In this study, researchers targeted long noncoding RNA HOTAIR, an epigenetic regulator induced by hyperglycemia that promotes retinal angiogenesis and inflammation. A GaLNAc-modified siHOTAIR was engineered to silence HOTAIR. HOTAIR knockdown reduced vascular mediators (VEGF-A, VEGF-C, ANGPTL4), inflammatory cytokines (IL-1β, IL-6, CCL2), endothelial permeability, and angiogenic activity. Topical delivery as eyedrops achieved comparable results to intravitreal anti-VEGF injection in diabetic rats. GalNAc-modified siHOTAIR is a promising noninvasive, multi-target alternative to current injection-based diabetic retinopathy therapies.

Journal: Ophthalmology Science

Machine learning combines OCT with clinical data to predict post-operative outcomes in cataract patients

Seeing better than your eye doctor? Researchers in China conducted a multicenter prospective cohort study to validate a machine learning model (OCT-PRO), which they developed to integrate OCT and clinical data and predict postoperative outcomes among cataract patients. OCT imaging, laser interferometry, and clinical metadata were used to develop the model to predict BCVA. 1304 cataract patients were used in model development and 607 cataract patients were used in external testing. Six hospitals across China were involved in this prospective validation study. OCT-PRO significantly outperformed OCT-only models and metadata-only models. The OCT-PRO also outperformed senior ophthalmologists in predictive accuracy. OCT-PRO also performed superiorly across all cataract subtypes. The study highlights the generalizability and advantages of combining OCT and clinical data for predicting BCVA after cataract surgery.

Cornea

When infection meets inequity: Barriers in microbial keratitis care

Even the most aggressive antibiotics won’t provide coverage over a missed appointment. Microbial keratitis (MK) is an ocular emergency that often requires follow-up to prevent vision loss. In this mixed retrospective and prospective cohort study conducted at a tertiary academic eye center, investigators examined how social risk factors (SRFs) influence MK care using the modified Penchansky-Thomas access-to-care framework. 100 patients with newly diagnosed MK were evaluated through structured interviews and chart review to identify SRFs across domains such as accessibility, affordability, and accommodation. Common SRFs included travel distance, transportation, and cost, which may be reflective of the burden of receiving specialized care at referral centers. Low-income patients experienced a higher total number of SRFs and these challenges were linked to failure to complete follow-up. All patients lost to follow-up reported at least one SRF, often multiple, and most disengaged within the first month of care, a critical time for MK management. These findings highlight how social context directly shapes adherence in acute ophthalmic disease, extending prior work that has largely focused on chronic eye conditions. Systematic screening for SRFs and early social support may reduce loss to follow-up and improve visual outcomes in MK.

The Age-Related Eye Disease Study (AREDS 2) - 2012

If at first you don’t “fully” succeed, try, try again. While AREDS1 showed that an oral supplement decreased the risk of developing advanced AMD in 5 years by 25%, observational data suggested that other nutrients may offer an additional protective benefit. AREDS2 aimed to evaluate the safety and efficacy of adding the antioxidant carotenoids lutein and zeaxanthin (L+Z) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) in decreasing the risk of progressing to advanced AMD. The study also sought to determine the effect of reducing the amount of zinc in the AREDS oral supplement and omitting beta-carotene completely.

Key Points

• No statistically significant reduction in disease progression was found in the groups assigned to take L+Z and/or omega-3 LCPUFAs in addition to the AREDS supplement
• No statistically significant reduction in disease progression was found with differing doses or zinc or with omission of beta-carotene.
• Significantly more cases of lung cancer occurred in patients who had history of smoking cigarettes and were taking beta-carotene (2%) versus those not taking beta carotene (0.9%); substituting beta-carotene for L+Z is appropriate

Together with AREDS1, which showed a 25% decrease in progression to advanced AMD, AREDS2 fine-tuned the notable vitamin formula by adding lutein and zeaxanthin and removing beta-carotene.