June 8, 2022

The most important ophthalmology research updates, delivered directly to you.

In this week's issue

  • An artificial iris prosthesis reduced photophobia and glare, improved subjective visual function and cosmetic appearance for patients with iris defects.
  • Beta-carotene supplementation, which was removed from AREDS2, continued to show link with lung cancer at 10-year follow up.
  • Vitamin C is potentially protective against diabetic retinopathy.
  • A code-free deep learning system can differentiate clinically significant from non-clinically significant PCO as compared to expert human graders.
  • Punctal plugs may be beneficial for reducing post-injection ocular discomfort in patients with severe dry eye disease.

CustomFlex: clinical trial for the world’s first artificial iris implant


Beyond its vibrant colors, complex crypts and furrows, the iris serves a key role in ocular physiology. The iris controls the amount of light reaching the posterior segment by controlling the pupil size and aids in focusing the lens during accommodation. Iris deformities can be life-altering as they cause reduced quality of vision, photophobia, glare, and cosmetic challenges. Historically, iris defects were managed with tinted glasses, occlusive devices, contact lenses, and iris suturing, but recently, artificial implants have been proposed as a newer solution. A multicenter, prospective, non-randomized interventional clinical trial was conducted to evaluate the safety and efficacy of an artificial iris device (CustomFlex) for congenital and acquired iris defects. A total of 447 eyes were enrolled and included 330 primary eyes, 28 fellow eyes, and 89 compassionate cohort eyes (individuals meeting some but not all inclusion criteria). Photosensitivity, glare, visual symptoms, and cosmetic results were evaluated, as well as safety of the device itself. At the one year postoperative examination, patients reported reductions in light sensitivity (60% in daytime, 42% in nighttime) and reductions in glare (53% in daytime, 49% in nighttime). They also had significant improvements in visual function as determined by a questionnaire and aesthetic appearance as determined by a previously validated examiner scale. Visual acuity and endothelial cell density were followed as safety measures and found to be stable postoperatively. The CustomFlex artificial iris is safe, effective, and cosmetically appropriate for the treatment of congenital and acquired iris defects.

Long-term impact of AREDS2 formulation changes on AMD and lung cancer

JAMA Ophthalmology

Wheaties cereal might fuel champions, but lutein and zeaxanthin may help prevent progression from intermediate to late age-related macular degeneration! The original Age-Related Eye Disease Study (AREDS), which took place between 1992 and 2001, demonstrated that a combination of beta-carotene, ascorbic acid, vitamin E, zinc, and copper decreased the risk of progression from intermediate to late age-related macular degeneration (AMD) by 25% over the study period. However, concurrent studies showed an association between beta-carotene and lung cancer, especially for patients who smoke. Thus, the Age-Related Eye Disease Study 2 (AREDS2) investigated the effects of adding lutein/zeaxanthin and/or omega-three fatty acids to the AREDS formulation, with and without the removal of beta-carotene. Over five years, AREDS2 showed two-fold increased risk of lung cancer in the beta-carotene group and the formulation without beta-carotene maintained its protective effect. Including lutein and zeaxanthin in the formulation showed a modest protective effect limited to patients with low dietary intake of these carotenoids. The present study, AREDS2 Report 28, investigates the long-term effect of AREDS2 formulation changes on AMD progression and lung cancer during the AREDS2 study and the following five years. In the 3882 patients and 6351 eyes with intermediate AMD that were included in the study, the 10-year odds ratio for lung cancer was 1.82 (95% CI 1.06-3.12) for the beta-carotene group and 1.15 (95% CI 0.79-1.66) for the lutein/zeaxanthin group. Hazard ratios for progression from intermediate to late AMD were 0.91 (95% CI 0.84-0.99) in the lutein/zeaxanthin group and 1.01 (95% CI 0.93-1.09) in the omega-3 fatty acids group. These results show that the association between beta-carotene supplementation and lung cancer persisted even five years after the AREDS2 study endpoint. Furthermore, they suggest that lutein/zeaxanthin supplementation may provide a modest protective effect against progression of intermediate AMD.

Vitamin C or vitamin “see”?

American Journal of Ophthalmology

Orange juice has always been a popular choice as part of breakfast or when you’re sick - but for patients with diabetic retinopathy, it might play a larger role than you think! Diabetes mellitus (DM) requires lifestyle modifications, dietary restriction of glucose, and sometimes insulin administration in order to prevent progression of disease and end-organ dysfunction, which includes diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy (DR). As oxidative stress contributes to the pathophysiology of DR, researchers sought to explore the potential protective abilities of antioxidant micronutrients including vitamins A, C, D, E, and carotenoids. This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) and included 517 participants with diabetes mellitus, 159 of whom had DR based upon evaluation of existing fundus photography by a team of graders. Logistic regression was used to determine the relationships between circulating levels of each serum micronutrient and DR. Of the micronutrients, only serum vitamin C levels were associated with a lower risk of DR (odds ratio [OR]: 0.60; 95% confidence interval [CI]: 0.38-0.95). Further meta analysis showed lower circulating levels of vitamins C, D, and E in patients with DR than those without DR. Given the nature of the study design, certain factors limit its reach, including the absence of data to stratify for different types of DM and interpreting data from a single micronutrient measurement per participant. While further studies are still needed to determine the relationship between micronutrient levels and DR, it seems that vitamin C deficiency is associated with DR in patients with DM.

Code-free deep learning to detect posterior capsule opacification

BMJ Open Ophthalmology

It’s possible to know very little code but still benefit from using AI! The most common complication after cataract surgery with IOL implantation is the development of a posterior capsule opacification (PCO). PCO becomes clinically significant either when it causes symptoms for the patient or precludes examination by the physician. Recent developments of automated neural networks allow clinicians with little coding skills to analyze datasets with AI. This retrospective study investigates a code-free deep learning system (CFDLS) trained to distinguish clinically significant from non-clinically significant PCO using retroillumination photography, and to compare its performance to human expert graders (three board-certified ophthalmologists). PCO in the central 3mm is associated with clinical significance. In total, 279 images (100 externally validated images and 179 images from a training dataset) with varying grades of PCO were examined three separate times by both CFDLS and the expert graders. Performance of the CFDLS compared to human graders was examined, as well as performance between examiners (interobserver) and performance of each examiner (intraobserver). Interobserver κ for the final grading for all three observers was 0.84 (95% CI 0.78 to 0.89) and that for all nine gradings was 0.82 (95% CI 0.76 to 0.86). The CFDLS performance using the internally validated dataset had an AUC was 0.99 (95% CI 0.92 to 1.0), a sensitivity of 0.89, and a specificity of 1. The CFDLS performance using the externally validated dataset had an  AUC of 0.97 (95% CI 0.93 to 0.99), a sensitivity of 0.84, and a specificity of 0.92. This proof of concept shows that CFDLS can be used to develop tools to help guide clinical decision-making. It also allows clinicians that may not have a background in computer science to participate in AI research.

Do punctal plugs reduce dry eyes after intravitreal injections?


Should we also be using punctal plugs in retina clinic? A sensation of dry, scratchy eyes following intravitreal injection is a common patient complaint heard by retinal providers and is likely secondary to irritation due to iodine. The efficacy of dissolved collagen punctal plugs (CPP) in lowering ocular surface discomfort following intravitreal injections was investigated. 64 patients were given CPP after intravitreal injections as compared to 62 controls who received a post-injection rinse. Dry eye symptoms were evaluated using Ocular Surface Disease Index (OSDI) and Standardized Patient Evaluation of Eye Dryness II (SPEED II) scores. There was no statistically significant difference in pre to post injection OSDI and SPEED II scores between the two groups (CPP versus control). However, subgroup analysis revealed that individuals in the moderate/severe dry eye category (i.e. with objective clinical evidence of dry eye) had improvement of their symptoms with CPP. This study suggested that standard eye rinses are a simple, effective, and low-cost method of reducing post-injection ocular discomfort in the majority of patients. However, for patients with severe dry eye, punctal plugs may be beneficial.


Reading the signs: OCT biomarkers in uveitic macular edema 

American Journal of Ophthalmology

Predicting the future just got a little easier when it comes to treating uveitic macular edema. Uveitis is a sight-threatening intraocular inflammatory condition that is estimated to be responsible for 30,000 new cases of legal blindness in the United States each year. Non-infectious uveitis (NIU) is the most common subset, and vision loss in NIU is usually due to macular edema (ME), which can be quantified as having increased central subfield thickness (CST) on optical coherence tomography (OCT). While there is limited prior work correlating BCVA and CST in patients with NIU ME, subfield OCT findings are important anatomic endpoints for treatment decisions in clinical practice. In this clinical cohort study from post hoc analysis of two phase 3 clinical trials, 198 eyes with known NIU were evaluated to assess the relationship between BCVA and OCT macular features before and after treatment. Pretreatment ellipsoid zone (EZ) integrity and the presence of baseline central cystoid spaces or subretinal fluid were associated with improved therapeutic response to treatment. Following treatment for ME, CST reached 90% maximal improvement by week 3, while BCVA was not achieved until week 9. This study provides anatomic and temporal biomarkers for NIU ME that may help predict future therapeutic response and manage patient expectations following intervention.

Lens Landmarks

Now that you see it, what do you do with it? The COMS was a prospective multicenter trial organized by the National Eye Institute in 1985 to examine mortality outcomes of different treatment options for uveal melanoma. They also examined cancer free survival, metastasis free survival, and years of functional vision. There were three main arms of the study, which differentiated melanomas based upon tumor size. It is important to note that this study is not applicable to melanomas of the ciliary body or peripapillary choroid.

Key Points:
  • Small choroidal melanomas can be observed safely.
  • Plaque brachytherapy is a viable option for medium sized melanomas, long-term data for brachytherapy survival is still pending.
  • Pre-enucleation radiotherapy is no longer used as it is ineffective. 
The COMS is a landmark study because it helped guide physicians on when and how to treat ocular melanomas, which are the most common primary eye tumors in adults. Although nonmalignant choroidal nevi are more common than choroidal melanomas, all nevi should be evaluated for features concerning for melanoma as choroidal melanomas have high mortality rates.

Question of the Week

A 32 year-old female with a history of anorexia nervosa and nodular acne presents to the Emergency Room complaining of blurry vision, headache, and nausea. The emergency medicine physician consults ophthalmology to evaluate the patient for potential Idiopathic Intracranial Hypertension (IIH) and papilledema.
Which of the following are risk factors for IIH? 
A. Male gender
B. Anorexia
C. Use of retinoids 
D. All of the above

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Quiz Answer: C
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