October 19, 2022

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

In this week's issue

  • Retinoblastoma tumor cells rely on estrogen-related receptor gamma (ESRRG) for survival, demonstrating potential of ESRRG as a therapeutic target in retinoblastoma.
  • Doxycycline is effective in improving mild thyroid eye disease signs and symptoms.
  • Phacoemulsification cataract surgery is found to decrease mean IOP in glaucomatous eyes post-operatively.
  • A meta-analysis shows visually-impaired children have greater symptoms of depression and anxiety.

ESRRG as a potential therapeutic target in retinoblastoma


Retinoblastoma, have you met your match? Retinoblastoma (Rb) is a pediatric cancer of the eye which commonly causes visual impairment and loss of the affected eye. Inactivation of the retinoblastoma (RB) 1 tumor suppressor in retinal progenitor cells is the most common form of initiating event for this form of cancer. However, this inactivation is hypothesized to be accompanied by secondary aberrations in order to initiate Rb, but no aberrations currently have relevant targeted therapies. This study worked to determine Rb dependencies by using integrative multi-omics analysis of whole-exome sequencing, whole-genome sequencing, single-cell RNA and RNA sequencing, as well as additional methods to identify secondary aberrations. Estrogen-related receptor gamma (ESRRG), a gene involved in the regulation of retinogenesis and metabolism, was investigated and was found to be directly inhibited by RB1. In vivo Rb cells were found to be reliant on ESRRG for survival in hypoxic conditions, and inhibition of ESRRG was shown to cause RB cell death in hypoxia. Overall, this study is the first to not only identify ESRRG’s role in Rb cell survival, but also demonstrate the potential of ESRRG as a therapeutic target.

Doxycycline improves mild thyroid eye disease symptoms

JAMA Ophthalmology

Can antibiotics help with thyroid eye disease? Thyroid eye disease (TED) is an inflammatory condition that has been classically managed with topical lubricants in mild cases and with glucocorticoids, immunosuppressants, and biologics reserved in advanced cases. Tetracyclines, such as doxycycline, have anti-inflammatory and immunomodulatory effects in addition to antibiotic properties. The authors aimed to evaluate the efficacy of doxycycline for treating mild TED. This multicenter, randomized, double masked, placebo-controlled parallel group trial compared patients with mild thyroid eye disease (TED) receiving doxycycline 50mg daily (n=50) with patients receiving placebo (n=50). The primary outcome was the composite of the rate of improvement of mild TED signs and symptoms, including eyelid aperture, proptosis, ocular motility, and a quality of life survey about dry eye symptoms. At week 12, there was a 38% (19/50) improvement in the doxycycline group compared to 16% (8/50) in the placebo group (difference 22.0%; 95%CI, 5.0-39.0; P=0.01). The authors conclude that doxycycline may be an efficacious treatment for mild TED. The authors note that the study is limited by the small cohort size and short follow-up. 

Does cataract surgery lead to long-term postoperative IOP decreases in glaucoma patients?

American Journal of Ophthalmology

Turns out the phaco, like Flo Rida, can help get you low low low low low low low low. Previous studies have investigated the effect of stand-alone phacoemulsification on post-op intraocular pressure (IOP) in patients with glaucoma, noting that pressures tend to be high right after surgery and typically decrease below baseline during the post-op course. This large-scale, retrospective cohort study of 1,334,868 patients from the IRIS registry investigated changes in IOP following stand-alone phacoemulsification cataract surgery in eyes with (n=336,060) and without (n=998,808) glaucoma as compared to the fellow control eye. When compared to control eyes, surgical eyes had a significantly greater daily mean IOP for post-operative days 1-9. Glaucomatous eyes showed a statistically significant decrease in IOP as compared to control eyes beginning on day 13, which was maintained throughout the remainder of the 90-day postoperative period. Glaucomatous eyes were found to have a statistically significant decrease (1.61 ± 4.16 mmHg [6.93%]) in final mean IOP from baseline IOP. These results use big data from a population-based registry to confirm the IOP lowering effect seen following cataract surgery in eyes with glaucoma. 

See better to feel better: vision impairment and depression


We all learned the PHQ-9 criteria, but could ocular symptoms also identify underlying depression and anxiety? A recent meta-analysis of 36 studies confirmed the association between vision impairment and depression/anxiety among children. Eleven studies showed significantly higher scores of depression (SMD: 0.57; 95% CI: 0.26-0.89) and anxiety (SMD: 0.62; 95% CI 0.40-0.83) among children with vision impairment when compared to children with normal visual acuity, particularly children with myopia. Seven studies showed strabismus surgery significantly reduced both scores of depression (SMD=0.59; 95% CI: 0.12-1.06) and anxiety (SMD: 0.69; 95% CI 0.25-1.14) among children. The results of these studies suggest many cases of childhood depression and anxiety may be addressed through intervention or programs to decrease childhood vision impairment and increase access to strabismus surgery. However, the studies included in this meta-analysis did not utilize standard criteria to assess psychological symptoms, making additional research in this space imperative.

HIF1-α promotes photoreceptor survival in retinal detachment


Could HIF1-α be the key to vision preservation in retinal detachment? Retinal detachment (RD) causes hypoxia by separating the outer retina from its choroidal blood supply. In response, photoreceptors (PRs) upregulate pro-survival pathways. However, upstream regulation of these pathways is not well understood. HIF1-α, the main transcription factor in the hypoxia-inducible pathway, regulates the expression of hundreds of genes in response to tissue hypoxia and could play a major role in promoting PR survival in RD. To simulate RD, the authors injected hyaluronic acid into the subretinal space of mice with HIF1-α knocked-out in rods. HIF1-α protein levels were significantly increased in the control mice after RD, while HIF1-α knock-out mice had a compensatory increase in the related HIF2-α protein. HIF1-α knock-out mice had significant photoreceptor cell death and thinning of the outer nuclear layer after RD. These findings, combined with the work of previous studies that have shown reduced cell death post-RD with retro-orbital administration of prolyl-4-hydroxylase inhibitors (which stabilize HIF1-α), suggest that this class of drugs could serve an important role in preserving PRs in hypoxic conditions.


Inferonasal glaucoma drainage device for childhood glaucoma


Talk about under pressure… Angle surgery is usually the first line treatment for childhood glaucoma, but glaucoma drainage devices (GDDs) are being increasingly used as a second-line option. In children, success rates for superotemporal Ahmed and Baerveldt GDDs vary after surgery and decline after a few years. Superotemporal quadrant placement has multiple advantages compared with other quadrants, including wider surgical exposure and greater eyelid coverage. The purpose of this retrospective study was to evaluate outcomes of Ahmed and Baerveldt GDDs placed in the inferonasal quadrant in children. 68 eyes from 52 patients ≤18 years of age at inferonasal GDD placement, from 2013 to 2021, were included. For all eyes, the mean IOP was significantly reduced from 29.7±7.4 preoperatively to 21.3±8.3 mmHg. Success rates by survival analysis (95% CI) at 1, 2, 3, and 5 years were 62.2% (49.4-72.7), 49.0% (36.3-60.6), 36.8% (24.0-49.8), and 31.9% (18.5-44.5), respectively. Though inferonasal GDDs had modest success in this study, the success rate was lower than those previously reported for adults and for superotemporal GDDs in children. Future studies with a larger sample and a control group might better elucidate factors that limit or improve outcomes. 

Lens Landmarks

Keep your friends close, but your anti-VEGF injections closer… The BRAVO and CRUISE trials looked to find the best course of treatment for macular edema in the setting of branch and central retinal vein occlusions. Prior to this, laser therapy had proven to be ineffective and patients were simply observed with little hope in visual improvement. In the BRAVO and CRUISE trials, patients with macular edema following BRVO (n=397) and CRVO (n=392) were randomized to receive monthly intravitreal injections of 0.3 or 0.5 mg of ranibizumab or sham injections.

Key Points:
  • For BRVO, an increase in at least 15 letters in BCVA at 6 months was seen in 55.2% (0.3 mg) and 61.2% (0.5 mg) of patients compared to only 28.8% in the placebo arm; for CRVO, the respective groups yielding 46.2% (0.3 mg), 47.7% (0.5 mg), and 16.9% (placebo).
  • Central foveal thickness at 6 months following BRVO/CRVO had decreased by a mean of 337/434 mircons (0.3 mg) and 345/452 microns (0.5 mg) in the ranibizumab groups compared to 158/168 mircons in the placebo group.
  • The BRAVO trial saw more placebo patients (54.5%) receive rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups.
The importance of this study was showing that anti-VEGF injections were effective in treating macular edema following retinal vein occlusions leading to marked improvement in visual acuity while still maintaining a very low risk of complications.

Question of the Week

A 4-year old boy was forwarded by his pediatrician for a change in the appearance of his left eye, associated with decreased vision. His mother reports that this occurred shortly after they purchased a litter of puppies. Physical exam demonstrates the following: 
What is the most likely diagnosis?

A. Retinoblastoma
B. Toxocariasis
C. Rubella
D. Varicella

Keep scrolling for answer or click here

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Quiz Answer: B
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