THE LATEST PUBLISHED RESEARCH

Welcome to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• Persistent Hyper-transmission Defects Detected on En Face SS-OCT & Formation of GA
• Cataract Surgery & Risk of Developing Late AMD: AREDS2 Report Number 27
• Spectral Fundus Autofluorescence Peak Emission Wavelength in Aging and AMD
• Associations Between Systemic Medications and Development of Wet AMD
• Correlation of Photoreceptor Integrity with Retinal Vessel Density & Choriocapillaris in DR Eyes
• Macular Thickness Fluctuations in Anti-VEGF-treated Patients With CRVO or HRVO
• Anti-TNF-α vs. Tocilizumab in the Treatment of Refractory Uveitic Macular Edema
• MacTel type 2: Multimodal Assessment of Retinal Function and Microstructure
• Predictive Scoring System for Visual Outcomes After RRD Repair
• Epiretinal Proliferation After RRD
  
• Clinical & Genetic Features of Retinoschisis in Families with RS1 Mutations
• Noteworthy

Persistent Hyper-transmission Defects Detected on En Face SS-OCT & Formation of GA

Investigators sought to determine if persistent hyper-transmission defects (hyperTDs)—shown to have a greatest linear dimension (GLD) ≥250 µm on en face swept-source OCT images—serve as a stand-alone early biomarker for the future formation of geographic atrophy.

The post-hoc cohort study using a subgroup of a prospective study included patients with intermediate age-related macular degeneration.

All subjects underwent 6 × 6 mm SS-OCT raster scans at baseline and during their follow-up period. En face images were generated using a slab with segmentation boundaries positioned 64 to 400 µm beneath Bruch's membrane. Two graders independently evaluated all en face structural images for the presence of hyperTDs with a GLD ≥250 µm and GA.

A total of 190 eyes were included with a mean follow up of 31 (SD: 13.2) months. Here are some of the findings:
• At baseline, 31 eyes (16 percent) had at least one hyperTD ≥250 µm, and 13 eyes (42 percent) progressed to GA.
• In eyes without a hyperTD ≥250 µm at baseline, 42 (26 percent) developed hyperTDs ≥250 µm during their follow-up and 11 (7 percent) progressed to GA.
• At the last available follow-up visit, 25 eyes (13 percent) progressed to GA and of them, 24 had a prior hyperTD ≥250 µm detected before GA formed.
• A time-dependent Cox-survival regression analysis estimated an eightyfold (CI, 10.7 to 614, p<0.001) increased risk of developing GA once a hyperTD ≥250 µm appeared.

Investigators found that persistent hyperTDs detected on en face OCT images were shown to serve as an early stand-alone OCT biomarker for the future formation of GA.

SOURCE: Laiginhas R, Shi Y, Shen M, et al. Persistent hyper-transmission defects detected on en face swept source OCT images predict the formation of geographic atrophy in AMD. Am J Ophthalmol 2021; Nov 12. [Epub ahead of print].

Cataract Surgery & Risk of Developing Late AMD: AREDS2 Report Number 27  

Researchers evaluated the risk of developing late age-related macular degeneration following incident cataract surgery, as part of a prospective cohort study within a randomized controlled clinical trial of oral supplementation for the treatment of AMD: the Age-Related Eye Disease Study 2 (AREDS2).

AREDS2 participants ages 50 to 85 years with either bilateral large drusen or unilateral late AMD were included.

In eyes free of cataract surgery and late AMD at baseline, two groups were compared for incident late AMD: 1) eyes that received cataract surgery after the baseline visit and before any evidence of late AMD, and 2) eyes that remained phakic until the study completion. Eyes that had at least two years of follow-up after cataract surgery were included in the analysis. Researchers used Cox regression models, matched-pairs analysis and logistic regression models adjusted for baseline age, sex, smoking, education, study treatment group and AMD severity.

Late AMD was defined as the presence of geographic atrophy or neovascular AMD detected on annual stereoscopic fundus photographs or as documented by medical records, including intravitreous injections of anti-vascular endothelial growth factor medication.

Here are some of the findings:
• A total of 1,767 eligible eyes (1,195 participants) received cataract surgery, and 1,981 eyes (1,524 participants) developed late AMD during a mean follow-up of nine (range: 1 to 12) years.
• The Cox regression model showed no increased risk of developing late AMD after cataract surgery: HR, 0.96; CI 0.8 to 1.13; p=0.60) for the right eye and HR, 1.05; CI, 0.89 to 1.25; p=0.56 for the left eye.
• Of the matched pairs, late AMD was identified in 412 eyes that received cataract surgery and in 433 phakic controls, resulting in an OR, 0.92; CI, 0.77 to 1.10; p=0.34.
• The risk of late AMD after cataract surgery from the logistic regression model wasn’t statistically significant (risk ratio, 0.92; CI, 0.56 to 1.49; p=0.73).

Researchers reported that cataract surgery didn’t increase the risk of developing late AMD among the AREDS2 participants with up to 10 years of follow-up. They added the findings provide data for guiding AMD patients who might benefit from cataract surgery.

SOURCE: Bhandari S, Vitale S, Agrón E, et al. Cataract surgery and the risk of developing late age-related macular degeneration: The age-related eye disease study 2 report number 27. Ophthalmology 2021; Nov 15. [Epub ahead of print].

Spectral Fundus Autofluorescence Peak Emission Wavelength in Aging and AMD

Scientists assessed the spectral characteristics of fundus autofluorescence in AMD patients and controls.

Fundus autofluorescence spectral characteristics were described by the peak emission wavelength of the spectra. Peak emission wavelength was derived from the ratio of FAF recordings in two spectral channels at 500 to 560 nm, and 560 to 720 nm by fluorescence lifetime imaging ophthalmoscopy. The ratio of FAF intensity in both channels was related to peak emission wavelength by a calibration procedure. Peak emission wavelength measurements were done in 44 young (mean age: 24 ±3.8 years) and 18 elderly (mean age: 67.5 ±10.2 years) healthy subjects, as well as 63 patients with AMD (mean age: 74.0 ±7.3 years) in each pixel of a 30-degree imaging field. The values were averaged over the central area, and the inner and the outer rings of the ETDRS grid.

Here are some of the findings:

• No significant differences were found between peak emission wavelength in young and elderly controls.
• Peak emission wavelength was significantly shorter in AMD patients (ETDRS grid center: 571 ±26 nm vs. 599 ±17 nm for elderly controls: inner ring: 596 ±17 nm vs. 611 ±11 nm; outer ring: 602 ±16 nm vs. 614 ±11 nm).
• After a mean follow-up time of 50.8 ±10.8 months, the peak emission wavelength in the patients decreased significantly by 9 ±19 nm in the inner ring of the grid.
• Patients, showing progression to atrophic AMD in the follow-up, had significantly (p≤0.018) shorter PEW at baseline than non-progressing patients.

Scientists wrote that peak emission wavelength was related to AMD pathology and might be a diagnostic marker in AMD. They added that a short peak emission wavelength could predict progression to retinal and/or pigment epithelium atrophy.

SOURCE: Schultz R, Schwanengel L, Meller D, et al. Spectral fundus autofluorescence peak emission wavelength in ageing and AMD. Acta Ophthalmol 2021; Dec 1. [Epub ahead of print].

Associations Between Systemic Medications and Development of Wet AMD

Investigators examined whether systemic medications were associated with the subsequent development of wet age-related macular degeneration, as part of a retrospective study of 259,562 individuals based on registry data from January 1, 2001, to December 31, 2017.

Endpoint events were classified by the International Classification of Diseases-10 diagnosis for wet AMD. The association between use of systemic medication covering 85 generic drugs categorized according to Anatomical Therapeutic Chemical (ATC) codes and the incidence of wet AMD was evaluated using a multivariate Poisson regression model (adjusted for age, sex, diabetes, cancer and socioeconomic group) and nested case-control design.

The mean length of follow-up was 9.84 years. The number of cases with wet AMD was 2,947 and incidence rate was 1.15 per 1,000 person-years. Here are some of the findings:
• After adjustment, investigators observed an increased risk for the development of wet AMD for patients exposed to amlodipine (IRR 1.33; CI 1.16 to 1.53) or felodipine (CI, 1.02 to 1.50).
• Similarly, an increased risk of wet AMD was associated with the use of bicalutamide (2.14; CI, 1.14-4.02), estradiol (1.20; CI, 1.03 to 1.40) and atorvastatin (1.22; CI, 1.05 to 1.43).
• Digoxin (0.72; CI, 0.57 to 0.91) and ramipril (0.80; CI, 0.65 to 0.99) users had a lower incidence of wet AMD.

Investigators wrote that their findings suggested that the use of second-generation calcium channel blockers could be associated with an increased risk for wet AMD development. They added that the incidence of wet AMD seemed to be lower in patients using ramipril and digoxin, although more studies would be needed to elucidate the associations further.

SOURCE: Loukovaara S, Auvinen A, Haukka J. Associations between systemic medications and development of wet age-related macular degeneration. Acta Ophthalmol 2021; Nov 14. [Epub ahead of print].

Correlation of Photoreceptor Integrity with Retinal Vessel Density & Choriocapillaris in DR Eyes

Researchers evaluated the correlation of foveal photoreceptor integrity with the vessel density of the retina and choriocapillaris using swept-source optical coherence tomography angiography in eyes with diabetic retinopathy.

They retrospectively reviewed subjects with DR who underwent OCTA using swept-source OCT (Triton, Topcon). In addition, they:
• analyzed the area of the foveal avascular zone, vessel densities of the superficial capillary plexus, deep capillary plexus and choriocapillaris;
• measured the length of the lateral extent of ellipsoid zone disruption, central subfield thickness and subfoveal choroidal thickness; and
• analyzed factors closely associated with the length of EZ disruption.

A total of 159 eyes with DR, and 30 healthy control eyes were included in this study. In all eyes, the lengths of EZ disruption were positively correlated with the FAZ area (p=0.009). However, they were negatively correlated with the parafoveal vessel density of the SCP (p=0.049), the foveal vessel density of DCP (p=0.003) and that of the choriocapillaris (p=0.036).

Researchers determined that the size of the FAZ and ischemia at the DCP may play an important role in maintaining foveal photoreceptor integrity in eyes with DR. They added that future studies were needed to reveal the correlation between EZ disruption and the VD of the choriocapillaris, given the issue of OCTA artifacts, such as projection and shadowing.

SOURCE: Kim JT, Park EJ. Correlation of photoreceptor integrity with retinal vessel density and choriocapillaris in eyes with diabetic retinopathy. Retina 2021 Nov 2. [Epub ahead of print].

Macular Thickness Fluctuations in Anti-VEGF-treated Patients With CRVO or HRVO

Investigators evaluated macular thickness fluctuations and their associations with visual acuity outcome in eyes with macular edema secondary to central or hemiretinal vein occlusion treated initially with intravitreal aflibercept or bevacizumab.

This post hoc analysis of 362 patients with ME secondary to CRVO or HRVO initially randomized to six monthly intravitreal injections of aflibercept or bevacizumab. Three spectral-domain optical coherence tomography central subfield thickness fluctuation measures were investigated over months one to 12: standard deviation; number of turning points (T) for each participant; and a measure denoted as “Zigzag” reflecting the magnitude of alternating ups and downs in a participant's CST. The main outcome measure was month 12 visual acuity letter score.

Here are some of the findings:

• More fluctuations occurred in eyes randomized to bevacizumab than aflibercept: SD (59.98 vs. 32.12; p<0.0001), T (4.03 vs. 3.53; p=0.02) and Zigzag (24.91 vs. 11.60; p=0.0003).
• Month 12 visual acuity letter score was significantly lower for the fourth (highest) quartile of the CST fluctuation measure than for the first (lowest) quartile for both SD (mean difference in VALS of 7.87; CI, 3.03 to 12.70) and Zigzag (mean difference in VALS of 5.11; CI, 0.29 to 9.93).
• SD and Zigzag quartiles were no longer significantly different after month one VALS was added to the regression analysis.

Investigators reported that greater CST fluctuation, as assessed by SD and Zigzag, was negatively associated with month 12 visual acuity letter score. However, they noted that early post-treatment visual acuity letter score was a stronger predictor of VALS outcomes than the CST fluctuation measures.

SOURCE: Scott IU, Oden NL, VanVeldhuisen PC, et al; SCORE2 Investigator Group. SCORE2 Report 17: Macular thickness fluctuations in anti-VEGF-treated patients with central or hemiretinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2021; Nov 29. [Epub ahead of print].

Anti-TNF-α vs. Tocilizumab in the Treatment of Refractory Uveitic Macular Edema

Scientists analyzed the factors associated with response (control of ocular inflammation and corticosteroid sparing effect) to biologics (anti-TNF-α agents and tocilizumab) in patients with refractory uveitic macular edema, as part of a multicenter, retrospective observational study.

Adult patients with uveitic macular edema refractory to systemic corticosteroids and/or disease modifying anti-rheumatic drugs were included.

Patients received anti-TNF-α agents [IFX 5 mg/kg at weeks 0, two, six, and every four to six weeks (n=69); and ADA 40 mg/14 days (n=80)] and tocilizumab [8 mg/kg every four weeks intravenously (n=39) and 162 mg/week subcutaneously (n=16)].

Main outcome measures included:

• analysis of complete and partial response rates;
• relapse rate, low vision (visual acuity in at least one eye ≥1 logMAR);
• corticosteroid sparing effect; and
• adverse events at six months.

A total of 204 patients (median age, 40 years [28 to 58]; 42.2 percent men) were included. Here are some of the findings:

• Main etiologies of uveitis included Behçet's disease (17.2 percent), birdshot chorioretinopathy (11.3 percent) and sarcoidosis (7.4 percent).
• The overall response rate at six months was:
• 46.2 percent (21.8 percent of complete response) with anti-TNF-α agents; and
• 58.5 percent (35.8 precent of complete response) with tocilizumab.
• In multivariate analysis, treatment with tocilizumab (OR, 2.10; CI, 1.06 to 4.06; p=0.03) was independently associated with complete response of uveitic macular edema, compared with anti-TNF-α agents.
• Anti-TNF-α agents and tocilizumab didn’t differ significantly in terms of relapse rate (HR,1.00; CI, 0.31 to 3.18; p=0.99), occurrence of low vision (OR, 1.02; CI, 0.51 to 2.07; p=0.95) or corticosteroid-sparing effect (p=0.29).
• Adverse events were reported in 20.6 percent of patients, including 10.8 percent of serious adverse events.

Scientists wrote that tocilizumab appeared to improve complete response of uveitic macular edema compared with anti-TNF-α agents.

SOURCE: Leclercq M, Andrillon A, Maalouf G, et al. Anti-TNF-α versus tocilizumab in the treatment of refractory uveitic macular edema: A multicenter study from the French Uveitis Network. Ophthalmology 2021; Nov 15. [Epub ahead of print].

MacTel type 2: Multimodal Assessment of Retinal Function and Microstructure

Researchers assessed the impact of neurodegenerative morphologic alterations due to macular telangiectasia type 2 on microperimetry (MP) and multifocal electroretinography.

Thirty-five eyes of 18 patients with MacTel were examined using spectral domain optical coherence tomography, fundus autofluorescence (FAF), mfERG and MP. Software was used to match SD-OCT B-scans with the corresponding retinal sensitivity map and mfERGs, enabling direct structure/function correlation.

Here are some of the findings:

• Loss of the ellipsoid zone (EZ) had the strongest negative association with retinal sensitivity (16.77 dB vs. 4.58 dB, adjusted; p<0.001) of all parameters examined, and had a limited negative effect on mfERGs (0.32 SD vs. -1.97 SD, adjusted; p=0.121).
• EZ irregularity was associated with reduced MP values but preserved mfERGs.
• A significant association was found between areas of inner retinal hyporeflectivity and loss of MP sensitivity (adjusted; p<0.001) but the reduction in sensitivity was less than in locations with EZ loss.
• Areas of mfERG abnormality showed similar sensitivity loss with either inner retinal hyporeflectivity or EZ loss (adjusted; p=0.063).
• In areas with EZ loss alone, preservation of the external limiting membrane (ELM) was associated with higher MP values than in areas with additional ELM loss; the integrity of the ELM alone wasn’t associated with changes either in MP or mfERG.
• Increased FAF was observed in 51 percent of eyes, mixed/reduced FAF was observed in 40 percent of eyes, and no abnormality was detected in 9 percent of eyes.

Researchers wrote the data suggested both MP and mfERG were useful noninvasive modalities for detecting localized macular dysfunction in MacTel. They added, the findings suggested the two methods had different sensitivities to inner and outer retinal changes in macular function and were complementary.

SOURCE: Ledolter AA, Ristl R, Palmowski-Wolfe AM, et al. Macular Telangiectasia type 2: Multimodal assessment of retinal function and microstructure. Acta Ophthalmol 2021; Dec 1. [Epub ahead of print].

Predictive Scoring System for Visual Outcomes After RRD Repair

Researchers compared risk factors for poor visual outcomes in patients undergoing primary rhegmatogenous retinal detachment repair and developed a scoring system.

They analyzed the Primary Retinal detachment Outcomes (PRO) study, a multicenter interventional cohort of consecutive primary RRD surgeries performed in 2015. The main outcome measure was a poor visual outcome (Snellen VA ≤20/200).

A total of 1,178 cases were included. Here are some of the findings:

• The mean preoperative logMAR was 1.1 ±1.1 (20/250) and postoperative logMAR was 0.5 ±0.7 (20/63).
• Multivariable logistic regression identified preoperative risk factors predictive of poor visual outcomes (≤20/200), including:
• proliferative vitreoretinopathy (PVR) (OR, 1.26; CI, 1.13 to 1.40);
• history of anti-vascular endothelial growth factor (VEGF) injections (OR: 1.38; CI, 1.11 to 1.71);
• >1-week vision loss (OR: 1.17; CI, 1.08 to 1.27);
• ocular comorbidities (OR, 1.18; CI, 1.00 to 1.38);
• poor presenting VA (1.06 per initial logMAR unit; CI, 1.02 to 1.10); and
• age >70 (OR: 1.13; CI, 1.04 to 1.23).
• The data were split into training (75 percent) and validation (25 percent), and a scoring system was developed and validated.
• The risk for poor visual outcomes was:
• 8 percent with a total score of 0;
• 17 percent with 1;
• 29 percent with 2;
• 47 percent with 3; and
• 71 percent with 4 or higher.

Researchers concluded that the Primary Retinal detachment Outcomes score developed to provide a scoring system for independent risk factors for poor visual outcomes after RRD surgery may be useful in clinical practice.

SOURCE: Cai LZ, Lin J, Starr MR, et al; Primary Retinal Detachment Outcomes (PRO) Study Group. PRO score: Predictive scoring system for visual outcomes after rhegmatogenous retinal detachment repair. Br J Ophthalmol 2021; Nov 23. [Epub ahead of print].