FEATURED ARTICLE

Exploring the Effect of the Gut Microbiome on the Risk of Age-Related Macular Degeneration From
the Perspective of Causality.
Investigative Ophthalmology & visual science. 2023 Jun 1;
Liu K, Zou J, Yuan R, Fan H, Hu H, Cheng Y, Liu J, Zou H, You Z.

Purpose: To Explore the mechanisms relating the gut microbiome (GM) to age-related macular
degeneration (AMD), as they remain unclear. GM taxa that appear to act within the gut-retina axis
may affect the risk of AMD.

Methods: Single-nucleotide polymorphisms (SNPs) of 196 GM taxa were obtained from the
MiBioGen consortium, and a Mendelian randomization (MR) study was carried out to estimate the
causality between GM taxa and AMD (defined as an endpoint based on ICD-9 and ICD-10). Using the
data from the FinnGen consortium (6157 patients and 288,237 controls), we explored the GM taxa
for causality and verified the results at the replication stage based on the MRC-IEU consortium (3553
cases and 147,089 controls). Inverse variance weighting (IVW) was the main method used to analyze
causality, and the MR results were verified using heterogeneity tests and pleiotropy tests.

Results: According to the MR results, order Rhodospirillales (P = 3.38 × 10-2), family Victivallaceae (P
= 3.14 × 10-2), family Rikenellaceae (P = 3.58 × 10-2), genus Slackia (P = 3.15 × 10-2), genus
Faecalibacterium (P = 3.01 × 10-2), genus Bilophila (P = 1.11 × 10-2), and genus Candidatus
Soleaferrea (P = 2.45 × 10-2) were suggestively associated with AMD. In the replication stage, only
order Rhodospirillales (P = 0.03) passed validation. The heterogeneity (P > 0.05) and pleiotropy (P >
0.05) tests in two stages confirmed the robustness of the MR results.

Conclusions: We confirmed that order Rhodospirillales influenced the risk of AMD based on the gut-
retina axis, providing new impetus for the development of the GM as an intervention to prevent the
occurrence and development of AMD.

DOI: 10.1167/iovs.64.7.22

DRUG TREATMENT
Intraocular Inflammation Incidence Following Intravitreal Brolucizumab Injection for Exudative
Age-Related Macular Degeneration.
Retina (Philadelphia,Pa.) 2023 Jun 13.
Pakravan P, Patel V, Lai J, Shaheen A, Kalahasty K, Reyes-Capo DP, Chau V, Rosenfeld PJ, Haddock LJ,
Schwartz SG, Smiddy WE, Kovach JL, Sridhar J, Flynn HW Jr, Albini TA, Yannuzzi NA.

Purpose: We evaluated the clinical outcomes of Intraocular inflammation (IOI) of eyes with
neovascular age-related macular degeneration (AMD) injected with brolucizumab in our tertiary
referral center.

Methods: A retrospective case series for which clinical records of all eyes that received intravitreal
brolucizumab at Bascom Palmer Eye Institute between December 1, 2019, and April 1, 2021 were
reviewed.

Results: There were 345 eyes of 278 patients who received 801 brolucizumab injections. IOI was
detected in 16 eyes of 13 patients (4.6%). In those patients, baseline logMAR best-corrected visual
acuity (BCVA) was 0.32 0.2 (20/42), while it was 0.580.3 (20/76) at IOI presentation. The mean
number of injections among eyes experiencing IOI was 2.4, and the interval between the last
brolucizumab injection and IOI presentation was 20 days. There were no known case of retinal
vasculitis. Management of IOI included topical steroids in 7 eyes (54%), topical and systemic steroids
in 5 eyes (38%), and observation in one eye (8%). BCVA returned to baseline and inflammation
resolved in all eyes by last follow-up examination.

Conclusions: Intraocular inflammation following brolucizumab injection for neovascular AMD was
not uncommon. Inflammation resolved in all eyes by last follow-up visit.

DOI: 10.1097/IAE.0000000000003862

NUTRITION AND LIFESTYLE

Low-dose supplementation with retinol improves retinal function in eyes with age-related macular
degeneration but without reticular pseudodrusen.
Retina (Philadelphia, Pa.) 2023 Jun 9.
Pfau K, Jeffrey BG, Cukras CA.

Aims: To determine the functional impact of oral Vitamin A supplementation in patients with
intermediate age-related macular degeneration (iAMD) with and without reticular pseudodrusen
(RPD) demonstrating dysfunction in dark adaptation (DA).

Methods: Five patients with iAMD and without RPD (AMD group; mean ± SD age 78.0 ± 4.7 years)
and seven with RPD (RPD group; age 74.1 ± 11.2 years) were supplemented with 16,000 IU of
Vitamin A palmitate for 8 weeks. Assessment at baseline, 4, 8 and 12 weeks included scotopic
thresholds, dark adaptation, best-corrected and low luminance visual acuities and the low-luminance
quality of life questionnaire.

Results: In the linear mixed model, RIT improved significantly in the AMD group (mean[95% CI]
change -1.1 min [-1.8; -0.5] after 4 weeks (p<0.001) and -2.2 min[-2.9; 1.6] after 8 weeks of Vitamin A
supplementation (p<0.001). The DA cone plateau also significantly improved (i.e. more sensitive cone
threshold) at 4 and 8 weeks (p=0.026 and p=0.001). No other parameters improved in the AMD
group and there was no significant improvement in any parameter in the RPD group despite
significantly elevated serum Vitamin A levels measurable in both groups after supplementation
(p=0.024 and p=0.013).

Conclusions: Supplementation with 16,000IU Vitamin A, a lower dose than used in previous studies,
partially overcomes the pathophysiologic functional changes in AMD eyes. The lack of improvement
in the RPD group may indicate structural impediments to increasing vitamin A availability in these
patients, and/or may reflect the higher variability observed in the functional parameters for this
group.

DOI: 10.1097/IAE.0000000000003840

REVIEWS
Diet and ideal food pyramid to prevent or support the treatment of diabetic retinopathy, age-
related macular degeneration, and cataracts.
Frontiers in medicine (Lausanne). 2023 May 30;
Rondanelli M, Gasparri C, Riva A, Petrangolini G, Barrile GC, Cavioni A, Razza C, Tartara A, Perna S.

Many eye diseases, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and
cataracts are preventable and treatable with lifestyle. The objective of this review is to assess the
most recent research on the ideal dietary approach to prevent or support the treatment of DR, AMD,
and cataracts, as well as to construct a food pyramid that makes it simple for people who are at risk
of developing these pathologies to decide what to eat. The food pyramid presented here proposes
what should be consumed every day: 3 portions of low glycemic index (GI) grains (for fiber and zinc
content), 5 portions (each portion: ≥200 g/day) of fruits and vegetables (spinach, broccoli, zucchini
cooked, green leafy vegetables, orange, kiwi, grapefruit for folic acid, vitamin C, and
lutein/zeaxanthin content, at least ≥42 μg/day, are to be preferred), extra virgin olive (EVO) oil
(almost 20 mg/day for vitamin E and polyphenols content), nuts or oil seeds (20-30 g/day, for zinc
content, at least ≥15.8 mg/day); weekly: fish (4 portions, for omega-3 content and eicosapentaenoic
acid (EPA) + docosahexaenoic acid (DHA) 0.35-1.4 g/day), white meat (3 portions for vitamin B12
content), legumes (2 portions for vegetal proteins), eggs (2 portions for lutein/zeaxanthin content),
light cheeses (2 portions for vitamin B6 content), and almost 3-4 times/week microgreen and spices
(saffron and curcumin). At the top of the pyramid, there are two pennants: one green, which
indicates the need for personalized supplementation (if daily requirements cannot be met through
diet, omega-3, and L-methylfolate supplementation), and one red, which indicates that certain foods
are prohibited (salt and sugar). Finally, 3-4 times per week, 30-40 min of aerobic and resistance
exercises are required.

DOI: 10.3389/fmed.2023.1168560

Complement inhibitors for age-related macular degeneration.

The Cochrane database of systematic reviews 2023 Jun 14;
Tzoumas N, Riding G, Williams MA, Steel DH.

Background: Age-related macular degeneration (AMD) is a common eye disease and leading cause of
sight loss worldwide. Despite its high prevalence and increasing incidence as populations age, AMD
remains incurable and there are no treatments for most patients. Mounting genetic and molecular
evidence implicates complement system overactivity as a key driver of AMD development and
progression. The last decade has seen the development of several novel therapeutics targeting
complement in the eye for the treatment of AMD. This review update encompasses the results of the
first randomised controlled trials in this field.

Objectives: To assess the effects and safety of complement inhibitors in the prevention or treatment
of AMD.

Search Methods: We searched CENTRAL on the Cochrane Library, MEDLINE, Embase, LILACS, Web of
Science, ISRCTN registry, ClinicalTrials.gov, and the WHO ICTRP to 29 June 2022 with no language
restrictions. We also contacted companies running clinical trials for unpublished data.

Selection Criteria: We included randomised controlled trials (RCTs) with parallel groups and
comparator arms that studied complement inhibition for advanced AMD prevention/treatment.

Data Collection And Analysis: Two authors independently assessed search results and resolved
discrepancies through discussion. Outcome measures evaluated at one year included change in best-
corrected visual acuity (BCVA), untransformed and square root-transformed geographic atrophy (GA)
lesion size progression, development of macular neovascularisation (MNV) or exudative AMD,
development of endophthalmitis, loss of ≥ 15 letters of BCVA, change in low luminance visual acuity,
and change in quality of life. We assessed risk of bias and evidence certainty using Cochrane risk of
bias and GRADE tools.
Main Results: Ten RCTs with 4052 participants and eyes with GA were included. Nine evaluated
intravitreal (IVT) administrations against sham, and one investigated an intravenous agent against
placebo. Seven studies excluded patients with prior MNV in the non-study eye, whereas the three
pegcetacoplan studies did not. The risk of bias in the included studies was low overall. We also
synthesised results of two intravitreal agents (lampalizumab, pegcetacoplan) at monthly and every-
other-month (EOM) dosing intervals. Efficacy and safety of IVT lampalizumab versus sham for GA For
1932 participants in three studies, lampalizumab did not meaningfully change BCVA given monthly
(+1.03 letters, 95% confidence interval (CI) -0.19 to 2.25) or EOM (+0.22 letters, 95% CI -1.00 to 1.44)
(high-certainty evidence). For 1920 participants, lampalizumab did not meaningfully change GA
lesion growth given monthly (+0.07 mm², 95% CI -0.09 to 0.23; moderate-certainty due to
imprecision) or EOM (+0.07 mm², 95% CI -0.05 to 0.19; high-certainty). For 2000 participants,
lampalizumab may have also increased MNV risk given monthly (RR 1.77, 95% CI 0.73 to 4.30) and
EOM (RR 1.70, 95% CI 0.67 to 4.28), based on low-certainty evidence. The incidence of
endophthalmitis in patients treated with monthly and EOM lampalizumab was 4 per 1000 (0 to 87)
and 3 per 1000 (0 to 62), respectively, based on moderate-certainty evidence. Efficacy and safety of
IVT pegcetacoplan versus sham for GA For 242 participants in one study, pegcetacoplan probably did
not meaningfully change BCVA given monthly (+1.05 letters, 95% CI -2.71 to 4.81) or EOM (-1.42
letters, 95% CI -5.25 to 2.41), as supported by moderate-certainty evidence. In contrast, for 1208
participants across three studies, pegcetacoplan meaningfully reduced GA lesion growth when given
monthly (-0.38 mm², 95% CI -0.57 to -0.19) and EOM (-0.29 mm², 95% CI -0.44 to -0.13), with high
certainty. These reductions correspond to 19.2% and 14.8% versus sham, respectively. A post hoc
analysis showed possibly greater benefits in 446 participants with extrafoveal GA given monthly (-
0.67 mm², 95% CI -0.98 to -0.36) and EOM (-0.60 mm², 95% CI -0.91 to -0.30), representing 26.1%
and 23.3% reductions, respectively. However, we did not have data on subfoveal GA growth to
undertake a formal subgroup analysis. In 1502 participants, there is low-certainty evidence that
pegcetacoplan may have increased MNV risk when given monthly (RR 4.47, 95% CI 0.41 to 48.98) or
EOM (RR 2.29, 95% CI 0.46 to 11.35). The incidence of endophthalmitis in patients treated with
monthly and EOM pegcetacoplan was 6 per 1000 (1 to 53) and 8 per 1000 (1 to 70) respectively,
based on moderate-certainty evidence. Efficacy and safety of IVT avacincaptad pegol versus sham for
GA In a study of 260 participants with extrafoveal or juxtafoveal GA, monthly avacincaptad pegol
probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95% CI -5.89
to 8.67) or 4 mg (-0.28 letters, 95% CI -8.74 to 8.18), based on moderate-certainty evidence. Despite
this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5%
reduction at 2 mg (-0.70 mm², 95% CI -1.99 to 0.59) and 25.6% reduction at 4 mg (-0.71 mm², 95% CI
-1.92 to 0.51), based on moderate-certainty evidence. Avacincaptad pegol may have also increased
the risk of developing MNV (RR 3.13, 95% CI 0.93 to 10.55), although this evidence is of low
certainty. There were no cases of endophthalmitis reported in this study.

Authors' Conclusions: Despite confirmation of the negative findings of intravitreal lampalizumab

across all endpoints, local complement inhibition with intravitreal pegcetacoplan meaningfully
reduces GA lesion growth relative to sham at one year. Inhibition of complement C5 with intravitreal
avacincaptad pegol is also an emerging therapy with probable benefits on anatomical endpoints in
the extrafoveal or juxtafoveal GA population. However, there is currently no evidence that
complement inhibition with any agent improves functional endpoints in advanced AMD; further
results from the phase 3 studies of pegcetacoplan and avacincaptad pegol are eagerly awaited.
Progression to MNV or exudative AMD is a possible emergent adverse event of complement
inhibition, requiring careful consideration should these agents be used clinically. Intravitreal
administration of complement inhibitors is probably associated with a small risk of endophthalmitis,
which may be higher than that of other intravitreal therapies. Further research is likely to have an
important impact on our confidence in the estimates of adverse effects and may change these. The
optimal dosing regimens, treatment duration, and cost-effectiveness of such therapies are yet to be
established.

DOI: 10.1002/14651858.CD009300.pub3

Antioxidants and neurodegenerative eye disease.

Critical reviews in food science and nutrition 2023 Jun 13:
Semenova Y, Bjørklund G.

Neurodegenerative ocular disorders mostly develop with aging and present great complications in
the quality of life. Glaucoma and age-related macular degeneration (ARMD) rank as the third and
fourth leading causes of blindness and low vision. Oxidative stress is one factor in the pathogenesis
of neurodegenerative eye disease. In addition, ocular ischemia and neuroinflammation play an
important role. It can be hypothesized that the influence of antioxidants through diet or oral
supplementation can counteract the harmful effects of reactive oxygen species accumulated
secondary to oxidative stress, ischemia, and inflammation. A range of studies has been published
over the past decades focusing on the possible adjuvant effect of antioxidants in ARMD, while there
were fewer reports on the potential role of antioxidants in glaucoma. Although certain reports
demonstrated positive results, others were discouraging. As there is a controversy between the
studies favoring and disfavoring supplementation with different types of antioxidants, it is important
to revise the existing evidence on the role of antioxidants in neurodegenerative ocular disorders with
a special focus on glaucoma and ARMD.

DOI: 10.1080/10408398.2023.2215865

RISK OF DISEASE
Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases.
Journal of translational medicine. 2023 Jun 12;
Zhong P, Tan S, Zhu Z, Bulloch G, Long E, Huang W, He M, Wang W.

Background: We aimed to evaluate the impacts of metabolomic body mass index (metBMI)
phenotypes on the risks of cardiovascular and ocular diseases outcomes.

Methods: This study included cohorts in UK and Guangzhou, China. By leveraging the serum
metabolome and BMI data from UK Biobank, this study developed and validated a metBMI
prediction model using a ridge regression model among 89,830 participants based on 249
metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal
weight (NW, metBMI of 18.5-24.9 kg/m2), overweight (OW, metBMI of 25-29.9 kg/m2), obesity (OB,
metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE,
metBMI-actBMI < - 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES)
were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-
cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction
[MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts,
glaucoma, and diabetic retinopathy [DR]).

Results: In the UKB, although OE group had lower actBMI than NW group, the OE group had a
significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI
1.16-2.43). Similarly, the OE group had a 1.7-3.6-fold higher risk than their NW counterparts for
cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 
0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02-3.77) was
significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality
and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had
significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of
metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different
metabolomic approach.

Conclusions: Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit
distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites
were at higher risk of mortality and morbidity than those with normal health metabolites.
Metabolomics allowed for leveraging the future of diagnosis and management of 'healthily obese'
and 'unhealthily lean' individuals.

DOI: 10.1186/s12967-023-04244-x

DIAGNOSIS AND IMAGING

Performance of retinal fluid monitoring in OCT imaging by automated deep learning versus human
expert grading in neovascular AMD.
Eye (London, England). 2023 Jun 13.
Pawloff M, Gerendas BS, Deak G, Bogunovic H, Gruber A, Schmidt-Erfurth U.

Purpose: To evaluate the reliability of automated fluid detection in identifying retinal fluid activity in
OCT scans of patients treated with anti-VEGF therapy for neovascular age-related macular
degeneration by correlating human expert and automated measurements with central retinal
subfield thickness (CSFT) and fluid volume values.

Methods: We utilized an automated deep learning approach to quantify macular fluid in SD-OCT
volumes (Cirrus, Spectralis, Topcon) from patients of HAWK and HARRIER Studies. Three-dimensional
volumes for IRF and SRF were measured at baseline and under therapy in the central millimeter and
compared to fluid gradings, CSFT and foveal centerpoint thickness (CPT) values measured by the
Vienna Reading Center.

Results: 41.906 SD-OCT volume scans were included into the analysis. Concordance between human
expert grading and automated algorithm performance reached AUC values of 0.93/0.85 for IRF and
0.87 for SRF in HARRIER/HAWK in the central millimeter. IRF volumes showed a moderate correlation
with CSFT at baseline (HAWK: r = 0.54; HARRIER: r = 0.62) and weaker correlation under therapy
(HAWK: r = 0.44; HARRIER: r = 0.34). SRF and CSFT correlations were low at baseline (HAWK: r = 0.29;
HARRIER: r = 0.22) and under therapy (HAWK: r = 0.38; HARRIER: r = 0.45). The residual standard
error (IRF: 75.90 µm; SRF: 95.26 µm) and marginal residual standard deviations (IRF: 46.35 µm; SRF:
44.19 µm) of fluid volume were high compared to the range of CSFT values.

Conclusion: Deep learning-based segmentation of retinal fluid performs reliably on OCT images. CSFT
values are weak indicators for fluid activity in nAMD. Automated quantification of fluid types,
highlight the potential of deep learning-based approaches to objectively monitor anti-VEGF therapy.

DOI: 10.1038/s41433-023-02615-8