MD Research News · intraocular inflammatory cytokines in the poor responder to ranibizumab...

Issue 397 | 17 October | 2018

Drug Treatment

Clin Ophthalmol. 2018 Sep 26;12:1877-1885. eCollection

2018.

Neovascular age-related macular degeneration:

intraocular inflammatory cytokines in the poor

responder to ranibizumab treatment.

Pongsachareonnont P, Mak MYK, Hurst CP, Lam WC.

Purpose: To determine the levels of interleukin (IL)-6, vascular

endothelial growth factor-A, platelet-derived growth factor,

placental growth factor (PLGF), and other cytokines in the

aqueous fluid of patients with neovascular age-related macular

degeneration who respond poorly to ranibizumab.

Patients and methods: This is an observational, prospective

study. Thirty-two eyes from 30 patients were included in the

study: 11 patients who responded poorly to ranibizumab and

were switched to aflibercept (AF group), 8 patients who received

ranibizumab and photodynamic therapy (PDT group), and 13

patients who responded to ranibizumab (control group). Aqueous fluid samples were collected for analysis

of cytokine levels at baseline and after 1, 2, and 3 months of treatment. The effect of treatment on cytokine

levels was compared between the study groups and between different time points using a linear mixed-

effect regression model.

Results: In the AF group, there was an increase in vascular endothelial growth factor-C, IL-7, and

angiopoeitin-2 levels (P=0.01) and a decrease in intercellular adhesion molecule and IL-17 levels (P=0.01)

between baseline and 3 months. After adjustment for age, sex, race, and type of lesion at baseline, the

PLGF level was higher (P=0.02) and the IL-7 level was lower (P=0.04) in the ranibizumab non-responder

group than in the ranibizumab responder group.

Conclusion: Switching from ranibizumab to aflibercept did not reduce intraocular levels of angiogenesis

cytokines, but resulted in improvement of central subfield thickness. PLGF levels were higher in poor

responders to ranibizumab. The response of lesions to medication might be related to the stage of

choroidal neovascularization.

PMID: 30310267 PMCID: PMC6165786 DOI: 10.2147/OPTH.S171636

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Retina. 2018 Oct 3. doi: 10.1097/IAE.0000000000002351. [Epub ahead of print]

Comparative risk of endophthalmitis after intravitreal injection with bevacizumab,

aflibercept, and ranibizumab.

Bavinger JC, Yu Y, VanderBeek BL.

Purpose: To determine whether sterile preloading of anti-vascular endothelial growth factor agents

reduces the risk of postintravitreal injection endophthalmitis.

Methods: This is a retrospective cohort study using medical claims data from a large, national US insurer.

Cohorts were created using intravitreal injections of anti-vascular endothelial growth factor injections from

2005 to 2016. For inclusion, patients had to have at least 6 months of data before the injection and were

excluded for any previous diagnosis of endophthalmitis, multiple injected drugs on the day of injection, or

intraocular surgery within 15 days of the injection or between an injection and a diagnosis of

endophthalmitis. The primary outcome was the odds of endophthalmitis after an intravitreal injection.

Results: A total of 706,725 bevacizumab, 210,849 ranibizumab, and 177,731 aflibercept injections were

given to 130,327 patients. Multivariate analysis showed that ranibizumab and aflibercept together had an

increased odds of endophthalmitis (odds ratio = 1.29, 95% confidence interval: 1.04-1.59, P = 0.02)

compared with bevacizumab. Individually, ranibizumab (odds ratio = 1.25, 95% confidence interval: 0.97-

1.61, P = 0.08) and aflibercept (odds ratio = 1.34, 95% confidence interval: 0.99-1.81, P = 0.06) each had

higher odds of endophthalmitis, but neither result met significance. Also, when compared with male

patients, female patients had a higher odds of getting endophthalmitis (odds ratio: 1.30, 95% confidence

interval: 1.05-1.61, P = 0.02).

Conclusion: The odds of endophthalmitis with aflibercept and ranibizumab combined were higher

compared with the sterilely preloaded bevacizumab, arguing for a safety advantage of sterile preloading of

anti-vascular endothelial growth factor injections.

PMID: 30312260 DOI: 10.1097/IAE.0000000000002351

Ophthalmologica. 2018 Oct 10:1-7. [Epub ahead of print]

Onset of retinal pigment epithelium atrophy subsequent to anti-VEGF therapy in patients

with neovascular age-related macular degeneration.

Sitnilska V, Altay L, Enders P, et al.

Purpose: The aim of this study was to evaluate risk factors for the development of retinal pigment

epithelium (RPE) atrophy in patients with neovascular age-related macular degeneration (nAMD).

Procedures: This post hoc analysis of the prospective RESPONSE study includes 52 therapy-naive

nAMD patients without baseline RPE atrophy, who were treated with ≥9 anti-vascular endothelial growth

factor (VEGF) injections for ≥3 years. RPE atrophy was assessed via multimodal imaging. Baseline

aqueous VEGF and serum complement levels (C3d/C3) were measured. Risk factors for atrophy

development were evaluated via logistic regression analysis.

Results: Atrophy onset was significantly associated with the duration of nAMD (mean 5.34 years; odds

ratio = 1.83, p = 0.012). Anti-VEGF injection number, age, C3d/C3 ratio, baseline intraocular VEGF, or

delay to the first treatment had no influence on RPE atrophy.

Conclusions: The duration of treatment-requiring nAMD was identified as primary risk factor for the onset

of concomitant RPE atrophy after commencing therapy. Targeting concomitant atrophy in nAMD patients

might improve the long-term prognosis of the disease.

PMID: 30304737 DOI: 10.1159/000492924



Biomed Res Int. 2018 Sep 13;2018:1585803. eCollection 2018.

Treatment of punctate inner choroidopathy with choroidal neovascularization using

corticosteroid and intravitreal ranibizumab.

Wu W, Li S, Xu H, et al.

Background: To evaluate the treatment outcomes of patients with punctate inner choroidopathy (PIC) and

secondary choroidal neovascularization (CNV).

Methods: This is a retrospective study of 24 eyes in 22 patients suffering from PIC with CNV. Patients

were treated with intravitreal ranibizumab monotherapy (14 eyes) or combined oral corticosteroid and

intravitreal ranibizumab therapy (corticosteroid-ranibizumab group, 10 eyes). Mean follow-up duration was

24.0 months. We evaluated best-corrected visual acuity (BCVA), fundus autofluorescence, fluorescein

angiography, indocyanine green angiography, and optical coherence tomography, before and after

treatment. The following variables were compared between groups: number of intravitreal ranibizumab

injections, BCVA, recurrence of CNV, and change in PIC lesions.

Results: The ranibizumab monotherapy group received an average of 3 intravitreal ranibizumab

injections; mean logMAR visual acuity improvement was 0.34, and 8 eyes developed recurrent CNV during

follow-up. The corticosteroid-ranibizumab group received an average of 1.9 intravitreal ranibizumab

injections; mean logMAR visual acuity improvement was 0.61, and there was no recurrence of CNV.

Combined corticosteroid-ranibizumab therapy also resulted in better resolution of PIC lesions and fewer

new PIC lesions.

Conclusion: Both corticosteroid-ranibizumab treatment and ranibizumab monotherapy could significantly

improve the vision of PIC patients with CNV. Combined corticosteroid and intravitreal ranibizumab

treatment appeared to reduce CNV recurrence and development of new PIC lesions compared with

ranibizumab monotherapy.

PMID: 30302336 PMCID: PMC6158959 DOI: 10.1155/2018/1585803

Ophthalmology. 2018 Oct 6. pii: S0161-6420(17)33849-6. [Epub ahead of print]

Intralesional macular atrophy in anti-vascular endothelial growth factor therapy for age-

related macular degeneration in the IVAN Trial.

Bailey C, Scott LJ, Rogers CA, et al; writing committee for the IVAN Study Group.

Purpose: To report on the development and progression of macular atrophy (MA) and its relationship with

morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial

growth factor (VEGF) in Age-related Choroidal Neovascularisation trial.

Design: Reading center analysis of data from a randomized controlled trial.

Participants: Participants with previously untreated neovascular age-related macular degeneration

(nAMD) in the study eye.

Methods: Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year

follow-up were graded systematically for presence of MA. Regression models were constructed to explore

relationships between MA and lesion morphology and vision measures (best-corrected distance and near

acuity, reading speed and index, contrast sensitivity).

Main Outcome Measures: Primary outcome was development of intralesional MA (≥175 μm greatest

linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum

footprint of the neovascular lesion.

Results: Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at



baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%.

In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed

intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident

intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio

[OR], 0.39; 95% confidence interval [CI], 0.19-0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95%

CI, 0.25-0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21-0.74; P =

0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these

findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09-5.44;

P = 0.030). No significant associations were observed between development of intralesional MA and any

other morphologic or visual function measure.

Conclusions: Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti-VEGF

therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual

function were detected, providing some reassurance to clinicians; however, the longer-term effects remain

unknown.

PMID: 30301555 DOI: 10.1016/j.ophtha.2018.07.013

Curr Eye Res. 2018 Oct 7. [Epub ahead of print]

Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and

Extended Release of Bioactive Aflibercept in Vitro.

Liu W, Lee BS, Mieler WF, Kang-Mieler JJ.

Purpose: Current standard of care for neovascular eye diseases require repeated intravitreal bolus

injections of anti-vascular endothelial growth factors (anti-VEGFs). The purpose of this study was to

validate a degradable microsphere-thermoresponsive hydrogel drug delivery system (DDS) capable of

releasing bioactive aflibercept in a controlled and extended manner for six months.

Materials & Methods: The DDS was fabricated by suspending aflibercept-loaded poly(lactic-co-glycolic

acid) (PLGA) microspheres within a biodegradable poly(ethylene glycol)-co-(L-lactic acid) diacrylate/N-

isopropylacrylamide (PEG-PLLA-DA/NIPAAm) thermoresponsive hydrogel. Encapsulation efficiency of

DDSs and in vitro release profiles were characterized by Iodine-125 radiolabeled aflibercept. The

degradation of hydrogel was determined by dry weight changes. The cytotoxicity from degraded DDS

byproducts was investigated by quantifying cell viability using LIVE/DEAD® assay. In addition, dot blot and

enzyme-linked immunosorbent assay (ELISA) were used to determine the bioactivity of released drug.

Finally, morphology of microspheres and hydrogel were investigated by cryo-scanning electron microscopy

(SEM) before and after thermal transformation.

Results: The microsphere-hydrogel DDS was capable of releasing bioactive aflibercept in a controlled and

extended manner for six months. The amount and rate of aflibercept release can be controlled by both the

cross-linker concentration and microspheres load amount. The initial burst (release within 24 hr) was from

37.35 ± 4.92 µg to 74.56 ± 6.16 µg (2 mM and 3 mM hydrogel, each loaded with 10 mg/ml and 20 mg/ml of

microspheres, respectively), followed by controlled drug release of 0.07 µg/day to 0.15 µg/day. Higher PEG

-PLLA-DA concentration (3 mM) degraded faster than the lower concentration (2 mM). No significant

cytotoxicity from degraded DDS byproducts was found for all investigated time points. Bioactivity of

released drug was maintained at therapeutic level over entire release period.

Conclusions: The microsphere-hydrogel DDS is safe and can deliver bioactive aflibercept in a controlled

manner. This may provide a significant advantage over current bolus injection therapies in the treatment of

ocular neovascularization.

PMID: 30295090 DOI: 10.1080/02713683.2018.1533983



Diagnosis & other treatment

Lancet. 2018 Sep 29;392(10153):1147-1159.

Age-related macular degeneration.

Mitchell P, Liew G, Gopinath B, Wong TY.

Abstract: Age-related macular degeneration is a

leading cause of visual impairment and severe vision

loss. Clinically, it is classified as early-stage (medium-

sized drusen and retinal pigmentary changes) to late-

stage (neovascular and atrophic). Age-related macular

degeneration is a multifactorial disorder, with

dysregulation in the complement, lipid, angiogenic,

inflammatory, and extracellular matrix pathways

implicated in its pathogenesis. More than 50 genetic

susceptibility loci have been identified, of which the most

important are in the CFH and ARMS2 genes. The major

non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids).

Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant

vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab,

aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration,

and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no

proven therapies for atrophic disease are available, but several agents are being investigated in clinical

trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification,

personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or

other agents, and regenerative therapies.

PMID: 30303083 DOI: 10.1016/S0140-6736(18)31550-2

Retina. 2018 Oct 10. [Epub ahead of print]

Eyes with subretinal drusenoid deposits and no drusen: progression of macular findings.

Spaide RF, Yannuzzi L, Freund KB, et al.

Purpose: To investigate the macular changes over time in eyes containing subretinal drusenoid deposits

(also known as pseudodrusen) with no drusen >63 µm.

Methods: A consecutive series of patients were examined with color fundus photography, optical

coherence tomography, and autofluorescence imaging with fluorescein angiography used as necessary.

Exclusionary criteria included macular neovascularization, history of retinal surgery, pseudoxanthoma

elasticum, and drusen >63 µm.

Results: There were 85 eyes of 54 patients. The mean age at baseline was 83.6 (±7.8) years, and there

were 17 men. The mean follow-up was 5.0 (±2.9) years. At initial optical coherence tomography

examination, 12 eyes had extrafoveal atrophy and 17 eyes had vitelliform deposits, which were yellowish

white subretinal collections that showed intense hyperautofluorescence. During follow-up, 11 eyes lost

vitelliform material. After the disappearance of small deposits, focal hyperpigmentation remained. Loss of

larger deposits was associated with noteworthy sequela; six developed subfoveal atrophy and one macular

neovascularization close to regressing vitelliform material. Subfoveal geographic atrophy developed in four

other eyes without vitelliform material by extension from areas of extrafoveal atrophy. Macular

neovascularization developed in seven eyes over follow-up. The CFH Y402H and ARMS2 A69S allele

frequencies were 57% and 48.9%, respectively, which is similar to a group of age-related macular

degeneration controls. One patient had a novel PRPH2 mutation, but did not have a vitelliform deposit; the



remainder had a normal PRPH2 and BEST1 coding sequences.

Conclusion: Eyes with subretinal drusenoid deposits and no drusen >63 mm have significant risk for the

development of both neovascularization and geographic atrophy, the fundamental components of late age-

related macular degeneration. An intermediate step in some eyes was the development of a vitelliform

deposit, an entity not traditionally associated with age-related macular degeneration, but in these patients,

the material seemed to be an important component of the disease pathophysiology. This vitelliform deposit

was not associated with genetic markers for pattern dystrophy or Best disease.

PMID: 30312263 DOI: 10.1097/IAE.0000000000002362

Clin Ophthalmol. 2018 Sep 26;12:1887-1893. eCollection 2018.

Characteristics of diabetic macular edema on optical coherence tomography may change

over time or after treatment.

Sheu SJ, Lee YY, Horng YH, et al.

Purpose: To investigate optical coherence tomography (OCT) characteristics in diabetic macular edema

(DME) over time and after treatment.

Patients and methods: OCT morphological features in DME eyes treated with ranibizumab with at least

1 year of follow-up were retrospectively analyzed.

Results: Thirty-five eyes were included. From baseline to Month 12, mean visual gain was 7.2±13.6 letters

and mean central retinal thickness reduction was 61.9±121.8 μm. Fovea-involving ellipsoid zone (EZ)

disruption was significantly associated with final vision of <70 letters. Subretinal fluid at baseline was

present only in eyes naïve to previous intravitreal pharmacotherapy and was related to better visual gain

and fewer injections. Treatment-naïve eyes had shorter DME duration and less EZ damage.

Conclusion: DME characteristics on OCT may change over time or after treatment. Subretinal fluid may

be associated with earlier change and less EZ damage in DME.

PMID: 30310268 PMCID: PMC6165769 DOI: 10.2147/OPTH.S173956

Eye (Lond). 2018 Oct 11. [Epub ahead of print]

Changes in volume of various retinal layers over time in early and intermediate age-related

macular degeneration.

Lamin A, Oakley JD, Dubis AM, et al.

Purpose: To evaluate longitudinally volume changes in inner and outer retinal layers in early and

intermediate age-related macular degeneration (AMD) compared to healthy control eyes using optical

coherence tomography (OCT).

Methods: 71 eyes with AMD and 31 control eyes were imaged at two time points: baseline and after 2

years. Automated OCT layer segmentation was performed using OrionTM. This software is able to

measure volumes of retinal layers with distinct boundaries including Retinal Nerve Fibre Layer (RNFL),

Ganglion Cell-Inner Plexiform Layer (GCIPL), Inner Nuclear Layer (INL), Outer Plexiform Layer (OPL),

Outer Nuclear Layer (ONL), Photoreceptors (PR) and Retinal Pigment Epithelium-Bruch's Membrane

complex (RPE-BM). The mean retinal layer volumes and volume changes at 2 years were compared

between groups.

Results: Mean GCIPL and INL volumes were lower, while PR and RPE-BM volumes were higher in AMD

eyes than controls at baseline (all P < 0.05) and year 2 (all P < 0.05). In AMD eyes, RNFL and ONL volumes

decreased by 0.0232 (P = 0.033) and 0.0851 (P = 0.001), respectively. In contrast, OPL and RPE-BM

volumes increased in AMD eyes by 0.0391 (P = 0.000) and 0.0209 (P = 0.000) respectively. Moreover, there



were significant differences in longitudinal volume change of OPL (P = 0.02), ONL (P = 0.008) and RPE-BM

(P = 0.02) between AMD eyes and controls.

Conclusions: There were abnormal retinal layer volumes and volume changes in eyes with early and

intermediate AMD.

PMID: 30310161 DOI: 10.1038/s41433-018-0234-9

PLoS One. 2018 Oct 9;13(10):e0205513. eCollection 2018.

Quantitative optical coherence tomography angiography biomarkers for neovascular age-

related macular degeneration in remission.

Coscas F, Cabral D, Pereira T, et al.

Purpose: To characterize quantitative optical coherence tomography angiography (OCT-A) parameters in

active neovascular age-related macular degeneration (nAMD) patients under treatment and remission

nAMD patients.

Design: Retrospective, cross-sectional study.

Participants: One hundred and four patients of whom 72 were in Group 1 (active nAMD) and 32 in Group

2 (remission nAMD) based on SD-OCT (Spectral Domain OCT) qualitative morphology.

Methods: This study was conducted at the Centre Ophtalmologique de l'Odeon between June 2016 and

December 2017. Eyes were analyzed using SD-OCT and high-speed (100 000 A-scans/second) 1050-nm

wavelength swept-source OCT-A. Speckle noise removal and choroidal neovascularization (CNV) blood

flow delineation were automatically performed. Quantitative parameters analyzed included blood flow area

(Area), vessel density, fractal dimension (FD) and lacunarity. OCT-A image algorithms and graphical user

interfaces were built as a unified tool in Matlab coding language. Generalized Additive Models were used to

study the association between OCT-A parameters and nAMD remission on structural OCT. The models'

performance was assessed by the Akaike Information Criterion (AIC), Brier Score and by the area under

the receiver operating characteristic curve (AUC). A p value of ≤ 0.05 was considered as statistically

significant.

Results: Area, vessel density and FD were different (p<0.001) in the two groups. Regarding the

association with CNV activity, Area alone had the highest AUC (AUC = 0.85; 95%CI: 0.77-0.93) followed by

FD (AUC = 0.80; 95%CI: 0.71-0.88). Again, Area obtained the best values followed by FD in the AIC and

Brier Score evaluations. The multivariate model that included both these variables attained the best

performance considering all assessment criteria.

Conclusions: Blood flow characteristics on OCT-A may be associated with exudative signs on structural

OCT. In the future, analyses of OCT-A quantitative parameters could potentially help evaluate CNV activity

status and to develop personalized treatment and follow-up cycles.

PMID: 30300393 DOI: 10.1371/journal.pone.0205513

Retina. 2018 Oct 8. [Epub ahead of print]

Mesopic and dark-adapted two-color fundus-controlled perimetry in geographic atrophy

secondary to age-related macular degeneration.

Pfau M, Müller PL, von der Emde L, et al.

Purpose: To investigate retinal sensitivity in the junctional zone of geographic atrophy (GA) secondary to

age-related macular degeneration using patient-tailored perimetry grids for mesopic and dark-adapted two-

color fundus-controlled perimetry.

Methods: Twenty-five eyes with GA of 25 patients (prospective, natural-history Directional Spread in



Geographic Atrophy study [DSGA; NCT02051998]) and 40 eyes of 40 normal subjects were included.

Patient-tailored perimetry grids were generated using annotated fundus autofluorescence data. Customized

software positioned test-points along iso-hulls surrounding the GA boundary at distances of 0.43°, 0.86°,

1.29°, 2.15°, and 3.01°. The grids were used for duplicate mesopic and dark-adapted two-color (cyan and

red) fundus-controlled perimetry. Age-adjusted reference-data were obtained through regression analysis of

normative data followed by spatial interpolation.

Results: The mean sensitivity loss for mesopic testing decreased with the distance to GA (-10.3 dB

[0.43°], -8.2 dB [0.86°], -7.1 dB [1.29°], -6.8 dB [2.15°], and -6.6 dB [3.01°]; P < 0.01). Dark-adapted cyan

sensitivity loss exceeded dark-adapted red sensitivity loss for all iso-hulls (-14.8 vs. -11.7 dB, -13.5 vs. -

10.1 dB, -12.8 vs. -9.1 dB, -11.6 vs. -8.2 dB, -10.7 vs. -8.0 dB; P < 0.01).

Conclusion: Patient-tailored fundus-controlled perimetry grids allowed for testing of retinal function in the

junctional zone of GA with high spatial resolution. A distinct decrease in mesopic sensitivity loss between

0.43° (125 µm) and 1.29° (375 µm) was observed that leveled off at more distant test-points. In proximity to

the GA boundary, the results indicate that rod exceeded cone dysfunction.

PMID: 30300264 DOI: 10.1097/IAE.0000000000002337

Clin Exp Optom. 2018 Oct 8. [Epub ahead of print]

Reticular pseudodrusen: current understanding.

Wightman AJ, Guymer RH.

Abstract: Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, represent a

morphological change to the retina distinct from other subtypes of drusen by being located above the level

of the retinal pigment epithelium. Although they can infrequently appear in individuals with no other

apparent pathology, their highest rates of occurrence are in association with age-related macular

degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage

disease sub-types, choroidal neovascularisation and geographic atrophy. Reticular pseudodrusen are also

found in other diseases, most notably Sorsby's fundus dystrophy, pseudoxanthoma elasticum and acquired

vitelliform lesions. They are found more frequently in females, with increased age and more commonly

bilaterally than unilaterally. Increased risk of RPD formation is conveyed by genetic variants known to

increase risk of AMD development, including complement factor H, age-related maculopathy susceptibility

2, and high-temperature requirement A serine peptidase 1; however, to date, no genetic factor has been

found to predispose to RPD independent of those that carry risks for AMD. They have typical features

visible on multimodal imaging, identifiable either as single lesions or more commonly in yellowish-white net-

like patterns on colour fundus photography and are particularly distinguishable using spectral domain

optical coherence tomography, fundus auto-fluorescence, and near infrared reflectance imaging. On

histological examination, RPD have been shown to have distinct compositions in comparison to typical

drusen, suggesting different pathways of pathogenesis. Although their aetiology remains unclear, presence

of opsin within lesions, a high topographic association with areas of highest rod-photoreceptor

concentration and functional deficits most pronounced within the scotopic range, has implicated rod

photoreceptor dysfunction as a component of RPD.

PMID: 30298528 DOI: 10.1111/cxo.12842

Ophthalmology. 2018 Oct 4. pii: S0161-6420(18)31427-1. [Epub ahead of print]

Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular

telangiectasia type 2: a randomized clinical trial.

Macular Telangiectasia Type 2-Phase 2 CNTF Research Group, Chew EY, Clemons TE, Jaffe GJ, et al.

Purpose: To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary

neurotrophic factor (CNTF) on progression of macular telangiectasia type 2, a neurodegenerative disease



with no proven effective therapy.

Design: Randomized sham-controlled clinical trial

Participants: 99 study eyes of 67 eligible participants were enrolled.

Methods: Single-masked randomized clinical trial of 24 months duration conducted May 2014 to April

2017 in eleven clinical centers of retinal specialists in United States and Australia. Participants were

randomized 1:1 surgical implant of intravitreal sustained delivery of human ciliary neurotrophic factor

(CNTF) vs. sham procedure.

Main Outcome Measures: The primary outcome was the difference in the area of neurodegeneration as

measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral domain

optical coherence tomography (SD-OCT) images at 24 months from baseline between the treated and

untreated groups. Secondary outcomes included comparison of visual function changes between treatment

groups.

Results: Among the 67 participants who were randomized (mean age, 62 ± 8.9 years, 41 (61%) women,

58 (86%) white), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 (4 eyes) were

found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration

than the CNTF-treated eyes, the difference in mean area of photoreceptor loss was 0.05 ± 0.03 mm2 (p =

0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were highly correlated

with the changes in the area of photoreceptor loss (r = 0.86, p < 0.0001). The mean retinal sensitivity loss

of the sham group was 45% greater than the treated group (decrease of 15.81±8.93 dB [p=0.07]). Reading

speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated eyes (p = 0.02).

Serious adverse ocular effects were found in 2/51 (4%) of the sham group and 2/48 (4%) in the treated

group.

Conclusions: In participants with macular telangiectasia type 2, a surgical implant that released CNTF

into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration.

Further research is needed to assess longer-term clinical outcomes and safety.

PMID: 30292541 DOI: 10.1016/j.ophtha.2018.09.041

Pathogenesis

Exp Eye Res. 2018 Oct 5. pii: S0014-4835(18)

30398-1. [Epub ahead of print]

The impact of lipids, lipid oxidation, and

inflammation on AMD, and the potential

role of miRNAs on lipid metabolism in

the RPE.

Jun S, Datta S, Wang L, et al.

Abstract: The accumulation of lipids within

drusen, the epidemiologic link of a high fat diet,

and the identification of polymorphisms in genes

involved in lipid metabolism that are associated

with disease risk, have prompted interest in the

role of lipid abnormalities in AMD. Despite intensive investigation, our understanding of how lipid

abnormalities contribute to AMD development remains unclear. Lipid metabolism is tightly regulated, and its

dysregulation can trigger excess lipid accumulation within the RPE and Bruch's membrane. The high

oxidative stress environment of the macula can promote lipid oxidation, impairing their original function as

well as producing oxidation-specific epitopes (OSE), which unless neutralized, can induce unwanted

inflammation that additionally contributes to AMD progression. Considering the multiple layers of lipid

metabolism and inflammation, and the ability to simultaneously target multiple pathways, microRNA



(miRNAs) have emerged as important regulators of many age-related diseases including atherosclerosis

and Alzheimer's disease. These diseases have similar etiologic characteristics such as lipid-rich deposits,

oxidative stress, and inflammation with AMD, which suggests that miRNAs might influence lipid metabolism

in AMD. In this review, we discuss the contribution of lipids to AMD pathobiology and introduce how

miRNAs might affect lipid metabolism during lesion development. Establishing how miRNAs contribute to

lipid accumulation in AMD will help to define the role of lipids in AMD, and open new treatment avenues for

this enigmatic disease.

PMID: 30292489 DOI: 10.1016/j.exer.2018.09.023

Sci Rep. 2018 Oct 11;8(1):15175.

Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in

macular degeneration.

Nashine S, Cohen P, Nesburn AB1, et al.

Abstract: Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat

development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered

MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA

(mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-

added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19

cell model. In AMD cells, we observed significant down-regulation of the MDP-coding MT-RNR2 gene, and

remarkably reduced levels of all five oxidative phosphorylation (OXPHOS) complex I-V protein subunits that

are involved in the electron transport chain; these results suggested mitochondrial toxicity and abnormal

OXPHOS complex protein subunits' levels in AMD cells. However, treatment of AMD cells with SHLP2: (1)

restored the normal levels of OXPHOS complex protein subunits, (2) prevented loss of viable cells and

mitochondria, (3) increased the number of mtDNA copies, (4) induced anti-apoptotic effects, and (5)

attenuated amyloid-β-induced cellular and mitochondrial toxicity. Cumulatively, our findings established the

protective role of SHLP2 in AMD cells in vitro. In conclusion, this novel study supports the merit of SHLP2

in the treatment of AMD, a primary retinal disease that is a leading cause of blindness among the elderly

population in the United States as well as worldwide.

PMID: 30310092 DOI: 10.1038/s41598-018-33290-5

Diet

Am J Ophthalmol. 2018 Oct 9. pii: S0002-9394(18)30578-6. [Epub ahead of print]

Intake of vegetables, fruit, and fish is beneficial for Age-related Macular Degeneration.

de Koning-Backus APM, Buitendijk GHS, Kiefte-de Jong JC, et al.

Purpose: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still

unclear. We investigated the effect of a diet recommended by Health Councils on AMD.

Design: Prospective population-based cohort study.

Methods: 4202 participants from the Rotterdam Study aged 55+ years, free of AMD at baseline, were

included and followed up for 9.1±5.8 years. Incident AMD was graded on fundus photographs. Dietary data

were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized

into food patterns based on guidelines from Health Councils. Associations with incident AMD were

analyzed using Cox-proportional hazards models, and adjusted for age, sex, total energy intake, smoking,

body mass index, hypertension, education, and income.

Results: A total of 754 persons developed incident AMD. Intake of the recommended amounts of

vegetables (≥200gr/day), fruit (2x/day), and fish (2x/week) was 30.6%, 54.9% and 12.5%, respectively. In



particular the intake of fish (2x/week) decreased the risk of incident AMD; hazard ratio (HR) 0.76 [95%

Confidence Interval (CI) 0.60-0.97]). Intake of the recommended amounts of all three food groups was only

3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (HR 0.58 [95%CI

0.36-0.93]). Younger age, higher income, and nonsmoking were associated with this food pattern, but risk

lowering effects remained significant after additional adjustment for these factors.

Conclusion: A diet of 200 grams of vegetables/day, 2x fruit/day, and 2x fish/week is associated with a

significantly reduced risk of AMD.

PMID: 30312575 DOI: 10.1016/j.ajo.2018.09.036

Low vision

Vision Res. 2018 Oct 4. pii: S0042-6989(18)30208-6. [Epub ahead of print]

Benefits of low vision aids to reading accessibility.

Latham K.

Abstract: The Reading Accessibility Index (ACC) has been proposed as a single-value reading parameter

that can capture information on both reading speed and print sizes that can be read. It is defined as the

average reading speed across a relevant range of print sizes (1.3-0.4logMAR), normalised by typical young

-adult reading speed of 200wpm, and with values typically in the range of 0-1. This study determines the

impact of low vision aids (LVAs) on reading by evaluating ACC values for visually impaired observers

reading both without and with an optical LVA. A secondary analysis of previously published data obtained

from 100 visually impaired observers attending low vision assessments was undertaken. Observers had

mixed causes of visual impairment but predominantly macular degeneration (n=55). All used an LVA for

reading, with 88% using it 'often' or 'very often'. MNREAD reading parameters, including ACC, were

determined both for reading without an LVA (clinical function) and with the LVA habitually used for reading

(aided function). There was a significant (p<.001) improvement in ACC from clinical (0.31 (95% CI 0.25,

0.36)) to aided conditions (0.47 (0.41, 0.52)). Average improvement in ACC with an LVA was 0.16 (0.13,

0.18), but the benefits of LVAs in terms of improvement in ACC could not be predicted from clinical visual

function. Even with an LVA reading accessibility is, on average, markedly reduced from normal levels. The

ACC is a potentially valuable outcome measure for reading rehabilitation interventions.

PMID: 30292724 DOI: 10.1016/j.visres.2018.09.009

Case Reports

Retin Cases Brief Rep. 2018 Oct 9. [Epub ahead of print]

Idiopathic full-thickness macular hole in an 8-year old boy.

Manayath GJ, Jain A, Ranjan R, et al.

Purpose: To report a case of idiopathic full-thickness macular hole in a young boy, which was managed

surgically with good visual and anatomical outcomes.

Method: Single case report.

Results: An 8-year-old boy presented for defective vision in the left eye noticed for the past 2 weeks with

best-corrected visual acuity of 6/24. A large full-thickness macular hole was diagnosed clinically and was

confirmed on optical coherence tomography. There was no clinical or tomographic findings suggestive of

trauma or retinal degeneration. After observation for 8 weeks, the patient underwent macular hole surgery

in the left eye including internal limiting membrane peeling and C3F8 gas tamponade. Intraoperatively

abnormally tight vitreoretinal adherence was noted during the induction of posterior vitreous detachment.



Optical coherence tomography at 1 month after surgery showed decrease in the size of macular hole

suggestive of incomplete closure. Repeat optical coherence tomography at 3 months showed closed

macular hole with mild foveal thinning and ellipsoid zone discontinuity with best-corrected visual acuity

improving to 6/18. The tomographic features and best-corrected visual acuity remained stable at 6-month

follow-up.

Conclusion: We hereby report the first case, to the best of our knowledge, of a truly idiopathic full-

thickness macular hole in an 8-year-old boy. Surgical treatment offers the best outcomes in these cases

and should be considered at the earliest without waiting for spontaneous closure unlike in the case of

traumatic full-thickness macular hole.

PMID: 30308527 DOI: 10.1097/ICB.0000000000000830

BMC Ophthalmol. 2018 Oct 12;18(1):267.

Optic disk melanocytoma associated with polypoidal choroidal vasculopathy lesions, after

combination treatment of photodynamic therapy and intavitreal aflibercept (Eylea), a case

report.

Rouvas A, Gouliopoulos NS, Moschos MM, Theodossiadis P.

Background: We report a rare case of a woman with optic disk melanocytoma (ODMC) in conjunction

with polypoidal choroidal vasculopathy (PCV). We also present, for the first time in literature, the clinical

and morphological outcomes of the applied treatment, consisting of a session of photodynamic therapy

(PDT) and three monthly intravitreal aflibercept injections.

Case Presentation: An 83-year-old Greek woman, complaining for visual decline at her left eye, referred

to our department and was diagnosed with ODMC associated with PCV. At presentation, best corrected

visual acuity (BCVA) was 2/10, fundus examination revealed a pigmented lesion covering partially the optic

nerve head and extending into the peripapillary choroid and retina, while hard exudates were observed

temporal to it. Blocked hypofluorescence in the area covered by the lesion and diffuse hyperfluorescence at

its temporal rim were shown by fluorescein angiography (FA). Indocyanine green angiography (ICGA)

identified 3 hyperfluorescent polypoidal lesions arising from the choroidal vasculature. Optical coherence

tomography (OCT) revealed subretinal fluid and retinal pigment epithelium detachment (RPE) at the region

corresponding to polyps. The treatment included a PDT session combined with 3 monthly intravitreal

aflibercept injections. Three months since the treatment initiation, new BCVA was 5/10, ICGA demonstrated

total polyps occlusion, while OCT detected RPE detachment without subretinal fluid. Ten months later,

ODMC was stable, BCVA rose to 7/10, no polyps were present, and total resolution of RPE detachment

was achieved.

Conclusions: This is the first case report of PCV coexisting with ODMC, presenting both ICGA and OCT

findings, and the applied treatment and its outcomes. Furthermore, we demonstrated that PDT combined

with intravitreal aflibercept injections seems to be a promising treatment for PCV.

PMID: 30309335 DOI: 10.1186/s12886-018-0927-7

Disclaimer: This newsletter is provided as a free service to eye care professionals by the Macular Disease Foundation

Australia. The Macular Disease Foundation cannot be liable for any error or omission in this publication and makes no

warranty of any kind, either expressed or implied in relation to this publication.

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