Volume 10, Number 3
WELCOME to Review
of Ophthalmology's Retina
Online e-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.
Risk Factors for Scar Formation in the CATT
Researchers conducted a prospective cohort study within a randomized clinical trial to describe risk factors for
scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).
They included patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment
in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
The researchers assigned eyes to ranibizumab or bevacizumab treatment and to one of three dosing regimens for two
years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features
on photography and optical coherence tomography (OCT), as well as genotypes associated with AMD risk were evaluated
as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars
were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with
discrete flat areas of hyperpigmentation with varying amounts of central depigmentation. Scar formation was the
main outcome measure.
According to the researchers, scar developed in 480 of 1,059 eyes (45.3%) by two years. Baseline
characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization
(CNV) (aHR, 3.1; CI, 2.4 to 3.9) vs. occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1 to 1.8), foveal retinal
thickness >212 µm (aHR, 2.4; CI, 1.7 to 3.6) vs. <120 µm, foveal subretinal tissue complex
thickness >275 µm (aHR, 2.4; CI, 1.7 to 3.6) vs. ≤75 µm, foveal subretinal fluid (aHR, 1.5; CI,
1.1 to 2.0) vs. no subretinal fluid, and subretinal hyper-reflective material (SHRM) (aHR, 1.7; CI, 1.3 to 2.3) vs.
no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5 to 0.8) vs. no
elevation. Drug, dosing regimen and genotype had no statistically significant association with scarring. Fibrotic
scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for
the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely
to develop fibrotic scars.
In conclusion, approximately half of eyes enrolled in CATT developed scar by two years. Eyes with
classic neovascularization, a thicker retina and more fluid or material under the foveal center of the retina are
more likely to develop scar.
Source: Daniel E, Toth CA, Grunwald JE, et al; Comparison of Age-related Macular Degeneration
Treatments Trials Research Group. Ophthalmology. 2014;121(3):656–666.
Genetic and Clinical Factors Associated with
Reticular Pseudodrusen in Exudative AMD
Reticular pseudodrusen (RPD) is considered to be a distinct entity from soft drusen and a risk factor
for age-related macular degeneration (AMD). The authors of this study investigated the genetic and clinical
factors associated with RPD in patients with exudative AMD, including polypoidal choroidal vasculopathy
(PCV), typical neovascular AMD and retinal angiomatous proliferation (RAP).
They studied the presence or absence of RPD among 408 patients with exudative AMD in at least one eye, and
they investigated the clinical characteristics of those with RPD as well as genetic polymorphisms of ARMS2
A69S (rs10490924) and CFH I62V (rs800292). The authors also evaluated subfoveal choroidal thickness in a limited
number of subjects using the EDI mode of spectral-domain optical coherence tomography.
The prevalence of RPD was significantly higher in RAP eyes than in typical neovascular AMD or in PCV eyes (38.2% of
26 eyes, 13.6% of 132 eyes and 0% of 250 eyes respectively, p<0.0001), the authors found. They
also observed that RPD was significantly more prevalent in the elderly (p<0.0001) and female
(p<0.0001) subjects. The subfoveal choroidal thickness was thinner in eyes with RPD than in those
without (129.7 ± 61.7 µm vs. 42.6 ± 84.9 µm, p<0.0001). The frequency of risk variants
of ARMS2 A69S was significantly higher in eyes with RPD than in those without RPD (85.7% vs. 63.8%,
p=0.0009), although the frequency of CFH I62V was not significantly different between those with and without
RPD. Logistic regression analysis revealed that age (odds ratio [OR]: 1.10; 95% confidence interval [CI]: 1.04
to 1.18; p=0.002), female gender (OR: 4.26; 95% CI: 1.72 to 10.4; p=0.002), T-allele at ARMS2 A69S
(OR: 3.23; 95% CI: 1.36 to 7.68; p=0.008) and RAP (OR: 4.25; 95% CI: 1.49 to 12.1; p=0.007)
were risk factors for RPD.
Among eyes with exudative AMD, RPD is more common in eyes with RAP having a thin choroid at the fovea, especially in
old, female patients with the risk variant of ARMS2 A69S, the study authors discovered.
Source: Yoneyama S, Sakurada Y, Mabuchi F, et al. Genetic and clinical factors associated with
reticular pseudodrusen in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol.
2014; March [Epub ahead of print]. DOI: 10.1007/s00417-014-2601-y.
Frequency of Retinal Vascular Abnormalities in Neovascular AMD
Investigators undertook a post hoc subanalysis of images acquired during a Phase III randomized controlled trial
to determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular
They selected images from participants with untreated, neovascular AMD in at least one eye and acquired
protocol-mandated fundus photographs and fluorescein angiograms at baseline and at year two from 107 sham-treated
study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center
for the presence of RVA, defined as at least one of the following: microaneurysms; vessel staining or leakage; dilated
or tortuous vessels; intraretinal hemorrhage; vessel sheathing or narrowing; capillary nonperfusion; or
The investigators noted that the baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of
104 gradable images) vs. 8.3% (five of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual
RVAs in study eyes was: microaneurysms (6.7%); vessel staining or leakage (6.7%); dilated or tortuous vessels
(4.8%); intraretinal hemorrhage (4.8%); vessel sheathing or narrowing (2.9%); capillary nonperfusion
(0%); and capillary infarcts (0%). Results were similar at 24 months.
Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography
and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.
Source: Jackson TL, Danis RP, Goldbaum M, et al. Retinal vascular abnormalities in neovascular
age-related macular degeneration. Retina. 2014;34(3):568–575.
Systemic Complement Inhibition with Eculizumab for GA in AMD
To evaluate the effect of eculizumab, a systemic inhibitor of complement component (C5), on the growth
of geographic atrophy (GA) in patients with age-related macular degeneration (AMD), this
prospective, double-masked, randomized clinical trial included patients with GA measuring from 1.25 to
18 mm² based on spectral-domain optical coherence tomography imaging.
Patients were randomized 2:1 to receive intravenous eculizumab or placebo over six months. In the eculizumab
treatment arm, the first 10 patients received a low-dose regimen of 600 mg weekly for four weeks followed by 900 mg
every two weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for four
weeks, followed by 1,200 mg every two weeks until week 24. The placebo group was infused with saline. Patients
were observed off treatment for an additional 26 weeks. Both normal-luminance and low-luminance visual acuities
were measured throughout the study, and the low-luminance deficits were calculated as the difference between the
letter scores. Change in area of GA at 26 weeks was the main outcome measure.
Thirty eyes of 30 patients were enrolled; 18 fellow eyes also met inclusion criteria and were analyzed as a
secondary endpoint. For the 30 study eyes, mean square root of GA area measurements ± standard deviation at
baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively
(p=0.13). At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab
and placebo groups, respectively (p=0.96). At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ±
0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (p=0.93,
two sample t test). None of the eyes converted to wet AMD and no drug-related adverse events were identified.
Systemic complement inhibition with eculizumab was well-tolerated through six months, but did not decrease the growth
rate of GA significantly. However, there was a statistically significant correlation between the low-luminance deficit
at baseline and the progression of GA over six months.
Source: Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition
with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE Study.
Use of Ranibizumab for Patients with CNV Secondary to Pathologic Myopia
This Phase III, 12-month, randomized, double-masked, multicenter, active-controlled study compared the efficacy and
safety of ranibizumab 0.5 mg, guided by visual acuity (VA) stabilization or disease activity criteria, versus
verteporfin photodynamic therapy (vPDT) in patients with visual impairment due to myopic choroidal neovascularization (CNV).
Participants consisted of patients (n=277) with visual impairment due to myopic CNV. Patients were randomized to
receive ranibizumab on day one, month one and thereafter as needed guided by VA stabilization criteria (group one,
n=106); ranibizumab on day one and thereafter as needed guided by disease activity criteria (group two, n=116); or vPDT
on day one and disease activity treated with ranibizumab or vPDT at investigators' discretion from month three
(group three, n=55). Mean average best-corrected visual acuity (BCVA) change from baseline to month one through
months three (primary) and six, mean BCVA change and safety over 12 months were the main outcome measures.
Ranibizumab treatment in groups one and two was superior to vPDT based on mean average BCVA change from baseline to
month one through month three (group one: +10.5, group two: +10.6 vs. group three: +2.2 Early Treatment
Diabetic Retinopathy Study [ETDRS] letters; both p<0.0001). Ranibizumab treatment guided by disease
activity was noninferior to VA stabilization-guided retreatment based on mean average BCVA change from baseline to
month one through month six (group two: +11.7 vs. group one: +11.9 ETDRS letters; p<0.00001). Mean BCVA
change from baseline to month 12 was +13.8 (group one), +14.4 (group two), and +9.3 ETDRS letters (group three). At
month 12, 63.8% to 65.7% of patients showed resolution of myopic CNV leakage. Patients received a median of
4.0 (group one) and 2.0 (groups two and three) ranibizumab injections over 12 months. No deaths or cases
of endophthalmitis and myocardial infarction occurred.
Ranibizumab treatment, irrespective of retreatment criteria, provided superior BCVA gains versus vPDT up to month
three. Ranibizumab treatment guided by disease activity criteria was noninferior to VA stabilization criteria up to
month six. Over 12 months, individualized ranibizumab treatment was effective in improving and sustaining BCVA and
was generally well-tolerated in patients with myopic CNV.
Source: Wolf S, Balciuniene VJ, Laganovska G, et al; RADIANCE Study Group. RADIANCE: a randomized
controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic
myopia. Ophthalmology. 2014;121(3):682–692.
Combination Therapy for BRVO: Dexamethasone
Intravitreal Implant and Macular Grid Laser
Italian researchers performed the following prospective, interventional, randomized, multicenter study to test
a combination of dexamethasone intravitreal implant with macular grid laser for macular edema in patients with
branch retinal vein occlusion (BRVO).
Patients with macular edema secondary to BRVO underwent an Ozurdex intravitreal implant at baseline. After one month,
the researchers randomly assigned patients to two study groups. Patients in group one were followed up monthly
and retreated with Ozurdex implant whenever there was a recurrence of macular edema or a decrease in best-corrected
visual acuity (BCVA). In group two patients, macular grid laser was performed between weeks six and eight. After
that, patients were followed up and retreated as for group one.
According to the study researchers, in group one at four months, mean BCVA was 0.49 ± 0.35 logMAR and central
retinal thickness (CRT) was 391 ± 172 µm; both improved significantly at six months, to 0.32 ± 0.29
logMAR and 322 ± 160 µm, respectively. In group two, CRT was reduced significantly to 291 ± 76 µm
at four months, and BCVA improved to 0.25 ± 0.20 logMAR. At the final visit, BCVA was 0.18 ± 0.14 logMAR
and mean CRT was 271 ± 44 µm. The number of Ozurdex implants at four months was 12 of 25 (48%) in group
one patients vs. three of 25 (12%) in group two patients (p=0.012). At six months, three of 25 patients
(12%) in group one vs. zero of 25 (0%) in group two (p=0.23) were retreated.
The combination of Ozurdex implant and macular grid laser is synergistic in increasing BCVA and lengthening the
time between injections, the researchers concluded.
Source: Pichi F, Specchia C, Vitale L, et al. Combination therapy with dexamethasone intravitreal implant
and macular grid laser in patients with branch retinal vein occlusion. Am J Ophthalmol. 2014;157(3):607–615.
Link Between FAF with Foveal Microstructures
and Vision in BRVO
To investigate the correlation of fundus autofluorescence (FAF) with the findings of spectral-domain
optical coherence tomography (SD-OCT) and visual acuity in patients with branch retinal vein occlusion (BRVO) and
to determine the visual prognostic factors, scientists conducted this study.
Retrospectively, they obtained an evaluation of FAF, SD-OCT images and visual acuity before and after
intravitreal injection of bevacizumab (IVB) (pre- and post-IVB) was obtained in 42 patients with BRVO who underwent
IVB as their first treatment. They also graded FAF of fovea on a scale of one to four.
The study scientists reported that the visual acuity post-IVB was associated with the visual acuity pre-IVB.
Preservation of external limiting membrane and photoreceptor inner and outer segment junction pre- and post-IVB
were associated with better visual acuity post-IVB. Furthermore, eyes with less FAF pre-IVB were closely associated
with better visual acuity post-IVB.
To conclude, the shorter length of photoreceptor inner and outer segment junction and external limiting membrane
defect and less FAF pre-IVB showed a significant association with better visual acuity post-IVB. These associations
could help to predict potential restoration of photoreceptor integrity and visual recovery in patients with BRVO, in
whom photoreceptor integrity before treatment could not be adequately evaluated, even with SD-OCT.
Source: Park B, Kim J, Chung H, Kim HC. Correlation of fundus autofluroescence with foveal
microstructures and vision in branch retinal vein occlusion. Retina. 2014;34(3):531–538.
OCT Hyperreflective Foci and Visual
Outcomes Following Intravitreal Bevacizumab for Macular Edema in BRVO
In the following study, the authors investigated the correlation between hyperreflective foci (HF) on
spectral-domain optical coherence tomography (SD-OCT) at baseline and visual outcomes after intravitreal
bevacizumab injection (IVB) in branch retinal vein occlusion (BRVO).
They retrospectively studied 97 eyes of 97 patients with macular edema secondary to BRVO, who were treated with IVB,
and divided the eyes into three groups according to the location of HF on SD-OCT: HF in outer retinal layers; HF in
inner retinal layers; and no HF. The baseline and final best-corrected visual acuity (BCVA), foveal thickness
(FT), external limiting membrane (ELM) status, junction between photoreceptor inner and outer segments (IS/OS) status,
and the number of HF were evaluated and compared among three groups.
The authors noted that baseline BCVA was correlated with baseline FT (R=0.366, p<0.001), but final BCVA was
not correlated with final FT (R=–0.008, p=0.942). They also reported that baseline BCVA was
significantly better in eyes with intact ELM at baseline (p=0.006), and final BCVA was significantly better
in eyes with intact ELM and IS/OS at final visit (p<0.001, p=0.003 respectively). At the final
visit, the authors observed that 15 of 37 eyes (40.5%) with HF in outer retinal layers had a disrupted ELM
(p=0.001), while 28 of 37 eyes (75.7%) with HF in outer retinal layers had a disrupted IS/OS
(p< 0.001). Final BCVA was poorer in eyes with HF in outer retinal layers groups than those in the
other two groups (p< 0.001), although baseline BCVA was not different between them.
HF on SD-OCT at baseline might predict the photoreceptor status and final VA after IVB in BRVO.
Source: Kang JW, Lee H, Chung H, Kim HC. Correlation between optical coherence tomographic
hyperreflective foci and visual outcomes after intravitreal bevacizumab for macular edema in branch retinal
vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2014; March [Epub ahead of print].
A Closer Look at Mortality in Patients with CRVO
Danish investigators sought to assess mortality in patients with central retinal vein occlusion (CRVO) by conducting
this registry-based cohort study.
The study consisted of 439 photographically verified CRVO patients and a control cohort of 2,195 unexposed
subjects matched by age and gender and alive on the date CRVO was diagnosed in the corresponding case. The
investigators used data from nationwide registries to compare mortality rates in CRVO patients with a control cohort
over a mean follow-up of 5.1 years for cases and of 5.7 years for controls. Main outcome measures were hazard ratios
(HRs) obtained by Cox regression and standardized mortality ratios (SMRs) stratified by age and gender served as
measures of relative mortality risk.
The investigators reported that mortality was higher in patients with CRVO (HR, 1.45; 95% confidence interval
[CI], 1.19 to 1.76) than in the control cohort, adjusted for age, gender and time of diagnosis. They also found
that mortality was comparable between the two groups (HR, 1.19; 95% CI, 0.96 to 1.46) when adjusting for
overall occurrence of cardiovascular disease and diabetes. Subgroup analysis found that the age-stratified mortality
rate was increased significantly in the total group of men (SMR, 1.27; 95% CI, 1.03 to 1.56) and in women 60 to
69 years of age (SMR, 1.94; 95% CI, 1.22 to 3.08).
In conclusion, CRVO was associated with an overall increase in mortality compared with controls that was
attributed statistically to cardiovascular disorders and diabetes. The investigators recommend treatment of
hypertension and diabetes, if present, and referral of patients found to have CRVO who are not already being
treated by a primary-care physician.
Source: Bertelsen M, Linneberg A, Christoffersen N, et al. Mortality in patients with central retinal
vein occlusion. Ophthalmol. 2014;121(3):637–642.
Impact of Thyroid Hormone Signaling Suppression
on Cone Photoreceptors in Retinal Degeneration
Cone phototransduction and survival of cones in the human macula are essential for color vision and for visual
acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt's disease, and recessive
cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell
proliferation, differentiation and apoptosis, plays a central role in cone opsin expression and patterning
in the retina.
Here, researchers investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse
models. They used retinol isomerase RPE65-deficient mice (a model of Leber's congenital amaurosis [LCA] with rapid
cone loss) and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) to determine
whether suppressing TH signaling with anti-thyroid treatment reduces cone death. Further, they used cone
cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient
mice (LCA with slower cone loss) to determine whether triiodothyronine (T3) treatment (stimulating TH signaling)
causes deterioration of cones.
The study researchers found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function
loss type 1 mice increased about sixfold, following anti-thyroid treatment. Additionally, cone density in cone
cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about
40% following T3 treatment.
To conclude, the effect of TH signaling on cone viability appears to be independent of its regulation on cone
opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective
of cones, providing insights into cone preservation and therapeutic interventions.
Source: Ma H, Thapa A, Morris L, et al. Suppressing thyroid hormone signaling preserves cone
photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci U S A. 2014; Jan 24.
[Epub ahead of print]. DOI: 10.1073/pnas.1317041111.