Volume 10, Number 7
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.
Injection With Intravitreal Aflibercept for
Macular Edema Caused by CRVO
To evaluate the efficacy and safety of intravitreal aflibercept injection for the treatment of macular edema secondary
to central retinal vein occlusion, the following randomized, double-masked, Phase III trial was performed.
It included 188 patients with macular edema secondary to CRVO. Patients received IAI 2 mg (IAI 2Q4) (n=114) or
sham injections (n=74) every four weeks up to week 24. During weeks 24 to 52, patients from both arms were evaluated
monthly and received IAI as needed, or pro re nata (IAI 2Q4 + p.r.n. and sham + IAI p.r.n.). During weeks 52 to
100, patients were evaluated at least quarterly and received IAI p.r.n. The primary efficacy end point was the proportion
of patients who gained ≥15 letters in best-corrected visual acuity from baseline to week 24. This study reports week
The proportion of patients gaining ≥15 letters was 56.1% vs. 12.3% (p<0.001) at week 24, 55.3% vs.
30.1% (p<0.001) at week 52, and 49.1% vs. 23.3% (p<0.001) at week 100 in the IAI
2Q4 + p.r.n. and sham + IAI p.r.n. groups, respectively. The mean change from baseline BCVA was also significantly higher
in the IAI 2Q4 + p.r.n. group compared with the sham + IAI p.r.n. group at week 24 (+17.3 vs. –4.0 letters;
p<0.001), week 52 (+16.2 vs. +3.8 letters; p<0.001), and week 100 (+13.0 vs. +1.5 letters;
p<0.0001). The mean reduction from baseline in central retinal thickness was 457.2 vs. 144.8 µm
(p<0.001) at week 24, 413.0 vs. 381.8 µm at week 52 (p=0.546), and 390.0 vs. 343.3 µm at
week 100 (p=0.366) in the IAI 2Q4 + p.r.n. and sham + IAI p.r.n. groups, respectively. The mean number
(standard deviation) of p.r.n. injections in the IAI 2Q4 + p.r.n. and sham + IAI p.r.n. groups was 2.7 ± 1.7 vs.
3.9 ± 2.0 during weeks 24 to 52 and 3.3 ± 2.1 vs. 2.9 ± 2.0 during weeks 52 to 100, respectively. The
most frequent ocular serious adverse event from baseline to week 100 was vitreous hemorrhage (0.9% vs. 6.8% in
the IAI 2Q4 + p.r.n. and sham + IAI p.r.n. groups, respectively).
To conclude, the visual and anatomic improvements after fixed dosing through week 24 and p.r.n. dosing with
monthly monitoring from weeks 24 to 52 were diminished after continued p.r.n. dosing, with a reduced monitoring
frequency from weeks 52 to 100.
Source: Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due
to central retinal vein occlusion: two-year results from the COPERNICUS Study. Ophthalmology.
Sporadic Visual Acuity Loss During Anti-VEGF
Treatment for Neovascular AMD
To evaluate transient, large visual acuity decreases, termed sporadic vision loss, during anti-vascular
endothelial growth factor treatment for neovascular age-related macular degeneration, investigators created a
cohort within a randomized clinical trial (Comparison of Age-Related Macular Degeneration Treatments Trials).
In total, they evaluated 1,185 CATT patients. Main outcome measures were the incidence of sporadic vision loss and
odds ratio for association with patient and ocular factors. They reported that sporadic vision loss was a decline
of ≥15 letters from the previous visit, followed by a return at the next visit to no more than five letters worse
than the visit before the VA loss.
There were 143 sporadic vision loss events in 122 of 1,185 patients (10.3%), the investigators noted. They also
observed that mean VA at two years for those with and without sporadic vision loss was 58.5 (~20/63) and 68.4
(~20/40) letters, respectively (p<0.001). Among patients treated pro re nata, no injection was
given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors
for sporadic vision loss included worse baseline VA (OR 2.92, 95% confidence interval [CI]: 1.65 to 5.17 for
≤20/200 compared with ≥20/40), scar (OR 2.21, 95% CI: 1.22 to 4.01), intraretinal foveal fluid on
optical coherence tomography (OR 1.80, 95% CI: 1.11 to 2.91) and medical history of anxiety (OR 1.90, 95%
CI: 1.12 to 3.24) and syncope (OR 2.75, 95% CI: 1.45 to 5.22). Refraction decreased the likelihood of sporadic
vision loss (OR 0.62, 95% CI: 0.42 to 0.91).
In conclusion, approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included
AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those
involved in clinical trials.
Source: Kim BJ, Ying GS, Huang J, et al., on behalf of the CATT Research Group. Sporadic visual acuity loss
in the comparison of age-related macular degeneration treatments trials (CATT). Am J Ophthalmol.
Exacerbation of RPE and Choroidal Atrophy Following
Treatment With Anti-VEGF in Neovascular AMD
Researchers studied the progression of retinal pigment epithelium and choroidal atrophy in patients with
neovascular age-related macular degeneration and assessed for a possible association with the number and type
of anti-vascular endothelial growth factor treatments.
They reviewed patients with neovascular AMD and a minimum of one-year follow-up. They used fellow eyes with
non-neovascular AMD as control eyes and determined retinal pigment epithelial atrophy area and choroidal thickness
using spectral-domain optical coherence tomography. Moreover, they used multivariable regression models for statistical analyses.
The study researchers noted that 415 eyes were included in the study, with a mean follow-up of 2.2 years. They also
reported that eyes with neovascular AMD had greater progression of RPE atrophy and choroidal atrophy compared with
those with non-neovascular AMD (p<0.001). Progression of RPE atrophy and choroidal atrophy was
independently associated with the total number of injections of bevacizumab and ranibizumab (all p values
≤ 0.001). In the subgroup of 84 eyes with neovascular AMD and without RPE atrophy at baseline, only bevacizumab
was associated with the progression of RPE atrophy (p=0.003). This study likely lacked statistical power to
detect an association with ranibizumab in this subgroup.
RPE atrophy and choroidal atrophy in neovascular AMD seem to be exacerbated by anti-VEGF treatment. Possible
differences between bevacizumab and ranibizumab require further investigation.
Source: Young M, Chui L, Fallah N, et al. Exacerbation of chroidal and retinal pigment epithelial atrophy
after anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.
Link Between Retinal Microstructures on OCT
and Microperimetry in AMD
The authors of this prospective, observational study sought to determine the relationship between
structural parameters of the outer retina on spectral-domain optical coherence tomography and
microperimetric retinal sensitivity in early stages of age-related macular degeneration.
They included 75 eyes of 75 participants with early stages of AMD (drusen ≥125 µm, with/without
pigmentary abnormalities) and 25 control participants of a similar age.
Participants underwent microperimetry testing and high-resolution SD-OCT scans, the authors reported. They
compared structural parameters at five central points (0°, 1° and 2.33° nasal and temporal to the fovea
along the horizontal axis) corresponding to areas tested by microperimetry. Structural parameters included outer
segment length, thickness and elevation of the retinal pigment epithelium band, grading of the inner-segment ellipsoid
(ISe) band integrity and presence of hyperreflective foci. Relationship between structural parameters and
retinal sensitivity was the main outcome measure.
According to the authors, retinal sensitivity was significantly correlated with RPE elevation (p<0.001),
ISe grading (p<0.001) and presence of HF (p≤ 0.018) at all test points, but not with OS length
(p≥ 0.093) or RPE thickness (p≥ 0.125). However, multiple linear regression analyses revealed that
only ISe grading (p≤ 0.011) and RPE elevation (p≤ 0.030) remained significantly associated with
retinal sensitivity at all points. By using a simple linear model incorporating ISe grading and RPE elevation to
predict values of retinal sensitivity, the 95% limits of agreement between the predicted and the actual value was
The study authors determined that the integrity of the ISe band and drusen-associated RPE elevation are
significant independent predictors of microperimetric retinal sensitivity. Their findings imply that these two
structural parameters may be surrogate markers of retinal function in the early stages of AMD.
Source: Wu Z, Ayton LN, Guymer RH. Relationship between retinal microstructures on optical coherence
tomography and microperimetry in age-related macular degeneration. Ophthalmology. 2014;121(7):1445–1452.
Subretinal Hyperreflective Exudation Associated
With Neovascular AMD
To describe the multimodal imaging findings of subretinal hyperreflective exudation observed in association with
choroidal neovascularization and to distinguish SHE from other forms of subretinal hyperreflective material seen
in patients with age-related macular degeneration and other macular disorders, this retrospective study was performed.
It included 46 eyes of 42 patients with SHE associated with types one, two and three CNV secondary to neovascular
AMD. Patients were examined using multimodal imaging, including color photography, near-infrared reflectance
imaging, spectral-domain optical coherence tomography, fluorescein angiography, fundus autofluorescence imaging
and indocyanine green angiography. Clinical and imaging characteristics were evaluated at baseline, after the initiation
of intravitreal anti-vascular endothelial growth factor therapy, and during the resolution of SHE.
It was reported that 45 of the 46 eyes were treatment naïve and that the mean ± SD age at the first detection of
SHE was 77.2 ± 10.1 years. Additionally, the mean ± SD follow-up was 2.1 ±0.6 years and FA was performed
in 42 eyes and demonstrated leakage and/or staining of underlying or adjacent CNV, but not of the SHE itself in all eyes.
On FA, SHE was transparent in 29 eyes and blocking in seven eyes. In 32 eyes, SHE showed isoautofluorescence on FAF
imaging, and in eight eyes, SHE showed varying degrees of hyperautofluorescence. Indocyanine green angiography was
performed in eight eyes and demonstrated hyperfluorescence of SHE in seven eyes. In eight eyes, SHE was the only evidence
of neovascular activity. All eyes having follow-up (42 eyes) showed resolution of the subretinal material with partial
or full reconstitution of the ellipsoid zone after a median of two injections range (one to 16 injections).
Furthermore, subretinal hyperreflective exudation persisted for a median of nine weeks (range, four to 60 weeks) after
the initiation of treatment. The mean visual acuity before treatment was 0.619 (20/83), and it improved to 0.380
(20/48) (p=0.03) after the resolution of SHE.
To conclude, subretinal hyperreflective exudation differs from other types of SHM based on the findings from
multimodal imaging. This novel type of SHM likely represents a sign of active neovascular AMD distinct from
subretinal fluid, hemorrhage, neovascular tissue, lipid, pigment hyperplasia, subretinal fibrosis and the SHM observed
with acquired vitelliform lesions. Intravitreal anti-VEGF agents can be used to successfully resolve SHE, often resulting
in better visual outcomes in eyes manifesting this form of exudation.
Source: Shah VP, Shah SA, Mrejen S, Freund KB. Subretinal hyperreflective exudation associated with
neovascular age-related macular degeneration. Retina. 2014;34(7):1281–1288.
Multilayered PED in Neovascular AMD
The following retrospective, observational case series aimed to describe the spectral-domain optical
coherence tomography findings in eyes with chronic fibrovascular pigment epithelial detachment receiving
intravitreal anti-vascular endothelial growth factor therapy.
Participants consisted of patients with chronic fibrovascular PEDs receiving serial intravitreal anti-VEGF t
herapy. Corresponding SD-OCT scans of chronic PEDs were studied in detail over multiple visits. The internal
structure within the sub-PED compartment was analyzed, characteristic features were identified, and then correlated
with visual outcome.
A total of 38 eyes of 34 patients with fibrovascular PEDs were included. Mean and median Snellen visual acuity was
20/50 (range, 20/20 to 20/400). Eyes received a mean of 28.2 intravitreal anti-VEGF injections (median, 23.0; range,
three to 70) administered over a mean of 36.9 months (median, 37.5; range, six to 84). A fusiform, or
spindle-shaped, complex of highly organized layered hyperreflective bands was noted within each PED. Additionally,
19 eyes demonstrated heterogenous, dilated, irregular neovascular tissue adherent to the undersurface of the retinal
pigment epithelium. Twenty-five eyes demonstrated a hyporeflective cavity separating the choroidal
neovascularization complex from the underlying choroid.
Chronic fibrovascular PEDs receiving serial anti-VEGF therapy demonstrate a characteristic fusiform complex of
highly organized, layered, hyperreflective bands, termed a “multilayered PED,” which is often seen
in conjunction with neovascular tissue adherent to the undersurface of the RPE monolayer. On the basis of
previous histopathologic correlations, these bands may represent a fibrous tissue complex with contractile properties.
An associated hyporeflective space, termed a “pre-choroidal cleft,” separates the fusiform complex from
the underlying choroid and may be due to contraction, the exudation of fluid, or both. Many of these eyes maintain
good visual acuity, presumably because the neovascular and cicatricial process is suppressed within the sub-RPE space
by chronic anti-VEGF therapy, thus permitting the viability of the photoreceptor population through preservation of the RPE.
Source: Rahimy E, Freund KB, Larsen M, et al. Multilayered pigment epithelial detachment in neovascular
age-related macular degeneration. Retina. 2014;34(7):1289–1295.
Prediction Model for Advanced AMD
The purpose of the following study was to develop a clinical eye-specific prediction model for advanced
age-related macular degeneration. The Age-Related Eye Disease Study cohort, followed up for eight years, served as
the training dataset, and the Blue Mountains Eye Study cohort, followed up for 10 years, served as the validation
The study consisted of 4,507 AREDS participants (contributing 1,185 affected vs. 6,992 unaffected eyes) and 2,169
BMES participants (contributing 69 affected vs. 3,694 unaffected eyes). Using Bayes' theorem in a logistic model,
eight baseline predictors (age, sex, education level, race, smoking status, presence of pigment abnormality, soft drusen
and maximum drusen size) were employed to devise and validate a macular risk scoring system (MRSS). Additionally,
the performance of the MRSS was assessed by calculating sensitivity, specificity and the area under the receiver
operating characteristic curve (i.e., c-index). Advanced AMD was the main outcome measure.
The internally validated c-indexAREDS (0.88; 95% confidence interval, 0.87 to 0.89) and the
externally validated c-indexBMES (0.91; 95% CI, 0.88 to 0.95) suggested excellent performance of the
MRSS. The sensitivity and specificity at the optimal macular risk score cutoff point of zero were 87.6% and
73.6%, respectively. An application for the iPhone and iPad also was developed as a practical tool for the MRSS.
The MRSS was developed and validated to provide satisfactory accuracy and generalizability. It may be used to
screen patients at risk of developing advanced AMD.
Source: Chiu CJ, Mitchell P, Klein R, et al. A risk score for the prediction of advanced age-related
macular degeneration: development and validation in 2 prospective cohorts. Ophthalmology. 2014;121(7):1421–1427.
Use of Aflibercept to Treat Patients With Exudative
AMD Who Were Incomplete Responders to Multiple Ranibizumab Injections
In this prospective, open-label, single-arm clinical trial, scientists aimed to determine the efficacy of 2.0 mg
aflibercept in the management of patients with recalcitrant exudative age-related macular degeneration.
They saw patients monthly and gave them mandatory 2.0 mg aflibercept at baseline, months one, two and four. They
performed pro re nata retreatment at months three and five upon evidence of disease on spectral-domain
optical coherence tomography. End point at month six: mean change in Early Treatment Diabetic Retinopathy Study
best corrected visual acuity and central subfield thickness, mean number of aflibercept injections, percentage of
p.r.n. injections required, patients with no fluid on SD-OCT and patients losing >15 letters.
At baseline, the scientists noted that 46 patients with a mean of 42 prior anti-vascular endothelial growth
factor-A intravitreal treatments had a mean of 74.2 letters (Snellen equivalent 20/32) and mean CST of 347 µm.
ETDRS letters remained stable throughout the trial; at month six, mean BCVA change was +0.2 letters (range –10 to
+13, p=0.71). Anatomically, mean CST improved significantly from baseline at each study visit including
–23.6 µm at month one and –27.3 µm at month six (p=0.018). Seventy-one of 90 (79%)
possible p.r.n. injections were required and a mean of 5.6 aflibercept injections out of the maximum six were
administered. Ten of 45 (22%) patients had no retinal fluid on SD-OCT at month six. No patient lost more than 15 letters.
The study scientists determined that aflibercept 2.0 mg treatment maintained mean visual acuity improvements
previously achieved with high-dose 2.0-mg ranibizumab injections in recalcitrant wet AMD patients. Aflibercept 2.0
mg treatment led to significant anatomic improvement and was required monthly in most patients.
Source: Wykoff CC, Brown DM, Maldonado ME, Croft DE. Aflibercept treatment for patients with
exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections
(TURF trial). Br J Ophthalmol. 2014;98(7):951–955.
Subfoveal Choroidal Thickness in RAP
In the study below, researchers investigated the subfoveal choroidal thickness in patients with retinal
angiomatous proliferation. They found that eyes with RAP had a significantly thinner subfoveal choroid compared with
normal eyes. Such morphologic features may be related to the pathologic mechanism of RAP.
In consecutive patients with RAP, the researchers retrospectively measured subfoveal choroidal thickness by the use
of enhanced depth imaging spectral-domain optical coherence tomography in comparison with age-matched control subjects.
Included in the study were 19 eyes of 19 patients with RAP and 32 eyes of 32 control subjects. The study researchers
found no significant differences between the eyes with RAP and the control eyes regarding age, gender, spherical
equivalent and axial length. They noted that mean subfoveal choroidal thickness in 19 eyes with RAP was significantly
less than that in the control eyes (129.5 ± 35.8 µm vs. 201.3 ± 55.0 µm, p<0.0001).
The difference in mean subfoveal choroidal thickness between eyes with Stage II RAP (132.8 ± 38.2 µm) and
eyes with Stage III RAP (126.4 ± 36.6 µm) was not significant, they observed, though each measurement
was significantly less than that in the control eyes (p<0.001 and p=0.002, respectively).
Source: Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness in retinal
angiomatous proliferation. Retina. 2014;34(7):1316–1322.
RNFL Thinning in Glaucoma Suspect Eyes
The authors of this prospective, observational cohort study compared the rates of retinal nerve fiber layer loss in
patients suspected of having glaucoma who developed visual field damage with those who did not develop VFD and aimed
to determine whether the rate of RNFL loss can be used to predict the development of VFD.
Participants consisted of glaucoma suspects, defined as having glaucomatous optic neuropathy or ocular
hypertension (intraocular pressure, >21 mmHg) without repeatable VFD at baseline, from the Diagnostic Innovations
in Glaucoma Study and the African Descent and Glaucoma Evaluation Study.
The authors measured global and quadrant RNFL thickness with spectral-domain optical coherence tomography
(Spectralis HRA+OCT, Heidelberg Engineering). They defined visual field damage as having three consecutive abnormal
visual fields. They also compared the rate of RNFL loss in eyes developing VFD to eyes not developing VFD using
multivariate linear mixed-effects models. Furthermore, a joint longitudinal survival model used the estimated RNFL
thickness slope to predict the risk of developing VFD, while adjusting for potential confounding variables. The rate of
RNFL thinning and the probability of developing VFD were the main outcome measures.
Four hundred fifty-four eyes of 294 glaucoma suspects were included, the authors reported. They noted that the
average number of SD-OCT examinations was 4.6 (range, two to nine), with median follow-up of 2.2 years (0.4 to 4.1
years). They also observed that 40 eyes (8.8%) developed VFD. The estimated mean rate of global RNFL loss
was significantly faster in eyes that developed VFD compared with eyes that did not develop VFD (–2.02 µm/year
vs. –0.82 µm/year; p<0.001). The joint longitudinal survival model showed that each 1-μm/year
faster rate of global RNFL loss corresponded to a 2.05-times higher risk of developing VFD (hazard ratio, 2.05;
95% confidence interval, 1.14 to 3.71; p=0.017).
According to the study authors, the rate of global RNFL loss was more than twice as fast in eyes that developed VFD than
in eyes that did not develop VFD. A joint longitudinal survival model showed that a 1-µm/year faster rate of
RNFL thickness loss corresponded to a 2.05-times higher risk of developing VFD. These results suggest that measuring
the rate of SD-OCT RNFL loss may be a useful tool to help identify patients who are at a high risk of developing
visual field loss.
Source: Miki A, Medeiros FA, Weinreb RN, et al. Rates of retinal nerve fiber layer thinning in glaucoma
suspect eyes. Ophthalmology. 2014;121(7):1350–1358.
Brimonidine's Effect on Retinal
Vascular Autoregulation and Short-Term Visual Function in NTG
Investigators performed this nonrandomized, prospective clinical trial to assess whether brimonidine 0.15%
alters retinal vascular autoregulation and short-term visual function in normal-tension glaucoma patients who
demonstrate retinal vascular dysregulation.
In this study, 46 NTG patients not previously treated with brimonidine underwent retinal vascular autoregulation testing
and visual function assessment using frequency doubling technology perimetry and equivalent noise motion
sensitivity testing. The study investigators measured blood flow in a major temporal retinal artery with subjects
seated and then while reclined for 30 minutes. They classified patients having a change in retinal blood flow with
posture change outside the range previously found in healthy subjects as having retinal vascular dysregulation.
They then treated these patients with brimonidine 0.15% for eight weeks and designated them for retesting.
The investigators noted that 23 patients demonstrated retinal vascular dysregulation at the initial visit. Younger age
(p=0.050) and diabetes (p=0.055) were marginally significant risk factors for retinal vascular
dysregulation. After the eight-week course with brimonidine, 14 of the 17 patients who completed the study showed
a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation
(p<0.0001). No significant changes in frequency doubling technology perimetry or in motion detection
parameters were found following treatment with brimondine (p>0.09 for all tests performed).
Brimonidine significantly improved impaired retinal vascular autoregulation in NTG patients, but short-term alteration
in visual function could not be demonstrated.
Source: Feke GT, Bex PJ, Taylor CP, et al. Effect of brimonidine on retinal vascular autoregulation
and short-term visual function in normal tension glaucoma. Am J Opthalmol. 2014;158(1):105–112.