Volume 10, Number 6
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.
Switch from Intravitreal Ranibizumab to Aflibercept
for Treatment of Neovascular AMD
The authors of the following study sought to describe the treatment response to aflibercept in patients with
exudative age-related macular degeneration that showed insufficient or diminishing treatment effects under ranibizumab.
Between December 2012 and June 2013, they collected and retrospectively reviewed clinical data such as visual acuity or
central subfield retinal thickness on optical coherence tomography scans for all patients receiving intravitreal injections
of aflibercept after previous treatment with ranibizumab. They analyzed the data for the time frame before, during and
shortly after the aflibercept injections. Of particular interest was the comparison of clinical features under
ongoing ranibizumab treatment to the time during aflibercept treatment.
A total of 71 eyes of 65 patients were included in the study. The authors noted that all eyes had previous
ranibizumab injections in their medical history, the average number of which was nine (range three to 43). They also
reported that for the total group, the mean visual acuity before the first ranibizumab injection was 0.54 logMAR, and
after the last ranibizumab injection was 0.57 logMAR. Mean VA changed from 0.47 logMAR before the first aflibercept
injection to 0.25 logMAR after the last aflibercept injection. Central subfield retinal thickness on OCT changed from a
mean of 417.28 µm to 349.52 µm under ranibizumab treatment and from 338.76 µm to 272.00 µm
under aflibercept treatment. Interestingly, 33% of cases that did not show a functional improvement under
ranibizumab therapy gained visual acuity after aflibercept treatment.
In conclusion, aflibercept appears to be an effective choice for patients with neovascular AMD who were resistant to
previous therapy of ranibizumab. The longevity of this effect still remains questionable.
Source: Heussen FM, Shao Q, Ouyang Y, et al. Clinical outcomes after switching treatment from
intravitreal ranibizumab to aflibercept in neovascular age-related macular degeneration. Graefes Arch
Clin Exp Ophthalmol. 2014;252(6):909–915.
Reticular Pseudodrusen and GA in Fellow Eyes of
Individuals with Unilateral CNV
To determine whether reticular pseudodrusen confer an increased risk of progression to late-stage age-related
macular degeneration in fellow eyes of those recently diagnosed with unilateral choroidal neovascularization,
the following retrospective study was conducted.
It included 200 consecutive participants with CNV secondary to AMD in one eye and no signs of late-stage AMD in the fellow
eye. Clinical examination and comprehensive retinal imaging—including spectral-domain optical coherence
tomography, near-infrared reflectance (NIR), and color fundus photography—were performed at baseline and every
follow-up visit. Incidence of geographic atrophy and CNV in the fellow eye were the main outcome measures.
It was reported that mean age ± standard deviation was 77 ± seven years, and 61% of the cohort were
female. Fifty-eight percent (n=116) had RPD, 68% had drusen of 125 µm or more, 36% had pigmentary changes,
10% had both drusen of 125 µm or more and pigmentary changes, and 17% had only RPD in their fellow eyes. After
a mean follow-up of 2.3 years, CNV developed in 36% of patients and GA developed in 14% of patients. Those with
RPD demonstrated late-stage AMD (61% vs. 33.4% p< 0.001) and GA (22.4% with RPD vs. 2.4%
without RPD; p<0.001) more often. The presence of reticular pseudodrusen was an independent risk factor for
the development of GA (hazard ratio [HR], 4.93; p=0.042), but not for CNV (HR, 1.19; p=0.500), at least
within the follow-up of this study. Both drusen of 125 µm or more and pigmentary changes at baseline were significant
risk factors for the development of CNV and GA (HR, 1.96 to 11.73; p<0.020).
To conclude, reticular pseudodrusen seem to confer an increased risk of progression to GA, in addition to drusen and
pigmentary changes. The presence of RPD needs to be taken into account when discussing a patient's prognosis and
Source: Finger RP, Wu Z, Luu CD, et al. Reticular pseudodrusen: a risk factor for geographic atrophy in
fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology. 2014; 121(6):1252–1256.
Vitreoretinal Interface Changes in GA
Geographic atrophy is the end-stage manifestation of atrophic age-related macular degeneration. The disease
progresses slowly over time, eventually causing loss of central vision. Its cause and patho-mechanism are not
fully known. Previous studies have suggested that vitreoretinal traction may contribute to the progression
of neovascular AMD. The aim of this study was to examine whether an association between changes at the
vitreoretinal interface, in particular traction, and the characteristics and progression of GA in eyes with dry AMD
can be established.
Researchers in Switzerland conducted this clinic-based prospective cohort study, which enrolled 97 patients (age range,
61 to 90 years; mean, 78.4 years) with GA secondary to dry AMD. Patients exhibiting neovascular signs on
fluorescein angiography in either eye were excluded.
The researchers examined VRI changes using spectral-domain optical coherence tomography. They examined characteristics of
GA using fundus autofluorescence imaging and performed all imaging using a Spectralis SLO+OCT device (Heidelberg
Engineering). Additionally, they measured GA area using the Region Finder (Heidelberg Engineering) software native to
the Spectralis platform. Area and increase in area of GA were the main outcome measures.
The study researchers found vitreoretinal traction in 39 eyes (40%) and reported that the GA area at baseline was
6.65 ± 5.64 mm² in eyes with VRT and 5.73 ± 4.72 mm² in eyes with no VRT. They also noted that the
annual rate of progression of GA area progression was 2.99 ± 0.66 mm² in eyes with VRT and 1.45 ±
0.67mm² in eyes without VRT. Differences between groups in both parameters were statistically significant (n=97
total number of eyes; p<0.001). Multiple regression analysis confirmed this finding (B=0.714, p<0.001;
F3,93=72.542, p<0.001; adjusted R²=0.691).
The result of this study indicate an association between VRT and an increased rate of progression of GA area in dry
AMD. Monitoring VRT may contribute to an improved estimate of the prospective time of visual loss and to a better timing
of emerging therapies in dry AMD.
Source: Abdillahi H, Enzmann V, Wittwer VV, et al. Vitreoretinal interface changes in geographic
atrophy. Ophthalmology. 2014; May 26. [Epub ahead of print].
Changes in FAF Following Treatments for PCV
Japanese investigators evaluated changes in fundus autofluorescence after treatments for polypoidal
choroidal vasculopathy. They found that elimination of the hyperautofluorescent ring is highly associated with
the resolution of the polyp on indocyanine green angiography.
A total of 36 eyes of 35 patients with treatment-naïve PCV underwent intravitreal injection of ranibizumab,
photodynamic therapy or a combination of both treatments. The investigators compared FAF and indocyanine green
angiography (ICGA) at baseline with those obtained 12 months later about the changes at the affected lesion.
The study investigators detected 88 polyps in the 36 eyes on ICGA at baseline, and 65 (73.9%) of those showed
centered hypoautofluorescence and a circumferential hyperautofluorescent ring on FAF. Twelve months later, ICGA
revealed resolution of 42 of those 65 polyps. Of those 42 resolved polyps, 30 hyperautofluorescent rings (71.4%)
were eliminated concurrently with the resolution of polyp. Statistical analysis revealed that an elimination of
the hyperautofluorescent ring was more frequently observed in association with the resolved polyps than with the
persistent polyps (p<0.0001). All the hypoautofluorescent findings corresponding to branching vascular networks
at baseline were unchanged during the follow-up period.
The investigators propose that FAF has a potential as a noninvasive method of evaluating the therapeutic efficacy of
treatments for PCV.
Source: Yamagishi T, Koizumi H, Yamazaki T, Kinoshita S. Changes in fundus autofluorescence after treatments
for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2014;98(6):780–784.
Changes in the Retinal Microstructure of Eyes with
Scientists in Japan conducted this prospective, observational, cross-sectional case series to assess macular
photoreceptor abnormalities in eyes with resolved branch retinal vein occlusion using adaptive optics scanning
After complete resolution of macular edema and retinal hemorrhage, 21 eyes (21 patients) with BRVO underwent
full ophthalmologic examination and imaging with optical coherence tomography and a prototype AO-SLO system. Cone density
and spatial mosaic organization were assessed using AO-SLO images.
Regular parafoveal cone mosaic patterns were clearly visualized with the prototype AO-SLO imaging system in the
BRVO-unaffected side, the scientists reported. However, in the side of the retina previously affected by the BRVO,
they observed that cone mosaic patterns were disorganized and dark regions missing wave-guiding cones were
apparent. Additionally, retinal capillaries were dilated, no longer had a uniform caliber, and had less direct paths
through the retina. In the affected side, parafoveal cone density was significantly decreased, compared with the
corresponding retinal area on the unaffected side (p<0.001). Furthermore, the hexagonal Voronoi domain ratio
and the nearest-neighbor distances were significantly lower than in the unaffected side (p<0.05). These
parameters were also correlated with photoreceptor layer integrity in the parafovea.
After BRVO-associated retinal hemorrhage and macular edema resolved, affected parafoveal cone density decreases and the
cone mosaic spatial arrangement is disrupted, becoming more irregular. These cone microstructural abnormalities may extend
to parafovea in the BRVO-unaffected side.
Source: Akagi-Kurashige Y, Tsujikawa A, Oota S, et al. Retinal microstructrual changes in eyes with
resolved branch retinal vein occlusion: an adaptive optics scanning ophthalmoscopy study.
Am J Ophthalmology. 2014;157(6):1239–1249.
Effect of Intravitreal Bevacizumab Injection for DME
on Fellow Uninjected Eyes
Anti-vascular endothelial growth factor compounds are routinely used for the treatment of diabetic macular edema.
In Israel, researchers aimed to evaluate for the existence and magnitude of treatment effect on fellow uninjected eyes.
They retrospectively evaluated a consecutive group of patients with bilateral DME who received unilateral
bevacizumab injections. Data collected included demographics, ophthalmic and systemic findings, and optical
coherence tomography measurements of macular thickness.
All told, they evaluated 35 patients. Mean follow-up was 245 days (range: 30 to 800), and the mean number of
bevacizumab injections was 3.6 (range: one to 11). At the end of follow-up, the mean (SD) OCT central subfield
thickness reduced by 72 ± 112 µm in the injected eye (from 469 ± 139 to 397 ± 120 µm;
p=0.001), while in the non-injected eye it reduced by 49 ± 75 µm (from 380 ± 130 to 331 ±
106 µm p<0.001). Sixteen injected eyes (45.7&37;) showed central subfield thickness reduction of ≥50
µm while 10 (28.6%) non-injected eyes showed such thickness reduction. Improved VA following treatment was detected
in 14 (40%) injected eyes and in 15 (43%) non-injected eyes.
Unilateral bevacizumab injections in patients with bilateral DME are often associated with bilateral response, the
Source: Hanhart J, Tiosano L, Averbukh E, et al. Fellow eye effect of unilateral intravitreal bevacizumab
injection in eyes with diabetic macular edema. Eye. 2014;May 23. [Epub ahead of print]. DOI: 10.1038/eye.2014.94.
Macular Hypotrophy After ILM Removal for DME
The following retrospective comparative study was conducted to compare the anatomic and functional effects of
three different approaches to nontractional diabetic macular edema.
Sixty eyes of 60 patients diagnosed with cystoid DME and treated with 1.25 mg/mL intravitreal bevacizumab (Group A),
laser photocoagulation (Group B) or vitrectomy with inner limiting membrane peeling (Group C) were included in the
study. Changes in number of Early Treatment Diabetic Retinopathy Study letters, central macular thickness, largest diameter
of the intraretinal cysts (IC) and choroidal thickness were investigated. Additionally, analyses were performed
during follow-up visits at months one, three, six, nine and 12.
It was reported that visual acuity only significantly improved in Group A at the last follow-up (p=0.004) and
that central macular thickness significantly decreased in every group throughout the follow-up period. Differences in
central macular thickness between Groups A and B (p<0.01), A and C (p<0.01), and B and C
(p<0.01) were significant. Intraretinal cysts also significantly decreased in each group throughout the
follow-up period. Differences in IC size between Groups A and B (p=0.8), A and C (p=0.1), and B and C
(p=0.1) were not significant. Choroidal thickness did not undergo any significant change in any group throughout
the follow-up period. A significant correlation was also found in Group A between best-corrected visual acuity at month 12
and baseline central macular thickness (r=0.3; p=0.006), and in Group B between postoperative best-corrected
visual acuity at month 12 and baseline IC size (r=0.8; p<0.01, negatively correlated at 92.4%).
According to this study's retrospective data, DME with intraretinal cysts >390 µm should not be treated
with vitrectomy with ILM peeling because this may induce subfoveal atrophy, defined as the “Floor Effect,”
and subsequent visual deterioration.
Source: Romano MR, Romano V, Vallejo-Garcia JL, et al. Macular hypotrophy after internal limiting
membrange removal for diabetic macular edema. Retina. 2014; 34(6):1043–1260.
Anti-Angiogenic Therapy and Choroidal Thickness
in Diabetic Retinopathy
To analyze the effect of anti-vascular endothelial growth factor agents in submacular choroidal thickness of
diabetic retinopathy patients, the authors of this cross-sectional study divided 25 DR patients (50 eyes) into two
groups according to DR stage and previous treatments: nonproliferative DR and diffuse diabetic macular edema in both
eyes, submitted to macular laser in both eyes and anti-VEGF injection only in one eye (nonproliferative diabetic
retinopathy + diabetic macular edema group, n=11); and proliferative DR in both eyes, treated with panretinal
photocoagulation in both eyes and anti-VEGF injection only in one eye (proliferative diabetic retinopathy group, n=14).
In the study visit, all patients underwent optical coherence tomography with enhanced depth imaging protocol.
Choroidal segmentation was performed manually. The medium CT in central macular area (CCT) and the CT in centrofoveal
B-scan were obtained automatically.
The study authors noted that 25 eyes treated with anti-VEGF showed a reduction on CCT (p=0.002) and subfoveal CT
(p=0.004), compared with the fellow eyes treated with laser only. They also found that independent evaluation of
PDR group revealed similar results (CCT, p=0.02; subfoveal CT, p=0.03). In nonproliferative diabetic
retinopathy + diabetic macular edema group, CCT was also significantly thinner in eyes treated with anti-VEGF
(p=0.04). A correlation between the number of injections and a thinner CT was found in this group (p=0.03) and
in the evaluation of all eyes together (p=0.03).
In conclusion, diabetic eyes treated with anti-VEGF agents have reduced CT.
Source: Laíns I, Figueira J, Santos AR, et al. Choroidal thickness in diabetic retionpathy: The influence
of antiangiogenic therapy. Retina. 2014;34(6):1199–1207.
SD-OCT Predictors of Visual Outcome in Diabetic
CME After Injection with Bevacizumab
Investigators aimed to examine prognostic spectral domain optical coherence tomography parameters in diabetic cystoid
macular edema after anti-vascular endothelial growth factor therapy.
Their retrospective cohort study included 49 eyes with the new-onset diabetic CME that had to have a macular SD-OCT
and fluorescein angiography at presentation. They analyzed the baseline OCT scans for variables indicative of the extent
of retinal involvement by the cystoid change and its location about the center. They also performed univariate and
multivariate analyses comparing the OCT findings between the two groups of eyes: the “No Improvement” and
the “Improvement” groups, based on at least two Snellen lines improvement after treatment.
According to the investigators, there were 30 and 19 eyes in the No Improvement and Improvement groups, respectively.
In the univariate analysis, the baseline OCT parameters associated with visual improvement included the photoreceptor
inner segments thickness centrally (p=0.009) and within the central 1-mm subfield (p<0.0001), and
the presence of bridging retinal processes centrally (p=0.004). Multivariate analysis showed both presence and
central location of bridging retinal processes within the central 1-mm subfield to be significantly associated with
visual improvement (p=0.041 and 0.005, respectively), with an odds ratio of 13.4 (95% confidence interval,
1.336 to 636.18; p=0.010) for their central location.
The study investigators concluded that, in diabetic CME, visual improvement after anti-VEGF therapy is more likely to
occur in eyes with residual central retinal processes on baseline macular spectral domain OCT. This finding may be helpful
in patient counseling, case selection and clinical trial planning.
Source: Al Faran A, Mousa A, Al Shamsi H, et al. Spectral domain optical coherence tomography predictors of
visual outcome in diabetic cystoid macular edema after bevacizumab injection. Retina. 2014;34(6):1208–1215.
Relationship Between Oral Fluoroquinolones and
Incidence of Rhegmatogenous Retinal Detachment and Symptomatic Retinal Breaks
In an effort to examine whether oral fluoroquinolone antibiotics are associated with an increase in subsequent
rhegmatogenous retinal detachment and symptomatic retinal breaks in a large population-based cohort, the study below
was conducted. It included adult residents of Olmsted County, Minnesota, who were prescribed oral fluoroquinolone
medications from January 1, 2003 to June 30, 2011. Comparison cohorts consisted of patients prescribed oral macrolide
and β-lactam antibiotics during the study period.
Procedure codes were used to identify retinal detachment repair and prophylaxis procedures occurring within one year
of prescription dates. Travel clinic, pro re nata, and self-treatment prescriptions were excluded. Patients
with tractional retinal detachment, previous retinal detachment repair, endophthalmitis and necrotizing retinitis
were excluded, as were those with intraocular surgery or severe head/eye trauma ≤90 days before the procedure.
Rates of retinal detachment repair and prophylaxis procedures within seven, 30, 90 and 365 days of the first prescription
were calculated and compared between antibiotic prescription cohorts using chi-square tests. Retinal detachment repair
rates also were compared with the expected Olmsted County, Minnesota, rates using the one-sample log-rank test.
Oral fluoroquinolones were prescribed for 38,046 patients (macrolide n=48,074, β-lactam n=69,079) during the study
period. Retinal detachment repair procedures were performed within 365 days of the first prescription in 0.03%
(95% confidence interval [CI], 0.01 to 0.06) of the fluoroquinolone cohort, 0.02% (95% CI, 0.01 to 0.03) of
the macrolide cohort, and 0.03% (95% CI, 0.02 to 0.05) of the β-lactam cohort (p>0.05).
Retinal detachment prophylaxis procedures for symptomatic retinal breaks were performed within 365 days of the
first prescription in 0.01% (95% CI, 0.00 to 0.03) of the fluoroquinolone cohort, 0.02% (95% CI,
0.01 to 0.04) of the macrolide cohort, and 0.02% (95% CI, 0.01 to 0.04) of the β-lactam cohort
(p>0.05). Similar comparisons of treatment rates within seven, 30 and 90 days of the first prescription were
all insignificant between cohorts. Post-fluoroquinolone retinal detachment repair rates were similar to expected rates
(36.8 per 100 000/year vs. 28.8 per 100 000/year for age- and sex-matched historical rates, p=0.35).
To conclude, oral fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment
or symptomatic retinal breaks in this population-based study.
Source: Kapoor KG, Hodge DO, St. Sauver JL, Barkmeier AJ. Oral fluoroquinolones and the incidence
of rhegmatogenous retinal detachment and symptomatic retinal breaks: a population-based study.
12-Month Outcomes with the Argus II Retinal Prosthesis
In Italy, researchers performed the following interventional case series to study the anatomic and functional outcomes
of Argus II Retinal Prosthesis System implantation in patients with retinitis pigmentosa.
The study population included six patients with visual acuity no better than light perception. After the Argus II
Retinal Prosthesis System was implanted, the researchers studied complications, as well as anatomic and functional results.
The main outcome measures were mobility, square localization, direction of motion, grating visual acuity, and Goldmann
visual field, all of which were assessed. Optical coherence tomography was performed.
According to the study researchers, implantation of the Argus II Retinal Prosthesis System was safely performed in
all patients. They noted that one patient experienced postoperative elevation in intraocular pressure, which was
controlled medically. Also, they reported that in one patient, moderate detachment of the choroid occurred postoperatively,
and it resolved spontaneously. One patient withdrew from the study. The researchers did not observe wound
dehiscence, endophthalmitis or retinal detachment. All patients were able to locate a bright light on the ceiling and a
dark line on the floor after the surgery. Performance in square localization tests improved in four patients, and direction
of motion improved in three patients. One patient achieved grating visual acuity. Goldmann visual field test results
improved in all patients.
The patients showed improvement in visual tasks after the surgery, and the device was well-tolerated and functional over
a one-year follow-up period. A rigorous patient-selection process is necessary to maximize patient compliance with the
rigorous follow-up testing schedule. Both patients and medical staff should be prepared for a lengthy, arduous
Source: Rizzo S, Belting C, Cinelli L, et al. The Argus II retinal prosthesis: 12-month outcomes from
a single-study center. Am J Ophthalmol. 2014; 157(6):1282–1290.