Volume 10, Number 5
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.
Subfoveal Choroidal Thickness as
a Potential Predictor of Visual Outcome and Treatment Response Following Intravitreal
Ranibizumab Injections for Typical Exudative AMD
South Korean researchers performed this retrospective study to investigate the prognostic implication
of subfoveal choroidal thickness on treatment outcome after intravitreal ranibizumab injections
for typical exudative age-related macular degeneration (AMD).
They analyzed 40 eyes of 37 patients who completed six-month follow-up and retrieved patients'
data from medical records including best-corrected visual acuity (BCVA). Researchers measured
subfoveal choroidal thickness at baseline, three months, and six months using enhanced depth
imaging optical coherence tomography (OCT) and they adjusted for age and sex before
statistical analysis. Treatment response was after three monthly intravitreal ranibizumab
injections. Responders (responder group) were defined as a 100 µm or more decrease or
complete resolution of subretinal fluid, whereas nonresponders (nonresponder group) were defined
as changes <100 µm or =100 µm increase of subretinal fluid by OCT.
The study researchers reported that mean age at diagnosis was 72.1 ± 8.1 years, and 22 eyes
(55.0%) were responders. They also noted that the responder group had thicker subfoveal
choroid (257.2 ± 108.3 µm) and smaller lesions (1.3 ± 0.8 µm) at baseline than
the nonresponder group (167.1 ± 62.4 µm, p=0.003; and 2.0 ± 1.0 µm,
p=0.008). The responder group showed significantly better BCVA and thicker subfoveal choroid
than the nonresponder group at three months (p=0.002 and p=0.023) and six months
(p=0.004 and p=0.031). Furthermore, stepwise and binary regression analysis
demonstrated that subfoveal choroidal thickness was significantly correlated with visual outcome
(B=–0.002, p=0.003) and treatment response (B=8.136, p=0.018).
Subfoveal choroidal thickness may be a predictive factor for visual outcome and treatment response
in typical exudative AMD after intravitreal ranibizumab injections.
Source: Kang HM, Kwon JH, Yi JH, et al. Subfoveal choroidal thickness as a ptoential
predictor of visual outcome and treatment response after intravitreal ranibizumab injections
for typical exudative age-related macular degeneration. Am J Ophthalmol. 2014; 157(5):1013–21.
Injection Frequency and
Anatomic Outcomes One Year After Conversion to Aflibercept in Patients with Neovascular AMD
The authors of this retrospective review sought to evaluate the clinical, anatomic and
functional effects of conversion to aflibercept following ranibizumab and/or bevacizumab
in patients with neovascular age-related macular degeneration (AMD).
The primary outcome was change in injection frequency in the year following the change.
Secondary outcomes included change in central macular thickness (CMT) at six months and one
year, presence of intraretinal and subretinal fluid at six months and visual acuity at one year.
A total of 109 eyes with neovascular AMD were switched to aflibercept and met inclusion
criteria. Overall, aflibercept injection frequency was unchanged with patients receiving
7.4 anti-vascular endothelial growth factor (anti-VEGF) injections the year prior to conversion
compared with 7.2 aflibercept injections in the year following (p=0.47). However, the change
to aflibercept was associated with improvement in CMT from 324 to 295 µm (p=0.0001) at
six months and 299 µm (p=0.0047) at one year. There was no effect on visual acuity at
one year, the authors noted. They also reported that in a subgroup analysis, patients who had
received ≥10 anti-VEGF injections in the year prior had fewer injections (11.1 to 8.4,
p<0.0001) and clinic visits (13.9 to 9.6, p<0.0001) as well as a significant
decrease in CMT (–35 µm, p=0.02).
To conclude, in this population, switching to aflibercept therapy was not associated with a change
in injection frequency or improved visual acuity, but was associated with improved CMT at six months
and one year. In patients who received at least 10 anti-VEGF injections in the year prior, the
authors found that transitioning to aflibercept was associated with a reduced injection frequency
and CMT, suggesting potential cost savings in this population.
Source: Messenger WB, Campbell JP, Faridi A, et al. Injection frequency and
anatomic outcomes 1 year following conversion to aflibercept in patients with
neovascular age-related macular degeneration. Br J Ophthalmol. 2014;May 2. [Epub ahead
of print]. DOI: 10.1136/bjophthalmol-2013-304829.
Outcomes of Individualized
Ranibizumab Treatment in Patients with DME
In the following Phase IIIb, multicenter, 12-month, randomized core study and 24-month
open-label extension study, scientists evaluated long-term efficacy and safety profiles
during three years of individualized ranibizumab treatment in patients with visual impairment
due to diabetic macular edema (DME).
Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the
extension study. According to the study scientists, in the extension study, patients were eligible
to receive individualized ranibizumab treatment as of month 12 guided by best-corrected visual
acuity (BCVA) and disease progression criteria at the scientists' discretion. Concomitant
laser treatment was allowed according to the Early Treatment Diabetic Retinopathy Study
(ETDRS) guidelines, and based on the treatments received in the core study, the extension study
groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser. Change in BCVA
and incidence of ocular and nonocular adverse events (AEs) over three years was the main outcome measure.
Overall, 208 patients (86.7%) completed the extension study, the scientists reported. In
patients treated with ranibizumab during the core study, they noted that consecutive
individualized ranibizumab treatment during the extension study led to an overall maintenance of
BCVA and central retinal subfield thickness (CRST) observed at month 12 over the two-year
extension study (+8.0 letters, –142.1 µm [prior ranibizumab] and +6.7 letters,
–145.9 µm [prior ranibizumab + laser] from baseline at month 36) with a median of
6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections;
prior ranibizumab + laser). In the prior laser group, the scientists observed a progressive
BCVA improvement (+6.0 letters) and CRST reduction (–142.7 µm) at month 36 after
allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5
injections) from months 12 to 35. Patients in all three treatment groups received a mean of less
than three injections in the final year. No cases of endophthalmitis, retinal tear, or
retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects
over three years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were
reported during the extension study, but none were suspected to be related to the study drug/procedure.
Ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a
progressively declining number of injections over three years of individualized dosing, the
study scientists concluded. Moreover, ranibizumab was generally well-tolerated with no new
safety concerns over three years.
Source: Schmidt-Erfurth U, Lang GE, Holz FG, et al; RESTORE Extension Study Group.
Three-year outcomes of individualized ranibizumab treatment in patients with diabetic
macular edema: the RESTORE Extension Study. Ophthalmology. 2014; 121(5):1045—1053.
Functional and Structural Effects
of Ranibizumab vs. Laser in DME
London investigators compared the functional and structural effects of ranibizumab
versus macular laser therapy in patients with center-involving diabetic macular edema (DME)
in this prospective, randomized, single-masked clinical trial.
They examined 33 eyes of 33 patients with center-involving DME, with best-corrected visual acuity of
55 to 79 Early Treatment Diabetic Retinopathy Study letters at baseline, completing the 48-week
study period. The investigators randomized subjects 2:1 to three loading doses of ranibizumab,
then retreatment every four weeks as required; or macular laser therapy at baseline, repeated
as required every 12 weeks. For exploratory outcome measures, structural imaging studies
included greatest linear dimension and area of foveal avascular zone, perifoveal capillary
dropout grade, and presence of morphologic features of diabetic macular edema on Spectralis
optical coherence tomography (Heidelberg Engineering GmbH). Functional measures consisted of
visual acuity, retinal sensitivity in the central four and 12 degrees on microperimetry, color
contrast sensitivity protan and tritan thresholds, pattern and full-field electroretinogram
amplitudes and implicit times, and multifocal electroretinogram amplitude distribution. These
were reported at 12, 24, and 48 weeks.
Ranibizumab-treated subjects gained 6.0 vs. 0.9 letters lost for laser, demonstrated improved tritan
and protan color contrast thresholds, and improved retinal sensitivity, the investigators
observed. Additionally, they reported that electrophysiologic function improved after
ranibizumab therapy. No safety issues were evident. Better retinal thickness reduction and
structural improvement in optical coherence tomography features of DME were seen with
ranibizumab therapy than in the laser group. There was no evidence of progressive ischemia
with ranibizumab therapy.
In conclusion, ranibizumab therapy in the treatment of DME seems to improve retinal function
and structure as demonstrated by this evaluation of different assessment methods.
Source: Comyn O, Sivaprasad S, Peto T, et al. A randomized trial to assess functional
and structural effects of ranibizumab versus laser in diabetic macular edema
(the LUCIDATE study). Am J Ophthalmol. 2014;157(5):960–970.
The Incidental Findings of
AMD During Screening for Diabetic Retinopathy
The purpose of this prospective study was to determine the reliability of detecting age-related
macular degeneration (AMD) during screening for diabetic retinopathy (DR).
A total of 2,003 subjects with diabetes mellitus who underwent photographic screening for DR
were included and the reliability of detecting AMD lesions was tested by interobserver and
intraobserver agreement. Additionally, the sensitivity and specificity of diagnosing AMD at
different grades of severity were tested using the consensus grading of a group as the reference standard.
It was reported that DR affected 24.7% of the subjects and that the age-standardized prevalence
of early AMD was 17.9%, and late AMD was 0.1%. The interobserver and intraobserver agreement
for grading AMD was substantial (k=0.72 and 0.71 respectively, p<0.001). It
was equally good in those with different severities of DR. There was also no difference in
sensitivity and specificity of detecting AMD in those with different levels of DR (sensitivity
62% to 68% and specificity 97% to 98%).
Intermediate- and high-risk AMD that warrant treatment with zinc and antioxidant supplements could
be reliably detected during screening for diabetic retinopathy.
Source: Gangwani R, Lai WW, Sum R, et al. The incidental findings of age-related
macular degeneration during diabetic retinopathy screening. Graefes Arch Clin Exp
Time to Clinically Significant
VA Gains Following Ranibizumab Treatment for RVO
The post hoc analyses of two Phase III clinical trials assessing efficacy and safety
of ranibizumab in patients with branch retinal vein occlusion (RVO) (Ranibizumab for the Treatment
of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety
[BRAVO] study) and central RVO (Ranibizumab for the Treatment of Macular Edema after Central
Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]) over 12 months sought
to assess time to first achievement of clinically significant visual acuity (VA) gains from
baseline in patients with RVO receiving ranibizumab versus sham treatment.
A total of 789 (BRAVO, n=397; CRUISE, n=392) were included. There was randomization to
monthly intraocular ranibizumab injections (0.3 mg/0.5 mg) or sham. After six monthly
injections (treatment period), patients meeting prespecified criteria received as-needed (pro
re nata [p.r.n.]) ranibizumab at their assigned dose (sham patients, ranibizumab 0.5 mg)
through month 12 (observation period). BRAVO patients meeting specific eligibility criteria
could receive rescue laser treatment once during the treatment and once during the observation
Time to first gain of 15 letters or more from baseline, analyzed using Kaplan-Meier methods, was
the main outcome measure. To evaluate the effect of delaying ranibizumab treatment, sham
patients' VA data also were analyzed, with month six considered as baseline to assess vision
gains during the six months of receiving ranibizumab p.r.n.
Median time to first 15-letter or more gain from baseline was 12.0 (sham), 4.8 (ranibizumab 0.3 mg),
and 4.0 months (ranibizumab 0.5 mg) in BRAVO and 12.2, 5.9, and 5.2 months, respectively, in CRUISE.
The cumulative proportion of patients who had ever gained ≥15 letters from baseline by month 12
was 50% (sham), 68% (ranibizumab 0.3 mg), and 71% (ranibizumab 0.5 mg) in BRAVO and
42%, 61%, and 66%, respectively, in CRUISE. After six months of ranibizumab
p.r.n. treatment, a cumulative 10.8% (BRAVO) and 26.2% (CRUISE) of initially
sham-treated patients ever gained ≥15 letters.
This retrospective analysis shows that >50% of patients treated with monthly
ranibizumab achieved clinically significant vision gains during the initial six months of
treatment, which were largely maintained using p.r.n. treatment to 12 months. In comparison,
<50% of patients initially randomized to sham (and later receiving ranibizumab 0.5 mg
p.r.n. treatment) ever achieved clinically significant vision gains. These results suggest
that initiating treatment immediately after diagnosis may provide the greatest vision gains.
The potential benefits of early treatment should be evaluated further in prospective clinical studies.
Source: Thach AB, Yau L, Hoang C, Tuomi L. Time to clinically significant visual acuity
gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials.
Ophthalmology. 2014; 121(5):1059–1066.
Impact of Early Peripheral
Laser Photocoagulation of Nonperfused Retina on Vision in Patients with CRVO
This prospective, proof-of-concept study randomized 22 central retinal vein occlusion
(CRVO) patients into two arms to evaluate the effect of the combination of ranibizumab and
laser photocoagulation to peripheral retinal areas of nonperfusion in patients with
non-ischemic central retinal vein occlusion (CRVO) without neovascularizations.
The RL group (ranibizumab + laser; n=10) received ranibizumab with additive
laser photocoagulation, while the control R group (n =12) was treated with ranibizumab only.
All patients received three initial monthly ranibizumab injections followed by PRN regimen.
Changes in best-corrected visual acuity (BCVA) and in central retinal thickness (CRT) were
documented over six months.
It was reported that median of BCVA improved in the RL group from 65 ETDRS letters (interquartile
range IQR=10 letters) at baseline to 70 (IQR=23.2) letters at month six. In the control R group,
BCVA remained stable [baseline: 61 (IQR=19.5) and month six: 61 (IQR=22) letters]. CRT decreased
between baseline and final visit in the RL group from 547 (IQR=513) µm to 246.5 (IQR=346.3)
µm, and in the control group from 637.5 (IQR=344) µm to 423 (IQR=737) µm. More
pronounced improvements in BCVA were seen in the RL group (medians=14 vs. 6.5 letters) although
the observed group differences were not statistically significant due to small samples.
It was determined that the selective laser photocoagulation of peripheral areas of nonperfusion seems
to lead to additional visual improvement in patients with CRVO. A larger replication trial is
necessary to confirm the results of this proof of concept study.
Source: Rehak M, Tilgner E, Franke A, et al. Early peripheral laser photocoagulation
of nonperfused retina improves vision in patients with central retinal vein occlusion
(results of a proof of concept study). Graefes Arc Clin Exp Ophthalmol. 2014; 252(5):745–752.
Half-Fluence vs. Half-Dose PDT
in Chronic CSC
Researchers in Italy aimed to compare the efficacy and safety of half-fluence with
half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (CSC) in the
following multicenter retrospective comparison study.
They performed a review of 56 patients affected by chronic CSC, including 28 patients (31 eyes)
who received half-fluence PDT and 28 patients (29 eyes) who received half-dose PDT. They
assessed best-corrected visual acuity (BCVA), central foveal thickness (CFT), and resolution
of subretinal fluid on optical coherence tomography (OCT) at one and 12 months.
According to the researchers, the mean logarithm of the minimum angle of resolution BCVA
improved significantly (p<0.001), both in the half-fluence group (from 0.187
[± 0.187] to 0.083 [± 0.164]) and in the half-dose group (from 0.126 [± 0.091] to 0.068
[± 0.091]), at 12 months, without significant difference between the two groups. At one month,
they observed a complete resolution of subretinal fluid in 19 half-fluence-treated eyes (61.3%)
and in 25 half-dose-treated eyes (86.2%) (p=0.04). They also found that at 12 months,
a complete resolution of subretinal fluid was achieved in 26 half-fluence-treated eyes (83.9%)
and 29 half-dose-treated eyes (100%) (p=0.0529). Additionally, nine eyes (29%) in
the half-fluence group and five eyes (17.2%) in the half-dose group had at least one recurrence
of subretinal fluid during the follow-up. Overall, there were 15 and five recurrences in
the half-fluence PDT and half-dose PDT groups, respectively (p=0.07). In no eye of either
groups was atrophy of the retinal pigment epithelium observed in the area of treatment.
Half-dose PDT induced a more rapid reabsorption of the fluid, a more lasting effect, and equal
safety with respect to half-fluence PDT, the study researchers determined.
Source: Nicoló M, Eandi CM, Alovisi C, et al. Half-fluence versus half-dose
photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol.
PDT for Chronic CSC
To assess the visual and anatomic outcomes of central serous chorioretinopathy (CSC) after
verteporfin photodynamic therapy (PDT), investigators conducted this retrospective case series.
They surveyed members of the Macula Society to retrospectively collect data on PDT treatment for
CSC. They collected patient demographic information, PDT treatment parameters, fluorescein
angiographic information, optical coherence tomography (OCT) metrics, pre- and post-treatment
visual acuity (VA), and adverse outcomes online using standardized forms. Visual acuities over time
and presence or absence of subretinal fluid (SRF) served as the main outcome measures.
Data were submitted on 265 eyes of 237 patients with CSC with a mean age of 52 (standard deviation
[± 11]) years; 61 were women (26%). The investigators reported that mean baseline logarithm
of the minimum angle of resolution (logMAR) VA was 0.39 ± 0.36 (20/50) and that baseline VAs
were ≥20/32 in 115 eyes (43%), 20/40 to 20/80 in 97 eyes (37%), and ≤20/100 in 47 eyes
(18%). Normal fluence was used for PDT treatment in 130 treatments (49%), half-fluence was
used in 128 treatments (48%), and very low fluence or missing information was used in
seven treatments (3%). The number of PDT treatments was one in 89%, two in 7%, and three
in 3% of eyes. Post-PDT follow-up ranged from one month to more than one year. Post-PDT VA
was correlated with baseline VA (r=0.70, p<0.001). Visual acuity improved three
or more lines in <1%, 29%, and 48% of eyes with baseline VA ≥20/32, 20/40 to
20/80, and ≤20/100, respectively, the study investigators noted. Moreover, subretinal fluid
resolved in 81% by the last post-PDT visit. There was no difference in the response to PDT
when analyzed by age, race, fluence setting, fluorescein angiography leakage type,
corticosteroid exposure, or fluid location (subretinal or pigment epithelial detachment; all
p>0.01). Complications were rare. Retinal pigment epithelial atrophy was seen in 4%
of patients, and acute severe visual decrease was seen in 1.5% of patients.
In conclusion, PDT was associated with improved VA and resolution of SRF. Adverse side effects
Source: Lim JI, Glassman AR, Aiello LP, et al; Macula Society CSC Collaborative
Study Group, Research and Education Comittee and Website Committee.
Collaborative retrospective Macula Society study of photodynamic therapy for chronic
central serous chorioretinopathy. Ophthalmology. 2014;121(5):1073–1078.
Effects of Chlorogenic Acid
and Coffee on Hypoxia-Induced Retinal Degeneration
This study explored whether chlorogenic acid (CGA) and coffee have protective effects against
Under hypoxic conditions, the viability of transformed retinal ganglion (RGC-5) cells was
significantly reduced by treatment with the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine
(SNAP). However, pretreatment with CGA attenuated cell death in a concentration-dependent manner.
In addition, CGA prevented the up-regulation of apoptotic proteins such as Bad and cleaved
caspase-3. Similar beneficial effects of both CGA and coffee extracts were observed in mice that
had undergone an optic nerve crush (ONC) procedure. CGA and coffee extract reduced cell death
by preventing the down-regulation of Thy-1.
These in vitro and in vivo studies demonstrated that coffee and its major component,
CGA, significantly reduce apoptosis of retinal cells induced by hypoxia and NO, and that
coffee consumption may help in preventing retinal degeneration.
Source: Jang H, Ahn HR, Jo H, et al. Chlorogenic acid and coffee prevent
hypoxia-induced retinal degeneration. J Agric Food Chem. 2014;62(1):182–191.