Volume 8, 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.
Ranibizumab for the Treatment of CNV Secondary to AMD
In this open-label, multicenter, extension study, investigators evaluated the long-term safety and efficacy of
multiple intravitreal ranibizumab injections (Lucentis, Genentech, Inc.) administered at the investigator's
discretion in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
Patients who completed the controlled treatment phase of 1 of 3 prospective, randomized, 2-year clinical trials of ranibizumab
were eligible for enrollment. The investigators performed analyses for 3 groups: (1) patients treated with ranibizumab in the
initial study (ranibizumab treated-initial; n = 600); (2) patients randomized to control who crossed over to receive
ranibizumab (ranibizumab treated-XO; n = 190); and (3) ranibizumab-naïve patients (ranibizumab untreated; n = 63).
Ranibizumab 0.5 mg was administered at the investigator's discretion and adverse events (AEs) and Early Treatment
Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) assessments were conducted at study visits every
3 to 6 months. Incidence and severity of AEs were the main outcome measures.
According to the study investigators, there was 1 occurrence of mild endophthalmitis per 3,552 HORIZON injections in the
ranibizumab treated-initial/ranibizumab treated-XO groups. They reported were no serious AE reports of lens damage,
retinal tears, or rhegmatogenous retinal detachments in the study eyes. They also noted that the proportion of patients with
any single post-dose intraocular pressure (IOP) ≥30 mmHg was 9.2%, 6.6%, and 0%, and the proportion of patients
with glaucoma was 3.2%, 4.2%, and 3.2% in the ranibizumab treated-initial, ranibizumab treated-XO, and
ranibizumab untreated groups, respectively. Cataract AEs were less frequent in the ranibizumab untreated group: 6.3% versus
12.5% and 12.1% in the ranibizumab treated-initial and ranibizumab treated-XO groups, respectively. The proportion of
patients with arterial thromboembolic events as defined by the Antiplatelet Trialists' Collaboration was 5.3% in
the ranibizumab treated-initial and ranibizumab treated-XO groups, and 3.2% in the ranibizumab untreated group. At month
48 (2 years of HORIZON), the mean change in BCVA (ETDRS letters) relative to the initial study baseline was +2.0 letters in
the ranibizumab treated-initial group versus –11.8 letters in the pooled ranibizumab treated-XO and ranibizumab untreated groups.
The investigators determined that multiple ranibizumab injections were well tolerated for ≥4 years. With less frequent
follow-up leading to less treatment, there was an incremental decline of the visual acuity (VA) gains achieved with monthly treatment.
Source: Singer MA, Awh CC, Sadda SV, et al. HORIZON: an open-label extension trial of ranibizumab for
choroidal neovascularization secondary to age-related macular degeneration. Ophthalmol. 2012;119(6):1175–1183.
Detection of Early Exudative AMD with OCT
Optical coherence tomography (OCT) provides microscopic retinal images and is noninvasive, using light waves to
produce detailed retinal images. The authors of the following prospective, observational, nonrandomized study investigated
the ability of OCT to detect early choroidal neovascularization (CNV) in age-related macular degeneration (AMD).
They enrolled 79 patients, diagnosed with nonexudative macular degeneration in one eye and exudative macular degeneration in
the other. Participants underwent examination (visual acuity, intraocular pressure [IOP], biomicroscopy and ophthalmoscopy)
followed by OCT in the study eye (nonexudative macular degeneration eye) every 3 months for 2 years. If examination did not show
CNV, but OCT images raised suspicion, the authors re-examined patients in 4 to 6 weeks and/or performed fluorescein angiography.
They also examined visual acuity, OCT anomaly detected, and time between OCT and fluorescein angiography detection.
The study authors found that 15 (19%) patients developed exudative macular degeneration, as confirmed by fluorescein
angiography, in the study eye. Four additional patients showed potential exudative macular degeneration on OCT only. Of the
15 patients who developed exudative macular degeneration, 13 had disease progression identified on OCT before examination
and/or fluorescein angiography showed changes. The authors also noted that subretinal pigment epithelium fluid was the most
common OCT anomaly, with development of sub-/intraretinal fluid also visible.
OCT could be a powerful screening tool for patients with AMD at high risk for developing CNV.
Source: Padnick-Silver L, Weinberg AB, Lafranco FP, Macsai MS. Pilot study for the detection of early
exudative age-related macular degeneration with optical coherence tomography. Retina. 2012;32(6):1045–1056.
Impact of Intravitreal Bevacizumab Injection on Retinal Blood Flow Velocity in CNV
Scientists studied the short-term effects of intravitreal bevacizumab (Avastin) on retinal blood flow velocity and
compared them to clinical outcomes assessed by optical coherence tomography (OCT) and tests of visual acuity.
They used the Retinal Function Imager (RFI) noninvasively and quantitatively to measure retinal blood flow velocity and they
included 8 patients receiving intravitreal injection of Avastin for choroidal neovascularization (CNV) in this study. All were
imaged by the RFI preinjection and 1 and 7 days postinjection. The study scientists recorded visual acuity (VA) and OCT
preinjection and 1 month postinjection. They then performed comparisons using paired Student t test and correlation using
Spearman rank test.
The scientists found a good correlation between the 1-month change in VA and OCT measurements and the short-term change induced
in blood flow velocity. They noted that arterial and venous velocity changes 1 day after the injection correlated with the VA
change (p<0.05). Moreover, the 1-day arterial velocity changes correlated with total macular volume (p=0.02)
and venous velocity changes correlated to central macular thickness (p=0.04).
To conclude, the RFI provides a noninvasive technique to assess early hemodynamic responses to intravitreal injection of
Avastin. These early changes may prove important for better understanding of the mechanism underlying this treatment and serve
as a quantitative marker for treatment optimization.
Source: Barak A, Burgansky-Eliash Z, Barash H, et al. The effect of intravitreal bevacizumab (Avastin) injection
on retinal blood flow velocity in patients with choroidal neovascularization. Eur J Ophthalmol. 2012;22(3):423–430.
Long-term Treatment Results of Intravitreal Ranibizumab with PDT and
Intravitreal Triamcinolone with PDT for Retinal Angiomatous Proliferation
Researchers compared intravitreal ranibizumab, intravitreal ranibizumab plus photodynamic therapy (PDT) and
intravitreal triamcinolone plus PDT in retinal angiomatous proliferation, presenting the results of a 3-year follow-up.
They randomized 37 eyes of 37 patients with retinal angiomatous proliferation to 1 of the 3 groups. Group 1 (n = 13) received
3 monthly injections of 0.5 mg ranibizumab, Group 2 (n = 13) received 1 session of PDT and 3 monthly injections of ranibizumab,
and Group 3 (n = 11) received 1 session of PDT and 1 injection of 4 mg triamcinolone. Retreatment, with the same therapeutic
scheme in each group, was considered in case of persistence or recurrence of subretinal/intraretinal fluid.
According to the researchers, 12 patients in Groups 1 and 2 and 9 patients in Group 3 completed the 3-year follow-up. They
reported that a total of 58% of patients in Group 1, 50% in Group 2, and 88.9% in Group 3 had the same or better
visual acuity at the end of the follow-up (p = 0.081). They also noted that patients in Group 3 exhibited
considerable improvement in visual acuity (p = 0.032) and statistically significant decrease in central retinal thickness
(p < 0.0001) than the 2 other groups at the end of the follow-up. Also, the patients in Group 3 received on average
the lowest number of injections (p < 0.0001). Of note, geographic atrophy mainly at the place of previous
retinal angiomatous proliferation lesion was detected in 0% in Group 1, 25% in Group 2, and 55.6% in Group 3
(p = 0.203), while 33.3% of patients in Group 1 developed retinal scar.
To conclude, treatment with ranibizumab or ranibizumab plus PDT resulted in stabilization of the disease, while treatment
with IVT plus PDT achieved better results in terms of functional and anatomical features compared with the other groups.
Source: Rouvas AA, Chatziralli IP, Theodossiadis PG, et al. Long-term results of intravitreal ranibizumab
with photodynamic therapy, and intravitreal triamcinolone with photodynamic therapy for the treatment of retinal
angiomatous proliferation. Retina. 2012;32(6):1181–1189.
Visual Prognosis in Eyes with Submacular Hemorrhage Secondary to AMD or PCV
To determine clinical or imaging prognostic features for visual outcome in eyes with submacular hemorrhage secondary
to age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV), the following prospective case series of
11 eyes from 11 patients with submacular hemorrhage secondary to AMD or PCV were examined.
All participants had measurement of clinical characteristics, fundus angiogram, and indocyanine green angiography, spectral
domain optical coherence tomography (OCT, Cirrus, Zeiss) at baseline and 6 months.
It was noted that median visual acuity improved from 20/132 to 20/63 at month 6 and that the median improvement in vision was
0.20 LogMAR units. Proportion of eyes with best-corrected visual acuity (BCVA) ≥1.0 increased from 6/11 (54.5%) at
baseline to 8/11 (72.7%) at month 6. Eyes with BCVA > 1.0 were more likely to have larger area of hemorrhage and
thinner subfoveal neurosensory retinal thickness at baseline and at month 6.
Thinner neurosensory retina demonstrated on OCT at baseline may be a useful prognostic sign for limited visual recovery.
Source: Cheung CM, Bhargava M, Xiang L, et al. Six-month visual prognosis in eyes with submacular hemorrhage secondary
to age-related macular degeneration or polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol. 2012;
May 26. [Epub ahead of print]. DOI: 10.1007/s00417-012-2029-1.
Microperimetric Correlations of Autofluorescence and OCT Imaging in Dry AMD
Researchers in France investigated the microperimetric correlations of autofluorescence imaging and optical coherence
tomography (OCT) in dry age-related macular degeneration (AMD) in the following retrospective, observational,
Consecutive patients with dry AMD underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA),
blue fundus autofluorescence (FAF), near-infrared autofluorescence, and spectral-domain (SD)-OCT with integrated microperimetry.
The researchers included 58 eyes of 29 patients (21 women; mean age 73 ± 9 years). They reported that mean BCVA was
0.28 ± 0.3 logarithm of the minimal angle of resolution (logMAR) and that overall, 2,842 points were analyzed as regards
FAF and near-infrared autofluorescence patterns, the status of inner segment/outer segment (IS/OS) interface, and retinal
sensitivity. They also observed a good correlation between the FAF and near-infrared autofluorescence patterns for all the
points graded (increased FAF/near-infrared autofluorescence, Pearson rho = 0.6, p = .02; decreased
FAF/near-infrared autofluorescence, Pearson rho = 0.7, p = .01; normal FAF/near-infrared autofluorescence, Pearson
rho = 0.7, p = .01). The study researchers noted that mean retinal sensitivity was significantly reduced in cases of
decreased FAF (4.73 ± 2.23 dB) or increased FAF (4.75 ± 2.39 dB) compared with normal FAF (7.44 ± 2.34 dB)
(p = .001). Additionally, they reported that mean retinal sensitivity was significantly reduced in case of
decreased near-infrared autofluorescence (3.87 ± 2.28 dB), compared with increased near-infrared autofluorescence
(5.76 ± 2.44 dB) (p = .02); mean retinal sensitivity in case of increased near-infrared autofluorescence was
significantly reduced compared with normal near-infrared autofluorescence (7.15 ± 2.38 dB) (p = .002). On SD-OCT,
there was a high inverse correlation between retinal sensitivity and rate of disruptions in IS/OS interface
(Pearson rho = –0.72, p = .001).
In conclusion, reduced retinal sensitivity consistently correlates with decreased FAF/near-infrared autofluorescence and a
disrupted IS/OS interface. Increased near-infrared autofluorescence may represent a useful method for detection of
retinal abnormalities early in dry AMD development.
Source: Querques L, Querques G, Forte R, Souied EH. Microperimetric correlations of autofluorescence and
optical coherence tomography imaging in dry age-related macular degeneration. Am J Ophthalmol. 2012;153(6):1110–1115.
Half-Fluence PDT and Chronic CSC
To report long-term functional and anatomic results of safety-enhanced photodynamic therapy (PDT) with half-dose verteporfin
for chronic central serous chorioretinopathy (CSC), researchers performed a retrospective analysis of 29 eyes of 27 patients
with chronic CSC.
They reported that all eyes received half-dose PDT and they evaluated visual acuity, central foveal thickness and
According to the researchers, mean follow-up time was 20 months (range 12-40) and mean best-corrected visual acuity improved
from 0.45 ± 0.23 logMAR to 0.08 ± 0.08 logMAR. They also found that 25 eyes (86%) had a complete resolution of
the subretinal fluid after only one session and 4 eyes had recurrences, 3 of them at the same leaking area observed at baseline.
At the end of the follow-up, all eyes (100%) showed resolution of the subretinal fluid. There was no visual loss secondary
to exaggerated response to the PDT, nor any other adverse events.
The long-term results of this study further support the safety and effectiveness of safety-enhanced PDT with half dose of
verteporfin for the treatment of chronic CSC.
Source: Rouvas A, Stavrakas P, Theodossiadis PG, et al. Long-term results of half-fluence photodynamic therapy
for chronic central serous chorioretinopathy. Eur J Ophthalmol. 2012;22(3):417–422.
Treatment of Macular Edema in CRVO with Bevacizumab
In Sweden, investigators evaluated the efficacy of intraocular injections with bevacizumab in patients with macular edema
(ME) secondary to central retinal vein occlusion (CRVO) in this prospective, randomized, sham injection-controlled,
double-masked clinical trial.
They included 60 patients with ME secondary to CRVO. At baseline, they randomized patients 1:1 to receive intraocular injections
of bevacizumab or sham injections every 6 weeks for 6 months. The primary outcome measure was the proportion of patients gaining
at least 15 letters at 6 months. Secondary outcome measures included mean change from baseline best-corrected visual acuity
(BCVA), foveal thickness and neovascular glaucoma.
At the end of follow-up, the investigators noted that 18 of 30 patients (60%) in the study group had gained ≥15
letters compared with 6 of 30 patients (20%) in the control group (p=0.003). They reported that the BCVA improved by
14.1 letters at 24 weeks compared with a decrease of 2.0 letters in the control group (p<0.003) and that the mean
decrease in central retinal thickness (CRT) was significantly greater in the study group (426 µm) than in the control group
(102 µm) at all time points up to week 24 (p<0.001). The study investigators found no residual edema, defined as
CRT <300 µm at 24 weeks, in 26 of 30 patients (86.7%) in the treatment group compared with 6 of 30 patients (20%)
in the control group (p<0.001). They also reported that in the sham group, 5 of 30 patients (16.7%) had developed
iris rubeosis at week 24 and that no patients in the study group at rubeosis at week 24 (p=0.052). Furthermore, there were
no events of endophthalmitis, retinal tear or retinal detachment during the 24-week treatment period and no serious non-ocular
adverse events were reported.
Intraocular injections of bevacizumab given every 6 weeks for 6 months improve visual acuity (VA) and reduce ME significantly
compared with sham.
Source: Epstein DL, Algvere PV, von Wendt G, et al. Bevacizumab for macular edema in central retinal vein occlusion:
a prospective, randomized, double-masked clinical study. Ophthalmol. 2012;119(6):1184&3150;1189.
Impact of Duration of Macular Edema on Clinical Outcomes in RVO Treated
with Dexamethasone Intravitreal Implant
The following post hoc analysis of pooled data from 2 randomized, controlled trials assessed the effect of duration of macular
edema (ME) on clinical outcomes after treatment with dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan, Inc.) in
patients with ME following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
Patients with vision loss resulting from ME of 6 weeks' duration or more after BRVO or CRVO (n = 690) were included and
the relationship between ME duration at the time of first treatment and treatment outcomes was assessed using logistic
regression. Other factors potentially associated with ME duration or patient outcomes were adjusted for in the analyses. Main
outcome measures were the proportion of patients achieving at least 15 letters improvement in best-corrected visual acuity (BCVA)
or at least 200-µm or more reduction in central retinal thickness 6 or 12 months after the first treatment with
dexamethasone intravitreal implant 0.7 mg.
In the 6-month analysis, each 1-month increase in ME duration was associated with a significantly lower likelihood of achieving a
BCVA improvement of 15 letters or more (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.83–0.94;
p<0.001) or a CRT reduction of 200-µm or more (OR, 0.91; 95% CI, 0.86–0.97; p<0.01) 6 months
after treatment. In the 12-month analysis, increased ME duration was associated with a significantly lower likelihood of
achieving BCVA improvement of 15 letters or more improvement in BCVA (OR, 0.85; 95% CI, 0.76–0.95; p<0.01)
12 months after treatment; duration was not significantly associated with the likelihood of a CRT reduction of 200-µm or more
at 12 months. In general, the effect of ME duration on outcomes was stronger and statistically significant in BRVO patients,
but weaker and not statistically significant in CRVO patients.
It was concluded that, in eyes with retinal vein occlusion, longer ME duration at the time of first treatment with the
dexamethasone intravitreal implant 0.7 mg was associated with a significantly lower likelihood of achieving clinically
meaningful improvements in vision or CRT 6 or 12 months after treatment. This suggests that prompt treatment for retinal
vein occlusion—particularly BRVO—may be associated with improved clinical outcomes.
Source: Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in
retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmol. 2012;119(6):1190–1198.
Effects of Ranibizumab on DR Severity and Progression
To evaluate effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity over time in 2 phase 3 clinical trials
(RIDE, NCT00473382; RISE, NCT00473330) of ranibizumab for diabetic macular edema, scientists randomized
participants with diabetic macular edema (DME, n = 759) to monthly sham, 0.3-mg ranibizumab or 0.5-mg ranibizumab
Macular laser was available per protocol-specified criteria. Fundus photographs, taken at baseline and periodically, were graded
by a central reading center; clinical examinations were performed monthly. The main outcome measures of this report
are secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic
Retinopathy Study severity scale in the study eye and a composite DR progression outcome including photographic changes
plus clinically important events such as occurrence of vitreous hemorrhage or need for panretinal laser.
At 2 years, the percentage of participants with DR progression (worsening by ≥2 or ≥3 steps) was significantly reduced
in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥2 or ≥3 steps) was
significantly more likely, the scientists reported. They also discovered that the cumulative probability of clinical progression
of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5%
of ranibizumab-treated eyes.
The study scientists concluded that intravitreal ranibizumab reduced the risk of DR progression in eyes with DME, and
many ranibizumab-treated eyes experienced improvement in DR severity. Because these results are exploratory, the use of
intravitreal ranibizumab specifically to reduce DR progression or cause DR regression requires further study.
Source: Ip MS, Domalpally A, Hopkins JJ, et al. Long-term effects of ranibizumab on diabetic retinopathy severity
and progression. Arch Ophthalmol. 2012; May 14. [Epub ahead of print]. DOI: 10.1001/archophthalmol.2012.1043.
Treatment of DME with Oral Minocycline
Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal
microglia demonstrate increased activation and aggregation in areas of DME. The authors of the following U.S.
single-center, prospective, open-label phase I/II clinical trial investigated the safety and potential efficacy of
oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.
They enrolled 5 participants with fovea-involving DME who received oral minocycline 100mg twice daily for 6 months. Main
outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST) and central macular
volume (CMV) using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA).
The authors found that the study drug was well-tolerated and not associated with significant safety issues. They reported that,
in study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8
letters, respectively, while mean retinal thickness (CST) on OCT decreased by –2.9%, –5.7%, –13.9,
and –8.1% for the same time points. At Month 6, mean area of late leakage on FA decreased by –34.4% in study
eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Additionally, improvements in outcome measures
were not correlated with concurrent changes in systemic factors.
According to the authors, in this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with
improved visual function, central macular edema and vascular leakage, comparing favorably with historical controls from
previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the
inflammatory etiology of DME.
Source: Cukras CA, Petrou P, Chew EY, et al. Oral minocycline for the treatment of diabetic macular edema (DME):
results of a phase I/II clinical study. Invest Ophthalmol Vis Sci. 2012; May 15. [Epub ahead of print].
Imaging Patterns of RNFL Progression with SD-OCT
To examine the use of the retinal nerve fiber layer (RNFL) thickness map generated by a spectral-domain optical
coherence tomography (SD-OCT) to detect RNFL progression and identify the pattern of progressive changes of RNFL defects
in glaucoma, this prospective, longitudinal study included 186 eyes of 103 glaucoma patients.
Patients were followed at 4-month intervals for ≥36 months for RNFL imaging and visual field examination. Both eyes were
imaged by the Cirrus HD-OCT (Carl Zeiss Meditec Inc.) and had visual field testing at the same visits. RNFL progression was
defined by Guided Progression Analysis (Carl Zeiss Meditec) of serial RNFL thickness maps and the pattern of RNFL progression
was evaluated by comparing the baseline RNFL thickness deviation map and the RNFL thickness change map. Additionally, visual
field progression was defined by trend analysis of visual field index and event analysis based on the Early Manifest Glaucoma
Trial criteria. Main outcome measures were the presence and the pattern of RNFL progression.
A total of 2,135 OCT images were reviewed and 28 eyes (15.1%) from 24 patients (23.3%) had RNFL progression detected by
RNFL thickness map analysis. Three RNFL progression patterns were observed: (1) widening of RNFL defects (24 eyes, 85.7%),
(2) deepening of RNFL defects (2 eyes, 7.1%, both had concomitant widening of RNFL defects), and (3) development of new
RNFL defects (5 eyes, 17.9%). The inferotemporal meridian (324°–336°) 2.0 mm away from the optic disc center
was the most frequent location where RNFL progression was detected. It was reported that 13 eyes (46.4%) had concomitant
visual field progression; 61.5% (n = 8) of these had RNFL progression that preceded or occurred concurrently with visual
field progression. It was also observed that 42 eyes from 37 patients (22.6%) had visual field progression by trend and/or
event analyses without progression in the RNFL thickness map.
Analysis of serial RNFL thickness maps generated by the spectral-domain OCT facilitates the detection of RNFL progression in glaucoma.
Source: Leung CK, Yu M, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical
coherence tomography: patterns of retinal nerve fiber layer progression. Ophthalmol. 2012; June 6 [Epub ahead of print].