Volume 7, Number 9
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.
VEGF Trap-Eye in DME Patients: Phase 2 Primary Results
To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF)
Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME), the following
multicenter, randomized, double-masked, phase 2 clinical trial was performed.
Included in the trial were 221 diabetic patients with clinically significant macular edema involving the central macula. Patients
were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF
Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an
as-needed (p.r.n.) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter.
Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks were the main outcome measures.
It was reported that patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5
to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group
(p≤0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+ and 15+ letters were seen
in up to 93%, 64% and 34% of VEGF Trap-Eye groups versus up to 68%, 32% and 21% in the laser group,
respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from –127.3 to –194.5 µm compared with
only –67.9 µm in the laser group (p=0.0066 for each VEGF Trap-Eye group vs. laser), it was noted. Furthermore,
VEGF Trap-Eye was generally well tolerated and ocular adverse events in patients treated with VEGF Trap-Eye were generally
consistent with those seen with other intravitreal anti-VEGF agents.
It was concluded that intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement
in visual acuity when compared with macular laser photocoagulation in patients with DME.
Source: Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA-VINCI Study: phase 2 primary results of VEGF
Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118(9):1819–1826.
Differential Association of Serum Lipids with DR and DME
The authors of the following study sought to assess the association of serum lipids with diabetic retinopathy (DR),
diabetic macular edema (DME) and macular thickness in adults with diabetes. They found that serum lipids are
independently associated with the clinically significant macular edema (CSME), but not with DR, mild or moderate DME
or macular thickness.
The authors prospectively recruited diabetic patients aged ≥18 years from specialized eye clinics in Melbourne, Australia
and assessed fasting total-C (cholesterol), HDL-C and LDL-C. They graded DR from fundus photographs, and classified it into
mild, moderate, severe non-proliferative and proliferative DR, and separately graded it for presence of DME, including
CSME. Additionally, they assessed macular thickness using optical coherence tomography (OCT).
The study authors examined a total of 500 participants (median age = 65 years). They found DR, DME and CSME present in 321
(66.2%), 149 (33.0%) and 68 (15.0%) patients, respectively. They also noted that serum lipid levels were not related
to DR or DME. In multivariate models adjusting for traditional risk factors and lipid medications, persons with higher total-,
LDL- and non-HDL-C were more likely to have CSME (odds ratio of 1.54, 1.49 and 1.63 per 1 SD increase, respectively; all
p<0.05). The authors of this study found no association for serum lipids with macular thickness as assessed from
OCT. The pattern of these associations remained similar in both type 1 and 2 diabetes, although it was statistically significant
only in type 2 diabetes.
These data reflect the different impact of hyperlipidemia in the pathogenesis of DR and DME, and may explain the discrepancies
in previous studies.
Source: Benarous R, Sasongko MB, Quershi S, et al. Differential association of serum lipids with diabetic retinopathy
and diabetic macular edema. Invest Ophthalmol Vis Sci. 2011;Aug 23 [Epub ahead of print]. DOI: 10.1167/iovs.11-7598.
Link Between Macular Sensitivity and Retinal Thickness in Eyes with DME
In a prospective, observational study, researchers investigated the relationship between macular sensitivity and
retinal thickness in diabetic macular edema (DME).
At a University-based retina practice, they performed fundus microperimetry and retinal thickness tomography simultaneously on
22 eyes of 11 patients with DME using an automatic fundus perimetry/tomography system. Main outcome measures were quantification
of macular sensitivity, fixation pattern and relationship between macular sensitivity and retinal thickness.
According to the researchers, fixation stability revealed that 21 eyes (95.4%) had stable fixation (>75% within central
2 degrees of point of fixation) and 1 eye (4.5%) had relatively unstable fixation (<75% of fixation points located
within 2 degrees, >75% located within 4 degrees). Their evaluation of fixation location revealed that 15 eyes (68.2%)
had central (>50% of fixation points within 0.5 mm of fovea), 3 eyes (13.6%) pericentral (25% to 50% within
0.5 mm of fovea) and 4 eyes (18.2%) eccentric (<25% of fixation points within 0.5 mm of fovea) fixation location.
They reported that macular sensitivity increased by an average of 0.03 decibel (dB) (95% confidence interval [CI]: 0.00, 0.06)
per 1 µm increase in retinal thickness for thickness values 280 µm measured with the OPKO/OTI spectral-domain OCT.
The macular sensitivity decreased by an average 0.05 dB (95% CI: –0.08, –0.02) per 1-µm increase in thickness
for thickness values >280 µm.
In this pilot study, the majority of eyes with DME had stable, central fixation and macular sensitivity varied depending on
the thickness of the retina. Additional studies are needed to determine the role of microperimetry in eyes with DME.
Source: Hatef E, Colantuoni E, Wang J, et al. The relationship between macular sensitivity and retinal thickness
in eyes with diabetic macular edema. Am J Ophthalmol. 2011;152(3):400–405.e2.
Clinical Outcomes of Vitrectomy with or Without Bevacizumab Pretreatment for Severe DR
The authors of the following Chinese study sought to examine possible benefits of intravitreal bevacizumab (IVB) pretreatment
in vitrectomy for severe diabetic retinopathy (DR).
They performed a comprehensive literature search using the Cochrane Collaboration methodology to identify randomized controlled
trials and comparative studies of vitrectomy with or without IVB pretreatment for severe or complicated DR. They also
performed meta-analyses for intraoperative (including intraoperative bleeding, endodiathermy, iatrogenic retinal tears and
mean surgical time) and postoperative outcome parameters (including best-corrected visual acuity, recurrent vitreous
hemorrhage, reabsorption time of blood and other complications).
The authors identified six randomized controlled trials and one comparative study, which they used for comparing vitrectomy alone
(142 eyes, control group) with vitrectomy with IVB pretreatment (139 eyes). They reported that the intraoperative findings showed
that the incidence of intraoperative bleeding and frequency of endodiathermy were statistically significantly less in the IVB
pretreatment group (p<0.01) than in the vitrectomy alone group. The authors also noted that the IVB pretreatment
group took significantly less surgical time than the control group (p=0.003). Postoperative results indicated that
reabsorption time of blood was significantly shorter (p=0.04), incidence of recurrent VH was almost significantly
less (p=0.05) and final best-corrected visual acuity was significantly better (p=0.003) in the IVB group than
in the control group, they found. Furthermore, other complications, including final retinal detachment, and reoperation,
were statistically insignificant.
IVB pretreatment in vitrectomy can achieve excellent clinical outcomes for severe DR and it potentially facilitates
surgeons' maneuvers and reduces intra- and postoperative complications.
Source: Zhao LQ, Zhu H, Zhao PQ, Hu YQ. A systematic review and meta-analysis of clinical outcomes of vitrectomy
with or without bevacizumab pretreatment for severe diabetic retinopathy. Br J Ophthalmol. 2011;95(9):1216–1222.
RPE Tears Following Intravitreal Ranibizumab Injection for Neovascular AMD
To explore the association between treatment for neovascular age-related macular degeneration (AMD) and incidence and timing
of retinal pigment epithelium (RPE) tears in ranibizumab-treated patients versus control treatment, researchers
retrospectively reviewed results from 3 phase III clinical trials (ANti-VEGF antibody for the treatment of
predominantly classic CHORoidal neovascularization in age-related macular degeneration [ANCHOR], Minimally
classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular
Age-related macular degeneration [MARINA] and A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham
Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal
Choroidal Neovascularization [CNV] with or without Classic CNV Secondary to Age-Related Macular Degeneration [PIER]) to
identify patients who developed RPE tears during the study period, detected on fluorescein angiography performed at
They administered intravitreal ranibizumab (0.3 or 0.5 mg) or control treatment (verteporfin photodynamic therapy [PDT] in ANCHOR
and sham intravitreal injections in ANCHOR, MARINA and PIER) in patients with baseline and post-baseline angiographic
assessments. Main outcome measures were incidence and timing of RPE tears during the treatment period.
The researchers analyzed data from 1,298 patients and they observed no statistically significant differences in RPE tear
incidence. They observed that the pooled rate of RPE tears was 1.8% with 0.5 mg ranibizumab, 3.0% with 0.3 mg ranibizumab
and 1.6% in the control group. They identified most (76%; 16/21) RPE tears in ranibizumb-treated patients within 3 months
of initiating treatment, whereas the majority (80%; 4/5) of late-onset RPE tears occurred in control patients. In patients
who developed RPE tears, the study researchers observed better visual acuity (VA) outcomes in those treated with ranibizumab
versus control treatment.
As studied in these trials, no statistically significant differences in the incidence of RPE tears within a 2-year treatment
period were observed in patients who received ranibizumab (0.5 or 0.3 mg) versus control treatment, although most RPE tears
with ranibizumab occurred within 3 months of initiating treatment. According to the researchers, mean VA was better in patients
who developed RPE tears while receiving ranibizumab than in those who received control treatment, suggesting a potential benefit
of continued ranibizumab therapy in patients with neovascular AMD who developed RPE tears.
Source: Cunningham ET, Feiner L, Chung C, et al. Incidence of retinal pigment epithelial tears after intravitreal
ranibizumab injection for neovascular age-related macular degeneration. Ophthalmology. 2011; Aug 29 [Epub ahead of
print]. DOI: 10.1016/j.ophtha.2011.05.026.
Prognostic Implication of PED in Bevacizumab-Treated Eyes with AMD
and Choroidal Neovascularization
Investigators evaluated the response to primary bevacizumab treatment of eyes with age-related macular degeneration (AMD)
and choroidal neovascularization (CNV) with a large pigment epithelial detachment (PED) component and compared the increase
in visual acuity and reabsorption of retinal fluid in PED eyes to eyes with CNV and AMD with a minimal to no PED component.
They reviewed 43 consecutive eyes with CNV and AMD on primary bevacizumab therapy. There were 13 eyes with a large PED component
in AMD with CNV and 30 eyes with a minimal to no PED in CNV. The investigators took only patients with no previous treatment for
AMD and those started on purely intravitreal bevacizumab treatment in the study. They determined pigment epithelial detachment
size, time to PED collapse and retinal or subretinal fluid resolution as well as Early Treatment Diabetic Retinopathy Study
vision. They also compared time to resolution of intraretinal and subretinal fluid between the PED group and the non-PED group
using survival analysis.
In AMD with CNV eyes having a large PED component, sub- and intraretinal fluid initially resolved faster than the sub-PED fluid
(p=0.03). Moreover, the subretinal pigment epithelial fluid itself was highly resistant. Visual acuity improvement was
similar to both groups.
In conclusion, despite monthly intravitreal bevacizumab injections for neovascular AMD patients with a large component PED,
the majority had minimal to no response of the PED. The investigators found that sub- and intraretinal fluid response was faster
in neovascular AMD without large PEDs, but after 7 months, vision change and reabsorption of intra- and subretinal fluid were
similar in the two groups. Sub- and intraretinal fluid response did not appear to be related to PED size. Finally, bevacizumab
was very effective in reducing more of the sub- and intraretinal fluid than the PED fluid in AMD with CNV.
Source: Freeman WR, Kozak I, Yuson RM, et al. Prognostic implications of pigment epithelial detachment in bevacizumab
(Avastin)-treated eyes with age-related macular degneration and choroidal neovascularization. Retina. 2011;Aug 23
[Epub ahead of print]. DOI: 10.1097/IAE.0b013e31821987a4.
Use of Intravitreal Ranibizumab for Polypoidal Choroidal Vasculopathy with
Recurrent or Residual Exudation
The aim of the following study was to clarify the efficacy of ranibizumab for polypoidal choroidal vasculopathy in patients
with regressed polypoidal lesions after previous photodynamic therapy (PDT) applications but recurrent or residual exudation
from branching vascular network vessels.
A total of 59 eyes of 59 Japanese patients (47 men and 12 women) with polypoidal choroidal vasculopathy were retrospectively
reviewed and treatments were chosen according to the period. Of the 59 patients, 34 were treated with PDT (PDT group) and 25
were treated with intravitreal injections of ranibizumab (ranibizumab group).
In the ranibizumab group, the mean best-corrected visual acuity (BCVA) levels at baseline and 6 months were 0.27 and 0.41,
respectively, showing a significant (p<1 x 10[–5]) improvement from baseline. In the PDT group, the mean BCVA
levels at baseline and 6 months were 0.29 and 0.24, respectively, showing a significant (p<0.01) decline from baseline.
It was reported that the mean numbers of treatments at 6 months in the ranibizumab and the PDT groups were 3.6 and 1.4,
respectively. Lastly, a subretinal hemorrhage (>1 disk diameter) developed in 5 eyes in the PDT group.
In conclusion, intravitreal ranibizumab is an effective treatment for maintaining or improving visual acuity and the
anatomical changes in patients with polypoidal choroidal vasculopathy with recurrent or residual exudation from branching
vascular network vessels.
Source: Saito M, Iida T, Kano M. Intravitreal ranibizumab for polypoidal choroidal vasculopathy with recurrent
or residual exudation. Retina. 2011;31(8):1589–1597.
Identification of Risk Factors for Incidence and Progression of AMD
This population-based prospective cohort study aimed to identify risk factors for 4–year incidence and progression
of age-related macular degeneration (AMD) in adult Latinos.
Participants, aged 40 or older, from The Los Angeles Latino Eye Study (LALES) underwent standardized comprehensive
ophthalmologic examinations at baseline and at 4 years of follow up. AMD was detected by grading 30–degree stereoscopic
fundus photographs using the modified Wisconsin Age–Related Maculopathy Grading System. Multivariate stepwise logistic
regression was used to examine the independent association of incidence and progression of AMD and baseline sociodemographic,
behavioral, clinical and ocular characteristics.
Multivariate analyses revealed that older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure
(OR per 10 mmHg: 2.54; 95% CI: 1.36, 4.76) were independently associated with the incidence of any AMD. It was reported that
the same factors were associated with early AMD, soft indistinct drusen and retinal pigmentary abnormalities. Additionally,
presence of clinically diagnosed diabetes mellitus was independently associated with increased retinal pigment (OR: 1.66; 95%
CI: 1.01, 2.85) and male gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI: 1.48, 4.23).
Moreover, older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current smoking (OR: 2.85; 95% CI: 1.66, 4.90)
were independently associated with progression of AMD.
To conclude, several modifiable risk factors were associated with 4-year incidence and progression of AMD in Latinos. The
results suggest that interventions aimed at reducing pulse pressure and promoting smoking cessation may reduce incidence
and progression of AMD, respectively.
Source: Choudhury F, Varma R, McKean-Cowdin R, et al; Los Angeles Latino Eye Study Group. Risk factors for
four-year incidence and progression of age-related macular degeneration: The Los Angeles Latino Eye Study.
Am J Ophthalmol. 2011;152(3):385–395.
Drusen Extent and Foveolar Choroidal Blood Flow in AMD
To investigate the relationship between drusen extent and foveolar choroidal blood flow in nonexudative age-related
macular degeneration (AMD), scientists determined total drusen area, average druse area and total drusen number using
a computer program developed to quantify the extent of manually outlined drusen from fundus photographs of 157 patients
(239 eyes) with nonexudative age-related macular degeneration. They also used Laser Doppler flowmetry to assess
relative choroidal blood velocity (ChBVel), volume (ChBVol) and flow (ChBFlow) in the center of the fovea.
The study investigators found a significant inverse relationship between total drusen area and ChBVol or ChBFlow. They found that
for every 1-mm² increase in total drusen area, ChBVol decreased by 0.0061 arbitrary units (p=0.03) and ChBFlow
decreased by 0.23 arbitrary units (p=0.049). They also noted that average druse area was also significantly inversely
related to ChBVol and ChBFlow. For every 0.01-mm² increase in average druse area, the ChBVol decreased by 0.0149 arbitrary
units (p=0.001) and the ChBFlow decreased by 0.4951 arbitrary units (p=0.003). Adjustment for age weakened
the significant, although it remained strong for average druse area versus ChBFlow (p=0.017) and ChBVol (p=0.004).
Additionally, the computer-aided quantification of drusen used in this study showed high intra- and intergrader agreement.
According to the investigators, in patients with nonexudative AMD, there is an association between increased drusen extent
and decreased ChBVol and ChBFlow, which suggests the presence of ischemia and is possibly the reason why patients with
high-risk drusen are prone to advanced disease.
Source: Berenberg TL, Metelitsina TI, Madow B, et al. The association between drusen extent and foveolar choroidal
blood flow in age-related macular degeneration. Retina. 2011;Aug 25 [Epub ahead of print].
Macular Pigment in ARM
As the role of macular pigment (MP) in age-related maculopathy (ARM) is still not clearly understood, recent studies
have reported on variations in the spatial distribution of MP optical density (MPOD) including a secondary peak
(“ring”) in the slope of the MPOD profile. In Germany, researchers investigated in a cross-sectional manner
the presence of ring-like structures, its determinants and its relationship with ARM.
They examined 369 participants of the Muenster Aging and Retina Study using dual-wavelength analysis of autofluorescence images
and graded ARM using digital fundus photographs according to the International Classification System.
They observed a ring-like structure in 73 (19.8%) study participants, noting that the MP maximum of the ring was located
on average at 0.85° and the minimum at 0.48° from the center of the fovea. Their concordance between pairs of eyes
was highly significant. According to the researchers, MPOD measured at eccentricities of 0°, 0.25° and 0.5° from
the fovea was significantly lower in eyes with ring-like structure while it was significantly higher at 1.0° and 2.0°
than in those without the ring. Moreover, the resrachers found that ring-like structures were significantly more common in women
and never smokers and that they were found significantly less often in eyes with ARM than in healthy eyes, even after adjustment
for influential factors (adjusted odds ratio: 0.347, 95% confidence interval 0.196–0.617).
To conclude, ring-like structures in the MP spatial profile are fairly common, show a high degree of bilaterality and
appeared inversely related with ARM.
Source: Dietzel M, Zeimer M, Heimes B, et al. The ring-like structure of macular pigment in age-related
maculopathy – results from the Muenster Aging and Retina Study (MARS). Invest Ophthalmol Vis Sci. 2011;Sept 6
[Epub ahead of print]. DOI: 10.1167/iovs.11-7610.
Clinically Meaningful Threshold for Change in Uveitic Macular Edema Evaluated by OCT
Investigators in the following cross-sectional and longitudinal study attempted to identify a clinically meaningful
threshold for change in retinal thickness measured by optical coherence tomography (OCT) for patients with uveitic
macular edema using correlation with change in visual acuity.
They enrolled 128 eyes (101 individuals) with macular edema in the Multicenter Uveitis Steroid Treatment trial. At enrollment
and after 6 months of follow up, they measured retinal thickness at the central subfield with time-domain optical coherence
tomography and measured visual acuity with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts.
The investigators classified participants as having macular edema if the retinal thickness was 260 µm or more.
They found a threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives
and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity
of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or
more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared
with a –0.4-letter change (95% confidence interval, –4.1 to 3.3) in visual acuity for those without a 20%
The study investigators determined that, in addition to being above the level of measurement uncertainty, a 20% change in
retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may
be considered as an outcome for clinical trials of treatment for uveitic macular edema.
Source: Sugar EA, Jabs DA, Altaweel MM, et al; Multicenter Uveitis Steroid Treatment (must) Trial Research
Group. Identifying a clinically meaningful threshold for change in uveitc macular edema evaluated by optical
coherence tomography. Am J Ophthalmol. 2011; Aug 22 [Epub ahead of print]. DOI: 10.1016/j.ajo.2011.05.028.
Underestimation of Peripapillary RNFL Thickness in SD-OCT
Although studies using optical coherence tomography (OCT) reported that the retinal nerve fiber layer (RNFL) thickness
of myopic eyes was thinner than those of normal controls, it was unclear if this finding indicated the difference in
actual structural thickness or that created by sources affecting accuracy of OCT measurement. The aim of the following
Korean study was to evaluate the effect of refraction power on the measurement of the RNFL thickness using spectral-domain
OCT scans to measure RNFL thickness were repeated in 15 cycloplegic eyes of 15 participants, while different refraction powers
were induced by wearing soft contact lenses of eight different diopters (–6 to +8).
It was reported that measured RNFL thicknesses decreased significantly with soft contact lenses of higher plus diopters and
increased with those of more minus diopters. This finding was consistent with or without controlling factors including the
signal strength and test-retest variability of the machine. Measurement of peripapillary RNFL thicknesses was not varied between
scans performed with and without plano contact lenses.
In SD-OCT, RNFL thickness was underestimated in eyes with increasing negative refraction power and overestimation with
increasing positive refraction power.
Source: Lee J, Kim NR, Han J, et al. Negative refraction power causes underestimation of peripapillary retinal
nerve fibre layer thickness in spectral-domain optical coherence tomography. Br J Ophthalmol.
False Positives in RNFL Color Codes from SD-OCT
The authors of the following prospective, cross-sectional Korean study sought to determine the factors that contribute
to false-positive retinal nerve fiber layer (RNFL) color code results from spectral-domain optical coherence tomography (OCT).
They included 149 eyes from 77 healthy participants who were consecutively enrolled from June 2009 to December 2009.
The participants underwent Cirrus OCT and recorded demographic and clinical factors included age, gender, eye side,
intraocular pressure, central corneal thickness, spherical equivalent, axial length, anterior chamber depth, disc area and
the extent of retinal vasculature. The authors defined an abnormal finding in RNFL color codes as ≥ 1 yellow or red sectors
by quadrant and clock-hour maps and a wedge-shaped color pattern represented by yellow or red in the deviation map. The incidence
of false-positive color codes was determined and the influence of clinical and demographic factors on the incidence of
false-positive RNFL color codes was assessed using generalized linear mixed model analysis.
The authors reported that the false-positive rate for ≥1 of the quadrant, clock-hour and deviation maps was 26.2% and
that longer axial length and smaller disc area were significantly associated with an increased incidence of false-positives when
other factors were controlled (odds ratios, 2.422 and 0.165; p=0.008 and 0.035, respectively).
The factors that significantly affected the false-positive RNFL color code results using spectral-domain OCT were axial length
and disc area, which may significantly affect the specificity of spectral-domain OCT. Therefore, axial length and disc area should
be considered during RNFL thickness profile analysis.
Source: Kim NR, Lim H, Kim JH, et al. Factors associated with false positives in retinal nerve fiber layer color
codes from spectral-domain optical coherence tomography. Ophthalmology. 2011;118(9):1774–1781.