Volume 7, Number 11
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.
Resolved Retinal Fluid Following Intravitreal Ranibizumab for PCV
This Japanese study investigated the predictive factors for the resolution of retinal fluid after intravitreal injections of ranibizumab
(IVRs) for polypoidal choroidal vasculopathy (PCV).
A total of 47 eyes of 45 patients with symptomatic PCV received 0.5 mg of IVR monthly for 3 months. One month after the third IVR, the presence
of dry macula, defined as absence of retinal fluid as detected by the use of optical coherence tomography (OCT), was retrospectively evaluated
and correlated with clinical characteristics at baseline. Most of the eyes were followed for more than 6 months.
Of the 47 eyes, 31 eyes (66%) achieved the dry macula along with increased best-corrected visual acuity (BCVA) (0.64 to 0.46 logarithm of
the minimum angle of resolution (logMAR) units, p<0.0001), while the other 16 eyes without dry macula showed no significant change of
BCVA. It was noted that univariate analyses of the baseline characteristics identified the smaller size of the largest polyp (p=0.0008) and
the absence of serous or hemorrhagic pigment epithelial detachment (p=0.045) as predictive factors for the dry macula. Multivariate
logistic regression found the independent predictor for the dry macula to be the smaller size of the largest polyp (p=0.001). Furthermore,
no severe systemic or ocular adverse events were observed.
IVR may be helpful for resolution of retinal fluid and increased BCVA in the short term, but larger polyps and pigment epithelial detachments
at baseline may be negative prognostic factors for a therapeutic response. Further studies are needed to clarify the long-term efficacy of IVR for PCV.
Source: Koizumi H, Yamagishi T, Yamazaki T, Kinoshita S. Predictive factors of resolved retinal fluid after intravtireal ranibizumab
for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2011;95(11):1555–1559.
Association of Elastin Gene Polymorphism to AMD and Polypoidal Choroidal Vasculopathy
In Japan, investigators genotyped five single nucleotide polymorphisms (SNPs), rs2301995, rs2856728, rs868005, rs884843 and rs13239907 at
Kyoto University and Saitama Medical University to determine whether an association exists in Japanese between elastin gene polymorphisms
and neovascular age-related macular degeneration (AMD) or its subtypes: typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV).
They performed a case-control study on 1,296 patients with AMD and 478 controls.
They detected a statistically significant association between the rs2301995 SNP and AMD (p=0.018). The investigators reported that
subtype analysis revealed a significant association of rs2301995 with tAMD (p=0.0018), but not with PCV. They noted that the genotype
distribution of rs2301995 also differed significantly between tAMD and PCT (p=0.00030). They also found that the trend in genotype
distribution of rs2301995 was similar between the Kyoto and the Saitama studies. Additionally, the A allele frequency was higher in tAMD while it
was similar in PCV and in controls, which is opposite to a previous report that A allele frequency is higher in PCV while it is similar in tAMD
and in controls. Haplotype analysis also showed that elastin gene polymorphism is significantly associated with tAMD (p=0.0055), but not
The elastin gene is associated with AMD in Japanese. The investigators' findings suggest that the elastin gene is a susceptibility gene for
tAMD but not for PCV, which is opposite to a previous report that the elastin gene is the susceptibility gene for PCV but not for tAMD.
Source: Yamashiro K, Mori K, Nakata I, et al. Association of elastin gene polymorphism to age-related macular degeneration and
polypoidal chroidal vasculopathy. Invest Ophthalmol Vis Sci. 2011;Oct. 14 [Epub ahead of print]. DOI : 10.1167/iovs.11-8205.
Evaluation of Type 2 CNV Using SD-OCT, ICGA AND FA
In an observational case series, Austrian scientists evaluated the diagnostic characteristics of type 2 (classic) choroidal neovascularizations
(CNVs) secondary to age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT), indocyanine green
angiography (ICGA) and fluorescein angiography (FA).
Included in this study were 13 treatment-naïve eyes with type 2 CNV without an occult component. Main outcome measures were greatest
horizontal dimension, based on the anatomic features of the neosvacular complex by SD-OCT (Spectralis; Heidelberg Engineering), ICGA and FA;
retinal leakage area in late-phase FA and ICGA; and the area of retinal edema in SD-OCT. For direct comparison, the scientists manually overlaid
ICGA and FA images on infrared plus SD-OCT images using VirtualDub and Paint.NET software. They measured greatest horizontal dimension using Image
J software (National Institutes of Health).
The study scientists found that the mean greatest horizontal dimension of the neovascular complex and the retinal leakage area consistently were
smaller on ICGA compared with the area of retinal edema on SD-OCT. According to the FA, the greatest horizontal dimension of early,
well-demarcated hyperfluorescence was significantly smaller than the neovascular complex on SD-OCT. Furthermore, the greatest horizontal dimension
of the retinal leakage area in late-phase FA consistently was smaller than the area of retinal edema on SD-OCT.
In classic CNV, ICGA and FA seem to underestimate the extension of the neovascular complex and the associated retinal pathologic features compared
with SD-OCT imaging.
Source: Sulzbacher F, Kiss C, Munk M, et al. Diagnostic evaluation of type 2 (classic) choroidal neovascularization: optical
coherence tomography, indocynanine green angiography, and fluorescein angiography. Am J Ophthalmol. 2011;152(5):799–806.
Enhancing Cell Survival on Bruch's Membrane in Eyes Affected by Age and AMD
Retinal pigment epithelium (RPE) derived from human embryonic stem cells (hES-RPE) and cultured fetal and aged adult RPE were seeded onto
the inner collagenous layer of submacular Bruch's membrane (BM)-choroid-sclera explants generated from aged and age-related macular
degeneration (AMD) human donor eyes to determine whether conditioned medium (CM) derived from bovine corneal endothelial cells (BCEC) can
support transplanted cells on aged and AMD BM.
Paired explants were cultured in BCEC-CM or vehicle. Explants were harvested after 21 days in culture to assess cell behavior after attachment to
BM was established. To assess whether sustained exposure to BCEC-CM was necessary for improved cell survival on BM, short exposure to BCEC-CM
(3,7,14 days) was compared to 21-day exposure. Additionally, explants were harvested and evaluated by scanning electron (SEM) and light microscopy
and extracellular matrix (ECM) deposition after exposure to BCEC-CM was evaluated following RPE removal after day-21 on tissue culture dishes or
It was determined that BCEC-CM significantly enhanced hES-RPE, fetal RPE and aged adult RPE survival on BM, regardless of submacular pathology.
While shorter BCEC-CM exposure times showed significant improvement in cell survival compared to culture in CM vehicle, longer BCEC-CM exposure
times were more effective. Moreover, it was reported that BCEC-CM increased RPE ECM deposition on tissue culture plastic and on BM.
The results of this study indicate that RPE survival is possible on AMD BM and offer a method that could be developed for enhancing transplanted
cell survival on AMD BM. Increased ECM deposition may account for improved cell survival following culture in BCEC-CM.
Source: Sugino IK, Rapista A, Sun Q, et al. A method to enhance cell survival on Bruch’s membrane in eyes affected by age and
age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2011;Oct. 28 [Epub ahead of print]. DOI: 10.1167/iovs.11-8400.
Anti-VEGF Monotherapy vs. Combination Treatment with PDT for Subfoveal CNV Secondary to Causes Other than AMD
To compare the visual outcomes and retreatment rates of monotherapy with intravitireal bevacizumab versus combination with photodynamic
therapy (PDT) for choroidal neovascularization (CNV) secondary to causes other than age-related macular degeneration (AMD),
researchers administered intravitreal bevacizumab to 17 patients and intravitreal bevacizumab combined with verteporfin PDT to 6 patients
within 3 days. They administered additional bevacizumab if there was persistent fluorescein leakage or subretinal fluid on optical
coherence tomography (OCT).
According to the researchers, the mean change in visual acuity was vision gain of 1.7 lines in the monotherapy group compared with 2.8 lines
in the combination therapy group at 12-month follow up (p=0.45). They noted that at 12 months, 93% in the monotherapy group and 100%
in the combination group lost <2 lines of vision (p=1.0); 36% gained >3 lines of vision in the monotherapy compared with 60%
in the combination therapy group (p=0.60). The monotherapy group received a mean of 4.8 reinjections, while the combination group received
2.6 reinjections over 12 months (p=0.11). The study researchers also reported that a subgroup analysis of cases of CNV caused by
pathologic myopia demonstrated a mean change in visual acuity of vision gain of +2.0 lines in the monotherapy group versus +2.3 lines in the
combination therapy group (p=0.82) and a mean of 7.2 reinjections versus 2 in monotherapy and combination group, respectively
(p=0.0498) at 12 months.
They found that the majority of patients had stabilization or improvement in vision in both treatment groups and that combination therapy
with bevacizumab plus PDT showed lower retreatment rates in patients with myopia. According to the researchers, randomized clinical trials
are necessary to confirm these findings.
Source: Chen L, Miller JW, Vavvas D, Kim IK. Anti-vascular endothelial growth factor monotherapy versus combination treatment
with photodynamic therapy for subfoveal choroidal neovascularization secondary to causes other than age-related macular degeneration.
Low-Fluence PDT vs. Intravitreal Ranizibumab for Chronic CSC
The following prospective, randomized, single-center pilot study in Korea reported 6-month outcomes of a prospective, randomized study comparing
the efficacy and safety between low-fluence photodynamic therapy (PDT) and intravitreal injections of ranibizumab in the treatment of chronic
central serous chorioretinopathy (CSC).
A total of 16 eyes with chronic CSC were randomized to receive either low-fluence PDT or intravtireal injections of ranibizumab: 8 eyes in
the low-fluence PDT group and 8 in the ranibizumab group. Rescue treatment was considered if subretinal fluid was sustained after completion
of primary treatment: low-fluence PDT for the ranibizumab group and ranibizumab injection for the low-fluence PDT group. Main outcome measures
were excess foveal thickness, resolution of subretinal fluid, choroidal perfustion on indocyanine green angiography and best-corrected visual acuity.
At 3 months, the mean excess foveal thickness was reduced from 74.1 ± 56.0 µm to –35.4 ± 44.5 µm in the low-fluence PDT group
(p=.017) and from 26.3 ± 50.6 µm to –23.1 ± 56.5 µm in the ranibizumab group (p=.058). After a single session
of PDT, it was noted that 6 eyes (75%) in the low-fluence PDT group achieved complete resolution of subretinal fluid and reduction of
choroidal hyperpermeability, whereas 2 (25%) eyes in the ranibizumab group achieved this after consecutive ranibizumab injections. It was
also reported that four eyes (50%) in the ranibizumab group underwent additional low-fluence PDT and accomplished complete resolution.
At 3 months, significant improvement of best-corrected visual acuity (BCVA) was not demonstrated in the low-fluence PDT group (p=.075),
whereas it was observed in the ranibizumab group (p=.012). However, the tendency toward improvement to BCVA was not maintained.
To conclude, in terms of anatomic outcomes, the effect of ranibizumab injections was not promising compared with that of low-fluence PDT.
Source: Bae SH, Heo JW, Kim C, et al. A randomized pilot study of low-fluence photodynamic therapy versus intravitreal ranibizumab
for chronic central serous chorioretinopathy. Am J Ophthalmol. 2011;152(5):784–792.
Link Between Efficacy of Half-Dose PDT with ICGA and OCT Findings in the Treatment of CSC
The authors of this Italian observational case series sought to determine the efficacy of half-dose photodynamic therapy (PDT) in relation
to indocyanine green angiography (ICGA) and optical coherence tomography (OCT) findings for treating chronic central serous chorioretinopathy (CSC).
They recruited 38 eyes of 37 patients with chronic CSC and symptoms for at least 6 months and performed PDT using half the normal dose of
verteporfin. The authors noted that a total light energy of 50 J/cm² over 83 seconds was delivered to the area of choroidal hyperfluorescence
as observed on ICGA. They assessed the resolution of the subretinal fluid and recurrence rates in relation to the different degrees of
choroidal hyperfluorescence and the distribution of fluid in the neuroepithelium, namely subretinal fluid or posterior retinal cystoid degeneration.
The study authors reported that after half-dose PDT, a dry macula was obtained in 86.8% and 92.1% of the eyes at 1 month and at the
last follow-up (14.2 ± 5.8 months) respectively. They observed that ICGA at baseline showed intermediate and intense hyperfluorescence in
39.4% and 60.5% of the eyes respectively. Also, that all eyes with intermediate hyperfluorescence had only subretinal fluid at OCT and a
dry macula was obtained in 87% and 100% at 1 month and at the last follow-up after half-dose PDT. In the intense hyperfluorescence group,
the authors found that 82.6% and 17.4% of the eyes had subretinal fluid only or both subretinal fluid and posterior retinal cystoid
degeneration respectively. They noted that in the intense hyperfluorescence group with subretinal fluid only, a dry macula was obtained in 89.5%
and 100% of the eyes at 1 month and at the last follow-up respectively. In the intense hyperfluorescence group with both subretinal fluid
and posterior retinal cystoid degeneration, a dry macula was obtained in 75% and 25% of the eyes at 1 month and at the last
follow-up respectively. Overall, of the 23 eyes with intense hyperfluorescence, 20 eyes (87%) had a dry macula starting from 1 month for
the entire follow-up period.
The half-dose PDT success rate in eyes with chronic CSC depends also on the distribution of fluid in the neuroepithelium, the authors
concluded. Half-dose PDT might not be effective or the recurrence rate might be high in eyes with posterior retinal cystoid degeneration.
Source: Nicolò M, Zoli D, Musolino M, Traverso CE. Association between the efficacy of half-dose photodynamic therapy with
indocyanine green angiography and optical coherence tomography findings in the treatment of central serous chorioretinopathy.
Am J Ophthalmol. Oct. 24 [Epub ahead of print]. DOI: 10.1016/j.ajo.2011.08.015.
Relationship Between Photopsias, Perceived Stress and Positive Mood in RP
Researchers measured the relationship between the occurrence of photopsias (spontaneous phosphenes) and retinitis pigmentosa (RP) subjects' level
of vision, light exposure and psychosocial factors to attempt to confirm RP patients' previous reports of these associations.
A total of 36 RP subjects self-administered PC-based binocular visual acuity, contrast sensitivity and visual field tests at home twice a week, for
16 session in 2–3 months and after each session, subjects reported photopsias during the vision tests and completed questionnaires: Scale, and
Positive and Negative Affect Schedules.
The study researchers found that across all subjects, photopsias occurred during 47% of sessions. They noted that five (14%) subjects
never noted photopsias, while five others noted photopsias at every session. Two-thirds of subjects experienced photopsias frequently (>20%
of sessions). On average, the odds of noticing photopsias increased by 57% for every 1-point increase in mean perceived stress
(OR=1.57; 95% CI: 1.04, 2.4; p=0.03) or reduced by 38v for every 1-point increase in positive mood (OR=0.62; 95% CI: 0.39,
0.98; p=0.04), after adjusting for age, gender and vision. Similarly, the odds of experiencing photopsias during a session increased by
16% for every 3-point increase in perceived stress and decreased by 17% for every 3-point increase in positive mood, after adjusting
for age and gender (OR=1.16; 95% CI: 1.01, 1.33; p=0.048) (OR=0.83; 95% CI: 0.73, 0.94; p=0.004), respectively. The
researchers reported that frequency of photopsias was not statistically significantly related to other factors measured.
Increased photopsias appear to be related to times when subjects report increased perceived stress and/or decreased positive mood, rather
than RP patients' age, level of vision, reported light exposure or sleepiness.
Source: Bittner AK, Haythornthwaite JA, Diener-West M, Dagnelie G. Photopsias are related in part to perceived stress and positive
mood in retinitis pigmentosa. Eye. 2011; Oct. 14 [Epub ahead of print]. DOI: 10.1038/eye.2011.247.
Evaluation of Vascular Disease Progression of ROP
U.S. investigators measured accuracy and speed for detection of vascular progression in retinopathy of prematurity (ROP) from serial images
in this prospective comparative study. They compared two strategies: static side-by-side presentation and dynamic flickering of superimposed
They took 15 de-identified, wide-angle retinal image pairs from infants who eventually developed plus disease. They also took image pairs
representing vascular disease progression ≥1 week apart and control images without progression on the same day and also created dynamic
flickering pairs by digital image registration. Ten experts independently reviewed each image pair on a secure website using both strategies
and were asked to identify progression or state that images were identical. The investigators measured accuracy and speed using examination date
and ophthalmoscopic findings as a reference standard.
They determined that experts were accurate in a mean (%) ± standard deviation (SD) of 11.4 of 15 (76%) ± 1.7 image pairs using
static images and that using dynamic flickering images, experts were accurate in a mean (%) ± SD of 11.3 of 15 (75%) ± 1.7
image pairs. The investigators found no significant difference in accuracy between these strategies (p=.420). They noted that diagnostic
speed was faster using dynamic flickering (24.7 ± 8.3 seconds) vs static side-by-side images (40.3 ± 18.3 seconds) (p=.002).
Experts reported higher confidence when interpreting dynamic flickering images (p=.001).
The study investigators found that retinal imaging provides objective documentation of vascular appearance, with potentially improved ability
to recognize ROP progression compared to standard ophthalmoscopy. Speed of identifying vascular progression was faster by review of dynamic
flickering image pairs than by static side-by-side images, although there was no difference in accuracy.
Source: Myung JS, Gelman R, Aaker GD, et al. Evaluation of vascular disease progression of retinopathy of prematurity using static
and dynamic retinal images. Am J Ophthalmol. 2011;Oct. 24 [Epub ahead of print]. DOI: 10.1016/j.ajo.2011.08.030.
A Look at Macular Microcirculation in Patients with Epiretinal Membrane Before and After Surgery
The authors of the following Japanese study investigated blood flow velocity (BFV) in the perifoveal capillaries before and after vitreous
surgery for patients with epiretinal membrane (ERM).
They included 21 eyes in patients with ERM and 16 eyes in healthy subjects and performed fluorescein angiography using a scanning laser
ophthalmoscope. They also analyzed BFV by the tracing method and measured foveal thickness (FT) by optical coherence tomography (OCT).
The authors reported that BFV was significantly slower in the ERM patients (1.04 ± 0.10 mm/s) than in the healthy subjects (1.49 ± 0.11
mm/s) (p=0.0010). They noted that BFV in the ERM patients 6 months after vitreous surgery (6 m) (1.21 ± 0.02 mm/s) significantly
increased compared with BFV before surgery (0 m) (1.04 ± 0.10 mm/s) (p=0.0061). BFV 1 year after vitreous surgery (1 y)
significantly increased (1.38 ± 0.02 mm/s) compared with BFV (6 m) (1.21 ± 0.02 mm/s) (p=0.0235). According to the authors,
FT was significantly greater in the ERM patients (351.7 ± 87.1 µm) than in the healthy subjects (158.9 ± 16.9 µm)
(p=0.0011). They found that FT (6 m) significantly decreased (285.3 ± 36.9 µm) compared with FT before surgery (0 m)
(351.7 ± 87.1 µm) (p=0.0212). FT did not show significant differences between (6 m) and (1 y). No significant correlation
was found between BFV and FT before surgery.
In conclusion, perifoveal capillary BFV in patients with ERM was slower than that in the healthy subjects, and significantly improved after
vitreous surgery as time progressed. It can be said that perifoveal capillary BFV is related to the development and improvement of ERM in the long term.
Source: Yagi T, Sakata K, Funatsu H, et al. Macular microcirculation in patients with epiretinal membrane before and after surgery.
Graefes Arch Clin Exp Ophthalmol. 2011; Oct. 15 [Epub ahead of print]. DOI: 10.1007/s00417-011-1838-y.
Retinal Vessel Caliber in Patients with AIDS
In this longitudinal, observational cohort study, researchers evaluated relationships between retinal vessel caliber and tests of visual
function among people with AIDS. They found that variation in retinal vascular indices is associated with abnormal visual function in
people with AIDS, manifested by visual field loss and possibly by reduced contrast sensitivity (CS).
They evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the
Ocular Complications of AIDS (1998–2008). They also evaluated visual function with best-corrected visual acuity (BCVA), Goldmann
perimetry, automated perimeter and CS testing. The researchers noted that semi-automated grading of fundus photographs (1 eye/participant)
determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE) and arteriole-to-venule ratio (AVR) at baseline.
Multiple linear regression models, using forward selection, sought independent relationships between indices and visual function variables.
A total of 1,250 participants were included and the researchers noted that smaller AVR was associated with reduced visual field by Goldmann perimetry
(p=.003) and worse mean deviation (p=.02) on automated perimetry and possibly with worse pattern standard deviation (PSD) on
automated perimetry (p=.06). They found that there was a weak association between smaller AVR and worse CS (p=.07). The study
researchers also reported that relationships were independent of antiretroviral therapy and level of immunodeficiency (CD4+ T lymphocyte count,
human immunodeficiency virus [HIV] RNA blood level. They observed that on longitudinal analysis, retinal vascular indices at baseline did not
predict changes in visual function.
They concluded that relationships are consistent with the hypothesis that HIV-related retinal vasculopathy is a contributing factor to
vision dysfunction among HIV-infected individuals and that longitudinal studies are needed to determine whether changes in indices predict change
in visual function.
Source: Kalyani PS, Fawzi AA, Gangaputra S, et al. Retinal vessel caliber among people with acquired immunodeficiency
syndrome: relationships with visual function. Am J Ophthalmol. 2011;Oct. 24 [Epub ahead of print].