Volume 7, Number 12
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.
The Incidence of RPE Tears Following Intravitreal Ranibizumab Injection for Neovascular AMD
Investigators explored the association between treatment for neovascular age-related macular degeneration (AMD) and
incidence and timing of retinal pigment epitheilium (RPE) tears in ranibizumab-treated patients versus control treatment.
They 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 prespecified intervals.
Participants included patients with baseline and post-baseline angiographic assessments who received 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). Main outcome measures included incidence and timing of RPE tears during the treatment period.
The study investigators analyzed data from 1,298 patients and observed no statistically significant differences in RPE
tear incidence. They reported 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. The investigators also noted that most (76%; 16/21) RPE tears
in ranibiuzmab-treated patients were identified 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, better visual acuity (VA) outcomes
were observed 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. Additionally, 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. Ophthlamol.
Outcomes After Three-Line Vision Loss During Treatment of Neovascular AMD
Researchers in this study assessed the impact of continued ranibizumab treatment for neovascular age-related
macular degeneration (AMD) on patients from the MARINA and ANCHOR randomized clinical studies who lost ≥3 lines
of best-corrected visual acuity (BCVA) at any time during the first year of treatment.
They evaluated baseline characteristics, mean BCVA over time and ocular adverse events (AEs) both for patients whose BCVA
loss occurred at any post-baseline visit and for patients whose BCVA loss was acute. They defined the visit when the ≥3-line
BCVA loss was detected as the new baseline.
According to the researchers, continued monthly ranibizumab treatment led to an improvement in mean BCVA from the new baseline
and on average, patients with acute BCVA loss gained 11.9 letters at 3 months after the new baseline, compared with 0.3
letters gained with sham. They detected no strong signals in patient demographics and baseline characteristics for prognostic
markers of BCVA loss. Furthermore, they found no pattern in the AE profile of patients with acute BCVA loss to suggest that
BCVA recover could be attributed to spontaneously resolving AEs.
Continued ranibizumab treatment appears to be beneficial for patients with neovascular AMD who experience a ≥3-line BCVA
loss during the first year of treatment.
Source: Wolf S, Holz FG, Korobelnik JF, et al. Outcomes following three-line vision loss during treatment of
neovascular age-related macular degeneration: subgroup analyses from MARINA and ANCHOR. Br J Ophthalmol.
Evaluation of Retinal and Choroidal Thickness in Early AMD
The following cross-sectional study was conducted in the UK to compare retinal thickness and choroidal thickness at
increasing retinal eccentricity in individuals with early age-related macular degeneration (AMD) and in healthy controls
using enhanced choroidal penetration, 3-dimensional optical coherence tomography (OCT) at 1060 nm.
Individuals with early AMD (n=16; mean age, 71.6 ± 8.5 years) and a comparison group of healthy controls
(n=16; 67.6 ± 5.4 years) were recruited and three-dimensional (20° x 20°) long-wavelength optical coherence
tomography (1060 nm) images (approximately 8-µm axial resolution; 47,000 A scans/second, centered on the fovea) were
obtained from all participants after pupil dilation. Additionally, retinal thickness was measured between the inner limiting
membrane and the retinal pigment epithelium and choroidal thickness was measured between the retinal pigment epithelium and
the choroid-scleral interface. Thickness measurements were obtained subfoveally and at 0.5-mm intervals to a maximum of
2.0 mm nasally, temporally, superiorly and inferiorly. The main outcome measures were retinal and choroidal thickness (measured
in micrometers) at different eccentricities on vertical and horizontal meridians.
It was reported that mean retinal thickness was reduced significantly in the group of participants with early AMD compared with
the control group at multiple locations within 2.0 mm of the fovea. This difference was most significant at the fovea, where
the mean retinal thickness of the early AMD group was 179 ± 27 µm and that of the control group was 202 ±
18 µm (p=.008). No significant difference in choroidal thickness between groups at any location was observed.
To conclude, retinal thickness is reduced in early AMD, but choroidal thickness seems to be unaffected by the early disease process.
Source: Wood A, Binns A, Margrain T, et al. Retinal and choroidal thickness in early age-related macular
degeneration. Am J Ophthalmol. 2011;152(6):1030–1038.
Copy Number Polymorphism and AMD Risk
Researchers previously identified a genetic copy number polymorphism (CNP147) that was statistically associated
with age-related macular degeneration (AMD) and that resides downstream of the complement factor H (CFH) gene.
(Factor H protein is polymorphic at amino acid 402, in which the resulting histidine containing moiety has been established
to impart significant risk of AMD.) In this case-control study, the researchers present a method to precisely determine
the exact copy number of CNP147 and examine in more detail the association with AMD.
Participants included 421 Age-Related Eye Disease Study (AREDS) subjects, of whom approximately 35% were diagnosed
with neovascular disease, 19% were diagnosed with geographic atrophy, 16% were diagnosed with both, 30% were
diagnosed with large drusen and 215 were controls. By using copy number assays available from Applied Biosystems Inc., the
study researchers examined 4 loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. They
analyzed these data by copy number while controlling for 2 high-risk CFH variants, rs1061170 (Y402H) and rs1410996.
They also phased the high-risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To
further validate copy numbers, the researchers typed 6 Utah Centre D'etude du Polymorphism Humaine (CEPH) families for
CNP147, and assessed the segregation. Main outcome measures were increased or decreased risk of AMD from genetic loci.
They found that having fewer than 2 copies of CNP147 was associated with an estimated 43% reduction in odds of having AMD
in this sample set (adjusted odds ratio [OR]=0.57, p=0.006). CNP148 variation is rare in Caucasians and was not
statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate
with higher copy numbers for CNP147, but not exclusively, and that 1 haplotype that carried a deletion of CNP147 was
highly protective (OR=0.25 p=1.3x10–13) when compared with the reference.
According to these researchers, in this matched subset of AREDS subjects, after adjusting for 2 known risk variants in
CFH, CNP147 deletion statistically associates with diminished risk for AMD.
Source: Sawitzke J, Im KM, Kostiha B, et al. Association assessment of copy number polymorphism and risk of
age-related macular degeneration. Ophthalmol. 2011;118(12):2442–2446.
New and Established AMD Susceptibility Genes in Women
The authors of this multicenter case-control study assessed whether established and newly reported genetic variants,
independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among
women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study.
A total of 146 women with intermediate and late stages of AMD and 1,269 subjects without AMD underwent ocular examinations
and fundus photography to determine stage of AMD. Using logistic regression analysis, the study authors assessed 14 polymorphisms
at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3 and CFI; recently reported AMD genes in
the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP and LPL; TIMP3/SYN3, a known ocular gene recently
linked with AMD; and APOE.
After adjusting for demographic, behavioral and other genetic factors, the authors detected a protective effect among TT
carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95%
confidence interval]: 0.3 [0.2–0.7], p=.003). They determined that variants in CFH rs1410996, ARMS2/HTRA1 A69S
and C3 R102G were significantly associated with an increased risk of AMD. They also noted that individuals with the homozygous
CFI rs10033900 TT genotype had a 2.9 [1.2–7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2
[1.0–4.8]-fold higher risk of developing AMD compared with non-carriers. The authors believe that APOE4 carriers may have
a reduced risk of intermediate/late AMD (OR = 0.5 [0.3–0.9], p=.015. They also saw suggestive associations between
AMD and the HDL pathway genes CETP and LPL.
In this unique national cohort of women, the study authors found associations with established AMD-related genetic factors and
the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or
delay the onset of the disease.
Source: Peter I, Huggins GS, Ordovas JM, et al. Evaluation of new and established age-related macular
degeneration susceptibility genes in the Women's Health Initiative Sight Exam (WHI-SE) Study.
Am J Ophthalmol. 2011;152(6):1005–1013.
Prognostic Factors for Visual Outcome Following Intravitreal Anti-VEGF Injection for Naïve Myopic CNV
The investigators of this study aimed to evaluate the prognostic factors of visual outcome after intravitreal
anti-vascular endothelial growth factor (anti-VEGF) injection in patients with myopic choroidal neovascularization (CNV).
They retrospectively reviewed 40 eyes of 40 consecutive patients with myopic CNV who had received intravitreal ranibizumab
or bevacizumab injections. They also evaluated baseline visual acuity, presence of lacquer crack, dark rim, peripapillary
choroidal atrophy size and location of myopic CNV using fluorescein angiography and indocyanine green angiography.
The investigators reported that the logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) at
12 months after treatment was 0.23 ± 0.28, and there was a significant improvement compared with the baseline BCVA
(p=0.001). After multiple linear regression analysis, they found that baseline BCVA, presence of lacquer crack extending
the fovea and peripapillary choroidal atrophy size were the factors that significantly correlated with BCVA at 12 months
(p=0.001, p=0.04 and p=0.04). They also observed that for mean change in BCVA over 12 months, there were
noted significant correlations with baseline BCVA, lacquer crack extension to the fovea and peripapillary choroidal atrophy size
(p=0.001, p=0.03 and p=0.03). The mean number of anti-VEGF injections was 2.8 ± 2.0 over 12 months.
The study investigators noted complete resolution of myopic CNV in 22 eyes (55.0%) after initial first injection, and
no additional treatment was required in 12 eyes (30%).
They concluded that better baseline BCVA, lacquer crack extension to the fovea and peripapillary atrophy were negative
prognostic factors of visual acuity improvement, and there was quite a promising result of anti-VEGF treatment in patients
with myopic CNV.
Source: Yoon JU, Kim YM, Lee SJ, et al. Prognostic factors for visual outcome after intravitreal anti-VEGF
injection for naïve myopic choroidal neovascularization. Retina. 2011;Nov.16 [Epub ahead of print].
Intravitreal Bevacizumab Injection for the Treatment of Primary DME
To compare intravitreal bevacizumab (IVB) injection versus macular photocoagulation (MPC) or a combination of
intravitreal bevacizumab and intravitreal triamcinolone acetonide (IVB/IVTA) injection in improving visual acuity (VA) of
patients with primary diabetic macular edema (DME), the authors of this study searched the following databases: Medline
(1950 – December week 3, 2009), The Cochrane Library (Issue 4, 2009), EMBASE (up to 24 December 2009), and the TRIP
database (up to 23 December 2009), using no language or other limits. They also included randomized controlled trials that
consisted of patients with primary DME (not with refractory DME), those comparing IVB injection with MPC or IVB/IVTA injection,
those reporting VA outcomes and those having a minimum follow-up of 6 weeks.
In the four randomized clinical trials comparing IVB injection with MPC, the authors found that IVB injection
demonstrated significantly greater improvement in VA at 6 weeks, but not at 12 weeks. They also reported that in the three
randomized clinical trials comparing IVB injection with IVB/IVTA, IVB injection demonstrated greater improvement in VA at
6 weeks but the benefit was again no longer significant at 12 weeks. Moreover, no adjunctive effect of IVTA was demonstrated.
The study authors determined that IVB injection is effective in improving VA in patients with primary DME for 6 weeks,
but the benefits are no longer present 12 weeks following the injection.
Source: Yilmaz T, Cordero-Coma M, Gallagher MJ, Teasley LA. Systemic review of intravitreal bevacizumab
injection for treatment of primary diabetic macular oedema. Acta Ophthalmol. 2011;89(8):709–717.
12-Month Results of Dexamethasone Intravitreal Implant in Patients with
ME Related to BRVO or CRVO
Scientists evaluated the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over
12 months in eyes with macular edema (ME) owing to branch or central retinal vein occlusion (BRVO or CRVO, respectively).
Their two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase
followed by a 6-month open-label extension. They included 1,256 patients with vision loss owing to ME associated with BRVO or CRVO.
According to the scientists, patients received DEX implant 0.7 mg (n=421), DEX implant 0.35 mg (n=412) or sham (n=423) in the
study eye at baseline. At day 180, they could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84
letters or retinal thickness was >250 µm. The primary outcome for the open-label extension was safety; BCVA was
At day 180, 997 patients received open-label DEX implant, the study scientists noted. They reported that except for cataract,
the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. They also found
that over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg
injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88
(1.1%) eyes, respectively.
The scientists noted a ≥10-mmHg IOP increase from baseline in the group receiving two 0.7-mg DEX implants (n=341; in
12.6% of patients after the first treatment and 15.4% after the second). The IOP increases were usually transient
and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after
the second treatment. A ≥15-letter improvement in BCVA from baseline was achieved by 30%and 32% of patients 60 days
after the first and second DEX implant, respectively.
Among patients with ME owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over
12 months, the scientists determined. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety
of the 2 implants were similar with the exception of cataract progression.
Source: Haller JA, Bandello F, Belfort, et al; Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant
in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results.
Structure of Outer Retina in Patients with Acute Zonal Occult Outer Retinopathy
The following observational case series sought to correlate visual function with high-resolution images of retinal structure
using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 4 patients with acute zonal occult outer retinopathy (AZOOR).
Four women, aged 18 to 51, with acute focal loss of visual field or visual acuity, photopsia and minimal funduscopic changes
were studied with best-corrected visual acuity (BCVA), Goldmann kinetic and automated perimetry and fundus-guided
microperimetry, full-field and multifocal electroretinography (ffERG and mfERG), spectral-domain optical coherence
tomography (SD-OCT) and AOSLO imaging. Cone spacing was measured in 4 eyes and compared with 27 age-similar normal eyes
and additional functional testing in 1 patient suggested that cones were absent but rods remained. Additionally, serum from
all patients was analyzed for anti-retinal antibody activity.
In all patients, vision loss was initially progressive, then stable. It was noted that symptoms were unilateral in 2 and
bilateral but asymmetric in 2 patients and that, in each patient, loss of retinal function correlated with structural changes
in the outer retina. It was also reported that AOSLO showed focal cone loss in most patients, although in 1 patient with
central vision loss, such change was absent. In another patient, structural and functional analyses suggested that cones
had degenerated but rods remained. Furthermore, anti-retinal antibody activity against a ~45 kd antigen was detected in
1 of the patients; the other 3 patients showed no evidence of abnormal anti-retinal antibodies.
To conclude, focal abnormalities of retinal structure correlated with vision loss in patients with AZOOR. High-resolution imaging
can localize and demonstrate the extent of outer retinal abnormality in AZOOR patients.
Source: Mkrtchyan M, Lujan BJ, Merino D, et al. Outer retinal structure in patients with acute zonal occult
outer retinopathy. Am J Ophthalmol. 2011;Nov. 21 [Epub ahead of print]. DOI : 10.1016/j.ajo.2011.09.007.
Measurement of RNFL and Macular Thickness in Amblyopia by SD-OCT
To study peripapillary retinal nerve fiber layer (RNFL) and macular thickness in amblyopia using high-definition
spectral-domain optical coherence tomography (SD-OCT) and to compare the results with available literature using the
time-domain modality, researchers conducted a prospective institutional study of patients ≥6 years of age with
unilateral amblyopia (strabismic or anisometropic) and non-amblyopic anisometropia. They measured RNFL and macular
thicknesses using SD-OCT and compared the results between fellow eyes.
The mean age was 20 (±12) years; 45 patients had amblyopia: 14 strabismic and 31 anisometropic. Also, 20 patients
had non-amblyopic anisometropia. According to the researchers, the mean macular thickness was significantly increased in
the amblyopic (273.8 µm) vs fellow eyes (257.9 µm), p=0.001. They found that this difference remained significant
in the anisometropic group (p=0.002) but not the strabismic group. They also noted that the mean RNFL thickness was similar
in amblyopic (95.4 µm) and fellow eyes (94.0 µm) and that they obtained similar results regardless of the level of
visual acuity, age or refractive error. In the control group of non-amblyopic anisometropia, the interocular difference did not
reach statistical significance.
In conclusion, central macular thickness was significantly increased in anisometropic amblyopia using SD-OCT. Anisometropia alone
did not produce such a difference, which points to a possible correlation between amblyopia and the development of the
Source: Al-Haddad CE, Mollayess GM, Cherfan CG, et al. Retinal nerve fibre layer and macular thickness
in amblyopia as measured by spectral-domain optical coherence tomography. Br J Ophthalmol. 2011;95(12):1696–1699.
Presence of Retinal Crystals in Type 2 Idiopathic Macular Telangiectasia
The aim of this case-control study was to characterize the phenotype and investigate the associations of
intratretinal crystalline deposits in a large cohort with type 2 idiopathic macular telangiectasia (MacTel).
Participants included patients with and without retinal crystals from the Macular Telangiectasia Project, an
international multicenter prospective study of type 2 MacTel.
Grading of stereoscopic 30-degree color fundus (CF), confocal blue light reflectance (CBR), red-free (RF) and infrared (IR)
images was performed according to the MacTel Natural History Study protocol and staged using the classification system devised
by Gass and Blodi. Spectral domain-optical coherence tomography (SD-OCT) and adaptive optics imaging were used for a finer
analysis of the phenotype. Finally, associations between crystals and other characteristics of the disease, as well as potential
risk factors, were investigated. Presence of crystals, fundus signs of MacTel, clinical characteristics and presence of
potential risk factors of MacTel were the main outcome measures.
It was reported that of 443 probands enrolled in the MacTel study, 203 (46%) had crystalline deposits present; 60% of
the cases were bilateral at baseline. It was also noted that eyes with crystals had a mean letter score of 70.7 (standard
deviation [SD] = 15.9), whereas those without crystals had a mean letter score of 66.5 (SD=15.5, p<0.001). Crystals
were present at all stages of the disease and showed high reflectivity within a wide wavelength range. They were located at
the anterior surface of the nerve fiber layer, arranged along the nerve fibers, within an annular area centered on the
fovea. Significant associations of crystalline deposits were found with a loss of retinal transparency, macular pigment
optical density (MPOD) loss, fluorescein leakage, retinal thickness and a break in the inner segment/outer segment
junction line. Furthermore, associations with environmental risk factors were not found.
Intraretinal crystals are a frequent phenomenon associated with type 2 MacTel and may appear at all stages and aid in the
early diagnosis of the disease. Their morphology further implicates Müller cells in the pathogenesis of the disease.
Insight into their physical and chemical properties may provide clues to the metabolic pathways involved in the pathogenesis
of the disease.
Source: Sallo FB, Leung I, Chung M, et al; MacTel Study Group. Retinal crystals in type 2 idiopathic
macular telangiectasia. Ophthalmol. 2011;118(12):2461–1467.