Volume 9, 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.
Use of Stereotactic Radiotherapy for Neovascular AMD
To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (nvAMD), researchers conducted the following randomized, double-masked, sham-controlled, multicenter, clinical trial.
They included 230 patients with onset of nvAMD within three years who received three or more injections of ranibizumab or bevacizumab within the preceding year and who needed continuing ranibizumab or bevacizumab treatment. The researchers randomized participants 2:1:2:1 to 16 Gy plus pro re nata (p.r.n.) ranibizumab, sham 16 Gy plus p.r.n. ranibizumab, 24 Gy plus p.r.n. ranibizumab, or sham 24 Gy plus p.r.n. ranibizumab, respectively. The primary efficacy endpoint was the mean number of ranibizumab injections at 52 weeks. Secondary endpoints were change in mean best-corrected visual acuity (BCVA), loss of fewer than 15 Early Treatment Diabetic Retinopathy Study letters, gain of zero or more and 15 or more letters, and change in angiographic total lesion size and choroidal neovascularization (CNV) lesion size.
According to the researchers, both the 16-Gy and 24-Gy SRT arms received significantly fewer ranibizumab treatments compared with the sham arms: mean number of treatments, 2.64 (median, 2), 2.43 (median, 2) and 3.74 (median, 3.5), respectively (p=0.013 and p=0.004, respectively, vs. sham). They also noted that change in mean VA was −0.28, +0.40, and −1.57 letters for the 16-Gy, 24-Gy and sham arms, respectively. The 16-Gy, 24-Gy and sham arms lost fewer than 15 letters in 93%, 89% and 91% of eyes, respectively, with 531%, 571% and 561% gaining zero or more letters, respectively, and 41% gaining 15 letters or more in all arms. Mean total angiographic lesion area changed by −1.15 mm², +0.49 mm² and +0.75 mm², respectively; mean CNV lesion area decreased by 0.16 mm², 0.18 mm² and 0.10 mm², respectively. Optical coherence tomography central subfield thickness decreased by 85.90 µm, 70.39 µm and 33.51 µm, respectively. The number of adverse events (AEs) and number of serious AEs (SAEs) was similar across arms. No AEs were attributed to radiation. No SAEs occurred in the study eye.
A single dose of SRT significantly reduces ranibizumab retreatment for patients with nvAMD, with a favorable safety profile at one year, the study researchers determined. Whereas chronic nvAMD typically results in loss of VA over time, SRT is associated with relatively well-preserved VA over one year.
Source: Jackson TL, Chakravarthy U, Kaiser PK, et al; INTREPID Study Group. Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID Study. Ophthalmology. 2013;120(9):1893–1900.
Ranibizumab Plus Dexamethasone Combination Therapy vs. Ranibizumab Monotherapy for Neovascular AMD
The LuceDex prospective randomized pilot trial compared the combination of intravitreal ranibizumab and dexamethasone with ranibizumab monotherapy for treatment of neovascular age-related macular degeneration (AMD).
A total of 37 eyes of 37 patients were randomized 1:1 between combination therapy with intravitreal ranibizumab and dexamethasone (Group One) and intravitreal ranibizumab monotherapy (Group Two). All study eyes received four monthly treatments followed by monthly treatment on indication.
It was reported that eyes gained an average of 11.1 and 5.9 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in Groups One and Two, respectively, at month 12. No more than zero ETDRS letters were lost in 88% of Group One eyes and 70% of Group Two eyes. The average number of treatments per study eye by month 12 was 7.1 in Group One and 6.6 in Group Two. Choroidal neovascular membrane size decreased in Group One significantly compared with Group Two (p<0.05).
The LuceDex pilot study suggests a possible benefit of adding intravitreal dexamethasone to treatment of neovascular AMD with intravitreal ranibizumab. A larger study is needed to further identify and define possible benefits of this combination therapy.
Source: Ranchod TM, Ray SK, Daniels SA, et al. LUCEDEX: a prospective study comparing ranibizumab plus dexamethasone combination therapy versus ranibizumab monotherapy for neovascular age-related macular degeneration. Retina. 2013;33(8):1600–1604.
Incidence and Risk Factors for the Development of RPE Tears Following High- and Low-Dose Ranibizumab
Researchers sought to prospectively determine the incidence and risk factors for retinal pigment epithelial (RPE) tears in eyes with vascularized pigment epithelial detachments (PED) and exudative age-related macular degeneration (AMD) receiving antivascular endothelial growth factor (anti-VEGF) therapy.
They prospectively randomized eyes into one of four arms: 1) 0.5 mg of ranibizumab monthly for 12 months; 2) 0.5 mg of ranibizumab monthly for three months and then pro re nata on the basis of clinical and optical coherence tomography–guided indications; 3) high-dose 2.0 mg of ranibizumab monthly for 12 months; or 4) 2.0 mg of ranibizumab monthly for three months and then pro re nata thereafter. They measured all PEDs for height, greatest linear diameter and surface area at baseline and determined the incidence of RPE tears in the entire four-arm cohort at the end of 12 months. Additionally, the researchers divided eyes into two groups (tear vs. nontear) and statistically compared them to determine risk factors for the development of RPE tear.
They reported that of 37 eyes, a total of five developed post-ranibizumab RPE tears during the course of the study (incidence 14%). They also noted that four of the five tears occurred in the high-dose 2.0-mg groups. Baseline PED height, surface area and greatest linear diameter were significantly greater in the group that developed RPE tears versus the nontear group (p=0.018, 0.031, and 0.048, respectively). There were significantly more eyes with PED height >550 µm in the RPE tear group (four of five, 80%) compared with the nontear group (nine of 32, 18%) (p=0.042). The presence of PED height >550 µm was associated with an increased tear rate from 14% to 31%. Furthermore, retrospective identification of a ring sign or grade 1 tear at baseline, in addition to PED height >550 µm, was associated with a further increase in the tear rate to 67%.
In this study, the prospective incidence of RPE tears was ~14%. A baseline PED height >550 µm and presence of a grade 1 tear, or positive ring sign, were identified as high-risk factors for the subsequent development of an RPE tear.
Source: Sarraf D, Chan C, Rahimy E, Abraham P. Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab. Retina. 2013;33(8):1551–1557.
Accuracy of Predicting CNV and GA
In this cohort study, investigators evaluated the accuracy of predicting conversion from early-stage age-related macular degeneration (AMD) to the advanced stages of choroidal neovascularization (CNV) or geographic atrophy (GA) to determine whether inclusion of clinically relevant genetic markers improved accuracy beyond prediction using phenotypic risk factors alone.
Participants consisted of white, non-Hispanic subjects participating in the Age-Related Eye Disease Study (AREDS) sponsored by the National Eye Institute who consented to provide a genetic specimen. Of 2,415 DNA specimens available, 940 were from disease-free subjects and 1,475 were from subjects with early or intermediate AMD. The investigators genotyped DNA specimens from study subjects for 14 single nucleotide polymorphisms (SNPs) in genes shown previously to associate with CNV: ARMS2, CFH, C3, C2, FB, CFHR4, CFHR5 and F13B. They also evaluated clinical demographics and established disease associations, including age, sex, smoking status, body mass index (BMI), AREDS treatment category and educational level. Additionally, they tested four multivariate logistic models (phenotype; genotype; phenotype + genotype; and phenotype + genotype + demographic + environmental factors) using two endpoints (CNV, GA) and fitted models using Cox proportional hazards regression to use time-to-disease onset data. The study investigators used Brier score (measure of accuracy) to identify the model with the lowest prediction error in the training set. They subjected the most accurate model to independent statistical validation, and described final model performance using area under the receiver operator curve (AUC) or C-statistic.
According to the investigators, the CNV prediction models that combined genotype with phenotype with or without age and smoking revealed superior performance (C-statistic=0.96) compared with the phenotype model based on the simplified severity scale and the presence of CNV in the nonstudy eye (C-statistic = 0.89; p<0.01). They found that for GA, the model that combined genotype with phenotype demonstrated the highest performance (AUC=0.94). Furthermore, they then noted that smoking status and ARMS2 genotype had less of an impact on the prediction of GA compared with CNV.
To conclude, inclusion of genotype assessment improves CNV prediction beyond that achievable with phenotype alone and may improve patient management. Separate assessments should be used to predict progression to CNV and GA because genetic markers and smoking status do not equally predict both endpoints.
Source: Perlee LT, Bansal AT, Gehrs K, et al. Inclusion of genotype with fundus phenotype improves accuracy of predicting choroidal neovascularization and geographic atrophy. Ophthalmology. 2013;120(9):1880–1892.
Characteristics of Incident GA
This retrospective cohort study was performed within a larger clinical trial and sought to characterize the size, location, conformation and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs).
Participants were patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during five to six years of follow-up. GA was defined according to the Revised GA Criteria for identifying early GA23 and color-optimized fundus photographs were viewed concurrently with the FAs during grading. Main outcome measures were size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye.
At presentation, the median total GA area was 0.26 mm2 (0.1 disc area). GA presented as a single lesion in 89 (78%) eyes and the median distance from the fovea was 395 µm. Of the incident GA lesions, 20% were subfoveal, and an additional 18% were within 250 µm of the foveal center. Development of GA was associated with a mean decrease of seven letters from the baseline VA level compared with one letter among matched early age-related macular degeneration eyes without GA. GA that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm²; p=0.0001), were more central (50 vs. 500 µm from the center of the fovea; p<0.0001) and were associated with significantly worse visual outcome (20/50 vs. 20/25; p=0.0003) than GA with other drusen types as precursors.
In conclusion, incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA vary with precursor drusen types. These data can facilitate design of future clinical trials of therapies for GA.
Source: Brader HS, Ying G, Martin ER, Maguire MG; Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group. Characteristics of incident geographic atrophy in the Complications of Age-Related Macular Degeneration Prevention Trial. Ophthalmology. 2013;120(9):1871–1879.
Risk Factors for Recurrence of Myopic CNV
The authors of this study investigated factors associated with long-term recurrence of myopic choroidal neovascularization (CNV) after treatment with photodynamic therapy (PDT) and/or intravitreal antivascular endothelial growth factor (anti-VEGF) injections.
A total of 76 eyes with myopic CNV completed at least a 48-month follow-up after treatments. The baseline characteristics of the eyes were compared, including age, gender, refractive errors, axial lengths, location of CNV, lacquer cracks, chorioretinal atrophy, dark rim, great linear dimension, and prior PDT.
During mean follow-up of 71.21 ± 26.43 months, 35 eyes (46.1%) experienced at least one recurrence. The study authors reported that the mean interval between initial treatment and first recurrence was 24.15 ± 18.10 months. They also noted that presence of lacquer crack (p=0.022, Χ² test), absence of dark rim (p=0.031, Χ² test) and prior PDT (p=0.041, Χ² test) were significantly different between the eyes with and without recurrence. Among baseline characteristics, they found that presence of lacquer crack (ß=1.272, p=0.012) prior PDT (ß=1.607, p=0.027) and absence of dark rim (ß=−0.758, p=0.020) were significantly associated with the recurrence of myopic CNV after treatment by multiple logistic regression.
Long-term follow-up revealed recurrence of myopic CNV in 46.1% of the patients after treatment. Presence of lacquer cracks, prior PDT, and absence of dark rim were risk factors for recurrence of myopic CNV.
Source: Kang HM, Koh HJ. Ocular risk factors for recurrence of myopic choroidal neovascularization: long-term follow-up study. Retina. 2013;33(8):1613–1622.
Injection Frequency and Response to Bevacizumab Monotherapy for DME
This study explored the parameters that influence injection frequency in patients treated with intravitreal bevacizumab (ivB) for diabetic macular edema (DME). Injection frequency was considered a surrogate marker of persistent or recurrent edema.
A post hoc analysis of the patients randomized to the ivB arm of a prospective, randomized controlled trial (A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of DME [BOLT study]) was done to assess the factors that may determine the injection frequency at 12 and 24 months. The injection response patterns were classified based on the specific time point at which the macula was first defined as "dry."
Eyes with better baseline visual acuity less frequently had persistent edema and had fewer recurrences in the second year. All eyes with baseline subretinal detachment showed persistent macular edema at 24 months. None of the other factors assessed influenced injection frequency or response in the first or second year.
It was concluded that good long-term response is predicted by resolution of macular edema by four months. However, approximately 20% of patients with persistent edema at 12 months achieved a dry macula and 50% gained more than 15 letters at 24 months with sustained treatment, suggesting that edema at four or 12 months should not be used as a stopping criterion for treatment.
Source: Sivaprasad S, Crosby-Nwaobi R, Ling ZH, et al. Injection frequency and response to bevacizumab monotherapy for diabetic macular oedema (BOLT Report 5). Br J Ophthalmol. 2013;97(9):1177–1180.
Association of CFH and SERPING1 Polymorphisms with Anterior Uveitis
Chinese investigators examined the association of the complement factor H (CFH) and complement component 1 inhibitor (SERPING1) genes with anterior uveitis (AU).
They recruited 406 subjects (98 patients with AU and 308 controls) for this study and the genotyped two CFH polymorphisms (rs3753394 and rs1065489) and two SERPING1 polymorphisms (rs1005511 and rs3824988) using TaqMan genotyping assays. They stratified analyses for gender and human leukocyte antigen (HLA)-B27 status and evaluated correlations of the genotypes with multiple clinical features.
The investigators found no significant association between any of the four polymorphisms and AU after multiple testing corrections. However, stratified analyses showed that there were significant increases in the frequencies of T allele and TT homozygosity for CFH-rs1065489 in female patients compared with that of controls (pcorr=0.004 and pcorr=0.012 respectively). In addition, CFH-rs1065489 was also associated with AU in patients who were HLA-B27 positive. No significant association with AU was found for the other three single nucleotide polymorphisms (SNPs), even stratified by gender or HLA-B27 status. Genotype–phenotype analyses found that CFH-rs1065489 TT genotype was associated with higher uveitis recurrence frequency. No correlation was found between CFH-rs1065489 and other clinical features.
This study revealed an association of CFH-rs1065489 with AU as well as uveitis recurrence frequency. The influence on AU could be gender-specific and dependent on HLA-B27 status. The results also suggested that SERPING1 does not play a significant role in the development of AU.
Source: Yang M, Lai TY, Tam PO, Chiang SW, et al. Association of CFH and SERPING1 polymorphisms with anterior uveitis. Br J Ophthalmol. 2013 ;Aug 21. [Epub ahead of print]. DOI: 10.1136/bjophthalmol-2013-303679.
Management of Uncomplicated Retinal Detachments
In an effort to study success and failure in the treatment of uncomplicated rhegmatogenous retinal detachments (RRDs), scientists conducted the following nonrandomized, multicenter retrospective study.
A total of 176 surgeons from 48 countries spanning five continents provided information on the primary procedures for 7,678 cases of RRDs including 4,179 patients with uncomplicated RRDs. Reported data included specific clinical findings, the method of repair and the outcome after intervention. Main outcome measures consisted of final failure of retinal detachment repair (level one failure rate), remaining silicone oil at the study’s conclusion (level two failure rate) and need for additional procedures to repair the detachment (level three failure rate).
Included were 4,179 uncomplicated cases of RRD. Combining phakic, pseudophakic and aphakic groups, those treated with scleral buckle alone (n=1,341) had a significantly lower final failure rate than those treated with vitrectomy, with or without a supplemental buckle (n=2723; p=0.04). In phakic patients, final failure rate was lower in the scleral buckle group compared with those who had vitrectomy, with or without a supplemental buckle (p=0.028). In pseudophakic patients, the failure rate of the initial procedure was lower in the vitrectomy group compared with the scleral buckle group (p=3×10–8). There was no statistically significant difference in failure rate between segmental (n=721) and encircling (n=351) buckles (p=0.5). Those who underwent vitrectomy with a supplemental scleral buckle (n=488) had an increased failure rate compared with those who underwent vitrectomy alone (n=2,235; p=0.048). Pneumatic retinopexy was found to be comparable with scleral buckle when a retinal hole was present (p=0.65), but not in cases with a flap tear (p=0.034).
In the treatment of uncomplicated phakic retinal detachments, repair using scleral buckle may be a good option. There was no significant difference between segmental versus 360-degree buckle. For pseudophakic uncomplicated retinal detachments, the surgeon should balance the risks and benefits of vitrectomy versus scleral buckle and keep in mind that the single-surgery reattachment rate may be higher with vitrectomy. However, if a vitrectomy is to be performed, these data suggest that a supplemental buckle is not helpful.
Source: Adelman RA, Parnes AJ, Ducournau D; European Vitreo-Retinal Society (EVRS) Retinal Detachment Study Group. Strategy for the management of uncomplicated retinal detachments: The European Vitreo-Retinal Society Retinal Detachment Study Report 1. Ophthalmology. 2013;120(9):1804–1808.