Volume 8, Number 10
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.
Treating Vitreomacular Traction and Macular Holes Using Enzymatic Vitreolysis
Vitreomacular adhesion can lead to pathologic traction and macular hole and the standard treatment for severe, symptomatic
vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin,
components of the vitreoretinal interface.
Researchers conducted two multicenter, randomized, double-blind, Phase III trials to compare a single intravitreal injection
of ocriplasmin (125 µg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary endpoint
was resolution of vitreomacular adhesion at day 28. Secondary endpoints were total posterior vitreous detachment and nonsurgical
closure of a macular hole at 28 days, avoidance of vitrectomy and change in best-corrected visual acuity (BCVA).
The researchers treated a total of 652 eyes: 464 with ocriplasmin and 188 with placebo. They reported that vitreomacular
adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (p<0.001). They
also found that total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those
injected with placebo (13.4% vs. 3.7%, p<0.001). Nonsurgical closure of macular holes was achieved in 40.6%
of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (p<0.001), according to the
researchers. They also noted that the BCVA was more likely to improve by a gain of at least three lines on the eye chart
with ocriplasmin with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia or injection-related eye
pain—all self-reported—or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in
53.5% of placebo-injected eyes (p<0.001), and the incidence of serious ocular adverse events was similar in the
two groups (p=0.26).
In conclusion, intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular
holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular
adverse events, which were mainly transient.
Source: Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction
and macular holes. N Engl J Med. 2012;367(7):606–615.
Topical Bromfenac Used as Adjunctive Treatment With Intravitreal Ranibizumab for Exudative AMD
Intravitreal injection of ranibizumab is highly effective for wet age-related macular degeneration (AMD). Its limitation
is that most patients require repeated intravitreal injections to achieve and maintain the visual gain. The authors of
the following study assessed the effectiveness of adjunctive topical bromfenac, a nonsteroidal antiinflammatory drug,
They randomized patients with wet AMD with lesions smaller than two disk diameters 2:3 to adjunctive topical bromfenac (n=16)
or sham (n=22) and a 0.5-mg ranibizumab injection in a double-masked fashion. The authors examined subjects monthly and
injected ranibizumab as needed from baseline. The primary endpoint was the comparison of the number of ranibizumab injections
over six months. The authors also compared visual and anatomic responses.
They reported that the mean number of ranibizumab injections over six months was 2.2 in the bromfenac group and 3.2 in the sham,
a difference that reached significance (p=0.0274). They noted that the changes in visual acuity did not differ significantly
(p=0.3141), although the central retinal thickness tended to decrease more in the bromfenac group (p=0.0604).
Multivariate analysis showed that topical bromfenac is significantly associated with fewer ranibizumab injections.
To conclude, topical bromfenac might reduce the frequency of ranibizumab over six months in eyes with relatively small AMD lesions.
Source: Gomi F, Sawa M, Tsujikawa M, Nishida K. Topical bromfenac as an adjunctive treatment with intravitreal
ranibizumab for exudative age-related macular degeneration. Retina. 2012;32(9):1804–1810.
Sustained IOP Elevation Following Intravitreal Injections of Bevacizumab
in Eyes with Neovascular AMD
The use of intravitreal anti-vascular endothelial growth factor (VEGF) agents in general, and of bevacizumab (Avastin)
in particular, has become the common first-line treatment of neovascular age-related macular degeneration (AMD). Several
reports addressed the possible elevation of intraocular pressure (IOP) following intravitreal injection of anti-VEGF.
Researchers in Israel performed this retrospective cohort study to determine the prevalence of sustained IOP elevation
following intravitreal bevacizumab injections for neovascular AMD and to identify possible risk factors for the development
of increased IOP.
They included 174 consecutive patients (201 eyes) receiving intravitreal bevacizumab (1.25 mg/0.05 ml) as treatment for
neovascular AMD. They reviewed the records of the study patients for age, gender, history of glaucoma, phakic status,
IOP levels, length of follow-up, total number of injections, intervals between injections and IOP management in eyes that
exhibited IOP elevation. Sustained IOP elevation was defined as IOP ≥22 mmHg and a change from baseline of ≥6 mmHg
recorded on at least two consecutive visits and lasting ≥30 days. Risk factors for an IOP increase were identified from
the association between the studied variables and IOP elevations.
The study researchers found sustained IOP elevation in 22 of 201 eyes (11%). The increased IOP was controlled with
topical medications in all eyes. Among the variables studied, only male gender [OR=3.1, 95% CI (1.1, 8.5) p=0.029]
and length of interval between injections less than eight weeks [OR=3.0, 95% CI (1.1, 7.9), p= 0.028] emerged as
risk factors for IOP elevation in a multivariable model. The prevalence of IOP elevation was significantly higher when the
interval between injections was less than eight weeks than when it was eight or more weeks (17.6 and 6%, respectively,
p=0.009). Pre-existing glaucoma was not associated with IOP elevation (p=0.9).
Sustained IOP elevations can occur in normotensive eyes undergoing intravitreal bevacizumab treatment for neovascular AMD.
This phenomenon was related to shorter intervals between injections, with eight weeks being taken as the cut-off point.
AMD eyes that receive intravitreal bevacizumab injections need to be monitored for IOP changes, especially those in which
the intervals between injections are less than eight weeks.
Source: Mathalone N, Arodi-Golan A, Sar S, et al. Sustained elevation of intraocular pressure after intravitreal
injections of bevacizumab in eyes with neovascular age-related macular degeneration. Graefes Arch Clin Exp
Subretinal Drusenoid Deposits and PED in AMD
To characterize retrospectively subretinal drusenoid deposits (SDD) in patients with pigment epithelium detachment
(PED) secondary to age-related macular degeneration (AMD), confocal scanning laser ophthalmoscopy near-infrared
reflectance images (820 nm) were recorded in 208 eyes of 104 patients with serous, drusenoid or vascularized PED
because of AMD in at least one eye.
The digital images were evaluated by two independent readers with subsequent senior reader arbitration for prevalence of SDD.
They found that serous PED was present in only two patients and therefore did not include it in the statistical analysis. The
independent readers detected subretinal drusenoid deposits in 55 of 102 (53.9%) patients in at least one eye. Additionally,
they reported that 46 of those 55 patients showed SDD bilaterally (83.6%). SDD were present in 51 (50%) of right eyes and
50 (49.0%) of left eyes. A total of 146 of 204 eyes showed a PED secondary to AMD, of which 111 (76%) were vascularized
and 35 (24%) drusenoid. Prevalence of SDD was correlated with age (p<0.0001) and female gender (p=0.014),
but not with the type of PED (p=0.174). Cohen kappa statistics showed good inter-observer agreement for infrared imaging
(0.78 for right eyes, 0.74 for left eyes).
SDD represent a common phenotypic characteristic in eyes with PED because of AMD. As described in previous studies, SDD are
readily identified using confocal scanning laser ophthalmoscopy imaging technology. Future studies should pursue the
pathophysiologic role and the predictive value of the presence of SDD in the development of PED and a subsequent rip of the
retinal pigment epithelium.
Source: Alten F, Clemens CR, Milojcic C, Eter N. Subretinal drusenoid deposits associated with pigment
epithelium detachment in age-related macular degeneration. Retina. 2012;32(9):1727–1732.
Retinal Function in Early AMD Following Lutetin and Zeaxanthin Supplementation
Chinese investigators examined the effects of lutein and zeaxanthin supplementation on retinal function using
multifocal electroretinograms (mfERG) in patients with early age-related macular degeneration (AMD) in this randomized,
double-masked, placebo-controlled trial.
They randomly assigned 108 subjects with early AMD to receive 10 mg/d lutein (n=27), 20 mg/d lutein (n=27), 10 mg/d lutein plus
10 mg/d zeaxanthin (n=27) or placebo (n=27) for 48 weeks. They also enrolled 36 age-matched controls without AMD to compare
baseline data with early AMD patients. Additionally, they recorded MfERG responses and macular pigment optical densities (MPODs)
and analyzed these at baseline and at 24 and 48 weeks.
The investigators found significant reductions in N1P1 response densities in ring 1 to ring 3 in early AMD patients compared with
the controls (p<.05), whereas neither N1P1 response densities in ring 4 to ring 6 nor P1 peak latencies
significantly changed. After 48-week supplementation, the N1P1 response densities showed significant increases in ring 1 for
the 20 mg lutein group and for the lutein and zeaxanthin group, and in ring 2 for the 20 mg lutein group. The increases in MPOD
related positively to the increases in N1P1 response density in ring 1 and ring 2 for nearly all active treatment groups. N1P1
response densities in ring 3 to ring 6 or P1 peak latencies in all rings did not change significantly in any group.
Early functional abnormalities of the central retina in the early AMD patients could be improved by lutein and
zeaxanthin supplementation, the investigators concluded. These improvements may be potentially attributed to the elevations
Source: Ma L, Dou HL, Huang YM, et al. Improvement of retinal function in early age-related macular degeneration
after lutein and zeaxanthin supplementation: a randomized, double-masked, placebo-controlled trial.
Am J Ophthalmol. 2012;154(4):625–634.
Results of Reduced-Fluence PDT for PCV
In Japan, the following prospective interventional case series was performed to report the results of a two-year follow-up
of Japanese polypoidal choroidal vasculopathy (PCV) patients treated with reduced-fluence photodynamic therapy (PDT) monotherapy.
A total of 38 eyes of 38 consecutive patients underwent PDT with a reduced laser fluence of 25 J/cm². During the
two-year follow-up, visual acuity (VA) and optical coherence tomography measurements were performed every three months
following the PDT procedure and were then compared with baseline values. Additionally, PCV vascular lesions were evaluated
by indocyanine green and fluorescein angiography.
At baseline, the mean logarithm of the minimal angle of resolution (logMAR) best-corrected VA (BCVA) was 0.43. It was noted
that there was a significant improvement of the mean logMAR BCVA to 0.28 and 0.29 at 12 and 24 months, respectively
(p<.0001, p=.001). It was also reported that the logMAR BCVA was stable or improved by ≥0.3 in 36 (95%)
of the eyes at the two-year follow-up. In 13 eyes in which the baseline VA was better than 20/40, there was a significant
improvement of the mean logMAR BCVA at 12 months, with the acuities continuing to be stable at 24 months. Moreover, the mean
number of treatment sessions during the 24-month study period was 1.9.
It was concluded that reduced-fluence PDT monotherapy for PCV effectively improved and maintained the VA over a 24-month period,
even in eyes with a baseline VA better than 20/40. Also, the number of treatments could be much smaller as compared with
intravitreal injection of anti–vascular endothelial growth factor agents.
Source: Yamashita A, Shiraga F, Shiragami C, et al. Two-year results of reduced-fluence photodynamic therapy for
polypoidal choroidal vasculopathy. Am J Ophthalmol. 2012;Sept 30. [Epub ahead of print]. DOI: 10.1016/j.ajo.2012.06.027.
Treatment of Myopic CNV With Intravitreal Pegaptanib
To report the morphologic and functional outcomes resulting from the use of intravitreal pegaptanib (IVP) sodium (Macugen)
in patients with myopic choroidal neovascularization (CNV), investigators performed an open-label, nonrandomized,
prospective clinical trial.
They assessed morphologic outcome, such as foveal thickness, by optical coherence tomography (OCT) and functional outcomes
by best-corrected visual acuity (BCVA) and microperimetry. Treatment protocol consisted of three consecutive IVP
(0.3 mg/0.05 mL; baseline, 6th week, and 12th week). The investigators then scheduled follow-up checks at the following
intervals: baseline, 18, 24, 36 and 48 weeks.
They studied 20 eyes from 20 patients. All patients completed follow-up at 48 weeks. Following IVP, a significant decrease in
foveal thickness occurred (–20%), and at the end of follow-up, CNV closure was obtained in all eyes. The study
investigators recorded an improvement of functional parameters in all patients (BCVA from 25.5 ± 8.09 letters to 45.5 ±
8.16 letters, p<0.0001; microperimetry from 8.40 ± 2.14 dB to 10.8 ± 2.05 dB, p<0.01). They
reported that mean number of IVP was three, and none of patients met the re-treatment criterion during the entire follow-up period.
They observed neither ocular nor systemic side effects.
The findings demonstrate that the selective inhibition of VEGF-165 isoform by IVP is an effective treatment for myopic CNV.
Source: Rinaldi M, Chiosi F, dell'Omo R, et al. Intravitreal pegaptanib sodium (Macugen) for treatment of
myopic choroidal neovascularization: a morphologic and functional study. Retina. 2012;Sept 17. [Epub ahead of print].
Comparison of Intravitreal Triamcinolone and Intravitreal Bevacizumab in the
Treatment of Exudative Retinal Detachment Secondary to Posterior Uveal Melanoma
Scientists in Italy sought to evaluate the efficacy and safety of prompt intravitreal triamcinolone acetonide injection
(4 mg/0.1 mL) vs. intravitreal bevacizumab injection (1.25 mg/0.05 mL) compared with observation in the management of
extensive exudative retinal detachment secondary to posterior uveal melanoma.
They included 96 patients affected by posterior uveal melanoma with large exudative retinal detachment (>10 mm in
largest basal diameter) in this retrospective, nonrandomized, interventional case series.
According to the scientists, patients received intravitreal triamcinolone acetonide (32 eyes) or intravitreal bevacizumab (32 eyes)
at plaque removal; 32 patients served as controls (observation group). All groups were matched for age, sex, initial tumor thickness
and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. Patients underwent monthly follow-up examinations in the first six months and every three months thereafter. Follow-up was longer than
24 months. Exudative retinal detachment resolution (B-scan ultrasonography), steroid-induced cataract and steroid-induced increased
IOP were the main outcome measures.
Follow-up was 37 ± 7 months. The scientists documented marked exudative retinal detachment regression in 22 (69%)
intravitreal triamcinolone acetonide–treated vs. 11 (34%) intravitreal bevacizumab–treated and nine (28%) untreated eyes
(p=.0007 and p=.0001, respectively). They found no statistical significance between intravitreal bevacizumab group
vs. observation group (p=.45) and they observed steroid-induced cataract in four intravitreal triamcinolone
acetonide–treated patients (12%). Moreover, they documented no steroid-induced increased IOP nor other short- or long-term
The scientists concluded that intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative
retinal detachment resolution after brachytherapy of posterior uveal melanoma. Thus, risk and benefit should be balanced
vs. steroid-induced cataract.
Source: Parrozzani R, Pilotto E, Dario A, et al. Intravitreal triamcinolone vs. intravitreal bevacizumab in the
treatment of exudative retinal detachment secondary to posterior uveal melanoma. Am J Ophthalmol. 2012;Sept 20.
[Epub ahead of print]. DOI: 10.1016/j.ajo.2012.06.026.
Evaluation of Intravitreal Ranibizumab for DME with Prompt vs. Deferred Laser Treatment
To report the three-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred
(for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema
(DME), scientists conducted the following multicenter, randomized clinical trial.
They reported that the trial included 361 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and
DME involving the fovea. They also noted that the participants received ranibizumab every four weeks until no longer improving
(with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment.
Best-corrected visual acuity and safety at the 156-week (three-year) visit was the main outcome measure.
According to the study scientists, the estimated mean change in visual acuity letter score from baseline through the three-year
visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4–5.4
letters; p=0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group
and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% (p=0.02),
whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% (p=0.12). Up to the
three-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively
(p=0.007), including one and two injections, respectively, from the two-year up to the three-year visit. At the three-year
visit, the percentages of eyes with central subfield thickness of 250 µm or more on time-domain optical coherence tomography
were 36% in both groups (p=0.90). In the deferral group, 54% did not receive laser treatment during the trial.
Systemic adverse events seemed to be similar in the two groups.
These three-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better,
and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea
and with vision impairment. Some of the observed differences in visual acuity at three years may be related to fewer
cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through five years continues.
Source: Elman MJ, Qin H, Aiello LP, et al.; Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab
for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results.
Ophthalmology. 2012;Sept 20. [Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.08.022.
Longitudinal Changes of RNFL Thickness Following PRP in DR
The authors of this prospective study examined 31 eyes in 25 patients undergoing panretinal photocoagulation (PRP), who were
diagnosed with severe nonproliferative diabetic retinopathy (DR) or non-high-risk proliferative DR to investigate longitudinal
changes in retinal nerve fiber layer (RNFL) thickness. They conducted optical coherence tomography (OCT) before PRP and at three,
six, 12 and 24 months after PRP to investigate changes in peripapillary RNFL thickness.
According to the authors, superior, nasal, inferior, temporal and mean peripapillary RNFL thickness increased until six months after
PRP and then decreased. They also found that superior RNFL thickness increased significantly at three and six months and
decreased significantly at 24 months compared with the baseline RNFL thickness. The study authors also reported that nasal
RNFL thickness declined significantly at 24 months compared with the baseline RNFL thickness without any significant increase
in thickness during the follow-up period. They noted that inferior RNFL thickness increased significantly at six months and
decreased significantly at 24 months compared with its baseline RNFL thickness. Temporal thickness increased significantly at
three, six, 12 and 24 months compared with the baseline RNFL thickness. Mean RNFL thickness increased significantly at six months
and decreased significantly at 24 months. Central subfield thickness increased significantly at three, six, 12 and 24 months
compared with its baseline thickness.
Peripapillary RNFL thickness increased at six months after PRP and then decreased at 24 months after PRP compared with
baseline peripapillary RNFL thickness in DR patients. This finding suggests that in addition to diabetes itself, DR, and
associated glaucoma, PRP may be a cause of RNFL thickness loss in patients with diabetes.
Source: Lee SB, Kwag JY, Lee HJ, et al. The longitudinal changes of retinal nerve fiber layer thickness after
panretinal photocoagulation in diabetic retinopathy patients. Retina. 2012; Sept 17 [Epub ahead of print].
Prevalence of Sleep Disordered Breathing in Patients with DME
Diabetic retinopathy (DR) is more common and severe in patients with sleep disordered breathing (SDB). Researchers aimed to
establish whether this is also true for patients with diabetic clinically significant macular edema (CSME). It is hypothesized
that SDB, through intermittent hypoxia and blood pressure oscillations, might provoke worsening of CSME.
Patients with CSME had a home sleep study (ApneaLink; ResMed) to identify SDB. The researchers compared these results with
relevant control populations and measured macular thickness using optical coherence tomography (OCT). They also graded
retinal photographs to assess the severity of retinopathy.
A total of 80 of 195 patients (40 men) consented, with average age of 64.7 (11.7) years, neck circumference of 40.4 (5.4) cm,
body mass index of 30.2 (6.2) kg/m², glycosylated hemoglobin (HbA1c) 7.8% (1.4%) [62 (8.0) mmol/mol], and
Epworth sleepiness scale of 7.4 (4.8). Overall, 54% had an oxygen desaturation index ≥10, and 31% had an apnea-hypopnea
index ≥15. This SDB prevalence is probably higher than would be expected from the available matched control data. Those with SDB
were not sleepier, but they were older and more obese. No significant relationship was identified between the degree of
macular thickness and the severity of SDB.
Individuals with CSME have a high prevalence of SDB, the researchers concluded. Sleep disordered breathing may contribute to
the pathophysiology of CSME, but the mechanism remains unclear. Given the high prevalence, retinal specialists should perhaps
consider a diagnosis of SDB in patients with CSME.
Source: Mason RH, West SD, Kiire CA, et al. High prevalence of sleep disordered breathing in patients with diabetic
macular edema. Retina. 2012;32(9):1792–1798.
Variation of OCT-Measured Retinal Thickness in DME
In the following study, investigators examined 24-hour variation in retinal thickness in patients with diabetic macular
edema (DME) using optical coherence tomography (OCT).
A total of 53 eyes of 53 diabetic patients with clinically significant macular edema (CSME) and central subfield thickness
(CST) >225 µm, 36 eyes of 36 healthy individuals (normal controls), and 22 eyes of 22 diabetic patients without
macular pathology (diabetic controls) underwent five OCT measurements at 7 am, 10 am, 3 pm, 8 pm and 1 am. The investigators
also measured visual acuity, blood pressure, blood glucose and body temperature.
They reported that the CST (p<0.0005), total macular volume (p<0.0005) and visual acuity
(p<0.0005) showed significant variation in patients and that the CST (450 µm at 7 am) reached a minimum
at 3 pm (absolute change of –49 µm, relative change of –17%) before increasing again. The investigators
also noted that thickening changes were higher in more thickened retinas (p<0.0005, p=0.024, absolute and
relative change, respectively). They also observed that visual acuity was worse in the morning (0.38 logMAR) and improved to
a maximum at 8 pm (0.30 logMAR) (p<0.0005). Moreover, blood pressure, blood glucose and body temperature did not
vary over time.
To conclude, the 24-hour variation of retinal thickness is observed in a large proportion of patients with DME, with a decrease
from morning to afternoon. Time of examination should be taken into account when managing such patients.
Source: Kotsidis ST, Lake SS, Alexandridis AD, et al. 24-hour variation of optical coherence tomography-measured
retinal thickness in diabetic macular edema. Eur J Ophthalmol. 2012;22(5):785–791.