Volume 8, Number 3
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.
Efficacy and Safety of Ranibizumab in Patients with Subfoveal CNV Secondary to AMD
This 12-month, open-label, single-arm, multi-center, phase III study investigated the efficacy and safety of intravitreal
ranibiumab 0.5 mg in South Korean and Taiwanese patients with subfoveal choroidal neovascularization (CNV) secondary
to age-related macular degeneration (AMD).
A total of 95 patients (51 Taiwanese, 44 South Korean) were included in the study and key outcome measures assessed included
mean change in best-corrected visual acuity (BCVA) from baseline to months 4 (primary endpoint) and 12 (secondary endpoint);
other secondary endpoints comprising categorized mean change in BCVA from baseline at month 4 and month 12, mean change in BCVA
from baseline at month 4 and month 12 per baseline characteristics; and incidence of ocular and non-ocular adverse events
and serious adverse events (SAEs) at month 12.
It was noted that the mean BCVA change improved significantly (p<0.0001) from baseline to both month 4 (+9.3 letters)
and month 12 (+10.1 letters) and that at month 12, the proportion of patients who gained ≥5, 10, or 15 letters from baseline
was 75.8%, 54.7%, and 32.6% respectively. It was also reported that total and CNV lesion area significantly
decreased from baseline (p<0.0001) and that roughly 57% of patients showed complete absence of fluorescein leakage
at month 12. Mean change from baseline visual acuity scores also increased significantly over time for all subgroups. At month
12, it was observed that ocular SAEs occurred in 2.1% of patients (out of which one patient [1.1%] experienced
endophthalmitis) and 16.8% of patients experienced non-ocular SAEs. No deaths were reported during the study.
Consistent with previous studies in Caucasian and Japanese populations, EXTEND III confirms that monthly intravitreal injections
of ranibizumab 0.5 mg administered over 12 months is effective and well-tolerated in South Korean and Taiwanese patients
with subfoveal CNV secondary to AMD.
Source: Kwon OW, Lee FL, Chung H, et al; and on behalf of the EXTEND III study group. EXTEND III: efficacy and
safety of ranibizumab in South Korean and Taiwanese patients with subfoveal CNV secondary to AMD. Graefes Arch Clin
Exp Ophthalmol. 2012; March 2 [Epub ahead of print]. DOI: 10.1007/s00417-012-1970-3.
Management of Neovascular AMD with Fixed-Interval Versus OCT-Guided Variable Dosing
of Intravitreal Bevacizumab
To compare the efficacy of as-needed or variable dosing of intravitreal bevacizumab to continuous fixed-interval dosing
in the management of neovascular age-related macular degeneration (AMD), investigators conducted the following
prospective, open-label, randomized clinical study.
A total of 120 eyes of 120 patients with treatment-naïve subfoveal neovascular AMD participated in this study at the
American University of Beirut and Hotel Dieu de France Retina Clinics. The investigators randomized eyes (1:1) to
fixed-interval dosing (every 4 to 6 weeks) or variable dosing with intravitreal bevacizumab (1.25 mg/0.05 mL) and
measured best-corrected visual acuity (BCVA) and central retinal thickness (CRT) using optical coherence tomography (OCT)
at baseline and at each follow-up visit. Presence or recurrence of fluid on OCT was the main indicator for retreatment in
variable dosing. Main outcome measure was improvement in BCVA and CRT at 12 months.
Compared to baseline, variable dosing had a mean improvement in BCVA of 11.0 letters after 12 months vs 9.2 letters
for fixed-interval dosing (p = .81), the investigators noted. Similarly, they found that CRT decreased after 12 months
by 80.7 µm for variable dosing vs 100.5 µm for fixed-interval dosing (p = .37). They also reported that the
average number of injections over 12 months was higher for fixed-interval dosing than variable dosing (9.5 vs 3.8 injections, p<.001).
In conclusion, fixed-interval and variable dosing regimens of intravitreal bevacizumab improved visual acuity and anatomic
outcomes after 12 months in eyes with neovascular AMD. However, variable dosing had a reduced treatment burden. Larger trials
are needed to confirm these results.
Source: El-Mollayess GM, Mahfoud Z, Schakal AR, et al. Fixed-interval versus OCT-guided variable dosing of
intravitreal bevacizumab in the management of neovascular age-related macular degeneration: a 12-month randomized
prospective study. Am J Ophthalmol. 2012;153(3):481–489.
Combination Ranibizumab (Lucentis) and Bromfenac (Xibrom) for Neovascular AMD
This single-site, multi-investigator, prospective, open-label, interventional, Phase II study of patients with new or
recurrent exudative/neovascular age-related macular degeneration (AMD) evaluated whether bromfenac eyedrops and ranibizumab
intravitreal injections would provide added efficacy over ranibizumab alone.
All told, 30 eyes were enrolled consecutively and were randomized in a ratio of 2:1 to combination therapy with
intravitreal ranibizumab and topical bromfenac, and ranibizumab alone. All patients received ranibizumab monthly therapy
for 4 months then as needed monthly in accordance with standard of care. Patients receiving bromfenac self-administered 1 drop
twice a day for 12 months. Patients were followed for 12 months.
No safety concerns were reported with the combination therapy and no statistically significant differences were identified in
Early Treatment Diabetic Retinopathy Study best-corrected visual acuity or the number of injections required. However, the
mean 12-month change in central macular thickness in the combination group was –81.56 µm, while in the ranibizumab
group alone the change was –42.50 µm (p = 0.03). Moreover, the proportion of eyes experiencing a decrease in
CMT of 50 µm or more was also significantly higher in those receiving combination therapy (p = 0.046).
This pilot study is the first to prospectively identify a biologic signal that may indicate combination therapy with an
easily administered well-tolerated eyedrop and ranibizumab is efficacious for the treatment of neovascular age-related
macular degeneration. Further studies are warranted to validate this finding.
Source: Flaxel C, Schain MB, Hamon SC, Francis PJ. Prospective randomized controlled trial of combination
ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration: a pilot study.
Population-Based Incidence of Exudative AMD and Ranibizumab Treatment Load
The use of intravitreal vascular endothelial growth factor (VEGF) antibodies for exudative age-related macular
degeneration (AMD) has stressed ophthalmology services and drug budgets throughout the world. The authors of the
following prospective study looked at the population-based incidence of exudative AMD in Iceland and the use of
intravitreal ranibizumab in a defined population.
They included 439 consecutive patients aged 60 years and older with exudative AMD starting intravitreal ranibizumab for
exudative AMD in Iceland from March 2007 to December 2009. All patients initially received three consecutive ranibizumab
injections, with regular follow-up visits and re-treatment as needed.
According to the authors, 517 eyes from 439 patients received treatment for exudative AMD (mean age 79 years). They noted that
the annual incidence of exudative AMD in the population 60 years and older is 0.29% and that the incidence increased
with advancing age, double for patients 85 years and older compared with those 75–79 years. Approximately 2,400
ranibizumab injections per 100,000 persons aged 60 years and older were given each year for exudative AMD.
These data allow an estimation of the incidence of exudative AMD in a Caucasian population and the treatment load with
ranibizumab, which may help plan anti-VEGF treatment programs and estimate costs.
Source: Geirsdottir A, Jonsson O, Thorisdottir S, et al. Population-based incidence of exudative age-related
macular degeneration and ranibizumab treatment load. Br J Ophthalmol. 2012;96(3):444–447.
Determinants of Fixation in Eyes with Neovascular AMD Treated with Intravitreal Ranibizumab
In London, researchers performed a retrospective analysis to correlate the anatomic features of the macula with
functional parameters such as location and stability of fixation in patients with neovascular age-related macular
degeneration (AMD) treated with intravitreal ranibizumab injections.
They determined the location and stability of fixation in 41 eyes of 41 patients treated with ranibizumab for neovascular AMD
for at least 12 months. All patients underwent 3 injections of ranibizumab 1 month apart and were retreated according to
predefined criteria and the researchers correlated the fixation parameters measured with microperimetry to visual
acuity, qualitative measures on optical coherence tomography and patterns of autofluorescence.
The location of fixation was predominantly central in 68.29%, poor central in 2.4%, and predominantly eccentric in
29.27%, the study researchers reported. They also noted that the fixation was stable in 80.5%, relatively unstable in
7.3%, and unstable in 12.2%. The factors that determined central and stable location of fixation were better visual
acuity (p = .004), absence of subretinal thickening (p = .003), intact subfoveal third hyperreflective band
(p = .006), and intact external limiting membrane (p = .036). Furthermore, while autofluorescence pattern within
the 4-degree circle of fovea did not correlate with fixation characteristics, complete absence of autofluorescence in this
area was a poor prognostic indicator for central fixation.
To conclude, anatomic characteristics of the macula determine fixation patterns in patients with neovascular AMD treated
with intravitreal ranibizumab injections. Further studies focused on eyes with complete absence of autofluorescence in the
central 4-degree circle of fovea may help to define the disease characteristics in this group.
Source: Mathew R, Pearce E, Silvaprasad S. Determinants of fixation in eyes with neovascular age-related
macular degeneration treated with intravitreal ranibizumab. Am J Ophthalmol. 2012;153(3):490–496.
Use of Intravitreal Bevacizumab for Exudative Branching Vascular Networks in PCV
To assess the long-term efficacy of intravitreal bevacizumab for recurrent leakage owing to the residual branching vascular
networks in polypoidal choroidal vasculopathy (PCV) after photodynamic therapy (PDT), researchers in Japan used
intravitreal bevacizumab to treat 45 eyes with exudative branching vascular networks and followed them for at least 24 months.
They had successfully treated original polypoidal lesions with previous PDT in all eyes. The researchers assessed the
best-corrected visual acuity and retinal morphological changes retrospectively.
They characterized exudative branching vascular networks as occult choroidal neovascularization (38 eyes) or classic
choroidal neovascularization (7 eyes) on fluorescein angiography. Intravitreal bevacizumab maintained or improved vision in
38 eyes (84%) over 12 months and in 36 eyes (80%) over 24 months, they reported, although the mean visual acuity at
12 and 24 months did not differ significantly compared with baseline. The study researchers noted that complete resolution
of macular fluid was achieved in 26 eyes (58%) during 24 months and that 16 eyes (36%) responded once to treatment
but became unresponsive to additional injections for recurrent exudation. They also found that three eyes (7%) were
refractory to treatment throughout follow-up. Cystoid macular oedema eventually developed in 10 eyes and was a poor prognostic
sign for visual outcome.
Intravitreal bevacizumab improved the retinal morphology and maintained vision over 1 year in most eyes with recurrent fluid
owing to persistent abnormal vascular networks in polypoidal choroidal vasculopathy. The therapeutic response, however, may
decrease during the second year.
Source: Wakabayashi T, Gomi F, Sawa M, et al. Intravitreal bevacizumab for exudative branching vascular networks
in polypoidal choroidal vasculopathy. Br J Ophthalmol. 2012;93(3):394–399.
Assessment of Treatments for Macular Edema Due to BRVO
Scientists studied 228 eyes of 228 patients in this retrospective, interventional case series to evaluate the effectiveness
of intravitreous bevacizumab (Avastin), intravitreous tissue plasminogen activator, and vitrectomy for the macular edema
secondary to branch retinal vein occlusion (BRVO).
They noted that 41 eyes received 1.25 mg of intravitreous bevacizumab, 71 eyes received tissue plasminogen activator, and 116
eyes underwent vitrectomy. They based a reinjection of 1.25 mg of bevacizumab on the morphologic and functional findings.
The main outcome measures were the best-corrected visual acuity (BCVA) and optical coherence tomography-determined foveal thickness.
The study scientists reported that the mean postoperative follow-up period was 32.2 months with a range of 12 months to 69
months and that the mean number of intravitreous bevacizumab was 2.8 with a range of 1 to 5. They also noted that the mean
BCVA and foveal thickness significantly improved after all 3 treatments, and the differences in the BCVA between the 3 groups
were not significant at 12 months. Additionally, 14 eyes (34%) in the intravitreous bevacizumab group and 21 eyes (30%)
in the tissue plasminogen activator group required additional surgeries.
The 3 treatments appear to provide similar visual outcomes at 12 months, concluded the scientists; however, in some eyes
treated with intravitreous bevacizumab or tissue plasminogen activator, additional surgeries were required, and a longer
follow-up period was required to determine the final outcome.
Source: Kumagai K, Ogino N, Furukawa M, Larson E. Three treatments for macular edema because of branch retinal
vein occlusion: intravitreou bevacizumab or tissue plasminogen activator, and vitrectomy. Retina. 2012;32(3):520–529.
Relationship Between the Efficacy of Half-Dose PDT with Indocyanine Green
Angiography and OCT Findings in the Treatment of CSC
The authors of the following 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. A total light energy of 50 J/cm² over 83 seconds was delivered to the area of
choroidal hyperfluorescence as observed on ICGA. The authors 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.
They noted that after half-dose PDT, they obtained a dry macula 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 also reported that ICGA at baseline showed intermediate and
intense hyperfluorescence in 39.4% and 60.5% of the eyes respectively. 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, 82.6% and 17.4% of the eyes had subretinal fluid only or
both subretinal fluid and posterior retinal cystoid degeneration respectively. In the intense hyperfluorescence group
with subretinal fluid only, a dry macula was obtained in 89.5% and 100v 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 study authors concluded that the half-dose PDT success rate in eyes with chronic CSC depends also on the distribution of
fluid in the neuroepithelium. 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. 2012;153(3):474–480.
Nonarteritic Central Retinal Artery Obstruction Treated with Early Hyperbaric Oxygen
Investigators in Germany compared hyperbaric oxygen treatment combined with hemodilution with hemodilution only in central retinal artery obstruction in the following retrospective, nonrandomized case series.
They reviewed records of all patients diagnosed with central retinal artery obstruction between 1997 and 2010. In these
patients, hyperbaric oxygen and hemodilution therapy had been administered routinely (oxygen group). Where hyperbaric
oxygenation could not be performed, patients were underwent hemodilution only (control group). The investigators included
patients with presenting visual acuity (VA) of up to 20/200 within 12 hours of onset in their analysis. Exclusion criteria
included cilioretinal vessels or arteritic occlusion.
They noted that the oxygen group comprised 51 patients, and the control group comprised 29 patients; also that mean baseline
VA was counting fingers (oxygen group) and 20/1000 (control group; p = .1). The study investigators found that most
other potential confounders, including duration of symptoms, also did not differ significantly at baseline. They observed that
in the oxygen group, mean VA improvement was 3 lines (p < .0001) and this was sustained over a follow up of 3 months
(p = .01). In the control group, mean improvement was 1 line (p = .23 at discharge, p = .17 at
follow-up). Differences between both groups were not significant (p = .07 at discharge, p = .26 at
follow up). Furthermore the number of patients gaining 3 lines or more was 38.0% versus 17.9% at discharge
(p = .06) and 35.7% versus 30.8% at follow-up (p = .76).
The investigators in this study saw significant VA improvement after the combined treatment, but not when using hemodilution
only. In conclusion, confirming superiority of the combination treatment requires a randomized, prospective trial. A high
number of nonresponders highlights the need to improve our understanding and treatment of hypoxia-related metabolic insults
after central retinal artery obstruction.
Source: Menzel-Severing J, Siekmann U, Weinberger A, et al. Early hyperbaric oxygen treatment for nonarteritic
central retinal artery obstruction. Am J Ophthlamol. 2012;153(3):454–459.
Asymmetry in Hemifield Macular Thickness as an Early Indicator of Glaucomatous Change
This study examined whether asymmetry in hemifield macular thickness can serve as an early indicator of glaucomatous
structural damage using spectral domain optical coherence tomography.
Five zones in the macular thickness map were defined and each zone included reciprocal areas in the superior and inferior
hemifield. Differences in average retinal thickness (DRT) between corresponding regional pairs were measured in each of the
five zones in 50 healthy eyes. An abnormality was defined as the DRT value lying outside the 95% confidence intervals and
an eye was considered to yield an “abnormal macular hemifield test” (MHT) if abnormality was evident in any zone.
The sensitivity and specificity for glaucoma detection of MHT and average circumpapillary retinal nerve fiber layer
(cRNFL) classification were determined.
Included were 114 healthy, 103 glaucoma-suspect, and 74 glaucomatous eyes. Overall, 5.8%, 36.9%, 88.4%, and
77.4% of the eyes of the healthy, glaucoma-suspect (GS), early glaucoma (EG), and advanced glaucoma (AG) groups yielded
abnormal MHT results, respectively. It was noted that in EG eyes, the sensitivity of an abnormal MHT result was
significantly greater than that of abnormal average cRNFL classification (p = 0.008) and that in the GS and AG groups,
the sensitivity did not significantly differ between an abnormal MHT result and an average cRNFL classification
(p = 0.880, 0.180). Compared with sectoral cRNFL thickness measurements, MHT showed a similar level of
diagnostic performance. Specificity was not different between an abnormal MHT result and an average cRNFL classification
(p = 0.687).
In conclusion, evaluation of asymmetry in hemifield macular thickness may serve as an assessment tool in the early
diagnosis of glaucoma.
Source: Um TW, Sung KR, Wollstein G, et al. Asymmetry in hemifield macular thickness as an early
indicator of glaucomatous change. Invest Ophthlamol Vis Sci. 53(3):1139–1144.
Efficacy of a Low-Volume, Intermediate-Dose Regimen: Intravitreal
Ganciclovir Maintenance Injection for Cytomegalovirus Retinitis
To report the clinical outcomes of highly active antiretroviral therapy (HAART)-naïve, human immunodeficiency virus
(HIV)-positive patients with newly diagnosed cytomegalovirus (CMV) retinitis receiving intravitreal injections of
a low-volume intermediate maintenance dose (1.0 mg/0.02 ml) of ganciclovir, the authors of this nonrandomized,
retrospective, interventional series included a consecutive cohort of 34 eyes from 24 HAART-naïve patients with
AIDS and diagnosed with CMV retinitis by retinal specialists at the Singapore Communicable Disease Centre.
They administered to patients cohort of 34 eyes from 24 HAART-naïve patients with AIDS and diagnosed with CMV retinitis
by retinal specialists at the Singapore Communicable Disease Centre. Main outcome measures were time to progression, visual
acuity and complications. They observed progression using photographic documentation.
According to the authors of this study, the median time to progression was 152 days (mean, 380.1 days, 95% confidence
interval, 240.8–519.4) and the median follow-up was 95 days (mean, 207.9 days). They reported that three eyes
developed rhegmatogenous detachments, but there was no endophthalmitis after 1858 injections. They also found that
contralateral involvement of CMV retinitis occurred in 17.6% of the patients and that the cost estimate for
intravitreal injections over a 6-month period was 11.7% that of sustained-release implants for unilateral treatment
and 11.1% that of daily continuous intravenous infusions and oral valganciclovir compared with bilateral treatments.
They determined that weekly low-volume, intermediate-dose (1.0 mg/0.02 ml) ganciclovir is an efficacious option in
developing countries where newer options of sustained-release implants and oral valganciclovir are unavailable or
prohibitively expensive. The regimen maintains a long time to progression, preserving vision while minimizing retinal
Source: Teoh SC, Ou X, Lim TH. Intravitreal ganciclovir maintenance injection for cytomegalovirus retinitis:
efficacy of a low-volume, intermediate-dose regimen. Ophthalmol. 2012;119(3):588–595.
Evaluation of Anterior Extension in Retinoblastoma with Ultrasound Biomicroscopy
Extension of retinoblastoma cells into the posterior chamber is a criterion for group E according to the
international classification of intraocular retinoblastoma. Currently, the anterior extension of retinoblastoma
is based on the presence of tumour cells in the anterior chamber assessed by biomicroscopy. Swedish scientists
sought to determine the value of ultrasound biomicroscopy (UBM) in the assessment of posterior chamber involvement
in advanced retinoblastoma.
Retrospective review of all retinoblastoma cases enucleated at the Jules Gonin Eye Hospital from January 1996 to December
2009 for which UBM (35 MHz) evaluation was available. The scientists reviewed the records for patient and tumor features
and histopathological findings. They also compared UBM findings with histopathological features.
UBM documentation was available in 31 cases. According to the study scientists, they detected retinoblastoma by UBM in the
posterior chamber in 18 cases and found it absent in 13 cases while histopathological analysis demonstrated its presence
in the posterior chamber in 22 cases and its absence in 9 cases. Among the 18 UBM-positive cases, 7 had biomicroscopic
detectable involvement of the anterior chamber. There was a significant correlation between echodensities consistent
with retinoblastoma on UBM in the posterior chamber and histopathological tumorous involvement of the posterior chamber
(p=0.0001). Moreover, the sensitivity of UBM in the assessment of posterior chamber invasion by retinoblastoma
was 81% and the specificity was 100%.
To conclude, in selected cases of advanced retinoblastoma, UBM appears to represent a valuable tool in the precise evaluation
of anterior extension of disease, with good sensitivity and specificity for the assessment of posterior chamber involvement.
UBM may provide useful criteria governing the indication for enucleation.
Source: Moulin AP, Gaillard MC, Balmer A, Munier FL. Ultrasound biomicroscopy evaluation of anterior extension
in retinoblastoma: a clinicopathological study. Br J Ophthalmol. 2012;96(3):337–340.