Volume 10, Number 2
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.
Anti-Factor D Monoclonal Antibody Fragment Fcfd4514s in Patients with GA
In this multicenter, open-label, single-dose, dose-escalation Phase Ia study, investigators sought to determine the
safety, tolerability, maximum tolerated dose and immunogenicity of FCFD4514S, an antigen-binding fragment from a humanized
monoclonal antibody directed against complement factor D, in patients with geographic atrophy (GA).
They sequentially enrolled 18 patients with GA (lesion size: ≥0.75 disk areas; best-corrected visual acuity [BCVA]: 20/125
to 20/400 Snellen equivalent). Each patient received one of six escalating doses of intravitreal FCFD4514S subject to
dose-limiting toxicity criteria. The investigators conducted follow-up assessments (clinical examination, BCVA, intraocular
pressure) at post-administration days one, three, seven, 14, 30, 60 and 90. They also evaluated serum pharmacokinetics,
immunogenicity and complement activity.
All patients completed the study with no reported FCFD4514S-related dose-limiting toxicities or ocular or systemic adverse events.
The maximum tolerated dose for this study was 10 mg, the highest dose tested. The study investigators observed no
anti-therapeutic antibody response or adverse effects on systemic complement activity. Time to maximum serum concentration was
one day to three days after dosing; serum terminal half-life was 5.9 days.
According to the investigators, single-dose intravitreal FCFD4514S administrations were safe and well-tolerated and not associated
with any study drug-related ocular or systemic adverse events. These data support a multi-dose safety and tolerability assessment
of FCFD4514S in GA.
Source: Do D, Pieramici DJ, van Lookeren Campagne M, et al. A phase Ia dose-escalation study of the anti-factor
D monoclonal antibody fragment Fcfd4514s in patients with geographic atrophy. Retina. 2014; 34(2):313–320.
SD-OCT to Analyze the Thickness and Vascular Layers of the Choroid in Eyes with GA
A cross-sectional retrospective review was performed to analyze the total choroidal thickness and thickness of the
individual vascular layers of the choroid in eyes with geographic atrophy (GA) using spectral-domain optical
coherence tomography (SD-OCT).
The review identified 17 patients with GA (17 eyes) and 14 age-matched healthy subjects (14 eyes) who underwent high-definition
raster scanning at New England Eye Center in Boston. Patients were diagnosed with GA based on clinical examination and
investigations. Two independent raters evaluated the thickness and vascular layers of the choroid.
Mean choroidal thickness was significantly lower in eyes with GA when compared with age-matched healthy eyes
(p<0.0001). Subfoveal choroidal thickness in eyes with GA was significantly less when compared with healthy
eyes (158.1 ± 23.65 µm versus 267.5 ± 19.27 µm, p=0.001). Additionally, subfoveal large choroidal
vessel layer thickness and medium choroidal vessel layer/choriocapillaris layer thickness were significantly reduced in eyes
with GA when compared with healthy eyes (p=0.001 and p<0.0001, respectively).
In conclusion, the choroid is significantly thinner in eyes with GA involving the fovea when compared with healthy eyes.
Choroidal thinning in GA involves all its vascular layers. Further studies involving prospective correlation of choroidal
vascular changes to the quantitative progression of GA are expected to provide further insight on the choroidal angiopathy
associated with GA.
Source: Adhi M, Lau M, Liang M, et al. Analysis of the thickness and vascular layers of the choroid in eyes
with geographic atrophy using spectral-domain optical coherence tomograhy. Retina. 2014;34(2):306–312.
Use of Intravireal Anti-VEGF for RAP in Treatment-Naïve Eyes
Investigators looking to evaluate the long-term outcome of intravitreal anti-vascular endothelial growth factor
(anti-VEGF) monotherapy in retinal angiomatous proliferation (RAP) performed a prospective, interventional case
series that included 21 treatment-naïve eyes. Treatment consisted of three monthly injections of bevacizumab
and/or ranibizumab with a modified PrONTO-style regimen. The investigators evaluated best-corrected visual acuity
(BCVA) and assessed the influence of baseline BCVA and pretreatment pigment epithelial detachment (PED) on BCVA
outcome or retreatment by Pearson’s correlation analysis.
They evaluated results at two years and three years for 21 and 13 eyes, respectively. They reported that mean baseline BCVA
improved significantly from 44.5 (±11.0) (20/32) to 51.1 (±9.7) (20/24) and 50.8 (±10.4) letters (20/24) at
two and three years, respectively (p=0.02 and p=0.049). Additionally, they found that PED correlated negatively
with BCVA outcome (r=–0.65, p=0.002 and r=–0.67, p=0.01 at two years and three years, respectively) and
was significantly associated with retreatment (r=0.62, p=0.003 and r=0.87, p<0.0001 at two years and three
years, respectively). The investigators obtained complete occlusion of the lesion in 71% and 69% of eyes at two years
and three years, respectively, with a mean of 9.4 injections at three years.
They found that intravitreal anti-VEGF monotherapy was a valid option for RAP. Stable or improved visual acuity was obtained
in 95% and 100% of eyes at two years and three years, respectively.
Source: Gharbiya M, Parisi F, Cruciani F, et al. Intravitreal anti-vascular endothelial growth factor for
retinal angiomatous proliferation in treatment-naïve eyes: long-term functional and anatomical results using
a modified PrONTO-style regimen. Retina. 2014;34(2):298–305.
A Home Monitoring System for the Early Detection of CNV
To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd.), using macular visual field testing
with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular
degeneration (AMD)-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared
with standard care, an unmasked, controlled, randomized clinical trial was performed. The main predictor of treatment
outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment.
The authors of the study screened 1,970 participants aged 53 to 90 years at high risk of developing CNV. Of these, they enrolled
1,520 participants with a mean age of 72.5 years in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2
(AREDS2) clinical centers. In the standard care and device arms, the authors provided investigator-specific instructions
for self-monitoring vision at home, followed by a report of new symptoms to the clinic. In the device arm, they provided the
device with recommendations for daily testing. The device-monitoring center received test results and reported changes to the
clinical centers, which contacted participants for examination. The main outcome measure was the difference in best-corrected
visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical
examination, color fundus photography, fluorescein angiography and optical coherence tomography findings. Masked graders at a
central reading center evaluated the images using standardized protocols.
The authors randomized 763 participants to device monitoring and 757 participants to standard care. They followed patients for
a mean of 1.4 years between July 2010 and April 2013. At the pre-specified interim analysis, 82 participants progressed to CNV,
51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants
in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection
(median, –4.0 letters; interquartile range [IQR], –11.0 to –1.0 letters) compared with standard care
(median, –9 letters; IQR, –14.0 to –4.0 letters; p=0.021), resulting in better visual acuity at CNV
detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy.
Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development,
which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.
Source: The AREDS2-HOME Study Research Group, Chew EY, Clemons TE, Bressler SB, et al. Randomized trial of a
home monitoring system for early detection of choroidal neovascularization home monitoring of the eye (HOME)
study. Ophthalmology. 2014;121(2):535–544.
Markers of Inflammation, Oxidative Stress and
Endothelial Dysfunction and the 20-Year Cumulative Incidence of Early AMD
Modifying levels of factors associated with age-related macular degeneration (AMD) may decrease the risk for visual impairment in
older persons. Scientists in this longitudinal, population-based cohort study examined the relationships of markers of
inflammation, oxidative stress and endothelial dysfunction to the 20-year cumulative incidence of early AMD. The study involved
a random sample of 975 persons in the Beaver Dam Eye Study without signs of AMD who participated in the baseline examination
between 1988–1990 and up to four follow-up examinations between 1993–1995, 1998–2000, 2003–2005, and
The study scientists measured serum markers of inflammation (high-sensitivity C-reactive protein, tumor necrosis
factor–α receptor 2, interleukin-6, and white blood cell count), oxidative stress (8-isoprostane and total
carbonyl content), and endothelial dysfunction (soluble vascular cell adhesion molecule–1 and soluble intercellular
adhesion molecule–1). They also examined interactions with complement factor H (rs1061170), age-related maculopathy
susceptibility 2 (rs10490924), complement component 3 (rs2230199), and complement component 2/complement factor B (rs4151667)
using multiplicative models. Additionally, they assessed age-related macular degeneration from fundus photographs. The main
outcomes and measures were early AMD defined by the presence of any size drusen and the presence of pigmentary abnormalities
or by the presence of large-sized drusen (≥125-µm diameter) in the absence of late AMD.
The 20-year cumulative incidence of early AMD was 23.0%, the scientists discovered. They found that adjusting for age, sex
and other risk factors, high-sensitivity C-reactive protein (odds ratio comparing fourth with first quartile, 2.18;
p=0.005), tumor necrosis factor–α receptor 2 (odds ratio, 1.78; p=0.04), and interleukin–6
(odds ratio, 1.78; p=0.03) were associated with the incidence of early AMD. They also noted that increased incidence
of early AMD was associated with soluble vascular cell adhesion molecule–1 (odds ratio per SD on the logarithmic scale,
They found modest evidence of relationships of serum high-sensitivity C-reactive protein, tumor necrosis factor–α
receptor 2, interleukin–6, and soluble vascular cell adhesion molecule–1 to the 20-year cumulative incidence of early
AMD independent of age, smoking status and other factors. It is not known whether these associations represent a cause and
effect relationship or whether other unknown confounders accounted for the findings. Even if inflammatory processes are a cause
of early AMD, it is not known whether interventions that reduce systemic inflammatory processes will reduce the incidence of early AMD.
Source: Klein R, Myers CE, Cruickshanks KJ, et al. Markers of inflammation, oxidative stress, and endothelial
dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: The Beaver Dam Eye Study.
JAMA Ophthalmol. 2014; Jan 30. [Epub ahead of print]. DOI: 10.1001/jamaophthalmol.2013.7671.
Risk of Parkinson's Disease Following a Diagnosis
of Neovascular AMD
Researchers in Taiwan performed the following retrospective, matched-cohort study to investigate the risk for
Parkinson's disease during a three-year follow-up period after a diagnosis of neovascular age-related macular degeneration
(AMD) using a nationwide population-based dataset in Taiwan.
They identified 877 subjects with neovascular AMD as the study cohort and randomly selected 8,770 subjects for a comparison
cohort. They followed each subject individually for a three-year period to identify those who subsequently developed
Parkinson's disease. Stratified Cox proportional hazard regressions were performed as a means of comparing the three-year
risk of subsequent Parkinson's disease between the study and comparison cohorts.
The incidence rate of Parkinson's disease was 5.32 (95% confidence interval [CI]: 3.03 to 8.72) per 1,000 person-years
in patients with neovascular AMD and 2.09 (95% CI: 1.59 to 2.70) per 1,000 person-years in comparison patients. The
study researchers noted that the log-rank test indicated that subjects with neovascular AMD had a significantly lower
three-year Parkinson's disease–free survival rate than comparison subjects (p<0.001). After censoring cases
in which patients died during the follow-up period and adjusting for monthly income, geographic region, hypertension,
diabetes, hyperlipidemia and coronary heart disease, the hazard ratio of Parkinson's disease during the three-year
follow-up period for subjects with neovascular AMD was 2.57 (95% CI: 1.42 to 4.64) that of comparison subjects.
In this study, the researchers found subjects with neovascular AMD to be at a significant risk of Parkinson's disease
during a three-year follow-up period after their diagnosis among Taiwanese Chinese. Further study is needed to confirm our
findings and explore the underlying patho-mechanism.
Source: Chung SD, Ho JD, Hu CC, et al. Increased risk of Parkinson disease following a diagnosis of neovascular
age-related macular degeneration: a retrospective cohort study. Am J Ophthalmol. 2014;157(2):464–469.
Intravitreal Bevacizumab for the Treatment of Nonsubfoveal
CNV Associated with Angioid Streaks
Italian researchers completed this nonrandomized, interventional, prospective case series to evaluate the effects of
intravitreal bevacizumab injections in the treatment of nonsubfoveal choroidal neovascularization (CNV) associated with angioid streaks.
They enrolled 15 patients (15 eyes) affected by juxtafoveal or extrafoveal CNV secondary to angioid streaks. All patients
underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measurement on Early Treatment
Diabetic Retinopathy Study (ETDRS) chart, optical coherence tomography (OCT), and fluorescein angiography (FA). The protocol
treatment included a first injection, followed by repeated injections over a 12-month follow-up period on the basis of the detection
of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures
were mean changes in BCVA and proportion of eyes gaining at least 10 letters (two ETDRS lines) at the end of the follow-up.
Secondary outcomes were mean changes of central macular thickness (CMT) and extension to the fovea.
Mean BCVA did not change throughout the follow-up period, being 0.2 ± 0.2 logMAR at baseline and 0.2 ± 0.3 logMAR at
the 12-month examination, the researcher noted. They also reported that a functional improvement of at least two ETDRS lines
was achieved by five eyes (33%), with three eyes (20%) gaining three lines. Furthermore, mean CMT at baseline was
215 µm ± 13 µm and 225 µm ± 85 µm at the 12-month examination. Two eyes (13.3%) showed CNV
extension to the fovea.
The study researchers determined that intravitreal bevacizumab injection can be a beneficial approach for the management
of nonsubfoveal CNV secondary to angioid streaks over a one-year follow-up.
Source: Parodi MB, Iacono P, La Spina C, et al. Intravitreal bevacizumab for nonsubfoveal choroidal
neovascularization associated with angiod streaks. Am J Ophthalmol. 2014;157(2):374–377.
Clinical Findings of Acquired Vitelliform Lesions
Associated with RPE Detachments
To study clinical findings associated with acquired vitelliform lesions in retinal pigment epithelial detachments (PEDs), the
authors of the following retrospective, interventional, consecutive case series reviewed 32 eyes of 24 patients (22 men, two
women; age range [mean], 58 to 85 [73.7] years) with acquired vitelliform lesions. They found that intravitreal injections
of ranibizumab were ineffective because of the absence of resolution of the PEDs and the declines in visual acuity.
All eyes had acquired vitelliform lesions in the central macula associated with a serous PED at baseline. Of the 32 eyes, the
authors observed 30 (93.8%) for 12 months, 26 (81.3%) for 24 months and 17 (53.1%) for 36 months. They found that
the mean logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) levels were 0.19 at month 12,
0.28 at month 24 and 0.25 at month 36, none of which differed significantly from baseline. They also noted that mean changes in
the BCVA were declines of 0.38, 1.29 and 1.21 lines at months 12, 24 and 36, respectively. Of the seven eyes treated with
three consecutive monthly intravitreal injections of ranibizumab, the serous PEDs remained in all seven eyes and the mean
changes of BCVA were a decline of 2.40 lines 12 months after the first injection and a decline of 3.58 lines at the final visit.
In the 24 untreated eyes, the mean change in the BCVA was a decline of 0.25 lines at the final visit, which differed significantly
(p=0.021) compared with that of the treated eyes at the final visit.
Source: Saito M, Iida T, Freund KB, et al. Clinical findings of acquired vitelliform lesions associated with
retinal pigment epithelial detachments. Am J Ophthalmol. 2014;157(2):355–365.
Comparison Between Low-Fluence PDT and Ranibizumab for Chronic CSC
Investigators in Korea used this prospective, randomized, single-center, parallel-arm, controlled trial to compare the efficacy
and safety between low-fluence photodynamic therapy (PDT) and the intravitreal ranibizumab in the treatment of chronic central
serous chorioretinopathy (CSC).
They randomly placed 34 eyes of 32 patients with chronic CSC with more than six months' duration of symptoms or recurrent CSC
into the low-fluence PDT group (n=18) or the ranibizumab group (n=16). The patients underwent a single session of low-fluence PDT
or three consecutive monthly injections of ranibizumab. Rescue treatment was available from month three if the subretinal fluid
(SRF) persisted or recurred after primary treatment; low-fluence PDT was given to the ranibizumab group and intravitreal ranibizumab
to the low-fluence PDT group. The primary outcome was the proportion of eyes with complete resolution of SRF without rescue
treatment. Secondary outcomes included the mean changes in logarithm of the minimum angle of resolution (logMAR) best-corrected
visual acuity (BCVA), central retinal thickness (CRT) and angiographic findings from baseline to 12 months.
According to the investigators, at month 12, 16 eyes (88.9%) of the low-fluence PDT group maintained complete resolution of
SRF without rescue treatment versus two eyes (12.5%) in the ranibizumab group (p<0.001). They also reported that
two eyes (11.1%) in the low-fluence PDT group and 11 eyes (68.8%) in the ranibizumab group met the criteria for rescue treatment (p=0.001). In the low-fluence PDT group, the mean decrease in CRT from baseline was significantly greater than
that in the ranibizumab group until month six (p<0.05), but the differences became insignificant thereafter. The
improvement in BCVA from baseline was superior in the low-fluence PDT group to that in the ranibizumab group, but the differences
were not statistically significant except at month three (p=0.025). On indocyanine green angiography, the study
investigators noted that a significantly greater proportion of the low-fluence PDT group (16 eyes; 88.9%) showed a marked
reduction in choroidal hyperpermeability after primary treatment than that of the ranibizumab group (zero eyes;
p<0.001). They observed no serious adverse events related to the drugs or procedures.
This study represents the overall superiority of low-fluence PDT compared with intravitreal ranibizumab in the treatment
of chronic CSC.
Source: Bae SH, Heo J, Kim C, et al. Low-fluence photodynamic therapy versus ranibizumab for chronic central
serous chorioretinopathy: one-year results of a randomized trial. Ophthalmology. 2014;121(2):558–565.
Retinal Layer Segmentation in MS Patients Using SD-OCT
The following Spanish observational, cross-sectional study evaluated the thickness of the 10 retinal layers in the paramacular area
of patients with multiple sclerosis (MS) compared with healthy subjects using the new segmentation technology of
spectral-domain optical coherence tomography (SD-OCT). The aim was to examine which layer has better sensitivity for
detecting neurodegeneration in patients with MS.
The study included 204 patients with MS and 138 age-matched healthy subjects and the Spectralis OCT system (Heidelberg
Engineering Inc.) was used to obtain automated segmentation of all retinal layers in a parafoveal scan in one randomly
selected eye of each participant, using the new segmentation application prototype. The thicknesses of 512 parafoveal points
in the 10 retinal layers were obtained in each eye, and the mean thickness of each layer was calculated and compared between
patients with MS and healthy subjects. The analysis was repeated, comparing patients with MS with and without previous optic
neuritis. Correlation analysis was performed to evaluate the association between each retinal layer mean thickness, duration
of disease, and functional disability in patients with MS. A logistic regression analysis was performed to determine which
layer provided better sensitivity for detecting neurodegeneration in patients with MS.
It was determined that all retinal layers, except the inner limiting membrane, were thinner in patients with MS compared with
healthy subjects (p<0.05). Greater effects were observed in the inner retinal layers (nerve fiber, ganglion cells,
inner plexiform and inner nuclear layers) of eyes with previous optic neuritis (p<0.05). The retinal nerve fiber layer
and ganglion cell layer thicknesses were inversely correlated with the functional disability score in patients with MS and
moreover, the ganglion cell layer and inner plexiform layer thicknesses could predict axonal damage in patients with MS.
In conclusion, analysis based on the segmentation technology of the Spectralis OCT revealed retinal layer atrophy in patients with
MS, especially of the inner layers. Reduction of the ganglion cell and inner plexiform layers predicted greater axonal damage
in patients with MS.
Source: Garcia-Martin E, Polo V, Larrosa JM, et al. Retinal layer segmentation in patients with multiple sclerosis
using spectral domain optical coherence tomography. Ophthalmology. 2014;121(2):573–579.
Severity of Obstructive Sleep Apnea Syndrome and RNFL Thickness
Japanese researchers sought to determine whether there is a significant correlation between the peripapillary retinal nerve fiber
layer (RNFL) thickness, foveal thickness, total macular volume, and the severity of obstructive sleep apnea syndrome in
this prospective study.
They studied 128 consecutive subjects who underwent polysomnography and used optical coherence tomography (OCT) to measure
the peripapillary RNFL, foveal thickness and total macular volume. The researchers used the Pearson correlation coefficient
to determine the relationship between the apnea-hypopnea index and OCT and other parameters. They also used multiple
regression analysis to determine the independent factors for the RNFL sectors that were the most strongly correlated with
the apnea-hypopnea index.
According to the researchers, the apnea-hypopnea index was significantly and negatively correlated (right eye, r=–0.31,
p=0.0004; left eye, r=–0.39, p<0.0001) with the nasal RNFL thickness (Pearson's correlation analysis).
They determined that foveal thickness and total macular volume were not correlated; however, the intraocular pressure, body mass
index, plaque score and incidence of hypertension were negatively correlated and the lowest oxygen saturation and mean
oxygen saturation were positively correlated with the nasal RNFL thickness in the left eye. Multiple regression analysis showed
the apnea-hypopnea index and age were independent contributors to the nasal RNFL thickness in the left eye (apnea-hypopnea
index, standard regression coefficient, –0.30, t value, –2.76, p=0.007; age, –0.24, –2.36,
0.02, respectively). Moreover, the nasal RNFL thickness in both eyes decreased significantly based on the severity of the
obstructive sleep apnea syndrome.
Exacerbation of obstructive sleep apnea syndrome may produce unique retinal neurodegenerative disorders that decrease the nasal
RNFL thickness, the researchers concluded.
Source: Shiba T, Takahashi M, Sato Y, et al. Relationship between severity of obstructive sleep apnea syndrome and
retinal nerve fiber layer thickness. Am J Ophthalmol. 2014;Feb 6. [Epub ahead of print]. DOI: 10.1016/j.ajo.2014.01.028.